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a33c687394bc3a12b757cc7a9852632c54763da1	pubmed	Osteoporosis Management in the Era of COVID‐19	Osteoporosis Management in the Era of COVID‐19 Osteoporosis is a chronic condition that reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID-19 pandemic has brought unprecedented disruption to the provision of health care globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID-19 era and provide clinical recommendations based primarily on expert opinion when data are absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available. Effect of stopping risedronate after long-term treatment on bone turnover. J Clin Endocrinol Metab. 2011;96(11):3367-73. 23. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res. 2012; 27(2):243-54. 24. Henneman ZJ, Nancollas GH, Ebetino FH, Russel RG, Philipps RJ. Bisphosphonate binding affinity as assessed by inhibition of Journal of Bone and Mineral Research n 1012 YU ET AL. # Introduction S evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially caused clusters of severe respiratory illness in Wuhan, China, in late 2019 [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] and has since rapidly spread in Europe and the United States. As of May 5, 2020, a total of 3,517,345 persons were reported to be infected by SARS-CoV-2 and 243,401 persons to have died of coronavirus disease . COVID-19 was characterized as a pandemic by the World Health Organization on .In response, many countries have implemented a series of unprecedented measures to mitigate the spread of the virus, including large-scale social isolation, travel bans, restriction of public gatherings, and nationwide lockdowns. Although these social distancing strategies have been necessary from a public health standpoint, they have understandably introduced challenges in the management of many chronic medical conditions. [bib_ref] The untold toll-the pandemic's effect on patients without Covid-19, Rosenbaum [/bib_ref] Because osteoporosis is a chronic disease, continued treatment is a prerequisite in many patients in order to sustain therapeutic benefits, as is the case with other chronic conditions. With the exception of bisphosphonates, which have a long biologic half-life, other anti-osteoporosis drugs need to be provided in a regularly scheduled manner. Delaying the administration of certain categories of osteoporosis drugs can have ominous consequences for patients, ranging from loss of bone mass to increases in bone turnover and fracture risk. Hip fractures, the most devastating type of fracture, significantly impair mobility and independence and lead to an approximately 25% 1-year mortality rate. [bib_ref] Medical expenditures for the treatment of osteoporotic fractures in the United States..., Ray [/bib_ref] Recognizing the potential detrimental effects of abruptly terminating antiosteoporosis therapy, the American Society of Bone and Mineral Research (ASBMR) formed a Steering Committee of bone specialists to address this issue.Here we review available evidence and provide clinical guidance for the management of patients with osteoporosis during the COVID-19 pandemic. We acknowledge both that there is a paucity of data to provide evidence-based clinical recommendations and that treatment modalities are likely to vary according to the status of local and national facilities, such as phlebotomy and infusion therapy centers, as well as outpatient clinics. Thus, these recommendations are based primarily on expert opinion and will require reassessment as the worldwide response to COVID-19 evolves. ## Bone mineral density scans Although bone mineral density (BMD) testing is a helpful tool to assist in the identification and management of patients at high risk of fractures,these scans should be considered as elective. Thus, BMD examinations may need to be postponed when public health guidance recommends the halting of elective imaging procedures. In the absence of BMD testing, fracture risk stratification can still be performed for treatment-naive adults with the use of the Fracture Risk Assessment Tool (FRAX). [bib_ref] FRAX and its applications to clinical practice, Kanis [/bib_ref] Laboratory monitoring Standard pretreatment laboratory studies, including serum calcium, creatinine, and/or 25-hydroxyvitamin D, are often obtained before the administration of potent antiresorptive agents, such as intravenous (iv) bisphosphonates and denosumab, in order to minimize risk of inducing hypocalcemia. In patients who are initiating new osteoporosis treatment with a potent antiresorptive agent, we recommend obtaining relevant laboratory studies before first administration. However, the absolute risk of inducing clinically significant hypocalcemia after treatment with either zoledronic acid [bib_ref] Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, Black [/bib_ref] or denosumab [bib_ref] A single-dose of denosumab in patients with various degrees of renal impairment, Block [/bib_ref] is very low in the absence of significant renal insufficiency. Both to facilitate social distancing guidelines and to minimize patient exposure at phlebotomy centers, we suggest that pretreatment laboratory studies before retreatment with iv bisphosphonates and/or denosumab need not be performed if laboratory values obtained within the preceding year were normal and it is the clinical judgment of the medical provider that the patient's health has been stable. However, we do recommend obtaining laboratory studies for patients with fluctuating renal function and for those who are at higher risk of developing hypocalcemia, such as those with malabsorptive disorders, hypoparathyroidism, or advanced renal dysfunction (chronic kidney disease stages 4 or 5) or those maintained on loop diuretics. ## Pharmacologic osteoporosis treatment The initiation of osteoporosis therapy can be done as an outpatient via a non-face-to-face (ie, telephone or video) visit and should not be delayed in patients at high risk for fracture (eg, patients who have recently sustained an osteoporotic fragility fracture or patients taking chronic high-dose glucocorticoids). In particular, oral osteoporosis regimens can be easily initiated during a telemedicine visit; teriparatide and abaloparatide initiation may also be considered but require additional patient training for subcutaneous self-injections that may be more difficult to arrange. Patients who have fractures requiring hospital admission should be considered for osteoporosis medication initiation while hospitalized to minimize the risk of being lost to follow-up in the post-discharge period, which may be further fragmented during the COVID-19 pandemic. Specifically, there is no evidence for impaired fracture healing in patients who receive early initiation of osteoporosis treatment, including bisphosphonates. [bib_ref] Timing of the initiation of bisphosphonates after surgery for fracture healing: a..., Li [/bib_ref] It should be acknowledged, however, that the administration of iv bisphosphonates may cause a post-infusion inflammatory reaction, particularly in treatment-naive patients. Symptoms of the inflammatory reaction, including fever and myalgias, have the potential to complicate the care of hospitalized patients by triggering a COVID-19 evaluation and may prolong hospitalization. When possible to do safely, patients who are already treated with osteoporosis medications should continue to receive ongoing therapies including oral and iv bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab. There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course (in either a positive or negative way). However, there are early signals that COVID-19 may be accompanied by an increased risk for hypercoagulable complications, [bib_ref] Hematological findings and complications of COVID-19, Terpos [/bib_ref] [bib_ref] COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute..., Spiezia [/bib_ref] in which case caution may be warranted for estrogen and raloxifene use, both of which may modestly increase thrombotic risk. [bib_ref] American Association of Clinical Endocrinologists and American College of Endocrinology position statement..., Cobin [/bib_ref] [bib_ref] The adverse effects of estrogen and selective estrogen receptor modulators on hemostasis..., Artero [/bib_ref] It may therefore be prudent to instruct patients to temporarily discontinue these hormonal agents if they develop viral respiratory symptoms. Denosumab also bears particular consideration because it is a monoclonal antibody that inhibits receptor activator of NF-κB ligand (RANKL), and RANKL plays a role in T-cell activation. Studies of denosumab in postmenopausal osteoporosis indicate an increased risk of skin and soft tissue infections. [bib_ref] 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from..., Bone [/bib_ref] However, no infection safety signals have been found in studies of denosumab in patients receiving concurrent immunomodulatory treatment for rheumatoid arthritis [bib_ref] Denosumab versus risedronate in glucocorticoid-induced osteoporosis: final results of a twentyfour month..., Saag [/bib_ref] [bib_ref] Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a..., Curtis [/bib_ref] [bib_ref] Occurrence of serious infection in patients with rheumatoid arthritis treated with biologics..., Lau [/bib_ref] and among patients receiving concomitant chemotherapy for solidorgan tumors. [bib_ref] Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled,..., Coleman [/bib_ref] Depending on the severity of the local COVID-19 outbreak, we acknowledge that there may be disruptions in the administration of osteoporosis treatments. We thus aim to provide guidance about (i) alternative methods of delivering parenteral osteoporosis treatments that are not self-administered (eg, iv bisphosphonates, denosumab, and romosozumab); and (ii) how to handle temporary disruptions in the pharmacologic management of osteoporosis patients. ## Alternative methods of delivering parenteral osteoporosis treatments - Off-site clinics: The administration of treatments at locations geographically isolated from COVID-19 "hot spots" should be considered whenever possible. However, it should be recognized that this may disadvantage socioeconomically challenged communities if public transportation options are not available. - Home delivery and administration: This is an option if available but may be logistically difficult to arrange due to reliance on home-visiting medical staff. Self-injection of denosumab (and/or romosozumab) has been proposed and is reportedly available in some locales. However, there are important medico-legal issues to consider surrounding the proper product handling and administration, including the small risk of drug-related hypersensitivity reactions that could occur in the absence of a medical provider, although steps to mitigate such potential risks may be in place in some communities. - Drive-through administration of denosumab and/or romosozumab: This may also be logistically difficult to arrange. Further, it is recommended that patients be monitored by a medical provider for 15 minutes after injection in the unlikely event of a hypersensitivity reaction. ## Temporary disruptions of pharmacologic osteoporosis treatment In the event that temporary disruption of osteoporosis treatment is necessitated due to COVID-19, we have reviewed evidence about treatment discontinuation effects and have provided recommendations for the delay or temporary transition to other osteoporosis agents. In general, we recommend the resumption of the original osteoporosis treatment plan once circumstances allow. ## Bisphosphonates After bisphosphonate discontinuation, suppressed bone turnover markers (BTMs) slowly return to their baseline concentrations and BMD remains stable or decreases very gradually over a period of years. [bib_ref] Alendronate in early postmenopausal women: effects on bone mass during long-term treatment..., Ravn [/bib_ref] The persistent antiresorptive effect of bisphosphonates after treatment discontinuation is dependent on their high affinity for binding hydroxyapatite. To this effect, bisphosphonates with a more pronounced binding capacity for hydroxyapatite, such as alendronate and zoledronate, have been shown to have a more sustained effect on maintenance of BMD and suppression of BTMs compared with risedronate. (24) Some studies also indicate a persistent anti-fracture effect after bisphosphonate discontinuation, although these data are less well-substantiated. [bib_ref] Fracture risk remains reduced one year after discontinuation of risedronate, Watts [/bib_ref] [bib_ref] Efficacy of continued alendronate for fractures in women with and without prevalent..., Schwartz [/bib_ref] Finally, randomized controlled trials indicate that less frequent dosing of zoledronic acid may provide skeletal benefit and protection against fractures. [bib_ref] Fracture prevention with zoledronate in older women with osteopenia, Reid [/bib_ref] [bib_ref] Five years of anti-resorptive activity after a single dose of zoledronate-results from..., Grey [/bib_ref] [bib_ref] Ten years of very infrequent zoledronate therapy in older women: an open-label..., Grey [/bib_ref] In summary, for patients in whom continued treatment with iv bisphosphonates is not feasible, delays of even several months are unlikely to be harmful. ## Denosumab There is evidence that delay of denosumab treatment causes rebound high bone turnover, [bib_ref] Effect of denosumab on bone mineral density and biochemical markers of bone..., Miller [/bib_ref] [bib_ref] Effects of denosumab treatment and discontinuation on bone mineral density and bone..., Bone [/bib_ref] rapid bone loss within 1 year, [bib_ref] Effect of denosumab on bone mineral density and biochemical markers of bone..., Miller [/bib_ref] [bib_ref] Effects of denosumab treatment and discontinuation on bone mineral density and bone..., Bone [/bib_ref] and increases the risk for the development of multiple vertebral fractures. [bib_ref] Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the..., Cummings [/bib_ref] Reports of vertebral fractures after denosumab discontinuation have occurred as early as 7 months after the last denosumab injection. [bib_ref] Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage..., Gonzalez-Rodriguez [/bib_ref] The optimal regimen of antiresorptive drugs to mitigate the rebound phenomenon that characterizes denosumab discontinuation is currently being investigated in a number of randomized controlled trials. There is some evidence that oral alendronate may provide protection from denosumab-discontinuation rebound bone loss, especially in the setting of a short period of previous denosumab treatment. [bib_ref] Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month,..., Freemantle [/bib_ref] [bib_ref] Bone mineral density after transitioning from denosumab to alendronate, Kendler [/bib_ref] However, multiple vertebral fractures have been described in two patients provided with alendronate after treatment with denosumab for an average of 3.5 years. [bib_ref] Alendronate after denosumab discontinuation in women previously exposed to bisphosphonates was not..., Lamy [/bib_ref] In comparison to oral bisphosphonate treatment, there is conflicting evidence regarding whether zoledronic acid can prevent rebound bone loss associated with denosumab discontinuation, with most data showing this potent antiresorptive agent to be less effective at maintaining BMD when previous denosumab treatment exceeded 2 years compared with a shorter duration of denosumab therapy. [bib_ref] Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment...., Anastasilakis [/bib_ref] [bib_ref] Bone loss after denosumab: only partial protection with zoledronate, Reid [/bib_ref] [bib_ref] A single infusion of zoledronate in postmenopausal women following denosumab discontinuation results..., Everts-Graber [/bib_ref] Furthermore, there is controversy over the optimal timing and dosing of bisphosphonate therapy after denosumab discontinuation, although ongoing randomized controlled trials are expected to shed more light into this matter. It also remains unclear whether less potent antiresorptive medications, such as raloxifene, may be able to prevent the high bone turnover state after denosumab discontinuation. [bib_ref] Assessment of the effects of sequential treatment after discontinuing denosumab in 64..., Ebina [/bib_ref] Regarding transitioning from denosumab to osteoanabolic treatment, there is evidence that switching to teriparatide leads to a high bone turnover state and a temporary but rapid decrease in BMD, especially at cortical skeletal sites. [bib_ref] Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-switch study): extension of..., Leder [/bib_ref] Finally, recent evidence has shown that romosozumab treatment after denosumab discontinuation results in BMD gains, albeit of a smaller magnitude compared with romosozumab administration alone in treatment-naive patients. [bib_ref] Bone mineral density gains with a second 12-month course of romosozumab therapy..., Kendler [/bib_ref] Based on the available data, we strongly recommend the temporary transition to an oral bisphosphonate (such as weekly alendronate) for patients in whom continued treatment with denosumab is not feasible within 7 months of their most recent prior denosumab injection. For patients with known upper gastrointestinal (GI) disorders, we suggest that these patients be transitioned to monthly ibandronate or weekly/monthly risedronate based on reports that these medications may have fewer upper GI side effects. [bib_ref] The gastrointestinal tolerability and safety of oral bisphosphonates, Marschall [/bib_ref] Bisphosphonates are contraindicated for patients with chronic renal insufficiency (estimated glomerular filtration rates [eGFR] levels <30 to 35 mL/min); however, in such patients, the off-label provision of lower-dose oral bisphosphonate (eg, alendronate 35 mg weekly, or alendronate 70 mg every 2 weeks) may be cautiously considered. We note that there is no published evidence to support these off-label regimens, and therefore clinicians should weigh the unknown benefits and potential risks of these regimens against the concern for rebound-associated loss of bone mass and vertebral fracture occurrence after denosumab discontinuation in the setting of the COVID-19 pandemic. ## Teriparatide and abaloparatide After teriparatide discontinuation, BMD progressively declines over the course of the first year, [bib_ref] Effects of teriparatide treatment and discontinuation in postmenopausal women and eugonadal men..., Leder [/bib_ref] but there is no evidence of increased rebound fracture risk. On the contrary, follow-up of the pivotal Fracture Prevention Trial with teriparatide (FPT) [bib_ref] Effect of parathyroid hormone (1-34) on fractures and bone mineral density in..., Neer [/bib_ref] suggested that some anti-fracture efficacy was maintained for up to 18 months after teriparatide was discontinued. [bib_ref] Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women..., Lindsay [/bib_ref] However, given the aforementioned progressive bone loss after discontinuation, it is likely that most of the beneficial anti-fracture effects of teriparatide will eventually dissipate unless followed by an antiresorptive agent. Multiple antiresorptive agents have been demonstrated to further increase BMD after teriparatide discontinuation. [bib_ref] Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-switch study): extension of..., Leder [/bib_ref] [bib_ref] Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by..., Rittmaster [/bib_ref] [bib_ref] One year of alendronate after one year of parathyroid hormone (1-84) for..., Black [/bib_ref] Interestingly, regimens of cyclical teriparatide treatment (ie, 3 months on-treatment followed by 3 months off-treatment) given for 4 years cumulatively showed similar increases in BMD compared with standard daily teriparatide treatment provided over 2 years, [bib_ref] Daily or cyclical teriparatide treatment in women with osteoporosis on no prior..., Cosman [/bib_ref] [bib_ref] Administration of teriparatide for four years cyclically compared to two years daily..., Cosman [/bib_ref] demonstrating proof of concept that short-term interruptions of teriparatide may not negatively impact long-term BMD increases, so long as treatment can be restarted within 3 months. On the other hand, pretreatment with bisphosphonates appear to blunt the efficacy of teriparatide, [bib_ref] Effects of previous antiresorptive therapy on the bone mineral density response to..., Boonen [/bib_ref] [bib_ref] Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate, Ettinger [/bib_ref] [bib_ref] Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or..., Cosman [/bib_ref] evidence that may dampen enthusiasm for using bisphosphonates as bridging agents during a temporary disruption of teriparatide treatment. Given that abaloparatide has a similar physiologic action as teriparatide, it is presumed that abaloparatide also has no prolonged BMD effects after its discontinuation. Fewer data are available about approaches to transition from abaloparatide to other osteoporosis agents, although the specific regimen of abaloparatide followed by alendronate has been shown to be an effective sequential regimen in postmenopausal osteoporosis. [bib_ref] Fracture and bone mineral density response by baseline risk in patients treated..., Leder [/bib_ref] Based on the data above, for patients in whom continued treatment with teriparatide or abaloparatide is not feasible, we suggest a delay in treatment. If this delay exceeds 2 to 3 months, consider a temporary transition to an oral bisphosphonate. ## Romosozumab There is evidence that romosozumab discontinuation causes rapid bone loss within 1 year if not followed by another osteoporosis treatment. [bib_ref] Effects of 24 months of treatment with romosozumab followed by 12 months..., Mcclung [/bib_ref] Indices of bone resorption also increase within 3 months of romosozumab cessation, [bib_ref] Effects of 24 months of treatment with romosozumab followed by 12 months..., Mcclung [/bib_ref] although there is no indication that discontinuation leads to an increased risk of fractures. There is evidence that transitioning from romosozumab to either alendronate or denosumab leads to continued gains in BMD. [bib_ref] Romosozumab treatment in postmenopausal women with osteoporosis, Cosman [/bib_ref] [bib_ref] Romosozumab or alendronate for fracture prevention in women with osteoporosis, Saag [/bib_ref] However, pretreatment with alendronate might somewhat blunt the increases in hip BMD anticipated to occur with romosozumab [bib_ref] Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning..., Langdahl [/bib_ref] compared with the increases found in treatment-naive patients. [bib_ref] Romosozumab treatment in postmenopausal women with osteoporosis, Cosman [/bib_ref] [bib_ref] Romosozumab or alendronate for fracture prevention in women with osteoporosis, Saag [/bib_ref] Finally, bone turnover marker data suggest that the most active period of bone formation with romosozumab occurs within the first 6 months of treatment, after which time romosozumab mirrors the biomarker profile of an antiresorptive agent. [bib_ref] Romosozumab treatment in postmenopausal women with osteoporosis, Cosman [/bib_ref] [bib_ref] Romosozumab or alendronate for fracture prevention in women with osteoporosis, Saag [/bib_ref] Based on the available evidence, we suggest a delay in treatment for patients in whom continued treatment with romosozumab is not feasible. If this delay exceeds 2 to 3 months, consider a temporary transition to oral bisphosphonate. In patients who have already received >6 months of romosozumab treatment, it is possible that a more permanent transition to oral bisphosphonates could be considered. # Conclusion Although it is hoped that widespread lockdowns may begin to be eased as we gain better control of COVID-19, it is increasingly likely that intermittent social distancing will be required over the next 18 months.During this time of uncertainty, it is imperative that we continue to provide the best care possible for our patients by addressing the clinically important issue of osteoporosis, while acknowledging various logistic challenges that have the potential to disrupt care. We hope that these recommendations can provide a practical guide to the management of osteoporosis patients during this unprecedented pandemic. # Disclosures EWY has received an investigator-initiated grant from Amgen. ET has received research funding from MSD, honoraria for lectures from Amgen, UCB, Shire, and Kyowa Kirin, and educational grants from Shire and UCB. BLC, DAB, and MTD have no relevant disclosures. n 1010 YU ET AL. AcknowledgmentsThis work was not supported by any grant.Authors' roles: Drafting manuscript: EWY, ET, and MTD. Revising manuscript content: EWY, ET, BLC, DCB, and MTD. Approving final version of manuscript: EWY, ET, BLC, DCB, and MTD.	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jbmr.4049	Osteoporosis is a chronic condition that reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID‐19 pandemic has brought unprecedented disruption to the provision of health care globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID‐19 era and provide clinical recommendations based primarily on expert opinion when data are absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available. © 2020 American Society for Bone and Mineral Research.
11d15c53ac780ec7554a948837cc9a0d8817ebd5	pubmed	ESMO Management and treatment adapted recommendations in the COVID-19 era: Breast Cancer	ESMO Management and treatment adapted recommendations in the COVID-19 era: Breast Cancer # Abstract The global preparedness and response to the rapid escalation to severe acute respiratory syndrome coronavirus (SARS-CoV)-2-related disease to a pandemic proportion has demanded the formulation of a reliable, useful and evidence-based mechanism for health services prioritisation, to achieve the highest quality standards of care to all patients. The prioritisation of high value cancer interventions must be embedded in the agenda for the pandemic response, ensuring that no inconsistency or discrepancy emerge in the health planning processes. The aim of this work is to organise health interventions for breast cancer management and research in a tiered framework (high, medium, low value), formulating a scheme of prioritisation per clinical cogency and intrinsic value or magnitude of benefit. The public health tools and schemes for priority setting in oncology have been used as models, aspiring to capture clinical urgency, value in healthcare, community goals and fairness, while respecting the principles of benevolence, non-maleficence, autonomy and justice. We discuss the priority health interventions across the cancer continuum, giving a perspective on the role and meaning to maintain some services (undeferrable) while temporarily abrogate some others (deferrable). Considerations for implementation and the essential link to pre-existing health services, especially primary healthcare, are addressed, outlining a framework for the development of effective and functional services, such as telemedicine. The discussion covers the theme of health systems strategising, and why oncology care, in particular breast cancer care, should be maintained in parallel to pandemic control measures, providing a pragmatic clinical model within the broader context of public healthcare schemes. # Introduction The global preparedness and response to the rapid escalation of severe acute respiratory syndrome coronavirus (SARS-CoV)-2-related disease at a pandemic proportion has demanded the prompt development of a reliable, applicable and evidenceinformed mechanism for the priority-setting of health services, to assure the attainment of the highest standards of quality care to all. [bib_ref] Cancer guidelines during the COVID-19 pandemic, Burki [/bib_ref] While the response strategy to the global spread of COVID-19 must be immediately integrated into public health policy, these actions require non-COVID-19 health priorities to be urgently identified and defined to reshape health systems, which are struggling to meet the health demands in view of the rapid spread of the pandemic. [bib_ref] Fair allocation of scarce medical resources in the time of Covid-19, Emanuel [/bib_ref] In oncology, the definition of essential services must be developed within a value framework for organisational and clinical decision making-as the clinical response to COVID-19 should never be developed a latere, but integrated in the multisectoral approach, to pursue overarching community goals, while preserving the perspectives of patient-centred care.No response from the oncology community should be disconnected from the broader healthcare priority setting mechanisms. A horizontal approach is envisioned, engaging with the continuum of care and embracing the primary healthcare sector to guide patients with cancer at home, including effectively developing telemedicine systems. Globalisation has propelled the rapid spread of the disease, inundating healthcare systems, in particular, intensive healthcare capacities, thus necessitating the abrogation of some health services of deferrable priority as a key strategic approach. Therefore, integrated healthcare planning is the bedrock of success in the preparation and response to COVID-19-including oncology. [bib_ref] Essential care of critical illness must not be forgotten in the COVID-19..., Baker [/bib_ref] The need for value-based priority setting mechanisms has been envisioned by the global agencies for public health, especially when planning in health environments with impaired availability or accessibility to essential health resources, including epidemic outbreaks and disruptions of procurement chains and intermittent health service delivery-one of the global dividend of equitable quality care between well-resourced and resource-constrained settings.In the era of COVID-19related constraints and the need to meet the goals of population health against threats that challenge the resilience of the health systems as we know them, the development of clinical guidelines must embrace an evidence-based mechanism to make choice, thus refusing the easy ways of perspectives or opinions approached per silos. The key to succeed in the management of cancer, when resources are limited or impaired by extraordinary events, is to define a methodology and create a value-enhanced framework with the most salient cancer interventions-attaining the principles of benevolence, non-maleficence, autonomy and justice. [bib_ref] Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic, Hanna [/bib_ref] Contemporary oncology research and care models are sophisticated and resource intensive in many countries. However, the necessary restrictions posed by the public health interventions in the pandemic control demand a practical framework for resource prioritisation, maintaining high standards of quality cancer care while protecting patients from health-related financial distress. Patients with cancer have been suggested as a more fragile population, namely more vulnerable to SARS-CoV-2 infection, reporting poorer outcomes from COVID-19 for multicomorbid and/or older patients-cancer history positioning as a possible independent prognostic risk factor. [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] However, a general under-representation of patients with cancer in the mixed series published to date limits any articulated dissertation. In such an uncertain area of healthcare, the knowledge of protecting the vulnerable defines the needs for research implementation, addressing the spectrum of noncommunicable diseases including cancer, as mandated by WHO in strategising the response to COVID-19 in the operational guidance for maintaining essential health services during an outbreak. The mandate is to ensure the essential services to all, prioritising per value.The trajectory of the present work aligns in parallel with the WHO indications to 'redirect chronic disease management to focus on maintaining supply chains for medications and needed supplies, with a reduction in provider encounters'approaching across the continuum of care and shaping a multidisciplinary dialogue across societies and diverse stakeholders. 8 ## Methodology for the selection of priority interventions The present manuscript is the result of an international panel of expert health providers in the management of breast cancer and is proposed to guide healthcare professionals treating patients with breast cancer during the COVID-19 pandemic. The expert consensus-based recommendations are not intended to replace the current guidelines but rather adapt breast cancer care during the COVID-19 pandemic, using a value-based framework to set priorities. All the adaptations and prioritisations have been formulated by the experts via teleconferences and e-mails discussions. In the aim to provide a framework for the response of the medical community to COVID-19, the European Society for Medical Oncology (ESMO) has established a guidance for clinicians, defining three levels of priorities regarding medical interventions, namely: tier 1 (high priority intervention), tier 2 (intermediate priority) and tier 3 (low priority)-informed by the Ontario Health Cancer Care Ontario framework of resource-prioritisation and by the ESMO Magnitude of Clinical Benefit Scale (MCBS), a public health tool intended to support the uptake of medical interventions in oncology. Overall, the prioritisation has been developed to incorporate both the information on the value-based prioritisation and clinical cogency of the interventions (figure 1). ► Tier 1 (high priority): patient's condition is immediately life-threatening, clinically unstable and/or the magnitude of benefit qualifies the intervention as high priority (eg, significant overall survival (OS) gain and/or substantial improvement of the quality of life (QoL)). ► Tier 2 (medium priority): patient's situation is noncritical but delay beyond 6-8 weeks could potentially impact overall outcome and/or the magnitude of benefit qualifies for intermediate priority. ► Tier 3 (low priority): patient's condition is stable enough allowing services to delay for the duration of the COVID-19 pandemic and/or the intervention is non-priority based on the magnitude of benefit (eg, no survival gain with no change or reduced QoL). Of note, some interventions included in the tier 3 and considered safely deferrable should be re-discussed after 6-8 weeks, to re-assess the priority and deliberate on the clinical cogency. The clinical guidance defined by ESMO must be interpreted in the broader context of healthcare response to the pandemic, and always linked to the Global Norms of WHO, the lead public health agencies and health technical governmental boards, for the definition of the strategies for the preparedness and response on populations-including the interventions to ensure the safest conditions for the health workforce, the proper provision of personal protective equipment, the testing strategy for healthcare personnel, patients and communities. Inconsistencies of clinical guidelines developed outside the global strategy and not in coordination with the strategic population policies of pandemic control will inevitably harm communities, with the earliest impact being on the most vulnerable patients-patients with cancer being first among them.prIorItIes for the ManageMent of breast CanCer: reorganIsIng the outpatIent settIng and sharIng deCIsIons Meeting the community goals and perspectives of physical distancing and the overall public health measures for the mitigation of SARS-CoV-2 spread may necessitate a reinforcement and reorganisation of the outpatient setting. Triaging patients for fever and COVID-19-related symptoms is mandatory and an entry checkpoint should be considered by all healthcare facilities. In the outpatient setting, postsurgical haematoma and infectious complications of surgical wounds may prompt ambulatory clinical interventions, like a drainage or an incision, to reduce the burden of serious, but preventable complications from cancer interventions, applying the priority criteria of clinical cogency. Prioritisation is guided by magnitude of benefit, tumour biology and stage together with clinical scenarios. Quality of care should remain unchanged for the prioritised interventions. For example, for the treatment planning of all patients with cancer, a multidisciplinary board discussion must be assured, as retaining a major prognostic significance: thus while the format may change (eg, videoconferencing), the principle of multidisciplinary care is non-negotiable [bib_ref] Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional..., Kesson [/bib_ref] [fig_ref] Table 1: Azambuja E, et al [/fig_ref]. Visits to hospital should be minimised and if necessary, all protective measures should be taken (eg, physical distancing recommendations and use of masks). Also, there should be a triage for possible symptoms of COVID-19 prior to enter into the hospital premises. The use of home-based services should be considered as much as possible while hospital procedures are still indicated for patients with cancer where delaying treatment may compromise cancer prognosis. For specific conditions resulting from treatment-related toxicities, such as febrile neutropenia [bib_ref] Influence of neutropenia on mortality of critically ill cancer patients: results of..., Georges [/bib_ref] with clinical and anamnestic adverse prognostic factors, a rapid clinical intervention can make a difference in the prognosis as well as optimise the treatment delivery plan, thus must be included in the priorities. [bib_ref] The financial burden and distress of patients with cancer: understanding and stepping-up..., Carrera [/bib_ref] Accordingly, the safety monitoring of patients receiving oral treatments (eg, biological agents, endocrine agents and chemotherapeutics) should be organised through a quality system of telemedicine, assuring the requirements for a patient-centred connection with the oncologists and the cancer nurses. All the non-priority outpatient visits may be shifted to the telemedicine platform. The telemedicine delivery is best suited to non-urgent situations for established patients with no new complaints as well as survivorship and follow-up care of patients with cancer and of people referred to high-risk clinics (eg, BRCA carriers) for preventive interventions. In asymptomatic patients, follow-up exams can be delayed unless there are symptomatic clinically emergent conditions. The patient-centred model of care requires addressing all of a patients care needs and as such, psychosocial supports must be assured and may be converted to telemedicine or other web-based platforms. Although telemedicine has been recognised as an efficient delivery platform for deferrable healthcare services, limiting factors must be considered. Aspects of legal frameworks and data protection regulations, along with the management of the workforce for tele-health are of prominent interest. The consensus recognises the multiple legal and ethical issues, especially in the area of patient privacy and confidentiality-fostering the engagement with the competent vertices for healthcare professionals, healthcare facilities and academic institutions, communities, health managers and policy makers-to Mammography-based population screening and risk-adapted breast screening programmes for asymptomatic subjects (eg, MRI or ultrasound). Clinical evidence of locoregional relapse with surgical radical approach feasible (according to stage, histology and biological features of the disease) Image-guided or clinically guided biopsy to ascertain a suspect of metastatic relapse. Patients with abnormal findings at screening mammograms who can go to 6-month interval imaging (BIRADS 3). Pathology assessment (histopathology or cytopathology) for abnormal mammograms or breast symptoms or a symptomatic metastatic relapse Initial metastatic workup (according to stage and biological features) in patients with early stage invasive breast cancer. In patients with early stage breast cancer, followup imaging, restaging studies, echocardiograms, ECGs and bone density scans can be delayed if clinically asymptomatic. In patients with metastatic breast cancer, we recommend symptoms-oriented follow-up. Imaging, restaging studies, echocardiograms and ECGs can be delayed or done at lengthened intervals. Implement telemedicine follow-up. Further diagnostic imaging for BIRADS 5 screening mammogram in asymptomatic subjects Echocardiograms in patients with early stage invasive breast cancer requiring with indication to anthracycline-based or anti-HER2 treatment. BIRADS, Breast Imaging-Reporting and Data System. develop a socially accountable infrastructure of cancer service delivery. A public health approach is essentially endorsed, as the implementation of new service delivery models cannot be framed under a pure clinical indication but approached by multiple competent stakeholders. In principle, telemedicine is envisioned as part of the clinical service of the health personnel, thus accounted entirely in the clinical workload. Eventually, although beyond the scope of the present work, sustainability, financing, reimbursability and health impact of telemedicine must be accountable, on the longer term, to inspire a durable set-up of innovative paradigms of healthcare via telehealth applications. From this angle, an assessment of the baseline capacity and interim registration of the efficiency of telemedicine should orient the entire process of capacity building and, if appropriate, prompt the establishment of the programmes. To date, the telemedicine model is interpreted across several applications and webbased platforms, within the national and local perimeters of legal frameworks-variable across the settings, and a definite optimum has not been defined in oncology, as data are still warranted. While the efficiency of the prescription of multiple treatment cycles (eg, several months of endocrine therapy and target agents for patients with metastatic breast cancer) to reduce the healthcare admissions is recognised, it may be critical to intersect the cancer institution activity in a service delivery model based on a primary healthcare approach-engaging with community-based healthcare providers, including general practitioners and nurses. 14 Overall, in the context of oncology care, telemedicine is indeed a mechanism to rethink the intersection of cancer care within the existing healthcare system. While providing clinical recommendations for telemedicine, all the key elements of the healthcare contexture are to be included in the discussion, to ensure that the clinical guidance is truly offering a valid alternative option for patients and not an ideal structure unfeasible on the pre-existing community services. Of note, it is of utmost importance that all medical and strategic decisions regarding a patient's care programme are made with careful consideration by a multidisciplinary team and shared with the patient. An informed consent process needs to be performed ensuring that the patient fully understand the risks and benefits she/he can expect from any medical intervention in the context of the current public health crisis, with all its limitations. prIorItIes for the radIologICal and pathologICal dIagnosIs of breast CanCer Understanding the implications of the delay in diagnosis and access to treatment of breast cancer cannot be entirely captured unless contextualised to the biology of the cancer and patterns of clinical presentation, for example, the stage and the setting of care. [bib_ref] Delay in breast cancer: implications for stage at diagnosis and survival, Caplan [/bib_ref] All patients presenting with a new breast lump with high suspicion of malignancy or who have already undergone a screening procedure with an imaging finding highly suspicious for malignancy (eg, BIRADS 5 at mammography) should be promptly referred for tissue diagnosis and imaging and pathology are to be designated as high priority [fig_ref] Table 2: Priorities for breast diseases [/fig_ref]. Similarly, patients experiencing locoregional disease recurrence of breast cancer can still pursue a radical intention for the treatment-with a combination of locoregional treatments, either surgery and/or radiation therapy, and complemented with risk-reducing medical therapies: targeted, endocrine or chemotherapy. [bib_ref] Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated..., Anderson [/bib_ref] [bib_ref] Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer..., Waeber [/bib_ref] [bib_ref] Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast..., Wapnir [/bib_ref] In this setting, it becomes essential to share the clinical decision, informed by the primary intention of the approach. Although often complex across a spectrum of clinical presentations, some disease recurrence patterns are more prone to radical approaches and, long-lasting disease-free intervals can be expected. Thus, based on clinical and pathological criteria, priority must be based on the intention of the care to identify the undeferrable cases, always in a multidisciplinary assessment. Overall, histopathology diagnosis can have an immediate impact and sometimes cannot be deferred to complete the differential diagnosis. For patients with symptomatic metastatic relapse, whenever the provision of a treatment can be life-saving and/or significantly modify the quality of life, a histopathology diagnosis will be included in the set of undeferrable health services. Besides the primary treatment intentions, the safe delivery and safety monitoring of treatments may require specific imaging techniques. Commonly, patients under treatment with anthracyclines or anti-HER2 agents require a regular assessment of cardiac function, prompting treatment interruptions, dose-reductions or cardio-oncology interventions, where indicated. [bib_ref] Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus..., Curigliano [/bib_ref] Similarly, the ECG assessment for potentially arrhythmogenic changes, including the QT tract prolongation, should be considered in selected patients receiving some biological agents or carrying specific comorbidities.Overall, the cardio-oncology consultation could be reshaped in a riskadapted scheme, adapting the monitoring intensity to the baseline risk of cardiac adverse events and the treatments received. During the pandemic outbreak, mammography-based screening for breast cancer in asymptomatic women should be temporarily abrogated, as the risk-benefit ratio (risk of infection related to healthcare admissions for second-level procedures vs lives saved by screening) is not predicted to be high during the pandemic and appointments may be postponed by a few weeks or months without disproportionate predicted harms. Similarly, imaging for follow-up of patients with early breast cancer and metastatic patients may be delayed if necessary, with tailoring of radiological assessments per symptoms or other suspicion of progression, as clinically assessed-while still preferring telemedicine for non-priority complains and interventions. [bib_ref] Intensive follow-up for women with breast cancer: review of clinical, economic and..., Lafranconi [/bib_ref] prIorItIes for breast surgICal onCology Cancer surgery is one of the cancer interventions bringing the greatest benefits for patients with cancer, principally in the curative setting, resulting in gains in cancer survival.The priority-setting framework of breast cancer surgery aims to understand how reasonably and for how long cancer surgery can be delayed, assuring the attainment of the highest standards for quality care delivery. Once again, the question must take into account cancer biology, clinical presentation pattern, patients' conditions and preference [fig_ref] Table 3: Priorities for breast disease [/fig_ref]. [bib_ref] Breast cancer, Harbeck [/bib_ref] The clinical cogency for intervention is dictated by the risk for serious complications or irreversible health conditions, like for postsurgical breast cancer complications. Where relatively simple surgical interventions can determine a change in the natural process of a potentially adverse pathological condition at rapid evolution, it represents a surgical priority. This also includes surgery complications demanding haemostatic procedures, incision, drainage or packing material insertion and certain wound dressing. However, relatively more complex procedures can sometimes still retain a priority, when inaction is associated with potentially fatal outcomes (eg, for the delay of adjuvant treatments). [bib_ref] Mastectomy skin flap necrosis: challenges and solutions, Robertson [/bib_ref] Several respected professional societies have proposed classifications of urgency/ benefit/postponability. Based on the magnitude of benefit criteria, patients completing neoadjuvant chemotherapy-based treatments or, less commonly, progressing during such treatments, should receive curative surgery with no postponement. In situations in which this is absolutely impossible in terms of crisis healthcare resources, adding another cycle of neoadjuvant therapy in patients responding well to therapy may 'protect' the patient from the postponement of surgery. Primary surgery of low-risk early breast cancer can safely be postponed up to 12 weeks, based on experts' opinion, although no firm data exist, unless very aggressive tumour biology is present. In latter situations, neoadjuvant treatment approaches may be considered anyway. For luminal-like breast cancers, using appropriate preoperative endocrine treatment might be an option for avoiding harm due to the delay of surgery in selected cases. The psychological strain for patients who experience delays of their surgical procedures must not be underestimated, and appropriate psychological support offered. Surgery for in situ ductal carcinomas could be transiently deferred in some cases, and the use of endocrine therapy if hormone receptor positive may be considered. Reconstructive procedures can/should be postponed, also because their perioperative morbidity risk is higher than that of standard breast surgery. [bib_ref] Challenges and controversies in breast surgery, Gnant [/bib_ref] As discussed above, patients experiencing locoregional relapse should be discussed in a multidisciplinary setting to weigh the potential benefits of offering an immediate radical surgical excision with subsequent durable survival gain versus postponing surgery after a primary systemic treatment. As for all the other clinical presentations, the discussion about surgical indications must be individualised. Of note, all decisions must be shared with the patients, assessing the preference and expectations while informing on the threats and advantages of the adapted treatment plans in the context of the COVID-19 crisis. prIorItIes for breast radIatIon onCology The indications for radiation therapy in breast oncology are wide, and must be interpreted in the multidisciplinary care settings. According to clinical prioritisation, immediate radiation therapy should be initiated, in accordance with current clinical practice, in patients with acute spinal cord compression, symptomatic brain metastases not improving with steroidal medication and any urgent irradiation with an expected impact in survival or a modifying effect on the risk of disabling sequelae and/or quality of life ( breast mass-related symptoms for fungating or bleeding neoplasia can usually be obtained with supportive care interventions, including advanced wound dressings, there may exist a need to provide surgery or radiation therapy for haemostasis or to alleviate pain due to inoperable breast masses for improving the quality of life for patients with advanced disease. The optimisation of locoregional control and the improvement of survival define the priority of the interventions in radiation therapy. Thus, post-operative radiation therapy for high-risk patients (eg, inflammatory breast cancer, node-positive or high-risk biology) should be scheduled as high priority, respecting the highest standards of quality for radiation therapy when proposing alternative (shorter) radiation regimens. [bib_ref] International guidelines on radiation therapy for breast cancer during the COVID-19 pandemic, Coles [/bib_ref] Most patients are eligible for short-course treatments using hypofractionated schedules, being the treatment of choice. Accelerated partial breast irradiation should be proposed for low-risk patients, when indicated and technically feasible, given available technology and the capacity of the centres. Also for this, shorter treatment courses should be favoured, including single dose intra-operative electron radiation therapy or up to 5 fractions of preferably external beam radiation therapy and not brachytherapy as this implicates a second intervention and more intense hospital visits. Where the expected clinical benefit of irradiation is very low, as in the older population with lowrisk breast cancer under adjuvant endocrine therapy, deferral is possible or omission could even be considered in some circumstances. [bib_ref] Breast-Conserving surgery with or without irradiation in women aged 65 years or..., Kunkler [/bib_ref] The aim is to maintain a balance between respecting COVID-19 restrictive measures such as limiting number of contacts and physical distance, while at the same time preventing jeopardising the outcomes of cancer interventions, considering that radiation therapy usually requires a sometimes long series of treatments with repeated admissions to the institutions. This should be an additional argument for applying the abundance of evidence in favour of the use of hypofractionation in clinical practice. prIorItIes for breast MedICal onCology In the early settIng of Care The role of presurgical, perisurgical and postsurgical systemic therapies has evolved to become the backbone of care in breast oncology, and over the last decade a paradigm shift in systemic care has occurred, with the tailoring of type and timing of care to tumour subtypes. The delivery of systemic treatments usually demands a resource-intense effort of the health institutions, built around the patient, with optimal safety conditionsstating that the quality of medical oncology must attain the highest standards, when priority interventions are established [fig_ref] Table 5: Priorities for breast cancer [/fig_ref]. During pandemics, the disruption of the procurement chain for medicines and the changed contexts of drug selection can have an impact on the availability and accessibility of medicines, including irregular provision or shortage of medicines for the supportive care.Optimising the medical oncology service during COVID-19 means assuring the assignment of the treatments at the highest benefit to the eligible population, in the safest conditions and guaranteeing punctual monitoring mechanisms for the adverse effects, implemented by telemedicine systems and engaging with primary healthcare sectors-an effort of one health system working in synchrony. Decisions at national and institutional level can be readily informed by public health tools of selection and prioritisation of the medical interventions, including the ESMO MCBS. [bib_ref] ESMO-Magnitude of clinical benefit scale version 1.1, Cherny [/bib_ref] According to the MCBS, the priority interventions in the curative setting are scored A, on a scale from A to C, from high to low priority, respectively. While the score has been applied to a several novel compounds for breast cancer treatment, mostly in the advanced setting, less scoring has been performed in the early breast cancer setting, particularly with chemotherapy regimens, and this should be considered when balancing risk and benefits. [bib_ref] ESMO-Magnitude of clinical benefit scale version 1.1, Cherny [/bib_ref] Patients with the highest risk breast cancers are to be prioritised for systemic treatments (ie, either triplenegative or HER2-positive early breast cancer). Overall, adjuvant endocrine treatments are not expected to be substantially changed, not impacting significantly on immune functions, while the monitoring for side effects and treatment compliance could be readily performed via telemedicine. Of note, in case of SARS-CoV-2 infection in a patient with breast cancer taking tamoxifen, the hormone therapy should be suspended and preventive measures against thrombosis proposed, given the high risk of thromboembolic events in patients with COVID-19 with severe disease, and the well-known increased thromboembolic risk associated with tamoxifen. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] For some patients, a neoadjuvant endocrine approach could be considered, according to the current clinical recommendations, and possibly to delay the time to surgery in selected clinical presentations. This group encompasses patients with postmenopausal stage I cancers, low-grade to intermediate-grade tumours and lobular breast histology variants, deferring the surgery up to 6-12 months, as indicated in existing guidelines.Aromatase inhibitors (AI) should be preferred. While for postmenopausal women neoadjuvant endocrine therapy is an established approach, this is not so for premenopausal women but may be considered on a case-bycase basis under these extenuating circumstances. All premenopausal women receiving an AI should receive LHRH (Luteinizing hormone-releasing hormone) analogue. Monthly injections should be preferred but in some cases (particularly women in their mid-late 40s), one may discuss 3-monthly formulation of LHRH analogue, in order to reduce patient visits. Overall, homebased monthly administrations would be the preferred choice. The possibility to deliver treatments at home, including some antineoplastic agents (eg, subcutaneous trastuzumab, LHRH agonists) is framed in the national -Continuation of standard adjuvant endocrine therapy in premenopausal and postmenopausal setting. Use telemedicine to manage potential toxicity reported by patients Continuation of treatment in the context of a clinical trial, provided patient benefits overweight risks, with possible adaptation of procedures without affecting patient safety and study conduct. Regulatory agencies and sponsors may provide guidance on rules on study conduct during the pandemics -and regional competencies in the matter of healthcare organisation and regulations on medicines-conditioning the grades of operational flexibilities for the treatment delivery at the time of COVID-19.However, any initiative for home-based care should be built under the COVID-19 agenda, to ensure consistency with the physical distancing measures and protection of both the patients and the workforce. Moreover, for selected HER2-positive breast cancer, low-risk or elderly patients with cardiovascular or other comorbidities adjuvant trastuzumab may reasonably be discontinued after 6 months instead of 12 months of treatment, according to clinical guidelines. [bib_ref] 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer..., Earl [/bib_ref] Ongoing treatments should be fully completed, as any compromise in dose density and intensity may adversely impact prognosis. For triple-negative and HER2-positive patients with breast cancer treated with neoadjuvant therapies and not reaching a pathological complete response, postneoadjuvant systemic treatments are highly recommended as they provide durable disease control and improved survival. The selection of the most appropriate schedules of chemotherapy will make considerations of at least three factors: the number of monthly admissions to the institutions, preferring 2-weekly or 3-weekly schedules; the need to escalate immunosuppressive supportive medications (eg, steroids for premedication); the informed patient's preference. In the midst of uncertainties of the impact of immune-suppressive agents or steroids used for premedication at non-immunosuppressive doses on the risk of SARS-CoV-2 infection and COVID-19 outcome, the use of these agents should be carefully evaluated. The use of granulocyte growth factors may be considered to minimise neutropenia. prIorItIes for breast MedICal onCology In the advanCed and MetastatIC settIng of Care The decision making for priority positioning in the metastatic setting is more complicated. In the clinical landscape of effective treatments that impact on the quality of life and the survival, the best treatment approaches should be part of the health priorities [fig_ref] Table 6: Priorities for breast cancer [/fig_ref]. The health cogency criterion demands prompt cancer treatments in patients where a delay can result in fatal outcomes. For example, patients experiencing cancerrelated treatment organ dysfunctions or at increased risk of it, namely patients in visceral crisis, should be prioritised for the start of antineoplastic treatments. Consider, discussing case-bycase, inclusion in a clinical trial, provided patient benefits overweight risks, with possible adaptation of procedures without affecting patient safety and study conduct. -mTOR, mammalian target of rapamycin; PD-L1, programmed death-ligand 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TNBC, triple-negative breast cancer. According to the MCBS, the priority interventions in the advanced setting are scored 3, 4 or 5, in a descending scale for value, from 5 to 1. [bib_ref] ESMO-Magnitude of clinical benefit scale version 1.1, Cherny [/bib_ref] For such, the magnitude of benefit and the expected treatment benefits should guide the clinical indications. Early line chemotherapy, endocrine therapy and targeted agents with higher MCBS score are of choice, and should be delivered in the eligible population-for example, in the prescription of the double anti-HER2 blockade plus chemotherapy as first line for patients with HER2-positive disease, where affordably accessible (MCBS score 4). The use of immunotherapy (eg, atezolizumab) and CDK4/6 inhibitors and endocrine therapy (MCBS scores of 3-4), should be considered after a case-by-case discussion taking into account baseline risk factors of the patient and their functional status, along with considerations on the disease pattern of spread and biology-to ensure a critical decision making by tailoring for the single patient, in accordance with local practice and resource availability. In the midst of uncertainty related to some immune-modulating agents with limited value in cancer treatment, avoiding or delaying the addition of mTOR inhibitors to endocrine therapy could be prudent, especially in multicomorbid older patients (MCBS score for everolimus: 2). This means that the contingency plan during the pandemic could result in the temporary withdrawal of some interventions, or predefined safe delays. The use of oral bisphosphonate or subcutaneous denosumab can be considered in some cases, as to the choice of longer intervals for intravenous bisphosphonates, for example, every 3 months. Similarly, in late treatment lines, patients with poorer prognosis and impaired functional status could be considered for a best supportive care (BSC) approach and/or drug holiday periods-with consideration given for the benefits in terms of quality of life, while attaining to the highest standards of care: an early start of home-based supportive care plan and the judicious referral of some patients to BSC is a priority, overall, when the available therapies are known to provide only a narrow benefit and they may incur on the patient excessive of toxicity. [bib_ref] Determinants of Last-line treatment in metastatic breast cancer, Cinausero [/bib_ref] Treatment de-escalation and/or maintenance with oral agents may be considered, although largely based on experts' opinions. ## Covid-19 and its impact on cancer research The continuation of treatment in the context of a clinical trial is valuable for cancer clinical research, provided patient benefits outweigh risks, with possible adaptation of trial procedures without affecting patient safety and study conduct. To date, the social distancing measures have partially frozen the preclinical laboratory-based research in many countries, in response to the urgent need to prioritise the services with an immediate role in COVID-19 response and to serve community needs. Overall, the national and regional regulatory agencies have formulated guidance for the management of patients enrolled in clinical trials, providing recommendations on the exploitation of the study procedures and the safe delivery of the study medications, including concrete information on changes and protocol deviations which may be needed in the conduct of clinical trials to deal with extraordinary situations. In such a context, protocol deviations are expected and some are justified, when not exposing patients to safety issues and facilitating procedural barriers or bureaucratic aspects of study procedures: a real moment to re-think the clinical trial conductions tout court. [bib_ref] Conducting phase 1 cancer clinical trials during the severe acute respiratory syndrome..., Tarantino [/bib_ref] For instance, in Europe the recommendations of the European Medicines Agency can be found at: https://www. ema. europa. eu/ en/ news/ guidance-sponsors-how-manage-clinical-trialsduring-covid-19-pandemic In the USA, the Food and Drug Administration also released guidance on clinical research and COVID-19 (https://www. fda. gov/ media/ 136238/ download). While avoiding a total distraction of the cancer research community from the goals and research questions and slowing the progress in cancer care-research questions of immediate clinical interest for cancer and COVID-19 have been implemented, bridging the need to provide responses to patients with cancer and the advancement of knowledge. Several ongoing trials are addressing the safety and trying to dissect the interplay of anticancer and antiviral immune responses. Generating quality evidence is now the real priority, to enhance the clinical decision-making: the observational series of the first waves are now expected to leave room for controlled studies, mechanistic explanations and translational experiences, ensuring the best research at the service of the cancer and pandemic response. There is an ongoing list of clinical trials testing different strategies in patients with COVID-19 and they can be found at http://www. redo-project. org/ COVID-19_ db-summaries/ # Conclusions For cancer care, COVID-19 is presenting a challenging period in medicine, demanding a re-focus on the value and priorities of health interventions, including the reshaping of cancer care-catalysing a review of valuebased and patient-centred decision making. Setting priorities based on the intrinsic value of the interventions about patients' outcomes and ensuring simultaneously population and societal benefits is the perspective in which the response to COVID-19 has been designed. The priority-setting mechanism that is envisioned aligns with the global, regional and national standards proposed in several work streams, including the development and implementation of the MCBS scale, which is based on patient-related end points and aimed to provide a statement and guidance on priority setting, to support and enable decision making when resources need to be rationed and cautiously allocated. WHO has defined differentiated preparedness and response plans, according to the disease spread in single countries, providing global guidance and guidance for local action. This means that the degree of SARS-CoV-2 spread in a country dictates the type and intensity of the public health interventions and should also orient the selection and prioritisation of the health interventions in oncology-with a tiered approach. The perimeters and limits of this work should be interpreted and adapted within the national and regional dispositions in terms of the ability towards health system reorganisation and reshaping of the existing model. While some countries have interpreted a segregation model, and suggestions from WHO seems to propend more for the identification of a COVID-19 health pathway for prompt referral, policies can vary across countries, related to the stage of the pandemic as well as the health sector specificities. In such a complex setting, this clinical guidance for breast cancer management is intended to orient and not decree local guidelines, and guide the development of action plans to maintain a quality cancer service, setting a minimal array of required interventions. Useful information can be found at https://www. esmo. org/ guidelines/ cancer-patient-management-during-thecovid-19-pandemic/ breast-cancer-in-the-covid-19-era Correction notice This paper has been updated since first published to correct name of author 'Philip Poortmans'. twitter Evandro de Azambuja @E_de_Azambuja, Dario Trapani @darioT_ and Michael Gnant @MichaelGnant acknowledgements The authors would like to thank ESMO for allowing the use of the tables in this manuscript. Contributors GC developed the first outline and coordinated the authors' contributions, engaged for competencies and expertise in the management of breast cancer, development of adapted guidelines in special circumstances and its methodology. GC and DT formulated the first draft to organise the authors' work, and with EdA developed a draft zero. All the authors were involved in writing and, when the first draft had been developed, all the authors refined the contents with feedbacks and comments, incorporated by GC, EdA and DT. All the authors approved the final draft before the submission. While the authors are affiliated to different institutions for cancer research and care, the perspectives expressed in the present paper should not be intended to mirror the societal and institutional positions. [fig] Figure 1: Priority-setting of the health interventions in oncology during COVID-19. [/fig] [table] Table 1: Azambuja E, et al. ESMO Open 2020;5:e000793. doi:10.1136/esmoopen-2020-000793 Outpatient visit priorities for the management of breast cancer treatment patients with new symptoms or side effects (depending on severity of symptoms/side effects, burden of progression, etc). Convert as many visits as possible to telemedicine visits. Intensify safety monitoring for those patients on oral chemotherapy or endocrine therapy plus biological agents [/table] [table] Table 2: Priorities for breast diseases: diagnostics and imaging [/table] [table] Table 4: Priorities for breast cancer: radiation oncology [/table] [table] Table 3: Priorities for breast disease: surgical oncology [/table] [table] Table 5: Priorities for breast cancer: medical oncology-early breast cancer [/table] [table] Table 6: Priorities for breast cancer: medical oncology-metastatic breast cancer [/table]	None	http://www.esmoopen.com/article/S2059702920326727/pdf	The global preparedness and response to the rapid escalation to severe acute respiratory syndrome coronavirus (SARS-CoV)-2-related disease (COVID-19) to a pandemic proportion has demanded the formulation of a reliable, useful and evidence-based mechanism for health services prioritisation, to achieve the highest quality standards of care to all patients. The prioritisation of high value cancer interventions must be embedded in the agenda for the pandemic response, ensuring that no inconsistency or discrepancy emerge in the health planning processes. The aim of this work is to organise health interventions for breast cancer management and research in a tiered framework (high, medium, low value), formulating a scheme of prioritisation per clinical cogency and intrinsic value or magnitude of benefit. The public health tools and schemes for priority setting in oncology have been used as models, aspiring to capture clinical urgency, value in healthcare, community goals and fairness, while respecting the principles of benevolence, non-maleficence, autonomy and justice. We discuss the priority health interventions across the cancer continuum, giving a perspective on the role and meaning to maintain some services (undeferrable) while temporarily abrogate some others (deferrable). Considerations for implementation and the essential link to pre-existing health services, especially primary healthcare, are addressed, outlining a framework for the development of effective and functional services, such as telemedicine. The discussion covers the theme of health systems strategising, and why oncology care, in particular breast cancer care, should be maintained in parallel to pandemic control measures, providing a pragmatic clinical model within the broader context of public healthcare schemes.
1782efee99fef8d030618c03bd3727f679cd1b0c	pubmed	Facial nerve electrodiagnostics for patients with facial palsy: a clinical practice guideline	Facial nerve electrodiagnostics for patients with facial palsy: a clinical practice guideline Purpose Facial nerve electrodiagnostics is a well-established and important tool for decision making in patients with facial nerve diseases. Nevertheless, many otorhinolaryngologist-head and neck surgeons do not routinely use facial nerve electrodiagnostics. This may be due to a current lack of agreement on methodology, interpretation, validity, and clinical application. Electrophysiological analyses of the facial nerve and the mimic muscles can assist in diagnosis, assess the lesion severity, and aid in decision making. With acute facial palsy, it is a valuable tool for predicting recovery. Methods This paper presents a guideline prepared by members of the International Head and Neck Scientific Group and of the Multidisciplinary Salivary Gland Society for use in cases of peripheral facial nerve disorders based on a systematic literature search. Results Required equipment, practical implementation, and interpretation of the results of facial nerve electrodiagnostics are presented. Conclusion The aim of this guideline is to inform all involved parties (i.e. otorhinolaryngologist-head and neck surgeons and other medical specialists, therapeutic professionals and the affected persons) and to provide practical recommendations for the diagnostic use of facial nerve electrodiagnostics. # Introduction Guillaume-Benjamin Duchenne in the 1800 s was one of the earliest practitioners of electrodiagnostic. Duchenne noted that patients with persistent facial palsy had absent muscular contractility with nerve stimulation. He, therefore, claimed that electrostimulation could predict prognosis. Blink reflex testing evoked by electrical stimulation was the first neurological test used for facial nerve diagnostics by Kugelberg, in 1952. In 1963 Laumans and Jongkees introduced the nerve excitability test (NET) [bib_ref] On the prognosis of peripheral facial paralysis of endotemporal origin, Laumans [/bib_ref] for the direct facial nerve and facial muscle testing. With this electrostimulation test, the lowest current eliciting a twitch in the mimetic muscles was defined as the threshold of excitation and the difference in thresholds between the two hemifaces was calculated [bib_ref] Which electrophysiological measure is appropriate in predicting prognosis of facial paralysis?, Ozgur [/bib_ref] [bib_ref] Clinical efficacy of electroneurography in acute facial paralysis, Lee [/bib_ref]. May et al. described the maximal stimulation test (MST) [bib_ref] The prognostic accuracy of the maximal stimulation test compared with that of..., May [/bib_ref]. During MST, facial movement of the paretic side was compared with the contralateral side at the stimulation level where the greatest amplitude of facial movement was seen on the normal side. NET and MST both are dependent upon the cooperation of the patient and on the examiner's visual evaluation of the electrically elicited facial movement. This factor limits the reliability of both tests. These limitations were overcome by electroneurography (ENoG; sometimes also called evoked electromyography). ENoG was popularized by . ENoG objectively records the amplitude of electrically evoked muscle action potentials. Finally, electromyography (EMG) measures volitional responses of the facial muscles without electrostimulation. ENoG and EMG are now the most important facial electrodiagnostic tools. Electrostimulation with a visual inspection of the face (as it was used for the NET and MST) still are relevant for facial nerve mapping (FNM). Electrodiagnostics remain valuable tools for patients with facial palsy. Nevertheless, many practitioners do not routinely use them [bib_ref] Inpatient treatment of patients with acute idiopathic peripheral facial palsy: a population-based..., Plumbaum [/bib_ref]. The situation has been the same for laryngeal electrodiagnostics until recently. To overcome this, the European Laryngological Society published a guideline for laryngeal EMG [bib_ref] Laryngeal electromyography: a proposal for guidelines of the European Laryngological Society, Volk [/bib_ref]. The idea behind was to find an agreement on methodology, interpretation, validity, and clinical application of laryngeal EMG as an important step to promote the use of laryngeal electrodiagnostics. The present proposal has now the same goal for facial electrodiagnostics. An overview of the most important facial electrodiagnostic tests is shown in [fig_ref] Table 1: Overview about the most important facial electrodiagnostic tests Transcutaneous electrostimulation of the... [/fig_ref]. A careful review was done of a comprehensive overview of facial nerve electrophysiology that was published in 2016. We conducted a systematic literature search for the most recent publications using PubMed and ScienceDirect database, with the following MeSH terms: "facial nerve", "Bell palsy", "facial nerve diseases", "electrodiagnostics", and "humans" (period: 2015-2019; last search on 21-October 2019) in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. A total of 32 articles were included in the present review based on relevance and scientific evidence. The highest level of evidence reached the level of retrospective observational cohort studies (Oxford Centre for Evidence-based Medicine Level III-IV). Due to the lack of high-quality evidence, the presented recommendations reached the level of recommendation B, i.e. considerable benefit substantiated by non-first-class evidence, according to international standards and the Association of the Scientific Medical Societies guidelines (Arbeitsgemeinschaft Wissenschaftlich Medizinischer Fachgesellschaften, AWMF; https ://www. awmf.org/en/clini cal-pract ice-guide lines /awmf-guida nce. html). The most important diagnostics tests are discussed in depth and a consensus is introduced. Recommendations for the use of ENoG and EMG as well as the role of less often employed techniques like blink reflex testing or transcranial magnetic stimulation (TMS) are also presented in detail. The manuscript circulated among the authors in four rounds until a consensus was reached for all recommendations. A strong consensus (Agreement among > 95% of participants) was reached for all recommendations. These electrophysiological tests are mainly used to determine the severity and prognosis of a peripheral facial nerve lesion. Transcutaneous electrostimulation is helpful for preoperative FNM. EMG in the form of surface EMG (sEMG) is an important tool for facial muscle expression analysis. Intraoperative nerve monitoring was not part of this study: instead, we refer to other recently published recommendations [bib_ref] Contemporary management of benign and malignant parotid tumors, Thielker [/bib_ref] [bib_ref] Management of the facial nerve in parotid cancer: preservation or resection and..., Guntinas-Lichius [/bib_ref]. Facial electrodiagnostics are also used for other diseases than facial nerve palsy i.e. for hemifacial spasm or facial myokymia [bib_ref] Excitability of facial nucleus and related brain-stem reflexes in hemifacial spasm, post-facial..., Oge [/bib_ref]. Electrodiagnostics for these diseases were not part of this study. ## Facial nerve physiology, pathophysiology, and definitions The facial nerve can be stimulated volitionally by the first motoneuron in the facial nerve nucleus, or artificially by electrostimulation of the peripheral facial nerve. A sequence of action potentials is then evoked, and the facial nerve is depolarized between the nodes of Ranvier. The action potentials are transmitted to the facial muscles via the motor endplates. A motor unit (MU) consists of a facial motoneuron and its innervated muscle fibers. In small facial muscles, the number of muscle fibers per MU is low. This is needed for the precise motor control of the muscles. The activation of the muscle fibers by its motor neuron results in a motor unit action potential (MUAP). In facial electrodiagnostics, one normally measures the muscle response visually (NET, MST) or through the interpretation of the electrical signals derived from the muscle (ENoG, EMG). Unlike other nerves, direct analysis of only the facial nerve is not possible due to its early extratemporal branching. Most facial nerve injuries take place in the temporal bone. Nerve stimulation proximal to the pathologic lesion site is therefore often not feasible. Disturbances of facial muscle function can occur from central and peripheral pathology. Peripheral lesions are more relevant for an otorhinolaryngologist-head and neck surgeon. Peripheral facial nerve dysfunction is classified according to Seddon into three subtypes: neurapraxia, axonotmesis, and neurotmesis [bib_ref] Three types of nerve injury, Seddon [/bib_ref]. Neurapraxia is characterized by functional nerve deficits with no morphological nerve failure. Axonotmesis is defined as a lesion in the axonal nerve fibers, but the covering myelin sheath is intact. Neurotmesis is distinguished as a complete disconnection of the facial nerve. Facial electrodiagnostic testing tries to differentiate between these three aforementioned subtypes. Depending on the time after a facial nerve injury, electrodiagnostics cannot always differentiate between the three types of nerve injury. The significance of electrodiagnostics can be increased by repeated testing during the time course of a facial nerve lesion. If the lesion lies in the intratemporal segment such as Bell's palsy, it takes about 72 h before the Wallerian degeneration has reached the extratemporal segment distal to the stylomastoid foramen. Electrostimulation distal to the Needle electromyography (nEMG) Does not work with external stimulation; The MUAP in the range of the needle electrode is recorded during insertion, at rest, and during voluntary movements Most important 2-3 weeks after onset of the palsy, because pathologic activity can occur in case of facial nerve degeneration. In the later time course, nEMG is important to detect reinnervation potentials as signs of reinnervation of the facial muscles Surface electromyography (sEMG) Like nEMG, sEMG works with voluntary activity of the facial muscles and not with external stimulation. The recording field and therefore the depiction of MUAPs is more superficial but the field is larger than when using nEMG sEMG is not used for prognostication. Multichannel sEMG is important if the interplay of different facial muscles should be analyzed Blink reflex Electrostimulation of the supraorbital branch of the trigeminal nerve (V1) and simultaneous sEMG recording from the orbicularis oculi muscle on both sides If ENoG and EMG is performed, the additional value is low. Blink reflex testing might be helpful if the lesion site is suspected or lies within the brainstem Transcranial magnetic stimulation (TMS) Recording setup like for ENoG, but the stimulation is performed using a magnetic field instead of electric stimulation. Typically, a stimulation over the ipsilateral parietoocciptal region is performed. A stimulation via the contralateral motor cortex is also possible If ENoG and EMG is performed, the additional value is low for routine cases. TMS is less reliable. It might be helpful in selected cases to confirm an intratemporal lesion site or in unconscious patients lesion site such as ENoG can show completely normal results during this 72-h window. The segment will continue to conduct the stimulus as it takes 10-14 days following an intratemporal insult before degeneration reaches the mimetic muscles. Signs of muscle degeneration cannot be seen by EMG before 10-14 days. The final window of post-injury time is at 21 days post-onset. After this time, nerve excitability is definitively lost, and nerve degeneration is complete. Electrodiagnostic studies can be further complicated by the interference of first regenerating fibers, which is why ENoG is most valuable if initially performed 72 h post-onset and repeated several times until day 14-21. After neurotmesis, the degeneration of the muscle takes much longer. EMG can record signs of degeneration up to 3-6 months post-injury. Synaptic and muscular lesions are typically related to neurological diseases and are relevant mainly for differential diagnosis. Disturbed neuromuscular transmission can be assessed in the facial muscles with diseases such as the ocular form of myasthenia gravis. These patients have a reduced duration of MUAP and an increase of polyphasic potentials in EMG. EMG amplitudes can also be reduced. Furthermore, myopathies can show pathologic spontaneous activity and even a synchronous increase of polyphasic potentials as a sign of simultaneous degeneration and regeneration. Findings of a synaptic or muscular lesion mandate referral of the patient to a neurologist. ## Electrophysiological diagnostic evaluation The recommended use of facial electrodiagnostics can be found in the clinical guidelines for treating idiopathic facial palsy (Bell's palsy). The American Academy of Otolaryngology-Head and Neck Surgery Foundation guideline recommends electrodiagnostic testing only for cases of complete paralysis [bib_ref] Clinical practice guideline: Bell's palsy, Baugh [/bib_ref]. Patients with incomplete paresis have good prognosis. In contrast, the German and the Spanish guidelines recommend electrodiagnostics for all patients with Bell's palsy [bib_ref] The new s2k awmf guideline for the treatment of bell's palsy in..., Heckmann [/bib_ref] [bib_ref] Facial paralysis: Clinical practice guideline of the Spanish society of otolaryngology, Lassaletta [/bib_ref] [bib_ref] The diagnosis and treatment of idiopathic facial paresis (bell's palsy), Heckmann [/bib_ref]. Some recommend electrodiagnostics for all patients with facial nerve disorder. In patients with an invasive malignant parotid tumor, facial nerve infiltration can result in an incomplete paresis when the facial nerve branches peripheral to the main trunk are affected. In these patients, electrodiagnostics can show signs of nerve degeneration. This may be the first suggestion of a malignant lesion and may influence preoperative and surgical planning. Electrodiagnostics can also be helpful to clearly differentiate a central facial palsy from an incomplete peripheral facial palsy that spares the upper face. Patients seen 2-3 months after onset with worsening neurologic findings often have an incomplete facial recovery. In these cases, electrodiagnostic tests provide a clearer picture of the severity of the lesion. Recommendation: Most patients with facial nerve disorder should undergo facial electrodiagnostics. ## Equipment There are many licensed stationary or portable electrodiagnostic machines that perform all the recommended facial electrodiagnostic tests. The machine should perform ENoG, EMG, and blink-reflex testing. A simultaneous display of at least two EMG channels should also be available. All data should be storable. A bipolar nerve stimulator or adhesive stimulation electrodes are needed for transcutaneous stimulation during ENoG. This stimulator is also needed for transcutaneous FNM. Surface electrodes are needed to record the compound action potential during ENoG and as ground (reference) electrodes. Needle EMG (nEMG) and surface EMG (sEMG) require surface and ground electrode potential differences (in voltage) which are measured during EMG recording. There are monopolar, concentric, bipolar concentric, and single-fiber EMG needle electrodes. The monopolar needle electrode is a stainless-steel needle fully insulated with a thin insulating coating, except for the tip. These solid needles are used for diagnostic purposes. Potentials recorded by monopolar needle electrodes tend to be larger and longer with more phases than those recorded with concentric needle electrodes. For nEMG one uses concentric bipolar needle electrodes. Bipolar electrodes are primarily useful for experimental studies. The same type of electrodes should be used for every routine procedure to facilitate comparison of results in the same patient and between different patients. Solid needle electrodes are needed for facial electrodiagnostics. If an EMG-guided injection, for instance of botulinum toxin is planned, the needle needs to be hollow. For singlefiber EMG (sfEMG), special fine wires are needed for special research purposes. sfEMG is not presented here, as it is not employed for clinical routine facial electrodiagnostics. Recommendation: Facial electrodiagnostic equipment should perform ENoG, and at least 2-channel EMG and blink-reflex testing. ## Electroneurography (enog) Electroneurography (ENoG; also called neuronography, electroneuronography, neuromyography, evoked electromyography; [fig_ref] Figure 1: Electroneurography [/fig_ref] analyzes the evoked compound muscle action potential (CMAP) of a specific facial muscle after transcutaneous stimulation of the main trunk of the facial nerve [bib_ref] Total intratemporal exposure of the facial nerve. Pathologic findings in bell's palsy, Fisch [/bib_ref] [bib_ref] The acute facial palsies: Investigations on the localization and pathogenesis of meato-labyrinthine..., Esslen [/bib_ref] [bib_ref] Maximal nerve excitability testing vs electroneuronography, Fisch [/bib_ref]. The main trunk is stimulated supramaximally at its exit from the stylomastoid foramen with a bipolar stimulator or stimulating electrodes. The CMAP is recorded using a bipolar pair of surface electrodes placed on the target muscle. Typically, ENoG is recorded in the nasolabial fold, the most reliable recording site [bib_ref] The prognostic value of electroneurography of bell's palsy at the orbicularis oculi..., Kim [/bib_ref]. ENoG is performed first on the healthy side of the face and then on the affected side. Nerve damage or nerve fiber degeneration leads to a decrease or loss of the CMAP. The amplitude of the CMAP on the affected side is compared to the CMAP of the healthy side and expressed as percent (amplitude of the paralyzed side divided by the amplitude of the normal side). ENoG has a re-test variability of about 20%, [bib_ref] Optimizing of electroneuronography of the facial nerve, Neuwirth-Riedl [/bib_ref] [bib_ref] Facial electroneurography: analysis of techniques and correlation with degenerating motoneurons, Coker [/bib_ref] [bib_ref] Variability of repeated facial nerve electroneurography in healthy subjects, Sittel [/bib_ref]. The high test-retest variation in ENoG results is the most important criticism of this test [bib_ref] Maximal nerve excitability testing versus neuromyography: prognostic value in patients with facial..., Adour [/bib_ref]. Therefore, it is important to minimize factors (cleaning of the skin, electrode type, room temperature) that can influence results. A side difference of 30% or bigger is considered pathologic. For prognosis, a side difference of 70-95% is considered to be relevant (see below). It is important to note that ENoG alone is not a reliable tool to differentiate between neurapraxia and a more severe lesion [bib_ref] Prognostic value of electroneurography and electromyography in facial palsy, Grosheva [/bib_ref]. Rarely, ENoG will not show a CMAP, but nEMG still detects voluntary muscle contraction. Fisch called this phenomenon the early deblocking of the facial nerve fibers [bib_ref] Prognostic value of electrical tests in acute facial paralysis, Fisch [/bib_ref]. Actually, this finding is still not completely understood. The lesion site and the onset of an acute palsy are important factors to consider when scheduling and interpreting ENoG. For instance, if the intratemporal portion of the facial nerve is affected (as in Bell's palsy) it takes about 72 h for Wallerian degeneration to reach the extratemporal nerve distal to the stylomastoid foramen. Since the stylomastoid foramen is the area for electrostimulation for ENoG, ENoG can be normal in the 72 h after onset of such a lesion. Over the next 5-6 days, the response to ENoG will be quickly lost. 21 days after onset, nerve degeneration is complete. ENoG will not change after 21 days. ENoG is helpful for predicting recovery within the time window of 3-21 days [bib_ref] Clinical efficacy of electroneurography in acute facial paralysis, Lee [/bib_ref] [bib_ref] Prognostic factors of peripheral facial palsy: multivariate analysis followed by receiver operating..., Takemoto [/bib_ref] [bib_ref] Value of electroneurography as a prognostic indicator for recovery in acute severe..., Byun [/bib_ref] [bib_ref] Prognostication of recovery time after acute peripheral facial palsy: a prospective cohort..., Volk [/bib_ref] [bib_ref] Validity of late-term electroneurography in Bell's palsy, Arslan [/bib_ref]. The first ENoG is performed at about 3 days after the onset of nerve injury and repeated every 3-5 days [bib_ref] Is serial electroneuronography indicated following temporal bone trauma?, Remenschneider [/bib_ref]. Recommendation: ENoG is one of the standard facial electrodiagnostic tests. ENoG is most valuable within the time window of 72 h to 21 days after onset of the lesion. ENoG should be employed and interpreted in combination with EMG. ## Electromyography (emg) A facial MU consists of a facial motoneuron and all muscle fibers innervated by this motoneuron. Needle EMG (nEMG) is the method used to analyze a facial MUAP recorded from a needle electrode inserted in the facial muscle . A MUAP can only occur, if a motoneuron action potential activates a muscle. The amplitude and duration of facial MUAP is related to the number of innervated muscle fibers. Amplitude and duration are reduced if the number of innervated muscle fibers are reduced. In contrast to nEMG, surface electromyography (sEMG) is recorded on the skin surface. sEMG records the sum of MUAP in the area of the surface electrode. After the onset of acute facial palsy and before a lesion has become complete, EMG may detect the presence of voluntary MU action potentials. In traumatic cases, this proves that the facial nerve has not been completely transected. This finding directly impacts the decision to explore the lesion site. In contrast to ENoG, EMG is most helpful 2-3 weeks after the onset of the palsy and loss of nerve excitability. Pathological spontaneous activity in the form of fibrillation potentials or positive sharp waves is a sign of facial nerve degeneration. After 4-6 weeks, polyphasic reinnervation potentials are signs of reinnervation of the muscle and can only be seen if facial nerve regeneration occurs. Recommendation: EMG is most valuable in the time frame of 2-3 weeks to 3 months after the onset of a facial nerve injury. EMG is helpful in monitoring for regeneration ## Needle emg (nemg) All facial muscles can be studied with one needle type. Two or more needles are needed for the synchronous analysis of several muscles. A reference surface electrode is placed at a myoelectric inactive location of the body such as the area of the manubrium sterni. Bipolar concentric needle electrodes best provide a uniform field for MUAP waveform analysis. Which facial muscles are to be examined depends on what clinical information is needed. If all of the facial nerve is to be investigated, one chooses the frontalis, orbicularis oculi, orbicularis oris, and zygomaticus muscle. These muscles are easy to identify, with mimetic movement. Recommendation: A standardized scheme and sequence should be used for recording facial muscles. An EMG of the frontalis, orbicularis oculi, orbicularis oris, and zygomaticus muscles on the affected side gives a good overview of facial nerve function. If only part of the peripheral facial nerve is affected, nEMG also is abnormal only in the affected area. nEMG of the muscle of interest should follow a standard recording sequence: ## Insertion activity In the normal unaffected facial muscle, an insertion activity response occurs during the insertion of the needle into the muscle. The insertion causes bursts of electrical activity for several hundred milliseconds. During early facial nerve injury, the electrical charges surrounding the muscle membrane are unstable. This leads to a prolonged insertion activity. In contrast, the replacement of normal muscle with scar tissue or fat decreases insertion activity. ## Pathologic spontaneous activity at rest In the normal unaffected facial muscle, no pathologic spontaneous electrical activity is present at rest. If the patient has problems relaxing the muscle, it is helpful to have the patient tense the muscle before relaxation. When the infratemporal facial nerve fibers are injured, it takes about 10-14 days before degeneration reaches the facial muscle. If the first nEMG is performed early, a repeat measurement should be done at least 14 days later. If the nerve lesion is more distal, degeneration reaches the affected muscles earlier. A denervated facial muscle can show spontaneous activity in the form of unstable electrical charges during the phase of ongoing nerve injury. This pathologic spontaneous activity occurs as fibrillation potentials, complex repetitive discharges, and sharp positive waves [fig_ref] Figure 3: Needle electromyography [/fig_ref]. Most diagnostics are fibrillation potentials. These potentials are characterized as low-amplitude, short-duration units generated by a single muscle fiber. In general, spontaneous activity indicates a poor prognosis for nerve recovery [bib_ref] Significance of electromyography to predict and evaluate facial function outcome after acute..., Grosheva [/bib_ref]. If nerve regeneration occurs, the muscle receives new electrical impulses and pathologic spontaneous activity decreases and disappears about 2-4 weeks after the nerve injury. When facial nerve damage persists, such as with malignant tumor infiltration, Needle electromyography (nEMG) procedure. a frontalis muscle, b orbicularis oculi muscle, c the orbicularis oris muscle, d zygomaticus muscle. nEMG should be performed next to the endplate area of the muscle. nEMG is performed at rest and then during specific tasks pathologic spontaneous activity can be observed until the nerve is completely destroyed. ## Activity during voluntary muscle movement This part of the nEMG examination requires the assistance of the patient. The patient is instructed to follow a standard task, frowning for the frontalis muscle, closing the eye for the orbicularis oculi muscle, showing the teeth for the zygomatic muscle etc. The stronger the muscle contraction is, the result is a greater number of activated MU and a denser MU activation pattern [fig_ref] Figure 4: Needle electromyography [/fig_ref]. Facial nerve lesion may lead to a reduced number of normal MUAPs and reduced recruitment during voluntary activity. The patient is instructed to vary the force of activation from minimum to maximum and back. The maximum activation pattern is evaluated. The number of impaired facial nerve axons is directly related to a decrease in the EMG interference pattern. The electrophysiological configuration of MUs is normally not changed in patients with neurapraxia. The duration of MUs and the number of their potential phases typically are increased in patients with axonotmesis or neurotmesis. If the facial nerve regenerates, spontaneously or after nerve repair, facial axons reinnervate the target muscles. A typical sign of reinnervation is polyphasic regeneration potentials. These MUs have greater amplitudes than normal and a prolonged duration during the regeneration process. ## Synkinetic activity The regenerating axons branch randomly and reach separate facial muscles. This can finally result in synkinetic activity or post-paretic synkinesis, the involuntary movement of one facial muscle during voluntary movement of another facial muscle. Abnormal nerve regeneration can also lead to more nerve fibers than normal, called hyperinnervation. Clinically, this can cause a strong resting tone and movements, hyperkinesis. During nEMG, the synkinetic activity can be shown by placing the needle electrode in one muscle showing examples of different activation patterns in the frontalis muscle recorded with a concentric needle electrode 0.45 × 38 mm during contraction: a no activity in a patient with acute complete facial paralysis, b single-fiber pattern in a patient with acute incomplete facial palsy, c decreased recruitment pattern with some polyphasic reinnervation potentials in the phase of regeneration two months after the onset of acute palsy, d normal/dense recruitment pattern with some polyphasic reinnervation four months after the onset of acute palsy and having the patient move another facial muscle [fig_ref] Figure 5: 2-channel nEMG setting in patients with post-paretic synkinesis [/fig_ref]. Alternatively, a 2-channel or multiple channel recording is used. Two or more needle electrodes are placed in different muscles. A firing of one MUAP in two or more different muscles is recorded during voluntary contraction and proves synkinetic activity. ## Analysis of the waveform morphology Facial muscles are smaller than skeletal muscles and therefore, their MUAPs are also smaller. The shape, amplitude, and duration of the MU are the important parts of waveform analysis. A normal facial MU is bi-or triphasic, with a downward positive spike and an upward negative spike. The amplitude is dependent on the needle used. Generally, there is an amplitude of 200-500 mV that lasts about 5-7 ms with muscle-specific normal values. For example, a normal MUAP of the zygomaticus muscle can have 1000-2000 mV. The MUAP amplitude is the result of the number and the strength of the muscle fibers innervated by one axon in a normal facial nerve. In contrast, the duration of the MUAP is determined by the velocity and synchrony of the neural input. MUAPs recorded close to motor end plates can show more than three phases, i.e. polyphasic. There are physiological and normal polyphasic MUAPs that have to be differentiated from polyphasic potentials occurring during regeneration. Normal polyphasic MUAPs will disappear when the needle is shifted away from the endplate region. Due to the high variability of the location of the endplate regions in facial muscles, the interpretation can be more difficult than in big skeletal muscles. ## Interpretation of the nemg results The investigator should classify the electrophysiological findings according to neurapraxia, axonotmesis, or neurotmesis [bib_ref] Three types of nerve injury, Seddon [/bib_ref]. If nEMG results do not show signs of denervation, ENoG, especially when repeated during the facial palsy time course, can be helpful. If the patient with an acute lesion beyond 10-14 days shows normal insertion activity, no pathological spontaneous activity, and a rarified recruitment pattern or single action potentials during voluntary contraction, this is compatible with neurapraxia. If pathological spontaneous activity occurs, axonotmesis should be suspected. A differentiation between axonotmesis and neurotmesis based only on the nEMG is not possible. If the examination detects polyphasic regeneration potentials this indicates reinnervation. If the lesion site is located in the temporal bone or at the main trunk of the peripheral facial nerve, it can take 3-6 months to see the first regeneration potentials [bib_ref] Quantitative facial electromyography monitoring after hypoglossal-facial jump nerve suture, Flasar [/bib_ref]. That means that the electrophysiological signs of regeneration precede the clinical signs of recovery. Muscular movement in these situations will not occur until 5-9 months after injury or nerve repair. With recovery there is a continuous increase in the recruitment pattern during voluntary motion. With axonotmesis or neurotmesis, synkinetic activity increases during regeneration and reaches its maximum about 15 months after injury or nerve repair. A specific type of synkinesis is seen in the frontalis muscle. Due to synkinetic reinnervation of antagonistic muscles, the frontalis muscle may not show movement during active frowning; although the nEMG shows muscle activity. This synkinetic phenomenon is called autoparalytic syndrome. One hypothesis for this phenomenon is the simultaneous pathological activation of the frontalis muscle and its antagonist, the orbicularis oculi muscle. In cases of neurotmesis with regeneration, no sign of muscle reinnervation can be detected. Recommendation: nEMG is a helpful tool for monitoring spontaneous facial nerve regeneration or regeneration after facial nerve repair. nEMG can predict future recovery, as reinnervation can be detected about 2-3 months before clinical movements. ## Blink reflex The physiological involuntary eyelid blink reflex occurs in response to a corneal contact or stimulation by objects that appear rapidly in front of the eye [bib_ref] A neurophysiological approach to brainstem reflexes, Esteban [/bib_ref] [bib_ref] Observations on the blink reflex, Pearce [/bib_ref] [bib_ref] Reflex response of orbicularis oculi muscle to supraorbital nerve stimulation. Study in..., Kimura [/bib_ref]. The blink reflex occurs in 0.1 s. The reflex starts via the trigeminal nerve to the trigeminal nucleus, then it descends to the trigeminal spinal nucleus and facial nerve nucleus, from here to the facial nerve' triggering eyelid closure via the facial To prove the synkinetic activity, it is necessary to perform a simultaneous nEMG of the orbicularis oculi muscle (recording example in [fig_ref] Figure 3: Needle electromyography [/fig_ref] ## 3 nerve. Blink reflex testing takes advantage of the fact that the blink reflex can also be elicited from tactile, electric, optical and auditory stimuli. Since the reflex occurs via the trigeminal nerve (afferent part) to the facial nerve (efferent part), the blink reflex delivers information on facial nerve function with normal trigeminal function. The test can also be used for trigeminal nerve and brainstem testing. The blink reflex is the only clinical test that measures the facial nerve along its entire course. Normally, the amplitude of the repeated stimuli leads to a lower amplitude of the response measured in the orbicularis oculi muscle. Blepharospasm is characterized by involuntary closure of the eyelids and shows a lack of habituation of the blink reflex [bib_ref] Blink reflex studies in postparalytic facial syndrome and blepharospasm: trigeminal and extratrigeminal..., Benbir [/bib_ref]. Standard blink testing involves electrical stimulation of the supraorbital nerve on the affected side combined with a 2-channel simultaneous sEMG recording from both orbicularis oculi muscles. The exit of the supraorbital nerve in the supraorbital foramen is palpated on the rim of the orbit. Stimulation with 10-20 mA and 0.2 ms duration is used to produce a constant reflex. In routine clinical testing, two responses, R1 and R2, are analyzed. R1 is the fast ipsilateral response of the orbicularis oculi muscle with a latency of about 10-12 ms. The second bilateral response R2 has a latency of about 30-41 ms. R1 has a fixed latency and little variability. R2 is more variable and dependent on arousal and attention. The R2 latency differences between both sides should be less than 5-8 ms [bib_ref] Electrodiagnostic approach to cranial neuropathies, Kennelly [/bib_ref] [bib_ref] Electrophysiology of cranial nerve testing: trigeminal and facial nerves, Muzyka [/bib_ref]. Recommendation: If ENoG and nEMG are both performed, the additional benefit of blink reflex testing is low. Blink-reflex testing is a test that allows stimulation of the facial nerve proximal to the lesion site. It may be most helpful if facial nerve damage is suspected to occur within the brainstem. ## Transcranial magnetic stimulation (tms) and magnetic evoked potentials Transcranial magnetic stimulation (TMS) uses a magnetic field to stimulate the facial nerve [bib_ref] Electrical and transcranial magnetic stimulation of the facial nerve: diagnostic relevance in..., Happe [/bib_ref]. The responses are recorded from the facial muscles with surface electrodes. Typically, a paranasal recording is used (as for ENoG, cf. [fig_ref] Figure 1: Electroneurography [/fig_ref]. In contrast to ENoG that requires the facial nerve in proximity to a simulated electric field, a magnetic field can pass through the temporal bone and stimulate the facial nerve. TMS of the motor cortex via the cranial bone, is used to elicit a response in the contralateral hemiface. Stimulation in the parieto-occipital region is used to trigger a response in the ipsilateral hemiface. The exact location of the facial nerve stimulation, when stimulating the parieto-occipital region, is unknown. The ENoG setting with recording and ground electrodes can be used. First, unaffected facial muscles are recorded. Then, the affected side is measured. Like for ENoG, the stimulation intensity is slowly increased. When the amplitude CAMP is not increasing anymore, the intensity is slightly increased for the last time to measure the CAMP with supramaximal stimulation. Typically, a magnetic field of up to 2 T (with a short duration of only 2-3 ms) is generated. The intensity is indicated on the TMS machine in the percentage of the maximal magnetic field output. Normally, about 30-40% of the maximal output is sufficient to obtain supramaximal responses. In contrast to ENoG, one has not to wait 2-5 days before Wallerian degeneration reaches the stimulation site at the stylomastoid foramen because TMS allows a stimulation proximal to the lesion site. Theoretically, TMS should provide information on facial nerve function immediately after the onset of an injury. Unfortunately, TMS did not meet these expectations. Patients with minimally affected nerves also had a complete loss of excitability during TMS [bib_ref] Evaluation of proximal facial nerve conduction by transcranial magnetic stimulation, Schriefer [/bib_ref]. In contrast to ENoG, TMS does not provide the examiner a reliable scalable answer. Consequently, TMS is currently not recommended as a useful electrophysiological test for facial nerve injury. It may be an option for selected cases e.g. unconscious patients to help localize a suspected lesion site in the temporal bone [bib_ref] Electrical and transcranial magnetic stimulation of the facial nerve: diagnostic relevance in..., Happe [/bib_ref] [bib_ref] Comparison of transcranial magnetic stimulation and electroneuronography between Bell's palsy and Ramsay..., Hur [/bib_ref]. Recommendation: TMS is currently not recommended for routine facial electrodiagnostics. It may prove helpful for highly selected cases of intratemporal pathology. ## Surface electromyography (semg) The coordinated movement of facial muscles is important for facial eye mimic and emotional expression. Facial palsy and other diseases with impaired motor function can lead to impaired mimic and emotional expression. nEMG is used to characterize the degree of and prognostication of nerve damage and is restricted to small muscle areas near the insertion site. Due to its invasiveness, the number of synchronous recordings is limited. nEMG is not an optimal method to monitor muscle function over time. sEMG is the best test to characterize a whole facial muscle and to evaluate inter-muscular coordination. sEMG is not used for prognostication. sEMG is non-invasive, painless, and the number of surface electrodes used and therefore the number of facial muscles analyzed simultaneously, is unlimited. sEMG allows a detailed analysis of the coordinated muscle activation needed for specific tasks and emotional expressions [bib_ref] Surface electromyographic mapping of the orbicularis oculi muscle for real-time blink detection, Frigerio [/bib_ref] [bib_ref] Facial nerve regeneration after facial allotransplantation: a longitudinal clinical and electromyographic follow-up..., Letter [/bib_ref]. If several surface electrodes are placed on the same facial muscle, the intramuscular pattern of muscle recruitment can be analyzed. The disadvantage of surface electrodes is that they are not as spatially highly selective as needle electrodes. sEMG can be recorded with monopolar or bipolar electrodes. The bipolar electrodes are less prone to artificial interference than monopolar recordings. The disadvantage of bipolar electrodes is that they record from superficial portions of the facial muscles. Monopolar electrodes allow reliable whole muscle recording if the positions and interelectrode distance is held constant to the parallel axis of the muscle fibers. Like nEMG, an indifferent common reference electrode is placed in a muscle-free area. Superficial facial muscles the frontalis, orbicularis oculi, zygomatic, levator labii superioris, levator labii superioris alaeque nasi, orbicularis oris, depressor anguli oris, depressor labii, mentalis muscles are more easily detected with sEMG. If the muscles overlap, such as the depressor anguli oris, depressor labii and mentalis muscles, the sEMG recording will overlap, too. It is recommended to use small electrodes (for instance, with a diameter of 4 mm). Low-weight cables between electrodes and amplifiers are recommended not to disturb normal muscle movements. Standard movements for grading of facial palsy are used during the sEMG recordings. Each standard movement shows a typical sEMG activity profile. The typical pattern of electrode placement for the recording of specific muscle function are presented in detail elsewhere [bib_ref] Facial muscle activation patterns in healthy male humans: a multi-channel surface emg..., Schumann [/bib_ref]. The recordings are evaluated offline. Typical parameters for evaluation are mean EMG activity, e.g. the mean rectified EMG amplitude, root mean square, square root of the spectral EMG power, and the analysis for synchronous and sequential activation of certain mimic muscles during the task. Moreover, facial muscle can show different sEMG amplitudes during different tasks. It is also important to notice that an intra-individual side difference of up to 30% is normal. Patients with unilateral facial palsy have sEMG side differences of > 30% between the two sides of the face. Recommendation: Multichannel sEMG is not used for routine facial electrodiagnostics in patients with an acute facial nerve disorder. Multichannel sEMG is recommended only if detailed information on muscle activation with mimic expression is needed or if compensatory movement patterns in patients with chronic facial nerve disorder or post-paralytic synkinesis must be analyzed. This information may be helpful for surgical or medical treatment planning. ## Transcutaneous facial nerve mapping (fnm) Intraoperative direct facial nerve electrostimulation is widely used to prevent facial nerve damage during surgery. Less often used, although highly reliable, is transcutaneous FNM (Supplement [fig_ref] Figure 1: Electroneurography [/fig_ref]. Park already developed the concept of FNM using transcutaneous electrostimulation in 1998 [bib_ref] Preoperative percutaneous facial nerve mapping, Park [/bib_ref]. Nevertheless, as part of preoperative work-up FNM has so far mainly been established before surgery of vascular malformations [bib_ref] Preoperative facial nerve mapping to plan and guide pediatric facial vascular anomaly..., Bly [/bib_ref]. FNM helps to map the course of the peripheral facial nerve and its fine peripheral branches in patients with tumor or scar around the facial nerve. Before surgery, FNM is performed by percutaneous stimulation of the facial nerve and its branches. The resulting facial muscle activations are followed visually. The procedure takes about 25 min. Alternatively, the mapping can also be followed by sEMG and by the recording of the CMAPs. This is much more time-consuming and mainly needed for research questions but not for routine use. A monopolar electrode (for instance, in the form of a ball electrode, 8 mm) is used. A ground electrode is placed. Transcutaneous stimulation with a monopolar ball electrode at the stylomastoid foramen is done at the main trunk of the facial nerve. Electrostimulation is performed with monophasic, rectangular single pulses with a duration of 250 μs. The stimulation at each point starts with 0.1 mA and is increased in 0.1 mA steps. The increased stimulation intensity is stopped when a muscle contraction is seen. When the stimulation at one point is finished, the stimulation electrode is moved forward and the stimulation procedure is repeated. Each point triggering a motor response is marked with a pen on the skin. Ideally, the complete course of the facial nerve and its peripheral branches is marked on the skin at the end of FNM and prior to surgery. Recommendation: FNM can be another tool for surgical planning in complex cases to obtain more information on the general course of peripheral facial nerve branches. # Documentation of results Facial electrodiagnostics should be performed and documented in a standardized manner. A recommendation for the testing sequence is shown in [fig_ref] Table 2: Proposal for a routine examination for facial electrodiagnostics [/fig_ref]. Standard examinations are ENoG and nEMG. Blink-reflex testing, sEMG, TMS and FNM are reserved for select cases. A data documentation sheet is shown in [fig_ref] Table 3: Proposal for documentation of facial ENoG, nEMG, blink reflex testing [/fig_ref]. Recommendation: Documentation and evaluation of results should be recorded on a standardized form. # Conclusion Otorhinolaryngologists and head and neck surgeons should have basic knowledge of facial electrodiagnostics. ENoG and nEMG are facial electrodiagnostic tests most helpful for investigating patients with acute peripheral facial palsy. Validity is increased when the studies are repeated during the acute phase of the disease. nEMG is an important electrodiagnostic tool to monitor spontaneous regeneration in these patients or regeneration after facial nerve reconstruction surgery. Blink-reflex testing is only of additive value in selected cases. Multi-channel sEMG is a good tool to analyze mimic and emotional expressions in patients with post-paretic synkinesis. Transcutaneous FNM can define preoperatively the topographic cutaneous course of the peripheral facial nerve and its branches in complex surgical cases. Electroneurography (ENoG) Setting example: Sensitivity 10,000 mV; amplifier filtering 1-10 kHz; time frame 10 ms; stimulus duration 200 µs; Maximal stimulus limited to 20 mA; Stimulus rate 1.9 s; Data recorded and averaged using a stimulus rate of 1 Hz with sensitivity adjusted to 2 µV/division and filters set at 30 Hz to 3 kHz a) Ground electrode: Arm or neck; b) Stimulation first on the healthy, then on the paralyzed side; c) Recording electrodes: nasal alae next to each other; d) Stimulator placed on stylomastoid groove; e) Stimulation starts with 0.1 mA and is increased until the maximal CMAP occurs. Stimulation is then once more slightly increased (supramaximal stimulation); f) Storing of the CMAP and measurement of the other side g) Ratio of the peak-to-peak amplitude of the paralyzed side in relation to healthy in percent is calculated 3. Needle EMG (nEMG) nEMG of frontalis, orbicularis oculi, oris and zygomaticus muscle on the affected side gives an overview of the facial nerve function. Of course, the selection depends on the facial nerve lesion and the diagnostic questions. The sequence of evaluation is always the same for each muscle: 1. Insertion activity 2. Spontaneous activity at rest 3. Activity during voluntary muscle movement 4. In case of chronic palsy: Synkinetic activity 1. The needle electrode is softly inserted in an oblique angle into the first facial muscle of interest. Normally, the needle is moved during the evaluation to see and hear the optimal placement and recording The muscle activity is graded as follows: a) No activity b) Normal activity (< 300 ms) c) Increased activity d) Highly increased activity 2. The patient is instructed to relax the muscle. The observer should wait a while until the spontaneous activity occurs. Spontaneous activity should be recorded and classified as: a) No reproducible pathologic spontaneous activity b) Little pathologic spontaneous activity c) Moderate pathologic spontaneous activity d) Dense pathologic spontaneous activity 3 The patient is instructed to perform a standard talk for the specific muscle (For instance, frowning for the frontalis muscle, closing the eye for the orbicularis oculi muscle, showing the teeth for the zygomatic muscle). The maximal possible activation of the muscle is documented as follows: a. No activity b. Single fiber pattern c. Severe decreased recruitment pattern d. Mildly decreased recruitment pattern e. Normal/dense recruitment pattern The waveform of the MUAPs is also classified as: a. Normal biphasic motor unit potential b. Early (sometimes polyphasic) reinnervation potentials with low amplitude and long duration c. Giant polyphasic reinnervation potentials with high amplitude and long duration d. Myogenic polyphasic potentials with low amplitude but in many cases normal duration 4. If the patient should be examined for synkinetic activity, step 3 is repeated but the task for another muscle is used, for instance closing the eye while recording from the orbicularis oris muscle. Alternatively, and more precise is to record synchronously an nEMG from different muscles and varying the tasks. Synkinesis is documented as follows: f. Investigated muscles g. Used task h. Few/moderate/strong/very strong synkinesis ## 5. Surface EMG (sEMG) Baseline setting like for ENoG or nEMG a) Ground electrode: arm or neck; b) Selection of facial muscles and placement of the surface electrodes depends much on the question of the observer; c) Typically, bilateral recordings are performed, but for analysis of synkinetic activity, also unilateral recording may be the best option d) sEMG is recorded while subjects perform facial movements for test purposes, including: pressing the lips together, pulling the corners of the mouth downwards, smiling-pulling the corners of the mouth upwards and backwards, depressing the lower lip, protruding the lower lip, pulling the upper lip upwards, pulling the upper lip upwards and depressing the lower lip simultaneously, pursing lips, blowing out the cheeks, whistling with a similar tone pitch, exhaling forcefully with moderate closed lips (a more diffuse whistling), opening the lips as wide as possible while the jaw is closed, wrinkling the nose, raising the eyebrows up and wrinkling the forehead, contracting the eyebrows, closing the eyelids forcefully, squinting the eyes, closing the right eyelid, closing the left eyelid e) For documentation are important: 1. Analyzed muscles 2. Analyzed tasks 3. Observation of maximal sEMG activity 4. Sequence of recruitment if several facial muscles are involved in the specific task 5. Observation of synchronous and asynchronous activity [bib_ref] Clinical efficacy of electroneurography in acute facial paralysis, Lee [/bib_ref] Transcranial magnetic stimulation (TMS) Basis setting like for ENoG or nEMG a) Ground electrode: arm or neck; b) Stimulation first on the healthy, then on the paralyzed side; c) Recording electrodes: nasal alae next to each other; d) Magnetic stimulator placed on ipsilateral parieto-occiptal region (in special cases on contralateral motor cortex); e) Typically, a magnetic field of up to 2 T (with short duration of only 2-3 ms) is generated. The intensity is indicated on the TMS machine in percentage of the maximal magnetic field output Stimulation starts with 5% and is increased until the maximal CMAP occurs. Stimulation is slightly increased (supramaximal stimulation); Normally, about 30-40% of the maximal output are sufficient to obtain supramaximal response; f) Storing of the CMAP and measurement of the other side g) Ratio of the peak-to-peak amplitude of the paralyzed side in relation to healthy in percent is calculated Increase of the stimulation intensity is stopped when a muscle contraction is seen; e) Stimulation site is marked with a muscular response is seen at the stimulation place; f) When stimulation at one point is finished, stimulation electrode is moved forward, stimulation procedure is repeated g) Finally, each point triggering a motor response is marked on the skin [fig] Figure 1: Electroneurography (ENoG) procedure. Recording electrodes placed on each side of the nose. Stimulator placed in front of the ear.Stepwise increased levels of electrical current up to 50 mA. Test results of two repeated measurements of a patient with complete facial paralysis on the right side: Decreased amplitude on the right side with 75-79% amplitude reduction compared to the left side if reinnervation occurs. EMG should be used and interpreted in combination with clinical examinations. [/fig] [fig] Figure 3: Needle electromyography (nEMG) recordings at rest and during activity: a, b Two different examples of pathological spontaneous activity as a sign for nerve denervation in patients with facial nerve infiltration by a malignant parotid tumor and facial nerve lesion in temporal bone trauma, respectively, c 2-Channel-recording simultaneously of two muscles. Recording of the orbicularis oculi muscle (upper channel) and zygomaticus muscle (lower channel) showing synkinetic activity (setting shown in Fig. 5): While closing the eye not only the orbicularis oculi muscle is activated, but also simultaneously the zygomaticus muscle as a sign for aberrant reinnervation in a patient with post-paretic synkinesis 1 3 [/fig] [fig] Figure 4: Needle electromyography (nEMG) recordings during voluntary muscle movement [/fig] [fig] Figure 5: 2-channel nEMG setting in patients with post-paretic synkinesis: a The simultaneous eye closure is seen during nEMG recording of the zygomatic muscle. b [/fig] [fig] 7: Facial nerve mapping (FNM) FNM is not part of classical facial electrodiagnostics. FNM might be helpful as anpreoperative tool to foresee the course of the peripheral facial nerve and its main branches in the individual patients Baseline setting like for ENoG or nEMG a) Ground electrode: arm or neck; b) Transcutaneous stimulation normally only the paralyzed side; c) Stimulation with monopolar electrode (for instance, all ball electrode, 8 mm); d) Electrostimulation with monophasic, rectangular single pulses with duration of 250 µs. The stimulation at each stimulation point started with 0.1 mA; increase in 0.1 mA steps. [/fig] [table] Table 1: Overview about the most important facial electrodiagnostic tests Transcutaneous electrostimulation of the main trunk first on the healthy side, then on the affected side. Examiner watches the patient's face for the first sign of muscle contraction. Significant side difference of stimulation intensity should indicate poor prognosisCannot be recommended as prognostic test due to poor reliability [/table] [table] Table 2: Proposal for a routine examination for facial electrodiagnostics [/table] [table] Table 3: Proposal for documentation of facial ENoG, nEMG, blink reflex testing (adapted from [11]) used Of relevance, if there are several workplaces [/table]	None	https://link.springer.com/content/pdf/10.1007/s00405-020-05949-1.pdf	None
9c73a8ad75d653ace068838c2b28ced4ad059063	pubmed	Respiratory support in patients with COVID-19 (outside intensive care unit). A position paper of the Respiratory Support and Chronic Care Group of the French Society of Respiratory Diseases	Respiratory support in patients with COVID-19 (outside intensive care unit). A position paper of the Respiratory Support and Chronic Care Group of the French Society of Respiratory Diseases ## A b s t r a c t With first cases noted towards the end of 2019 in China, COVID-19 infection was rapidly become a devastating pandemic. Even if most patients present with a mild to moderate form of the disease, the estimated prevalence of COVID-19-related severe acute respiratory failure (ARF) is 15-20% and 2-12% needed intubation and mechanical ventilation. In addition to mechanical ventilation some other techniques of respiratory support could be used in some forms of COVID-19 related ARF. This position paper of the Respiratory Support and Chronic Care Group of the French Society of Respiratory Diseases is intended to help respiratory clinicians involved in care of COVID-19 pandemic in the rational use of non-invasive techniques such as oxygen therapy, CPAP, non-invasive ventilation and high flow oxygen therapy in managing patients outside intensive care unit (ICU). The aims are:to focus both on the place of each technique and in describing practical tips (types of devices and circuit assemblies) aimed to limit the risk of caregivers when using those techniques at high risk spreading of viral particles; [bib_ref] Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a..., Wang [/bib_ref] to propose a step-by-step strategy to manage ARF outside ICU. The SARS-CoV-2 has been identified as the agent of the pandemic known as Coronavirus disease 2019 . The first cases were noted towards the end of 2019 in Wuhan, China. COVID-19 infection is spontaneously resolutive in most cases. The clinical presentation can vary from mild respiratory symptoms to severe pneumonia progressing to fulminant acute respiratory failure (ARF). COVID-2019 pneumonia is characterized by bilateral infiltrates, which can progress to diffuse alveolar condensations. In less severe patients, computed tomography (CT) shows bilateral ground glass sub pleural opacities [bib_ref] Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a..., Wang [/bib_ref]. The estimated prevalence of COVID-19-related acute respiratory failure (ARF) is 15-20% [bib_ref] Clinical characteristics of Coronavirus Disease 2019 in China, Guan [/bib_ref] [bib_ref] Host susceptibility to severe COVID-19 and establishment of a host risk score:..., Shi [/bib_ref]. In different published series, 41% had received O 2 , 4-13% of patients non-invasive ventilation (NIV) and 2-12% needed intubation and mechanical ventilation [bib_ref] Clinical characteristics of Coronavirus Disease 2019 in China, Guan [/bib_ref] [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. In addition to MV some other techniques of respiratory support such as non-invasive ventilation (NIV), continuous positive airway pressure (CPAP) or high flow oxygen therapy (HFOT) could be used in some forms of ARF. Those techniques are currently applied in ICU but also in a pulmonary department. But the fact that this pandemics could go beyond the capacity of the health system, may lead that those techniques might be applied in less specialized services, These position paper is intended to help respiratory clinicians involved in care of COVID-19 pandemic in managing patients outside ICU. They cannot be regarded as recommendations and reflect only authors experience during COVID-19 pandemics, their expertise in the field of respiratory support and their critical review of the literature. ## Available tools ## Oxygen therapy Oxygen should be used in case of severe COVID-19 pneumonia probably as soon as SpO 2 < 92% with a SpO 2 target between 92 and 96%. There are no randomized controlled studies concerning O 2 in patients with COVID-19 but it is possible to extrapolate data from studies in severe ARF. A meta-analysis of 25 randomized controlled studies has shown that a strategy with no upper limit on O 2 flow ("liberal" approach) increases the risk of in-hospital death compared to a conservative ("targeted" approach) [bib_ref] Mortality and morbidity in acutely ill adults treated with liberal versus conservative..., Chu [/bib_ref]. This contrast with the results of a recent randomized controlled trial (RCT) comparing a "liberal" O 2 therapy strategy (target SpO 2 > 96%) to a conservative one (target SpO 2 > 88% < 92%). This study showed no difference in 28-days survival but an over mortality at 90 days in the conservative group [bib_ref] Liberal or conservative oxygen therapy for acute respiratory distress syndrome, Barrot [/bib_ref]. Thus, based on those data, a target of > 92 < 96% seems reasonable [bib_ref] Surviving sepsis campaign: guidelines on the management of critically ill adults with..., Alhazzani [/bib_ref]. There are no controlled studies concerning the better interface to deliver O 2 . Based on clinical recommendations, a nasal cannula should be used for mild hypoxia and, if an oxygen flow >6 L min −1 is needed, a switch for a simple face mask set to deliver 5 to 10 L min −1 should be proposed. A non-rebreather mask between 10 and 15 L min −1 should be used in patients remaining hypoxemic despite using a simple mask. These latter interfaces can ensure FiO 2 of 35-55% and 80-95% respectively FiO 2 depending on flow and breathing pattern [bib_ref] BTS guideline for oxygen use in adults in healthcare and emergency settings, O'driscoll [/bib_ref]. If available, it could be appropriate to use masks with filtered exhalation port (Filtamask TM or similar). Whatever the interface chosen, patient's comfort and decrease caregiver's risk will be prioritized when choosing the interface. ## Continuous positive airway pressure (cpap) ## Cpap with added o 2 could be used to improve oxygenation, if conventional o 2 failed and there is no urgent indication for intubation or as a surrogate while waiting for intubation. This solution is simpler, less expensive and possibly less harmful than NIV. CPAP must be applied under a strict supervision of a trained physician. ICU team must be prevented and readily available. The interfaces used to deliver CPAP must be those available or those more familiar for the team. A helmet could be an alternative to limit exposition to droplets dispersion, and remains an option for expert teams Circuits and masks must be adapted to reduce caregiver's risks [fig_ref] Figure 1: Different ventilator circuit assemblies to reduce viral spreading [/fig_ref]. In hypoxemic ARF, applying an extrinsic positive end expiratory pressure (PEEP) increases alveolar recruitment and improves oxygenation. Furthermore, there is high level of evidence about the efficacy of adding PEEP during invasive ventilation in ARDS patients. Nevertheless, we lack information about the effectiveness of applying non-invasive PEEP. Experiences from Italian and Chinese teams are shared but not published. As CPAP is easier to use than NIV, more available and need less expertise, this technique could be offered as a first line therapy in selected patients, as a gap to invasive MV, in particular when resources are limited or if there is no immediate access to invasive ventilation. A detail of CPAP-delivering devices, their limits and advantages is showed in [fig_ref] Figure 2: Different devices providing non-invasive CPAP therapy [/fig_ref]. ## Non invasive ventilation (niv) ## Niv with added o 2 could be used to improve oxygenation and/for providing ventilatory support, if conventional o 2 failed and there is no urgent indication for intubation or as a surrogate while waiting for intubation. In those cases NIV must be applied under a strict supervision of a trained physician. ICU team must be prevented and readily available. NIV should be considered in patients who will not be admitted to ICU for intubation. The interfaces used to deliver NIV must be those available or those more familiar for the team A helmet could be an alternative to limit exposition to droplets dispersion, and remains an option for expert teams. Circuits and masks must be adapted to reduce caregiver's risks [fig_ref] Figure 2: Different devices providing non-invasive CPAP therapy [/fig_ref]. The filter* must be interposed between the expiratory arm and the ventilator. (b) Ventilator using single-limb circuit with an active expiratory valve: the filter* must be interposed between the mask and the expiratory valve. (c) Ventilator using single limb circuit with intentional leaks. Not-vented mask must be preferred if available. In this case a deported exhalation port (Whisper Swivel or similar) must be added. The filter* must be interposed between the mask and the deported exhalation port. If a non-vented mask is not available an alternative is to seal the intentional leak of the vented mask. In the last case caution must be taken not to block anti-asphyxia valve. I: inspiratory arm; E: expiratory arm. * There are not published studies comparing the efficacy of different filters. There are no published data concerning NIV use outside ICU in patients with COVID-19. NIV indications in ICU patients with COVID-19-related ARF range from 11 to 34% [bib_ref] Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience..., Grasselli [/bib_ref]. Meta-analysis of RCT conducted in severe hypoxemic ARF showed that NIV could reduce the rate of intubation and mortality. However, they included patients with immunosuppression, acute heart failure (AHF) and postoperative ARF [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Noninvasive versus invasive mechanical ventilation for immunocompromised patients with acute respiratory failure:..., Wang [/bib_ref] [bib_ref] Noninvasive ventilation in acute hypoxemic nonhypercapnic respiratory failure: a systematic review and..., Xu [/bib_ref] [bib_ref] Noninvasive oxygenation strategies in immunocompromised patients with acute hypoxemic respiratory failure: a..., Zayed [/bib_ref]. Moreover, in ARF etiologies other than AHF, NIV has shown a high level of failure with higher mortality (28%) than those treated with O 2 (23%) or HFOT (13%) [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref] , In a cohort of patients with Middle East respiratory syndrome, NIV was associated with better survival and a shorter length of stay (LOS) compared patients who were intubated without previous NIV. However, NIV showed a high failure rate (92.4%) requiring intubation [bib_ref] Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome, Alraddadi [/bib_ref]. Finally, associating NIV and prone position reduced intubation in patients with moderate ARDS related to viral pneumonia [bib_ref] Efficacy and safety of early prone positioning combined with HFNC or NIV..., Ding [/bib_ref]. On the other side, NIV could be harmful in those patients as it could worsen lung damage due to high pressures and high VT and could delay intubation [bib_ref] Noninvasive ventilation for patients with hypoxemic acute respiratory failure, Brochard [/bib_ref] [bib_ref] Ventilator-induced lung injury, Slutsky [/bib_ref]. Moreover, NIV as CPAP is at high risk spreading of viral particles. In this field, WHO guidelines for the management of ARF in COVID-19 advocate the use of CPAP or NIV, provided that appropriate personal protective equipment is worn. Hence NIV could be considered as a first line therapy outside the ICU in particular when resources are limited or if there is no immediate access to invasive ventilation. In those cases NIV must be applied under a strict supervision of a trained physician to detect early and rapid worsening, a frequent condition in COVID-19 pneumonia. ICU team must be prevented and readily available. When a patient is treated with NIV, monitoring should be intensified. If hypoxemia worsens the patient must be transferred to ICU if eligible for intubation. This decision will integrate not only the clinical severity, but also underlying pathologies and the "living wills" or end-of-life decisions (if available) of the patient and his family. This requires previous discussion on a case-by-case basis. NIV should also be considered in patients no eligible to be admitted to ICU or in those with do not intubate (DNI) decision. In those cases, NIV must be continued only if it is well tolerated and a benefit is obtained. Otherwise, comfort measures only, including pharmacological measures, may be applied to relieve dyspnea [bib_ref] Withdrawing noninvasive ventilation at end-of-life care: is there a right time?, Tripodoro [/bib_ref]. Some patients with underlying respiratory disease (COPD, obesity hypoventilation, restrictive disease) complicated with COVID-19 pneumonia could benefit from de novo NIV. In patients on long term NIV, treatment must be adapted during hospitalization, possibly by temporarily lowering the pressures if excessive leaks are present. Circuits and masks must be adapted [fig_ref] Figure 2: Different devices providing non-invasive CPAP therapy [/fig_ref]. When available a helmet interface could be applied. A randomized controlled study conducted in ARDS has shown that NIV when delivered by a helmet decrease intubation rate and mortality [bib_ref] Effect of noninvasive ventilation delivered by helmet vs face mask on the..., Patel [/bib_ref]. Moreover helmet limits viral spreading [bib_ref] Exhaled air dispersion during noninvasive ventilation via helmets and a total facemask, Hui [/bib_ref]. It is imperative not to insist with NIV or O 2 in patients that worsen. This can lead to a delay in intubation, which can be fatal. Increased vigilance is necessary since muscle exhaustion is expressed late in those patients. In all cases, the intubation must be anticipated, carried out according to rigorous procedures and under conditions limiting the risk of caregivers. As NIV is at high risk spreading of viral particles circuits and masks must be adapted to reduce caregiver's risks [bib_ref] Noninvasive ventilation in acute hypoxemic nonhypercapnic respiratory failure: a systematic review and..., Xu [/bib_ref] [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] [bib_ref] Severe acute respiratory syndrome: historical, epidemiologic, and clinical features, Hui [/bib_ref] [fig_ref] Figure 2: Different devices providing non-invasive CPAP therapy [/fig_ref]. Moreover, caution may be taken to ensure a good interface fitting for CPAP or NIV systems, to minimize widespread dispersion of exhaled air and reduce risk of airborne transmission. ## High flow oxygen therapy (hfot) ## Hfot could be used to improve oxygenation, if conventional o 2 failed and there is no urgent indication for intubation or as a surrogate while waiting for intubation. As HFOT is at high risk spreading of viral particles, protective measures must be applied to reduce caregiver's exposition. HFOT delivers a high-flow gas mixture (up to 70 L/min) with variable FiO 2 (up to 100%) administered by a nasal cannula. Compared to conventional oxygen HFOT can ensure a constant and known FiO 2 . Other advantages are dead space reduction and generation of a low PEEP level allowing alveolar recruitment [bib_ref] High-flow nasal cannula oxygen in adults: an evidence-based assessment, Drake [/bib_ref]. There are no published data concerning HFOT in patients with COVID-19 pneumonia. In a RCT conducted in severe hypoxemic ARF, HFOT reduced 90-days mortality but not intubation rate compared to conventional oxygen [bib_ref] Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome, Alraddadi [/bib_ref]. Otherwise, a meta-analysis of 9 RCT shows a decrease in intubation rate but without improving survival or length of stay [bib_ref] The effect of high-flow nasal cannula in reducing the mortality and the..., Ni [/bib_ref] [bib_ref] Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic..., Ou [/bib_ref] [bib_ref] High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic..., Rochwerg [/bib_ref] an important issue in the field of COVID-19 pandemic considering an expected scarcity of ventilators. As with NIV, adding prone position to HFOT may help to avoid intubation in patients with moderate ARDS related to viral pneumonia [bib_ref] Efficacy and safety of early prone positioning combined with HFNC or NIV..., Ding [/bib_ref]. The same precautions cited above for NIV should be taken if HFOT is used as a first line therapy in patients qualifying for intubation. Even if published studies did not demonstrate an increased risk for caregivers when comparing HFOT to conventional O 2 [bib_ref] Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial..., Leung [/bib_ref] [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref] to limit the risk of contamination, the following measures are suggested when using HFOT: - ensure maximum sealing of the interface; - limit the flow rate to the minimum necessary. Prefer higher FiO 2 instead of higher flow (i.e.: start at 30 L/min and increase FiO 2 to ensure target SaO 2 ); - patient must wear a surgical mask during care. A detail of HFOT-delivering devices, their limits and advantages is showed in [fig_ref] Figure 3: Different devices providing HFOT therapy [/fig_ref]. ## Nebulized treatments As nebulization is at high risk spreading of viral particles, nebulized treatments should be limited as much as possible. Spray and powders should be preferred to provide inhaled therapy, preferably by using a personal inhalation chamber. If not possible, minimal distance of 1 m must be respected and the room must aerate during nebulization. ## Tracheal aspirations In the case of tracheostomized ventilator-dependent patients a "closed suction system" must be used. ## Patient management The proposed flow chart strategy to manage ARF outside ICU in COVID-19 patients is showed in [fig_ref] Figure 4: Flow chart strategy for managing ARF in COVID-19 patients [/fig_ref]. It is crucial to ensure an appropriate triage of patients at the admission. As those patients are at risk of early and rapid worsening, it seems reasonable that those with a rapidly progressive form (i.e presenting a SpO 2 < 94% and a RR > 30 while receiving > 6 L O 2 ) must be promptly assessed by the ICU staff to decide proper allocation. ## Step by step approach - Check and treat comorbidities. - Begin conventional oxygen therapy by using nasal prongs to obtain the target RR and SpO 2 : - if predominant oral breathing or intolerance to high flow, an oxygen mask could be proposed, - masks with filtered exhalation port could be used if available, - there is no limit in terms of O 2 flow rate but if > 6 L/min or a mask with reservoir bag is needed, ICU team must be prevented and promptly available, - venturi masks should be precluded; - then, if oxygen therapy failed, non-invasive respiratory assistance should be proposed with CPAP and/or HFOT as a first choice. NIV should be used as a second line therapy in case of CPAP or HFOT failure, and mainly if hypercapnia develops; - HFOT could be an alternative in the absence of CPAP/NIV or as a therapeutic ceiling option (HFOT allows higher FiO 2 but there is hypothetically a greater risk of drops diffusion and low PEEP levels are generated) . - Close monitoring is needed during at least the first 48-72 hours, including SpO 2 , RR and clinical assessment (ventilatory mechanics/use of accessory muscles). Three issues highlighted by different teams managing those patients requires particular attention: - an initially stable patient may suddenly become unstable (with refractory hypoxemia and high fever), - a delayed re-aggravation was noted in a significant percentage of patients (stability then rapid worsening after 48 h, up to 7 days), - it was described in some of these patients an impaired perception of dyspnea despite severe hypoxemia. A possible explanation is a neuroinvasive potential of COVID-19 that could spread in brainstem affecting respiratory center and/or mechano-/chemoreceptors [bib_ref] The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory..., Li [/bib_ref]. - In cases with DNI decision, it is recommended to dispose an end-of-life sedation protocol to be applied if patient's condition worsens (http://www.sfap.org/actualite/ outils-et-ressources-soins-palliatifs-et-covid-19). In summary: non-invasive respiratory support could be useful in treating COVID-19-related ARF. A rational use of different techniques (oxygen therapy, CPAP, NIV or HFOT) by a trained pulmonologist could allow to prevent clinical aggravation and reduce the risk of ICU admission. Then, those techniques should be considered as a first line therapy outside the ICU in particular when resources are limited or if there is no immediate access to invasive ventilation. A step-by step approach, under a strict supervision of a trained physician, must be applied to detect early and rapid aggravation. In patients eligible for intubation. ICU team must be prevented and readily available to an immediate transfer to ICU as soon as the patient's condition impairs. # Disclosure of interest The authors have not supplied their declaration of competing interest. ## Acknowledgements Stefano Nava (Italy), Javiers Sayas (Spain), Michelle Chatwin (UK), Manel Lujan (Spain), Annalisa Carlucci (Italy) for sharing information. Special acknowledgement to the colleagues of the Italian Thoracic Society (AIPO-ITS) and Italian Respiratory Society (SIP/IRS) for their original idea of the flow chart proposed in this paper. A French version of this document is available online in open format (http://www.splf.fr/wp-content/ uploads/2020/04/RespiPreREA-SPLF-GAVO2avril2020.pdf). [fig] Figure 1: Different ventilator circuit assemblies to reduce viral spreading. (a) Ventilator using double circuit with an integrated expiratory valve. [/fig] [fig] Figure 2: Different devices providing non-invasive CPAP therapy. [/fig] [fig] Figure 3: Different devices providing HFOT therapy. [/fig] [fig] Figure 4: Flow chart strategy for managing ARF in COVID-19 patients (modified from [33] ABG: Arterial Blood Gases; COPD: chronic obstructive pulmonary disease; RR: respiratory rate; HFOT: high flow oxygen therapy; CPAP: continuous positive airway pressure; NIV: non-invasive ventilation; EPAP: expiratory positive airway pressure; EI: endotracheal intubation). [/fig]	None	None	None
433cc99e12e7095037f763b1cbe53d0d29e4f30b	pubmed	Good practice guidelines for biomarker discovery from array data: a case study for breast cancer prognosis	Good practice guidelines for biomarker discovery from array data: a case study for breast cancer prognosis Background: Biomarker discovery holds the promise for advancing personalized medicine as the biomarkers can help match patients to optimal treatment to improve patient outcomes. However, serious concerns have been raised because very few molecular biomarkers or signatures discovered from high dimensional array data can be successfully validated and applied to clinical use. We propose good practice guidelines as well as a novel tool for biomarker discovery and use breast cancer prognosis as a case study to illustrate the proposed approach.Results: We applied the proposed approach to a publicly available breast cancer prognosis dataset and identified small numbers of predictive markers for patient subpopulations stratified by clinical variables. Results from an independent cross-platform validation set show that our model compares favorably to other gene signature and clinical variable based prognostic tools. About half of the discovered candidate markers can individually achieve very good performance, which further demonstrate the high quality of feature selection. These candidate markers perform extremely well for young patient with estrogen receptor-positive, lymph node-negative early stage breast cancers, suggesting a distinct subset of these patients identified by these markers is actually at high risk of recurrence and may benefit from more aggressive treatment than cur-rent practice.Conclusion:The results show that by following good practice guidelines, we can identify highly predictive genes in high dimensional breast cancer array data. These predictive genes have been successfully validated using an independent cross-platform dataset. # Introduction The goal of biomarker discovery from high dimensional array data is to find an individual or a set of genes (or any other molecular variables) whose expression pattern can predict certain phenotype or clinical outcome. Biomarker discovery holds the promise for advancing personalized medicine as the biomarkers can help match patients to optimal treatment and thus improve patient outcomes. During the past 15 years, numerous biomarkers and gene signatures have been published in the literature. However, few of these biomarkers can be successfully validated and applied in clinical setting, which have caused serious concerns in biomedical research community [bib_ref] Gene expression-based prognostic signatures in lung cancer: ready for clinical use?, Subramanian [/bib_ref]. The lack of success in biomarker discovery is mainly due to three issues. (1) Many published gene signatures cannot be validated independently. This is mainly due to flawed data analysis. For example, fail to keep completely untouched validation data or improperly use cross-validation technique can all cause overly optimistic results being reported. (2) Some gene signatures do not have additional clinical benefit over known clinical variables even though the gene signatures can be validated. For example, gene signatures discovered from a breast cancer patient population including both ER + and ER-patients for predicting treatment response could probably end up approximating ER status, an important clinical variable for predicting treatment response. (3) Some gene signatures contain large numbers of genes making them difficult to be applied in clinical setting. These gene signatures may include lot of unimportant genes due to the inefficiency of the standard feature selection techniques. For example, standard t test will either miss or rank certain important features below many non predictive features, if these important features do not conform to normality. The first two issues have been addressed in [bib_ref] Gene expression-based prognostic signatures in lung cancer: ready for clinical use?, Subramanian [/bib_ref] [bib_ref] Roadmap for developing and validating therapeutically relevant genomic classifi-ers, Simon [/bib_ref]. To address the third issue, we developed a two-way filtering based method to parsimoniously identify the most informative features from different types of distributions. Our method selects features by searching for the desired thresholds of a pair of statistics that are used to filter features. For any pair of thresholds, the features that satisfy both thresholds are used to build a diagonal linear discriminate analysis (DLDA) classifier [bib_ref] Comparison of Discrimination Methods for the Classification of Tumors Using Gene Expression..., Dudoit [/bib_ref]. When choosing the pair of statistics, we choose one that is more efficient at detecting strong signals such as mean difference test, and a second that is more efficient at controlling signal to noise ratio such as classical t-test or Mann-Whitney U test. By varying the thresholds of these two statistics in certain steps within their acceptable ranges, we can achieve various tradeoffs and control the size of the feature sets. The method and other supporting functions are implemented in a Java based tool called Array Data Analyzer (ADA). The detailed method is described in [bib_ref] An adaptive feature selection method for microarray data analysis, Cheng [/bib_ref]. Compared to standard feature selection tools, our ADA tool has the following advantages. (1) Because our approach does not select features based on any single statistic or fixed tradeoff of two statistics, it can adapt to different data and parsimoniously identify informative features from different distributions. Experimental result presented in [bib_ref] An adaptive feature selection method for microarray data analysis, Cheng [/bib_ref] shows that our approach yields much smaller models on average when compared to other standard approaches, yet achieving similar or better performance. (2) By using grid-search to explore different tradeoffs of a pair of statistics, our tool is very flexible to address different feature selection requirements in real world situations. For example, researchers at times are willing to sacrifice performance in order to gain other logistic properties, such as smaller numbers of features and larger fold change. These properties enable more tractable assays for clinical use (e.g. qPCR). By visually examining the performance at different combinations of cut points of the two statistics and checking the size of feature sets, researchers can decide which feature set would be best to use. (3) Our Java based tool is very efficient to run even though it conducts rigorous cross validation and grid search to find optimal feature sets. For example, finding an optimal gene signature from microarray gene expression dataset with 130 samples takes about 50 seconds on a modest laptop PC (Dell Latitude E4300 with 2GB of RAM). (Searching through 200 combinations of the threshold pairs of the two statistics; using 5 times 5 fold cross validation (CV) to measure performance of each combination). The ADA tool has been applied to various GSK drug discovery projects [bib_ref] Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines, Greshock [/bib_ref]. It has also been applied to the FDA MAQC-II project [bib_ref] The MicroArray Quality Control (MAQC)-II study of common practices for the development..., Maqc [/bib_ref] by the GSK data analysis team (DAT). The GSK DAT achieved highest mean area under the receiver operating characteristic curve (AUR-OCC) across all 11 endpoints among the participating DATs. Using ADA tool, we also achieved the second place in the "The Sage Bionetworks/DREAM breast cancer prognosis challenge 2012" (https://sagebionetworks. jira.com/wiki/display/BCC/Home) by simply identifying 8 genes from the provided training set. As a case study, we performed detailed prognostic analyses on the van de Vijver breast cancer dataset [bib_ref] Bernards R: A gene-expression signature as a predictor of survival in breast..., Van De Vijver [/bib_ref]. An independent cross-platform validation set TRANSBIG [bib_ref] Validation and clinical utility of a 70-gene prognostic signature for women with..., Buyse [/bib_ref] was then used to validate our findings. The results show that our 20-gene signature as well as many of the discovery individual prognostic biomarkers can achieve comparable or better performance compared to the clinical or gene signature based prognostic scores. These discovered biomarkers have the potential to be used in clinical settings to identify a subset of the lymph-nodenegative (Node-) and estrogen-receptor-positive (ER+) patients who are at a higher risk of relapse. # Methods The ADA tool The ADA tool allows users to choose different pairs of statistics to perform the two-way filtering. In this paper, the default pair of non parametric statistics is used, which are the mean difference test and the Mann-Whitney U test. More detailed information of the ADA tool is given in [bib_ref] An adaptive feature selection method for microarray data analysis, Cheng [/bib_ref]. ## Data preprocessing van de Vijver dataset and TRANSBIG dataset were downloaded from the public domain. For all datasets generated from Affymetrix platforms, if a gene intensity value is smaller than 40, we floor it to 40. The log transformed ex-pression values are used for analysis. Scoring and classification of validation data sets using 20 gene signature For the discovered genes that can be successfully mapped from Agilent Hu25K platform to Affymetrix HG-U133A, we arbitrarily decided to keep top 10 genes from each direction (i.e., over expression poor prognosis and over expression good prognosis) to validate. If a gene can be mapped to multiple probe sets of the Affymetrix HG-U133A chip, we use the probe set that has the largest interquartile range (IQR). To avoid bias, the scoring of validation samples using the 20 gene signature was done without any scaling or tuning. We simply calculated the scores by summing up the log expression values of genes of one direction and subtracting those of genes of the other direction. To classify the samples into "good prognosis" and "poor prognosis", we use zero as the threshold. # Results As a case study, we use the van de Vijver data set [bib_ref] Bernards R: A gene-expression signature as a predictor of survival in breast..., Van De Vijver [/bib_ref] to discover prognostic biomarkers for various patient subsets stratified by clinical variables. The markers discovered from the lymph node negative patient cohort are subsequently evaluated using an independent cross-platform dataset: TRANSBIG [bib_ref] Validation and clinical utility of a 70-gene prognostic signature for women with..., Buyse [/bib_ref]. [fig_ref] Table 1: Summary of the two data sets involved in this experiment [/fig_ref] summarizes the training and independent validation data sets. Both data sets are publicly available. Model training and prognostic biomarker discovery using van de Vijver dataset The van de Vijver data set contains samples from 295 patients with stage I and II breast cancer. The gene expression data was generated using Agilent Hu25K platform. A subset of the samples was used to develop a 70-gene signature for predicting breast cancer early relapse [bib_ref] Gene expression profiling predicts clinical outcome of breast cancer, Van 't Veer [/bib_ref]. To make the data less noisy, we only included patients who developed metastases in < 5 years and those who remained disease free for > 10 years (i.e. we removed the patients who developed metastases between 5-10 years) in the biomarker discovery phase. This left 78 patients who developed metastases within 5 years (poor prognosis) and 68 patients who remain disease free for at least 10 years. Besides analyzing all the data together, we also utilized the clinical information (ER status and lymph node status) to create subgroups of samples in order to search for prognostic markers within these clinical subgroups. By using the ADA tool, we were able to generate gene lists of various sizes for different subgroups of patients. After studying the gene lists, we found that many of the predictive markers were indeed more sig-nificant in certain subgroups. For example, the ER+/lymph node+ group harbors unique genes that are predictive of relapse. The prognosis of this group of patients was also more predictable (based on nested CV results) compared to that of the other groups. Some of the discovered genes are listed in [fig_ref] Table 2: Candidate markers identified from the van de Vijver data set using the... [/fig_ref]. Many genes discovered in larger groups can also be discovered in their subgroups. For example, BIRC5 can be discovered in most of the subgroups. These genes are not listed again in subgroups unless they are more significant in the subgroups. A gene may be listed in a larger group only because it is significant in one of its subgroups. For example, H1F2 is listed in lymph node-positive group only because it is significant in ER+/Node+ subgroup. The nested CV performance is listed with estimated standard error. ## Independent cross platform validation using transbig dataset To validate the candidate biomarkers discovered from van de Vijver data set, we download the TRANSBIG data set (198 patients with mean age equals 46), which is based on the Affymetrix HG-U133A platform instead of the Agilent Hu25K platform. An original objective of TRANSBIG data set was to validate the 70-gene signature and it is similar to the van de Vijver data set in term of patient age distribution -i.e., both data sets contains young breast cancer patients. Because all patients of the TRANSBIG data set are lymph node negative (Node-) patients, we evaluate the candi-date biomarkers discovered from the Node-patients. We picked the top 20 genes from our Node-gene list that can be mapped from Agilent Hu25K to Af-fymetrix HG-U133A. The performance of the 20 gene-signature as well as each of the individual gene was measured using AUROCC based on commonly used endpoints: time to distant metastasis(TDM) at 5 years and 10 years. Because 70% of Node-patients in the training data belong to the subgroup Node-/ER+, in addition to measure the performance on the whole validation sets (consisting of Node-patients), we also measured the performance on the Node-/ER+ subset of patients. Both results are shown in [fig_ref] Table 3: Validation performance [/fig_ref] , which also includes the performance of two commonly used clinical scores (Nottingham Prognostic Index Score [bib_ref] A prognostic index in primary breast cancer, Haybittle [/bib_ref] and Adjuvant! 10 year overall survival score [bib_ref] Computer program to assist in making decisions about adjuvant therapy for women..., Ravdin [/bib_ref] , three clinical variables (tumor grade, tumor size and age), two known markers (ESR1 and MKI67) and three gene signatures (16-gene signature, 70-gene signature [bib_ref] Gene expression profiling predicts clinical outcome of breast cancer, Van 't Veer [/bib_ref] and 76-gene signature [bib_ref] Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer, Wang [/bib_ref]. From the result we can see that our 20-gene signature performs better than other gene signature or clinical variable based prognostic factors. Most of the 20 candidate genes can also be successfully validated. About half of the 20 genes can individually achieve similar or better performance compared to clinical variable based risk scores, which further shows that the proposed approach can parsimoniously select high quality features. To further illustrate the added value of these markers over the traditional clinical criteria, we use survival curves to compare the 20-gene signature to the Adjvant! 10 year overall survival probability, which is based on known clinical markers. plots four Kaplan-Meier curves by dividing the TRANSBIG patients into four risk groups based on the predictions from 20-gene signature and the Adjvant! tool. The plots show that our 20-gene signature is superior in predicting cancer outcome, especially for the 66 patients (33% of the 198 samples) shown in the dotted blue survival curve where the 20-gene signature predicts good outcome and Adjvant! predicts poor outcome. This curve indeed traces the curve in solid blue where the patients were predicted to have good outcome by both classifiers. It is also worth noting that the 20-gene signature and the top performing genes based on the whole vali-dation There are two AUROCC numbers for each gene at each endpoint. The first number is from the whole validation set with 100% Node-patients; the second is from the Node-/ER+ subset of the validation set. The numbers in bold font are significant at 95% confidence level. The top portion of the table contains 10 genes of one direction (over expression poor prognosis). The middle portion contains 10 genes of the opposite direction (over expression good prognosis). The bottom portion contains our signature based on all 20 genes and other prognostic factors. The performance of the 70-gene signature for the TRANSBIG data set is copied from [bib_ref] Validation and clinical utility of a 70-gene prognostic signature for women with..., Buyse [/bib_ref]. The performance of the 76-gene signature is based on binary prediction of "good prognosis" and "poor prognosis" for each patient. Among the listed 20 genes, three genes (CENPA, GSTM3 and CEGP1) were included in the 70-gene signatures [bib_ref] Gene expression profiling predicts clinical outcome of breast cancer, Van 't Veer [/bib_ref] and four genes (BIRC5, PGR, SCUBE2 and CTSL2) were included in the 16-gene signature. There is no overlap between our 20-gene signature and the 76-gene signa-ture. set have even better performance when validated using Node-/ER+ patients only. For example, for end point TDM at 5 years, the 20-gene signature can achieve AUR-OCC 0.83; and the genes CCNB2, BUB1, CENPA, BIRC5 and CYP4B1 can each achieve AUROCC above 0.78. # Discussion Using the breast cancer prognosis experiment, the ADA tool was able to effectively discover both biologically relevant and class predictive genes. The tool has two important features: (a) because the model performance estimation is based on rigorous nested cross-validation, the tool does not return any feature when the dataset does not produce a strong signal. (b) It has a unique iterative procedure that attempts to find all important genes, which can be used for further analyses, such as pathway and ontology analysis. When doing biomarker discovery using the van de Vijver datasets, our approach relies heavily on robust cross validation to control over fitting rather than leaving out an artificial validation set. This is a more efficient way to use the relatively small number of samples -artificially defining a small validation set is unlikely to achieve much due to the large test data variability and reduced power of model development in the smaller training set. However, it is crucial that the cross-validation is done properly. For example, the feature selection must be performed within each run of cross validation; and the nested cross validation is often required when evaluating model performance (i.e., outer loop CV for model performance evaluation and inner loop CV for model parameter tuning). As we can see here, the proper cross-validation procedures can often be quite computationally expensive. This is one of the reasons that a simple modeling technique such as DLDA is preferred. We believe the best way to gain better performance is through improving performance of feature selection, rather than tuning modeling parameters of complex models. Complicated learning schemes can make proper cross-validation too computational expensive to run. Without proper crossvalidation, the result can be overly optimistic. Important guidelines for biomarker discovery are presented in Richard Simon's work [bib_ref] Roadmap for developing and validating therapeutically relevant genomic classifi-ers, Simon [/bib_ref]. As shown in [fig_ref] Table 2: Candidate markers identified from the van de Vijver data set using the... [/fig_ref] , when sample size allows, we try to discover biomarkers for patient subpopulations stratified by clinical variables. This also assures us that the discovered biomarkers indeed have added value over the traditional clinical variables, rather than approximating the clinical variables. To validate our findings from the van de Vijver data, we used the cross-platform validation dataset TRANSBIG. In addition to evaluate our 20-gene signature, we also evaluate individual genes. By doing so, we can carry forward those validated genes for further clinical validations. [fig_ref] Table 3: Validation performance [/fig_ref] shows that most of the 20 genes can be validated using the TRANSBIG data set and some of the discovered candidate genes can individually achieve similar or better performance compared to the state-of-the-art breast cancer prognostic tests, which suggest that our 20-gene signature contains mostly highly predictive genes. It is very likely Using Kaplan-Meier curves to compare 20-gene signature with the Adjvant! 10 year overall sur-vival score. Solid blue curve is for the risk group that both 20-gene signature and Adjvant! predict good prognosis (n = 38); Dotted blue curve is for the risk group that 20-gene signature predicts good prognosis and Adjvant! predicts poor prognosis(n = 66); Dotted red curve is for the risk group that 20-gene signature predicts poor prognosis and Adjvant! predicts good prognosis(n = 8); Solid red curve is for the risk group that both classifiers predict poor prognosis (n = 86). that large gene signatures contain many unimportant genes. We believe that a promising way to improve prediction accuracy is to combine gene signatures with traditional clinical variables. This can be achieved by developing gene signatures containing a small number of genes for each clinically homogeneous subset of patients. [fig_ref] Table 3: Validation performance [/fig_ref] also shows that for Node-/ER+ patients of younger age (as those in TRANSBIG dataset), there are a number of genes that can predict cancer recurrence at high accuracy. This suggests that there is a distinct subgroup of Node-/ER+ patients who have high risk of relapse and should be treated more aggressively. Our 20-gene signature is acquired from analyzing one public dataset for one patient subpopulation (Node-). We plan to analyze other datasets to refine this predictive gene list and develop gene lists for other patient subpopulations. Based on our past experience, we are confident that biomarker discovery can play important role in ad-vancing personalized medicine if the study design and data analysis is done properly. We would like to propose the following good practice guidelines for biomarker discovery. Most of the points have already been made in [bib_ref] Gene expression-based prognostic signatures in lung cancer: ready for clinical use?, Subramanian [/bib_ref] [bib_ref] Roadmap for developing and validating therapeutically relevant genomic classifi-ers, Simon [/bib_ref]. (1) Make sure no information leak from validation set. If a separate validation set is available, one need to make sure that the validation set is not used in any way in feature filtering or model building. The same rule also applies to cross validation. (2) Model performance evaluation and model parameter tuning cannot be done using the same cross va-lidation loop. In such case, nested cross validation is needed (i.e., outer loop CV for model performance evaluation and inner loop CV for model parameter tuning). (3) When sample size is not very large, cross validation is a preferred validation technique. (4) Consider patient stratification using known clinical variables. (5) Use simple modeling techniques. Simple models performs well [bib_ref] Comparison of Discrimination Methods for the Classification of Tumors Using Gene Expression..., Dudoit [/bib_ref] and are easy to train and easy to un-derstand. (6) When choosing feature filtering or feature selection methods, do not automatically assume that all va-riables are normally distributed. Many highly predictive biomarkers are far from normally distributed, especially in cancer research [bib_ref] Chinnaiyan AM: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in..., Tomlins [/bib_ref] [bib_ref] Outlier sums for differential gene expression analysis, Tibshirani [/bib_ref]. [table] Table 1: Summary of the two data sets involved in this experiment [/table] [table] Table 2: Candidate markers identified from the van de Vijver data set using the proposed method [/table] [table] Table 3: Validation performance (AUROCC) of the candidate biomarkers in TRANSBIG data sets [/table]	None	https://bmcsystbiol.biomedcentral.com/counter/pdf/10.1186/1752-0509-7-S4-S2	None
80c569c4fe657e988084cd27030db669ce1a90bf	pubmed	Preferred practice patterns in aphakia management in adults in India: A survey	Preferred practice patterns in aphakia management in adults in India: A survey Quick Response Code:Purpose: To assess different approaches in the management of aphakia in adults in Indian ophthalmologists via an online survey. Methods: A survey-monkey based online questionnaire was fielded to Indian ophthalmologists in accordance with the CHERRIES guidelines. We recorded participants' demographics, practice settings, and preferred surgical options including the type of intraocular lens (IOL) preferred when encountering a case of aphakia in adults with and without adequate capsular support. Differences between anterior segment (AS) surgeons and vitreoretinal (VR) surgeons as well as differences between surgeons with more or less than 10 years of surgical experience were evaluated using analytic statistics. Results: Of the 481 surgeons who responded to the survey, 369 (77%) were AS surgeons and the remaining 112 (23%) were VR surgeons and represented all regions of India. When encountering posterior capsular rent during cataract surgery, a three-piece IOL in the ciliary sulcus was the most preferred (n = 275, 57%) when there was adequate capsular support, while a retrofixated iris-claw IOL (n = 91, 19%) was the commonest choice in eyes without adequate capsular support. With associated nucleus drop, 85% of surgeons preferred to refer the patient to a VR surgeon and left the eye aphakic. Multivariable logistic regression showed that VR surgeons were more than six times likely to prefer a scleral fixated intraocular lens (SFIOLs) [odds ratio (OR) = 6.5, 95% confidence interval (CI) = 3.4-12.5, P < 0.001] and surgeons with >10 years of experience were also twice more likely to prefer an SFIOL (OR = 2.4, 95% CI = 1.2-4.9, P = 0.02). Conclusion: The choice of IOL in absence of capsular support in adult eyes differs between AS and VR surgeons and is also influenced by the surgeon's experience. The incidence of post-cataract surgery aphakia is <1% but causes a lot of morbidity in patients. [bib_ref] Postoperative aphakia in modern cataract surgery: Part 1: Analysis of incidence and..., Lundström [/bib_ref] Management of aphakia has undergone paradigm shifts from anterior chamber intraocular lenses (ACIOLs) of various designs to scleral fixated intraocular lenses (SFIOLs) and more recently, retrofixated iris-claw lenses. [bib_ref] Scleral fixafiguretion of intraocular lenses, Jacob [/bib_ref] [bib_ref] Flanged fixation: Yamane technique and its application, Yamane [/bib_ref] [bib_ref] Flanged intrascleral intraocular lens fixation with double-needle technique, Yamane [/bib_ref] [bib_ref] Choices in correction of aphakia during vitrectomy, Bastawrous [/bib_ref] The SFIOL fixation has also seen major shifts from being a predominantly suture-assisted surgery to being sutureless over the past decade. [bib_ref] Sutureless intrascleral posterior chamber intraocular lens fixation, Gabor [/bib_ref] [bib_ref] Comparison of sutured versus sutureless scleral-fixated intraocular lenses, Sindal [/bib_ref] [bib_ref] Sutureless 27-gauge needle-assisted transconjunctival intrascleral intraocular lens fixation: Initial experience, Kelkar [/bib_ref] [bib_ref] Comparison of two modified sutureless techniques of scleral fixation of intraocular lens, Kelkar [/bib_ref] After the introduction of the sutureless SFIOL by Gabor et al. [bib_ref] Sutureless intrascleral posterior chamber intraocular lens fixation, Gabor [/bib_ref] in 2007, the glued intraocular lens (IOL) by Narang et al. [bib_ref] Glued intrascleral haptic fixation of an intraocular lens, Narang [/bib_ref] and the flange fixation by Yamane [bib_ref] Flanged intrascleral intraocular lens fixation with double-needle technique, Yamane [/bib_ref] have increased the popularity and adoption of the sutureless SFIOL techniques. With a few other modifications such as the XNIT surgery by Baskaran et al., [bib_ref] Extraocular needle-guided haptic insertion technique of scleral fixation intraocular lens surgeries (X-NIT), Baskaran [/bib_ref] and the introduction of novel IOL designs for sutureless SFIOL fixation such as the one by Madanagopalan et al., [bib_ref] A novel sutureless scleral fixated lens that eliminates extra ocular haptic manipulation:..., Madanagopalan [/bib_ref] management of aphakia has truly come a long way in not only improving the ease of surgery but also improving patient comfort and visual outcomes. Given the myriad choice of IOLs in the management of aphakia, with many comparative studies showing similar visual outcomes, the choice of IOL depends upon the operating surgeon. Other factors include IOL availability, adequacy of capsular support, coexistent nucleus or cortex drop, white to white diameter, and primary (i.e., at the time of cataract surgery) vs. secondary surgery (after previous surgery). To the best of our knowledge, surgeon preferences for the management of aphakia in India, in terms of choice of IOL and the factors determining these choices, have not been elucidated to date. In this survey of cataract surgeons across India, we sought to assess preferences in the surgical management of aphakia, especially in the absence of adequate capsular support. # Methods The study was approved by the Institutional Ethics Committee and the study was carried out as per the tenets of the Declaration of Helsinki. The identity of all participating surgeons was kept anonymous during data collection and analysis. A questionnaire (Annexure 1) was used during the survey and its administration followed the guidelines from the CHERRIES checklist. [bib_ref] Improving the quality of web surveys: The checklist for reporting results of..., Eysenbach [/bib_ref] The questions were pilot tested by members of the core survey team and questions and/or their options were modified by consensus over an online zoom meeting. The survey was fielded to members of the All-India Ophthalmic Society (AIOS) with valid email ID and phone numbers using emails and WhatsApp messages from March to April 2021. Single responses from participants were ensured by hosting the survey on the survey-monkey platform and tagging responses using the participant's IP address. Participation was voluntary and was not remunerated. Responses were registered as complete when all the survey questions were answered. The initial part of the questionnaire recorded the type of surgeon (anterior segment (AS) vs. posterior segment), years of surgical experience, region of practice in India (north, east, west, south, and central), type of practice (institutional, private, and combined), area of practice (urban vs. rural), the number of cataract surgeries performed per month, and the number of aphakia patients encountered in practice per month. The next parts of the questionnaire were designed to assess surgeon preferences and choice of IOL for managing aphakia in adults under the following headings: [bib_ref] Postoperative aphakia in modern cataract surgery: Part 1: Analysis of incidence and..., Lundström [/bib_ref] planning when the patient is seen in the outpatient setting, [bib_ref] Scleral fixafiguretion of intraocular lenses, Jacob [/bib_ref] aphakia management during primary surgery without nucleus or cortex drop, [bib_ref] Flanged fixation: Yamane technique and its application, Yamane [/bib_ref] aphakia management during primary surgery with nucleus or cortex drop, and [bib_ref] Flanged intrascleral intraocular lens fixation with double-needle technique, Yamane [/bib_ref] IOL placement preferences during secondary surgery without adequate capsular support. For management during primary surgery, surgeons were asked about whether they manage the surgery themselves or refer, if managing themselves then do they place an IOL in the same or secondary sitting, how long they prefer to wait for IOL placement of choosing a secondary sitting and the type of IOL they prefer in cases with and without capsular support. Options for IOL types provided were single-piece IOL in sulcus and three-piece IOL in sulcus for eyes with capsular support, and SFIOL, anterior fixated iris-claw, retrofixated iris-claw, iris sutured IOL, and ACIOL for eyes without capsular support. Surgeons were also asked whether performed a peripheral iridectomy while placing a retrofixated iris-claw IOL. If preferring an SFIOL, surgeons were asked if they preferred a sutured or sutureless technique of fixation. If preferring a sutureless technique, the choices provided were glued SFIOL, Gabor Schariott's technique (or its modification), or the Yamane technique (or its modification). If preferring a sutured technique, surgeons were asked about the type of suture (9-0 prolene, 10-0 prolene, or Gortex) and the type of SFIOL preferred (SFIOL with eyelets, routine three-piece IOL anchored with haptics, or foldable acrylic IOL with plate haptics (Akreos IOL, Bausch and Lomb, USA). Lastly, surgeons were asked about their preference for managing cases with bilateral aphakia. # Statistical analysis All categorical variables were expressed as proportions (n, %) and denominators for each question were based on the total responses received for that particular question. Chi-square tests were used to analyze differences between groups. Logistic regression analysis was used to predict the choice of SFIOL in eyes without nucleus drop and no capsular support and covariates included were surgeon type (anterior vs. posterior segment surgeon), surgeon experience, and type of practice (institutional vs. private vs. both). All data were exported from the survey server into Microsoft Excel and analyzed using STATA 12.1 I/c (Stata Corp, Fort Worth, Texas, USA). All P values < 0.05 were considered statistically significant. # Results ## Surgeon characteristics The survey questionnaires were sent to 10,000 ophthalmologists. A total of 481 (4.8%) surgeons responded to our survey of which 369 (77%) were AS surgeons, whereas the remaining 112 (23%) were vitreoretinal (VR) surgeons. About two-thirds of the participating surgeons had surgical experience of more than 10 years (n = 319, 66%), majority were based in urban areas (n = 413, 86%), and there was good representation from north (n = 78, 16%), south (n = 114, 24%), east (n = 99, 21%), central (n = 42, 9%), and western (n = 142, 29%) Indian regions. Participants were almost equally distributed in terms of institutional (n = 194, 40%) and private practice (n = 184, 38%) while the remaining 103 practitioners were engaged in both institutional and private practice. In terms of surgical cataract volumes, 113 (24%) operated on fewer than 25 cases per month, 138 (28%) did between 25 and 50 surgeries, 107 (22%) did 50 and 100 surgeries, and 74 (15%) did more than 100 surgeries per month while 49 (10%) reported not doing regular cataract surgery. The majority (n = 375, 78%) preferred phacoemulsification as the primary mode of cataract surgery. ## Aphakia planning when seen in outpatient clinics Most participants saw fewer than 10 aphakia patients per month (n = 430, 89%) and postoperative aphakia was the commonest etiology encountered by participants (n = 351, 73%). Traumatic aphakia (n = 86, 18%) was the second commonest cause reported followed by spontaneous dislocation of IOL (n = 20, 4%). Nearly two-thirds of participants reported managing aphakia themselves when seeing cases in the clinic setting while the rest opted to refer patients to VR surgeons. Placing a three-piece IOL in the ciliary sulcus when available was the commonest choice for surgeons when planning for surgery in the operation department (OPD) [ [fig_ref] Table 1: Choice of IOL based on whether following PCR, there is nucleus/cortex drop... [/fig_ref] ], whereas an SFIOL was the commonest choice followed by retrofixated iris-claw IOL in the eyes with inadequate capsular support [ [fig_ref] Table 1: Choice of IOL based on whether following PCR, there is nucleus/cortex drop... [/fig_ref] ]. ## Aphakia management during primary surgery -without nucleus or cortex drop When encountering posterior capsule rent (PCR) during surgery without nucleus or cortex drop, 390 (81%) participants said that they managed the surgery themselves while 21 (4%) preferred to manage aphakia in a second sitting. A separate 20 (4%) preferred to call a VS in the same sitting and another 20 (4%) referred to a VS in a second sitting and 30 did not comment. [fig_ref] Figure 1: Management patterns in case of PCR with inadequate capsular support [/fig_ref] shows management patterns in the case of PCR with inadequate capsular support. A three-piece IOL in the ciliary sulcus was the preferred IOL of choice when there was adequate capsular support [ [fig_ref] Table 1: Choice of IOL based on whether following PCR, there is nucleus/cortex drop... [/fig_ref] ] while a retrofixated iris-claw IOL was the commonest choice in eyes without adequate capsular support. ## Aphakia management during primary surgery -with nucleus or cortex drop When encountering PCR during surgery with nucleus or cortex drop, nearly half (n = 202, 42%) preferred to refer the patient to a VR surgeon in a secondary sitting while about a third (n = 132, 27%) called a VR surgeon in the same sitting. In terms of IOL placement in this scenario, a vast majority (85%) preferred to leave the patient aphakic. The choice of IOL in the few that placed it is shown in [fig_ref] Table 1: Choice of IOL based on whether following PCR, there is nucleus/cortex drop... [/fig_ref]. ## Practices for iol placement during secondary surgery in eyes without capsular support Most participants who preferred retrofixated iris-claw IOLs (n = 246) performed a peripheral iridotomy (n = 183, 75%) at the time of its placement. The commonest response to a time interval between primary cataract surgery and a secondary IOL placement was 2-6 weeks [ [fig_ref] Figure 2: Response time interval between primary cataract surgery and a secondary IOL placement [/fig_ref] ]. For those who preferred SFIOL, 125 participants (54%) preferred a sutured IOL while 108 preferred a sutureless SFIOL. In those who went with sutured SFIOL, most preferred to use the polymethyl methacrylate (PMMA) SFIOL with eyelets on the haptics (n = 98/120, 82%), 20 (17%) used a foldable three-piece and 2 (2%) opted for the Akreos plate haptic IOL. Similarly, 10-O prolene suture was used most commonly for fixation (n = 68, 57%) followed by 9-O prolene (n = 44, 37%) and Gortex (n = 8, 7%). In those choosing sutureless SFIOL, the glued IOL was the most preferred (n = 42, 40%) followed closely by the Yamane technique (n = 37, 35%) and the Gabor technique (n = 26, 25%). In patients with bilateral aphakia already using spectacles or contact lenses, 212 (44%) participants offered a secondary IOL while 77 (16%) were advised to continue aphakic glasses and 125 (26%) would give the option of contact lenses for visual rehabilitation, and 67 (14%) did not comment. [fig_ref] Table 2: Comparison of practice settings and patterns in the management of aphakia between... [/fig_ref] shows a comparison of practice patterns between AS and VR surgeons. There were more AS surgeons with > 20 years of surgical experience. Only about half of the AS surgeons preferred to manage cases of aphakia when seeing them in the OPD compared to nearly all VR surgeons. In aphakia without [fig_ref] Figure 3: Difference in the choices among AS surgeons and VR surgeons while doing... [/fig_ref] ], though these differences were not statistically significant [ [fig_ref] Table 2: Comparison of practice settings and patterns in the management of aphakia between... [/fig_ref] ]. ## Comparison in practice patterns for aphakia management between anterior and posterior segment surgeons Comparison in practice patterns for aphakia management with respect to surgeon experience Participants with experience <10 years were most commonly in institutional practice while more experienced surgeons were in private practice [ [fig_ref] Table 3: Comparison of practice settings and patterns in the management of aphakia between... [/fig_ref] ]. A significantly higher proportion of younger surgeons preferred the retrofixated iris-claw IOL when encountering aphakia without adequate capsular support while senior surgeons preferred the SFIOL and retrofixated iris-claw almost equally [fig_ref] Table 3: Comparison of practice settings and patterns in the management of aphakia between... [/fig_ref] ]. Similarly, if doing sutureless SFIOL, younger surgeons preferred the Preferred practice in aphakia management in adults in India Yamane technique while older surgeons preferred the glued IOL. A multivariable logistic regression analysis with the type of surgeon, surgeon experience, and type of practice (institutional vs. private) found that VR surgeons were more than six times likely to prefer an SFIOL (OR = 6.5, 95% CI = 3.4-12.5, P < 0.001) compared to AS surgeons. In the same model, surgeons with >10 years of experience were more than twice likely to prefer an SFIOL (OR = 2.4, 95% CI = 1.2-4.9, P = 0.02). Institutional practitioners did not differ from private practitioners in terms of the type of IOL and for most other parameters (data not shown). # Discussion This study presents data on various preferences for management of aphakia from all parts of India with a good mix of institutional vs. private practitioners and a good distribution over years of surgical practice, hence possibly representing practice patterns across India. AS surgeons managed cases of aphakia with no nucleus drop about half the time and resorted to iris-claw IOL more frequently in the same sitting. As opposed to this, VR surgeons preferred an SFIOL more often in all scenarios. While choosing an SFIOL, AS surgeons preferred the sutured SFIOL while VR surgeons chose sutureless IOL more frequently. Additionally, VR surgeons and surgeons with more experience chose SFIOL more often. In aphakic eyes without adequate capsular support, AS surgeons were comfortable in managing cases with no nucleus drop about half the time and preferred assistance from a VR surgeon at other times. Also, they showed a trend toward using retro pupillary iris-claw IOL more frequently at the time of the primary surgery. Interestingly, when they saw patients in OPD, they chose SFIOL more frequently, showing that iris-claw is perceived to be an easier and quicker option at the time of encountering aphakia during primary cataract surgery. As opposed to this, VR surgeons preferred an SFIOL much more often and in all scenarios. Previous studies comparing iris-claw vs. SFIOL have shown delayed visual recovery in the iris-claw group compared to SFIOL. [bib_ref] Comparative analysis of retropupillary iris claw versus scleral-fixated intraocular lens in the..., Madhivanan [/bib_ref] [bib_ref] Five-year follow-up of secondary iris-claw intraocular lens implantation for the treatment of..., Toro [/bib_ref] [bib_ref] Retropupillary iris-claw intraocular lens implantation in aphakic patients, Sumitha [/bib_ref] Additionally, the long-term data on retro pupillary iris-claw IOLs is scant, [bib_ref] Five-year follow-up of secondary iris-claw intraocular lens implantation for the treatment of..., Toro [/bib_ref] and its influence on pupil dynamics has not been studied. The commonest complication with iris-claw IOLs is D-shaped disfigurement of the pupil, [bib_ref] Comparative analysis of retropupillary iris claw versus scleral-fixated intraocular lens in the..., Madhivanan [/bib_ref] [bib_ref] Retropupillary iris-claw intraocular lens implantation in aphakic patients, Sumitha [/bib_ref] localized iris atrophy, and poor mydriasis making future VR procedures difficult, likely prompting VR surgeons to avoid this approach. While choosing an SFIOL, AS surgeons preferred the sutured SFIOL while VR surgeons chose sutureless IOL more frequently. A previous robust study showed equivalent results with sutured vs. sutureless SFIOL, [bib_ref] Comparison of sutured versus sutureless scleral-fixated intraocular lenses, Sindal [/bib_ref] hence surgeon preference may not influence visual outcomes much. However, there may be a fear of IOL drop while performing sutureless SFIOLs due to the inherent maneuvers involved. This fear is also demonstrated when doing sutureless SFIOL where AS surgeons preferred glued IOL more often for security compared to the Yamane technique by VR surgeons. Lastly, VR surgeons and surgeons with more experience choose SFIOL more often. There could be several reasons to explain this trend. It is possible that this group had more exposure to the SFIOL technique during training, or this shows changing trends with time in view of retrofixated IOLs becoming recently available with ease of fixation making them preferable in recent times. It is also possible that retro pupillary iris-claw IOLs don't do well in the long term with pigment dispersion, secondary glaucoma, persistent uveitis, and poor mydriasis, and hence experienced surgeons' resort to SFIOL more, though these were not inquired in the survey. The limitations of this study are possible under-representation of rural practitioners. To the best of our knowledge, this is the first survey showing the preferences of Indian surgeons in the management of aphakia to the best of our knowledge. However, surveys with a larger sample are required to confirm or refute the preferences of surgeons in managing aphakia in the Indian context. # Conclusion In conclusion, this survey showed current trends in the management of aphakia among Indian ophthalmologists. Retro pupillary iris-claw IOLs are preferred increasingly by AS surgeons especially in the primary cataract setting without adequate capsular support, whereas VR surgeons and more experienced AS surgeons preferred SFIOL in this scenario. A similar survey may be repeated periodically to document changing trends in the surgical management of aphakia in the future, and results from this survey can be used as a benchmark for future comparisons. # Acknowledgments T h e a u t h o r s a c k n o w l e d g e t h e a s s i s t a n c e o f Dr. Sabyasachi Sengupta from Sengupta's Research Academy in statistics and content editing for this manuscript. ## Financial support and sponsorship Nil. ## Conflicts of interest There are no conflicts of interest. [fig] Figure 1: Management patterns in case of PCR with inadequate capsular support [/fig] [fig] Figure 2: Response time interval between primary cataract surgery and a secondary IOL placement [/fig] [fig] Figure 3: Difference in the choices among AS surgeons and VR surgeons while doing sutureless SFIOL [/fig] [table] Table 1: Choice of IOL based on whether following PCR, there is nucleus/cortex drop and whether there is adequate capsular support [/table] [table] Table 2: Comparison of practice settings and patterns in the management of aphakia between AS surgeons vs. VR surgeons [/table] [table] Table 3: Comparison of practice settings and patterns in the management of aphakia between surgeons with more or less than 10 years of surgical experienceChoice of IOL with aphakia and no capsular with no nucleus drop:SFIOL Retro-fixated iris-claw IOL ACIOL [/table]	None	None	Purpose: To assess different approaches in the management of aphakia in adults in Indian ophthalmologists via an online survey. Methods: A survey-monkey based online questionnaire was fielded to Indian ophthalmologists in accordance with the CHERRIES guidelines. We recorded participants’ demographics, practice settings, and preferred surgical options including the type of intraocular lens (IOL) preferred when encountering a case of aphakia in adults with and without adequate capsular support. Differences between anterior segment (AS) surgeons and vitreoretinal (VR) surgeons as well as differences between surgeons with more or less than 10 years of surgical experience were evaluated using analytic statistics. Results: Of the 481 surgeons who responded to the survey, 369 (77%) were AS surgeons and the remaining 112 (23%) were VR surgeons and represented all regions of India. When encountering posterior capsular rent during cataract surgery, a three-piece IOL in the ciliary sulcus was the most preferred (n = 275, 57%) when there was adequate capsular support, while a retrofixated iris-claw IOL (n = 91, 19%) was the commonest choice in eyes without adequate capsular support. With associated nucleus drop, 85% of surgeons preferred to refer the patient to a VR surgeon and left the eye aphakic. Multivariable logistic regression showed that VR surgeons were more than six times likely to prefer a scleral fixated intraocular lens (SFIOLs) [odds ratio (OR) = 6.5, 95% confidence interval (CI) = 3.4–12.5, P < 0.001] and surgeons with >10 years of experience were also twice more likely to prefer an SFIOL (OR = 2.4, 95% CI = 1.2–4.9, P = 0.02). Conclusion: The choice of IOL in absence of capsular support in adult eyes differs between AS and VR surgeons and is also influenced by the surgeon’s experience.
80cae81f5296673600d660b7918f54a52f0fb099	pubmed	Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference	Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference Blood pressure (BP) and volume control are critical components of dialysis care and have substantial impacts on patient symptoms, quality of life, and cardiovascular complications. Yet, developing consensus best practices for BP and volume control have been challenging, given the absence of objective measures of extracellular volume status and the lack of high-quality evidence for many therapeutic interventions. In February of 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference titled Blood Pressure and Volume Management in Dialysis to assess the current state of knowledge related to BP and volume management and identify opportunities to improve clinical and patient-reported outcomes among individuals receiving maintenance dialysis. Four major topics were addressed: BP measurement, BP targets, and pharmacologic management of suboptimal BP; dialysis prescriptions as they relate to BP and volume; extracellular volume assessment and management with a focus on technologybased solutions; and volume-related patient symptoms and experiences.The overarching theme resulting from presentations and discussions was that managing BP and volume in dialysis involves weighing multiple clinical factors and risk considerations as well as patient lifestyle and preferences, all within a narrow therapeutic window for avoiding acute or chronic volume-related complications. Striking this challenging balance requires individualizing the dialysis prescription by incorporating comorbid health conditions, treatment hemodynamic patterns, clinical judgment, and patient preferences into decision-making, all within local resource constraints. Qualitative data suggest that suboptimal BP and volume management negatively affect quality of life. [bib_ref] Developing a set of core outcomes for trials in hemodialysis: an international..., Evangelidis [/bib_ref] [bib_ref] Perspectives on symptom experiences and symptom reporting among individuals on hemodialysis, Flythe [/bib_ref] [bib_ref] Symptoms among patients receiving in-center hemodialysis: a qualitative study, Cox [/bib_ref] Efforts to develop consensus best practices in managing BP and volume in dialysis have been hampered by an absence of widely available, accurate, and objective measures of extracellular volume status, as well as a lack of high-quality evidence. As such, related practice patterns vary considerably, both within local communities and throughout the world. In February 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference, Blood Pressure and Volume Management in Dialysis, in Lisbon, Portugal (https://kdigo.org/conferences/bp-volume-management-in-dialysis/). The conference is the second of 4 conferences planned on dialysis (see Chan et al. [bib_ref] Dialysis initiation, modality choice, access, and prescription:conclusions from a Kidney Disease: Improving..., Chan [/bib_ref] for the first report, on dialysis initiation). Participants, who included both physicians and patients, considered how BP and volume management can be optimized and individualized across dialysis modalities and resource settings. ## Major themes As participants addressed specific issues relating to BP and volume in dialysis, multiple crosscutting themes emerged. First was the substantial heterogeneity of the dialysis population (e.g., incident vs. prevalent status, comorbid conditions, residual kidney function , and nutritional status) and the treatment setting (in-center vs. home therapies, medication use, etc.) that must be considered when prescribing dialysis. Second was the ever-present tension in balancing multiple, interlinked, volume-related factors within a narrow therapeutic window for avoiding complications. In some instances, correcting one volume-related abnormality (e.g., hypervolemia) may result in increasing risk associated with another volume-related parameter (e.g., ultrafiltration [UF] rate and RKF). Data to guide these decisions are limited. Third was recognition of the impact that poorly managed BP and volume have on patient lives, and the importance of incorporating patient priorities into management decisions. Fourth, availability of local resources and technologies vary globally and often dictate the bounds of dialysis prescriptions. Therefore, individualizing the dialysis prescription to manage BP and volume for each patient and setting is essential and requires incorporating numerous factors into decision-making. Finally, there was broad-based recognition of the lack of quality evidence to inform recommendations for the management of many of the BP and volume complications discussed, resulting in few strong recommendations, and calls for additional research. In many regions of the world, the dialysis community is well positioned to fill these knowledge gaps. Investigators and dialysis organizations must collaborate to leverage the predictable nature of dialysis treatments, large volumes of collected data, and research and clinical implementation capacities inherent to well-resourced dialysis delivery systems to address these fundamental questions. observational studies have shown that pre-and post-dialysis BP have either no association or a U-or J-shaped association with mortality. [bib_ref] Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves..., Foley [/bib_ref] [bib_ref] Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis..., Robinson [/bib_ref] [bib_ref] The optimal blood pressure target in different dialysis populations, Jhee [/bib_ref] These findings may stem in part from the inaccuracy of pre-and post-dialysis BP measurements. Pre-and post-dialysis BPs, even if measured using a standardized protocol, are imprecise estimates of interdialytic BPs [bib_ref] Pre-and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure, Agarwal [/bib_ref] and generally should not be used alone for diagnosing and managing hypertension. However, pre-, post-(i.e., peridialytic), and intradialytic BP measurements do have clinical importance for assessing and managing hemodynamic stability during the HD session. Ambulatory BP monitoring is considered the gold-standard method for BP evaluation. [bib_ref] Hypertension in chronic kidney disease part 1: Out-of-office blood pressure monitoring: Methods,..., Parati [/bib_ref] [bib_ref] Assessment and management of hypertension in patients on dialysis, Agarwal [/bib_ref] [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] Compared with peridialytic BP, 44-hour interdialytic BP has superior risk prediction for allcause and cardiovascular mortality. [bib_ref] Home blood pressures are of greater prognostic value than hemodialysis unit recordings, Alborzi [/bib_ref] Ambulatory BP monitoring use may be limited by patient intolerance, availability, and financial constraints in some countries. [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] When ambulatory BP monitoring is unavailable, home BP measurements may be taken twice a day, covering interdialytic days over 1-2 weeks or twice a day for 4 days following the midweek treatment. [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] [bib_ref] Chronobiology of arterial hypertension in hemodialysis patients: implications for home blood pressure..., Agarwal [/bib_ref] Compared with peridialytic BP measurement in HD, home BP measurement has superior agreement with mean 44-hour ambulatory BP monitoring, [bib_ref] Home blood pressure monitoring improves the diagnosis of hypertension in hemodialysis patients, Agarwal [/bib_ref] higher short-term reproducibility, [bib_ref] Home blood pressure measurements for managing hypertension in hemodialysis patients, Agarwal [/bib_ref] and improved prediction of adverse outcomes. [bib_ref] Home blood pressures are of greater prognostic value than hemodialysis unit recordings, Alborzi [/bib_ref] Key disadvantages of home BP monitoring are the absence of information on nocturnal dipping, and in some settings, cost. A third alternative is BP measurement in-office, not in the dialysis unit. Increased systolic BPs (SBPs) outside of the dialysis unit are an independent risk factor for mortality. [bib_ref] Blood pressure and risk of all-cause mortality in advanced chronic kidney disease..., Bansal [/bib_ref] Another alternative is mean or median peridialytic BP (pre-, inter-, and post-HD BP values), which has greater sensitivity and specificity in detecting interdialytic hypertension than preor post-dialysis BP measurements alone. [bib_ref] Diagnosing hypertension by intradialytic blood pressure recordings, Agarwal [/bib_ref] However, no studies have assessed the association of this approach with outcomes. Data assessing the validity of peridialytic, office, and home BP in patients receiving home HD or peritoneal dialysis (PD) are limited, and no studies have been conducted in these populations on the associations of out-of-unit BP measurements and the risk of cardiovascular outcomes. Research to identify valid methods for BP measurement in all dialysis modalities is recommended . ## Definition of hypertension and bp treatment targets Accepted definitions of hypertension and BP treatment targets in the dialysis population have not been determined, with just one relevant randomized controlled trial (RCT). The Blood-Pressure-in-Dialysis pilot (BID) study randomized 126 participants to either an intensive pre-dialysis SBP goal of 110-140 mm Hg or a standard SBP goal of 155-165 mm Hg, with the primary objective of assessing feasibility and safety to inform a larger RCT assessing hard clinical outcomes. [bib_ref] BP in dialysis: results of a pilot study, Miskulin [/bib_ref] The study demonstrated intervention feasibility; however, despite the protocol calling for site investigators to challenge post-dialysis weight as the initial step in attaining the assigned target SBP, the intensive SBP goal was achieved by use of additional antihypertensive medications. Target weights actually increased in the intervention group, suggesting inadequate management of the extracellular volume status. No population-specific evidence has established BP thresholds and targets for interdialytic BP (i.e., not pre-or post-dialysis) for the dialysis population. Extrapolating from current general population hypertension guidelines may be reasonable, but such guidelines do not account for differences in cardiovascular risk in dialysis patients. Specifically, numerous observational studies [bib_ref] Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves..., Foley [/bib_ref] [bib_ref] Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis..., Robinson [/bib_ref] [bib_ref] The optimal blood pressure target in different dialysis populations, Jhee [/bib_ref] and the Blood-Pressure-in-Dialysis study [bib_ref] BP in dialysis: results of a pilot study, Miskulin [/bib_ref] have suggested harm from lower BPs. Targeting too low of a threshold may heighten cardiovascular risk in some patients. The 2017 American College of Cardiology/American Heart Association Guidelines 29 BP threshold and target is 130/80 mm Hg; in contrast, the 2018 European Society of Hypertension/European Society of Cardiology Guidelines 30 recommend an SBP target of <130 mm Hg for ages <65 years, and an SBP target range of 130-140 mm Hg for all others. Based on existing evidence, definitive recommendations regarding BP treatment targets cannot be made. An individualized approach is a priori necessary for all patients receiving dialysis, with a particular focus on avoiding overly low BPs, and special consideration regarding intradialytic and interdialytic BP patterns, volume management, and ccomorbidities. ## Definitions of intradialytic hypotension and hypertension In a typical dialysis treatment session, BP decreases from preto post-dialysis; the magnitude of this reduction most closely relates to the magnitude of UF. [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] Intradialytic hypotension is a serious complication of HD, associated with vascular access thrombosis, inadequate dialysis dose, and mortality. [bib_ref] Association of mortality risk with various definitions of intradialytic hypotension, Flythe [/bib_ref] [bib_ref] Intradialytic hypotension and vascular access thrombosis, Chang [/bib_ref] [bib_ref] Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis..., Shoji [/bib_ref] Intradialytic hypotension prevalence ranges from 15% to 50% of HD treatments, depending on the definition [fig_ref] Table 2 \|: Definitions of intradialytic hypotension and intradialytic hypertension [/fig_ref]. Any symptomatic decrease in BP or a nadir intradialytic SBP of <90 mm Hg should prompt reassessment of BP management. This reassessment includes, but is not limited to, UF rate, dialysis treatment time, interdialytic weight gain (IDWG), dry-weight estimation, and antihypertensive medication use, in concordance with discussions in the following sections. Avoidance of intradialytic hypotension should not come at the expense of maintaining euvolemia or ensuring adequate dialysis time. Data on intradialytic hypotension during home HD or intermittent PD techniques are scarce. Intradialytic hypertension is the phenomenon of BP increase during or immediately after a dialysis session, and it involves activation of the sympathetic nervous and renin-angiotensin systems, endothelial stiffness, volume excess, and other mechanisms. [bib_ref] Intradialytic hypertension: a less-recognized cardiovascular complication of hemodialysis, Inrig [/bib_ref] [bib_ref] Intradialysis hypertension in end-stage renal disease patients: clinical epidemiology, pathogenesis, and treatment, Georgianos [/bib_ref] Intradialytic hypertension has an estimated prevalence of 5%-15%, depending on the definition used [fig_ref] Table 2 \|: Definitions of intradialytic hypotension and intradialytic hypertension [/fig_ref]. Defining it as an SBP increase of >10 mm Hg from pre-to post-dialysis accurately identifies persons with persistently elevated interdialytic BP [bib_ref] A comparative study of short-term blood pressure variability in hemodialysis patients with..., Bikos [/bib_ref] and demonstrates an association with hospitalization and mortality. [bib_ref] Decreased pulse pressure during hemodialysis is associated with improved 6-month outcomes, Inrig [/bib_ref] [bib_ref] Association of blood pressure increases during hemodialysis with 2-year mortality in incident..., Inrig [/bib_ref] An SBP increase of >10 mm Hg from pre-to post-dialysis into the hypertensive range in at least 4 of 6 consecutive dialysis treatments should prompt a more extensive evaluation of BP and volume management, including out-of-unit BP measurements and a critical assessment of dry weight. Currently, there are no data on intradialytic hypertension in home HD or PD. ## Bp variability Fluctuations of BP over the very short-term (beat-by-beat), short-term (within 24 hours), mid-term (day-by-day), and long-term (visit-to-visit) are associated with target-organ damage, cardiovascular events, and mortality in patients on HD. [bib_ref] The association of interdialytic blood pressure variability with cardiovascular events and all-cause..., Sarafidis [/bib_ref] [bib_ref] Association of intradialytic blood pressure variability with increased all-cause and cardiovascular mortality..., Flythe [/bib_ref] [bib_ref] Visit-to-visit blood pressure variability is a strong predictor of cardiovascular events in..., Rossignol [/bib_ref] [bib_ref] Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis, Chang [/bib_ref] However, whether BP variability is a modifiable risk factor or a marker of underlying pathology (e.g., volume shifts, arterial stiffness) remains uncertain. There are no studies of interventions targeting BP variability, so no treatment recommendations can be made, and further research is needed . ## Pharmacologic approaches to suboptimal bp and volume control Use of antihypertensive medications.-Deciding when to use antihypertensive medications requires consideration of indication (e.g., BP lowering alone or cardioprotection). In the first case, nonpharmacologic treatments should be considered first, as volume overload underlies most cases of BP elevation in dialysis. [bib_ref] Assessment and management of hypertension in patients on dialysis, Agarwal [/bib_ref] [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] [bib_ref] The clinical problems of hypertension treatment in hemodialysis patients, Loutradis [/bib_ref] [bib_ref] Antihypertensive medication use in older patients transitioning from chronic kidney disease to..., Chang [/bib_ref] If BP remains above target after nonpharmacologic measures directed at volume control, then initiation or up-titration of antihypertensive medications is necessary. If BP is well controlled and antihypertensive medications interfere with UF, reducing medications to allow for enhanced UF is reasonable. When antihypertensive medications are already being used for BP control and cardioprotection, it is reasonable to continue them unless they interfere with targeting euvolemia. Choice of antihypertensive medications.-Patient heterogeneity and scarcity of comparative evidence preclude recommending any one medication class over another for all patients. Antihypertensive medications considered first-line in the general population (e.g., angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and calcium channel blockers) can also be considered first-line to lower BP in patients receiving dialysis. It is reasonable to choose medications based on patient characteristics, cardiovascular indications, and availability [fig_ref] Table 3 \|: Medication classes for blood pressure management in dialysis blocker atenolol compared to... [/fig_ref]. Pharmacokinetics and dialyzability are also important considerations. For example, one retrospective study found that nondialyzable β-blockers (e.g., propranolol) but not highly dialyzable β-blockers (e.g., atenolol, metoprolol) are associated with lower mortality risk, possibly due to preserved intradialytic protection against arrhythmias. [bib_ref] Beta-blocker dialyzability and mortality in older patients receiving hemodialysis, Weir [/bib_ref] In contrast, another retrospective study showed higher mortality rates with the nondialyzable carvedilol versus the highly dialyzable metoprolol, which was attributed to a higher likelihood of intradialytic hypotension with carvedilol. [bib_ref] A comparative study of carvedilol versus metoprolol initiation and 1-year mortality among..., Assimon [/bib_ref] Additionally, the data assessing drug dialyzability contain uncertainties. For example, a recent study suggests that bisoprolol may in fact be dialyzable, contrary to what had been previously thought. [bib_ref] Beta-blocker dialyzability in maintenance hemodialysis patients: A randomized clinical trial, Tieu [/bib_ref] It is reasonable to consider intradialytic BP patterns with regard to drug dialyzability, and it may be prudent to avoid nondialyzable medications in the setting of frequent intradialytic hypotension. For relatively stable intradialytic BP, use of longer-acting, once-daily medication may improve adherence and reduce pill burden. The timing of antihypertensive medication administration should be individualized, taking into account interdialytic BP and the frequency of intradialytic hypotension. The effectiveness of withholding antihypertensive agents before dialysis in reducing intradialytic hypotension is unknown [bib_ref] Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension, Davenport [/bib_ref] and is being investigated in an ongoing RCT (NCT03327909). [bib_ref] Antihypertensive medication withholding practices in hemodialysis: a survey study of patients and..., Haase [/bib_ref] Medications to raise BP in intradialytic hypotension.-Nonmedication strategies for treating intradialytic hypotension, such as cardiovascular status optimization, UF rate minimization, and target-weight reassessment, should be prioritized. Medication options include midodrine, [bib_ref] Impact of drugs on intradialytic hypotension: antihypertensives and vasoconstrictors, Chang [/bib_ref] argi-nine-vasopressin, 72-76 sertraline, 77,78 droxidopa, amezinium metilsulfate, [bib_ref] Antihypotensive and hormonal effects of amezinium metilsulfate in hypotensive hemodialysis patients, Watari [/bib_ref] fludrocortisone, and carnitine. [bib_ref] Impact of drugs on intradialytic hypotension: antihypertensives and vasoconstrictors, Chang [/bib_ref] In general, the evidence base for these strategies is relatively weak, with most studies being small and of short duration. [bib_ref] Impact of drugs on intradialytic hypotension: antihypertensives and vasoconstrictors, Chang [/bib_ref] The most widely used is midodrine, an oral vasoconstrictor, although efficacy data are limited, [bib_ref] The impact of midodrine on outcomes in patients with intradialytic hypotension, Brunelli [/bib_ref] as is its availability outside the US [fig_ref] Table 3 \|: Medication classes for blood pressure management in dialysis blocker atenolol compared to... [/fig_ref]. ## The dialysis prescription as it relates to bp and volume target weight A critical element of the dialysis prescription is the target weight; a target weight that is too low may lead to hypotension and faster loss of RKF, whereas a weight that is too high results in hypervolemia . The result is a narrow therapeutic window in which to avoid acute and chronic complications of volume depletion and overload. Target weight differs in concept and in practice from the estimated dry weight, as target weight can vary from treatment to treatment. In some cases (e.g., acute illness, severe symptoms), it may be appropriate to maintain an individual slightly above the estimated dry weight; however, the long-term risks from chronic volume overload in this setting must be weighed carefully. 80 ## Intradialytic hypotension and the hd prescription Major contributors to intradialytic hypotension are insufficient intravascular volume to support the desired UF rate, and inadequate cardiovascular compensatory responses. The UF rate is a function of dialysis treatment time and volume removal. [bib_ref] Fluid first or not so fast: ultrafiltration rate and the ESRD Quality..., Weiner [/bib_ref] In observational data, higher UF rates, even as low as 6 ml/h per kg, are associated with higher mortality risk. [bib_ref] Ultrafiltration rate and mortality in maintenance hemodialysis patients, Assimon [/bib_ref] [bib_ref] Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality, Flythe [/bib_ref] Although no RCTs have demonstrated that lowering UF rates improves outcomes, biologic plausibility data support a relationship between higher UF rates and end-organ ischemia (heart, brain, liver, gut, kidneys). [bib_ref] Hemodialysis-induced cardiac injury: determinants and associated outcomes, Burton [/bib_ref] [bib_ref] Dying to feel better: the central role of dialysis-induced tissue hypoxia, Mcintyre [/bib_ref] [bib_ref] Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in..., Mcintyre [/bib_ref] [bib_ref] Hepato-splanchnic circulatory stress: an important effect of hemodialysis, Grant [/bib_ref] [bib_ref] Randomized clinical trial of dialysate cooling and effects on brain white matter, Eldehni [/bib_ref] [bib_ref] Intradialytic cardiac magnetic resonance imaging to assess cardiovascular responses in a short-term..., Buchanan [/bib_ref] [bib_ref] Renal perfusion during hemodialysis: Intradialytic blood flow decline and effects of dialysate..., Marants [/bib_ref] A critical unanswered question is how to balance the potential risks from higher UF rates with the potential risks from volume overload. [bib_ref] Target weight achievement and ultrafiltration rate thresholds: potential patient implications, Flythe [/bib_ref] In the absence of conclusive data, using one specific UF rate threshold for all patients at all times is likely inappropriate. Instead, clinicians should consider a range of factors, including intradialytic hemodynamics, comorbid medical conditions, symptoms, current conditions, and other factors as a means to weigh the potential harms of higher UF rates against their potential benefits. Decisions may differ on a treatment-to-treatment basis. Although questions about how to individualize UF rate prescriptions remain, patient and clinician awareness and frequent consideration of the UF rate are critically important to BPand volume-related decisions. UF rates can be lowered by increasing HD time and/or decreasing IDWG . Increased UF time can be accomplished by lengthening or adding treatments. Patient preference and local logistics and resources are important considerations. Strategies aimed at improving vascular compensation and/ or tolerance of UF may also lower the risk of UF-induced intradialytic hypotension and are listed in [fig_ref] Table 5 \|: Hemodialysate composition and blood pressure and volume status Further research needed regarding... [/fig_ref]. Altering dialysate sodium concentration is the most debated approach [fig_ref] Table 5 \|: Hemodialysate composition and blood pressure and volume status Further research needed regarding... [/fig_ref]. Prospective studies suggest that use of lower dialysate sodium is associated with lower IDWG and BP [bib_ref] Effect of lowering dialysate sodium concentration on interdialytic weight gain and blood..., Mendoza [/bib_ref] [bib_ref] High versus low dialysate sodium concentration in chronic haemodialysis patients: a systematic..., Basile [/bib_ref] but also show an association with intradialytic hypotension and symptoms, including cramps. [bib_ref] Low dialysate sodium levels for chronic haemodialysis, Dunlop [/bib_ref] Observational studies have yielded mixed results regarding the association of dialysate sodium and mortality. [bib_ref] Dialysate sodium concentration and the association with interdialytic weight gain, hospitalization, and..., Hecking [/bib_ref] [bib_ref] Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients:..., Hecking [/bib_ref] [bib_ref] Dialysate sodium, serum sodium and mortality in maintenance hemodialysis, Mc Causland [/bib_ref] The Sodium Lowering in Dialysate (SoLID) RCT [bib_ref] Rationale and design of the Sodium Lowering In Dialysate (SoLID) trial: a..., Dunlop [/bib_ref] [bib_ref] Update: rationale and design of the Sodium Lowering In Dialysate (SoLID) trial:..., Dunlop [/bib_ref] assesses the effects of low versus standard dialysate sodium concentration on regression of left ventricular mass, with results pending. Therefore, the ideal dialysate sodium concentration remains uncertain. A large multinational, pragmatic trial is ongoing (RESOLVE, NCT02823821). Moreover, the prescribed and delivered dialysate sodium concentrations can differ, rendering individualization of prescriptions challenging and potentially unsafe. [bib_ref] Comparison of prescribed and measured dialysate sodium: a quality improvement project, Gul [/bib_ref] In general, sodium balance should be negative during an HD treatment, 1 given the tension between enhanced vascular space viability during a single treatment and lower IDWG across many treatments. Additional questions include whether there is a role for UF profiling or isolated UF followed by HD (i.e., sequential dialysis) and how to address logistic issues such as the 3-day gap in some regions and limited access to thrice-weekly HD in resource-poor settings. ## Chronic hypotension and the hd prescription Chronically hypotensive patients are a particularly challenging group to manage. For many of these individuals, the same principles hold, most notably increasing dialysis time. Patients with chronic hypotension may tolerate PD better than HD, yet further study is required to confirm whether outcomes are better after a transition in modalities. ## Hypotension and the pd prescription Conditions associated with hypotension in PD include aggressive UF and/or failure to adjust PD prescription with decreased dietary intake or hypovolemia; failure to adjust antihypertensive medications; overly stringent salt restriction; and low cardiac output. Strategies to prevent hypotension include reducing UF volume by adjusting solutions (e.g., using less hypertonic glucose solutions or changing icodextrin to conventional 1.5% glucose solution); omitting day dwell (in automated PD [APD]) or night dwell (in continuous ambulatory PD) in those with significant RKF without compromising clearance; withholding antihypertensive medications; and liberalizing salt intake. ## Hypertension and the hd prescription Dialytic management of hypertension in patients receiving HD begins with addressing volume overload. Options include gently probing the prescribed target weight, [bib_ref] Dry-weight reduction in hypertensive hemodialysis patients (DRIP): a randomized, controlled trial, Agarwal [/bib_ref] increasing treatment time and/or frequency (possibly through home HD or center-based nocturnal HD), decreasing IDWG, and improving vascular stability during HD . ## Hypertension and the pd prescription As among HD patients, volume is a significant contributor to hypertension among PD patients. The principle behind preventing or treating hypertension in PD is to maximize peritoneal UF and urine output to achieve euvolemia with a prescription that has the lowest glucose load to patients and without jeopardizing RKF. Strategies to maximize UF for the long dwell include shortening the dwell with glucose-based solutions (high transporter), using higher tonicity glucose-based solutions (but this is less preferable), using icodextrin for long day dwell for APD or long overnight dwell for continuous ambulatory PD, restricting dietary salt, and in those with RKF, using diuretics to increase urine volume . 55,100 Experimental approaches include using a low-sodium dialysate, 101 a bimodal solution with glucose and icodextrin, [bib_ref] A combined crystalloid and colloid Pd solution as a glucosesparing strategy for..., Freida [/bib_ref] 2 icodextrin exchanges per day, [bib_ref] Effects of twice-daily icodextrin administration on blood pressure and left ventricular mass..., Sav [/bib_ref] and incorporating intermittent hybrid therapy, all of which require further evaluation. Assessment of membrane function may be considered as adjunctive to clinical measures of UF volume. The peritoneal equilibration test is used in solute removal modelling prediction software. However, this test alone should not guide PD prescriptions. The correlation between solute transport characteristics and UF capacity is poor. The test may be useful in identifying true membrane failure versus other causes of impaired UF and volume excess (such as mechanical causes or excess intake). [bib_ref] Analysis of ultrafiltration failure in peritoneal dialysis patients by means of standard..., Ho-Dac-Pannekeet [/bib_ref] No robust data suggest that continuous ambulatory PD or APD results in superior volume control relative to the other. [bib_ref] Comparative outcomes between continuous ambulatory and automated peritoneal dialysis: a narrative review, Bieber [/bib_ref] Therefore, PD modality selection considerations should go beyond BP and volume control, centering on broader concerns, such as patient preferences and local resources. APD has a potential for greater UF than continuous ambulatory PD, and mostly observational data suggest that APD may have a greater benefit for rapid transporters. [bib_ref] Comparative outcomes between continuous ambulatory and automated peritoneal dialysis: a narrative review, Bieber [/bib_ref] Changing the PD solution type, exchange number, and dwell time are important PD prescription strategies to optimize BP and volume management. Compared with standard glucose solutions, the more biocompatible, neutral pH, or low glucose degradation products solutions may prolong the time to anuria when used for more than 12 months, and this may indirectly benefit volume control. [bib_ref] Biocompatible dialysis fluids for peritoneal dialysis, Htay [/bib_ref] [bib_ref] Effects of biocompatible versus standard fluid on peritoneal dialysis outcomes, Johnson [/bib_ref] The more biocompatible PD solutions have also been associated with stable peritoneal membrane function and UF capacity over time, compared with conventional glucose-based solutions, which have been associated with a progressive decline in UF capacity over time. [bib_ref] The effect of low glucose degradation product, neutral pH versus standard peritoneal..., Johnson [/bib_ref] [bib_ref] Biocompatible solutions and long-term changes in peritoneal solute transport, Elphick [/bib_ref] [bib_ref] Effects of long-term treatment with low-GDP, pH-neutral solutions on peritoneal membranes in..., Tawada [/bib_ref] Icodextrin.-Moderate-certainty evidence indicates that icodextrin augments peritoneal UF compared with standard glucose solutions. [bib_ref] Biocompatible dialysis fluids for peritoneal dialysis, Htay [/bib_ref] Three RCTs have examined the effect of icodextrin in high or high-average transporters [bib_ref] Icodextrin improves the fluid status of peritoneal dialysis patients: results of a..., Davies [/bib_ref] [bib_ref] Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration, Finkelstein [/bib_ref] [bib_ref] Echocardiographic, electrocardiographic and blood pressure changes induced by icodextrin solution in diabetic..., Paniagua [/bib_ref] ; in general, higher transporters derived greater UF benefit from icodextrin. [bib_ref] Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role..., Mortier [/bib_ref] and clinical data [bib_ref] Peritoneal glucose exposure and changes in membrane solute transport with time on..., Davies [/bib_ref] suggest that hypertonic glucose solutions are deleterious to peritoneal health and may cause adverse metabolic effects. [bib_ref] Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role..., Mortier [/bib_ref] [bib_ref] Peritoneal glucose exposure and changes in membrane solute transport with time on..., Davies [/bib_ref] [bib_ref] ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients Part I-Assessment..., Wang [/bib_ref] Frequent use of 4.25% solutions should prompt evaluation of dietary salt and fluid intake, PD prescription, mechanical problems, and peritoneal membrane failure. ## 4.25% pd solutions.-animal ## Preserving residual kidney function In observational PD [bib_ref] Relative contribution of residual renal function and peritoneal clearance to adequacy of..., Bargman [/bib_ref] [bib_ref] The importance of residual renal function in dialysis patients, Wang [/bib_ref] and HD 119 studies, better-preserved RKF is associated with better survival rates and patient outcomes. Preserving RKF allows the incorporation of diuretics into regimens to help reduce IDWG. In addition, RKF preservation allows consideration of incremental PD prescriptions that reduce treatment burden. Likewise, the presence of significant RKF is an important consideration in incremental HD, [bib_ref] Hemodialysis prescription for incident patients: Twice seems nice, but is it incremental?, Toth-Manikowski [/bib_ref] although the purported benefits are untested by adequately powered RCTs. What the optimal approach is for measuring RKF is controversial. [bib_ref] Development and validation of residual kidney function estimating equations in dialysis patients, Steubl [/bib_ref] In many cases, urine volume measurement or potentially patient-reported urine volume 123 may be adequate. RCT data on RKF preservation strategies beyond the common-sense strategies of hypotension and nephrotoxin avoidance are limited [fig_ref] Table 6 \|: Residual kidney functionWhen to assess124 Limited consensus about frequency, which ranges from... [/fig_ref]. Moreover, the cardioprotective strategies of more intensive volume control and more frequent HD may hasten RKF loss. [bib_ref] Effect of frequent hemodialysis on residual kidney function, Daugirdas [/bib_ref] Thus, individualized approaches are necessary. ## Extracellular volume management and technologies RELEVANT TO VOLUME MANAGEMENT ## Measuring extracellular volume There are no widely available, precise methods for measuring extracellular volume. Evaluation of any approach to measuring volume is complicated by the absence of an accessible gold standard. In most instances, volume assessment relies on clinical markers, including patient history and physical examination. Volume assessment includes examining trends in weights, BPs, and signs and symptoms. The physical examination is the mainstay of volume assessment, but data suggest that BP, jugular vein distension, and edema may not correlate well with volume status. [bib_ref] On the importance of pedal edema in hemodialysis patients, Agarwal [/bib_ref] [bib_ref] Can the clinical examination diagnose left-sided heart failure in adults?, Badgett [/bib_ref] [bib_ref] The rational clinical examination. Is this patient hypovolemic?, Mcgee [/bib_ref] Despite these limitations, a physical examination should include evaluation for the presence of edema, degree of filling of the jugular vein, and lung auscultation. Physical examination paired with review of longitudinal weights, BPs, and symptoms should be performed at least once per month, with the optimal frequency individualized based on patient circumstances. Other tools for evaluating extracellular volume are listed in [fig_ref] Table 7 \|: Volume-assessment parameters and tools Data supporting associations between physical signs and volume... [/fig_ref]. Major challenges are limited availability and the lack of evidence-based protocols. Certain tools, such as bioimpedance spectroscopy and lung ultrasound, can be used to confirm clinical suspicion of extracellular excess and are of prognostic value. [bib_ref] The role of bioimpedance and biomarkers in helping to aid clinical decision-making..., Davies [/bib_ref] [bib_ref] Predicting mortality in haemodialysis patients: a comparison between lung ultrasonography, bioimpedance data..., Siriopol [/bib_ref] [bib_ref] Effective and timely evaluation of pulmonary congestion: qualitative comparison between lung ultrasound..., Donadio [/bib_ref] [bib_ref] Lung ultrasound during hemodialysis: the role in the assessment of volume status, Vitturi [/bib_ref] The use of bioimpedance to guide target weight estimation may improve BP and left ventricular mass. [bib_ref] Effect of fluid management guided by bioimpedance spectroscopy on cardiovascular parameters in..., Hur [/bib_ref] Data on the effectiveness of bioimpedance-guided volume management on symptoms and hospitalizations are mixed. [bib_ref] The role of bioimpedance and biomarkers in helping to aid clinical decision-making..., Davies [/bib_ref] [bib_ref] Bioimpedance-guided fluid management in hemodialysis patients, Moissl [/bib_ref] [bib_ref] Fluid management in haemodialysis: Conventional versus body composition monitoring (BCM) supported management..., Ponce [/bib_ref] Lung ultrasound-guided volume management improves BP control, [bib_ref] The effect of dry-weight reduction guided by lung ultrasound on ambulatory blood..., Loutradis [/bib_ref] and an ongoing trial of lung ultrasound-guided treatment and cardiovascular outcomes is underway (LUST Study, NCT02310061). The biggest barriers to using these technologies are cost (of the test itself and time to administer it) and availability. In resource-constrained environments, clinical examination remains the mainstay of volume assessment. ## Technical intradialytic strategies for managing bp and volume Temperature biofeedback.-Cooling the dialysate temperature through various methods (e.g., lowering temperature relative to measured body temperature or lowering temperature to a set threshold-35 °C or 36 °C-irrespective of body temperature) has been associated with hemodynamic stability, [bib_ref] Cool dialysate reduces asymptomatic intradialytic hypotension and increases baroreflex variability, Chesterton [/bib_ref] [bib_ref] Randomized controlled trial of individualized dialysate cooling for cardiac protection in hemodialysis..., Odudu [/bib_ref] [bib_ref] A systematic review of the clinical effects of reducing dialysate fluid temperature, Selby [/bib_ref] [bib_ref] Associations between hemodialysis facility practices to manage fluid volume and intradialytic hypotension..., Dasgupta [/bib_ref] and lowering temperature to 0.5 °C below body temperature is well tolerated by most patients. An ongoing trial (MY TEMP, NCT02628366) is evaluating the effect of dialysate cooling on cardiovascular events. Blood volume monitoring.-Evidence is conflicting regarding whether relative blood volume monitoring can predict intradialytic hypotension [bib_ref] Randomized crossover trial of blood volume monitoringguided ultrafiltration biofeedback to reduce intradialytic..., Leung [/bib_ref] [bib_ref] Relative plasma volume monitoring during hemodialysis AIDS the assessment of dry weight, Sinha [/bib_ref] [bib_ref] Linear decay of relative blood volume during ultrafiltration predicts hemodynamic instability, Mitra [/bib_ref] [bib_ref] Do changes in relative blood volume monitoring correlate to hemodialysis-associated hypotension?, Booth [/bib_ref] ; however, evidence suggests that relative blood volume monitoring is of prognostic value. [bib_ref] All-cause mortality in relation to changes in relative blood volume during hemodialysis, Preciado [/bib_ref] In the randomized Crit-Line Intradialytic Monitoring Benefit (CLIMB) trial, mortality and hospitalization rates were higher among patients undergoing intradialytic blood volume monitoring versus conventional clinical monitoring. However, the interpretation of the trial is limited by the atypically low hospitalization and mortality rates and questions regarding study protocol adherence. [bib_ref] Intradialytic blood volume monitoring in ambulatory hemodialysis patients: a randomized trial, Reddan [/bib_ref] [bib_ref] Why assistive technology is needed for probing of dry weight, Sinha [/bib_ref] In children, although there are no RCT data, evidence indicates that a relative blood volume-guided UF algorithm improves BP control. [bib_ref] A standard, noninvasive monitoring of hematocrit algorithm improves blood pressure control in..., Patel [/bib_ref] UF profiling.-RCT data on UF profiling, independent of relative blood volume monitoring and sodium profiling, are scarce, with a crossover RCT published in 2000 demonstrating no benefit. [bib_ref] Ultrafiltration profiling and measurement of relative blood volume as strategies to reduce..., Donauer [/bib_ref] Isolated UF.-Isolated UF is commonly used, 147 but currently there is limited evidence to support this approach. Sodium profiling.-Although data to support sodium profiling are scant, one metaanalysis suggests that stepwise versus linear sodium profiling is associated with greater hemodynamic stability.Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) suggest that the routine use of sodium modelling/profiling to limit or prevent intradialytic hypotension is associated with increased all-cause mortality. [bib_ref] Associations between hemodialysis facility practices to manage fluid volume and intradialytic hypotension..., Dasgupta [/bib_ref] Sodium profiling must be used judiciously, as it may result in sodium loading and hypervolemia. Bioimpedance.-Data from a study of 15 patients indicate that bioimpedance may have a role for assessing the relationship between plasma refilling and tissue hydration during dialysis, [bib_ref] Slope analysis of blood volume and calf bioimpedance monitoring in hemodialysis patients, Seibert [/bib_ref] but evidence is currently insufficient to justify routine use for intradialytic volume management. As reported above, bioimpedance may have a role in extracellular volume management. Hemodiafiltration.-Convective therapies such as hemodiafiltration may have a role in preventing intradialytic hypotension. An RCT including 146 patients demonstrated a significant reduction in intradialytic hypotension in the hemodiafiltration group compared with regular HD, [bib_ref] Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD, Locatelli [/bib_ref] and others have demonstrated better hemodynamic stability with increasing convection volume prescriptions. [bib_ref] Association of intradialytic hypotension and convective volume in hemodiafiltration: results from a..., Mora-Bravo [/bib_ref] Further research is needed. ## Remote monitoring and wearable health technologies For home-based dialysis, older technologies, such as telephone calls, remain important. However, systems are advancing, and many modern dialysis machines can transmit data, such as BP, weight, oxygen saturation, and UF rate, back to central locations. None of these tools has been proven to enhance outcomes, but more investigation is needed. Wearable devices, including dialysis apparatuses and cardiac tools for measuring volume status, heart rhythm, and other factors, are currently in development. Their roles in dialysis management remain nascent. These tools have the potential to improve patient autonomy and risk-factor management but will need to be aligned with local health and payment systems to realize widespread uptake. ## Volume-related patient experiences and nonpharmacologic ## Interventions for suboptimal bp and volume control ## Signs and symptoms of volume overload or depletion Various signs and symptoms are associated with volume overload or depletion: breathlessness, orthopnea, edema, elevated jugular venous pressure, cardiomegaly, lung congestion, light-headedness, cramps, erectile dysfunction, thirst, and weight gain and loss, among others. Small studies suggest that better BP and volume management may improve symptoms. [bib_ref] Treating hypertension in hemodialysis improves symptoms seemingly unrelated to volume excess, Agarwal [/bib_ref] Some dialysis patients have symptom clusters that relate to volume status, and it is helpful for both clinicians and patients to recognize these individualized indicators. Research aimed at understanding symptom constellations is needed. 162 ## Incorporating volume-related symptoms into dialysis prescription decision-making National guidelines suggest UF rate thresholds and dietary restrictions, [bib_ref] Assessment and management of hypertension in patients on dialysis, Agarwal [/bib_ref] [bib_ref] Hypertension in dialysis patients: a consensus document by the European Renal and..., Sarafidis [/bib_ref] [bib_ref] Japanese society for dialysis therapy clinical guideline for "Maintenance hemodialysis: hemodialysis prescriptions, Watanabe [/bib_ref] but none address the relationship between volume status and symptoms. In consensus-building exercises, patients prioritize symptoms that plausibly relate to volume, such as fatigue and cramping, for treatment and new research. [bib_ref] Developing a set of core outcomes for trials in hemodialysis: an international..., Evangelidis [/bib_ref] [bib_ref] Symptom prioritization among adults receiving in-center hemodialysis: a mixed methods study, Flythe [/bib_ref] Symptoms, especially when new or escalating, should trigger review of volume-related aspects of the dialysis prescription. However, symptoms are seldom formally assessed on a frequent basis, and patients describe under-reporting their symptoms. [bib_ref] Perspectives on symptom experiences and symptom reporting among individuals on hemodialysis, Flythe [/bib_ref] Patients should be engaged, educated, and encouraged to report symptoms routinely. [bib_ref] Perspectives on symptom experiences and symptom reporting among individuals on hemodialysis, Flythe [/bib_ref] Symptom assessment surveys have been developed for dialysis patients, [bib_ref] Development of a symptom assessment instrument for chronic hemodialysis patients: the Dialysis..., Weisbord [/bib_ref] but most instruments assess symptoms over 1 to 4 weeks, obscuring links between symptoms and the dialysis prescription. Ideally, a symptom measurement tool would capture relevant symptoms and their severity in real time, without being burdensome to patients. Incorporating symptoms into dialysis prescription considerations may focus discussions on aspects of care that are most important to patients. In considering symptoms, risk-versusbenefit tradeoffs must be carefully explained and weighed. Good communication, both among the dialysis team members and between the team and the patient, is essential to ensure that changes in target weight (or other prescription aspects) are carefully monitored. Inclusion of patient experience and well-being in benchmarking could help align the goals of patients and providers. ## Salt and fluid restrictions for bp and volume control Salt and fluid restrictions are the cornerstone nonpharmacologic strategies for BP and volume management; however, data supporting their effectiveness are surprisingly scant. A systematic review evaluated 16 studies of psychological interventions for addressing nonadherence to fluid restrictions in HD patients, [bib_ref] A systematic review of psychological interventions for the treatment of nonadherence to..., Sharp [/bib_ref] including behavior modification, cognitive therapy, social reinforcement, and stress management. At best, these studies indicated only a modest postintervention decrease in IDWG. However, small studies have shown that restricting salt intake can reduce IDWG in patients receiving HD, [bib_ref] The benefit of salt restriction in the treatment of end-stage renal disease..., Kayikcioglu [/bib_ref] and BP in patients receiving PD. [bib_ref] The effect of dietary salt restriction on hypertension in peritoneal dialysis patients, Inal [/bib_ref] Although the serum sodium level that triggers thirst varies across individuals,most patients maintain their pre-dialysis sodium levels within the normal range. This finding suggests that water intake is adjusted to match salt intake, underscoring the importance of emphasizing salt restriction, rather than the overly simplistic advice to just restrict fluid intake. For patients with low pre-dialysis sodium level, other issues should be considered, such as poorly controlled glucose levels or excessive drinking. Dietary restrictions and nutritional status.-Dietary interventions to reduce IDWG must be made cautiously so as not to compromise nutritional status. Such caution is particularly important in frail patients, who may tolerate UF poorly even when hypervolemic. In growing children, it is important to monitor volume status and body composition regularly to ensure that the target weight is adjusted to match growth. If fluid gains between treatments persist despite dietary changes, an augmented dialysis regimen should be considered. Goals of care should be reviewed frequently. ## Effects of dietary restrictions on ## Exercise for bp and volume control Although there are few studies of exercise and volume, 174 combined aerobic and resistance training has been associated with SBP and diastolic BP reductions. [bib_ref] Combined training is the most effective training modality to improve aerobic capacity..., Scapini [/bib_ref] Although many dialysis patients want to exercise, [bib_ref] Benefits and barriers to and desired outcomes with exercise in patients with..., Moorman [/bib_ref] barriers to exercise of any type include fatigue, dialysis access, time constraints, comorbidities, fear, and (for intradialytic exercise) clinic personnel workload. 177,178 # Conclusion Managing BP and volume in dialysis requires an individualized approach with integration of numerous clinical, dialysis treatment, and patient factors. Bolstered by shared commitments to improving volume management and focusing on patient-stated priorities, the conference participants identified numerous strategies and technologies that should be considered in the design and implementation of future RCTs in this critical, yet understudied area. APD, automated peritoneal dialysis; BMI, body mass index; CAPD, continuous ambulatory peritoneal dialysis; GDP, glucose degradation product; HD, hemodialysis; HDF, hemodiafiltration; IDWG, interdialytic weight gain; PD, peritoneal dialysis; RKF, residual kidney function; UF, ultrafiltration. Included studies were all of short duration and had small sample sizes , and none examined clinical endpoints such as death or cardiovascular events. [fig] Figure 1 \|: Tension in balancing volume status within a narrow therapeutic window. . Author manuscript; available in PMC 2021 May 01. [/fig] [fig] Figure 2 \|Figure 3 \|: Contributors to and consequences of blood pressure and volume abnormalities in dialysis.GI, gastrointestinal; HD, hemodialysis; IDWG, interdialytic weight gain; PD, peritoneal dialysis; UF, ultrafiltration. . Author manuscript; available in PMC 2021 May 01. . Conceptual framework for individualizing dialysis prescriptions. [/fig] [table] Table 2 \|: Definitions of intradialytic hypotension and intradialytic hypertension [/table] [table] Table 3 \|: Medication classes for blood pressure management in dialysis blocker atenolol compared to the ACEi lisinopril in HD patients with hypertension and left ventricular hypertrophy 52• RCT: Lower risk of death and cardiovascular death with carvedilol versus placebo in HD patients with dilated cardiomyopathy who were also receiving digoxin and ACEi or ARB53 Continuation of loop diuretics after HD initiation is associated with lower IDWG and lower intradialytic hypotension and hospitalization rates58 Mineralocorticoid receptor antagonists• RCT: Some trials in patients on dialysis have shown benefit on cardiovascular outcomes with spironolactone vs. pla-cebo,[59][60][61] whereas others have not 62•Ongoing RCTs: spironolactone and cardiovascular outcomes in HD patients (ACHIEVE and ALCHEMIST) 63Hypotension Midodrine• Meta-analysis: Nadir SBP improved by an average of 13 mm Hg (95% CI: 9-18 mm Hg, P < 0.0001), and 6 of the 10 studies reported an improvement in symptoms associated with intradialytic hypotension with use of midodrine vs. control.64 [/table] [table] • Observational: Matched midodrine users to non-users (including matching by mean peridialytic BP level) found that midodrine use was associated with significantly higher risks of cardiovascular events, all-cause hospitalization, and mortality.65 ACEi, angiotensin-converting enzyme inhibitor; ACHIEVE, Aldosterone Blockade for Health Improvement Evaluation in End-stage Renal Disease; ALCHEMIST, ALdosterone Antagonist Chronic HEModialysis; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; HD, hemodialysis; IDWG, interdialytic weight gain; PD, peritoneal dialysis; RCT, randomized controlled trial; SBP, systolic blood pressure.Kidney Int. Author manuscript; available in PMC 2021 May 01. Nonpharmacologic interventions to prevent intradialytic hypotension Facility logistics; patient preference; infeasible in resource-poor regions Increase frequency of dialysis treatments Facility logistics; patient preference; infeasible in resource-poor regions Utilize home dialysis modalities Not available in all regions Decrease weight gain Decrease sodium intake • Dietary counseling, including family members/food preparers • Dietary sodium restriction • Avoid sodium loading during dialysis Patient preferences and adherence; difficult in setting of high-salt diets Limited food choices; poverty; dietician, registered nurse, and physician skills Imprecise dialysate sodium prescriptions; increased cramping and hypotension Enhance nondialytic volume loss • Diuretics • Gastrointestinal, sweat, and respiratory Viable strategy only among individuals with residual kidney function Patient preference and symptom burden; limited evidence Improve tolerability of a specific UF rate Enhance vascular space viability Cooled dialysate Patient tolerance, although data suggest well tolerated May improve single-treatment BP but often leads to more IDWG and volume overload in the long-term Exposure to time-limited higher UF rate; limited evidence Isolated UF, followed by HD Exposure to time-limited higher UF rate; potential decrement in clearance; limited evidence Limited availability of beds for in-center HD Improve overall health Prevent protein energy wasting Chronic intervention that cannot be applied acutely Preserve residual kidney function Chronic intervention that cannot be applied acutely; may occur at the expense of volume overload; limited evidence Intradialytic exercise Chronic intervention that cannot be applied acutely; infeasible in resource-poor regions; limited evidence BP, blood pressure; HD, hemodialysis; IDWG, interdialytic weight gain; UF, ultrafiltration. Kidney Int. Author manuscript; available in PMC 2021 May 01. [/table] [table] Table 5 \|: Hemodialysate composition and blood pressure and volume status Further research needed regarding the optimal serum to dialysate Na + gradient • Further research needed to assess whether lower dialysate Na + Generally avoid very low dialysate Ca ++ • Optimal balance between risk of lower BP and increased heart failure and sudden cardiac death risk with lower dialysate Ca ++ needs to be weighed against the potential for increased vascular calcification and chronic loss of vascular elasticity resulting in maladaptive vascular and heart remodeling harm of acetate rather than benefits of varying the dialysate HCO BP, blood pressure; IDWG, interdialytic weight gain; HD, hemodialysis; N/A, not applicable.Kidney Int. Author manuscript; available in PMC 2021 May 01. [/table] [table] Table 6 \|: Residual kidney functionWhen to assess124 Limited consensus about frequency, which ranges from quarterly to far less frequent Limited consensus about frequency; not consistently measured in HD patientsHow to assessMean of urea and creatinine clearance using 24-h urine collection and simultaneous one-off blood sampling125 24-h urine collection only for volume vs. both urine collection and serum samples for clearance determination126 • Entire interdialytic period preferable• Clearance of urea or creatinine or mean of urea and creatinine • Neutral pH Low GDP solution 76 • Diuretics (increase urine volume and thus reduce UF rate, but do not specifically preserve RKF) 55 Low-protein diet with keto acid supplementation 128 RCT evidence • High flux vs. low flux (benefit) 130 • Frequent nocturnal dialysis may increase rate of loss (harm) 131 GDP, glucose degradation product; HD, hemodialysis; RAS, renin-angiotensin system; RCT, randomized controlled trial; RKF, residual kidney function; UF, ultrafiltration. Kidney Int. Author manuscript; available in PMC 2021 May 01. [/table] [table] Table 7 \|: Volume-assessment parameters and tools Data supporting associations between physical signs and volume status are weakBlood pressure • Studies suggest weak correlation between BP and volume status • Useful in monitoring patient safety • Minimal data on relative effectiveness of various BP measurements as they relate to volume assessment Lung water ultrasound • Good for evaluating for hypervolemia (but not hypovolemia) • Role in routine volume assessment is under way (NCT02310061) Some challenges in interpretation owing to reading variation across some patient subpopulations Biochemical markers (BNP/NT-proBNP, CD146, cGMP) • Generally low accuracy • Cost is variable and depends upon laboratory availability at centers Kidney Int. Author manuscript; available in PMC 2021 May 01. [/table]	None	http://www.kidney-international.org/article/S0085253820302313/pdf	None
31ce26b48bde5033d16758131291f9e88ac75740	pubmed	2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis	2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis Background: Acute calculus cholecystitis (ACC) has a high incidence in the general population. The presence of several areas of uncertainty, along with the availability of new evidence, prompted the current update of the 2016 WSES (World Society of Emergency Surgery) Guidelines on ACC.Materials and methods:The WSES president appointed four members as a scientific secretariat, four members as an organization committee and four members as a scientific committee, choosing them from the expert affiliates of WSES. Relevant key questions were constructed, and the task force produced drafts of each section based on the best scientific evidence from PubMed and EMBASE Library; recommendations were developed in order to answer these key questions. The quality of evidence and strength of recommendations were reviewed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (see https://www. # Background The estimated overall prevalence of gallstones is 10-15% in the general population, with some differences across countries. Between 20 and 40% of patients with gallstones will develop gallstone-related complications, with an incidence of 1-3% annually; acute calculus cholecystitis (ACC) is the first clinical presentation in 10-15% of the cases [bib_ref] Epidemiology and risk factors for gallstone disease: Has the paradigm changed in..., Shaffer [/bib_ref] [bib_ref] Prevalence of gallstones in sonographic surveys worldwide, Kratzer [/bib_ref] [bib_ref] Natural history of asymptomatic and symptomatic gallstones, Friedman [/bib_ref] [bib_ref] TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis, Kimura [/bib_ref] [bib_ref] Epidemiology of gallstones, Stinton [/bib_ref]. Cholecystectomy is the most common therapeutic approach for ACC and is considered the standard of care for gallstone disease for the majority of patients. However, considering the heterogeneity of clinical scenarios, the variability in hospital facilities and in the availability of expertise, the management of patients with right upper quadrant abdominal pain may vary. In 2016, the World Society of Emergency Surgery (WSES) published the first edition of their guidelines for ACC [bib_ref] WSES guidelines on acute calculous cholecystitis, Ansaloni [/bib_ref] , which presented different diagnostic and therapeutic algorithms, compared with the Tokyo Guidelines (TG), known at that time as Tokyo Guidelines 2013 (TG13) [bib_ref] TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos), Yokoe [/bib_ref]. In particular, the direct link between diagnostic criteria for ACC, severity classification and therapeutic indications described in the TG13 are limited by lack of quality evidence. The approach of the WSES guidelines was to simplify the initial management of patients presenting with suspected ACC. The literature review, the discussion of the relevant evidence and the statements made during the consensus conference (CC) held in Jerusalem in 2015 (Third WSES International Congress) supported surgery as the gold standard treatment for all patients with ACC, with two exceptions: patients who refuse surgery, and patients for whom surgery would be considered as 'very high risk', although no clear consensus was reached on this second issue. Moreover, the 2016 WSES Guidelines on ACC included discussions on unclear areas, such as diagnosis, evaluation of the surgical risk and appropriate management of associated common bile duct stones (CBDS). In 2017, the WSES joined the Italian Society for Geriatric Surgery during a CC regarding the management of ACC in the elderly, with the aim of investigating this subgroup of fragile patients, considered at 'very high risk' for surgery. There was lack of agreement supporting the surgical management of ACC in the elderly and considering old age as a contraindication for surgery by itself. The authors found substantial lack of high-quality studies on this topic [bib_ref] WSES and SICG guidelines on acute calcolous cholecystitis in elderly population, Pisano [/bib_ref]. The WSES, after evaluating the 2018 edition of the TG (TG18) on ACC [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref] , found that this new edition reached conclusions that were closer to the recommendations of the 2016 WSES guidelines on ACC, especially in terms of a more liberal indication for surgery including grade 3 ACC. However, some differences remain when comparing the WSES guidelines and the TG (all editions), as evident in the recommendations in the current updated guidelines. A combined event, WSES and TG group could be an opportunity to share experiences considering different perspectives. Since the publication of the 2016 WSES Guidelines and the TG18, the management of the high-risk patients with ACC was investigated in a randomized controlled trial (RCT), known as the CHOCOLATE trial [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref]. Loozen and collaborators compared cholecystectomy to percutaneous catheter drainage in high-risk surgical patients. This research group has joined with other experts in contributing to this edition of the WSES guidelines on ACC. # Materials and methods In 2018, the Scientific Board of the 6thWorld Congress of the WSES endorsed its president to organize a CC on ACC in order to update the previous WSES Guidelines. The WSES president appointed four members as a scientific secretariat, four members as an organization committee and four members as a scientific committee, choosing them from the expert affiliates of the WSES. Relevant key questions regarding the diagnosis and treatment of ACC were developed and divided into seven sections, in order to analyse the topic and update the guidelines with the currently available evidence. Under the supervision of the scientific secretariat, a bibliographic search related to these questions was performed, using electronic search of PubMed and EMBASE databases in May 2019, with no date or language restrictions. An additional manual search of the literature was performed by members of the working groups involved in the analysis of the papers and the development of the guidelines. The topics and sections, the key questions and the related key words used to develop the update on ACC are available in [fig_ref] Table 1: Sections/topics, key questions and key words [/fig_ref]. Before the CC, the statements and recommendations were reviewed by the representatives responsible for each of the sections, creating a draft version of the guidelines. The quality of evidence and strength of recommendations were reviewed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (see https://www.gradeworkinggroup.org/). Specifically, the quality of evidence was graded as 'High', 'Moderate', 'Low' or 'Very low' and the strength of a recommendation was indicated as either 'Strong' or 'Weak'. Consensus had previously been defined as 70% or more of the votes being in agreement. During the 6th World Congress of the WSES held in Nijmegen, the Netherlands in May 2019, each question was discussed and voted upon by the audience (votes were either 'agree' or 'disagree'). The percentage of agreement was recorded immediately; in case of disagreement, the statement was modified following discussion. After the CC, the president and representatives reviewed the guidelines in response to the comments and the revised version of the statements was voted upon via an online questionnaire until consensus was reached. Throughout the period of the elaboration of the current guidelines, repeated literature searches were carried out in order to maximize the inclusion of relevant evidence (last literature search: May 2020). These Guidelines should be considered an adjunctive tool for decision making, but they are not a substitute for the surgeon's judgement in specific clinical situations. In Appendix 1, the reader can find the summary of statements with short explanation of the supporting scientific evidence while details are in the body of the paper. [fig_ref] Figure 1 2020: WSES Flowchart for the management of patients with acute calcolus cholecystitis [/fig_ref] represents the 2020 WSES flowchart for the management of ACC patients. The WSES committee for guidelines development is responsible for the continuous evaluation of evidence available about acute cholecystitis. The present guidelines will be updated in case of significant changes based on new evidence. Section 1. Diagnosis of ACC As no feature has sufficient diagnostic power to establish or exclude the diagnosis of ACC, it is recommended not to rely on a single clinical or laboratory finding. #QoE: high; SoR: strong# 1.2 For the diagnosis of ACC, we suggest using a combination of detailed history, complete clinical examination, laboratory tests and imaging investigations. However, the best combination is not known. #QoE: very low; SoR: weak# Comment: useful features for the diagnosis of ACC are: History and clinical examination: fever, right upper quadrant pain or tenderness, vomiting or food intolerance; Murphy's sign Laboratory tests: elevated C-reactive protein, elevated white blood cell count Imaging: signs suggestive of gallbladder inflammation The recommendations of the 2016 WSES guidelines were mainly based on two studies: a systematic review and meta-analysis by Trowbridge et al. [bib_ref] Does This Patient Have Acute Cholecystitis?, Trowbridge [/bib_ref] and a prospective diagnostic study by Eskelinen et al. [bib_ref] Diagnostic approaches in acute cholecystitis: a prospective study of 1333 patients with..., Eskelinen [/bib_ref]. This evidence, although flawed by the limitations described below, remains relevant and the associated statement remains valid. The paper by Trowbridge et al. [bib_ref] Does This Patient Have Acute Cholecystitis?, Trowbridge [/bib_ref] included 17 studies, which reported a quantitative assessment of history, physical examination and/or laboratory tests for the diagnosis of acute cholecystitis. The results showed that, with the exception of Murphy's sign (positive likelihood ratio-LR 2.8; 95% CI 0. and right upper quadrant tenderness (negative LR0.4; 95% CI 0.2-1.1)-although the 95% confidence intervals included 1.0 in both cases, none of the clinical signs or laboratory tests showed LRs higher than 1.6 or negative LRs lower than 0.4. Limitations were identified in a possible selection bias, as patients with abdominal pain and patients with a suspected diagnosis of acute cholecystitis were included in the study, and in a heterogeneous definition of the diagnosis of acute cholecystitis. The article by Eskelinen et al. [bib_ref] Diagnostic approaches in acute cholecystitis: a prospective study of 1333 patients with..., Eskelinen [/bib_ref] evaluated more than 1300 patients and revealed a good diagnostic yield with a combination of findings from history, physical examination and laboratory tests, reporting a positive LR of 25.7 and a negative LR of 0.24. The TG criteria for the diagnosis of cholecystitis include clinical signs, laboratory tests and imaging features [bib_ref] Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with..., Yokoe [/bib_ref]. After the publication of the paper by Yokoe et al. in 2012 [bib_ref] New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo..., Yokoe [/bib_ref] reporting 91.2% sensitivity and 96.9% specificity, three studies reporting the validation of the TG diagnostic criteria were found. Although published in 2017, one study focused on the TG07 rather than the more recent TG13 [bib_ref] Useful of Tokyo guidelines in the diagnosis of acute cholecystitis. Anatomopathologie correlationship, Janikow [/bib_ref]. A cross-sectional study [bib_ref] The Yield of Fever, Inflammatory Markers and Ultrasound in the Diagnosis of..., Naidu [/bib_ref] evaluated the validity of fever, inflammatory markers and US findings as a validation of the TG13 criteria. At multivariate analysis, only neutrophil count was statistically associated with the diagnosis of acute cholecystitis (p <0.0001), with a 70% sensitivity and 65.8% specificity. Overall, accuracy of the TG13 criteria was low at 60.3%. The TG13 correctly predicted 83.1% of all confirmed ACC, but over-diagnosed ACC in 62.5% of normal gallbladders. More than half of eligible patients did not undergo US and were excluded from the study; this represents a major source of potential selection bias. A cross-sectional study on the possible limitations of the TG 13 has reported a 53.4% sensitivity in diagnosing acute cholecystitis [bib_ref] Evaluating the Relevance of the 2013 Tokyo Guidelines for the Diagnosis and..., Joseph [/bib_ref]. However, some uncertainty regarding the sample population and the lack of detail in sensitivity calculation indicates that the data should be interpreted with caution. The revision of the TG criteria performed in 2018 did not include a clinical evaluation of the diagnostic criteria [bib_ref] Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with..., Yokoe [/bib_ref]. Considering the heterogeneity of these findings, the reliability of the TG13 criteria for the diagnosis of ACC appears to be limited. Which initial imaging technique should be used in case of a suspected diagnosis of ACC? 1. [bib_ref] Natural history of asymptomatic and symptomatic gallstones, Friedman [/bib_ref] We recommend the use of abdominal ultrasound (US) as the preferred initial imaging technique, in view of its cost-effectiveness, wide availability, reduced invasiveness and good accuracy for gallstones disease. #QoE: high; SoR: strong# Comment: abdominal US is a reliable investigation method; however, it may be of limited utility to rule in or rule out the diagnosis of ACC according to the adopted US criteria. Neither meta-analysis nor studies with adequate quality of evidence have been published on this topic since the publication of the 2016 WSES guidelines. In 2012, Kiewet et al. published a systematic review and meta-analysis [bib_ref] A systematic review and meta-analysis of diagnostic performance of imaging in acute..., Kiewiet [/bib_ref] of diagnostic performance of different imaging techniques in ACC; abdominal ultrasound was not as accurate as it is for the diagnosis of gallstones. The meta-analysis was based on the results of 26 studies including a total of 2847 patients. The sensitivity in individual studies ranged from 50 to 100% and specificity from 33 to 100%. Summary sensitivity and specificity were 81% (95% CI 75 to 87%) and 83% (95% CI 74 to 89%), respectively. However, strong heterogeneity in the diagnostic performance of abdominal US was reported: the inconsistency index was 80% for sensitivity and 89% for specificity. Notwithstanding these limitations, the widespread availability, lack of invasiveness, lack of exposure to ionizing radiation and the reduced costs make abdominal US the preferred initial imaging technique in suspected ACC. Published data from eight cross-sectional studies [bib_ref] The Diagnosis of Acute Cholecystitis: Sensitivity of Sonography, Cholescintigraphy and Computed Tomography, Changphaisarnkul [/bib_ref] [bib_ref] Computed Tomography Is More Sensitive than Ultrasound for the Diagnosis of Acute..., Fagenholz [/bib_ref] [bib_ref] Is hepato-imino diacetic acid scan a better imaging modality than abdominal ultrasound..., Kaoutzanis [/bib_ref] [bib_ref] The Absence of Gallstones on Point-of-Care Ultrasound Rules Out Acute Cholecystitis, Villar [/bib_ref] [bib_ref] Clinical implications of hepatobiliary scintigraphy and ultrasound in the diagnosis of acute..., Rodriguez [/bib_ref] [bib_ref] Does ultrasongraphy predict intraoperative findings at cholecystectomy? An institutional review, Stogryn [/bib_ref] [bib_ref] Added value of point shear-wave elastography in the diagnosis of acute cholecystitis, Kim [/bib_ref] [bib_ref] Efficacy of Superb Microvascular Imaging for Diagnosing Acute Cholecystitis: Comparison with Conventional..., Ra [/bib_ref] confirmed the heterogeneity of diagnostic values, diagnostic index and standard reference for the final diagnosis of ACC. Traditional US presented wide ranges of sensitivity (from 26 to 100% [bib_ref] The Diagnosis of Acute Cholecystitis: Sensitivity of Sonography, Cholescintigraphy and Computed Tomography, Changphaisarnkul [/bib_ref] [bib_ref] Computed Tomography Is More Sensitive than Ultrasound for the Diagnosis of Acute..., Fagenholz [/bib_ref] [bib_ref] Is hepato-imino diacetic acid scan a better imaging modality than abdominal ultrasound..., Kaoutzanis [/bib_ref] [bib_ref] The Absence of Gallstones on Point-of-Care Ultrasound Rules Out Acute Cholecystitis, Villar [/bib_ref] [bib_ref] Clinical implications of hepatobiliary scintigraphy and ultrasound in the diagnosis of acute..., Rodriguez [/bib_ref] [bib_ref] Does ultrasongraphy predict intraoperative findings at cholecystectomy? An institutional review, Stogryn [/bib_ref] [bib_ref] Added value of point shear-wave elastography in the diagnosis of acute cholecystitis, Kim [/bib_ref] , specificity (from 62 to 88.1% [bib_ref] Is hepato-imino diacetic acid scan a better imaging modality than abdominal ultrasound..., Kaoutzanis [/bib_ref] [bib_ref] The Absence of Gallstones on Point-of-Care Ultrasound Rules Out Acute Cholecystitis, Villar [/bib_ref] [bib_ref] Clinical implications of hepatobiliary scintigraphy and ultrasound in the diagnosis of acute..., Rodriguez [/bib_ref] [bib_ref] Does ultrasongraphy predict intraoperative findings at cholecystectomy? An institutional review, Stogryn [/bib_ref] [bib_ref] Added value of point shear-wave elastography in the diagnosis of acute cholecystitis, Kim [/bib_ref] [bib_ref] Efficacy of Superb Microvascular Imaging for Diagnosing Acute Cholecystitis: Comparison with Conventional..., Ra [/bib_ref] , positive predictive value (PPV) and negative predictive value (NPV 35% to 93.7% and 52% to 97.1%, respectively), as well as positive LR (1.29 to 4.7) and negative LR (0.16 to 0.93) [bib_ref] The Absence of Gallstones on Point-of-Care Ultrasound Rules Out Acute Cholecystitis, Villar [/bib_ref] [bib_ref] Clinical implications of hepatobiliary scintigraphy and ultrasound in the diagnosis of acute..., Rodriguez [/bib_ref]. Global accuracy has been reported in two studies and varied from 70.1 to 79% [bib_ref] Added value of point shear-wave elastography in the diagnosis of acute cholecystitis, Kim [/bib_ref] [bib_ref] Efficacy of Superb Microvascular Imaging for Diagnosing Acute Cholecystitis: Comparison with Conventional..., Ra [/bib_ref]. In one study, the absence of gallstones was used to rule out the diagnosis of acute cholecystitis in patients presenting to the emergency department for suspected cholecystitis [bib_ref] The Absence of Gallstones on Point-of-Care Ultrasound Rules Out Acute Cholecystitis, Villar [/bib_ref]. Overall, the sensitivity of the simplified definition of a positive ultrasonography test was100%, as compared to the standard definition, i.e. the presence of gallstones and at least one of the ultrasonography signs of acute cholecystitis, which showed a sensitivity of 87% (95% CI 66-97%) and specificity of 82 (95% CI 74-88%); prevalence was less than 15%, NPV was 97% (95% CI 93--99%) and PPV was low at 44% (95% CI 29-59%). Considering the limits of abdominal US, one study has evaluated new ultrasonography criteria for the diagnosis of acute cholecystitis. Kim et al. [bib_ref] Added value of point shear-wave elastography in the diagnosis of acute cholecystitis, Kim [/bib_ref] evaluated the added value of point shear-wave elastography (pSWE) in the diagnostic performance of conventional US for the diagnosis of ACC. Based on the assumption that transient increase in hepatic blood flow observed in case of acute cholecystitis increases liver stiffness, the authors proposed to use a measure of liver stiffness by pSWE and to evaluate its diagnostic yield for ACC in a two-observer analysis. Compared to conventional US, pSWE significantly increased diagnostic accuracy (area under the curve-AUC from 79 to 96.3% and from 77 to 96.2%, p < 0.001) and specificity (from 62 to 95%, p < 0.001). The difference in sensitivity was not significant, being 88 versus 92% (p = 0.45) in the US only group and 86-92% (p = 0.26) in the US plus pSWE group. Although the results appear promising, the technique requires expertise; moreover, 18.5% of patients were excluded due to a potential limitation of the technique, therefore reducing the external validity of the study. Another study by Ra et al. [bib_ref] Efficacy of Superb Microvascular Imaging for Diagnosing Acute Cholecystitis: Comparison with Conventional..., Ra [/bib_ref] has reported the use of superb microvascular imaging (SMI) in the diagnosis of acute cholecystitis. The SMI technique is similar to Color-Doppler US and is used to detect the micro vasculature and slow flow of the liver, using a special filtering technique. The authors hypothesised that hyperaemic changes within the gallbladder bed of the liver, detected by SMI, and may be used for the diagnosis of acute cholecystitis. This inter-observer study on 54 patients showed a significant increase of the AUC from 72.9 to 85% (p = 0.02) with the use of SMI. The need for specific expertise, the small number of patients and the poor reference standard limit the significance of this study. What is the role of other imaging techniques (e.g. Hepatobiliary iminodiacetic acid -HIDA scan, Abdominal Computed Tomography -CT scan and Magnetic Resonance Imaging -MRI) in the diagnosis of ACC? 1.We suggest the use of further imaging for the diagnosis of ACC in selected patients, depending on local expertise and availability. Hepatobiliary iminodiacetic acid (HIDA) scan has the highest sensitivity and specificity for the diagnosis of ACC as compared to other imaging modalities. Diagnostic accuracy of computed tomography (CT) is poor. Magnetic resonance imaging (MRI) is as accurate as abdominal US. #QoE: moderate; SoR: strong# Comment: in clinical practice, HIDA scan utilisation is limited due to the required resources and time. No study with a high level of evidence was published on this topic since the publication of the 2016 WSES guidelines. A cross-sectional study [bib_ref] Cystic Duct Enhancement: A Useful CT Finding in the Diagnosis of Acute..., Kim [/bib_ref] evaluated the incremental benefits of cystic duct enhancement detected by CT for the diagnosis of cholecystitis in patients without visibly impacted gallstones. When considering cystic duct enhancement, the accuracy and sensitivity of the diagnosis increased significantly, while no significant difference was reported for specificity. Interestingly, diagnostic accuracy increased for the less experienced radiologist, from 75.4 to 87.3% (p = 0.015). However, this case control study has some methodological flaws limiting its quality. A study considering only patients with a definitive diagnosis of acute cholecystitis compared the diagnostic sensitivities of US, CT and HIDA scan [bib_ref] The Diagnosis of Acute Cholecystitis: Sensitivity of Sonography, Cholescintigraphy and Computed Tomography, Changphaisarnkul [/bib_ref]. The results confirmed the higher sensitivity of HIDA over US and CT with respective values of 84.2%, 67.3% and 59.8% (p = 0.017). No difference was found when comparing CT and US (p = 0.09). A study comparing sensitivity of CT and US [bib_ref] Computed Tomography Is More Sensitive than Ultrasound for the Diagnosis of Acute..., Fagenholz [/bib_ref] showed different results, reporting higher sensitivity of CT, compared with US(92% vs. 79%, p = 0.015). In this study, a retrospective cohort of patients was added based on prospectively collected data from patients with a diagnosis of ACC confirmed by pathology or intraoperative findings. Indication for CT and timing between index and reference standards were not reported. One study on a time-saving HIDA scan technique reported a high inter-rate agreement (Cohen's kappa coefficient = 0.92) between the novel time-saving technique and the conventional examination [bib_ref] A Novel Timesaving Method for Hepatobiliary Imaging for Suspected Acute Cholecystitis, Carter [/bib_ref]. Two other studies reported diagnostic values of HIDA scan as 86.7-89.3% for sensitivity and 66.8-79% for specificity [bib_ref] Computed Tomography Is More Sensitive than Ultrasound for the Diagnosis of Acute..., Fagenholz [/bib_ref] [bib_ref] Is hepato-imino diacetic acid scan a better imaging modality than abdominal ultrasound..., Kaoutzanis [/bib_ref]. Section 2. Associated common bile duct stones: which tools to use for suspicion and diagnosis at presentation? Choledocholithiasis, i.e. the presence of common bile duct stones (CBDS), is reported to occur in 10% to 20% of gallstone cases, with lower incidence, ranging from 5 to 15 %, in case of ACC [bib_ref] Role of liver function tests in predicting common bile duct stones in..., Peng [/bib_ref] [bib_ref] Validation of the Lacaine-Huguier predictive score for choledocholithiasis: prospective study of 380..., Khalfallah [/bib_ref] [bib_ref] Prevalence of common bile duct stones according to the increasing number of..., Csendes [/bib_ref] [bib_ref] Epidemiology and natural history of common bile duct stones and prediction of..., Ko [/bib_ref]. Investigations for CBDS require time and may delay surgical treatment. Due to the relatively low incidence of CBDS during ACC, the main issue is to select patients with a high likelihood of CBDS, who would benefit from further diagnostic tests and removal of CBDS. An uncommon condition that mimics CBDS is Mirizzi syndrome, which occurs in less than 1% of patients with gallstones. Preoperative investigations may help in the diagnosis, although the vast majority of cases are identified at surgery [bib_ref] An alternative surgical approach to a difficult case of Mirizzi syndrome: a..., Safioleas [/bib_ref] [bib_ref] Diagnosis and treatment of Mirizzi syndrome: 23-year Mayo Clinic experience, Erben [/bib_ref]. The only new study on this topic was a cross-sectional study on the role of liver function tests (LFTs) [bib_ref] Use of Liver Function Tests as First-line Diagnostic Tools for Predicting Common..., Ahn [/bib_ref]. The authors evaluated the role of LFTs and the role of early follow-up in the diagnosis of CBDS in ACC. The most reliable LFT was gamma-glutamyl transpeptidase (GGT), with a sensitivity of 80.6% and a specificity of 75.3%, using a cut-off level of 224 IU/L. PPV was 50%, while NPV was 91.4%. The results also showed a significant decrease of LFTs within the non-CBD groups at 4-day follow-up, which was not evident in the ACC + CBDS group-with the exception of alanine aminotransferase (ALT). Moreover, in the CBDS group, all LFTs values improved significantly after the removal of the CBDS at a mean follow-up time of 4.3 days. One flaw of the study is that index diagnosis depends to some extent on the reference standard. Given the retrospective design of the study, it should be considered that the diagnosis of CBDS is assessed with endoscopic retrograde cholangio-pancreatography (ERCP), which is mainly prompted by the presence of elevated LFTs; this may represent a source of bias. No systematic intraoperative cholangiography (IOC) was performed. Are elevated LFTs or bilirubin sufficient for the diagnosis of CBDS in patients with ACC? 2.1 We recommend against the use of elevated LFTs or bilirubin as the only method to identify CBDS in patients with ACC, in which case we recommend performing further diagnostic tests. #QoE: moderate; SoR: strong# Historically, LTFs have played a major role in determining the presence of CBDS. However, the majority of published studies did not consider patients with ACC and included asymptomatic gallstones. Normal LFTs have a NPV of 97%, whereas the PPV of any abnormal LFTs is only 15% [bib_ref] Biochemical predictors for absence of common bile duct stones in patients undergoing..., Yang [/bib_ref]. The elevation of LFTs is a poor tool for the prediction of CBDS, even in patients without ACC; the literature ranging from 25 to 50% [bib_ref] Role of liver function tests in predicting common bile duct stones in..., Peng [/bib_ref] [bib_ref] Useful Predictors of Bile Duct Stones in Patients Undergoing Laparoscopic Cholecystectomy, Barkun [/bib_ref] [bib_ref] Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis, Onken [/bib_ref]. In patients with ACC, LFTs may be altered due to the acute inflammatory process of the gallbladder and the biliary tree, rather than direct biliary obstruction; a proportion ranging between 15 and 50% of patients with ACC show elevation in LFTs without CBDS. Song et al. demonstrated that 424 out of 1178 patients with ACC had increased LFTs, namely ALT and aspartate transaminase (AST) greater than twice reference levels. Of these, only 246 (58%) had CBDS [bib_ref] Clinical characteristics of acute cholecystitis with elevated liver enzymes not associated with..., Song [/bib_ref]. showed that 51% and 41% of patients with ACC without CBDS had elevated ALT and AST, respectively. However, increased bilirubin levels with leucocytosis may predict gangrenous cholecystitis. Padda et al. found that approximately 30% of patients with ACC without CBDS had abnormal alkaline phosphatase (ALP) and/or bilirubin, and 50% had abnormal ALT. Among patients with ACC and CBDS, 77% had raised ALP, 60% had abnormal bilirubin and 90% had elevated ALT; multivariate analysis showed that increased common bile duct size and elevated ALT and ALP were predictors of CBDS [bib_ref] Liver test patterns in patients with acute calculous cholecystitis and/or choledocholithiasis, Padda [/bib_ref]. The diagnostic accuracy increases for cholestasis tests, such as serum bilirubin, with the duration and the severity of obstruction. Specificity of serum bilirubin levels for CBDS was 60% with a cut-off level of 1.7 mg/ day and 75% with a cut-off level of 4 mg/dl [bib_ref] Useful Predictors of Bile Duct Stones in Patients Undergoing Laparoscopic Cholecystectomy, Barkun [/bib_ref] ; however, mean level of bilirubin in patients with CBDS is generally lower (1.5 to 1.9 mg/dl) [bib_ref] Role of liver function tests in predicting common bile duct stones in..., Peng [/bib_ref] [bib_ref] Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis, Onken [/bib_ref]. A recent meta-analysis reported the diagnostic accuracy of serum bilirubin and serum ALP at two cutoff values for each test. Serum bilirubin at a cut-off of 22.23 μmol/L had a sensitivity of 0.84 (95% CI 0.65 to 0.94) and a specificity of 0.91 (95% CI 0.86 to 0.94). Bilirubin at a cut-off of greater than twice the normal limit, had a sensitivity of 0.42 (95% CI 0.22 to 0.63) and a specificity of 0.97 (95% CI 0.95 to 0.99). For ALP at a cut-off of greater than 125 IU/L, sensitivity was 0.92 (95% CI 0.74 to 0.99) and specificity was 0.79 (95% CI 0.74 to 0.84). For ALP at a cut-off of greater than twice the normal limit, sensitivity was 0.38 (95% CI 0.19 to 0.59) and specificity was 0.97 (95% CI 0.95 to 0.99) [bib_ref] Ultrasound versus liver function tests for diagnosis of common bile duct stones, Gurusamy [/bib_ref]. Which imaging features are predictive of CBDS in patients with ACC? 2.2 We suggest considering the visualization of a stone in the common bile duct at transabdominal US as a predictor of CBDS in patients with ACC. #QoE: very low; SoR: weak# 2.3 An increased diameter of common bile duct, an indirect sign of stone presence, is not sufficient to identify ACC patients with CBDS and we therefore recommend performing further diagnostic tests. #QoE: high; SoR: strong# Abdominal US is the preferred imaging technique for the diagnosis of ACC; the common bile duct can be visualized and investigated at the same time. A metaanalysis by Gurusamy et al. investigated the diagnostic potential of US [bib_ref] Ultrasound versus liver function tests for diagnosis of common bile duct stones, Gurusamy [/bib_ref] : sensitivity ranged from 0.32 to 1.00 with a summary sensitivity of 0.73 (95% CI 0.44 to 0.90), while specificity ranged from 0.77 to 0.97 with a summary specificity of 0.91 (95% CI 0.84 to 0.95). In a retrospective analysis, Boys et al. [bib_ref] Can ultrasound common bile duct diameter predict common bile duct stones in..., Boys [/bib_ref] found that the mean common bile duct diameter seen at abdominal US in ACC patients without and with CBDS was 5.8 and 7.1 mm, respectively (p = 0.004). A CBD diameter larger than 10 mm was associated with a 39 % incidence of CBDS, while diameter smaller than 9.9 mm was associated with CBDS in 14%. The authors concluded that common bile duct diameter is not sufficient on its own to identify patients having significant risk for CBDS. Which tests should be performed to assess the risk of CBDS in patients with ACC? 2.4 In order to assess the risk for CBDS, we suggest performing liver function tests (LFTs), including ALT, AST, bilirubin, ALP, GGT and abdominal US in all patients with ACC. #QoE: low; SoR: weak# Several scores for the prediction of CBDS have been proposed and validated; however, none of the proposed scores is specific for ACC. The implementation of these predictive scores in clinical practice remains poor [bib_ref] Useful Predictors of Bile Duct Stones in Patients Undergoing Laparoscopic Cholecystectomy, Barkun [/bib_ref] [bib_ref] Predicting the presence of choledocholithiasis in patients with symptomatic cholelithiasis, Onken [/bib_ref] [bib_ref] Clinical characteristics of acute cholecystitis with elevated liver enzymes not associated with..., Song [/bib_ref] ; all scores consider different combinations of the same clinical variables. Barkun et al. [bib_ref] Useful Predictors of Bile Duct Stones in Patients Undergoing Laparoscopic Cholecystectomy, Barkun [/bib_ref] combined age > 55 years, elevated serum bilirubin, dilated common bile duct and evidence of CBDS; Menezes et al. [bib_ref] Prospective analysis of a scoring system to predict choledocholithiasis, Menezes [/bib_ref] combined age > 55 years, male sex, ascending cholangitis, dilated common bile duct, CBDS and abnormal LFTs; Soltan et al. [bib_ref] A Simple Scoring System for Predicting Stones in Patients With Cholelithiasis, Soltan [/bib_ref] included history of symptomatic disease, abnormal liver function tests, dilated common bile duct and presence of CBDS; Sun et al. [bib_ref] Prospective study of scoring system in selective intraoperative cholangiography during laparoscopic cholecystectomy, Sun [/bib_ref] included male sex, abnormal liver function test and dilated common bile duct; Sarli et al. [bib_ref] Asymptomatic bile duct stones: selection criteria for intravenous cholangiography and/or endoscopic retrograde..., Sarli [/bib_ref] combined positive AUS and abnormal liver function tests. The American Society of Gastrointestinal Endoscopy and the Society of American of Gastrointestinal Endoscopic Surgeons combined the published validated clinical scores and proposed a risk stratification of CBDS in three different classes, defined as follows: low risk (< 10%), moderate risk (10 to 50%) and high risk (> 50%) of CBDS [bib_ref] The role of endoscopy in the evaluation of suspected choledocholithiasis, Maple [/bib_ref] (see [fig_ref] Table 2: Risk factors and classification of risk for CBDS [/fig_ref]. This proposed classification has clear clinical implications: patients with a low risk of CBDS should be operated on without further investigation; patients with moderate risk should be evaluated with a second-level examination, either preoperatively with endoscopic US (EUS) or magnetic resonance cholangiopancreatography (MRCP) or intraoperatively with laparoscopic US (LUS) or IOC, in order to select patients who need stone removal; finally, according to local expertise, laparoscopic transcystic CBD exploration is a valuable option. Patients with high risk of CBDS should undergo preoperative diagnostic and therapeutic ERCP. See [fig_ref] Figure 1 2020: WSES Flowchart for the management of patients with acute calcolus cholecystitis [/fig_ref] for the flowchart of management of ACC. What is the best tool to stratify the risk for CBDS in patients with ACC? 2.5 We suggest stratifying the risk of CBDS according to the proposed classification modified from the American Society of Gastrointestinal Endoscopy and the Society of American Gastrointestinal Endoscopic Surgeon Guidelines. #QoE: very low; SoR: weak# ASGE guidelines remains a valuable tool for the diagnosis and the management of CBDS in patients with ACC [bib_ref] The role of endoscopy in the evaluation of suspected choledocholithiasis, Maple [/bib_ref]. According to their classification, highrisk patients have a probability of having CBDS exceeding 50%, which in turn means that up to 49% of patients undergoing ERCP will not have evidence of CBDS and, given the potential complications of ERCP, this may not be considered acceptable. For this reason, we would recommend more cautious approach: only patients with evidence of CBDS at abdominal US should be considered at high risk of CBDS and should undergo diagnostic and therapeutic ERCP directly; patients with total serum bilirubin > 4 mg/dl or enlarged common bile duct diameter at US with concomitant bilirubin level 1.8 to 4 mg/dl should be considered as moderate risk and should undergo second level investigation such as endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP), laparoscopic ultrasound (LUS) or IOC, in order to avoid the complications related to ERCP. See [fig_ref] Table 2: Risk factors and classification of risk for CBDS [/fig_ref] for the modified risk stratification. Which actions are warranted in patients with ACC and at moderate risk for CBDS? 2. [bib_ref] Epidemiology of gallstones, Stinton [/bib_ref] We recommend that patients with moderate risk for CBDS undergo one of the following: preoperative magnetic resonance cholangiopancreatography (MRCP), preoperative endoscopic ultrasound (EUS), intraoperative cholangiography (IOC), or laparoscopic ultrasound (LUS), depending on local expertise and availability. #QoE: high; SoR: strong# Two preoperative imaging techniques are available for the detection of CBDS, namely MRCP and EUS. These diagnostic tests, according to the ASGE guidelines [bib_ref] The role of endoscopy in the evaluation of suspected choledocholithiasis, Maple [/bib_ref] should be reserved for patients with moderate risk for CBDS and have been shown to delay definitive ACC treatment [bib_ref] Can ultrasound common bile duct diameter predict common bile duct stones in..., Boys [/bib_ref]. On the other hand, these tests could exclude the presence of CBDS with high diagnostic accuracy, thereby avoiding further inappropriate invasive procedures, such as ERCP or IOC and therefore their complications. In fact, the implementation of these techniques resulted in a reduction of ERCP by 30 to 75% in non-selected patients [bib_ref] A Systematic Review and Economic Evaluation of Magnetic Resonance Cholangiopancreatography Compared With..., Kaltenthaler [/bib_ref] [bib_ref] Magnetic resonance cholangiopancreatography : utilization and usefulness in suspected choledocholithiasis, Toppi [/bib_ref]. A Cochrane meta-analysis compared these two different techniques [bib_ref] Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones, Giljaca [/bib_ref] : both had good diagnostic accuracy, showing summary sensitivities of 95% for EUS and 93% for MRCP and a summary specificity of 97% and 96%, respectively. As noted by some authors, considerations other than diagnostic efficacy, such as local availability, costs, expertise and delay of surgery, might play an important role in the decision making during the diagnostic work-up [bib_ref] Suspected choledocholithiasis : endoscopic ultrasound or magnetic resonance cholangio-pancreatography ? A systematic..., Ledro-Cano D [/bib_ref]. Which actions are warranted in patients with ACC and at high risk for CBDS? 2.7 We recommend that patients with high-risk for CBDS undergo preoperative ERCP, IOC or LUS, depending on the local expertise and the availability of the technique. #QoE: high; SoR: strong# ERCP has both a diagnostic and a therapeutic role in the management of CBDS, but it is an invasive procedure with potential severe complications. The literature underscores the risks of diagnostic ERCP. Morbidity associated with diagnostic ERCP includes pancreatitis, cholangitis, bleeding, duodenal perforation and allergic reaction to contrast medium. Complications occur in 1 to 2% and increase to 10% when associated with sphincterotomy [bib_ref] Complications of endoscopic biliary sphincterotomy, Freeman [/bib_ref] [bib_ref] Major early complications from diagnostic and therapeutic ERCP : a prospective multicenter..., Loperfido [/bib_ref] [bib_ref] Complications of diagnostic and therapeutic ERCP: a prospective, multicenter study, Masci [/bib_ref] [bib_ref] Risk factors for complications after ERCP : a multivariate analysis of 11..., Cotton [/bib_ref]. On the other hand, IOC significantly increases the length of surgery [bib_ref] Systematic review of intraoperative cholangiography in cholecystectomy, Ford [/bib_ref] and requires dedicated staff in the operating room, while this may not be available, especially in the acute setting with unplanned surgery. Positive findings on IOC often lead to intraoperative management of CBDS with additional operative time. A recently published meta-analysis compared ERCP and IOC [bib_ref] Systematic review of intraoperative cholangiography in cholecystectomy, Ford [/bib_ref]. The summary sensitivity for ERCP was 0.83 (95% CI 0.72 to 0.90) and specificity was 0.99 (95% CI 0.94 to 1.00). For IOC, the summary sensitivity was 0.99 (95% CI 0.83 to 1.00) and specificity was 0.99 (95% CI 0.95 to 1.00). Sensitivities showed a weak statistical difference (p = 0.05); however, due to the low quality and the methodology of the included studies, the two diagnostic techniques should be considered equivalent. LUS is a useful method for intraoperative detection of CBDS [bib_ref] Routine intraoperative laparoscopic ultrasonography with selective cholangiography reduces bile duct complications during..., Biffl [/bib_ref]. A meta-analysis has shown that IOC and LUS have the same pooled sensitivity and similar pooled specificity for the detection of CBDS. As in the case of IOC, intraoperative evidence of CBDS with LUS leads to intraoperative management of common bile duct with increased operative time. Which is the appropriate treatment of CBDS in patients with ACC? 2. [bib_ref] TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos), Yokoe [/bib_ref] We recommend removing CBDS, either preoperatively, intraoperatively, or postoperatively, according to the local expertise and the availability of several techniques. #QoE; high; SoR: strong# CBDS could be removed with several techniques and a variation of timing (see [fig_ref] Figure 1 2020: WSES Flowchart for the management of patients with acute calcolus cholecystitis [/fig_ref] : preoperative ERCP with sphincterotomy, intraoperative ERCP with sphincterotomy, laparoscopic or open common bile duct exploration, post-operative ERCP with sphincterotomy. A systematic review assessed the differences between these techniques [bib_ref] Surgical versus endoscopic treatment of bile duct stones, Dasari [/bib_ref]. No differences in terms of morbidity, mortality and success rate were reported. Therefore, these techniques can be considered suitable options, depending on local expertise and availability. Another meta-analysis compared preoperative and intraoperative (rendez-vous technique) ERCP with sphincterotomy [bib_ref] Preoperative versus intraoperative endoscopic sphincterotomy in patients with gallbladder and suspected common..., Wang [/bib_ref]. These two techniques were equal in terms of safety and efficacy; the intraoperative technique reduced the Laparoscopic cholecystectomy is generally considered the standard technique for the removal of gallstones. Local inflammation, especially in gangrenous and emphysematous ACC, has been considered to increase the risk of bile duct injuries, blood loss, operative time, general morbidity and mortality rates in comparison with open surgery [bib_ref] Laparoscopic cholecystectomy for severe acute cholecystitis. A meta-analysis of results, Borzellino [/bib_ref]. As technical difficulties usually decrease with experience and improvements in surgical technique and instrumentation, the hesitation to safely perform laparoscopic cholecystectomy in ACC has decreased over the years. Despite several studies, ranging from case series to randomized prospective clinical trials, confirming the feasibility and safety of laparoscopic cholecystectomy in the treatment of patients with ACC [bib_ref] Randomised trial of laparoscopic versus open cholecystectomy for acute and gangrenous cholecystitis, Kiviluoto [/bib_ref] [bib_ref] Randomized clinical trial of open versus laparoscopic cholecystectomy for acute cholecystitis, Johansson [/bib_ref] [bib_ref] Systemic immune response after open versus laparoscopic cholecystectomy in acute cholecystitis: A..., Boo [/bib_ref] [bib_ref] The ACTIVE (Acute Cholecystitis Trial Invasive Versus Endoscopic) study: Multicenter randomized, double-blind,..., Catena [/bib_ref] [bib_ref] Laparoscopic versus open cholecystectomy: A prospective comparative study in the elderly with..., Pessaux [/bib_ref] [bib_ref] Comparaison des resultats et facteurs predisposant a la conversion, Araujo-Teixeira [/bib_ref] [bib_ref] Laparoscopic cholecystectomy versus open cholecystectomy in elderly patients with acute cholecystitis: Retrospective..., Chau [/bib_ref] [bib_ref] A comparison of laparoscopic and open treatment of acute cholecystitis, Unger [/bib_ref] [bib_ref] Laparoscopic versus open cholecystectomy in acute cholecystitis, Eldar [/bib_ref] [bib_ref] Treatment of acute cholecystitis: A comparison of open vs laparoscopic cholecystectomy, Glavic [/bib_ref] , a recent survey on intra-abdominal infection, the CIAOW study [bib_ref] Complicated intra-abdominal infections worldwide : the definitive data of the CIAOW Study, Sartelli [/bib_ref] , showed unexpected results. It was a worldwide survey of 68 medical institutions during a 6-month study period demonstrating that 48.7% of patients with ACC still underwent open surgery. Nevertheless, evidence has clearly shown the safety of laparoscopic cholecystectomy in ACC. Laparoscopic cholecystectomy in ACC was associated with a lower complication rate and with a shorter hospital stay. There were no differences for the sameadmission cholecystectomy in terms of morbidity, operative time and intraoperative blood loss and bile leakage; however, the laparoscopic approach showed a decrease in mortality rate, postoperative hospital stay, wound infection and pneumonia. Moreover, the operative time progressively became shorter in laparoscopy when data were analysed its instances between 1998 and 2007 [bib_ref] Open versus laparoscopic cholecystectomy in acute cholecystitis. Systematic review and meta-analysis, Coccolini [/bib_ref]. A reaffirmation of the safety of laparoscopic cholecystectomy for ACC was shown in another systematic review comparing early laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC), including seven discordant meta-analyses and systematic reviews published from 2004 to 2015. The conclusions were that no differences in mortality, bile duct injury, bile leakage, overall complications and conversion to open surgery were seen. However, ELC had a significant reduction in wound infection, hospitalisation, duration of surgery and quality of life [bib_ref] Laparoscopic cholecystectomy for acute cholecystitis: early or delayed? Evidence from a systematic..., Song [/bib_ref]. TG18 widened the indications for laparoscopic cholecystectomy when compared with TG13, as they supported same-admission laparoscopic cholecystectomy for patients with all three severity grades of ACC [bib_ref] TG13 surgical management of acute cholecystitis, Yamashita [/bib_ref] [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref]. This is in line with the recommendations of the 2016 WSES Guidelines [bib_ref] WSES guidelines on acute calculous cholecystitis, Ansaloni [/bib_ref]. In summary, the review of the relevant recent literature confirmed strong support for the recommendation that laparoscopic cholecystectomy should be attempted in cases of ACC. Critical patient conditions, such as septic shock or anaesthesiology contraindication, are reasons to avoid laparoscopic cholecystectomy. Is laparoscopic cholecystectomy safe and feasible for patients with ACC who have liver cirrhosis, are older than 80 years or are pregnant? 3. [bib_ref] Natural history of asymptomatic and symptomatic gallstones, Friedman [/bib_ref] We suggest performing laparoscopic cholecystectomy for ACC patients with Child's A and B cirrhosis, patients with advanced age (including more than 80 years old) and patients who are pregnant. #QoE: low; SoR: weak# ## Patients with liver cirrhosis In cases of liver cirrhosis, surgical dissection could be difficult and there is a higher risk of bleeding and other serious complications. Unfortunately, the available evidence on both open and laparoscopic cholecystectomy for ACC in patients with liver cirrhosis is limited. Therefore, we mainly accept evidence that comes from elective procedures performed for biliary colic or chronic cholecystitis. According to a meta-analysis published by de Goede et al., elective laparoscopic cholecystectomy in patients with child A or B cirrhosis was associated with significantly fewer postoperative complications, a shorter duration of hospitalisation and a shorter time to resume a normal diet, when compared to the open technique [bib_ref] Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and..., De Goede [/bib_ref]. Lucidi et al. recommended laparoscopic cholecystectomy as the first-choice approach in cirrhotic patients. However, recommendation for laparoscopic cholecystectomy in patients with child C cirrhosis is unclear [bib_ref] Cholecystectomy in cirrhotic patients : Pitfalls and reasonable recommendations, Lucidi [/bib_ref]. Nevertheless, other studies showed that laparoscopic cholecystectomy in these cirrhotic patients was associated with a significantly prolonged duration of surgery and an increase in operative blood loss, conversion rate, length of hospital stay and overall morbidity and mortality when compared with non-cirrhotic patients [bib_ref] A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis, Puggioni [/bib_ref]. In cirrhotic patients, the morbidity associated with laparoscopic cholecystectomy is directly related to the Child-Pugh score [bib_ref] Laparoscopic cholecystectomy in cirrhotic patients with symptomatic cholelithiasis: A case-control study, Mancero [/bib_ref] [bib_ref] Utility of preoperative scores for predicting morbidity after cholecystectomy in patients with..., Perkins [/bib_ref]. In patients with advanced cirrhosis and severe portal hypertension, specific technical difficulties may be encountered due to the presence of a portal cavernoma, the difficulty in dissecting the Calot's triangle and the gallbladder hilum, the presence of adhesions and neovascularization or difficulty in controlling bleeding from the liver bed. Subtotal cholecystectomy is a valid option to avoid some of these difficulties [bib_ref] Laparoscopic Cholecystectomy in Cirrhotic Patients: The Role of Subtotal Cholecystectomy and Its..., Palanivelu [/bib_ref] [bib_ref] Subtotal cholecystectomy for "Difficult gallbladders": Systematic review and metaanalysis, Elshaer [/bib_ref]. In conclusion, the laparoscopic approach should be the first choice for cholecystectomy in child A and B patients. The approach to patients with child C or uncompensated cirrhosis remains a matter of debate. As a first recommendation, cholecystectomy should be avoided in these patients, unless clearly indicated, such as in ACC not responding to conservative management [bib_ref] Cholecystectomy in cirrhotic patients : Pitfalls and reasonable recommendations, Lucidi [/bib_ref]. ## Patients over 80 years old The true clinical relevance of age is difficult to assess and the impact of old age on the clinical outcomes in cases of surgical abdominal pathology is largely unknown. In 2017, the WSES and the Italian Society for Geriatric Surgery developed a CC and a consequent set of guidelines on this topic. Only retrospective studies have focused their interest on elderly patients with ACC. In general, no RCTs are available, population sizes of the studies were small and distributed over a long period of time. It should be noted that the prevalence of elderly people with ACC could increase in the future, due to the improvement in life expectancy and the consideration that the risk of biliary stones increases with age. Some of the recommendations were derived from evidence describing the general population, which includes the elderly. The level of evidence for surgery, timing and risk assessment ranged from 2 to 3, and the grade of recommendation ranged from B to C according the 2011 Oxford classification "(https://www.cebm.net/wp-content/uploads/2014/06/ CEBM-Levels-of-Evidence-2.1.pdf.)". With these limitations, the conclusion supported laparoscopic cholecystectomy for ACC in elderly patients, after considering the intrinsic surgical risk, life expectancy and the rate of relapse in cases of conservative management; and frailty scores, in the absence of a single universally accepted score, were evaluated as adjunctive tools to better characterize elderly patients in the clinical situation [bib_ref] WSES and SICG guidelines on acute calcolous cholecystitis in elderly population, Pisano [/bib_ref]. More recently, Wiggins et al. have published a retrospective study based on an administrative national database of all consecutive patients aged over 80, who were admitted for ACC in England between 1997 and 2012. It included a very large number of patients (47,500). On index admission, non-operative treatment was carried out for 89.7% of the patients. Then, 7.5% had a cholecystectomy, and the remaining 2.8% had a cholecystostomy. The three groups were slightly different in mean age (83, 85 and 85 years, respectively) and the Charlson Comorbidity Index was below 2 in 87.5%, 83.1% and 83.2%, respectively. When surgery was compared to non-operative management (NOM) and to cholecystectomy, the mortality rate showed a trend favouring surgical management. The 30-day mortality rates were 11.6% for surgery, 9.9% for NOM (p < 0.001) and 13.4% for cholecystectomy (p < 0.001); the 90-day mortality rates were 15.6% for surgery, 16.1% for NOM (p > 0.05) and 22.5% for cholecystectomy (p < 0.001); the 1-year mortality rates were 20.8% for surgery, 27.1% for NOM and 37% for cholecystostomy (p < 0.001). It should be noted that this study showed a readmission rate of more than 50% after conservative management, which probably contributed to the increased mortality rate at 90 days and 1 year in this group. Interestingly, the proportion of cholecystectomies performed laparoscopically increased from 27 to 59% between 2006 and 2012. Moreover, multivariate analysis showed that, among the surgical group at the index admission, laparoscopy played an independent protective role, with an 84% relative risk reduction in 30-day mortality (OR 0.16, 95% CI 0.10-0.25) when compared to open cholecystectomy. In the discussion, the authors pointed out that the results could have some relationship with the fact that they came from a nation in which early cholecystectomy in ACC patients, regardless of age, is applied only in 15.7% of cases, as compared to 52.7% in the USA [bib_ref] Evolution in the management of acute cholecystitis in the elderly: population-based cohort..., Wiggins [/bib_ref]. With a decreased cut-off at 70 years old for the definition of elderly patients, the safety of ELC in ACC has also been supported by Loozen et al. in a systematic review and meta-analysis published in 2017. The cumulative morbidity and mortality were 24% and 3%, respectively, and there was a higher rate of complications for non-elderly patients. The protective role of laparoscopy is therefore confirmed; however, the authors highlight that there are limitations to their findings, in that there was an absence of prospective studies included in the review [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref]. In conclusion, despite the low quality of evidence, the studies detailed here universally favour ELC for elderly patients, even for patients older than 80 years of age. Due to the generally small functional reserve in the elderly, care should be taken to ensure that a prompt therapeutic decision is taken and that a high level of expertise is provided, both intraoperatively and during the postoperative management. ## Patients who are pregnant The literature evidence for pregnant patients is limited. The incidence of ACC during pregnancy varies among reports, ranging from one case per 1600 pregnancies to one case per 10,000 pregnancies. However, ACC during pregnancy is the second reason for non-obstetrical abdominal emergency surgery after appendicitis [bib_ref] Cholelithiasis during pregnancy and lactation. Prospective study, Tsimoyiannis [/bib_ref] [bib_ref] A study of cholelithiasis during pregnancy and its relationship with age, parity,..., Basso [/bib_ref]. The diagnostic criteria and tools are the same used for the general population [bib_ref] Biliary disease in pregnancy: Strategy for surgical management, Hiatt [/bib_ref] , but it is of note that leucocytosis during pregnancy could be misleading, and that the Murphy sign could be difficult to evaluate in the late part of the third trimester. The best option for the management of ACC should be chosen considering a balance among the following factors: the risk of complications from ACC, limitations on medication availability depending on the trimester, the risk of relapse, the risk of other specific conditions which may occur during pregnancy and the time until delivery or maturation of the foetus. In general, in the absence of contraindications, surgery is suggested as first-line therapy in order to avoid complications and potential drug toxicity for the foetus. Retrospective studies stated that recurrent ACC or pancreatitis can occur in 10% of patients, while miscarriage can occur in 10-20% of patients [bib_ref] Gallstone disease and pancreatitis in pregnancy, Scott [/bib_ref]. NOM is an alternative option, but it must be highlighted that there is a risk of higher incidence of spontaneous abortion, threatened abortion, and premature birth when compared to patients who underwent cholecystectomy [bib_ref] Special problems in laparoscopic surgery. Previous abdominal surgery, obesity, and pregnancy, Curet [/bib_ref]. One systematic review and meta-analysis focused on the comparison of open cholecystectomy with laparoscopic cholecystectomy during pregnancy [bib_ref] Laparoscopic versus open cholecystectomy in pregnancy: a systematic review and meta-analysis, Sedaghat [/bib_ref]. The authors selected 11 studies, all of which were retrospective: two from national databases, one from a state database and the others were retrospective from single-or multiple-institutions. The analysis included [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref] In 2018, another Japanese nationwide retrospective cohort study reported similar results [bib_ref] Safety of Laparoscopic Surgery for Benign Diseases during Pregnancy: A Nationwide Retrospective..., Shigemi [/bib_ref]. With the limitations of the quality of the studies, laparoscopy should be suggested for the treatment of symptomatic gallstones including ACC. The vast majority of studies suggests the second trimester until the initial part of the third trimester as the best time to perform laparoscopic cholecystectomy, as there is a higher risk of miscarriage and toxic effect of anaesthesia in the first trimester, while concerns are related to the size of the uterus in the third trimester [bib_ref] Laparoscopic versus open cholecystectomy in pregnancy: a systematic review and meta-analysis, Sedaghat [/bib_ref] [bib_ref] Safety of Laparoscopic Surgery for Benign Diseases during Pregnancy: A Nationwide Retrospective..., Shigemi [/bib_ref] [bib_ref] Surgical management of biliary gallstone disease during pregnancy, Cosenza [/bib_ref]. A systematic review and set of guidelines from the British Society for Gynaecological Endoscopy, endorsed by the Royal College of Obstetricians and Gynaecologists, have been published in 2019 and they summarize the discussion, confirming the benefits of ELC over non-operative treatment, especially in the second trimester. Which surgical strategies should be adopted in case of difficult anatomic identification of structures during cholecystectomy for ACC? 3.We recommend laparoscopic or open subtotal cholecystectomy in situations in which anatomic identification is difficult and in which the risk of iatrogenic injuries is high. #QoE: moderate; SoR: strong# Reasons for a 'difficult gallbladder' vary, and can be related to obesity, adhesions, acute or chronic inflammation, distended gallbladder and liver cirrhosis. Due to the diversity of reasons and the variability of approaches among surgeons, a review conducted in 2011 showed no consensus on the ideal way to deal with a difficult gallbladder. The options include subtotal cholecystectomy, fundus first cholecystectomy, perioperative cholangiogram, open conversion or a combination of these options [bib_ref] Difficult laparoscopic cholecystectomy: Current evidence and strategies of management, Hussain [/bib_ref]. In this section, we focus on subtotal cholecystectomy, which is an option when the critical view of safety [bib_ref] Rationale and use of the critical view of safety in laparoscopic cholecystectomy, Strasberg [/bib_ref] cannot be obtained. In 2015, a systematic review and meta-analysis by Elshaer et al. reported that subtotal cholecystectomy was performed using laparoscopic (72.9%) open (19.0%) and laparoscopic converted to open (8.0%) techniques. In this study including over 1200 patients, the most common indications were severe cholecystitis (72.1%), followed by gallstones in liver cirrhosis and portal hypertension (18.2%) and empyema or a perforated gallbladder (6.1%). They concluded that subtotal cholecystectomy might be helpful during the surgical management of difficult cholecystectomy; also considering that it achieves morbidity rates comparable to those reported for total cholecystectomy in straightforward cases. The quality of evidence is limited, due to the absence of prospective randomized studies, which are not expected to be easily performed in the future [bib_ref] Subtotal cholecystectomy for "Difficult gallbladders": Systematic review and metaanalysis, Elshaer [/bib_ref]. Support for subtotal cholecystectomy has also been reported from other studies. In a retrospective study on severely difficult gallbladders [bib_ref] Safe laparoscopic subtotal cholecystectomy in the face of severe inflammation in the..., Purzner [/bib_ref] , 105 patients who underwent laparoscopic cholecystectomy were matched with 46 patients who underwent subtotal laparoscopic cholecystectomy. The authors observed no bile duct injury in the subtotal cholecystectomy group, but four instances in the complete cholecystectomy group. Bile leakage was greater in the subtotal group due to difficulty in the cicatrisation on the remaining gallbladder stump; however, bile leakage was managed easily by abdominal drainage or in combination with endoscopic biliary prosthesis placement. A recent nation-based database study evaluating 290, 855 cases between 2003 and 2014 showed an increased use of subtotal cholecystectomy from 0.1 to 0.52% for open subtotal cholecystectomy and from 0.12 to 0.28% for laparoscopic cholecystectomy. The conversion rate from laparoscopic to open total cholecystectomy decreased from 10.5 to 7.6%. Interestingly, the teaching hospitals significantly increased the rate of subtotal cholecystectomy. Furthermore, it should be highlighted that there are different techniques to achieve subtotal cholecystectomy: this aspect could add some difficulty in analysing data from different studies [bib_ref] Subtotal cholecystectomy as an effective and safe option for complicated cholecystitis: A..., Brahmbhatt [/bib_ref]. The quality of the available evidence ranges from low to moderate. However, the concordance of all the evidence, the large application of the technique globally, with the important clinical impact on patient safety, and the current absence of opportunities to achieve a better level of evidence strongly supports the recommendation for subtotal cholecystectomy in cases of difficult gallbladder. When should conversion from laparoscopic to open cholecystectomy be considered in patients with ACC? 3. [bib_ref] TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis, Kimura [/bib_ref] We recommend conversion from laparoscopic to open cholecystectomy in case of severe local inflammation, adhesions, bleeding from the Calot's triangle or suspected bile duct injury. #QoE: moderate; SoR: strong# This recommendation should be supported by studies in which the patients with difficult gallbladder have been randomized to conversion or to different laparoscopic procedures. However, this type of study is unlikely to be performed. The present update of the WSES Guidelines on ACC clarifies that, in 2016, the reasons for conversion were used as a proxy in the absence of high-quality studies; we maintained the same approach for the current version of the guidelines [bib_ref] WSES guidelines on acute calculous cholecystitis, Ansaloni [/bib_ref] [bib_ref] Reasons for conversion from laparoscopic to open cholecystectomy, Qazi [/bib_ref] [bib_ref] Open conversion for laparoscopically difficult cholecystectomy is still a valid solution with..., Mannino [/bib_ref]. When expertise in difficult instances of laparoscopic cholecystectomy is ensured, the conversion is not a failure and it represents a valid option to be considered. The quality of the evidence is moderate. However, the absence of opportunities to achieve a higher quality of evidence, along with the broadly used conversion to open surgery and the clinical impact on patients' safety, suggests a strong recommendation for conversion to open surgery after laparoscopy has been attempted at the best institutional level available. Nevertheless, according to Gupta et al., surgeons should adopt a philosophy of safe laparoscopic cholecystectomy. Understanding the mechanisms related to specific complications may help elaborating strategies to avoid or reduce those complications; in this context, the surgeon should define, in their own personal armamentarium, the indications for a bailout techniques among the available options [bib_ref] Safe laparoscopic cholecystectomy: Adoption of universal culture of safety in cholecystectomy, Gupta [/bib_ref] [bib_ref] A three-step conceptual roadmap for avoiding bile duct injury in laparoscopic cholecystectomy:..., Strasberg [/bib_ref]. ## Section 4. timing of cholecystectomy in people with acc When is the optimal timing for laparoscopic cholecystectomy in patients with ACC? 4.1 In the presence of adequate surgical expertise, we recommend ELC be performed as soon as possible, within 7 days from hospital admission and within 10 days from the onset of symptoms. #QoE: moderate; SoR: strong#. Comment: ELC so defined is preferable to intermediate laparoscopic cholecystectomy (ILC, performed between 7 days of hospital admission and 6 weeks) and DLC (performed between 6 weeks and 3 months). 4. [bib_ref] Prevalence of gallstones in sonographic surveys worldwide, Kratzer [/bib_ref] We suggest DLC to be performed beyond 6 weeks from the first clinical presentation, in case ELC cannot be performed (within 7 days of hospital admission and within 10 days of onset of symptoms). #QoE: very low; SoR: weak#. Surgery is currently the recommended treatment in people with acute cholecystitis. Conservative management with fluids, analgesia and antibiotics is an option for people with mildly symptomatic acute cholecystitis (i.e. people without peritonitis or those who have worsening clinical condition). In a RCT with long-term follow-up of 14 years, about 30% of patients treated conservatively developed recurrent gallstone-related complications and 60% of patients had undergone cholecystectomy subsequently [bib_ref] Long-term follow-up of a randomized controlled trial of observation versus surgery for..., Schmidt [/bib_ref] [bib_ref] Acute cholecystitis: Delayed surgery or observation. A randomized clinical trial, Vetrhus [/bib_ref]. The study included only 33 patients and had high risk of bias [bib_ref] Long-term follow-up of a randomized controlled trial of observation versus surgery for..., Schmidt [/bib_ref] [bib_ref] Acute cholecystitis: Delayed surgery or observation. A randomized clinical trial, Vetrhus [/bib_ref]. Therefore, until new high-quality evidence becomes available, laparoscopic cholecystectomy is considered the recommended treatment for patients who are fit to undergo surgery. In patients with moderate or severely symptomatic cholecystitis or in those with mildly symptomatic acute cholecystitis who prefer surgery, laparoscopic cholecystectomy is preferred over open cholecystectomy [bib_ref] Open versus laparoscopic cholecystectomy in acute cholecystitis. Systematic review and meta-analysis, Coccolini [/bib_ref]. The timing of laparoscopic cholecystectomy in these patients is controversial. A Cochrane review published in 2013 concluded that ELC for acute cholecystitis seems safe and may shorten the total hospital stay [bib_ref] Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis, Gurusamy [/bib_ref]. An update of the literature searches was performed for the purpose of this guideline. Sixteen trials were identified in the update (including the trials originally included in the systematic review) [bib_ref] Experience in the treatment (early vs. delayed) of acute cholecystitis via laparoscopy, Davila [/bib_ref] [bib_ref] Comparison of early and delayed laparoscopic cholecystectomy for acute cholecystitis: Experience from..., Gul [/bib_ref] [bib_ref] Early versus delayed laparoscopic cholecystectomy in treatment of acute cholecystitis, Rajcok [/bib_ref] [bib_ref] Early versus delayed cholecystectomy for acute cholecystitis, are the 72 hours still..., Roulin [/bib_ref] [bib_ref] Early versus Delayed Laparoscopic Cholecystectomy for Acute Cholecystitis: A Prospective Randomized Trial, Verma [/bib_ref] [bib_ref] A comparative study of early vs. delayed laparoscopic cholecystectomy in acute cholecystitis, Yadav [/bib_ref] [bib_ref] Early Vs Interval Cholecystectomy in Acute Cholecystitis: An Experience at Ghurki Trust..., Zahur [/bib_ref] [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref] [bib_ref] Management of Acute Cholecystitis in the Laparoscopic Era: Results of a Prospective,..., Johansson [/bib_ref] [bib_ref] Early vs delayed laparoscopic cholecystectomy for acute cholecystitis: A prospective randomized trial, Kolla [/bib_ref] [bib_ref] Randomized trial of early versus delayed laparoscopic cholecystectomy for acute cholecystitis, Lai [/bib_ref] [bib_ref] Prospective Randomized Study of Early Versus Delayed Laparoscopic Cholecystectomy for Acute Cholecystitis, Lo [/bib_ref] [bib_ref] Prospective randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy..., Macafee [/bib_ref] [bib_ref] Early vs Delayed Laparoscopic Cholecystectomy in Acute Cholecystitis, Issa [/bib_ref] [bib_ref] Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: A prospective, randomized study, Özkardeş [/bib_ref]. The number of participants with acute cholecystitis was not reported in one of the trials [bib_ref] Prospective randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy..., Macafee [/bib_ref]. In the remaining 15 trials, 1240 participants were included in 14 trials comparing ELC versus DLC and 618 participants were included in one trial comparing ELC versus intermediate laparoscopic cholecystectomy (ILC) [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref]. The country; recruitment period; number of participants; the duration of symptoms; the timing of ELC, DLC and ILC; and the surgical experience are reported in [fig_ref] Table 3: Timing of cholecystectomy in people with ACC [/fig_ref]. Overall, it appears that ELC was performed within 10 days of onset of symptoms in most trials. There were no significant differences in mortality or conversion to open cholecystectomy between the three groups. The proportion of patients with serious adverse events was significantly higher in ILC compared to ELC in the only trial included in the comparison between ILC and DLC [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref]. The number of serious adverse events was significantly less with ELC compared to DLC in the only trial comparing ELC with DLC that reported this information [bib_ref] Early versus delayed cholecystectomy for acute cholecystitis, are the 72 hours still..., Roulin [/bib_ref]. The total length of hospital stay (including all the admissions for treatment) was about 4 days shorter with ELC compared to DLC , and about 5 days shorter with ELC compared to ILC [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref]. The return to work was about 9 days sooner following ELC compared to DLC [bib_ref] Comparison of early and delayed laparoscopic cholecystectomy for acute cholecystitis: Experience from..., Gul [/bib_ref] [bib_ref] Prospective Randomized Study of Early Versus Delayed Laparoscopic Cholecystectomy for Acute Cholecystitis, Lo [/bib_ref]. Overall, it appears that ELC performed within 7 days of hospital admission and within 10 days of onset of symptoms is superior to either ILC performed between 7 days of hospital admission and 6 weeks or DLC performed between 6 weeks and 3 months of the initial hospital admission for acute cholecystitis. Since blinding cannot be achieved in these comparisons and the outcomes were subjective, all the trials were deemed to be at high risk of bias. However, trials with low risk of bias are difficult to conduct in this comparison. Since the evidence was consistent across trials and outcomes, it appears highly likely that ELC is superior to either ILC or DLC. Therefore, despite the moderate quality evidence (which is mainly because of the lack of blinding in the trials), the recommendation for ELC is strong. However, it should be noted that the study authors described that ELC was more complex; therefore, it should be attempted only by experienced surgeons. Referral to centres with high surgical expertise should be considered if adequate surgical expertise is not available. If ELC cannot be performed, DLC appears to be better than ILC. Although, there is no evidence of difference between DLC and ILC, the ACDC trial comparing ELC versus ILC showed that a significant proportion of patients undergoing ILC developed serious adverse events [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref]. Therefore, DLC may be preferable when ELC is not possible, although a proportion of patients with planned DLC approach may need unplanned earlier surgery (see [fig_ref] Figure 1 2020: WSES Flowchart for the management of patients with acute calcolus cholecystitis [/fig_ref] [bib_ref] Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis, Gurusamy [/bib_ref]. There are no trials comparing ILC and DLC and it is unlikely that they will performed, given the results of the ACDC trial [bib_ref] Acute cholecystitis: Early versus delayed cholecystectomy, a multicenter randomized trial (ACDC Study,..., Gutt [/bib_ref]. Therefore, there is significant uncertainty whether DLC is better than ILC when ELC is not possible and the recommendation to perform DLC when ELC is not possible is weak. ## Section 5. risk prediction in acc How can the prognosis and surgical risk be assessed for patients with ACC? 5.1 We cannot suggest the use of any prognostic model in patients with ACC. #QoE: very low; SoR: weak# Comment: There is currently significant uncertainty in the ability of prognostic factors and risk prediction models in predicting outcomes in patients with ACC. Cholecystectomy is currently the recommended treatment for patients with acute cholecystitis. Laparoscopic cholecystectomy is preferred over open cholecystectomy in patients with acute cholecystitis, but it is a major surgical procedure. While it is considered relatively safe, it is associated with a mortality rate between 0.1 and 1% [bib_ref] Nationwide variation in outcomes and cost of laparoscopic procedures, Huntington [/bib_ref] [bib_ref] Outcome trends and safety measures after 30 years of laparoscopic cholecystectomy: a..., Pucher [/bib_ref] [bib_ref] Effect of intended intraoperative cholangiography and early detection of bile duct injury..., Törnqvist [/bib_ref] , a risk of bile duct injury in approximately 0.2% to 1.5% of cases [bib_ref] Outcome trends and safety measures after 30 years of laparoscopic cholecystectomy: a..., Pucher [/bib_ref] [bib_ref] Impact of routine intraoperative cholangiography during laparoscopic cholecystectomy on bile duct injury, Alvarez [/bib_ref] and a risk of major complications (such as myocardial infarction, heart failure, acute stroke, renal failure, pulmonary embolism, lung failure or postoperative shock) in between 6 and 9% of cases [bib_ref] Nationwide variation in outcomes and cost of laparoscopic procedures, Huntington [/bib_ref]. Observation is an alternative option for patients with mildly symptomatic ACC (i.e. in patients without peritonitis or in those who have worsening symptoms). After a long-term follow-up of 14 years, about 30% of patients with mildly symptomatic acute cholecystitis who did not undergo cholecystectomy developed recurrent gallstonerelated complications, compared with 3% of patients who underwent cholecystectomy. These differences were not significant for recurrent disease or overall complications [bib_ref] Long-term follow-up of a randomized controlled trial of observation versus surgery for..., Schmidt [/bib_ref]. However, 60% of patients had undergone surgery, and the study was small and carried a high risk of bias; therefore, there is lot of uncertainty as to whether it is better to perform surgery or observation in patients with mildly symptomatic acute cholecystitis. Identification of patients at high risk of complications and mortality can help in optimising them prior to surgery or in deciding whether referral to high-volume centres and specialized centres, which may decrease the complications [bib_ref] Who should perform laparoscopic cholecystectomy? A 10-year audit, Boddy [/bib_ref] [bib_ref] Does concentration of surgical expertise improve outcomes for laparoscopic cholecystectomy? 9 year..., Andrews [/bib_ref] , is appropriate. Informed decisions about whether to opt for surgery or observation can also be made if information on the risks is available. We performed a systematic review of studies reporting on the ability of prognostic factors or risk prediction models to predict important patient-related outcomes, Main reasons for unclear or high risk of bias High risk of bias: at least one of random sequence generation, allocation concealment, missing outcome bias or selective outcome reporting bias was classified as high risk of bias Unclear risk of bias: at least one of random sequence generation, allocation concealment, missing outcome bias or selective outcome reporting bias was classified as unclear risk of bias without any of the domains being classified as high risk of bias a All studies were at high risk of bias due to lack of blinding. The risk of bias classification stated here is for the remaining domains b This was the only study in which intermediate laparoscopic cholecystectomy was performed; delayed laparoscopic cholecystectomy was performed in the remaining studies such as mortality, complications and conversion to open surgery in patients with ACC [bib_ref] Risk prediction in acute calculous cholecystitis : a systematic review of prognostic..., Tufo [/bib_ref]. In this systematic review and meta-analysis, we included 12 studies and 6827 patients in one or more analysis. Only a few factors (TG13, age, male gender, previous abdominal surgery, diabetes, hypertension and C-reactive protein) were reported in a format similar enough to allow comparisons between studies. The remaining factors were studied in single studies or using different thresholds. Therefore, there is no information on their reproducibility, and the results may be unreliable. Among the prognostic factors reported in at least two studies, TG13 grade 3 had an increased risk of all-cause mortality compared to grade 1. The risk increased from a median risk of 1.3% to 6.5% (95% CI 3.7-11.2). However, most studies included only people who underwent surgery, not all of whom were patients with ACC. There have been no RCTs of surgery versus observation in people with severe ACC. Laparoscopic cholecystectomy performed by experienced surgeons had lower major complication rates than percutaneous cholecystostomy with no planned cholecystectomy [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref]. Therefore, it appears that, despite the increased risk of mortality in TG13 grade 3 compared to TG13 grade 1, surgery seems to be the preferred option when possible. However, referral to high volume centres and specialized centres may decrease the complications [bib_ref] Who should perform laparoscopic cholecystectomy? A 10-year audit, Boddy [/bib_ref] [bib_ref] Does concentration of surgical expertise improve outcomes for laparoscopic cholecystectomy? 9 year..., Andrews [/bib_ref] and resulting mortality, and should be considered in people with TG13 grade 3 acute cholecystitis. Being male was associated with an increased risk of complications (from 10 to 15%; 95% CI 10.5-20.9) and an increased risk of conversion to open cholecystectomy (from 16 to 48.5%; 95% CI 27.5-70.0). The reasons for the difference in the complications and conversion between males and females are not clear, but may be due to a combination of increased skeletal muscle mass [bib_ref] Estimation of Skeletal Muscle Mass and Visceral Adipose Tissue Volume by a..., Schweitzer [/bib_ref] (particularly in the trunk [bib_ref] Sex differences in whole body skeletal muscle mass measured by magnetic resonance..., Abe [/bib_ref] and increased visceral abdominal fat in males [bib_ref] Estimation of Skeletal Muscle Mass and Visceral Adipose Tissue Volume by a..., Schweitzer [/bib_ref] [bib_ref] Gender differences of regional abdominal fat distribution and their relationships with insulin..., Rattarasarn [/bib_ref] [bib_ref] Visceral Adipose Tissue, Plasma Lipids, and Lipoprotein Lipase Activity in Men and..., Després [/bib_ref] , which could make laparoscopic surgery more difficult, and a common delay in males seeking medical help due to a misguided perception of masculinity [bib_ref] Gender differences in healthcare utilization and medical indicators among patients with diabetes, Shalev [/bib_ref] [bib_ref] Masculinity impediments: Internalized masculinity contributes to healthcare avoidance in men and women, Himmelstein [/bib_ref] , which could mean that the males had more severe disease than females at the time of presentation to the hospital. Previous upper abdominal surgery is a risk factor for conversion to open cholecystectomy. This is to be expected because of the intraabdominal adhesions related to previous abdominal surgery [bib_ref] Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study, Ellis [/bib_ref] However, it should be noted that the systematic review included only preoperative factors, and most of the studies included only patients undergoing cholecystectomy for ACC. Therefore, the findings of the review are applicable only for preoperative risk prediction in patients undergoing cholecystectomy for ACC. It should also be noted that most of the studies were retrospective, in which blinding of predictor or outcome measurement were not reported, and most of the studies were small. Overall, there is significant uncertainty in the ability of prognostic factors and risk prediction models in predicting outcomes in patients with ACC. TG13 grade 3 may be associated with greater mortality than grade 1 severity of acute cholecystitis. Despite the increased risk of mortality in TG13 grade 3 compared to TG13 grade 1, surgery seems to be the preferred option when possible. The TG18 adopted the TG13 severity grading criteria in predicting outcomes in patients with ACC [bib_ref] Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with..., Yokoe [/bib_ref]. High-quality studies are necessary to provide better information on the prognostic factors of patients with acute cholecystitis and to improve shared decision making. Section 6. Alternative treatment for patients with ACC who are not suitable for surgery: observation and techniques for gallbladder drainage When should Non-Operative Management be considered for patients with ACC? 6.1 We suggest considering NOM, i.e. best medical therapy with antibiotics and observation, for patients refusing surgery or those who are not suitable for surgery. #QoE: low; SoR: weak# 6.2 We suggest considering alternative treatment options for patients who fail NOM and who still refuse surgery or patients who are not suitable for surgery. #QoE: low; SoR: weak# Schimdt et al. [bib_ref] Long-term follow-up of a randomized controlled trial of observation versus surgery for..., Schmidt [/bib_ref] published an RCT comparing observation and surgery in cases of ACC, with a long median follow-up time of 14 years. In their analysis, about 30% of patients with mildly symptomatic acute cholecystitis who did not undergo cholecystectomy developed recurrent gallstone-related complications, as compared with 3% of patients who underwent cholecystectomy, but these differences were not significant for recurrent disease or complications. Overall, 60% of patients had undergone surgery, while 40% avoided surgery. There are significant limitations in the study, as recognized by the authors: firstly, a relevant percentage of eligible patients (41%) were excluded from randomization; secondly, the reasons for the exclusion were not stated in the paper; thirdly, the definitions of dropout and failure within the observation group were not clear. Brazzelli et al. [bib_ref] Systematic review of the clinical and cost effectiveness of cholecystectomy versus observation/conservative..., Brazzelli [/bib_ref] published a systematic review of two RCTs comparing observation with surgery in patients with symptomatic gallstone disease (in the first study) and patients with ACC (in the second study). From a total of 201 patients, the results confirmed the high rate of gallstone-related complications within the observation group (RR 6.63, 95% CI 1.57-28.51, p = 0.01).The authors, although noting the substantial lack of good quality evidence, reported that a policy of surgery for all patients with ACC, when compared to a policy of observation followed by surgery for symptomatic patients, represents a costly but more effective choice. In conclusion, relevant uncertainty exists regarding the best management between surgery or observation in cases of ACC, especially in uncomplicated disease; observation and best medical therapy are likely to be safe, but this latter approach is characterised by a high incidence of recurrent disease. Alternative treatment options may be considered for patients who fail NOM for ACC, also considering the individual patient's characteristics and the clinical situation. Which is the first-choice treatment for ACC in high risk patients? 6.3 Immediate laparoscopic cholecystectomy is superior to percutaneous transhepatic gallbladder drainage (PTGBD) in high risk patients with ACC. We recommend laparoscopic cholecystectomy as the first-choice treatment in this group of patients. #QoE: high; SoR: strong# TG13 on ACC [bib_ref] Tokyo Guidelines 2018 : management strategies for gallbladder drainage in patients with..., Mori [/bib_ref] considered gallbladder drainage as mandatory for patients with severe grade ACC (according to the Tokyo classification [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref] of acute cholecystitis) and also suggested its use in the moderate grade if conservative treatment fail. The revised TG18, based on recent studies, proposed that severegrade cholecystitis, under certain strict criteria, may be treated with laparoscopic cholecystectomy [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref] [bib_ref] Tokyo Guidelines 2018 : management strategies for gallbladder drainage in patients with..., Mori [/bib_ref]. A systematic review published in 2016 comparing percutaneous transhepatic gallbladder drainage (PTGBD) and cholecystectomy in critically ill patients reported no benefit for the use of PTGBD over cholecystectomy [bib_ref] The Treatment of Critically Ill Patients With Acute Cholecystitis, Ambe [/bib_ref]. Six studies were analysed with a total of 337,500 patients. Mortality rate, length of hospital stay and number of readmissions for gallstone-related diseases were all significantly higher in the PTGBD group than in the cholecystectomy group. It should be noted that all included studies had a retrospective design, which makes the results prone to bias. Recently, the first randomized trial on this subject was published (the CHOCOLATE trial). The results showed that laparoscopic cholecystectomy is superior to PTGBD [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref] also in high-risk patients with ACC. PTGBD was compared with ELC in critically ill patients (APACHE score [bib_ref] WSES guidelines on acute calculous cholecystitis, Ansaloni [/bib_ref] [bib_ref] TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos), Yokoe [/bib_ref] [bib_ref] WSES and SICG guidelines on acute calcolous cholecystitis in elderly population, Pisano [/bib_ref] [bib_ref] Tokyo Guidelines 2018: flowchart for the management of acute cholecystitis, Okamoto [/bib_ref] [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref] [bib_ref] Does This Patient Have Acute Cholecystitis?, Trowbridge [/bib_ref] [bib_ref] Diagnostic approaches in acute cholecystitis: a prospective study of 1333 patients with..., Eskelinen [/bib_ref] [bib_ref] Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with..., Yokoe [/bib_ref] with ACC, in terms of efficacy and safety. Patients who underwent ELC had significantly fewer major complications, which were mainly recurrent biliary events. Five percent of patients who underwent ELC had complications, compared with 53% of patients who underwent PTGBD. Mortality was low and remained the same in both groups. Early laparoscopic cholecystectomy also led to significantly less utilisation of health care resources. The trial concluded that immediate cholecystectomy in high-risk patients is safe and should be the standard of care. What is the role of gallbladder drainage in patients with ACC who are not suitable for surgery? 6.We recommend performing gallbladder drainage in patients with ACC who are not suitable for surgery, as it converts a septic patient with ACC into a non-septic patient. #QoE: moderate; SoR: strong# Patients who are not suitable for surgery, but who are septic due to gallbladder empyema, are effectively treated by PTGBD, as shown in the CHOCOLATE trial [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref]. Gallbladder drainage decompresses the infected bile or pus in the gallbladder, removing the infected collection without removing the gallbladder. The removal of the infected material can result in reduced inflammation and in improvement of the clinical conditions. Several case series, both retrospective and observational, exist on cholecystostomy. A systematic review of the literature included 53 studies with 1918 patients outlining a high success rate of the procedure (85.6%) with a low procedure-related mortality rate (0.36%); however, the 30-day mortality rate was high at 15.4% [bib_ref] Systematic review of cholecystostomy as a treatment option in acute cholecystitis, Winbladh [/bib_ref]. A major limitation of the study was the inclusion of patients with both acute acalculous cholecystitis and ACC. A review of additional 27observational studies on cholecystostomy [bib_ref] Acute cholecystitis: WSES position statement, Campanile [/bib_ref] showed significant heterogeneity in terms of inclusion criteria, results and conclusions reached by different authors. Considering these limitations, the reported inhospital mortality and morbidity rates for cholecystostomy range from 4 to 50 % and from 8.2 to 62%, respectively. Gallbladder drainage may be an option in patients who failed conservative management after a variable time of 24 to 48 h and who present with strict contraindications for surgery. A prospective study by reported that age over 70 years, diabetes, tachycardia and a distended gallbladder at admission are predictors for failure of NOM at 24-h follow-up, while a WBC of more than 15,000 cell/mm 3 , fever and age above 70 years were predictors for failure of NOM at 48-h follow-up. No specific antibiotic regimen is to be prescribed alongside PTGBD and no evidence exists supporting the need for a specific antibiotic regimen. For the antimicrobial therapy, please refer to the dedicated section. Should delayed cholecystectomy be offered to patients with ACC after the reduction of perioperative risk? 6.5 Delayed laparoscopic cholecystectomy is suggested after reduction of perioperative risks to decrease readmission for ACC relapse or gallstonerelated disease. #QoE: very low; SoR: weak# De Mestral et al. published a large retrospective epidemiologic analysis in 2013, showing that 40% of patients underwent a DLC after PTGD; the 1-year readmission rate for patients who did not undergo DLC after PTGD was 49% with an in-hospital mortality rate of 1% [bib_ref] A population-based analysis of the clinical course of 10,304 patients with acute..., De Mestral [/bib_ref]. No randomized trial currently exists comparing DLC to observation alone. Can endoscopic gallbladder drainage be considered an alternative to PTGBD in patients with ACC who are not suitable for surgery? 6.6 In patients with ACC who are not suitable for surgery, endoscopic transpapillary gallbladder drainage (ETGBD) or ultrasound-guided transmural gallbladder drainage (EUS-GBD) should be considered safe and effective alternatives to PTGBD, if performed in high-volume centers by skilled endoscopists. #QoE: high; SoR: strong# ACC is a frequent event in urgent surgical settings, and the gold standard for its treatment is laparoscopic cholecystectomy [bib_ref] Tokyo Guidelines 2018 : management strategies for gallbladder drainage in patients with..., Mori [/bib_ref] [bib_ref] TG13 indications and techniques for gallbladder drainage in acute cholecystitis ( with..., Tsuyuguchi [/bib_ref] [bib_ref] Current Status of Endoscopic Gallbladder Drainage, Ho [/bib_ref]. However, some patients are unfit for surgery, and for them non-surgical drainage represents a suitable option, either as a bridge to subsequent surgery, once their clinical conditions improve, or as a definitive treatment for those who remain poor candidates for surgery. Non-surgical approaches include PTGBD and endoscopic procedures. Among these, alternatives are endoscopic transpapillary gallbladder drainage (ETGBD), with placement of a transpapillary nasogallbladder drainage tube (ENGBD) or double-pigtails tent (EGBS), or transmural ultrasonography-guided gallbladder drainage (EUS-GBD) [bib_ref] Endoscopic ultrasound-guided transmural stenting for gallbladder drainage in high-risk patients with acute..., Anderloni [/bib_ref]. In a systematic review about options for endoscopic gallbladder drainage, Itoi et al. [bib_ref] Endoscopic gallbladder drainage for management of acute cholecystitis, Itoi [/bib_ref] Five years later, Itoi et al. [bib_ref] Endoscopic nasogallbladder tube or stent placement in acute cholecystitis : a preliminary..., Itoi [/bib_ref] , in a RCT of 73 consecutive patients with ACC, obtained overall technical success rates with ENGBD and EGBS of 91.9% and 86.1%, respectively, whereas the clinical success rates by intention-to-treat analysis were 86.5% and 77.8%, respectively. The authors argued that the lower clinical success rate may be ascribed to inadequate gallbladder drainage when large stones or pus were present, and to the use of small-diameter catheters or stents. EUS-GBD has been compared, in terms of technical feasibility and efficacy, to PTGBD [bib_ref] Endoscopic Ultrasound-Guided Transmural and Percutaneous Transhepatic, Jang [/bib_ref] inpatients with acute, high-risk or advanced stage cholecystitis who did not respond to initial medical treatment and could not undergo ELC. EUS-GBD and PTGBD showed similar technical (97% vs. 97%, p = 0.001) and clinical (100% vs. 96%, p = 0.0001) success rates, and similar rates of complications (7% vs. 1%, p = 0.492), indicating that EUS-GBD is a safe alternative to PTGBD in patients who are unsuitable for surgery. Irani and co-workers [bib_ref] Similar efficacies of endoscopic ultrasound gallbladder drainage with a lumen-apposing metal stent..., Irani [/bib_ref] reached similar conclusions after a retrospective multicenter study, in which the technical success rates of EUS-GBD and PTGBD were 98% and 100% (p = 0.88), respectively. Moreover, the EUS-GBD group had a shorter in-hospital length of stay and fewer repeat interventions (p < 0.05). Khan et al. [bib_ref] Ef fi cacy and safety of endoscopic gallbladder drainage in acute cholecystitis..., Khan [/bib_ref] , in a meta-analysis, evaluated the technical success rates and post-procedure adverse events of ETGBD compared with PTGBD. They found that the pooled OR for technical success of ETGBD versus PTGBD was 0.51 (95% CI 0.09-2.88; I 2 = 23%) and for post-procedures adverse events was 0.33 (95% CI 0.14-0.80; I 2 = 16%) in favour of ETGBD. The weighted pooled rates (WPRs) for EUS-GBD were as follows: technical success 93% (95% CI 87-96; I 2 = 0%), clinical success 97% (95% CI 93-99; I 2 = 0%), post-procedure adverse events 13% (95% CI 8-19; I 2 = 0%) and recurrent cholecystitis 4% (95% CI 2-9; I 2 = 0%). In a prospective study on long term-follow up after EUS-GBD [bib_ref] Endoscopic ultrasound-guided drainage in acute cholecystitis: results of a long-term follow-up, Ahmed [/bib_ref] , the recurrence of cholecystitis was observed in 7.7% of cases, suggesting that this endoscopic procedure is a safe alternative in the treatment of acute cholecystitis in high-risk patients. EUS-GBD has also been proven to be a feasible technique for the conversion of percutaneous cholecystostomy [bib_ref] Conversion of percutaneous cholecystostomy to internal transmural gallbladder drainage using an endoscopic..., Law [/bib_ref]. The advantages of EUS-GBD over PTGBD include an internalization of bile, obviating the risk of recurrent cholecystitis following percutaneous catheter removal and the risk of bleeding, and being associated with less post-procedural pain [bib_ref] Conversion of percutaneous cholecystostomy to internal transmural gallbladder drainage using an endoscopic..., Law [/bib_ref] [bib_ref] Feasibility of conversion of percutaneous cholecystestomy to internal transmural endoscopic ultrasound-guided gallbladder..., Chantarojanasiri [/bib_ref]. A recent RCT by Teoh et al. [bib_ref] Endosonography-guided gallbladder drainage versus percutaneous cholecystostomy in very high-risk surgical patients with..., Teoh [/bib_ref] identified patients with ACC at very high risk for surgery as patients older than 80 years, with an ASA grade ≥ 3 or an age-adjusted Charlson Comorbidity score > 5 and/or a Karnofsky score < 50. The authors randomized them to receive either EUS-GBD with LAMS or PTGBD within 4 to 6 h from diagnosis. Although 30-day mortality was equivalent between the two study groups, the results were in favour of EUS-GBD, which was associated with less adverse events at 30-day (12.8% vs. 47.5%, p = 0.001) and at 1-year follow-up (25.6% vs. 77.5%, p < 0.001), with a reduced number of re-interventions at 30 days (2.6% vs. 30%, p = 0.001) and with a reduced number of episodes of recurrent cholecystitis (2.6% vs. 20%, p = 0.029). 6.7 If endoscopic transpapillary gallbladder drainage is performed, both endoscopic nasogatric endoscopic gallbladder drainage (ENGBD) and endoscopic gallbladder stenting (EGBS) should be considered suitable options, based on patient characteristics and on the endoscopist's decision. #QoE: high; SoR: strong# Although ENGBD has certain advantages for patients in whom stent insertion is impossible or when there is stent dysfunction, it has two major drawbacks: the potential for inadvertent catheter dislodgement or patient removal, and discomfort. On the other hand, an indwelling stent may be suitable when there is a concern in patients with altered mental status or dementia [bib_ref] Epidemiology of gallstones, Stinton [/bib_ref]. A meta-analysis conducted in TG18 [bib_ref] Tokyo Guidelines 2018 : management strategies for gallbladder drainage in patients with..., Mori [/bib_ref] What is the role of endoscopic transmural ultrasound-guided gallbladder drainage (EUS-GBD) in patients with ACC who are not suitable for surgery? 6.8 EUS-GBD with lumen-apposing self-expandable metal stents (LAMSs) should be preferred to ETGBD, if performed by skilled endoscopists. #QoE: moderate; SoR: strong# In a recent meta-analysis, Khan et al. [bib_ref] Ef fi cacy and safety of endoscopic gallbladder drainage in acute cholecystitis..., Khan [/bib_ref] found that the proportional difference of WPRs for technical success and clinical success between EUS-GBD versus ETGBD were 10% and 4%, respectively. This difference is explained by the fact that the transpapillary procedures may be technically challenging, due to the anatomy of the cystic duct or stone impaction. On the other hand, if the distance between the gallbladder and the enteric lumen is less than 1 cm, EUS-GBD appears to be safe and feasible [bib_ref] Endoscopic ultrasound-guided drainage in acute cholecystitis: results of a long-term follow-up, Ahmed [/bib_ref] [bib_ref] Conversion of percutaneous cholecystostomy to internal transmural gallbladder drainage using an endoscopic..., Law [/bib_ref] [bib_ref] Feasibility of conversion of percutaneous cholecystestomy to internal transmural endoscopic ultrasound-guided gallbladder..., Chantarojanasiri [/bib_ref]. This technique results in a permanent fistula formation between the gallbladder and the hollow viscus, facilitating anatomic bile drainage [bib_ref] EUSguided transenteric gallbladder drainage with a new fistula-forming , lumen-apposing metal stent, Serna-Higuera [/bib_ref]. A variety of plastic stents (straight, single, doublepigtail) and self-expandable metal stents (SEMSs) have been used during EUS-GBD with similar treatment outcomes. However, plastic and SEMSs are tubular stents not specifically designed for EUS-GBD procedures; therefore, bile leakage, stent occlusion and migration are potential adverse events [bib_ref] Endoscopic ultrasound-guided transmural stenting for gallbladder drainage in high-risk patients with acute..., Anderloni [/bib_ref] [bib_ref] Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis : Long-term outcomes after removal..., Kamata [/bib_ref]. In order to overcome these limitations, modified stents with flared ends and LAMSs have been introduced [bib_ref] Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis : Long-term outcomes after removal..., Kamata [/bib_ref] [bib_ref] EUS-guided gallbladder drainage with lumenapposing metal stent (with video), Irani [/bib_ref]. LAMSs are fully covered self-expandable metal stents with bilateral flanges specifically designed for EUS-guided, trans-enteric drainage of a pseudocyst or nonadherent fluid collections [bib_ref] Endoscopic ultrasound-guided transmural stenting for gallbladder drainage in high-risk patients with acute..., Anderloni [/bib_ref]. The theoretical advantage of LAMSs over other stents is the ability to approximate the gallbladder wall to the enteric lumen, 'sealing off' any potential bile leaks and preventing migration, thus providing a robust lumen anchorage [bib_ref] EUS-guided gallbladder drainage with lumenapposing metal stent (with video), Irani [/bib_ref]. Furthermore, the large diameter of LAMSs (10 mm and 15 mm) may allow access to the gallbladder with a slim endoscope with the purpose of removing stones, or taking biopsies [bib_ref] Endoscopic ultrasound-guided transmural stenting for gallbladder drainage in high-risk patients with acute..., Anderloni [/bib_ref]. In a retrospective review of multi-center prospectively collected data, Irani et al. [bib_ref] EUS-guided gallbladder drainage with lumenapposing metal stent (with video), Irani [/bib_ref] achieved a technical success rate of 93% and a clinical success rate of 100% using LAMSs to decompress the gallbladder in patients who had ACC and who were poor surgical candidates. Dollhopf et al. [bib_ref] EUS-guided gallbladder drainage in patients with acute cholecystitis and high surgical risk..., Dollhopf [/bib_ref] , with a new LAMSs device, obtained technical and clinical success rates of 98.7% and 95.9%, respectively, with 10.7% of cases having adverse events. 6.9 If a EUG-GBD is performed using metal stents, we recommend their removal within 4 weeks, in order to avoid food impaction with subsequent high risk of recurrence of ACC. #QoE: low; SoR: weak# The long-term deployment of metal stents in EUS-GBD could cause adverse events, including food impaction, which, by impairing bile flow, may induce recurrence of cholecystitis. There are several evidences [bib_ref] Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis : Long-term outcomes after removal..., Kamata [/bib_ref] that a well formed fistula might develop between the gallbladder and the gastrointestinal tract within four weeks using a conventional biliary SEMS as well as a LAMS. Some authorshave argued that, in order to minimise the risk of recurrent cholecystitis or biliary leakage, LAMSs could be left in place for a longer period, without stent-related complications [bib_ref] Diagnostic approaches in acute cholecystitis: a prospective study of 1333 patients with..., Eskelinen [/bib_ref]. Although a more significant tissue reaction can be expected after a long stented well-time, it seems probable that stent location, whether gastric or duodenal, might also influence the degree of tissue overgrowth. The retroperitoneal location of the duodenum results in a more stable tract to the gallbladder than the stomach, in which peristaltic movements might result in a more pronounced tissue reaction, impairing the removal of the stent once the inflammatory process has subsided. ## Section 7. antibiotic treatment of acc Which is the optimal antibiotic treatment for patients with uncomplicated ACC? 7.1 In uncomplicated ACC, we recommend against the routine use of postoperative antibiotics when the focus of infection is controlled by cholecystectomy. #QoE: high; SoR: strong# An open-label non-inferiority prospective controlled trial by Regimbau et al. [bib_ref] Effect of Postoperative Antibiotic Administration on Postoperative Infection Following Cholecystectomy for Acute..., Regimbeau [/bib_ref] randomized 414 patients who underwent cholecystectomy for uncomplicated ACC to either no antibiotics after surgery or continuation of the preoperative antibiotic regimen for 5 days. An imputed intention-to-treat analysis showed no difference in the incidence of postoperative infection rates: 17% (35 out of 207) in the no-treatment group compared with 15% (31 out of 207) in the antibiotic group (absolute difference 1.93%; 95% CI − 8. . No studies were found on this topic since the publication of the 2016 WSES Guidelines on ACC. Which is the optimal antibiotic treatment for patients with complicated ACC? 7.2 In complicated ACC, we recommend prescribing the antimicrobial regimen based on the presumed pathogens involved and the risk factors for major resistance patterns. #QoE: high; SoR: strong# Empiric antibiotic treatment should be commenced according to the most frequently isolated microorganisms, taking into consideration the local trends of antibiotic resistance and the availability of drugs. In biliary infections, Gram-negative aerobes, such as Escherichia coli and Klebsiella pneumonia, and anaerobes, especially Bacteroides fragilis are the most commonly isolated bacteria [bib_ref] Complicated intra-abdominal infections worldwide : the definitive data of the CIAOW Study, Sartelli [/bib_ref] [bib_ref] Complicated intra-abdominal infections in Europe : a comprehensive review of the CIAO..., Sartelli [/bib_ref]. The potential pathogenicity of Enterococci in biliary sepsis remains unclear and specific coverage against these microorganisms is not routinely suggested for community-acquired biliary infections [bib_ref] WSES guidelines for management of intra-abdominal infections, Sartelli [/bib_ref]. In case of immunosuppression, i.e. transplant patients, infection lead by Enterococcus spp. should be presumed and pre-emptively treated [bib_ref] Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children :..., Solomkin [/bib_ref]. The main issue related to antibiotic resistance in biliary tract infections remains the production of extended spectrum betalactamase by Enterobacteriaceae; this is frequently found in community acquired infections in patients with previous exposure to antibiotics [bib_ref] Complicated intra-abdominal infections worldwide : the definitive data of the CIAOW Study, Sartelli [/bib_ref] [bib_ref] Complicated intra-abdominal infections in Europe : a comprehensive review of the CIAO..., Sartelli [/bib_ref]. Healthcare-related infections are commonly caused by resistant bacterial strains, requiring complex antibiotic regimens; the use of adequate broad-spectrum empiric therapy appears to be a crucial factor to reduce postoperative complications and deaths, especially in critically ill patients [bib_ref] Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children :..., Solomkin [/bib_ref]. The efficacy of antibiotics in the treatment of biliary infections may be associated with their biliary concentration, although few clinical or experimental data exists supporting the use of antibiotics with biliary penetration for these patients. Nevertheless, in patients with obstructed bile duct, the biliary penetration of antibiotics may be poor and the actual bile concentrations are reached only in a small percentage of patients [bib_ref] Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime, Dhalluin-Venier [/bib_ref]. Biliary penetration of different antibiotics (indicated as the ratio of bile-to-serum concentrations) are listed in . In the management of critically ill patients with ACC, the choice of the antimicrobial regimen may be challenging. In patients with sepsis of abdominal origin, the early administration of a correct empirical antimicrobial therapy has a significant impact on outcome [bib_ref] Current concept of abdominal sepsis : WSES position paper, Sartelli [/bib_ref]. Richè et al. prospectively studied a cohort of 180 consecutive patients with secondary generalized peritonitis and found that there was a significantly higher mortality rate in patients with septic shock than in those without septic shock (35% and 8%, respectively, OR 4.11; 95% CI 1.78-9.48, p = 0.0003) [bib_ref] Factors associated with septic shock and mortality in generalized peritonitis : comparison..., Riché [/bib_ref]. Furthermore, in patients with septic shock, the biliary origin of peritonitis was a risk factor for mortality at multivariate analysis (OR 3.5; 95% CI 1.09-11.70, p = 0.03). International guidelines for the management of severe sepsis and septic shock (the Surviving Sepsis Campaign) [bib_ref] Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic..., Dellinger [/bib_ref] recommend the administration of broad-spectrum intravenous antibiotics with good penetration into the presumed site of infection within the first hour. A recent CC (Sepsis-3) [bib_ref] The third international consensus definitions for sepsis and septic shock (sepsis-3), Singer [/bib_ref] proposed a new evidence-based definition of sepsis and septic shock, underscoring the importance of recognizing the septic focus and the infecting organism. In cases of biliary sepsis, drug pharmacokinetics may be significantly altered in patients with organ dysfunction and septic shock; therefore, the selection of antibiotics should be reassessed daily and be based on both the pathophysiological status of the patient and the pharmacokinetic properties of the specific drug [bib_ref] Bench-to-bedside review : Appropriate antibiotic therapy in severe sepsis and septic shock..., Pea [/bib_ref]. No significant additional evidence was found since the publication of the 2016 WSES Guidelines on ACC (see for recommended antibiotic regimens). What is the role of microbiological cultures and sensitivities in patients with ACC? 7.3 In patients with complicated ACC and patients at high risk for antimicrobial resistance, we recommend adapting the targeted antibiotic regimen to the results of microbiological analysis, ensuring adequate antimicrobial coverage. #QoE: moderate; SoR: weak# Identifying the causative organism(s) is an essential step in the management of ACC, especially in patients at high risk for antimicrobial resistance, such as immunocompromised patients and those with healthcareassociated infections. The rate of positive bile culture (from either gallbladder culture or bile samples from the common bile duct) ranges from 29 to 54% in cases of ACC [bib_ref] Bacteriological studies of bile from the gallbladder in patients with carcinoma of..., Csendes [/bib_ref] [bib_ref] Simultaneous bacteriologic assessment of bile from gallbladder and common bile duct in..., Csendes [/bib_ref] [bib_ref] Counts of bacteria and pyocites of choledochal bile in controls and in..., Csendes [/bib_ref] [bib_ref] Bacteriological study of choledochal bile in patients with common bile duct stones,..., Maluenda [/bib_ref] [bib_ref] Bacteriology and antimicrobial susceptibility in biliary tract disease: an audit of 10-year's..., Chang [/bib_ref] [bib_ref] Microbiology and antibiotic susceptibility of organisms in bile cultures from patients with..., Salvador [/bib_ref]. No additional studies have been found on this topic since the publication of the 2016 WSES Guidelines on ACC. ## Conclusions, knowledge gaps and research recommendations The WSES 2020 on ACC, based on the updated evidence, reinforces the pivotal role of ELC in the management of ACC, even in high-risk patients. The new developed algorithm, in our opinion, emphasizes the importance of two categories of patients: the high-risk patients and those who are not suitable for surgery. The CHOCOLATE Study [bib_ref] Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk..., Loozen [/bib_ref] defined high-risk patients as those with an APACHE score 7-14; this high-quality study improved our understanding of the management of this complex cohort of patients. Its results are in favour of surgery, when compared with biliary drainage in high-risk patients with ACC. However, there is not a single and universally accepted definition of this high-risk patients group; therefore, accepting the suggestion coming from Loozen et al., it appears reasonable to recommend the development of local clinical pathways after deciding which of the available scores fits local needs and expertise. In addition to the defined high-risk patients, the WSES proposes the category of patients who are not suitable for surgery. We suggest to include in this group all patients with ACC who are not fit for surgery, according to the specific surgeon's judgement, and patients who are not amenable for surgical treatment, due to the presence of clinical conditions which are not classifiable with clinical or physiologic scores (Appendix 2). For this cohort of patients, surgery may be unsafe or impossible and gallbladder drainage may be the best suitable option in case of uncontrolled sepsis and/or failure of NOM. Moreover, areas for important future research were identified. These include (1) high-quality studies on prognostic factors of ACC patients so as to improve shared decision making, (2) defining the best management option when ELC is not possible due to lack of surgical expertise or due to the duration of symptoms. This should include focus groups involving patients and clinicians, and using observational studies, and (3) defining the best option in the management of difficult operative scenarios. This needs a common language among researchers in order to obtain higher quality studies (in terms of classification of difficulties: e.g. adhesions with hollow viscus, difficulties in grasping the gallbladder, difficulties in view of safety, gangrene of the cystic duct, etc.). Finally, the WSES strongly advocates the adoption of a policy for safe laparoscopic cholecystectomy and encourages the development of local pathways, based on the available evidence. ## Supplementary information Supplementary information accompanies this paper at https://doi.org/1 0.1186/s13017-020-00336-x . [fig] Figure 1 2020: WSES Flowchart for the management of patients with acute calcolus cholecystitis [/fig] [fig] Additional file 1: Appendix 1 and 2 Abbreviations ACC: Acute calculous cholecystitis; GRADE: Grading of Recommendations Assessment, Development and Evaluation; TG: Tokyo Guidelines; CC: Consensus Conference; CBDS: Common bile duct stone; RCT: Randomized controlled trial; LR: Likelihood ratio; US: Ultrasound; pSWE: Point shear-wave elastography; AUC: Area under the curve; SMI: Superb microvascular imaging; HIDA: Hepatobiliary iminodiacetic acid; CT: Computed tomography; MRI: Magnetic resonance imaging; ERCP: Endoscopic retrograde colangio-pancreatography; LFTs: Liver function tests; GGT: Gamma-glutamyl transpeptidase; ALT: Alanine aminotransferase; IOC: Intra-operative cholangiography; PPV: Positive predictive value; NPV: Negative predictive value; ALP: Alkaline phosphatase; EUS: Endoscopic ultrasound; MCRP: Magnetic resonance colangio-pancreatography; LUS: Laparoscopic ultrasound; ELC: Early laparoscopic cholecystectomy; OR: Odds ratio; 95% CI: 95% confidence interval; ILC: Intermediate laparoscopic cholecystectomy; DLC: Delayed laparoscopic cholecystectomy; NOM: Non operative management; PTGBD: Percutaneous transhepatic gallbladder drainage; ETGBD: Endoscopic transpapillary gallbladder drainage; EUS-GBD: Ultrasound-guided transmural gallbladder drainage; ENGBD: Endoscopic transpapillary nasogastric gallbladder drainage; EGBS: Endoscopic gallbladderstent; LAMS: Lumen-apposing self-expandable metal stent; SEMS: Self-expandable metal stents [/fig] [table] Table 1: Sections/topics, key questions and key words [/table] [table] Table 2: Risk factors and classification of risk for CBDS (modified fromMaple et al. 2010) risk for post-ERCP pancreatitis, but required dedicated staff and prolonged the length of surgery.Section 3. Surgical treatment of ACCThe literature updated from the 2016 WSES Guidelines on ACC showed no remarkable publications to change the meaning of previous statements edited by the WSES in 2016[7]; however, they have been reviewed to ensure the best available evidence.Which is the preferred first line of treatment for patients with ACC?When should laparoscopic cholecystectomy be avoided in patients with ACC?3.1 We recommend laparoscopic cholecystectomy as the first-line treatment for patients with ACC. #QoE: high; SoR: strong# Comment: A low complication rate and shortened hospital stay are the major advantages.3.2 We recommend avoiding laparoscopic cholecystectomy in case of septic shock or absolute anaesthesiology contraindications. #QoE: high; SoR: strong# [/table] [table] Table 3: Timing of cholecystectomy in people with ACC [/table]	None	https://wjes.biomedcentral.com/track/pdf/10.1186/s13017-020-00336-x	None
f0e7626ddc6132d1e018ce54fa53967ec6d1d166	pubmed	Diagnostic approach to paediatric movement disorders: a clinical practice guide	Diagnostic approach to paediatric movement disorders: a clinical practice guide IEMInborn error of metabolism NGS Next-generation sequencing PMD Paediatric movement disorder WES Whole-exome sequencingPaediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This can make the diagnostic process time-consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next-generation sequencing, post-sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs. In recent years, the importance of recognition and treatment of paediatric movement disorders (PMDs) has increasingly been recognized.PMDs often comprise a mixed clinical picture with neurological and non-neurological features.In addition, the number of possible aetiologies is growing, especially those concerning genetic causes. Owing to a variable phenotype-genotype correlation, the diagnostic process for PMDs becomes challenging and time consuming, not only for the clinician but also for patients and caregivers. [bib_ref] Crossing barriers: a multidisciplinary approach to children and adults with young-onset movement..., Van Egmond [/bib_ref] Innovative next-generation sequencing (NGS) techniques have increased the diagnostic yield in paediatric neurology. [bib_ref] A post hoc study on gene panel analysis for the diagnosis of..., Van Egmond [/bib_ref] The use of NGS can speed up the diagnostic process and prevent unnecessary additional investigations, and shorten the time of uncertainty in patients and caregivers. Second, in some disorders, early treatment options are crucial to prevent further neurological decline. The goal of this overview is to present a diagnostic algorithm that can serve as a framework for paediatricians and/ or (paediatric) neurologists with less experience in PMDs [fig_ref] Figure 1: A diagnostic approach to paediatric movement disorders [/fig_ref]. ## Clinical phenotype Step 1. Is it a movement disorder? The first step is to distinguish normal, physiological developmental motor patterns and pathological movement disorders. Infantile fidgety movements and startles resembling chorea and myoclonus normally disappear around the age of 3 months. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] Dystonic-like features may appear from birth and can persist until the age of 16 years. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] The development of goal-directed movements coincides with the occurrence of ataxic-like features which can persist until the age of 12 years. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] It may be difficult to distinguish physiological developmental motor patterns from pathological movement disorders. Children should be monitored to evaluate how the movement pattern develops. In general, physiological patterns will subside with typical psychomotor development. Besides developmental features, other neurological diseases (such as epilepsy) may resemble movement disorders. Step 2. Classify the movement disorder phenotype and which movement disorder is the most prominent The second step is to classify the movement disorder phenotype and denote which movement disorder is the most prominent. Clinical clues can be used to distinguish between different movement disorder phenotypes. Movement disorders are classified into three major groups: hyperkinetic and hypokinetic movement disorders and ataxia. In children, hyperkinetic movement disorders are more prevalent and include tics, dystonia, chorea, myoclonus, stereotypies, and tremor. Hypokinetic movement disorders, including Parkinsonism, are rare in children. Ataxia is not a hypo-or hyperkinetic movement disorder, but includes disorganized and poorly executed movements, and is relatively common in children. [bib_ref] Movement disorders in children, Schlaggar [/bib_ref] ## Hyperkinetic movement disorders Tics. Tics are defined as sudden, rapid, recurrent, nonrhythmic movements or vocalizations (Video S1, online supporting information; descriptions of the videos are found in Appendix S1, online supporting information).A distinction is made between motor and phonic tics and each is subdivided as simple or complex. Simple motor tics comprise a single muscle or localized muscle group, such as eye blinking. Complex motor tics involve either a cluster of simple actions or a coordinated sequence of movements. Simple phonic tics include sounds and noises such as humming or sniffing, whereas complex phonic tics comprise the repetition of words, syllables, or phrases. Positive clues are a waxing and waning course, worsening by stress or excitement, the report of a premonitory sensation, and brief voluntary suppressibility followed by a rebound. [bib_ref] Diagnosis and assessment of Parkinson disease and other movement disorders, Jankovic [/bib_ref] Dystonia. Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous (Video S2, online supporting information). Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Symptoms can be present in one body part (focal), additional/adjacent body parts (segmental), unilateral (hemidystonia), or generalized. Slow, continuous, involuntary writhing movements that prevent maintenance of a stable posture, previously known as athetosis, are considered as part of a dystonic phenotype. Features supporting the diagnosis dystonia include mirror movements and a sensory trick. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] These features may help clinicians to differentiate between dystonia and 'dystonia mimics'. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] The most important dystonia mimic is spasticity. Key features in distinguishing spasticity from dystonia are the presence of velocity-dependent hypertonia, hyperreflexia, and pathological plantar responses. Spastic posturing reveals prominent flexion of the elbow and wrist with adduction of the thumb. Chorea. Chorea is characterized by an excess of brief, continuous, unpatterned involuntary movements (Video S3, online supporting information).The continuous, non-suppressible movements give the appearance of restlessness. The presence of involuntary movements at rest, worsening during action, and incorporation of excessive movements in voluntary movements are clues for this phenotype. Myoclonus. Myoclonus is the fastest movement disorder, characterized by brief involuntary, irregular jerks caused by muscle contraction (positive myoclonus) or loss of muscle activity in active postural muscles (negative myoclonus) (Video S4, online supporting information). Myoclonus is classified according to the anatomical origin into cortical, subcortical, spinal, and peripheral myoclonus. [bib_ref] Parkinson Disease and other Movement Disorders, Zutt [/bib_ref] Cortical myoclonus is the most common myoclonus subtype whereas peripheral myoclonus is rare. [bib_ref] Parkinson Disease and other Movement Disorders, Zutt [/bib_ref] Clinical features and electrophysiological testing can help to differentiate between myoclonus subtypes and tremor.Stereotypies. Stereotypies encompass non-goal-directed fixed movement patterns or vocalizations that are repeated continuously for a period of time (seconds to minutes) in the same form (Video S5, online supporting information). These patterns occur on multiple occasions, are purposeless, and are typically distractible. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] Examples are hand/arm flapping and head nodding. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] Stereotypies usually manifest before the age of 3 years. [bib_ref] Stereotypic movement disorders, Katherine [/bib_ref] The movements are triggered by excitement, stress, or fatigue. Stereotypies are frequently upsetting to caregivers, but usually of little concern to the child.Tremor. Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part (hands, legs, head, or jaw) or the voice (Video S6, online supporting information). 14 It can occur at rest, during sustained postures, during movements, and at the end of intentional movements. ## Hypokinetic movement disorders Parkinsonism. Parkinsonism is characterized by the core symptom bradykinesia with the occurrence of tremor, rigidity, or both (Video S7, online supporting information). [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Parkinsonism can be recognized by a generalized slowness of movements. When patients with bradykinesia are asked to perform repetitive movements, the amplitude decreases and becomes less rhythmic. The tremor in juvenile Parkinsonism is frequently a rest tremor, but postural or action tremor can also be found. [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Ataxia Ataxia is characterized by the presence of uncoordinated movements (Video S8, online supporting information). The symptoms are subdivided in four domains: (1) gait and stance with a broad-based gait, staggering, and swaying; (2) kinetic ataxia with an intentional tremor, dysmetria, and dysdiadochokinesis; (3) eye movements with nystagmus, saccadic intrusions, and dysmetria; and (4) cerebellar dysarthria.The difficulties in coordination are mainly present when turning during walking and the execution of faster, goal-directed movements. At rest, there are no involuntary movements. Step 3. Could the movement disorder be functional? Functional movement disorders can either be hyper-or hypokinetic, with the first being much more prevalent. The diagnosis of a functional movement disorder is no longer made per exclusion, but should be a positive diagnosis, based on features in the history and examination. [bib_ref] Functional neurologic symptoms: assessment and management, Stone [/bib_ref] These features are abrupt onset, varying (severity of) symptoms, and a temporary decrease of symptoms when the patient is distracted. Specifically in the case of tremor or jerky movements, entrainment can be objectified, a phenomenon in which the involuntary movements copy the rhythm of an externally cued voluntary movement (like finger-tapping).In functional dystonia, the posturing is frequently fixed instead of mobile.Additional features pointing in the direction of a functional movement What this paper adds - An up-to-date description and diagnostic framework for testing of paediatric movement disorders is presented. - The framework helps to determine which patients will benefit from nextgeneration sequencing. Clinical Practice Guide 253 disorder include a history of unexplained medical symptoms, prominent pain, paroxysmal symptoms, and sometimes a physical or psychosocial trigger and selective disability. [bib_ref] Psychogenic movement disorders in children, Ferrara [/bib_ref] Despite these characteristics, it sometimes remains difficult to distinguish functional movement disorders from non-functional ones, and they can coincide in the same patient. Step 4. Determine the clinical syndrome We denote the clinical syndrome as the constellation of all clinical features, including different movement disorders, as well as additional neurological signs (such as spasticity, epilepsy, polyneuropathy, deafness, blindness, and cognitive difficulties) and non-neurological signs (including dysmorphisms, skin and psychiatric abnormalities [e.g. obsessivecompulsive disorder, behavioural changes, apathy]). Sometimes the clinical syndrome strongly points to a specific diagnosis and prompts directed genetic testing. However, in children, clinical syndromes are usually less distinct. In these cases, it is advisable to select the main movement disorder as the starting point for diagnostic testing. In the following section we outline the basic approach grouped by the main movement disorder phenotype. We also provide references to diagnostic algorithms for some specific movement disorders. ## Tics Tics are divided into either primary or secondary tic disorders. Primary tic disorders are the most common. Transient tic disorder is the most frequent primary tic disorder in children followed by Tourette syndrome. Secondary tic disorders are rare and can be caused by acquired or genetic disorders (chromosomal or heredo-degenerative). It has been hypothesized that an acute onset of tics with neuropsychiatric symptoms (such as obsessive-compulsive disorder) might be associated with an aberrant immune response to an infectious episode, described as paediatric auto-immune neuropsychiatric disorder associated with streptococcal infection; however, the true relation with streptococcal infection is still debated. [bib_ref] Movement disorders in children, Schlaggar [/bib_ref] If the patient has an isolated tic disorder, further diagnostic testing is not necessary. ## Dystonia The aetiology of dystonia can be divided into acquired or genetic. Acquired causes can be divided in structural lesions, vascular insults, and infectious or auto-immune disorders. For genetic dystonia the list of causes is extensive. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] Classification of the clinical characteristics of dystonia is important, because of the implications for diagnostic testing and treatment. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] [bib_ref] Assessment of patients with isolated or combined dystonia: an update on dystonia..., Fung [/bib_ref] van Egmond et al. described a diagnostic algorithm to help clinicians decide which patients would benefit from NGS technologies or whether they would require other initial investigations. 8 ## Chorea To facilitate diagnosis, a (sub-)acute onset should be distinguished from chronic chorea. (Sub-)acute chorea is the most common form in children; the aetiology is frequently acquired and can be subdivided into auto-immune (Sydenham chorea), infectious/inflammatory, vascular, hypoxic, and drug-or toxin-induced. Chronic chorea is categorized as primary (isolated genetic chorea) or secondary (perinatal hypoxic ischemic injuries, neurodegenerative, and metabolic or auto-immune disorders). The secondary aetiologies are mainly multisystem diseases in which chorea can Could the MD be functional? be the main symptom, but it is often accompanied by other (non-)neurological symptoms. [bib_ref] Acute and chronic chorea in childhood, Gilbert [/bib_ref] In particular in the latter case, further genetic diagnostic work-up with NGS is warranted (see . ## Myoclonus Myoclonus can be the symptom of a wide variety of acquired and genetic disorders. A (sub-)acute onset and fast progression points towards acquired causes, whereas young-onset and a slow progressive course is more characteristic of a genetic disorder. The most common acquired causes include drug-induced, metabolic derangements, infection, or auto-immune disorders. In genetic disorders, myoclonus is often accompanied by ataxia, dystonia, or other movement disorders. Isolated myoclonic jerks can be seen in epileptic encephalopathies and familial cortical myoclonic tremor with epilepsy; for a comprehensive overview of genetic myoclonus disorders, see van der Veen et al. [bib_ref] Nomenclature of genetically determined myoclonus syndromes: recommendations of the International Parkinson and..., Van Der Veen [/bib_ref] A diagnostic approach to patients with myoclonus can be found in Zutt et al. [bib_ref] A novel diagnostic approach to patients with myoclonus, Zutt [/bib_ref] ## Stereotypies Causes of stereotypies can be divided into four groups. Physiological and primary stereotypies are seen during typical development and they will disappear over time. Secondary stereotypies are seen in children with a variety of underlying disorders, such as developmental delay, autism, (para)infectious, paraneoplastic, auto-immune, drug induced, or they are due to sensory deprivation. Only in rare cases are stereotypies due to genetic causes, including Rett syndrome. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] In a typically developing child, stereotypies will not need further diagnostic work-up. Further diagnostic work-up (such as infectious, auto-immune, and/or genetic testing) is indicated only if additional features are present. ## Tremor In patients with tremor it is advisable to look for additional signs, such as dystonia, Parkinsonism, and cerebellar or brainstem signs, pointing towards a combined clinical syndrome that warrants specific diagnostic tests. 14 If no additional signs are present, the patient has an isolated tremor syndrome, such as essential or enhanced physiological tremor. Enhanced physiological tremor can be caused by several reversible conditions, such as anxiety, fatigue, hyperthyroidism, and numerous drugs. 14 Essential tremor is familial in half of the patients. [bib_ref] Essential tremor, Haubenberger [/bib_ref] Parkinsonism Isolated Parkinsonism is rare in childhood and is observed in young-onset Parkinson disease; in most cases there is a positive family history. In children, Parkinsonism is frequently accompanied by other movement disorders or other neurological signs (cognitive decline, behavioural disturbances). [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Parkinsonism can be due to acquired (e.g. medication, toxins, infectious) or genetic/metabolic causes, including Wilson disease, neurodegeneration with brain iron accumulation, and neurotransmitter disorders. Importantly, juvenile Parkinsonism can be caused by different trinucleotide disorders (such as Huntington disease and spinocerebellar ataxia type 3). It is important to realize that these disorders are not identified by current NGS techniques and require specific genetic testing. In case of Parkinsonism the first step will be to perform magnetic resonance imaging (MRI) with susceptibility-weighted images to give guidance to further diagnostic work-up, especially genetics. ## Ataxia Paediatric-onset ataxia is also caused by acquired or genetic disorders. [bib_ref] The natural history of degenerative ataxia: a retrospective study in 466 patients, Klockgether [/bib_ref] Acquired causes are recognized by the (sub)acute onset as genetic disorders reveal a more insidious onset. Acquired causes can be medication, toxins, (para-)infectious, paraneoplastic, vascular, or auto-immune. Many genetic disorders can cause a mixed ataxic disorder, which is combined with other movement disorders or (non)-neurological signs. The most prevalent ataxic disorder in children, Friedreich ataxia, which is a trinucleotide disorder, will not be picked up by current NGS techniques. For a diagnostic approach of ataxia in children, see Case example (steps 1-4 of the algorithm) A 2-year-old male presented to the outpatient clinic with slowly progressive balance disturbances and frequent falls. The symptoms did not start after a febrile episode. Besides these complaints, there were no other problems. Cognitive development was typical. He was born at a gestational age of 40+3 weeks after an uncomplicated pregnancy. Apgar scores postpartum were normal. Gross motor development was delayed. Communicative skills and fine motor skills were normal. Family history was negative for movement disorders, epilepsy, or developmental disorders. Neurological examination revealed a severely unsteady and very broad-based gait. Beside the broad-based gait there were fast abrupt jerks of the extremities and the trunk resulting in more balance problems. During finger pointing these jerks were also present, without clear dysmetria. Reflexes were normal with normal plantar responses. Physical examination showed no abnormalities of the skin or signs of other organ involvement. The findings of the history and neurological examination were compatible with prominent gait ataxia combined with jerky movements, probably myoclonus. Therefore, we defined the clinical syndrome as a progressive ataxia with myoclonus. ## Diagnostic testing Step 5. Can the movement disorder be caused by an acquired cause? Almost all movement disorders can be caused by acquired causes, but, as previously discussed, the onset in acquired movement disorders is more (sub)-acute. In this section we briefly discuss the additional investigations besides careful Clinical Practice Guide 255 history taking including prescribed medication [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] and intoxication. ## Mri The first step in identifying an acquired cause is to perform MRI of the brain. Vascular and traumatic causes can be visualized. MRI might give clues for auto-immune disorders and some genetic/metabolic disorders. ## Laboratory testing Especially in the case of infectious or auto-immune disease, laboratory testing can be helpful by determining infectious and auto-immune parameters. Serological testing of viral and bacterial agents is also useful. ## Cerebrospinal fluid The presence of a pleiocytosis in cerebrospinal fluid points to an infectious or auto-immune disorder. Additional serological testing and determining auto-immune antibodies in cerebrospinal fluid can be performed thereafter. Step 6. Does the clinical syndrome fit a treatable inborn error of metabolism? Clinicians should be aware that, especially in children with more than one movement disorder, involvement of multiple organs, and/or cognitive difficulties, the underlying aetiology could be an inborn error of metabolism (IEM). Worsening of symptoms after dietary changes, fasting, or fever can be important clues for an IEM. Treatment options are increasing for metabolic disorders and more therapies are expected. A fast recognition of a treatable IEM is crucial as timely treatment can prevent or lessen (brain) damage. [bib_ref] Movement disorders in treatable inborn errors of metabolism, Ebrahimi-Fakhari [/bib_ref] Therefore, in many countries, several treatable IEMs are included in newborn screening programmes and treatment can be started before symptoms have occurred. It is important to realize that IEMs comprise a large group of disorders which are all based on genetic mutations and can be detected by NGS techniques similar to other genetic disorders. Therapeutic options for IEMs are divided into reduction of toxic substances, dietary interventions, vitamin supplementation, avoidance or management of triggers, specific medications, and others. [bib_ref] Treatable inherited rare movement disorders, Jinnah [/bib_ref] For a list of treatable metabolic disorders that can present with movement disorders, see [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] (online supporting information). [bib_ref] Movement disorders in treatable inborn errors of metabolism, Ebrahimi-Fakhari [/bib_ref] [bib_ref] Treatable inherited rare movement disorders, Jinnah [/bib_ref] [bib_ref] Clinical and biochemical footprints of inherited metabolic diseases. I. Movement disorders, Ferreira [/bib_ref] Step 7. Consider genetic testing If acquired causes are excluded, genetic testing should be the next step. Below, we discuss which genetic testing is most appropriated to perform first. (1) In the case of a clear phenotype/genotype correlation or in case of a positive family history, the performance of directed genetic testing of a single gene (Sanger sequencing) is warranted. (2) If there is no clear phenotype/genotype correlation, a first-tier test in PMD can be comparative genomic hybridization. The diagnostic yield will increase if patients have a movement disorder combined with cognitive difficulties, autism, and/or dysmorphisms. (3) We recommend that when there is a genetic differential diagnosis of two or more genes it is cheaper (and faster) to perform NGS instead of single gene analysis. Whole-exome sequencing (WES) is the most applied basic technique for NGS. [bib_ref] Exome sequencing: how to understand it, Keogh [/bib_ref] In general, the first step in the genetic diagnostic process of PMDs is the use of a WES with a movement-disorder-specific filter. In these cases, a filter with predefined genes associated with the main movement disorder phenotype will be analysed. When the diagnosis is not established by using this filter, an analysis of the data set of all the genes captured (open WES) can be performed next. When using NGS techniques one should be aware of the limitations: (1) the genes in the filter need to be selected carefully and be update regularly; (2) trinucleotide repeat expansion disorders, large rearrangement deletions and duplications, mutations in the non-coding part of the genome (such as deep intronic regions or promotor regions) are not detected; [bib_ref] Exome sequencing: how to understand it, Keogh [/bib_ref] (3) mitochondrial diseases due to mutations in mitochondrial DNA are not detected by most laboratories using WES; one should realize that the [formula] Anticonvulsants U U U U U U Antipsychotics U U U U Antidepressants U U U U Antihypertensives U Antiparkinson drugs U U Antibiotics U U Antineoplastic U U U Opiates U Anxiolytics U U Anaesthetics U Oral contraceptives U Anti-emetics U U Immunosuppressants U U Corticosteroids U U [/formula] The table shows groups of medication known to cause different movement disorders. The list is not complete and only shows the main classes of drugs that may induce movement disorders. current diagnostic yield of NGS techniques is only 15% to 40%, but probably will increase in forthcoming years. Step 8. Post-NGS phenotyping The results of NGS techniques can be difficult to interpret. Frequently, results reveal variants of unknown significance or heterozygotic mutations in a gene associated with a recessive disease. In these cases, it is extremely important that focused phenotyping for specific movement disorder features is performed. If the movement disorder phenotype is congruent with the phenotype of the disease (in which a variant of unknown significance or heterozygous mutation is present), further genetic investigations will be necessary to determine whether the variant(s) found explain the clinical phenotype of the patient. This includes a multiplex ligation-dependent probe amplification of the gene involved to find structural rearrangements such as duplications or deletions, which in combination with a heterozygous mutation may explain the phenotype. Also, genetic testing of parental DNA (for de novo mutations) and functional studies of the candidate gene may be warranted. Unfortunately, a definitive diagnosis cannot always be made with the help of post-NGS phenotyping. Case example (steps 5-8 of the algorithm) Brain MRI revealed slight hypoplasia/atrophy of the superior part of the vermis of the cerebellum, with no other cerebellar or cerebral abnormalities. Laboratory investigations were all normal. We performed genetic testing by using a WES technique with an ataxia filter (the most prominent movement disorder). This revealed a heterozygotic pathogenic mutation in the KCNC3 gene (c.1268G>A, p. [Arg423His]) compatible with autosomal dominant spinocerebellar ataxia type 13. However, spinocerebellar ataxia type 13 is not associated with (negative) myoclonus. By post-phenotyping with the help of a polymyography, we found that the jerky movements did not fit with myoclonus but were more compatible with an intention tremor, changing the clinical syndrome to a purer ataxic disorder. ## Treatment With or without a diagnosis, one should always consider treatment options. In movement disorders, mechanismbased treatment modalities for specific (especially metabolic) disorders or symptomatic treatment for the main movement disorder can be chosen. # Conclusion PMDs concern a large group of disorders with heterogeneous phenotypes and genotypes, and diagnostic work-up can be challenging and time-consuming. In this paper, we have presented an up-to-date overview of PMDs and provided a diagnostic framework to facilitate early recognition of movement disorder phenotypes and guidance during the diagnostic process. # Data availability statement Data sharing is not applicable to this article as no new data were created or analyzed in this study. ## Supporting information The following additional material may be found online: Video S1: Tics. Appendix S1: Legends to the videos. [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] : Treatable inborn errors of metabolism that can present with pediatric movement disorders [fig] Figure 1: A diagnostic approach to paediatric movement disorders (PMDs). The diagnostic approach of PMDs divided in a clinical part (history and examination) and diagnostic part (diagnostic testing). Each step of this approach is explained in the text. [Colour figure can be viewed at wileyonlinelibrary.com] [/fig] [table] Table 1: Medication with movement disorders as side effects [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/dmcn.14721	Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype–phenotype relationships. This can make the diagnostic process time‐consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next‐generation sequencing, post‐sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs.
f3a3e1831a6df0eeecb66e7f0625553bf1eaea0d	pubmed	American College of Rheumatology Guidance for COVID‐19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 3	American College of Rheumatology Guidance for COVID‐19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 3 Objective. To provide guidance to rheumatology providers on the use of coronavirus disease 2019 vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).Methods. A task force was assembled that included 9 rheumatologists/immunologists, 2 infectious disease specialists, and 2 public health physicians. After agreeing on scoping questions, an evidence report was created that summarized the published literature and publicly available data regarding COVID-19 vaccine efficacy and safety, as well as literature for other vaccines in RMD patients. Task force members rated their agreement with draft consensus statements on a 9-point numerical scoring system, using a modified Delphi process and the RAND/University of California Los Angeles Appropriateness Method, with refinement and iteration over 2 sessions. Consensus was determined based on the distribution of ratings.Results. Despite a paucity of direct evidence, 74 draft guidance statements were developed by the task force and agreed upon with consensus to provide guidance for use of the COVID-19 vaccines in RMD patients and to offer recommendations regarding the use and timing of immunomodulatory therapies around the time of vaccination.Conclusion. These guidance statements, made in the context of limited clinical data, are intended to provide direction to rheumatology health care providers on how to best use COVID-19 vaccines and to facilitate implementation of vaccination strategies for RMD patients.Due to the rapidly expanding information and evolving evidence related to COVID-19, which may lead to modification of some guidance statements over time, it is anticipated that updated versions of this article will be published, with the version number included in the title. Readers should ensure that they are consulting the most current version. A summary of revisions over time and their location is included in the Supplementary Tables. # Introduction The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused untold disruption to nearly all aspects of human health globally. The substantial morbidity and excess mortality attributed to coronavirus disease 2019 (COVID-19) has had a major impact on health and the delivery of health care. Given the role that rheumatology providers have in serving patients with rheumatic and musculoskeletal diseases (RMDs) (1), particularly those with autoimmune and inflammatory rheumatic diseases (AIIRDs), there is an urgent need to optimize strategies to curb the incidence of COVID- In addition to preventive measures such as physical distancing, mask-wearing, handwashing, and shelter-in-place orders, the newly available COVID-19 vaccines provide a powerful tool to mitigate the burgeoning growth of adverse outcomes resulting from COVID-19. Given the leadership role of the American College of Rheumatology (ACR) in facilitating dissemination of high-quality evidence and promoting best practices for the care of RMD patients, the ACR periodically convenes task forces charged with developing methodologically rigorous clinical practice guidelines and guidance documents. Previous ACR guidelines developed for the management of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have included some information regarding optimal use of vaccines for patients with those conditions. However, because the immunologic principles related to use of vaccines and the impact of vaccine-preventable illnesses on patients cross a broad range of RMDs, the ACR altered its approach in 2020 and convened a new guideline development group to focus exclusively on vaccination. This cross-cutting team was charged with developing encompassing vaccination considerations for all disease and treatment-related areas within rheumatology, rather than embedding them into narrower, disease-specific clinical practice guidelines. The development process of ACR guidelines follows a rigorous and formal methodology, is based on a reproducible and transparent systematic literature review, incorporates panelist expertise from rheumatology health care professionals and input from related medical experts in other disciplines (e.g., infectious disease, epidemiology), includes direct participation by patients that reflects their values and preferences, and is typically conducted over an extended time frame (e.g., 1 year or longer). In contrast, the ACR develops "guidance" documents when the components needed to develop a formal guideline are not present, e.g., if the need to provide guidance is more urgent than a longer guideline timeline would allow, there is not enough peerreviewed evidence available to conduct a formal literature review, or when there is very limited expertise and experience, particularly on the part of patients, to help inform the development of recommendations. In these situations, an expert task force is formed to provide the best guidance possible based on the limited information available. The ACR expects that guidance documents will need to be updated with some frequency as new data become available and greater experience is acquired. Responding to the need to provide timely guidance to practicing clinicians, the ACR COVID-19 Vaccine Guidance Task Force was created as a branch of the ACR Vaccine Guideline effort, to summarize the available evidence for newly available COVID-19 vaccines and to make timely clinical recommendations to rheumatology providers for their optimal use. It relied on a limited evidence base derived from clinical trials evaluating the COVID-19 vaccines in non-RMD populations and also included indirect evidence regarding the immunogenicity, clinical effectiveness, and safety of other vaccines administered to RMD patients receiving various immunomodulatory therapies. Armed with this information, task force members were asked to extrapolate across diseases and integrate relevant basic science and immunologic principles to inform the use, timing, and prioritization of the COVID-19 vaccines available in the US and apply them to the care of RMD patients. # Methods ## Convening the acr covid-19 vaccine guidance Task Force and defining the scope of the clinical guidance. In October 2020, the ACR began assembling the ACR COVID-19 Vaccination Guidance Task Force. Invitations were made following a general solicitation sent to the broad ACR membership seeking interested volunteers. The task force consisted of 13 members from North America and included 9 rheumatologists, 2 infectious disease specialists, and 2 public health experts. Rheumatology task force members were chosen to represent various areas of specialty expertise within the field and to achieve diversity in geographic region, career stage, practice setting, sex, and race/ethnicity, while also ensuring that the majority of task force members had no conflicts of interest. The task force defined the intended scope of the guidance based on input from individual members, and external input was obtained informally from various stakeholders. The process was informed by the previously published ACR Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic [bib_ref] American College of Rheumatology guidance for the management of rheumatic disease in..., Mikuls [/bib_ref]. The scope of this guidance includes clinically relevant questions that were intended to inform rheumatology patient care related to COVID-19 vaccination and treatment considerations around the time of vaccination. The scoping questions were agreed upon by all panel members at an initial teleconference conducted on December 14, 2020. Developing the evidence summary. The task force was divided into teams that worked in parallel, each charged with summarizing the published literature and other available evidence spanning 4 topics: 1) the efficacy, immunogenicity, and safety data derived from clinical trials of late-stage (i.e., phase III) COVID-19 vaccines ongoing within the US or COVID-19 vaccines already available under the US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) act; 2) the epidemiology of COVID-19 risk and outcomes in RMD patients; 3) the attenuation of immunogenicity to other vaccines (e.g., influenza, pneumococcal) associated with certain immunomodulatory therapies; and 4) the safety profile (e.g., disease flare, new-onset autoimmune conditions) of non-COVID-19 vaccines in RMD populations. The scoping questions were grouped into these domains and distributed to the teams, which were tasked with gathering and summarizing evidence that addressed the questions within their assigned domains. The task force agreed that the intended audience for the guidance was rheumatology health care providers managing their individual patients, but they felt that some attention should be directed to a societal perspective, when relevant, around the availability of COVID-19 vaccines and prioritization for individuals with RMDs. The task force took the perspective of developing guidance for a US audience, particularly in view of the fact that the review of COVID-19 vaccine clinical trials was US-focused. Recognizing that RMD patients exhibit high variability with respect to their underlying health conditions, disease severity, treatments, and degree of multimorbidity, these considerations were noted as important facets of individualizing care. Therefore, this guidance was not intended to supersede the judgment of rheumatology care providers nor override the values and perspectives of their patients. Foundational principles, guiding assumptions, and acknowledged limitations were discussed and agreed upon throughout the process and are discussed in this document where most relevant. Development of the evidence review summary document. Given the accelerated time frame for guidance development, a nonsystematic evidence review was completed and included serial PubMed searches supplemented by postings from the Centers for Disease Control and Prevention (CDC); briefings and other documents available from the FDA, such as dossiers submitted by vaccine manufacturers and transcripts of data presented . Foundational principles, assumptions, and considerations for the guidance statements* ACR guidance statements are not intended to supersede the judgment of rheumatology care providers nor override the values and perspectives of their patients. Guidance was based on weak and/or indirect evidence and required substantial extrapolation by an expert task force. All statements, therefore, should be considered conditional or provisional. The ACR is committed to updating this guidance document as new evidence emerges. The rheumatology community lacks important knowledge on how to best maximize vaccine-related benefits. RMD patients exhibit high variability with respect to their underlying health condition, disease severity, treatments, degree of multimorbidity, and relationship with their specialist provider. These considerations must be considered when individualizing care. There is no direct evidence about mRNA COVID-19 vaccine safety and efficacy in RMD patients. Regardless, there is no reason to expect vaccine harms will trump expected COVID-19 vaccine benefits in RMD patients. The future COVID-19 landscape is uncertain with respect to vaccine effectiveness and safety, uptake, durability, mitigating societal behavior, and emerging viral strain variants. Clinicians nevertheless must act with their best judgment despite this highly uncertain and rapidly changing landscape. The risk of deferring vaccination and thus failing to mitigate COVID-19 risk should be weighed against a possible blunted response to the vaccine if given under suboptimal circumstances. As a practical matter, this tension must be resolved in the context of imperfect prediction as to whether those circumstances may be transient as well as a paucity of scientific evidence. Both individual and societal considerations related to a limited vaccine supply should be considered in issuing vaccine guidance and making policy decisions. Given that context, simplicity should be the touchstone: to avoid confusion, improve implementation, and maintain scientific credibility. In the future, the ability to give an additional vaccine booster (if proven necessary or beneficial) will no longer be constrained by limited supplies. Any vaccination strategy is a reasonable starting point, and decisions about implementation details reflect tradeoffs in the allocation of scarce vaccine resources. * ACR = American College of Rheumatology; RMD = rheumatic and musculoskeletal disease; COVID-19 = coronavirus disease 2019. at the FDA's Vaccines and Related Biological Products Advisory Committee meetings; and other electronic media sources. References and original articles related to vaccination were culled from the systematic literature reviews developed for ACR guidelines for the management of RA in 2012, 2015, and 2021 (5-7), PsA in 2018 [bib_ref] American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic..., Singh [/bib_ref] , and vaccination guidelines for RMD patients published by European Alliance of Associations for Rheumatology in 2019 [bib_ref] Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory..., Rondaan [/bib_ref] [bib_ref] EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases, Van Assen [/bib_ref]. Articles were dated 1994 through January 2021 (English language, domestic and inter national). The scoping questions and the relevant evidence reviews contributed by team members were collated into a single evidence summary document, which was disseminated by email to the entire task force for review 2 days prior to initial ratings. Following the development of the evidence summary, regular PubMed searches were undertaken over the next 6 weeks, and new evidence was shared with the task force prior to follow-up webinars. As no direct evidence was anticipated to be immediately available for use of the COVID-19 vaccine in RMD patients, no formal assessment of evidence quality (e.g., using Grading of Recommendations Assessment, Development and Evaluation methodology [bib_ref] GRADE guidelines: 8. Rating the quality of evidenceindirectness, Guyatt [/bib_ref] was attempted, and all evidence was assumed to be indirect. For this reason, all guidance statements should be considered as provisional, or "conditional," until further evidence becomes available. Initial ratings. The standard guideline development processes currently used by the ACR (13) were deemed to be too time-intensive to be feasible, given the immediate need for the guidance document. Therefore, following distribution of the evidence review document, the scoping questions were transformed into proposed positive statements for which task force members were asked to rate their initial agreement or disagreement. These statements were grouped into 4 broad categories: 1) general medical considerations that provided foundational information for the guidance document; 2) specific recommendations related to COVID-19 vaccination in RMD patients; 3) treatmentspecific considerations regarding the timing of COVID-19 vaccination; and 4) the timing of RMD treatments in relation to vaccine administration. A modified Delphi approach conducted as part of the RAND/ University of California at Los Angeles Appropriateness Methodwas used for guidance development. This method has been used for some past ACR guidelines and the more recent ACR COVID-19 guidance; it has been shown to be reproducible and to have content, construct, and predictive validity. Using this method, an initial round of rating was conducted anonymously by email. Task force members were asked to rate their level of agreement, and all votes were weighted equally. Voting was completed using a numerical rating scale of 1-9 for all items. Ratings of 9 corresponded to "complete agreement," 5 to "uncertain," and 1 to "complete disagreement." Median ratings for each statement falling into intervals of 1-3, 4-6, and 7-9 were interpreted as disagreement, uncertainty, and agreement, respectively. Agreement with each of the proposed guidance statements submitted by individual panel members was tabulated for the entire panel and used to classify consensus. Consensus was deemed "strong" when all 13 panel members' ratings fell within a single tertile (e.g., 7-9, indicative of agreement); all other combinations were considered to reflect "moderate" consensus. A lack of consensus was identified when the median rating fell into the uncertain range (4-6 interval), or more than one-quarter of the ratings fell into the opposite extreme tertile from the median (e.g., ≥4 panelists rated 1-3 [disagree] when the overall median rating was in the 7-9 [agree] range). Review and iteration for the ratings of the proposed guidance statements by the task force. Results from the first round of rating were reviewed and discussed in a task force webinar on January 15, 2021. Discussion was focused on statements for which there was no consensus. Individuals were given the opportunity to comment on all items presented in the initial rating process. Informed by voting results and the group discussion, the task force members refined the wording of several of the rated statements. Revised statements were sent back to task force members and agreement was again assessed by email, using the same scoring approach described above. Results from the second round of voting were presented to the task force via webinar on January 22, 2021, and minor text revisions were made iteratively in real time until consensus was achieved. A draft manuscript was developed describing the results of the rating process, and all coauthors were given an opportunity to provide direct edits to the document. The ACR Guidance Subcommittee and ACR Quality of Care Committee were given the document in order to provide feedback. It was subsequently sent to the ACR Board of Directors, which approved these recommendations on February 8, 2021. Public vetting of the guidance document was held via an electronic and widely publicized "town hall" held on that was open to ACR members and the public, with questions solicited in advance and during the town hall webinar. Finally, given the multitude of uncertainties and evidence gaps considered by the task force, the panel proposed a research agenda of high-impact topics that would advance the science and inform the optimal use of COVID-19 vaccines in RMD patients treated with immunomodulatory therapies. After publication, an ACR project librarian will refresh the specified literature search on a regular basis and submit new articles to the task force for review, and this document will be updated through a similar process as new evidence emerges. # Results Of the 76 guidance statements considered across the 2 rounds of ratings, 74 were rated with a median score of 7, 8, or 9 (i.e., agreement), and 2 of them were not agreed upon. Among the 74 statements achieving agreement, consensus was strong for 16 and moderate for the remainder. One guidance statement related to COVID-19 vaccination in children age <16 years was rated with a median value of 5 (uncertain) by the task force, in part reflecting the desire to obtain more feedback from pediatric rheumatology providers. Additional input was therefore sought from the ACR Pediatric Rheumatology Clinical Guidance Task Force. This task force recognized the practical considerations related to the lack of any COVID-19 vaccine being currently available in the US under an FDA EUA for children younger than age 16 years, although it recognized that ≥1 COVID vaccine clinical trial has enrolled patients as young as age 12 years (ClinicalTrials.gov identifiers: NCT04649151 and NCT04368728) [bib_ref] A study to evaluate the safety, reactogenicity, and effectiveness of mRNA-1273 vaccine..., Modernatx [/bib_ref] [bib_ref] Study to describe the safety, tolerability, immunogenicity, and efficacy of RNA vaccine..., Biontech [/bib_ref]. It also acknowledged a dearth of evidence in children with RMDs regarding both the epidemiology of COVID-19 and the resulting complications. Therefore, the Pediatric Task Force recommended to await additional evidence from clinical trials regarding the safety and effectiveness of COVID-19 vaccination in children before providing formal guidance statements, with the expectation that once such evidence becomes available, this topic will be revisited. The second statement for which the task force was unable to reach consensus relates to vaccination in the context of ongoing treatment with high-dose glucocorticoids, discussed in detail below. ## General considerations related to vaccination against covid-19 in patients with rmds. Twelve guidance statements related to general considerations of COVID-19 vaccination in RMD patients achieved consensus [fig_ref] Table 2: General considerations related to COVID-19 vaccination in patients with RMD* [/fig_ref]. Statements were descriptively categorized into ≥1 domain to facilitate ease of reference. The panel concurred that rheumatology health care providers were responsible for engaging RMD patients in discussions to assess whether they had been vaccinated against COV-ID-19 and to document related details (e.g., which vaccine had been administered, timing of vaccination, whether the series had been completed). For those not vaccinated, and similar to other vaccination guidelines for immunocompromised patients such as those from the Infectious Diseases Society of America [bib_ref] IDSA clinical practice guideline for vaccination of the immunocompromised host, Rubin [/bib_ref] [bib_ref] IDSA clinical practice guideline for vaccination of the immunocompromised host, Rubin [/bib_ref] , it was thought that the rheumatology provider should share responsibility with the patients' primary care provider (when available) to ensure appropriate vaccinations are administered. Rheumatology providers should also engage patients in a shared decision-making process to discuss the following: their attitudes, intent, and concerns related to vaccination; local incidence of COVID-19; individual circumstances (e.g., disease activity, medications, comorbidities) that may affect risk; ability to adhere to nonpharmacologic public health interventions; and vaccine efficacy and potential safety concerns (e.g., local or systemic reactogenicity, potential for disease worsening or flare). The rheumatology health care provider is responsible for engaging the RMD patient in a discussion to assess COVID-19 vaccination status. ## Strong Clinical practice, 2 The rheumatology health care provider is responsible for engaging the RMD patient in a shared decision-making process to discuss receiving the COVID-19 vaccine. ## Moderate Epidemiology, 3 AIIRD patients are at higher risk for incident viral infections compared to the general population. ## Moderate Epidemiology, 4 After considering the influence of age and sex, AIIRD patients are at higher risk for hospitalized COVID-19 compared to the general population. ## Moderate Epidemiology, 5 Acknowledging heterogeneity due to disease-and treatment-related factors, AIIRD patients have worse outcomes associated with COVID-19 compared to the general population of similar age and sex. ## Moderate Epidemiology, 6 Across AIIRD conditions,and within any specific disease, there is substantial variability in disease-and treatment-related risk factors for COVID-19 that may put some patients at higher risk than others. † ## Moderate Public health, 7 Based on increased risk for COVID-19, AIIRD patients should be prioritized for vaccination before the nonprioritized general population of similar age and sex. ## Moderate Vaccine safety, [bib_ref] American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic..., Singh [/bib_ref] Beyond known allergies to vaccine components, there are no known additional contraindications to COVID-19 vaccination for AIIRD patients. ## Moderate Vaccine effectiveness, 9 The expected response to COVID-19 vaccination for many AIIRD patients receiving systemic immunomodulatory therapies is likely to be blunted in its magnitude and duration compared to the general population. ## Moderate Disease-related, 10 As a general principle, vaccination should optimally occur in the setting of well-controlled AIIRD. ## Moderate Disease-related, 11 A theoretical risk exists for AIIRD flare or disease worsening following COVID-19 vaccination. ## Moderate Vaccine safety, 12 The benefit of COVID-19 vaccination for RMD patients outweighs the potential risk for new-onset autoimmunity. ## Moderate ## \| e65 The epidemiology of viral infection risk in RMD patients, and specifically, the risk for infection due to SARS-CoV-2, was then discussed. For this topic, the task force elected to narrow the scope of the patient population under consideration and define a presumably higher-risk subgroup of patients with RMDs. Some RMD conditions would include those managed by rheumatology providers but not generally associated with high levels of systemic inflammation (e.g., osteoarthritis, fibromyalgia, osteoporosis) and for which conventional, biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) or other therapies with immunosuppressive effects are typically not indicated. The patient population was thus restricted to those with AIIRDs (see for definitions, available on the Arthritis & Rheumatology website at http:// onlin elibr ary.wiley.com/doi/10.1002/art.41928/ abstract). Among these individuals, the risk for incident viral infections (e.g., herpes zoster) was rated as being higher than for the general population [bib_ref] Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective..., Blumentals [/bib_ref] [bib_ref] Risk of herpes zoster in autoimmune and inflammatory diseases: implications for vaccination, Yun [/bib_ref]. There was also agreement that AIIRD patients are likely to be at increased risk for hospitalized SARS-CoV-2 infection [bib_ref] Incidence and severeness of COVID-19 hospitalisation in patients with inflammatory rheumatic disease:..., Cordtz [/bib_ref] [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] [bib_ref] COVID-19 outcomes in patients with systemic autoimmune rheumatic diseases compared to the..., Silva [/bib_ref] [bib_ref] Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis..., Topless [/bib_ref] and that age, race/ethnicity (especially for underrepresented minorities), and sex were important risk factors that needed to be considered [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref] [bib_ref] Association of race and ethnicity with COVID-19 outcomes in rheumatic disease: data..., Gianfrancesco [/bib_ref] [bib_ref] Factors associated with COVID-19-related death in people with rheumatic diseases: results from..., Strangfeld [/bib_ref] in evaluating risk at the individual patient level. Multimorbidity was felt to likewise play an important role in the risk for developing COVID-19. While some population-based epidemiologic studies of COVID-19 incidence and outcomes in AIIRD patients have controlled for general multimorbidity or specific comorbidities [bib_ref] Incidence and severeness of COVID-19 hospitalisation in patients with inflammatory rheumatic disease:..., Cordtz [/bib_ref] [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] [bib_ref] Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data..., Gianfrancesco [/bib_ref] , the panel recognized that some comorbidities that increase infection risk were shared risk factors for development of AIIRDs (e.g., smoking and related pulmonary conditions associated with incident RA). These may represent direct manifestations such as interstitial lung disease associated with some AIIRDs, or they could be downstream sequelae causally related to the underlying inflammatory processes of AIIRDs or their treatment (e.g., premature and advanced atherosclerotic vascular disease in systemic lupus erythematosus patients; obesity, diabetes, and features of the metabolic syndrome in PsA patients or those receiving long-term glucocorticoids). For that reason, adjustment for these comorbidities might be inappropriate and would underestimate the risk of COVID-19 infection in patients with AIIRDs. Therefore, age-and sex-adjusted risk estimates were preferred by some task force members when comparing risk and outcomes of COVID-19 in AIIRD patients to the general population. The few large population-based studies of COVID-19 incidence and outcomes in AIIRD patients had minimal demographic diversity, and therefore race/ethnicity could not be easily evaluated as an independent risk factor. Finally, the panel acknowledged challenges in being able to disentangle the independent role of the disease activity and severity of various AIIRDs from the medications used to treat them (e.g., higher-dose glucocorticoids [bib_ref] Autoimmune and chronic inflammatory disease patients with COVID-19, Ungaro [/bib_ref] , socalled confounding by severity, as risk factors for worse COVID-19 outcomes. Despite these important methodologic caveats and acknowledged limitations in the evidence base, AIIRD patients were rated as having worse outcomes (e.g., need for intensive care unit [ICU] treatment, mechanical ventilation, persistent infection, death) following COVID-19 compared to patients of similar age and sex without such conditions [bib_ref] Incidence and severeness of COVID-19 hospitalisation in patients with inflammatory rheumatic disease:..., Cordtz [/bib_ref] [bib_ref] Factors associated with COVID-19-related death using OpenSAFELY, Williamson [/bib_ref] [bib_ref] COVID-19 outcomes in patients with systemic autoimmune rheumatic diseases compared to the..., Silva [/bib_ref] [bib_ref] Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis..., Topless [/bib_ref]. In terms of the policy implications of this reasoning, the task force agreed that in general, AIIRD patients should be prioritized to be allocated to receive vaccination before the nonprioritized general population of similar age and sex. The panel recognized important heterogeneity across AIIRD conditions, such that (for example) an RA patient with quiescent disease treated only with hydroxychloroquine likely has a lower risk for COVID-19 and adverse outcomes compared to a patient with very active vasculitis treated with intravenous (IV) cyclophosphamide or rituximab (RTX) and high-dose glucocorticoids [bib_ref] Factors associated with COVID-19-related death in people with rheumatic diseases: results from..., Strangfeld [/bib_ref] , although the protection conferred by COVID-19 vaccination may also differ greatly. Turning attention to vaccination of individual patients, the task force felt that there were no additional known contraindications to receipt of the COVID-19 vaccine other than known allergies to vaccine components as stipulated by guidance from the CDC. Extrapolating evidence derived from studies of other vaccines, the expected response to vaccination in many AIIRD patients receiving certain systemic immunomodulatory therapies was deemed likely to be blunted, albeit with uncertain diminution in either the magnitude or duration of response compared to the general population [bib_ref] Longterm effectiveness of herpes zoster vaccine among patients with auto immune and..., Yun [/bib_ref]. The task force acknowledged a paucity of direct evidence supporting this assertion and placed great importance on prioritizing this topic as part of a future research agenda. The timing of vaccination was considered more ideal in the setting of well-controlled disease, yet the task force noted that patients and their providers should not be dissuaded from vaccination under less-than-ideal conditions, with additional timing considerations as discussed below. Based on data derived from the published literature, a potential risk for a flare of the patient's underlying AIIRD following vaccination was acknowledged. For example, based on randomized controlled trial data [bib_ref] Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal..., Park [/bib_ref] , the frequency of flare was higher in RA patients randomized to have methotrexate (MTX) withheld at the time of influenza vaccination compared to those randomized to continue (10.6% versus 5.1%, respectively), with flare defined as an increase in the Disease Activity Score in 28 joints (DAS28) of >1.2, or >0.6 if the baseline DAS28 was ≥3.2 [bib_ref] Construct and criterion validity of several proposed DAS28-based rheumatoid arthritis flare criteria:..., Van Der Maas [/bib_ref]. A subsequent pooled analysis that included that trial and another showed that while the mean change in DAS28 did not differ between groups, the adjusted flare rate in the 2-week withhold group (MTX withhold) was 2.90-fold higher (95% confidence interval 0.96-4.56; P = 0.063) compared to the group that continued MTX (MTX continue), with a difference in proportions experiencing flare of 10.8% (MTX withhold group) versus 5.8% (MTX continue group) [bib_ref] Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal..., Park [/bib_ref] [bib_ref] Effect of short-term methotrexate discontinuation on rheumatoid arthritis disease activity: post-hoc analysis..., Park [/bib_ref] [bib_ref] Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients..., Park [/bib_ref]. This risk of flare or disease worsening was catalogued as an important topic slated for the future research agenda. Finally, although some new-onset AIIRDs (e.g., RA, vasculitis) or flares of preexisting AIIRDs have been reported after COVID-19 in published case reports [bib_ref] First flare of ACPA-positive rheumatoid arthritis after SARS-CoV-2 infection, Perrot [/bib_ref] , the expected benefit of vaccination for AIIRD patients was thought to outweigh any theoretical risk for the development of new-onset autoimmune conditions or other potentially immune-mediated manifestations or abnormalities (e.g., Bell's palsy, Guillain-Barré syndrome, anti-RNA antibodies in systemic lupus erythematosus patients, immune thrombocytopenic purpura) following vaccination. Indications for vaccination and timing considerations. As summarized in [fig_ref] Table 3: Recommendations for use of the COVID-19 vaccine in RMD patients* Based on... [/fig_ref] , and consistent with guidance from the CDC for the general US population, the panel recommended that RMD and AIIRD patients be offered and receive [bib_ref] IDSA clinical practice guideline for vaccination of the immunocompromised host, Rubin [/bib_ref] , no direct head-to-head comparisons, and no data on the comparative performance of the different vaccines in patients with autoimmune and inflammatory rheumatic disease (AIIRD). In the absence of such evidence, the task force did not achieve consensus on whether to prefer one vaccine (or vaccine platform) over another, and recognized that prioritization may itself have important unintended effects. However, some rheumatologists may choose to recommend an mRNA vaccine to certain AIIRD patients based on their assessment of the relevant effectiveness and/or safety (e.g. risk of thrombosis) data. § The task force discussed the possibility of recommending additional and more sustained public health measures for patients with AIIRD. After deliberation, they did not elect to exceed current public health authority guidance given uncertainties about the clinical effectiveness of vaccination in such patients. The appropriateness for continued preventive measures (e.g. masking, physical distancing) should be discussed with patients as their rheumatology providers deem appropriate. vaccination against SARS-CoV-2. Discussion was held regarding the age cutoff for vaccination, and the panel agreed that guidance should be made consistent with the EUA of available vaccines (i.e., age ≥12 years as of June 7, 2021), with the potential for that cutoff to change in the future based on future revisions to EUAs for existing vaccines, forthcoming EUAs for new vaccines, or age restrictions applicable to FDA licensure. Recommendations on which patients should be vaccinated were extended to patients with RMDs who did not have conditions typically considered to be AIIRDs but for which immunomodulatory or DMARD therapies might be used off-label. For example, patients with erosive osteoarthritis might receive MTX, or gout patients treated with pegloticase might be concomitantly treated with MTX to reduce pegloticase immunogenicity. These circumstances, in which MTX or another immunomodulatory therapy is being used for a non-AIIRD condition, would be treated synonymously with the guidance for MTX offered in this document. However, within the category of patients with AIIRDs and/or those receiving immunomodulatory therapies, substantial heterogeneity of disease-and treatment-related risk factors was noted. Some AIIRD patients were expected to be at higher risk for infection and morbidity than others, and thus the impetus for COVID-19 vaccination might be stronger for some individual patients or patient groups (e.g., patients with systemic lupus erythematosus receiving cytotoxic therapy and higher-dose glucocorticoids, or patients receiving RTX therapy), although the vaccine might be less effective in these same individuals. Extensive discussion was held regarding whether consideration for a particular vaccine or vaccine platform (e.g., messenger RNA [mRNA] versus adenoviral vector) might be preferred in general, or for select patients, based on potential differences in effectiveness or safety. Based on the task force members' ratings and the vaccine options in the US, the expert panel reached consensus on the guidance that RMD patients undergoing vaccination are recommended to receive whichever SARS-CoV-2 mRNA vaccine is available to them. Whether to extend this same lack of preference to include the viral vector vaccines was debated, and a range of opinion within the expert panel was observed (ratings ranged from 4 to 9). The discussion included the potential risk of thrombosis in select patient groups receiving viral vector vaccines. Given the safety concerns raised by the FDA and CDC in the early weeks of April 2021, the decision to rate the preference for mRNA versus adenoviral vector vaccines was held in abeyance by the task force. Further deliberations will occur as new information becomes available. On April 23, 2021, the Advisory Committee on Immunization Practices lifted the pause on Janssen's adenoviral vector-based vaccine; there is no preference for one type of approved COVID-19 vaccine over another. The task force noted that none of the SARS-CoV-2 vaccine candidates in development would be classified as a canonical live virus vaccine, including the adenoviral vector-based vaccines which are replication deficient [bib_ref] First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype..., Baden [/bib_ref]. Thus, the usual prohibitions against the use of live virus vaccines in immunosuppressed patients do not apply. High importance was placed on updating this guidance document as additional data emerge. Following receipt of the first dose in a vaccine series, patients were recommended to receive the second dose of the same type of vaccine, assuming no contraindication to the second dose per CDC guidance (e.g., a severe allergic reaction, or an immediate allergic reaction of any severity to the vaccine or any of its components, including polyethylene glycol). Persons who develop SARS-CoV-2 infection between the first and second dose of a 2-dose vaccine series should delay the second dose until they have recovered from the acute illness (if symptomatic) and discontinued isolation, and then they should receive the second dose without delay. Consistent with CDC guidance (34), SARS-CoV-2infected patients who received monoclonal antibodies (e.g., bamlanivimab, casirivimab, imdevimab) or convalescent plasma as part of treatment for COVID-19 should defer vaccination for ≥90 days following receipt of antibody therapy. Also consistent with CDC guidance, providers may co-administer other vaccines at the same time as COVID-19 vaccines, and without regard to the timing of other vaccines. Thus far, there is no proven laboratory-based immune correlate of protection against SARS-CoV-2 following natural infection or vaccination. Moreover, some commercially available SARS-CoV-2 serologic assays do not detect antibody responses to spike protein generated by the currently available mRNA vaccines, but rather measure antibodies to nucleocapsid protein. Therefore, the task force recommended that health care providers not do any of the following: routinely order laboratory testing to assess the need for vaccination in an unvaccinated person, screen for asymptom atic SARS-CoV-2 shedding, or assess SARS-CoV-2 immunity following vaccination. The task force expressed strong interest in modifying this guidance once additional data evolve regarding the potential utility of laboratory-based testing that might be helpful in select patients. Household members and other frequent close contacts of AIIRD patients were recommended to undergo COVID-19 vaccination when available, in order to facilitate a "cocooning effect" that may help protect atrisk AIIRD patients. However, the priority for vaccination for these close contacts should not be elevated for this reason. A series of statements was rated by the panel with respect to the general timing of COVID-19 vaccination in relation to AIIRD disease activity, again acknowledging a dearth of direct evidence. Except for those with severe and life-threatening illness (e.g., a hospitalized patient receiving treatment in the ICU for any condition), vaccination was recommended irrespective of disease activity and severity. Even for ICU-treated patients for whom vaccination was recommended to be deferred for a short time, the task force felt that when the patient was well enough to be discharged from the hospital, vaccination would likely be appropriate. Acknowledging a balance between vaccinating and obtaining a blunted but still modest response, and the duty to allocate vaccine resources toward the settings in which they are likely to have the greatest benefit, the panel identified this scenario as an important evidence gap. For AIIRD patients in other settings, including those with either active but non-life-threatening disease, and certainly for patients with stable and/or low disease activity, vaccination was recommended. Finally, patients naive to or not currently receiving immunomodulatory therapies were recommended to receive their first dose of vaccine without delay. Additional considerations for medication timing are subsequently discussed. ## Treatment-specific timing of vaccination. Guidance regarding optimizing the timing of COVID-19 vaccination in relation to the use of various immunomodulatory therapies is provided in [fig_ref] Table 4: Guidance related to the timing of COVID-19 vaccination in relation to use... [/fig_ref]. There was recognition that the ability to carefully time COVID-19 vaccination is sometimes limited in a real-world setting, and the overarching view was that COVID-19 vaccination should be given rather than not given if timing in relation to immunomodulatory drugs is not under the provider's or patient's control. Strong consensus was achieved regarding the statement to not delay COVID-19 vaccination for patients receiving hydroxychloroquine, sulfasalazine, leflunomide, apremilast, or IV immunoglobulin [bib_ref] Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory..., Rondaan [/bib_ref] [bib_ref] Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus..., Elkayam [/bib_ref]. A similar recommendation with moderate consensus was achieved for most of the remaining immunomodulatory therapies considered [bib_ref] Antigen-specific antibody responses in lupus patients following immunization, Battafarano [/bib_ref] [bib_ref] Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with..., Mok [/bib_ref] [bib_ref] Humoral immune response to vaccines in patients with rheumatoid arthritis treated with..., Bingham [/bib_ref] [bib_ref] Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy, Mori [/bib_ref] [bib_ref] Impact of tocilizumab therapy on antibody response to influenza vaccine in patients..., Mori [/bib_ref] [bib_ref] COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses, Sahin [/bib_ref] [bib_ref] Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal..., Tsuru [/bib_ref] [bib_ref] Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tacrolimus, Migita [/bib_ref] [bib_ref] High immunogenicity to influenza vaccination in Crohn's disease patients treated with ustekinumab, Doornekamp [/bib_ref] [bib_ref] Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune..., Furer [/bib_ref] [bib_ref] Immunogenicity and safety of vaccination against seasonal influenza vaccine in patients with..., Furer [/bib_ref] [bib_ref] Secukinumab does not impair the immunogenic response to the influenza vaccine in..., Richi [/bib_ref]. One exception was RTX [bib_ref] Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory..., Rondaan [/bib_ref] [bib_ref] EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases, Van Assen [/bib_ref] [bib_ref] Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the..., Bar-Or [/bib_ref] [bib_ref] The effect of rituximab on vaccine responses in patients with immune thrombocytopenia, Nazi [/bib_ref] [bib_ref] Could anti-CD20 therapy jeopardise the efficacy of a SARS-CoV-2 vaccine?, Houot [/bib_ref] [bib_ref] Effect of methotrexate, antitumor necrosis factor α, and rituximab on the immune..., Hua [/bib_ref] , for which the panel recommended to schedule vaccination such that the vaccine series would be initiated ~4 weeks prior to the next scheduled RTX dose. For example, a patient receiving RTX as a 2-dose cycle (spaced 2 weeks apart), with cycles repeating every 6 months, would be recommended to initiate vaccination ~5 months after the start of the prior RTX cycle. RTX dosing could then be resumed 2-4 weeks after the second COVID-19 vaccination, as discussed in the next section. Those receiving RTX cycles at 4-month intervals would initiate vaccination 3 months after the prior RTX cycle. In order to follow this recommendation, the task force invoked the assumption that a patient's COVID-19 risk was low or able to be mitigated by preventive health measures. The rationale for this recommendation comes from a single study demonstrating minimal response to influenza vaccination in 11 patients vaccinated 4-8 weeks after RTX treatment, with modestly restored responses in patients vaccinated 6-10 months after their last RTX dose [bib_ref] Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid..., Van Assen [/bib_ref]. As the second statement for which consensus was not achieved, the panel was uncertain about whether to delay vaccination if an AIIRD patient was receiving glucocorticoids at a prednisone-equivalent dose of ≥20 mg per day. Controversy stemmed as to whether vaccine response might be blunted in this circumstance, which may relate to the glucocorticoids themselves or to the presumably high disease activity and severity [bib_ref] Glucocorticoid: major factor for reduced immunogenicity of 2009 influenza A (H1N1) vaccine..., Aikawa [/bib_ref] [bib_ref] Performance of the tuberculin skin test and interferon-γ release assay for detection..., Kim [/bib_ref]. Other factors discussed included the disease being treated and the medical management considerations if the patient were to manifest systemic reactogenicity (e.g., persistent high fever). Concern regarding an attenuated response to the vaccine in this circumstance would be partially mitigated if there was a possibility to later order serologies or other laboratory tests, and clinicians were able to assess vaccine-induced immunity and administer a booster or revaccinate if needed. However, such laboratory-based correlates of protection are not currently available, and the task force did not expect that the opportunity to revaccinate would be readily at hand. Use and timing of immunomodulatory therapies in relation to COVID-19 vaccination administration. No evidence was found to support concern regarding the use or timing of immunomodulatory therapies in relation to vaccine safety, and guidance regarding medication timing [fig_ref] Table 5: Guidance related to the use and timing of immunomodulatory therapies in relation... [/fig_ref] was therefore given in light of the intent to optimize vaccine response. For most ## Moderate ## Rituximab Assuming that a patient's COVID-19 risk is low or able to be mitigated by preventive health measures (e.g., self-isolation), schedule vaccination so that the vaccine series is initiated ~4 weeks prior to next scheduled rituximab cycle. Moderate * COVID-19 = coronavirus disease 2019; RMD = rheumatic and musculoskeletal disease; IVIG = intravenous immunoglobulin; TNFi = tumor necrosis factor inhibitor; SC = subcutaneous. † Examples of cytokine and kinase inhibitors include the following: for interleukin-6 receptor (IL-6R), sarilumab and tocilizumab; for IL-1 receptor antagonist (IL-1Ra), anakinra and canakinumab; for IL-17, ixekizumab and secukinumab; for IL-12/IL-23, ustekinumab; for IL-23, guselkumab and rizankizumab; for JAK inhibitors, baricitinib, tofacitinib, and upadacitinib. Consensus was not reached for patients receiving glucocorticoids (GCs) at prednisone-equivalent doses of ≥20 mg/day. \| e69 therapies, the task force recommended that no changes be made with respect to interrupting or otherwise optimizing the timing of immunomodulatory therapy [bib_ref] Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory..., Rondaan [/bib_ref] [bib_ref] Treatment with belimumab in systemic lupus erythematosus does not impair antibody response..., Nagel [/bib_ref] [bib_ref] A systematic review and metaanalysis of antirheumatic drugs and vaccine immunogenicity in..., Subesinghe [/bib_ref]. Based on preexisting data on the impact of mycophenolate on non-COVID-19 vaccine immunogenicity [bib_ref] Suppression of the humoral immune response by mycophenolate mofetil, Smith [/bib_ref] [bib_ref] Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine..., Keshtkar-Jahromi [/bib_ref] [bib_ref] Effect of immunosuppression on T helper 2 and B cell responses to..., Egli [/bib_ref] [bib_ref] Randomized controlled trial of high-dose intradermal versus standard-dose intramuscular influenza vaccine in..., Baluch [/bib_ref] [bib_ref] Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to..., Gabay [/bib_ref] [bib_ref] Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine, Siegrist [/bib_ref] , and based on emerging data suggesting that mycophenolate may impair SARS-CoV-2 vaccine response in RMD and transplant patients [bib_ref] Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients..., Boyarsky [/bib_ref] [bib_ref] Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid..., Boyarsky [/bib_ref] , the task force recommended that mycophenolate be withheld for 1 week following each vaccine dose, assuming that disease is stable. Nevertheless, panel members recognized that there are no data demonstrating that withholding mycophenolate for 1 week will ameliorate the negative impact that mycophenolate has on patient responses to COVID-19 vaccines. For MTX, the panel recommended that MTX be withheld 1 week after each mRNA vaccine dose for those with well-controlled disease, based on data from influenza vaccines [bib_ref] Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal..., Park [/bib_ref] [bib_ref] Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients..., Park [/bib_ref] [bib_ref] Protective effect of A/H1N1 vaccination in immune-mediated disease-a prospectively controlled vaccination study, Adler [/bib_ref] [bib_ref] Abatacept and reduced immune response to pandemic 2009 influenza A/H1N1 vaccination in..., Ribeiro [/bib_ref] and pneumococcal vaccines [bib_ref] Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B..., Kapetanovic [/bib_ref] [bib_ref] Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in..., Kapetanovic [/bib_ref]. The recommendation to withhold MTX for only a single week, rather than the 2-week interruption tested in an RA influenza vaccine trial, was based upon practical considerations for the complexity of withholding MTX for 2 weeks ## Moderate Abatacept (IV) Time administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total); no medication adjustments for the second vaccine dose. ## Moderate Cyclophosphamide (IV) Time cyclophosphamide administration so that it will occur ~1 week after each vaccine dose, when feasible. ## Moderate Acetaminophen, NSAIDs Assuming that disease is stable, withhold for 24 hours prior to vaccination (no restrictions on postvaccination use to treat symptoms). ## Moderate ## Rituximab Assuming that patient's COVID-19 risk is low or is able to be mitigated by preventive health measures (e.g., self-isolation), schedule vaccination so that the vaccine series is initiated ~4 weeks prior to next scheduled rituximab cycle; after vaccination, delay rituximab 2-4 weeks after final vaccine dose if disease activity allows. Moderate * Guidance to withhold a therapy was made based on the assumption that the patient had well-enough controlled disease to allow for a temporary interruption; if not, decisions should be made on a case-by-case basis considering the circumstances involved. For details on the history of updates to these guidance statements, see Supplementary around each of the 2 vaccine doses that are spaced 3-4 weeks apart and the potential for flare associated with withholding MTX for this long. For that reason, interrupting MTX for only 1 week around the time of each of the vaccine doses was recommended. In contrast, for single-dose COVID vaccine, the task force recommended that MTX be withheld for 2 weeks, which is consistent with the influenza vaccine MTX guidelines. Guidance was given for JAK inhibitors based on concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response [bib_ref] The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid..., Winthrop [/bib_ref] [bib_ref] Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis..., Winthrop [/bib_ref]. Given the immunologic considerations related to this concern, withholding JAK inhibitor therapy was recommended regardless of the patient's underlying disease activity. Emerging evidence regarding the influence of MTX and JAK inhibitors on vaccine response against COVID-19 was recognized by the task force as supporting the above guidance statements. In contrast, the panel recommended that subcutaneous abatacept (ABA) be withheld for both 1 week before and 1 week after the first dose of the vaccine (i.e., a total of 2 weeks) but not withheld for the second dose [bib_ref] COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses, Sahin [/bib_ref]. This recommendation was made in light of several studies suggesting a negative effect of ABA on vaccine immunogenicity [bib_ref] Efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory..., Rondaan [/bib_ref] [bib_ref] Protective effect of A/H1N1 vaccination in immune-mediated disease-a prospectively controlled vaccination study, Adler [/bib_ref] [bib_ref] Abatacept and reduced immune response to pandemic 2009 influenza A/H1N1 vaccination in..., Ribeiro [/bib_ref] [bib_ref] Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis..., Alten [/bib_ref] [bib_ref] Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in..., Kapetanovic [/bib_ref] [bib_ref] Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23)..., Migita [/bib_ref]. The additional ratio nale for withholding ABA around the time of the first vaccine dose, but not the second, was that the first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and ABA is a CTLA-4Ig construct. This consideration relates to the fact that the COVID-19 vaccine provides protection against a novel infectious agent, in contrast to most other vaccines which generally function by reactivating memory T cells. CTLA-4 should not, however, inhibit "boosts" of already primed T cells at the time of the second vaccine dose. This principle would theoretically also apply to subsequent booster doses of vaccine, should future evidence suggest that these are needed or beneficial in some patients. Additionally, as with MTX, the practical considerations surrounding guidance to withhold subcutaneous ABA for a total of 2 weeks around each of the 2 vaccine doses (4 weeks total) was raised as a concern. Following similar immunologic principles, the panel recommended to time IV ABA administration (typically given every 4 weeks) so that the first vaccine dose would occur 4 weeks after ABA infusion (i.e., the entire dosing interval), and postpone the subsequent ABA infusion by 1 week (i.e., such that infusion would occur 5 weeks following the previous dose). For those not yet receiving subcutaneous or IV ABA, therapy could be initiated following the recommended 1-week delay after the first vaccine dose. No ABA adjustments were recommended for the second vaccine dose. For AIIRD patients receiving IV cyclophosphamide, generally at 2-or 4-week intervals, the recommendation was made to coordinate timing so that cyclophosphamide infusion occurs ~1 week after each vaccine dose, when feasible [bib_ref] Antigen-specific antibody responses in lupus patients following immunization, Battafarano [/bib_ref]. For RTX, the panel recommended to time RTX administration (of the next/first dose, if given as part of a multidose cycle) 2-4 weeks after the final vaccine dose, if possible, but added the condition that the patient's disease should be under acceptable control to allow this delay, especially given the extended gap (e.g., 6 months) between RTX cycles [bib_ref] Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid..., Van Assen [/bib_ref] [bib_ref] Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a..., Bingham [/bib_ref] [bib_ref] Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in..., Westra [/bib_ref] [bib_ref] Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis..., Rehnberg [/bib_ref]. The task force acknowledged that the evidence base supporting the recommendations related to RTX timing was largely based on studies of humoral immunity following receipt of other vaccines [bib_ref] Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the..., Bar-Or [/bib_ref] [bib_ref] The effect of rituximab on vaccine responses in patients with immune thrombocytopenia, Nazi [/bib_ref] [bib_ref] Could anti-CD20 therapy jeopardise the efficacy of a SARS-CoV-2 vaccine?, Houot [/bib_ref] [bib_ref] Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid..., Van Assen [/bib_ref] [bib_ref] Protective effect of A/H1N1 vaccination in immune-mediated disease-a prospectively controlled vaccination study, Adler [/bib_ref] [bib_ref] Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a..., Bingham [/bib_ref] [bib_ref] Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in..., Westra [/bib_ref] [bib_ref] Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis..., Rehnberg [/bib_ref] [bib_ref] The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis..., Arad [/bib_ref] , which has uncertain generalizability to vaccination against COV-ID-19, especially since the degree to which efficacy is attributable to induction of host T cell versus B cell (antibody-based) immunity is uncertain at this time. However, some early data do suggest that B cell depletion diminishes the immunogenicity of COVID-19 vaccines. Finally, based on the literature suggesting that acetaminophen and/or nonsteroidal antiinflammatory drugs may somewhat impair vaccine response (95), the task force recommended withholding these for 24 hours prior to vaccination, assuming that disease is stable. There was no prohibition against their use in patients who experience local or systematic symptoms postvaccination. As an outgrowth of the evidence report, the task force assembled a research agenda where evidence was lacking [fig_ref] Table 6: Research agenda for future COVID-19 vaccine studies in RMD patients proposed by... [/fig_ref]. Given that there was little direct evidence in any RMD population, the topics were broad and spanned domains related to clinical effectiveness, safety, flare, reactogenicity, study design, immunogenicity, and laboratory-based correlates of protection. With the relatively small size of the task force, no attempt was made to prioritize these topics given the expectation that they would evolve over time and as new science in non-RMD populations was forthcoming. # Discussion This ACR guidance encompasses the optimal use of COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases. It is intended to aid in the care of individual patients but not to supplant personalized care or constrain shared decisionmaking with patients. The mRNA vaccine platform is novel, and considerations for vaccines developed on this platform may differ from those relevant to other vaccines. The guidance regarding the use and timing of immunomodulatory medications was based on extrapolation of the available evidence of their immunologic effects as they relate to other vaccines and vaccine platforms. As such, all of these recommendations are considered conditional. Finally, the task force advised health care providers to avoid being overly dogmatic in following these recommendations. The attempt to optimize vaccine response in relation to the use and timing of immunosuppressive medications should not compromise a willing patient's ability to undergo vaccination in a timely manner and risk a missed vaccination opportunity. As an overarching principle, the sparsity of information regarding COVID-19 vaccination in RMD patients yielded a need for extrapolation based on the literature published for other vaccines. The evidence base was, therefore, of low or very low quality and suffered from indirectness [bib_ref] GRADE guidelines: 8. Rating the quality of evidenceindirectness, Guyatt [/bib_ref] in almost all respects. The guidance provided herein represents a balance between evidence regarding efficacy, effectiveness, safety, feasibility (e.g., withholding a therapy with a long half-life or extended recirculation like leflunomide may be unrealistic), expected vaccine availability, and tradeoffs in resource utilization. For example, vigorous debate was held about whether it was preferable to vaccinate a high-risk patient in a suboptimal circumstance (e.g., active disease, receiving high-dose glucocorticoids, receiving cytotoxic therapy), under the assumption that the vaccine would confer at least some protection to a patient at high risk for a poor outcome if they contract COVID-19. Or rather, might it be preferable to wait until a more optimal circumstance presented itself? However, given the uncertainty in most medical settings to predict the future course of a patient's AIIRD or the need for additional immunomodulatory treatments, a more salutary setting to optimize vaccine response might never materialize. Thus, the task force typically favored proceeding more immediately with vaccination. If a laboratory-based correlate of protection existed that could serve as a proxy for immunity, and if a booster dose could be administered or the vaccine series repeated at a later time, there would be greater certainty to recommend vaccinating all patients immediately, regardless of setting or underlying treatment. These societal considerations regarding vaccine allocation in light of constrained vaccine supply and regional resource limitations to revaccinate posed important tradeoffs for the panel. Given tradeoffs like these, the extant uncertainties posed by the scoping questions informed by imperfect evidence, and the highly dynamic environment of vaccination implementation, the task force recommended as it did. The strengths of this effort are notable given the urgent need presented by the availability of new COVID-19 vaccines and critical questions about how to best use those vaccines for RMD patients. The task force generated an evidence summary over a very compressed time frame and leveraged a well-established consensus methodology process used previously by the ACR. Of high importance, the task force's composition included experts in rheumatology, infectious disease, and public health, representing a plurality of different stakeholder perspectives. Regarding important limitations, our ability to generalize from the literature for other vaccines and vaccine platforms in RMD patients to the novel COVID-19 vaccines now available in the US is limited. Vaccination against SARS-CoV-2 raises different issues than those for other vaccine-preventable illnesses, given the potential for ongoing public health measures to partially mitigate exposure. This guidance therefore must be interpreted by clinicians and patients in light of underlying principles rather than considering them either prescriptive or proscriptive. For example, an AIIRD patient with minimal public contact who is able to strongly adhere to all preventive health measures might choose to withhold RMD treatments or briefly defer vaccination in accordance with this guidance, whereas this same decision may not be possible for a patient employed in a high-risk setting (e.g., frontline health care, or long-term care facility). From a vaccine policy and recommendation context, the task force prioritized simplicity, noting that this guidance would be expected to apply to the care of most RMD patients in most settings. Finally, the procedures used to develop this guidance did not follow the rigorous methodology routinely used by the ACR when formal clinical practice guidelines are created, although they were adherent to the ACR standardized operating procedures for guidance documents. This was an expected limitation given the accelerated time frame desired by the ACR to issue practical and timely recommendations both to its membership and to the rheumatology community. Once the urgency of the pandemic has passed, the work of this task force will eventually be folded back under the aegis of the broader ACR vaccine guideline development group, charged with covering this and all other vaccines in the context of RMDs, and the more typical guideline development process favored by the ACR will be applied. Additional and important input from other stakeholders, including patients and patient advocates, will also be sought, as the ACR has done for past clinical practice guidelines [bib_ref] American College of Rheumatology guideline for the treatment of rheumatoid arthritis, Singh [/bib_ref]. As new safety and efficacy evidence becomes available for both mRNA vaccines and other vaccine platforms in patients with RMDs and AIIRDs, the ACR's guidance document will continue to be updated and expanded, consistent with the notion of a "living document." The ACR is committed to maintaining this process throughout the pandemic to facilitate evidence-based practice and promote optimal outcomes for all patients with RMDs and AIIRDs with respect to mitigating COVID-19 risk. [table] Table 2: General considerations related to COVID-19 vaccination in patients with RMD* [/table] [table] Table 3: Recommendations for use of the COVID-19 vaccine in RMD patients* Based on the data for the mRNA COVID-19 vaccines available in the US, there is no preference for one COVID-19 vaccine over another. Therefore, AIIRD patients should receive either vaccine available to them. ‡ [/table] [table] Table 4: Guidance related to the timing of COVID-19 vaccination in relation to use of immunomodulatory therapies in RMD patients* [/table] [table] Table 5: Guidance related to the use and timing of immunomodulatory therapies in relation to COVID-19 vaccination administration in RMD patients* [/table] [table] Table 6: Research agenda for future COVID-19 vaccine studies in RMD patients proposed by the task force* Directly compare vaccines and vaccine platforms for the above efficacy, immunogenicity, and safety outcomes: notable given the potential for some COVID-19 vaccines to achieve the minimum threshold for the FDA's EUA yet have seemingly lower vaccine efficacy based on large clinical trials in non-RMD patients. Long-term follow-up for durability and magnitude of vaccine protection in relation to various immunomodulatory medications, and as new SARS-CoV-2 strains emerge. Assess benefits and timing of additional COVID-19 vaccine administration (i.e., booster dose). Generate real-world evidence (e.g., large pragmatic trial or observational studies) embedded in routine clinical practice to study the above topics, especially to promote large-scale safety surveillance. Establish a biorepository with associated clinical data infrastructure to facilitate future COVID-19 (and possibly other) vaccine-related research in RMD patients, considering the future potential to identify laboratory-based correlates of protection relevant for individual patients. Identify laboratory-based serologic testing to identify patients with a suboptimal response to COVID-19 vaccination who might be candidates for a booster dose or need to repeat the vaccination series. Evaluate the impact of coadministration of the COVID-19 vaccine given concurrently with other, non-live-virus vaccines (e.g., shingles, influenza, pneumococcal) on vaccine immunogenicity and tolerability. Optimize approaches to address vaccine hesitancy for high-risk RMD patients who are reticent or unwilling to undergo vaccination, with particular attention to vulnerable populations (e.g., underrepresented racial/ethnic groups). Identify COVID-19 vaccine-induced immune parameters (immunogen-specific neutralizing antibody levels, total immunogen-specific antibody levels or isotypes, T cell immunity, innate immunity) or host determinants that are predictive of successful host response to vaccine, as reflected by protection from infection or mitigation of morbidity during subsequent infection. Conduct large epidemiology studies of COVID-19 outcomes (e.g., using large administrative databases of health plans, electronic health record data [e.g., the ACR RISE registry], or other data sources or methods) and examine the role of AIIRD disease features, treatments, and vaccination. While risk factors for incident disease may be shaped by confounding and unmeasured variability in exposure, examining outcomes conditioning on incident COVID-19 diagnosis may be more fruitful.* COVID-19 = coronavirus disease 2019; RMD = rheumatic and musculoskeletal disease; AIIRD = autoimmune and inflammatory rheumatic disease; GCs = glucocorticoids; FDA = US Food and Drug Administration; EUA = Emergency Use Authorization; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; ACR = American College of Rheumatology; RISE = Rheumatology Informatics System for Effectiveness. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/art.41928	To provide guidance to rheumatology providers on the use of coronavirus disease 2019 (COVID‐19) vaccines for patients with rheumatic and musculoskeletal diseases (RMDs).
f8416d3a22adddf69a970b55436b1e772ce64c2e	pubmed	2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families	2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families [bib_ref] Epidemiology of sudden cardiac death: global and regional perspectives, Wong [/bib_ref] [bib_ref] Systematic review of the incidence of sudden cardiac death in the United..., Kong [/bib_ref] [bib_ref] Nationwide improvements in survival from out-of-hospital cardiac arrest in Japan, Kitamura [/bib_ref] [bib_ref] Sudden coronary death in the United States: 1980-1985, Gillum [/bib_ref] [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias, Cronin [/bib_ref] [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] ## Purpose This expert consensus statement represents an international multidisciplinary effort led by the Asia Pacific Heart Rhythm Society (APHRS), in partnership with the Heart Rhythm Society (HRS) and in collaboration with the Association for European Cardiovascular Pathology (AECVP), the European Heart Rhythm Association (EHRA), the European Society of Human Genetics (ESHG), the Latin American Heart Rhythm Society (LAHRS), the National Society of Genetic Counselors (NSGC) (USA), the Pediatric and Congenital Electrophysiology Society (PACES), and the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. The intent is to provide clinicians with practical patientcentered recommendations for evaluating patients with sudden cardiac arrest (SCA), decedents with sudden cardiac death (SCD), and their families, based on all available evidence. Although the recommendations are for optimal care, the writing committee recognizes that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide. ## Organization of the writing committee The writing committee consisted of internationally recognized experts from 14 countries in the fields of cardiac electrophysiology, cardiology, pediatric cardiology, genetic counseling, community genetics and public health genomics, and cardiac pathology, representing APHRS, HRS, AECVP, EHRA, ESHG, LAHRS, NSGC, PACES, and ERN GUARD-Heart and selected according to each society's procedures. In addition, a patient representative was chosen to provide a consumer viewpoint. Each partner society nominated a chair, who did not have relevant relationships with industry and other entities (RWIs). In accordance with the APHRS policies, disclosure of any RWIs was required from the writing committee members (Appendix 1) and from the peer reviewers (Appendix 2); of the 28 committee members, 23 (82%) had no relevant RWIs. Recommendations were drafted by the writing committee members who did not have relevant RWIs. ## Methodology and evidence review After development of a preliminary outline, committee members were given writing assignments and a schedule of conference calls. Writing committee members conducted a comprehensive evidence search using MEDLINE/PubMed, Embase, and the Cochrane Library and summarized the evidence in standardized tables (Appendix 3), with attention to the study type, size, inclusion criteria, and key findings. The writing committee reviewed evidence and established consensus to generate recommendations, which are presented in a modular knowledge chunk format, with each chunk including a table of recommendations, a brief synopsis, recommendation-specific supportive text, flow diagrams or tables as appropriate, and references. Recommendations were formulated according to the American College of Cardiology (ACC)/American Heart Association (AHA) Class of Recommendation (COR) and Level of Evidence (LOE) system 1 [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] and were subject to a period of public comment. The COR indicates the strength of a recommendation based on assessment of the estimated benefits and risks; LOE rates the quality of evidence that supports the recommendation based on type, quantity, and consistency of data from clinical trials and other sources. Case reports were not used to support recommendations. The threshold for consensus was considered as 80% or higher agreement. The 74 recommendations were balloted by the 28 writing committee members and approved by an average of 94%. A quorum of two-thirds of the writing committee was met for all votes [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] prior to external review. The document underwent external peer review by reviewers appointed by the APHRS and HRS and each of the collaborating societies. After subsequent revisions and endorsement by the participating societies, the document was ready for publication. ## Scope of the document This document provides a framework for the investigation of 1) patients with SCA, 2) decedents with sudden unexplained death (SUD), and 3) families of both SCA survivors and SUD victims, as many conditions responsible for the cardiac arrest or unexplained death may be familial. Identifying a cause is important for preventing further events in the family, should an inherited condition be found. Integral to the process is the counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence the futures of the family members. The disciplines of cardiology, pediatrics, radiology, pathology, counseling, psychology, and genetics are all involved in this process. Therefore, the formation of multidisciplinary teams is essential to provide a complete service to the patients and their families. While this document endeavors to provide clinicians with practical recommendations for evaluating patients with SCA, [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] decedents with SUD, and their families, the best approach will vary with the situation and will be influenced by, for example, the subject's age and results of initial testing. Although some of the recommendations do specify an age cutoff, it is recognized that this age is somewhat arbitrary and may not be always appropriate for the disease being investigated for or the demographics of the patient's country. Nevertheless, where an age is specified in a recommendation, it has passed the consensus voting of the writing group. Referral to a center with a multidisciplinary team experienced in such evaluations is recommended because it can facilitate navigation of these complexities. A multidisciplinary team can also help organize interval follow-up evaluations for SCA survivors and their family members. Repeated interval follow-up can reveal important new clinical data and allows for integration of new knowledge into the continued evaluation and care of these patients. The writing committee members recognize that not all investigative modalities recommended will be available in all circumstances; however, this document is an attempt to outline an approach to which the clinician should aspire. [fig_ref] Table 2: Relevant clinical practice documents European Recommendations Integrating Genetic Testing into Multidisciplinary Management... [/fig_ref] lists pertinent guidelines and consensus statements that the writing committee considered for this document. ## Relevant clinical practice documents The included documents contain relevant information for the diagnosis of patients with SCA and SCD. ## Definitions The terms used in the consensus statement are defined in. Unexplained sudden death occurring in an individual younger than 1 year with negative pathological and toxicological assessment Note: Synonymous with "sudden unexplained infant death" [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] Section 2 Epidemiology 2.1. Epidemiology: Sudden Death "Sudden unexplained death" refers to an unexpected and sudden death in an individual older than 1 year. Sudden death occurring unexpectedly within the first year of life is termed "sudden unexplained death in infancy" (SUDI). Multiple definitions have been in use over the past decades, although most recent studies implement a definition that differs between witnessed and unwitnessed events; in witnessed cases, death has to occur within 1 hour of change in cardiovascular status, whereas unwitnessed cases have to be seen alive and functioning normally within 24 hours of being found dead. [bib_ref] guidelines for management of patients with ventricular arrhythmias and the prevention of..., Zipes [/bib_ref] [bib_ref] Sudden cardiac death prediction and prevention: report from a National Heart, Lung,..., Fishman [/bib_ref] SCD constitutes the majority of SUD. [bib_ref] Risk factors and causes of sudden noncardiac death: a nationwide cohort study..., Risgaard [/bib_ref] [bib_ref] Nationwide study of sudden cardiac death in persons aged 1-35 years, Winkel [/bib_ref] [bib_ref] Natural and undetermined sudden death: value of post-mortem genetic investigation, Sanchez [/bib_ref] Reported overall SCD incidence rates vary across studies and countries, in part due to large difference in SCD definitions and methods for estimation of SCD rates. Previous studies report overall SCD rates ranging from 15 to 159 SCD per 100,000 persons per annum, corresponding to 6-20% of all deaths. [bib_ref] Regional variation in out-of-hospital cardiac arrest incidence and outcome, Nichol [/bib_ref] [bib_ref] Current burden of sudden cardiac death: multiple source surveillance versus retrospective death..., Chugh [/bib_ref] [bib_ref] Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht..., De Vreede-Swagemakers [/bib_ref] [bib_ref] Public health burden of sudden cardiac death in the United States, Stecker [/bib_ref] [bib_ref] Epidemiology of sudden cardiac death: global and regional perspectives, Wong [/bib_ref] [bib_ref] Systematic review of the incidence of sudden cardiac death in the United..., Kong [/bib_ref] [bib_ref] Nationwide improvements in survival from out-of-hospital cardiac arrest in Japan, Kitamura [/bib_ref] [bib_ref] Sudden coronary death in the United States: 1980-1985, Gillum [/bib_ref] However, both incidence and causes of SCD vary markedly with age. Lowest SCD incidence is observed in children and adolescents. [bib_ref] Nationwide study of sudden cardiac death in persons aged 1-35 years, Winkel [/bib_ref] [bib_ref] Current burden of sudden cardiac death: multiple source surveillance versus retrospective death..., Chugh [/bib_ref] [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Sudden cardiac death among the young in Sweden from 2000 to 2010:..., Wisten [/bib_ref] [bib_ref] Burden of sudden cardiac death in persons aged 1 to 49 years:..., Risgaard [/bib_ref] [bib_ref] Multiple source surveillance incidence and aetiology of out-of-hospital sudden cardiac death in..., Byrne [/bib_ref] SCD incidence is low in children and the young under 35 years and increases dramatically up until the age of approximately 60-80 years. [bib_ref] Nationwide study of sudden cardiac death in persons aged 1-35 years, Winkel [/bib_ref] [bib_ref] Out-of-hospital cardiac arrest in the 1990's: a population-based study in the Maastricht..., De Vreede-Swagemakers [/bib_ref] [bib_ref] Public health burden of sudden cardiac death in the United States, Stecker [/bib_ref] [bib_ref] Sudden cardiac death in children (1-18 years): symptoms and causes of death..., Winkel [/bib_ref] [bib_ref] Epidemiology of sudden death in a population-based study of infants and children, Burns [/bib_ref] In young persons aged 1-35 years, most SCDs are caused by potentially inherited heart diseases, including primary arrhythmogenic disorders (eg, congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia [CPVT]), hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy; [bib_ref] Nationwide study of sudden cardiac death in persons aged 1-35 years, Winkel [/bib_ref] [bib_ref] Current burden of sudden cardiac death: multiple source surveillance versus retrospective death..., Chugh [/bib_ref] [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Sudden cardiac death among the young in Sweden from 2000 to 2010:..., Wisten [/bib_ref] [bib_ref] Burden of sudden cardiac death in persons aged 1 to 49 years:..., Risgaard [/bib_ref] [bib_ref] Multiple source surveillance incidence and aetiology of out-of-hospital sudden cardiac death in..., Byrne [/bib_ref] [bib_ref] Sudden cardiac death in children (1-18 years): symptoms and causes of death..., Winkel [/bib_ref] [bib_ref] Sudden death in young adults: an autopsybased series of a population undergoing..., Eckart [/bib_ref] [bib_ref] The Northeast Italy, Veneto Region experience, Thiene [/bib_ref] however, coronary artery disease, anomalous coronary arteries, aortic dissection, congenital heart disease, and myocarditis are also potential causes, potentially with a non-negligible genetic component [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. From the age of 35 years, coronary artery disease becomes the most common cause of SCD, although potentially inherited heart diseases remain a common cause of SCD at least until the age of 50 years. [bib_ref] Burden of sudden cardiac death in persons aged 1 to 49 years:..., Risgaard [/bib_ref] [bib_ref] Sudden cardiac death in children (1-18 years): symptoms and causes of death..., Winkel [/bib_ref] [bib_ref] Sudden cardiac death among general population and sport related population in forensic..., Chappex [/bib_ref] Individuals with SUD who subsequently have negative pathological and toxicological assessment may be assumed to have sudden arrhythmic death (syndrome), or SAD(S), a term synonymous with "autopsy-negative SUD." At any age, males have higher SCD rates compared with females, even after adjustment for risk factors of coronary heart disease. [bib_ref] Epidemiology and genetics of sudden cardiac death, Deo [/bib_ref] Ethnic background seems to have large effect. [bib_ref] Racial differences in the incidence of cardiac arrest and subsequent survival: the..., Becker [/bib_ref] [bib_ref] Racial differences in sudden cardiac death, Zhao [/bib_ref] Synopsis SUD is a tragedy and, in the case of an underlying genetic predisposition, may be preventable. The main cause of SUD is SCD. SCD in the young often occurs in people who were thought to be well, may occur without warning symptoms, and is often the first presentation of an underlying genetic heart disease. Across all ages, estimates differ from 5% to 20% of all deaths, and ethnicity-specific data on SCD incidences worldwide are sparse. Cause of death changes according to age [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. Exact estimates of the burden of SCD are crucial in order to adjudicate public health spending. Recommendation-Specific Supportive Text 1. and 2. Inherited cardiac disorders are the main cause of SCD in the young. Sudden death is SCD in 60-90% depending on age, of which the majority is potentially from inherited cardiac disease. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] Nationwide study of sudden cardiac death in persons aged 1-35 years, Winkel [/bib_ref] [bib_ref] Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings, Basso [/bib_ref] Exact estimates of the burden of SCD are crucial in order to adjudicate public health spending. 25 [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] 3. Estimates of SCD among different ethnic backgrounds are sparse worldwide. [bib_ref] Racial differences in the incidence of cardiac arrest and subsequent survival: the..., Becker [/bib_ref] Australia. For reported survival estimates, the percentage survival to discharge was 7.6% in Europe, 6.8% in North America, 3.0% in Asia, and 9.7% in Australia. [bib_ref] Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of..., Berdowski [/bib_ref] Significant geographical variation in the incidence of OHCA associated with poor outcomes has remained unchanged in the past 3 decades. [bib_ref] Regional variation in out-of-hospital cardiac arrest incidence and outcome, Nichol [/bib_ref] [bib_ref] Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis, Sasson [/bib_ref] [bib_ref] Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of..., Berdowski [/bib_ref] [bib_ref] Variation in out-of-hospital cardiac arrest resuscitation and transport practices in the Resuscitation..., Zive [/bib_ref] However, implementation of coordinated efforts targeted at improving the local chain of survival in some cities has improved regional survival to 20-40%. [bib_ref] Ventricular fibrillation in King County, Washington: a 30-year perspective, Becker [/bib_ref] [bib_ref] Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation, Bunch [/bib_ref] This survival benefit can be partially attributed to varying definitions of OHCA, 42 but it is primarily due to a coordinated effort to optimize the effectiveness of the local chain of survival. [bib_ref] Improving survival from sudden cardiac arrest: the "chain of survival" concept. A..., Cummins [/bib_ref] Identifying and improving weak links in the local chain of survival, paired with targeted approaches to improve the effectiveness, has resulted in positive outcomes achieved in several geographic regions. [bib_ref] Ventricular fibrillation in King County, Washington: a 30-year perspective, Becker [/bib_ref] [bib_ref] Epidemiology and outcomes from out-of-hospital cardiac arrests in England, Hawkes [/bib_ref] [bib_ref] Etiology of out-of-hospital cardiac arrest diagnosed via detailed examinations including perimortem computed..., Moriwaki [/bib_ref] [bib_ref] The epidemiology of out-of-hospital 'sudden' cardiac arrest, Engdahl [/bib_ref] Approximately 80% of individuals presenting with OHCA reached by EMS, and in whom resuscitation is considered possible, have a cardiac cause. [bib_ref] The epidemiology of out-of-hospital 'sudden' cardiac arrest, Engdahl [/bib_ref] OHCA can affect seemingly fit and healthy athletes, young adults, or children. The incidence of SCD in athletes can range from 1 in 23,000 to 1 in 200,000 athletes per year, depending on a number of factors including populations studied. [bib_ref] Management of young competitive athletes with cardiovascular conditions, Silva [/bib_ref] [bib_ref] Sports-related sudden cardiac deaths in the young population of Switzerland, Asatryan [/bib_ref] In a retrospective analysis of the Rescu Epistry database of consecutive OHCA attended by EMS in a specific area of Ontario, Canada, the incidence of SCD during participation in competitive sports was reported to be 0.76 cases per 100,000 athlete-years. [bib_ref] Sudden cardiac arrest during participation in competitive sports, Landry [/bib_ref] The main causes of SCD were stratified by age. In those younger than 35 years, structural heart and primary arrhythmic causes were most common. In those aged between 35 and 45 years, coronary artery disease was the most frequent underlying pathology. [bib_ref] Sudden cardiac arrest during participation in competitive sports, Landry [/bib_ref] In a prospective study of children and young adults aged 1-35 years, 490 cases of SCD were identified from centers in Australia and New Zealand. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] The cause of death was unexplained in 40% of these cases at autopsy, in whom a structurally normal heart was reported. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] In this study, the annual incidence of SCD was calculated to be 1.3 cases per 100,000 people. When stratified according to age group, the highest incidence (3.2 cases per 100,000 people per year) was observed in those aged 31-35 years. Coronary artery disease was the most common cause ascribed. Younger age and SCD occurring at night were independently associated with unexplained SCD, probably due to congenital channelopathies. Less common causes were inherited cardiomyopathies (eg, dilated, hypertrophic, and arrhythmogenic right ventricular), myocarditis, and aortic dissection. The Cardiac Arrest Registry to Enhance Survival (CARES), established by the Centers for Disease Control and Prevention (CDC), 60 evaluated OHCA events of presumed cardiac etiology that involve persons who received resuscitative effort. OHCA is defined in CARES as a cardiac arrest that occurred in the prehospital setting, had a presumed cardiac etiology, and involved a person who received resuscitative efforts, including cardiopulmonary resuscitation (CPR) or defibrillation. The registry includes 40,274 OHCA records, of which 31,689 OHCA events were presumed to be of cardiac etiology (eg, myocardial infarction or arrhythmia) that received resuscitation efforts in the prehospital setting (mean age 64.0 years [SD 18.2]; 61.1% male). The survival rate to hospital admission was 26.3%, and the overall survival rate from cardiac arrest to hospital discharge was 9.6% [fig_ref] Figure 2: Cumulative overall survival rates, by participating emergency medical services agency-Cardiac Arrest Registry... [/fig_ref]. Approximately 36.7% of OHCA events were witnessed by a bystander. Only 33.3% of all patients received bystander CPR, and only 3.7% were treated by bystanders with an automated external defibrillator (AED) before the arrival of EMS providers. The group most likely to survive an OHCA is persons who are witnessed to collapse by a bystander and found in a shockable rhythm (ie, arrhythmias leading to ventricular fibrillation or pulseless ventricular tachycardia). [bib_ref] Out-of-hospital cardiac arrest surveillance: Cardiac Arrest Registry to Enhance Survival (CARES), United..., Mcnally [/bib_ref] Among this group, survival to discharge was 30.1% [fig_ref] Figure 3: Cumulative Utstein survival rates [/fig_ref]. A subgroup analysis, performed among persons who experienced OHCA events unwitnessed by EMS, revealed that whites were significantly more likely to receive CPR than blacks, Hispanics, or members of other racial/ ethnic populations (p , 0.001). Overall survival to hospital discharge of patients whose events were not witnessed by EMS personnel was 8.5%. Of these, patients who received bystander CPR had a significantly higher rate of overall survival (11.2%) than those who did not (7.0%) (p , 0.001). shows bystander CPR and lay AED use by percentage of black residents in the area. Directing attention toward improving education, availability of AEDs, and treatment of cardiac arrest in predominantly black neighborhoods may save lives. [bib_ref] Association of neighborhood demographics with out-of-hospital cardiac arrest treatment and outcomes: where..., Starks [/bib_ref] Bystander AED use in OHCA in pediatric populations is variable and uncommon, with important variations based on print & web 4C=FPO neighborhood characteristics leading to marked disparities in survival and outcomes. Griffis et al. [bib_ref] Characteristics and outcomes of AED use in pediatric cardiac arrest in public..., Griffis [/bib_ref] reported that AED use (likely due to availability) was more common in neighborhoods with a median household income of .$50,000 per year (12.3%; p 5 0.016), ,10% unemployment (12.1%; p 5 0.002), and .80% high school education (11.8%; p 5 0.002). Greater survival to hospital discharge and neurologically favorable survival were among arrests with bystander AED use, varying by neighborhood characteristics. ## Public health implications The majority of persons who experience an OHCA event, irrespective of etiology, do not receive bystander CPR or other timely interventions that are known to improve the likelihood of survival to hospital discharge (eg, defibrillation). [bib_ref] Association of national initiatives to improve cardiac arrest management with rates of..., Wissenberg [/bib_ref] Because nearly half of cardiac arrest events are witnessed, efforts to increase survival rates should focus on timely and effective delivery of interventions by bystanders and EMS personnel . Education of public officials and community members regarding the importance of increasing rates of bystander CPR and promoting the use of early defibrillation by lay and professional rescuers is critical to increasing survival rates. Reporting at local and national levels can enable local and national public health and EMS agencies to coordinate their efforts to target improving emergency response for OHCA events, regardless of etiology, which can lead to improvement in OHCA survival rates . ## Synopsis OHCA remains a significant cause of mortality globally. Despite implementation of cardiac arrest protocols including CPR training and AEDs, only 33% of witnessed OHCA cases receive bystander CPR and less than 4% are defibrillated onsite. OHCA hospital discharge survival remains dismal at around 10% and has remained stagnant for the past 3 decades. Significant geographic variation in OHCA incidence and the role of social disparities merit further research. Public Agencies sorted by total number of out-of-hospital cardiac arrest events in CARES (from low to high). [bib_ref] Out-of-hospital cardiac arrest surveillance: Cardiac Arrest Registry to Enhance Survival (CARES), United..., Mcnally [/bib_ref] †Utstein survival refers to survival to hospital discharge of persons whose cardiac arrest events were witnessed by a bystander and had an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia (range: 0-598). health campaigns promoting CPR training in at-risk communities and greater availability of AEDs are needed. ## Recommendations for improving outcomes in sca survivors ## Recommendation-specific supportive text 1. Coordinated efforts targeted at improving the local chain of survival have improved regional survival. [bib_ref] Ventricular fibrillation in King County, Washington: a 30-year perspective, Becker [/bib_ref] [bib_ref] Long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation, Bunch [/bib_ref] Targeted approaches to improve the effectiveness of CPR have resulted in positive outcomes. [bib_ref] Continuous improvements in "chain of survival" increased survival after out-of-hospital cardiac arrests:..., Iwami [/bib_ref] [bib_ref] Improving outcome after out-of-hospital cardiac arrest by strengthening weak links of the..., Lund-Kordahl [/bib_ref] [bib_ref] Association of national initiatives to improve cardiac arrest management with rates of..., Wissenberg [/bib_ref] The group most likely to survive an OHCA is persons who are witnessed to collapse by a bystander and found in a shockable rhythm, so widespread CPR training is recommended. Subgroup analysis has revealed that whites were significantly more likely to receive CPR than other racial/ethnic populations. [bib_ref] Out-of-hospital cardiac arrest surveillance: Cardiac Arrest Registry to Enhance Survival (CARES), United..., Mcnally [/bib_ref] AED use was more common in neighborhoods with high median household income, ,10% unemployment, and .80% high school education. [bib_ref] Characteristics and outcomes of AED use in pediatric cardiac arrest in public..., Griffis [/bib_ref] Therefore, maximum benefit will be gained from targeting CPR training to groups of high socioeconomic need and ethnic minorities. 2. The burden of OHCA and the response of bystanders appears to vary according to ethnicity and socioeconomic status. [bib_ref] Racial differences in the incidence of cardiac arrest and subsequent survival: the..., Becker [/bib_ref] [bib_ref] Characteristics and outcomes of AED use in pediatric cardiac arrest in public..., Griffis [/bib_ref] [bib_ref] Association of neighborhood demographics with out-of-hospital cardiac arrest treatment and outcomes: where..., Starks [/bib_ref] [bib_ref] Out-of-hospital cardiac arrest surveillance: Cardiac Arrest Registry to Enhance Survival (CARES), United..., Mcnally [/bib_ref] Further investigation of these findings may result in targeted approaches to maximize outcome from investment when aimed at these communities. 3. Availability of AEDs has been shown to improve survival. [bib_ref] Public-access defibrillation and survival after out-of-hospital cardiac arrest, Hallstrom [/bib_ref] [bib_ref] Tripling survival from sudden cardiac arrest via early defibrillation without traditional education..., Capucci [/bib_ref] [bib_ref] Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators, Blom [/bib_ref] Therefore, as the majority of cardiac arrests are witnessed, AEDs at schools, stadiums, stations, etc, may be expected to increase survival. Venues where delivery of AEDs by emergency services is unlikely (eg, trains, ships, planes) are of particular importance. Appropriately maintained equipment and appropriate training of potential AED users are an essential component of this strategy. ## Section 3 multidisciplinary team # Introduction The investigation of SCD and resuscitated SCA requires input from a variety of different disciplines. The coordination and the communication between them mandate the formation of a multidisciplinary team. Numerous consensus statements agree on the importance of a dedicated combined cardiac genetic service in this setting. 2,11,65-67 ## Key features of an effective multidisciplinary team Certain key features can be identified in well-functioning multidisciplinary teams across specialties. Nancarrow et al. [bib_ref] Ten principles of good interdisciplinary team work, Nancarrow [/bib_ref] propose 10 key attributes including positive leadership and management, communication strategies and structures, appropriate resources, appropriate skill mix, and a supportive team climate with a focus on education of each other. There should be open communication and shared decision-making. The detection of inherited heart conditions by pathologists and by hospital clinicians requires heightened awareness of their existence and a simple referral pathway to a multidisciplinary service with cardiac genetic expertise. Clinical experience shows that the appointment of a coordinator, as well as an enthusiastic team leader, is essential to facilitate this process, and regular meetings increase relevance and improve attendance [bib_ref] Development of a cardiac inherited disease service and clinical registry: a 15-year..., Earle [/bib_ref] [fig_ref] Figure 8: Participants in a cardiac genetic service [/fig_ref]. ## Defining which disciplines should be represented The investigation of SUD is led by (forensic) pathology and the investigation of resuscitated SCA by pediatric or adult cardiology, with cardiac heart rhythm specialists and genetic cardiologists often being central. Clinical and molecular genetic specialists and genetic counselors are needed because of the significant role of molecular genetics in achieving a diagnosis and cascade screening, the consideration of multisystem genetic syndromes, and the high prevalence of genetic variants of uncertain significance. [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Long QT molecular autopsy in sudden unexplained death in the young (1-40..., Marcondes [/bib_ref] The high levels of psychological morbidity among SCA survivors and family members of both SCA survivors and decedents mandates access to psychology expertise, [bib_ref] Poor psychological wellbeing particularly in mothers following sudden cardiac death in the..., Yeates [/bib_ref] [bib_ref] Experiences, considerations and emotions relating to cardiogenetic evaluation in relatives of young..., Van Der Werf [/bib_ref] [bib_ref] Interdisciplinary psychosocial care for families with inherited cardiovascular diseases, Caleshu [/bib_ref] and input into the multidisciplinary team helps keep this in focus. [bib_ref] Minding the genes: a multidisciplinary approach towards genetic assessment of cardiovascular disease, Rhodes [/bib_ref] The presence of a specialist cardiac genetic nurse in the cardiology inpatient setting increases detection of inherited cardiac conditions following SCA. [bib_ref] The inpatient cardiology visit: missing the opportunity to detect inherited heart conditions, Waddell-Smith [/bib_ref] Other clinical specialists can be helpful and be drafted in for certain cases-neurologists, pediatricians, metabolic specialists, and intensivists, for example. ## Coordination across disciplines and other boundaries The fact that the many disciplines may not be co-located highlights the importance of a coordinator to a multidisciplinary service. Co-location is not critical for effective collaboration, and non-co-location should not be an excuse for failed collaboration. A regional or institutional coordinator could be a nurse specialist, genetic counselor, or other allied professional and is vital to facilitate team meetings and communication between specialists and between centers, with primary care and across regions or between states and countries where necessary to facilitate family screening 69,77 . ## Links to other services Links to other services as proposed in a recent scientific statement [bib_ref] Establishment of specialized clinical cardiovascular genetics programs: recognizing the need and meeting..., Ahmad [/bib_ref] and practiced by some centers already 69 include connections to molecular genetic expertise, researchers, primary health providers, between regions, and to a cardiac genetic clinical registry to facilitate family screening and follow-up across traditional boundaries [fig_ref] Figure 8: Participants in a cardiac genetic service [/fig_ref]. Clinical and genetic registries are generally voluntary and consent-based and have a research element. We do not consider that they are compulsory. However, in this setting they do have particular relevance because many cases remain unresolved after the initial investigation and families may find comfort in knowing that efforts to find a diagnosis continue. The multidisciplinary team also provides a mechanism to revisit family members if new findings appear in the wider family or if the pathogenicity of a genetic variant is redefined. ## Synopsis The cardiac and genetic investigation of SUD and resuscitated SCA should be overseen by a multidisciplinary team with appropriate expertise in this area. Recommendations include adequate resourcing, a dedicated coordinator, strong leadership, and a mutually supportive team that meets regularly. ## Recommendation-specific supportive text 1. For regions where coordinated cardiac genetic services exist that include the investigation of SUD, detection of inherited heart conditions is higher than in regions where they are not. [bib_ref] Detection of sudden death syndromes in New Zealand, Earle [/bib_ref] Families prefer specialized clinics that combine co-located cardiac and genetic expertise and genetic counseling. [bib_ref] Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy, Ingles [/bib_ref] Many such dedicated clinics internationally have led to the detection of inherited heart conditions following SCD and resuscitated SCA. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] It is therefore logical that multidisciplinary teams should have links to such clinics. Continued productive dialogue among pathology, coronial, police, and cardiac genetic services is recommended to improve the quality and relevance of forensic pathologists' reports. [bib_ref] Evaluation of autopsy and police reports in the investigation of sudden unexplained..., Wilms [/bib_ref] 2. Genetic testing in this context leads to a significant proportion of both pathogenic and unclassified variants, and precise evaluation of clinical phenotype is imperative for the correct assignation of such variants, so that a service that combines specialist cardiology and genetic expertise is essential. [bib_ref] Assessment and validation of a phenotype-enhanced variant classification framework to promote or..., Giudicessi [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] Specialized clinics that combine co-located cardiac and genetic expertise and genetic counseling are preferred, [bib_ref] Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy, Ingles [/bib_ref] and such combined clinics have a high detection of inherited cardiac conditions following resuscitated SCA. [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] Section 4 Counseling Families, the Bereaved and the Nearly Bereaved Genetic counseling is a process that aims to assist patients and their families to understand and adapt to the medical, psychosocial, and familial impact of inherited diseases. [bib_ref] Goals of genetic counselling, Biesecker [/bib_ref] [bib_ref] A new definition of Genetic Counseling: National Society of Genetic Counselors' Task..., Resta [/bib_ref] Genetic counseling goes beyond the discussion of genetic testing and is important for all patients with a genetic condition, at all stages of management. [bib_ref] Genetic counselling and testing in cardiomyopathies: a position statement of the European..., Charron [/bib_ref] Although genetic counseling may be performed by any number of health professionals, genetic counselors are specifically trained in this role and have grown to a large allied health workforce worldwide. [bib_ref] The global state of the genetic counseling profession, Abacan [/bib_ref] [bib_ref] A report on ten Asia Pacific countries on current status and future..., Laurino [/bib_ref] In some institutions, this role may be performed by a clinical/medical geneticist, genetic nurse, or other appropriately trained specialist. In the setting of SCD or resuscitated SCA where a genetic cause is suspected, the inclusion of genetic counselors in the multidisciplinary team is widely advocated. The role of the cardiac genetic counselor includes taking a detailed family history, investigating and confirming details such as postmortem reports, providing education and awareness, assisting in coordinating family clinical screening, and providing psychosocial support. [bib_ref] Interdisciplinary psychosocial care for families with inherited cardiovascular diseases, Caleshu [/bib_ref] [bib_ref] The emerging role of the cardiac genetic counselor, Ingles [/bib_ref] [bib_ref] Genetic evaluation of cardiomyopathy: a Heart Failure Society of America Practice Guideline, Hershberger [/bib_ref] [bib_ref] Genetic counseling and testing for hypertrophic cardiomyopathy: an adult perspective, Skrzynia [/bib_ref] [bib_ref] Psychological issues in managing families with inherited cardiovascular diseases, Ingles [/bib_ref] Throughout the process of genetic testing, genetic counselors provide important preand post-test genetic counseling, assist with interpretation of the results, help communicate this information to relatives, and assist with cascade genetic testing [bib_ref] Minding the genes: a multidisciplinary approach towards genetic assessment of cardiovascular disease, Rhodes [/bib_ref] [bib_ref] Genetic evaluation of cardiomyopathy: a Heart Failure Society of America Practice Guideline, Hershberger [/bib_ref] [bib_ref] Psychological issues in genetic testing for inherited cardiovascular diseases, Aatre [/bib_ref] [bib_ref] Genetic testing in the contemporary diagnosis of cardiomyopathy, Sturm [/bib_ref]. Where there are significant emotional difficulties (see Section 5), the process of effectively conveying genetic information can be challenging. [bib_ref] Factors influencing uptake of familial long QT syndrome genetic testing, Burns [/bib_ref] For families who have experienced a young SCD where a genetic cause is suspected, learning the potential inheritance risk to family members and need for clinical screening can add an additional stressor at a time of intense grief. Furthermore, with the increasing availability of postmortem genetic testing (see Sections 6.4 and 6.5), the need for complex genetic discussions with families is more commonplace. [bib_ref] Psychosocial care and cardiac genetic counseling following sudden cardiac death in the..., Ingles [/bib_ref] Genetic counseling prior to and after genetic testing is important, particularly where genetic test results are not straightforward such as identification of variants of uncertain significance or in the event of a variant reclassification. [bib_ref] Perceptions of genetic variant reclassification in patients with inherited cardiac disease, Wong [/bib_ref] [bib_ref] Psychological adaptation to molecular autopsy findings following sudden cardiac death in the..., Bates [/bib_ref] There is wide acknowledgment that genetic counseling as a process should go beyond just provision of information. [bib_ref] Assessment of the content and process of genetic counseling: a critical review..., Meiser [/bib_ref] [bib_ref] Interventions to improve risk communication in clinical genetics: systematic review, Edwards [/bib_ref] The psychosocial aspects of genetic counseling include psychological support, empathic listening, crisis intervention skills, knowledge of family dynamics, coping models, processes of grief, and adjustment to disease diagnoses, all of which align with the core competencies of genetic counseling accreditation. [bib_ref] Conceptualizing genetic counseling as psychotherapy in the era of genomic medicine, Austin [/bib_ref] Attending to the psychosocial needs, in addition to provision of education and information, has been demonstrated to positively impact patient outcomes, largely based around knowledge and recall, but healthy adjustment, empowerment, behavioral change, and satisfaction with decision-making also reduce anxiety and worry. [bib_ref] Interventions to improve risk communication in clinical genetics: systematic review, Edwards [/bib_ref] B-NR 1. The investigation of SUD and SCD due to a potentially heritable condition should be overseen by a multidisciplinary team with, as a minimum, appropriate expertise in pediatric and/or adult cardiology, genetics, genetic counseling, and pathology. ## 78-82 1 B-NR 2. The investigation of a sudden cardiac arrest survivor where a heritable condition is possible should be overseen by a multidisciplinary team with, as a minimum, appropriate expertise in pediatric and/or adult cardiology, genetics, and genetic counseling. ## 79,82-85 Synopsis Genetic counseling of patients and their families with genetic conditions is recommended, including those with SCD or resuscitated SCA where a genetic cause is suspected. Key aspects of the process include discussion of inheritance risks, education and awareness, pre-and post-test genetic counseling, interpretation of genetic results, taking a family history, coordination of clinical screening, and psychosocial support. Genetic counseling is focused on both information provision and psychosocial support and together has been shown to improve knowledge and recall; promote healthy adjustment, empowerment, and behavioral change; increase satisfaction with decision-making; and reduce anxiety and worry. While genetic counseling is a process often performed by a variety of health professionals, ideally a specifically trained genetic counselor or genetic nurse with appropriate skills in information provision and psychosocial support would perform this role. ## Recommendation-specific supportive text ## Genetic counseling includes both information provision and psychosocial support. It is ideally performed by health professionals with specific training and experience; this includes genetic counselors, genetic nurses, or other qualified health professionals. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] ,85,103,106,107,109 2. In the context of genetic testing, pre-and post-test genetic counseling must be performed. [bib_ref] Minding the genes: a multidisciplinary approach towards genetic assessment of cardiovascular disease, Rhodes [/bib_ref] [bib_ref] Psychological issues in managing families with inherited cardiovascular diseases, Ingles [/bib_ref] [bib_ref] Psychological issues in genetic testing for inherited cardiovascular diseases, Aatre [/bib_ref] [bib_ref] Psychosocial care and cardiac genetic counseling following sudden cardiac death in the..., Ingles [/bib_ref] In cases where there is uncertainty in the findings, such as a variant of uncertain significance or a variant reclassification, this is of particular importance. [bib_ref] Perceptions of genetic variant reclassification in patients with inherited cardiac disease, Wong [/bib_ref] [bib_ref] Psychological adaptation to molecular autopsy findings following sudden cardiac death in the..., Bates [/bib_ref] Section 5 Psychological Care SCD where a genetic cause is suspected has a profound psychological impact on the surviving members of the family. Grief is a normal emotional response to the loss of a loved one. Individuals will grieve differently, and while there is no single trajectory, Key goals of genetic counseling following sudden cardiac death/resuscitated sudden cardiac arrest ## Goal description Genetic counseling about inheritance risks Provide information tailored specifically to the family about their inheritance risks. ## Provide education and awareness Educate about inheritance risks, the need for clinical surveillance, and options for genetic testing to allow the family to make subsequent important medical decisions. Conveying information is not straightforward, given varying health literacy and competing health concerns; however, genetic counseling can support effective communication. [bib_ref] Communication of genetic information to families with inherited rhythm disorders, Burns [/bib_ref] Genetic counseling can also include connection of families with advocacy organizations and relevant research studies. Pre-and post-test genetic counseling Explain the process and discuss the options of genetic testing, all possible outcomes of testing, implications for patients and/or their family members, and worries and fears about testing; ensure consideration of all possible results and implications. [bib_ref] Genetic counselors' approach to postmortem genetic testing after sudden death: an exploratory..., Liu [/bib_ref] Care should be taken in conveying test results of uncertain significance, 101,110 specifically ensuring adequate understanding and confidence to communicate key risk information to family members. Pre-and post-test genetic counseling for cascade testing of asymptomatic relatives There are ethical, legal, and social implications when considering cascade genetic testing of asymptomatic at-risk relatives. Careful pre-test genetic counseling should explore the individual's feelings toward their risk, how they might feel if they are gene positive or gene negative, and implications for their own health and clinical management based on their genetic result. Discussion about the potential for reclassification of the genetic result is also important. 100,111 Provide input regarding classification of genetic variants Knowledge of variant and gene curation processes will enable review of any genetic test findings at all stages of family management. [bib_ref] Clinical cardiovascular genetic counselors take a leading role in team-based variant classification, Reuter [/bib_ref] Clinicians involved in family management (including genetic counselors) are more likely to provide conservative variant classifications compared to clinical laboratories, [bib_ref] Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a..., Bland [/bib_ref] and processes to guarantee regular review of variants will ensure appropriate reclassifications are made. [bib_ref] Care in specialized centers and data sharing increase agreement in hypertrophic cardiomyopathy..., Furqan [/bib_ref] Although genetic counseling is unlikely to resolve any significant psychopathologies, the process of providing information and a big picture perspective allowing a patient to normalize their experience and emotional response can have a positive impact, including patient empowerment. [bib_ref] Interventions to improve risk communication in clinical genetics: systematic review, Edwards [/bib_ref] [bib_ref] Genetic counselling: the psychological impact of meeting patients' expectations, Michie [/bib_ref] [bib_ref] The impact of cardiovascular genetic counseling on patient empowerment, Ison [/bib_ref] many will experience disbelief, yearning, anger, sadness, and acceptance. [bib_ref] Getting straight about grief, Shear [/bib_ref] After a death, an individual will not return to normal, but rather create a revised meaningful life without the deceased. In a small proportion of bereaved individuals, the initial grief response does not resolve and may result in prolonged grief, or persistent complex bereavement disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). [bib_ref] The prevalence and correlates of psychiatric comorbidity in individuals with complicated grief, Simon [/bib_ref] This occurs in approximately 7% of the general bereaved population, [bib_ref] Treating complicated grief, Simon [/bib_ref] and in 21% of first-degree relatives following SCD in the young. [bib_ref] Posttraumatic stress and prolonged grief after the sudden cardiac death of a..., Ingles [/bib_ref] Posttraumatic stress symptoms can also be experienced by family members. Posttraumatic stress occurs in response to a specific trigger, typically one that threatens one's own or a loved one's well-being. It is characterized by avoidance with hyperarousal and intrusive thoughts, including persistent and extreme fear and panic similar to that experienced by family members at the time of the event. [bib_ref] Post-traumatic stress disorder, Shalev [/bib_ref] Posttraumatic stress has been shown in 44% of first-degree relatives following a young SCD. [bib_ref] Posttraumatic stress and prolonged grief after the sudden cardiac death of a..., Ingles [/bib_ref] Individuals with prolonged grief and/or posttraumatic stress symptoms can benefit from intervention with a clinical psychologist or other appropriately trained clinicians, and there is extensive evidence to support the efficacy of psychological treatments for these conditions in other settings. [bib_ref] Treating complicated grief, Simon [/bib_ref] Further, there is greater risk of other psychiatric comorbidities, [bib_ref] The prevalence and correlates of psychiatric comorbidity in individuals with complicated grief, Simon [/bib_ref] suicide, [bib_ref] Suicidality and bereavement: complicated grief as psychiatric disorder presenting greatest risk for..., Latham [/bib_ref] and development of chronic medical conditions. [bib_ref] Traumatic grief as a risk factor for mental and physical morbidity, Prigerson [/bib_ref] Factors associated with poor psychological outcomes have been investigated. One study showed that mothers of the deceased were more likely to report anxiety and depression symptoms. [bib_ref] Poor psychological wellbeing particularly in mothers following sudden cardiac death in the..., Yeates [/bib_ref] In total, 53% of the mothers surveyed reported probable anxiety disorder on average 4 years after the death. In a larger study, after adjusting for factors including relationship to the decedent, those family members who witnessed the death or discovered the decedent's body had a 3-fold risk of posttraumatic stress symptoms (OR 3.3, 95% CI 1.2-8.7, p 5 0.02) and a 4-fold risk of prolonged grief (OR 4.0, 95% CI 1.3-12.5, p 5 0.02). [bib_ref] Posttraumatic stress and prolonged grief after the sudden cardiac death of a..., Ingles [/bib_ref] Given that half report symptoms indicating psychological difficulties, all first-degree relatives should be offered psychological evaluation and treatment. Although the evidence for psychological support is derived from studies investigating SCD where a genetic cause is suspected, it may logically apply to those individuals who have survived SCA and their families . There may be initial reluctance to seek psychological support given community stigma around mental health. Indeed, a recent study investigating families who had experienced a young SCD found that only 12% had sought psychological support, with most of those being self-referrals. [bib_ref] Psychological support and medical screening of first-degree relatives of sudden cardiac arrest..., Karam [/bib_ref] In discussing options for ongoing psychological support with patients and families, normalizing their response to a significant psychological stressor and describing common symptoms of prolonged grief and posttraumatic stress may reduce any perceived sense of stigma and increase interest in seeking support. A recent needs analysis of parents who had experienced the SCD of their child (including adult children) found that while medical information and support were the most important need, psychological information and support were the most unmet need. [bib_ref] A needs analysis of parents following sudden cardiac death in the young, Mcdonald [/bib_ref] Nearly three-quarters reported wanting access to professional counseling or psychological services. Further, many indicated access to genetic testing or understanding the genetic cause to be an important need, highlighting the importance of maintaining realistic expectations regarding the diagnostic yield of postmortem genetic testing with families. [bib_ref] Psychological adaptation to molecular autopsy findings following sudden cardiac death in the..., Bates [/bib_ref] At present, this is likely not greater than 15%, and there is a high likelihood of uncertain genetic findings especially with increasing gene panel sizes. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] A Swedish study of parents whose children died suddenly between 15 and 35 years of age likewise showed a critical lack of information and support in the acute grief stage. [bib_ref] Supportive needs of parents confronted with sudden cardiac death: a qualitative study, Wisten [/bib_ref] This included a need for better communication of the postmortem examination process (how long it would take, when they would get results), time with a health professional to discuss the death, and information about the cause of death. There was a lack of psychological support in the immediate aftermath, with many family members seeking their own care, including grief counselors and support groups. The need for support in the early aftermath has been shown to be important in other studies examining suddenly bereaved parents. [bib_ref] A study of bereavement care after a sudden and unexpected death, Dent [/bib_ref] [bib_ref] Perceptions, needs and mourning reactions of bereaved relatives confronted with a sudden..., Merlevede [/bib_ref] Community or peer-based bereavement support groups can also enhance social support. [bib_ref] Treating complicated grief, Simon [/bib_ref] Peer support programs come in many different forms but always involve people with similar backgrounds providing emotional, social, or practical support to each other. [bib_ref] Peer support/peer provided services underlying processes, benefits, and critical ingredients, Solomon [/bib_ref] Peer supporters draw on their shared experiences to provide empathic understanding, information, and advice to those they are helping. A key aim is to promote hope, recovery from illness or trauma, improved life skills, psychological well-being, and social integration. [bib_ref] An analysis of relationships among peer support, psychiatric hospitalization, and crisis stabilization, Landers [/bib_ref] A recent systematic review of peer support services for bereaved survivors of the sudden death of a loved one in multiple settings found evidence of reductions in grief and increased wellbeing and personal growth among participants, and improved personal growth and positive meaning in life among peer providers. [bib_ref] Peer support services for bereaved survivors: a systematic review, Bartone [/bib_ref] There is a current gap in care in addressing psychological support needs of families after the SCD of a young relative. [formula] 2a C-LD 2. [/formula] In the investigation of SUD where a genetic cause is suspected, provision of information and referral to support services such as support workers, grief counseling, and peer support services can be useful. ## 127,131-133 ## Synopsis The psychological impact to the family following an SCD where a genetic cause is suspected can be significant. Although many family members will navigate their way through this traumatic experience, up to 44% may require additional psychological support from an appropriately trained health professional such as a clinical psychologist. Addressing community stigma around mental health needs to be considered and discussed with families. In addition, support services such as social workers, grief counselors, psychosocial teams, and peer support groups may be useful to many families. Whereas the evidence for psychological support is derived from studies investigating SCD where a genetic cause is suspected, it may logically apply in those families where there has been an SCA. ## Recommendation-specific supportive text 1. and 2. A clinical psychologist or appropriately trained health professional includes those equipped to assess and treat trauma; for example, those experienced in delivering cognitive behavioral therapies. While the evidence to date supports a need for psychological support in family members following a young SCD where a genetic cause is suspected, this may likewise be important for relatives of a patient who suffers an SCA. [bib_ref] Poor psychological wellbeing particularly in mothers following sudden cardiac death in the..., Yeates [/bib_ref] [bib_ref] Posttraumatic stress and prolonged grief after the sudden cardiac death of a..., Ingles [/bib_ref] [bib_ref] When I go in to wake them ... I wonder: parental perceptions..., Farnsworth [/bib_ref] There is a need to train personnel in psychological care for SUD and SCA, as this is an area where the need is not currently met. Section 6 Investigation of Sudden Death 6.1. Investigation of Sudden Death: History-Personal and Family Despite being "low-tech" and inexpensive, the history, as a tool for clinical phenotyping, is the essential and fundamental basis of approaching a patient with SCA because it can guide appropriate use and interpretation of other diagnostic modalities. The history should be focused toward both the decedent proband and also the wider family for evidence of other potentially affected members prior to investigations. Surviving family members should be investigated by a multidisciplinary team within a specialist program for cardiovascular genetic disorders with the all appropriate medical, genetic, and psychological personnel and ability for comprehensive investigations 2,10 [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. The proband age may help define potential etiologies; CPVT and long QT syndrome are typically diseases of the young, whereas coronary artery disease and cardiomyopathies become more common with age [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. Although most deaths occur at rest or during sleep, [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] death during exertion may point to specific etiologies such as CPVT, long QT syndrome type 1, or arrhythmogenic cardiomyopathy. In addition to a detailed prior medical and medication history (including potential drugs of abuse), the decedent's health in the 24-48 hours preceding death including the presence of any viral prodrome or fever, as well as any prescribed medication, may be relevant. Myocarditis secondary to viral infection may be associated with viral and gastrointestinal symptoms, and both Brugada syndrome and long QT syndrome may be exacerbated by specific pharmacological agents through further inhibition of ion channel function. [bib_ref] Sudden cardiac death: pharmacotherapy and proarrhythmic drugs: a nationwide cohort study in..., Risgaard [/bib_ref] Fever is a well-recognized trigger of ECG changes and arrhythmia in Brugada syndrome [bib_ref] Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada..., Michowitz [/bib_ref] and in some long QT syndrome subtypes, [bib_ref] Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital..., Amin [/bib_ref] and in young children may be misdiagnosed as febrile seizures. [bib_ref] Clinical aspects and prognosis of Brugada syndrome in children, Probst [/bib_ref] Between 18% and 45% of sudden death cases may have experienced prior relevant symptoms, typically palpitations, chest pain, pre-syncope, or syncope, and may have undergone relevant investigations. [bib_ref] Sudden cardiac death in children (1-18 years): symptoms and causes of death..., Winkel [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Symptoms before sudden arrhythmic death syndrome: a nationwide study among the young..., Glinge [/bib_ref] All medical records relevant to the sudden death etiology should be sought. Relevant information from the family history should be collected by a health professional with specific experience in cardiovascular genetic disease (preferably a genetic counselor) and by an appropriately trained cardiologist. Symptoms and diagnoses in other family members as well as prior cardiovascular investigations should be sought. Noncardiac findings may be highly pertinent including unexplained epilepsy unresponsive to conventional therapy; skeletal muscle weakness; curled hair and subtle palmoplantar hyperkeratosis/keratoderma (arrhythmogenic cardiomyopathy) [bib_ref] Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a..., Maruthappu [/bib_ref] ; attention deficit disorder and intellectual disability (CPVT) [bib_ref] Linking the heart and the brain: neurodevelopmental disorders in patients with catecholaminergic..., Lieve [/bib_ref] ; and history of pneumothoraces, vascular disease, and gastrointestinal and uterine rupture (vascular Ehlers-print & web 4C=FPO Psychological care following a sudden cardiac arrest (SCA) or a sudden unexplained death (SUD) where a genetic cause is suspected. Colors correspond to the Class of Recommendation in [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. Danlos syndrome). [bib_ref] Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome, Byers [/bib_ref] Any other deaths or major cardiac events in the family should be recorded including those related to drowning in good swimmers, unexplained motor vehicle accidents, and sudden infant death or late fetal demise. If the SUD was observed, it is useful to collect witness accounts about the events occurring immediately prior to the collapse and during any resuscitation attempts. ## Synopsis The personal medical and three-generation family history provides the initial information on which subsequent investigations will be based. Specific features within the wider family may suggest diagnoses and help direct subsequent investigation. The history should be recorded by cardiologists, specialist nurses, and geneticists or genetic counselors experienced in cardiovascular genetic diseases, ideally within the confines of a multidisciplinary program that can address the medical, genetic, and psychological needs of the family (see Section 3). [bib_ref] HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic..., Towbin [/bib_ref] [bib_ref] Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of..., Priori [/bib_ref] In the general population, premature ventricular complexes (PVCs) are mostly benign; however, some frequent or complex PVCs significantly increase the risk of SCD. [bib_ref] Relation between ventricular premature complexes and sudden cardiac death in apparently healthy..., Abdalla [/bib_ref] [bib_ref] Meta-analysis of ventricular premature complexes and their relation to cardiac mortality in..., Ataklte [/bib_ref] [bib_ref] Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by..., Noda [/bib_ref] If an ECG is recorded by the AED or EMS just before SCD, features such as J-wave or ST segment elevation (especially if augmented after a long pause) may help in the diagnosis of coronary spasm, early repolarization syndrome, or Brugada syndrome. [bib_ref] Dynamicity of the J-wave in idiopathic ventricular fibrillation with a special reference..., Aizawa [/bib_ref] [bib_ref] Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients..., Kawata [/bib_ref] Interpretation of ECGs obtained immediately after resuscitation/ defibrillation should be performed with great caution (see Section 7.4). Syncope is a sentinel clinical symptom before SUD and may prompt investigations subsequently useful in making a retrospective diagnosis of the cause of SUD. In particular, the trigger for the syncopal event bears useful information. Ambulatory ECG monitoring during life may provide clues to the cause of SUD and should be sought. ## Recommendation-specific supportive text If transthoracic echocardiography, cardiac computed tomography (CT), or cardiac magnetic resonance imaging (CMR) are performed during the patient's life, detailed review may indicate features of dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic cardiomyopathy. [bib_ref] Clinical diagnosis, imaging, and genetics of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: JACC..., Gandjbakhch [/bib_ref] If blood or other tissue sample has been taken before SUD, this may be a source of DNA for genetic testing, should there not be a postmortem collection of tissue. [bib_ref] ESC guidelines for the management of patients with ventricular arrhythmias and the..., Priori [/bib_ref] [bib_ref] HRS/EHRA expert consensus statement on the state of genetic testing for the..., Ackerman [/bib_ref] [bib_ref] Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the..., Basso [/bib_ref] [bib_ref] Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of..., Priori [/bib_ref] Neurological findings such as developmental delay or seizures thought to be suspicious for epilepsy during life may contribute to a diagnosis of a cardiac channelopathy, such as CPVT or long QT syndrome. [bib_ref] Linking the heart and the brain: neurodevelopmental disorders in patients with catecholaminergic..., Lieve [/bib_ref] [bib_ref] Sudden unexpected death in epilepsy: the neuro-cardio-respiratory connection, Manolis [/bib_ref] [bib_ref] Misdiagnosis of long QT syndrome as epilepsy at first presentation, Maccormick [/bib_ref] If a patient with SUD has a cardiovascular implantable electronic device (CIED) implanted, postmortem interrogation of the CIED is useful to determine the cause and timing of SCD. [bib_ref] Cardiac implantable electronic device interrogation at forensic autopsy: an underestimated resource?, Lacour [/bib_ref] ## Synopsis During the investigation of SUD, pertinent investigations performed prior to death can aid in establishing the cause. Although ECG features such as QT interval, type 1 Brugada pattern, and early repolarization may be critical for diagnosis, many ECGs taken during life will be normal. Ambulatory ECG monitoring and cardiac imaging should be sought to provide clues to the diagnosis of SCD. Symptoms attributed to a neurological cause may be re-evaluated, in collaboration with neurologists. Any potential DNA sample before SUD should be stored if tissue is not gained at autopsy. ECG information from the AED, emergency services, or CIEDs may also be useful to determine the cause of SCD. Recommendation-Specific Supportive Text The critical components to the investigation of SUD include examining the circumstances of the death and the autopsy [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. Identification of SUD relies on the reporting of EMS, police, hospitals, and witnesses. Investigation of a death is determined by the jurisdiction in which the death occurs. [bib_ref] Risk factors and causes of sudden noncardiac death: a nationwide cohort study..., Risgaard [/bib_ref] [bib_ref] National Association of Medical Examiners. Forensic autopsy performance standards, Peterson [/bib_ref] [bib_ref] Improving forensic pathologic investigation of sudden death in the young: tools, guidance,..., Gulino [/bib_ref] Unexpected or unexplained deaths, when the individual was in apparent good health, should be carried out by a trained pathologist who has a thorough knowledge of cardiac pathology. [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] Autopsies vary not only by country but also by individual jurisdictions within countries. The autopsy should be comprehensive, examining all organs and conducted in a systematic and objective method with a focus on standardized reporting. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the..., Basso [/bib_ref] [bib_ref] Etiology of sudden death in sports: insights from a United Kingdom regional..., Finocchiaro [/bib_ref] [bib_ref] Harmonization of medico-legal autopsy rules: Committee of Ministers. Council of Europe, Brinkmann [/bib_ref] Cases should be referred to a cardiac pathologist when a cardiac cause is suspected. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] Imaging includes X-rays and photography. Photography is useful in providing documentation of syndromic features and highlighting individual organ pathology. Postmortem CT and magnetic resonance imaging (MRI) have been shown to be useful 179 but are not universally available. Noncardiac causes should be looked for including infection, thromboembolism, tumors, intracerebral lesions, respiratory disease, and abdominal causes such as ruptured abdominal aneurysm. Body mass index should be recorded along with waist circumference. Ancillary testing should be performed including microbiology/cultures for infectious disease, metabolic screening (particularly in younger children), toxicology, vitreous testing for biochemistry, genetic testing (see Sections 6.4 and 6.5), and other testing as indicated by the autopsy findings. Taking a sample for toxicology is recommended in all sudden unexpected deaths. [bib_ref] Post-mortem toxicology in young sudden cardiac death victims: a nationwide cohort study, Bjune [/bib_ref] Samples for genetic testing should be saved at the time of autopsy from every sudden death case. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] National Association of Medical Examiners position paper: recommendations for the investigation and..., Middleton [/bib_ref] Ideally, two of the following three should be saved: a small piece of fresh frozen heart, a small piece of fresh frozen spleen/liver/ thymus, and EDTA blood. If RNAlater (ThermoFisher Scientific, Waltham, MA, USA) or similar reagent to preserve DNA at room temperature is available, fresh tissue can be transported in this to the referral genetic center without need for freezing. The heart should be examined thoroughly [bib_ref] Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the..., Basso [/bib_ref] and at least 7-10 samples taken for histology. Cardiovascular disease is the leading cause of sudden death in the young and is divided into two major groups: morphologically positive (eg, congenital heart disease, coronary artery disease, and cardiomyopathy) and morphologically normal hearts. Combined with negative toxicology, those with morphologically normal hearts have been labeled as having "autopsy-negative sudden unexplained death" or "sudden arrhythmic death (syndrome) or SAD(S)." 182 Samples should always be taken, even from a macroscopically normal heart, as histology may reveal inflammation and cardiomyopathies. Always consider sudden unexpected death in epilepsy (SUDEP) and sudden death in alcohol misuse (SUDAM) [bib_ref] Sudden unexplained death in alcohol misuse (SU-DAM) patients have different characteristics to..., Sorkin [/bib_ref] where clinical history and circumstances are important. Pathologists and clinicians should not overinterpret findings in the heart at autopsy such as nonsignificant coronary artery disease, etc. [bib_ref] Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous..., Papadakis [/bib_ref] ## Synopsis A comprehensive autopsy is an essential part of the investigation of SUD and should include collection and storage of tissue suitable for genetic analysis. When the autopsy suggests a possible genetic cause, or no cause and the heart is normal, referral to a multidisciplinary team for further investigation is indicated (see Section 3). ## Recommendation-specific supportive text 1. SUD should have an autopsy done by a trained pathologist. [bib_ref] National Association of Medical Examiners. Forensic autopsy performance standards, Peterson [/bib_ref] [bib_ref] Improving forensic pathologic investigation of sudden death in the young: tools, guidance,..., Gulino [/bib_ref] [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] Studies have shown that autopsies performed by pathologists who have a thorough knowledge of cardiac pathology have a superior diagnostic yield. [bib_ref] National Association of Medical Examiners. Forensic autopsy performance standards, Peterson [/bib_ref] [bib_ref] Improving forensic pathologic investigation of sudden death in the young: tools, guidance,..., Gulino [/bib_ref] [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] In cases where autopsy is not possible (eg, for religious reasons), a full body MRI or CT scan is recommended. [bib_ref] Conventional autopsy versus minimally invasive autopsy with postmortem MRI, CT, and CT-guided..., Blokker [/bib_ref] ## Samples should be taken for infection and toxicology. Histological sampling of all important organs especially the heart (from multiple sites) is essential even when macroscopically normal. 174,175 3. Blood or tissue suitable for DNA extraction and postmortem genetic testing should be obtained at all autopsies. [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] Following the initial investigation, DNA should be extracted and banked if genetic disease is suspected or if the cause remains unknown. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] The importance of specialist cardiac histopathological examination in the investigation of young..., De Noronha [/bib_ref] Ideally, lack of cost coverage should not be a reason not to comply with these recommendations. 4. Frozen myocardial tissue may be useful for subsequent RNA analysis or expression studies of aberrant proteins. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the..., Basso [/bib_ref] 5. Cause of death should be discussed in a multidisciplinary meeting (see Section 3) and provided by a pathologist to the medical examiner/coroner. The findings and followup recommendations should be communicated to the family. . Finding of an abnormal or normal heart is important for family screening and directs much of the subsequent investigation (see Sections 6.4 and 6.5). 7. Autopsy phenotype should be established at a multidisciplinary meeting of pathologist, medical examiner, cardiologist, and clinical geneticist. ## Investigation of sudden death: genetic evaluation where the phenotype is known Genetic evaluation may be appropriate following SCD in two scenarios: most commonly, where the deceased individual is the proband with no prior medical history, or alternatively the deceased is part of a family where diagnosis is established but he/she has not yet undergone genetic evaluation. Initially, pathological examination should be performed by an experienced pathologist to ensure that all cardiac and extracardiac features relevant to the potential diagnosis are recognized (see Section 6.3). In cases where the deceased is the proband and a postmortem diagnosis is established, identification of a pathological variant may facilitate genetic testing in the wider family evaluation. Genetic testing of DNA from the deceased proband may be performed directly after autopsy or deferred until first-degree family members have been clinically evaluated [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. As part of familial evaluation, a three-generation pedigree (at a minimum) performed by a practitioner knowledgeable in the genetics of cardiovascular disease (eg, a genetic counselor or specialist nurse) is mandatory and should cover all potentially relevant cardiac and extracardiac features within the family (see Section 6.1). Genetic testing of deceased individuals may Autopsies for SUD should be comprehensive, including photography, imaging, toxicology, gross examination of all organs, and detailed examination of the brain, heart, and thorax, with histology being essential. 14,175-177,180 1 B-NR 3. EDTA blood and/or one type of fresh tissue (heart, liver, spleen, skeletal muscle) should be saved at autopsy for SUD and banked at 220 C or 280 C for potential genetic analysis; two sources are ideal, if possible. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Postmortem genetic testing for conventional autopsy-negative sudden unexplained death: an evaluation of..., Carturan [/bib_ref] [bib_ref] Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsynegative sudden..., Tester [/bib_ref] 2b C-LD 4. Storing frozen myocardial tissue may be considered at autopsy for SUD, as it may aid in assessing the significance of future genetic findings. ## 186,187 1 C-EO 5. Findings of an autopsy for SUD should be communicated to the family in a timely fashion in accordance with local legal requirements. 1 B-NR 6. Cases with likely cardiac causes for SUD should be referred to a pathologist with expertise in cardiac disease, as the finding of an abnormal or normal heart is important for family screening. ## 176,177,184 1 C-LD 7. When an autopsy for SUD reveals a possible genetic cause, or the heart is normal, then referral for clinical and genetic investigation of the family is recommended. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] Yield of molecular and clinical testing for arrhythmia syndromes: report of 15..., Hofman [/bib_ref] [bib_ref] The diagnostic yield of Brugada syndrome after sudden death with normal autopsy, Papadakis [/bib_ref] not be covered by health insurance in certain countries; in this instance, using a clinically affected family member as the testing proband with confirmatory testing in the deceased may be a more feasible strategy. Clinical and genetic testing in the proband and multiple family members will define segregation of the identified genetic variant(s), adding to the validity of the genetic findings. The yield of genetic testing in cases where a diagnosis of cardiomyopathy is established postmortem is significantly greater than where structural changes are uncertain. [bib_ref] The yield of postmortem genetic testing in sudden death cases with structural..., Lahrouchi [/bib_ref] In cases where no other family members are clinically affected and the deceased proband is an apparently isolated case, genetic testing can be used as evaluation of the single definitely affected individual within the family. Families should be counseled about the expected benefits and potential outcomes of genetic investigations prior to testing. If identified variants are considered likely pathogenic or pathogenic, cascade testing across the family can be considered to identify at-risk individuals with no current clinical features. In cases where the deceased is part of a family with a prior diagnosis of cardiovascular disease and known pathological variant, confirmatory genetic testing may be performed. [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. ## Synopsis A postmortem diagnosis following SCD significantly facilitates further clinical evaluation of family members and may provide an explanation for the family as to the underlying etiology. Genetic testing targeted toward the clinical diagnosis and phenotype is an important component of the overall evaluation of both the proband and family and provides additional support to the clinical diagnosis. Further investigations can be performed as clinically indicated. In cases where no other individuals within the family are clinically print & web 4C=FPO [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref] Clinical and genetic evaluation after sudden death where a phenotype is known. Colors correspond to the Class of Recommendation in [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] affected, identification of a definitively pathogenic variant in the proband facilitates cascade genetic testing in family members. ## Recommendation-specific supportive text 1. Genetic testing in the decedent proband is recommended to support the clinical diagnosis and facilitate cascade genetic testing within the family. [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] [bib_ref] HRS/EHRA expert consensus statement on the state of genetic testing for the..., Ackerman [/bib_ref] The yield of genetic testing is significantly higher when associated with a specific postmortem diagnosis. [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] The yield of postmortem genetic testing in sudden death cases with structural..., Lahrouchi [/bib_ref] 2. If a cardiac phenotype has been identified in the deceased proband, genetic testing should be targeted toward that specific phenotype to maximize the chances of a clinically actionable result and minimize the risk of ambiguous secondary findings. Targeted panels for cardiomyopathy, channelopathies, familial thoracic aortic aneurysm, and familial hyperlipidemia are the preferred option. However, given the limited availability of proband DNA and potential financial implications, broader genetic testing including whole exome and genome with selective reporting based on the phenotype may be considered. Robust evidence for gene-disease association is currently probably only available in the Clinical Genome Resource (ClinGen) expert panels for long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy. [bib_ref] Reappraisal of reported genes for sudden arrhythmic death, Hosseini [/bib_ref] [bib_ref] An international, multicentered, evidencebased reappraisal of genes reported to cause congenital long..., Adler [/bib_ref] [bib_ref] Evaluating the clinical validity of hypertrophic cardiomyopathy genes, Ingles [/bib_ref] Wider panels and whole-exome sequencing/whole-genome sequencing share the potential disadvantage of a high burden of variants of uncertain/unknown significance, but in experienced hands (ie, expert centers), this will not lead to unintended follow-up. [bib_ref] The promise and peril of precision medicine: phenotyping still matters most, Ackerman [/bib_ref] ## Clinical evaluation for family members of a proband with an evident or likely phenotype can be targeted based on that phenotype, although due to varied expressivity and overlap syndromes should be sufficiently broad to provide a comprehensive cardiovascular evaluation. If a pathogenic or likely pathogenic variant has been identified in the deceased proband in a gene consistent with the clinical diagnosis, genetic counseling and testing should be offered to family members. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] The diagnostic yield of Brugada syndrome after sudden death with normal autopsy, Papadakis [/bib_ref] [bib_ref] Active cascade screening in primary inherited arrhythmia syndromes: does it lead to..., Hofman [/bib_ref] Cascade testing for likely pathogenic variants should be done at the discretion of an experienced provider after reviewing the data. In cases with limited supporting data from the family, a more conservative approach may be appropriate. 4. Serial re-evaluation of variants should be performed based on new phenotype data in the family pedigree, or new data regarding both specific variants and whole genes, the pathogenicity of which may have been up-or downgraded based on contemporaneous evidence. [bib_ref] Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment, Das [/bib_ref] [bib_ref] Genetic misdiagnoses and the potential for health disparities, Manrai [/bib_ref] [bib_ref] Reappraisal of reported genes for sudden arrhythmic death, Hosseini [/bib_ref] [bib_ref] An international, multicentered, evidencebased reappraisal of genes reported to cause congenital long..., Adler [/bib_ref] [bib_ref] Recontacting patients in clinical genetics services: recommendations of the European Society of..., Carrieri [/bib_ref] Responsibility for re-evaluation is unclear, but the reevaluation is best carried out in a center of expertise. 5. Genetic variants identified in deceased probands and subsequently in family members should be correlated with clinical findings to determine segregation patterns within the family. ## Investigation of sudden death: genetic evaluation where the phenotype is unknown SCD may occur in an individual without any prior medical history or medical data. As indicated above, a threegeneration pedigree including examination of all potentially relevant cardiac and extracardiac features within the family should be performed by a cardiologist experienced in genetic heart disease or clinical geneticist experienced in cardiology in an effort to optimize the identification of subtle clinical features before defining the cause of death as unknown. Specific triggers (eg, competitive athlete, emotional or physical stress, drug use, swimming, acoustic triggers, seizure) leading to the SCD event may help focus clinical and genetic investigation. Collection of blood and/or suitable tissue for molecular autopsy/postmortem genetic testing is recommended in all victims of SUD. 2,10 Local protocols are recommended to ensure proper handling and extended storage of biosamples, as well as processes and consent allowing for contact of families for genetic testing in the future. Family members of sudden death victims where the phenotype remains unknown should be instructed to request re-evaluation of the index event in case of future developments in the family. Clinical signs or symptoms in firstdegree family members leading to a suspected phenotype of a sudden death victim may occur over many years and sometimes skip generations, so an unknown phenotype might prompt more extensive questioning of older family members. In an SCD case where the phenotype remains unknown after expert evaluation, re-evaluation of family members to assess for new information that may impact diagnosis should be performed periodically, although the yield is low. [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] We suggest every 3 to 5 years, but shorter intervals should be considered if there is more than one SCD event in the family. Periodic re-evaluation should be stopped for individuals after age 45 years, unless the decedent died in this age range or new findings emerge. Three scenarios may trigger arrhythmia syndromefocused genetic evaluation of SCD even if the phenotype remains unknown: 1) documented arrhythmic death suggestive of an arrhythmia syndrome; 2) specific triggers associated with familial arrhythmia syndromes; 3) young age (,40 years) [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. Families should be counseled about the expected benefits and potential outcomes of genetic investigations prior to testing. When genotyping is performed, the identification of a genetic variant as causal remains challenging and requires reassessing the correct classification or potential reclassification periodically. With rapidly advancing genotyping technologies and the availability of large gene panels, the identification of genetic variants of uncertain/unknown significance becomes more frequent. Medical uncertainty in general elicits a variety of responses from patients. It is important to consider patients' responses to the ambiguous nature of genetic testing. Medical professionals ordering genetic testing should be prepared for the possibility of their patients' misinterpretation of such results. Pre-test counseling should include a discussion of the possibility of a variant of uncertain significance and what it would mean for the patient's care and its potential psychosocial impacts. When a variant of uncertain significance is found, post-test counseling should include additional education and a discussion of the variant's implications and medical management recommendations based on the results. If identified variants are considered likely pathogenic or pathogenic, cascade testing across the family should be offered to identify atrisk individuals with no current clinical features. Cascade testing should not be performed with variants of uncertain significance; however, careful investigation within a multidisciplinary team (including genetic counseling) may allow eventual reclassification of the variant so that it may then be used for cascade testing (see Sections 3 and 4). ## Synopsis Collection and storage of blood and/or suitable tissue for postmortem genetic testing is recommended in all victims of SUD. In a large number of cases, the phenotype underlying SCD remains unknown despite comprehensive evaluation of the victim and their family. In SCD cases where the phenotype is determined as unknown after expert evaluation, reevaluation should be performed periodically to assess for new information that may impact diagnosis. While hypothesis-free genetic testing is not indicated in cases of SCD where the phenotype remains unknown, arrhythmia syndrome-focused genetic evaluation of SCD is advised if 1) an arrhythmic death is documented suggestive of an inherited arrhythmia syndrome, 2) specific triggers associated with familial arrhythmia preceded the SCD, and/or 3) SCD occurred at young age. print & web 4C=FPO [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref] Investigation of sudden death: genetic evaluation where the phenotype is unknown. Colors correspond to the Class of Recommendation in [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. SCD 5 sudden cardiac death. ## Recommendations for investigation of sudden death: genetic evaluation where the phenotype is unknown [formula] COR LOE Recommendations References 1 B-NR 1. [/formula] In an SUD case at a young age where the phenotype remains unknown after expert evaluation, re-evaluation of first-degree relatives to assess for new information that may achieve diagnosis should be performed every 3 to 5 years (shorter intervals should be considered if there is more than one SCD event in the family) until at least age 45 years. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Improving usual care after sudden death in the young with focus on..., Van Der Werf [/bib_ref] 1 B-NR 2. In an SUD case where the phenotype is unknown, arrhythmia syndrome-focused genetic testing is recommended if 1) documented arrhythmic death is suggestive of an arrhythmia syndrome, and 2) SCD is preceded by specific triggers associated with familial arrhythmia syndromes. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsynegative sudden..., Tester [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Improving usual care after sudden death in the young with focus on..., Van Der Werf [/bib_ref] [bib_ref] Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained..., Tester [/bib_ref] [bib_ref] Whole-exome molecular autopsy after exertion-related sudden unexplained death in the young, Anderson [/bib_ref] 2a B-NR 3. In an SUD case occurring in a patient younger than 40 years where the phenotype is unknown, arrhythmia syndromefocused genetic testing can be useful. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Improving usual care after sudden death in the young with focus on..., Van Der Werf [/bib_ref] [bib_ref] Whole-exome molecular autopsy after exertion-related sudden unexplained death in the young, Anderson [/bib_ref] [bib_ref] Role of genetic heart disease in sentinel sudden cardiac arrest survivors across..., Giudicessi [/bib_ref] 3: No Benefit B-NR 4. In an SUD case where the phenotype is unknown, hypothesisfree genetic testing using exome or genome sequencing is not indicated in routine patient care, as this may lead to misinterpretation of genetic variants (specifically variants of uncertain significance). ## 210,211 Recommendation-Specific Supportive Text 1. Genetic diseases may express with reduced penetrance. Hence, a negative clinical screening does not exclude the (silent) presence of a genetic disorder. It is, therefore, reasonable to suggest repeated screening with a time interval between 3 to 5 years until at least age 45 years. Studies demonstrating the yield of clinical screening after the sudden death of a close relative usually report only the result of the first screening. [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Improving usual care after sudden death in the young with focus on..., Van Der Werf [/bib_ref] Responsibility for the repeated (infrequent) screening lies in the hands of the individual, but the local team should make sure that he/she is appropriately informed. 2. In an SCD case where the phenotype is unknown, arrhythmia syndrome-focused genetic testing of the proband should be considered if 1) documented arrhythmic death (such as torsades de pointes arrhythmias leading to ventricular fibrillation) is suggestive of an arrhythmia syndrome, and/or 2) SCD is preceded by specific triggers (eg, competitive athlete, emotional or physical stress, swimming, drug use, acoustic triggers, seizure) associated with familial arrhythmia syndromes. [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] [bib_ref] A prospective study of sudden cardiac death among children and young adults, Bagnall [/bib_ref] [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Improving usual care after sudden death in the young with focus on..., Van Der Werf [/bib_ref] [bib_ref] Dual inheritance of sudden death from cardiovascular causes, Beckmann [/bib_ref] Collection and storage of blood and/or suitable tissue for postmortem genetic testing is recommended in all victims of SUD irrespective of an identified phenotype at the time of death. Long-term storage of biosamples of SCD victims is recommended in expert centers to allow for genetic testing if indicated at present or in the future. . In an SCD case where the phenotype is unknown, arrhythmia syndrome-focused genetic testing of the proband can be considered if SCD occurred at young age. Testing for cardiomyopathy genes (such as LMNA) has been studied and can increase the diagnostic rate, although it should be recognized that the yield is lower. . Hypothesis-free genetic testing is not indicated in cases of SCD where the phenotype remains unknown. Genetic testing using any range from large unfocused gene panels to whole-exome or whole-genome sequencing in the absence of a clinical phenotype or diagnosis may be considered in the context of a scientific effort but is not recommended for routine patient care and counseling. [bib_ref] Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance..., Ackerman [/bib_ref] [bib_ref] Patients' views on variants of uncertain significance across indications, Clift [/bib_ref] The aim of discouraging hypothesis-free testing in clinical settings is to reduce the misinterpretation of genetic variants and their causality, specifically, variants of uncertain significance. A specific problem in this field is the nonuniformity in calling variants across different laboratories. 215 [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref] summarizes the recommendations from Section 6. ## Section 7 investigation of sudden cardiac arrest survivors ## Investigation of sudden cardiac arrest survivors: history-personal and family When an individual has been resuscitated after SCA, the clinician must try to define the likely underlying cause, similar to that discussed in Section 6.1 focused on SCD. This should include information on age, sex, past medical history, recent symptoms, activity or emotional status at the time of SCA (eg, sleeping, exercising, or emotion), time of onset (eg, morning or night), and environment (eg, public or private location), exposure to medicinal or recreational drugs (particularly those that block potassium or sodium channels) or alcohol, and a detailed family history of three generations at least. To focus the history taking, one must consider the differential diagnosis of SCA, which is similar to that discussed in Section 6.1. If the SCA was observed, a description of the event by the observer can add useful information. All records of the primary event, including initial rhythm recordings and details of the resuscitation, should be collected in addition to any prior ECGs and imaging studies. A family history of heart disease, syncope, or sudden death may point to a genetic cause. A study by Waddell-Smith et al. [bib_ref] Inpatient detection of cardiac-inherited disease: the impact of improving family history taking, Waddell-Smith [/bib_ref] showed that while inpatient cardiology teams identified a familial condition in only about 8% of cases, nurses trained in taking a family history detected a familial condition in 32% of cases. Thus, although most patients with SCA will be in a nonspecialty environment at first, ideally specially trained members of the cardiology and genetic counselor team with experience in genetic heart disorders should be utilized to elicit relevant details of the family history. Practical educational assistance can be found at https://www.primarycaregenetics.org. ## Synopsis Observational studies have demonstrated that the cause of SCA can be determined in a substantial proportion of patients. Historical features, especially age, coronary risk factors, symptoms, activity at the time of SCA, exposure to drugs, and family history frequently provide important clues to the diagnosis and point the way to further investigation. ## Recommendations for investigation of sca survivors: personal and family history [formula] COR LOE Recommendations References 1 B-NR 1. [/formula] In the investigation of an SCA survivor, detailed personal and three-generation family history should be taken with the assistance of a multidisciplinary team, including witness accounts. [bib_ref] Inpatient detection of cardiac-inherited disease: the impact of improving family history taking, Waddell-Smith [/bib_ref] 1 B-NR 2. All possible details surrounding an SCA event should be sought, including patient's recollection, witness accounts, and medical records. ## 216-220 Recommendation-Specific Supportive Text 1. In a study of 37 patients with history of SCD, cardiomyopathy, or ventricular tachycardia, a family history obtained by specially trained personnel was far more likely to elicit a history of inherited cardiac disease than one obtained by an inpatient cardiac team. [bib_ref] Inpatient detection of cardiac-inherited disease: the impact of improving family history taking, Waddell-Smith [/bib_ref] ## Investigation of sudden cardiac arrest survivors: examination The next step in cardiac evaluation of SCA survivors is physical examination. The main purpose is to identify signs of syndromic and nonsyndromic diseases that can be associated with SCA. For example, obesity and/or the presence of xanthomata may indicate an increased likelihood of premature coronary atherosclerosis. [bib_ref] Obesity and sudden cardiac death in the young: clinical and pathological insights..., Finocchiaro [/bib_ref] [bib_ref] Achilles tendon xanthomas are associated with the presence and burden of subclinical..., Mangili [/bib_ref] Syndromic features that may be relevant to genetic disorders include woolly hair and palmoplantar keratoderma (arrhythmogenic right ventricular cardiomyopathy), 140 joint contractures (Emery-Dreifuss muscular dystrophy), 223 muscle weakness and atrophy (lamin A/C and desmin cardiomyopathies, Triadin knockout syndrome), 224 micrognathia, syndactyly, clinodactyly (Andersen-Tawil and Timothy syndromes), 224 chest and limb deformities, and tall stature (Marfan syndrome). [bib_ref] A multicentre study of patients with Timothy syndrome, Walsh [/bib_ref] [bib_ref] Marfan syndrome: a clinical update, Bitterman [/bib_ref] Fever, hypothermia, dehydration, and signs of drug abuse may be detected on physical examination, although these signs may be confounded by neurological impairment after cardiac arrest. These factors can trigger life-threatening arrhythmia in genetic heart disease. For example, fever has been associated with malignant arrhythmias in 6% of patients with cardiac arrest and Brugada syndrome. [bib_ref] Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada..., Michowitz [/bib_ref] Cardiac murmurs can raise the suspicion of left ventricular outflow tract obstruction, mitral mid-systolic click (valve prolapse) with or without regurgitation, and Ebstein anomaly. Signs of pulmonary edema and hepatosplenomegaly can be detected in patients with severe systolic myocardial dysfunction. Importantly, examination findings may be affected by the SCA event and evolve during a hospital stay, requiring repeated physical examination to determine whether findings are related to the cause of SCA or the effect of SCA. [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. AED 5 automated external defibrillator; CIED 5 cardiovascular implantable electronic device; ECG 5 electrocardiogram; SCD 5 sudden cardiac death. ## Synopsis There are no data describing the usefulness of physical examination in resuscitated SCD. However, it is a first basic step in the diagnostic process that will focus subsequent complementary investigations. ## Recommendation-specific supportive text ## Investigation of sudden cardiac arrest survivors: baseline investigations In most emergency settings, a patient resuscitated from cardiac arrest in whom myocardial infarction is suspected will have undergone a coronary reperfusion strategy to treat acute occlusion. It is critical to obtain blood tests (cardiac enzymes, inflammatory markers, glucose, serum electrolytes, and white blood cell count) and pertinent toxicological analysis at presentation. The latter may include testing for drugs of abuse such as ethanol, opiates, and stimulants, as well as levels of prescribed medication that may prolong QT interval/QRS duration or cause respiratory depression. [bib_ref] Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD..., Tseng [/bib_ref] While assisting in the acute management of a resuscitated patient, these results will also help to differentiate acute myocardial injury as a cause of cardiac arrest (eg, ischemia without clear evidence of coronary occlusion or myocarditis) and pick up other reversible causes such as drug overdose, electrolyte imbalance, or endocrine and metabolic disorders. Retention and storage of suitable blood samples on patient arrival in the emergency department will allow subsequent diagnostic evaluation including DNA extraction and analysis in a patient who dies prior to diagnosis or for later clinical and family review. In some cases, this may be the only opportunity to obtain genetic material for analysis. In an OHCA, the use of AEDs is ever more widespread and increases survival. [bib_ref] A national scheme for public access defibrillation in England and Wales: early..., Colquhoun [/bib_ref] Sensitivity for the diagnosis of cardiac rhythm at the time of arrest is about 99%. [bib_ref] Automated external defibrillator and operator performance in out-of-hospital cardiac arrest, Zijlstra [/bib_ref] Therefore, routine inspection of data from AED recordings may improve the quality of diagnosis (see Section 6.2). The underlying rhythm of cardiac arrest may provide information on the arrhythmogenic mechanism, assist in diagnosis, and eventually indicate any misdiagnosis of rhythm. [bib_ref] Inappropriate analyses of automated external defibrillators used during in-hospital ventricular fibrillation, Yamamoto [/bib_ref] Any ECG tracings from emergency services, as well as recordings from interrogation of CIEDs or wearables can also contribute to diagnosis. [bib_ref] Cardiac implantable electronic device interrogation at forensic autopsy: an underestimated resource?, Lacour [/bib_ref] The 12-lead ECG in sinus rhythm or during arrhythmia recurrence is fundamental to the diagnostic investigation and should be repeated daily during recovery. [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] It may support diagnoses of primary electrical disorders, pre-excitation, and heart muscle diseases. However, abnormalities of cardiac conduction and repolarization may result from myocardial injury during the cardiac arrest and patients undergoing post-arrest hypothermia protocols may have transient ECG changes including QT prolongation and J point elevation that should be interpreted with caution. Information about electrolyte levels, drug prescription, and body temperature should be added to the ECG to prevent misinterpretation of such ECG abnormalities. A high precordial lead ECG is an inexpensive tool to increase detection of Brugada syndrome pattern. [bib_ref] Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous..., Papadakis [/bib_ref] [bib_ref] A comprehensive electrocardiographic, molecular, and echocardiographic study of Brugada syndrome: validation of..., Savastano [/bib_ref] [bib_ref] Utility of high and standard right precordial leads during ajmaline testing for..., Govindan [/bib_ref] [bib_ref] Clinical presentation and outcome of Brugada syndrome diagnosed with the new 2013..., Curcio [/bib_ref] [bib_ref] Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher..., Miyamoto [/bib_ref] In addition to standard ECG, a signal-averaged ECG may demonstrate late potentials. Two or more abnormalities in the absence of a prolonged QRS duration (110 ms) on the standard ECG is a minor diagnostic criterion for arrhythmogenic cardiomyopathy and suggests ventricular depolarization abnormality. [bib_ref] HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic..., Towbin [/bib_ref] Continuous heart rhythm monitoring is recommended during hospitalization due to the transient nature of some arrhythmias. Recording the onset (including pause-dependent or tachycardia-associated initiation) and late and short-coupled ventricular ectopics as triggers for torsade de pointes, polymorphic ventricular tachycardia, or ventricular fibrillation will elucidate cardiac arrest mechanism and likely diagnosis. [bib_ref] Role of Purkinje conducting system in triggering of idiopathic ventricular fibrillation, Haïssaguerre [/bib_ref] Evidence of dynamic ST elevation associated with chest pain may also indicate likelihood of coronary vasospasm. [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] Echocardiography is the screening tool of choice for structural heart disease, although early myocardial dysfunction may be present after cardiac arrest and, if present early, the test should be repeated later during the patient's convalescence. CMR allows detection of inflammatory diseases, such as myocarditis and sarcoidosis, through recognition of subepicardial edema. Identification of an inflammatory etiology is important, as it may be self-limiting or treatable. If sarcoidosis is suspected, then positron emission tomography-CT scanning may be indicated. [bib_ref] Diagnostic accuracy of advanced imaging in cardiac sarcoidosis, Divakaran [/bib_ref] The presence of subendocardial edema would suggest ischemic injury. [bib_ref] Utility of cardiovascular magnetic resonance in identifying substrate for malignant ventricular arrhythmias, White [/bib_ref] Late gadolinium enhancement indicates chronic fibrosis, permitting detection of a cardiomyopathic etiology, and can also contribute to the diagnosis of mitral valve prolapse associated with a risk of SCD. [bib_ref] Arrhythmic mitral valve prolapse and sudden cardiac death, Basso [/bib_ref] [bib_ref] Mitral valve prolapse, ventricular arrhythmias, and sudden death, Basso [/bib_ref] Coronary imaging (at any age) will be important to exclude coronary artery disease not investigated at presentation as an emergency and ensure that an anomalous coronary circulation or coronary dissection is not missed. [bib_ref] Sudden death in young adults: a 25-year review of autopsies in military..., Eckart [/bib_ref] This may be by cardiac catheterization or by CT coronary angiography. [bib_ref] American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care, Neumar [/bib_ref] Coronary angiography will only be required in select pediatric and young survivors. Patients in whom the cause of their SCA remains undiagnosed may require periodic re-evaluation of the above investigations, as features may develop later that point to a cause of their SCA (similar to Section 6.5, Recommendation 1). ## Recommendation for investigation of sca survivors: examination ## Cor loe recommendation references ## Synopsis Systematic clinical testing is paramount in SCA survivors. This includes blood testing, toxicology, ECG, signalaveraged ECG, high precordial lead ECG, continuous ECG monitoring, echocardiography, and coronary imaging. If the diagnosis remains elusive and cardiac arrest is deemed unexplained, then CMR is important to identify subtle forms of cardiomyopathy or acquired structural disease. ## Recommendation-specific supportive text 1. The usefulness of blood testing and toxicology is by consensus, and a diagnostic role is unquestionable. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] [bib_ref] Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD..., Tseng [/bib_ref] Viral studies may be useful, but no systematic evidence is available as yet. [bib_ref] Sudden cardiac death in patients with myocarditis: evaluation, risk stratification, and management, Dalgaard [/bib_ref] A potential role for biomarkers specific for one of the arrhythmia syndromes is anticipated. 250,251 2. Results of a forensic study indicate the value of postmortem CIED interrogation to define the cause and timing of death more accurately and to detect potential CIED-related safety issues. CIED interrogation in unexplained deaths clarified the manner of death in 60.8% of the cases including cardiac and nonarrhythmic death and device concerns. [bib_ref] Cardiac implantable electronic device interrogation at forensic autopsy: an underestimated resource?, Lacour [/bib_ref] 3. Sensitivity for the diagnosis of cardiac rhythm via AED at the time of arrest is about 99%. [bib_ref] Automated external defibrillator and operator performance in out-of-hospital cardiac arrest, Zijlstra [/bib_ref] However, the AED seldom catches the initial rhythm of cardiac arrest and therefore may not contribute to the etiology of SCA. 4. Primary electrical disorders and specific cardiomyopathies may be detected by conventional ECG. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] [bib_ref] 12-Lead electrocardiogram to localize region of abnormal electroanatomic substrate in arrhythmogenic right..., Tschabrunn [/bib_ref] ECG findings in the immediate aftermath of a cardiac arrest, other than ST-segment elevation indicative of an acute coronary syndrome, may, however, have poor diagnostic accuracy. [bib_ref] The accuracy of an out-of-hospital 12-lead ECG for the detection of ST-elevation..., M€ Uller [/bib_ref] [bib_ref] Post-resuscitation ECG for selection of patients for immediate coronary angiography in out-of-hospital..., Staer-Jensen [/bib_ref] These could be caused by abnormal repolarization following electrical cardioversion, 255 metabolic and electrolyte abnormalities, or even subarachnoid hemorrhage. [bib_ref] The role of post-resuscitation electrocardiogram in patients with ST-segment changes in the..., Kim [/bib_ref] Therapeutic hypothermia may lead to misleading ECG changes such as prolongation in PR, QRS and QT intervals, and J point elevation. [bib_ref] Electrocardiographic changes in therapeutic hypothermia, Rolfast [/bib_ref] [bib_ref] Electrocardiographic changes during induced therapeutic hypothermia in comatose survivors after cardiac arrest, Salinas [/bib_ref] Interpretation of ECGs obtained immediately after resuscitation/defibrillation should be performed with great caution. 5. Although there are no data describing directly the value of high precordial lead ECGs in SCD survivors, there is ample evidence of an increased yield of the type 1 Brugada ECG pattern. 189 6. Cardiac monitoring during short-term follow-up demonstrates an arrhythmogenic mechanism of SCD in some registries. 216,236,246 7. Signal-averaged ECG is part of the Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy. [bib_ref] HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic..., Towbin [/bib_ref] Signal-averaged ECG has been proposed as useful in other conditions (ie, Brugada syndrome), although systematic evaluation has not been performed. 8. Echocardiography is a valuable screening tool for detection of arrhythmogenic cardiomyopathy and other structural abnormalities useful in elucidating the cause of SCA. [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] Patients with functional abnormalities on initial echocardiogram should have this test repeated after recovery, to allow for the effects of the SCA itself and drugs used around the time of the arrest to wear off. 9. and 10. The utility of CMR has been evaluated in a series of studies involving survivors of unexplained arrest and has repeatedly been shown to provide significant incremental diagnostic value. A study of 137 individuals with unexplained aborted cardiac arrest found that CMR provided a diagnosis or identified an arrhythmic substrate 1 B-NR 11. Coronary imaging is recommended in all adult SCA survivors, to exclude coronary artery disease, dissection, or anomalies not considered fully at first presentation, and in select younger cases. [bib_ref] Sudden death in young adults: a 25-year review of autopsies in military..., Eckart [/bib_ref] in 76% of individuals, including an infarct pattern suggestive of occult myocardial infarction in 44%. Notably, the presence of late gadolinium enhancement, reflective of myocardial fibrosis, was associated with a 6.7 hazard ratio (p , 0.001) of recurrent arrhythmic events on multivariate analysis. [bib_ref] Diagnosis and prognosis in sudden cardiac arrest survivors without coronary artery disease:..., Rodrigues [/bib_ref] The presence of subendocardial edema would suggest ischemic injury even when initial coronary imaging excludes significant obstruction. Coronary vasospasm and dissection might be misdiagnosed, and coronary reevaluation may then be reconsidered. [bib_ref] Utility of cardiovascular magnetic resonance in identifying substrate for malignant ventricular arrhythmias, White [/bib_ref] The frequency of occult infarcts is not insignificant, [bib_ref] Diagnosis and prognosis in sudden cardiac arrest survivors without coronary artery disease:..., Rodrigues [/bib_ref] although the risk of SCD in patients with myocardial infarction and nonobstructive coronary arteries is low. [bib_ref] Risk of ventricular arrhythmia in patients with myocardial infarction and non-obstructive coronary..., Bi Ere [/bib_ref] For Recommendation 10, primary electrical disease is not referring to an established diagnosis of long QT syndrome or CPVT, where MRI is unlikely to be of use. 11. Coronary artery disease is the leading cause of SCD in adults and might be treatable. Furthermore, coronary dissection and anomalies may also be relevant in this age group as well as in younger patients. ## Investigation of sudden cardiac arrest survivors: provocative testing Once a cardiac arrest survivor has undergone initial thorough baseline evaluation, most overt acquired or genetic etiologies will have been diagnosed. However, concealed disorders may be uncovered by provocative maneuvers such as lying to standing ECGs, exercise ECG testing, epinephrine challenge, sodium channel blocker challenge, or ergonovine and acetylcholine testing. Some may even be employed in a resuscitated cardiac arrest survivor who is unlikely to survive due to neurological injury. Exercise testing may uncover ventricular arrhythmia relevant to the cause of cardiac arrest. For example, evidence of monomorphic ventricular tachycardia arising from the right ventricle is part of Task Force Criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy (arrhythmogenic cardiomyopathy). [bib_ref] Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force..., Marcus [/bib_ref] [bib_ref] Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a..., Hamid [/bib_ref] [bib_ref] Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular..., Nava [/bib_ref] Exercise may also uncover concealed epsilon waves or even a type 1 Brugada ECG pattern. [bib_ref] Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of..., Perrin [/bib_ref] [bib_ref] Exercise-induced ECG changes in Brugada syndrome, Amin [/bib_ref] The generation of bidirectional ventricular ectopy or tachycardia and/or polymorphic ventricular tachycardia in the absence of ischemia, structural disease, or digoxin toxicity is typical of CPVT 265 and has been evaluated in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) protocol. [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] Abnormal dynamics of repolarization in response to challenges may also inform the likelihood of underlying long QT syndrome. To this end, maximum QT prolongation (QT stretch) and T-wave morphology changes during lying to standing and then return to baseline heart rate (QT stunning) may be useful markers, although they are less specific in children. [bib_ref] The phenomenon of "QT stunning": the abnormal QT prolongation provoked by standing..., Adler [/bib_ref] [bib_ref] Dynamic QT interval changes from supine to standing in healthy children, Dionne [/bib_ref] [bib_ref] The brisk-standing-test for long QT syndrome in prepubertal school children: defining normal, Filippini [/bib_ref] These discriminate well in genotyped families and may add to diagnostic utility, but evaluation in unexplained cardiac arrest survivors has not been undertaken. [bib_ref] The response of the QT interval to the brief tachycardia provoked by..., Viskin [/bib_ref] The recovery phase of exercise may also reveal readily measurable QT prolongation and T-wave abnormalities and has been validated in families with long QT syndrome for prediction of genotype [bib_ref] Derivation and validation of a simple exercise-based algorithm for prediction of genetic..., Sy [/bib_ref] [bib_ref] Utility of treadmill testing in identification and genotype prediction in long-QT syndrome, Wong [/bib_ref] and in cardiac arrest survivors [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] such that a QTc .480 ms at 4 min of recovery forms part of the long QT syndrome risk score. [bib_ref] QTc behavior during exercise and genetic testing for the long-QT syndrome, Schwartz [/bib_ref] Epinephrine challenge with ECG monitoring has been advocated as an alternative to exercise testing for the diagnosis of long QT syndrome and CPVT, particularly where the patient is unable to exercise. In long QT syndrome, QT prolongation and secondary T-wave changes have been able to discriminate LQT1 and LQT2 patients from unaffected family members even though they have normal baseline QTc intervals. [bib_ref] Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms..., Shimizu [/bib_ref] [bib_ref] Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT..., Ackerman [/bib_ref] The test has been assessed in unexplained cardiac arrest survivors and has suggested a low specificity for long QT syndrome. [bib_ref] Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden..., Krahn [/bib_ref] The finding would be unlikely to provide a secure diagnosis in isolation and was proposed as useful in association with exercise testing and genetic testing. Indeed, in normal subjects, pharmacological sympathetic stimulation does produce significant prolongation of QTc. [bib_ref] Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol..., Magnano [/bib_ref] Epinephrine testing has also shown some diagnostic utility for CPVT in cardiac arrest survivors by inducing ventricular ectopic activity, bidirectional couplets, and ventricular tachycardia. [bib_ref] Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden..., Krahn [/bib_ref] However, there is uncertainty as to the ideal cutoff for epinephrine-induced arrhythmia, and the diagnostic sensitivity compared to exercise testing in CPVT families is low. [bib_ref] Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia, Marjamaa [/bib_ref] Isoproterenol challenge for the diagnosis of arrhythmogenic right ventricular cardiomyopathy has also been advocated but has not been tested by other groups or in the unexplained cardiac arrest survivor without overt phenotype. [bib_ref] Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy, Denis [/bib_ref] Sodium channel blocker challenge (ajmaline, procainamide, flecainide, and pilsicainide) has been used extensively for investigating the possibility of Brugada syndrome in cardiac arrest survivors, although these are mainly reported in series of patients with a strong suspicion of Brugada syndrome [bib_ref] Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome, Meregalli [/bib_ref] [bib_ref] Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada..., Hong [/bib_ref] [bib_ref] Sodium channel blockers identify risk for sudden death in patients with ST-segment..., Brugada [/bib_ref] rather than in unexplained cardiac arrest survivors. [bib_ref] Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion, Krahn [/bib_ref] The use of leads V1 and V2 in the second and third intercostal space or high right precordial ECG leads during provocation increases the diagnostic yield. [bib_ref] Utility of high and standard right precordial leads during ajmaline testing for..., Govindan [/bib_ref] [bib_ref] New electrocardiographic leads and the procainamide test for the detection of the..., Sangwatanaroj [/bib_ref] In the CASPER registry, there was a yield from procainamide challenge, [bib_ref] Procainamide infusion in the evaluation of unexplained cardiac arrest: from the Cardiac..., Somani [/bib_ref] although this may underestimate the true burden, as different sodium channel blockers have different potencies for inducing the type 1 Brugada ECG pattern. For example, ajmaline is associated with an odds ratio of 8 for inducing the type 1 Brugada ECG pattern compared with procainamide [bib_ref] Comparison of ajmaline and procainamide provocation tests in the diagnosis of Brugada..., Cheung [/bib_ref] and a 4% yield in a small group of "healthy" controls. [bib_ref] High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant..., Hasdemir [/bib_ref] Furthermore, while recent consensus guidelines would give a definite diagnosis to a cardiac arrest survivor with a type 2 or 3 pattern converting to a type 1, the implication of a drug-induced type 1 pattern without a baseline type 2 or 3 is not addressed. [bib_ref] J-Wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge, Antzelevitch [/bib_ref] Yet cardiac arrest survivors from CASPER without a type 2 or 3 pattern had positive procainamide challenges. [bib_ref] Procainamide infusion in the evaluation of unexplained cardiac arrest: from the Cardiac..., Somani [/bib_ref] Other tests such as the full stomach test have been proposed but have not been taken up in general. [bib_ref] The full stomach test as a novel diagnostic technique for identifying patients..., Ikeda [/bib_ref] Different approaches for provocation of an underlying repolarization abnormality have been employed including drug challenge with quinidine and sotalol and mental stress tests. [bib_ref] Familial catecholamine-induced QT prolongation in unexplained sudden cardiac death, Huchet [/bib_ref] [bib_ref] Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives, Kannankeril [/bib_ref] [bib_ref] Mental stress test: a rapid, simple, and efficient test to unmask long..., Etienne [/bib_ref] [bib_ref] Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome: a..., Kaab [/bib_ref] These may offer utility in the future but have not been tested in the cardiac arrest survivor. Coronary vasospasm, while a recognized cause of cardiac arrest, may not be picked up clinically at presentation. [bib_ref] Significance of coronary artery spasm diagnosis in patients with early repolarization syndrome, Kamakura [/bib_ref] Ergonovine or acetylcholine challenge has been proposed as a Class 1 indication by recent guidelines [bib_ref] International standardization of diagnostic criteria for vasospastic angina, Beltrame [/bib_ref] and was employed selectively in the CASPER experience. [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] Hyperventilation has also been used as a diagnostic test. [bib_ref] Hyperventilation as a specific test for diagnosis of coronary artery spasm, Nakao [/bib_ref] Recent experience from the Paris Sudden Death Expertise Center investigators suggests that pharmacological challenge is useful for diagnosis and could be better employed. [bib_ref] Coronary vasospasm-related sudden cardiac arrest in the community, Waldmann [/bib_ref] Nonetheless, there are few centers with extensive experience in the use of the test, and there is a possibility of false-positive findings in the cardiac arrest survivor population. Adenosine challenge has been used to unmask preexcitation that may otherwise be missed. [bib_ref] Use of intravenous adenosine in sinus rhythm as a diagnostic test for..., Garratt [/bib_ref] [bib_ref] Unmasking latent preexcitation of a right-sided accessory pathway with intravenous adenosine after..., Foo [/bib_ref] In the absence of other causes, it will indicate the need for electrophysiological study to evaluate the risk of the accessory pathway (rapidity of antegrade conduction) followed by ablation therapy. However, electrophysiological study is not routinely included in the workup of unexplained cardiac arrest. [bib_ref] ESC guidelines for the management of patients with ventricular arrhythmias and the..., Priori [/bib_ref] Indeed, previous consensus guidelines proposed a Class 3 indication when assessing a suspected primary electrical disorder. [bib_ref] ESC guidelines for the management of patients with ventricular arrhythmias and the..., Priori [/bib_ref] It does not add additional diagnostic or prognostic value unless there is evidence to indicate otherwise. For example, pre-excited atrial fibrillation, bundle branch re-entrant ventricular tachycardia, and rapid supraventricular tachycardias that degenerate into ventricular fibrillation have all previously been described as culprits requiring an invasive approach to diagnosis and curative ablation therapy. [bib_ref] Patients with supraventricular tachycardia presenting with aborted sudden death: incidence, mechanism and..., Wang [/bib_ref] [bib_ref] Bundle branch re-entrant ventricular tachycardia: novel genetic mechanisms in a life-threatening arrhythmia, Roberts [/bib_ref] Electroanatomic voltage mapping of the right ventricle is a discretionary tool that may be considered to detect evidence of subclinical arrhythmogenic right ventricular cardiomyopathy. [bib_ref] Imaging of scar in patients with ventricular arrhythmias of right ventricular origin:..., Santangeli [/bib_ref] More recently, extensive endocardial and epicardial mapping of unexplained cardiac arrest cases has been employed to identify cases with either Purkinje triggers and/ or subtle depolarization abnormalities that may be suitable for ablation therapy. [bib_ref] Localized structural alterations underlying a subset of unexplained sudden cardiac death, Haissaguerre [/bib_ref] ## Synopsis Concealed Brugada syndrome, long QT syndrome, CPVT, arrhythmogenic cardiomyopathy, pre-excitation, and coronary vasospasm may be uncovered by provocative maneuvers in the cardiac arrest survivor whose cause of cardiac arrest remains unknown after baseline clinical, ECG, and imaging investigations. Exercise ECG testing and sodium channel blocker challenge appear to offer most potential utility, whereas lying to standing ECGs; epinephrine, isoproterenol, and adenosine challenge; and hyperventilation, ergonovine, and acetylcholine testing may be considered in specific patients. Electrophysiological study and electroanatomic mapping may be useful to provide patient- Adenosine challenge has not been tested systematically in cardiac arrest survivors, but there are limited data suggesting that it will uncover concealed pre-excitation that may cause cardiac arrest in the setting of rapidly conducted pre-excited atrial tachyarrhythmias. . There are limited case series describing the use of electrophysiological study in diagnosis and treatment of preexcited atrial arrhythmias and bundle branch re-entrant ventricular tachycardia. [bib_ref] Patients with supraventricular tachycardia presenting with aborted sudden death: incidence, mechanism and..., Wang [/bib_ref] [bib_ref] Bundle branch re-entrant ventricular tachycardia: novel genetic mechanisms in a life-threatening arrhythmia, Roberts [/bib_ref] 9. Studies of endocardial mapping report a higher sensitivity for detection of arrhythmogenic cardiomyopathy, but this has not been explored in SCA survivors. [bib_ref] Imaging of scar in patients with ventricular arrhythmias of right ventricular origin:..., Santangeli [/bib_ref] Sensitivity and specificity are unknown, particularly in patients where no other tests are abnormal. 10. Extensive endocardial and epicardial mapping of unexplained cardiac arrest cases has been employed to identify cases with either Purkinje triggers and/or subtle depolarization abnormalities that may be suitable for ablation therapy. [bib_ref] Localized structural alterations underlying a subset of unexplained sudden cardiac death, Haissaguerre [/bib_ref] ## Investigation of sudden cardiac arrest survivors: genetic evaluation Although most SCA survivors will have an indication for an implantable defibrillator for secondary prevention of a cardiac arrest, 6 genetic evaluation may influence final diagnosis, treatment recommendations, and family screening [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. In some cases, genetic evaluation may enable therapy specific to the disease mechanism. Recent technological advances in genetic evaluations, establishment of reference databases of genetic variants, systematic annotation of causal genes, [bib_ref] ClinGen: the clinical genome resource, Rehm [/bib_ref] and standardization of variant interpretation [bib_ref] Standards and guidelines for the interpretation of sequence variants: a joint consensus..., Richards [/bib_ref] have enabled efficient and comprehensive genetic assessment. However, the pace of genetic discovery and variant interpretation is evolving rapidly, creating a complex landscape surrounding genetic evaluation of SCA survivors. The decision to pursue genetic evaluation is an individualized one in which the patient, with proper (clinical and genetic) counseling, must weigh the benefits, limitations, and personal and familial implications. The genetic basis of SCA and most individual conditions that predispose to SCA remain incompletely understood. As such, caution is advised when interpreting negative genetic test results or when examining genes with low likelihood of causing SCA. Prior clinical practice guidelines have specifically addressed the diagnostic considerations regarding specific genetic cardiovascular conditions. 4,10,307 The ClinGen represents a systematic effort to enumerate causal genes and variation related to human disease, including SCArelated conditions. [bib_ref] ClinGen: the clinical genome resource, Rehm [/bib_ref] Previous reports have been developed for Brugada syndrome, [bib_ref] Reappraisal of reported genes for sudden arrhythmic death, Hosseini [/bib_ref] long QT syndrome, [bib_ref] An international, multicentered, evidencebased reappraisal of genes reported to cause congenital long..., Adler [/bib_ref] and hypertrophic cardiomyopathy. [bib_ref] Evaluating the clinical validity of hypertrophic cardiomyopathy genes, Ingles [/bib_ref] The yield of genetic testing varies substantially by condition. [bib_ref] Yield of molecular and clinical testing for arrhythmia syndromes: report of 15..., Hofman [/bib_ref] Variant interpretation may differ by laboratory [bib_ref] Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records, Van Driest [/bib_ref] despite recent efforts to standardize variant interpretation. [bib_ref] Standards and guidelines for the interpretation of sequence variants: a joint consensus..., Richards [/bib_ref] Given the rapid changes in available technology to evaluate the genome, complexities in variant interpretation, and nuances in the ethical and legal framework surrounding genetic testing in some settings, [bib_ref] Establishment of specialized clinical cardiovascular genetics programs: recognizing the need and meeting..., Ahmad [/bib_ref] [bib_ref] Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment, Das [/bib_ref] [bib_ref] Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records, Van Driest [/bib_ref] [bib_ref] Multiple gene variants in hypertrophic cardiomyopathy in the era of next-generation sequencing, Burns [/bib_ref] [bib_ref] Actionable exomic incidental findings in 6503 participants: challenges of variant classification, Amendola [/bib_ref] [bib_ref] Genetic insurance discrimination in sudden arrhythmia death syndromes: empirical evidence from a..., Mohammed [/bib_ref] it is recommended that SCA survivors undergoing genetic assessment have evaluations performed at centers with multidisciplinary experience in counseling, variant interpretation, and management of genetic heart disease (see Section 3). For SCA survivors who have undergone genetic testing, an offer of periodic re-evaluation of the genetic test results is advocated (similar to Section 6.4, Recommendation 4). ## Synopsis SCA can be caused by diverse etiologies, some of which may be predominantly or partially influenced by genetic predisposition. Whereas a thorough clinical evaluation leads to a diagnosis of the cause of SCA for most individuals, the cause of SCA may remain uncertain in others. [bib_ref] Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with..., Krahn [/bib_ref] In some cases, genetic evaluation of SCA survivors can confirm a molecular etiology that predisposed to the SCA event, support the diagnosis of a specific phenotype, influence management, and facilitate screening in family members at risk via cascade genetic testing. ## Recommendation-specific supportive text 1. Genetic testing, after appropriate genetic counseling and informed consent, may facilitate identification of a molecular cause of SCA by identifying pathogenic variants in genes associated with specific phenotypes and fulfilling formal disease-based diagnostic criteria. [bib_ref] HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic..., Towbin [/bib_ref] [bib_ref] HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with..., Priori [/bib_ref] Examples of scenarios in which discovery of a genetic cause of SCA may influence management recommendations include administration of beta blockade for patients with long QT syndrome, 311 sodium channel inhibition in long QT syndrome type 3, 312-314 flecainide administration for patients with CPVT, [bib_ref] Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia: a..., Kannankeril [/bib_ref] [bib_ref] Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular..., Van Der Werf [/bib_ref] or exercise restriction recommendations in patients with arrhythmogenic cardiomyopathy. [bib_ref] Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated..., James [/bib_ref] [bib_ref] Association of competitive and recreational sport participation with cardiac events in patients..., Ruwald [/bib_ref] Genetic evaluation may also influence family screening by facilitating cascade genetic testing and clinical surveillance in relatives at greatest risk for disease. 2. and 3. Genetic tests have variable yield and may result in discovery of variants of uncertain clinical significance, which can be frequent and challenging to interpret. Using genetic tests that comprise well-established genes related to a suspected or diagnosed genetic phenotype is most likely to result in discovery of disease-causing variants in an individual or family, while minimizing the probability of discovering a variant of uncertain clinical significance. In contrast, genetic tests with more comprehensive genomic coverage may lead to moderately increased diagnostic yield but at the expense of increased rates of discovery of variants of uncertain clinical significance. 84,308 Nevertheless, given a rapidly evolving understanding of the molecular causes of specific phenotypes and increased yield of broader genetic assessment, [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Diagnostic approach to unexplained cardiac arrest (from the FIVI-Gen Study), Jiménez-J Aimez [/bib_ref] [bib_ref] Usefulness of genetic testing in sudden cardiac arrest survivors with or without..., Asatryan [/bib_ref] [bib_ref] A comprehensive evaluation of the genetic architecture of sudden cardiac arrest, Ashar [/bib_ref] tests that include broader coverage may be considered in select circumstances, such as when a heritable phenotype is being mapped within a family or assessment for de novo variation is sought through sequencing of multiple family members. The latter examples would only be pertinent when it becomes apparent that a familial trait is likely or there has been exome sequencing in a trio of confirmed parents and the index case. 4. Genetic evaluation appears to be highest for individuals with a phenotype consistent with a genetic cause [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Usefulness of genetic testing in sudden cardiac arrest survivors with or without..., Asatryan [/bib_ref] [bib_ref] A comprehensive evaluation of the genetic architecture of sudden cardiac arrest, Ashar [/bib_ref] and is lower among SCA survivors without a clearly identifiable genetic phenotype. [bib_ref] Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death..., Kumar [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Diagnostic approach to unexplained cardiac arrest (from the FIVI-Gen Study), Jiménez-J Aimez [/bib_ref] [bib_ref] Usefulness of genetic testing in sudden cardiac arrest survivors with or without..., Asatryan [/bib_ref] [bib_ref] A comprehensive evaluation of the genetic architecture of sudden cardiac arrest, Ashar [/bib_ref] [bib_ref] Sudden cardiac arrest and rare genetic variants in the community, Milano [/bib_ref] [bib_ref] Next-generation sequencing of a large gene panel in patients initially diagnosed with..., Visser [/bib_ref] Nevertheless, individuals with an idiopathic cause of SCA may eventually develop a diagnosis of a genetic etiology during long-term follow-up. [bib_ref] Long-term outcome of patients initially diagnosed with idiopathic ventricular fibrillation: a descriptive..., Visser [/bib_ref] Genetic testing can identify variants during the concealed phase of a genetic disease such as arrhythmogenic cardiomyopathy, [bib_ref] Concealed arrhythmogenic right ventricular cardiomyopathy in sudden unexplained cardiac death events, Ingles [/bib_ref] or in individuals with conditions otherwise regarded as nongenetic such as in drug-induced long QT syndrome. [bib_ref] Allelic variants in long-QT disease genes in patients with drug-associated torsades de..., Yang [/bib_ref] As such, a low but non-negligible yield for genetic testing appears to be present among individuals with idiopathic SCA. 5. In individuals with a well-established nongenetic cause of SCA, the routine use of genetic evaluation is not recommended owing to the potential for discovery of variants of uncertain significance and misdiagnosis. The sudden death of a young, apparently healthy individual raises many questions for family members. Apart from mourning and the question "could we have done something to avoid this," a very relevant question is whether family members could be affected as well. Roles for health care providers include providing psychological support for the family, identifying a cause for the sudden death, and understanding the implications for family members (see Sections 4 and 5). For this chapter, it is especially relevant that families need support to organize clinical and genetic testing for family members and sometimes postmortem genetic testing of the deceased. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] Psychological adaptation to molecular autopsy findings following sudden cardiac death in the..., Bates [/bib_ref] [bib_ref] Sudden cardiac death in the young: the molecular autopsy and a practical..., Semsarian [/bib_ref] Currently, many cases and even familial forms of unexplained cardiac disease remain insufficiently investigated. [bib_ref] Molecular and genetic insights into progressive cardiac conduction disease, Asatryan [/bib_ref] When clinical symptoms indicate that a cardiomyopathy or arrhythmia may have contributed to the death, further steps are needed to specify the diagnosis. If blood or tissue of the deceased is available, DNA testing can be done for a range of arrhythmia syndromes and cardiomyopathies, nowadays often using gene panels. Without a specific diagnosis in the deceased, clinical investigation of the first-degree relatives (parents, siblings, and children) can identify a person with similar symptoms or signs, although sometimes mild. This relative of the deceased can be the proband for DNA testing and thus provide the key to a diagnosis for the family. Efforts are needed to increase the proportion of postmortem examinations (either forensic or medical autopsy) to clarify whether or not an underlying cause can be suspected or proven. The postmortem result should be communicated to the family as per local protocols. Without a postmortem diagnosis, efforts are needed to evaluate eventual clinical symptoms of the parents and other first-degree family members. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] Cardiac abnormalities in first-degree relatives of unexplained cardiac arrest victims: a report..., Steinberg [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] This is outlined in Section 6. If DNA of the deceased person can be used for testing, or a relative who has similar symptoms can be tested, a monogenic form of cardiomyopathy or arrhythmia may be recognized that may also be present in family members. Typically, first-degree relatives are at 50% risk of carrying the same pathogenic mutation, since many of these conditions follow an autosomal dominant pattern of inheritance. Depending on whether or not autopsy has been performed, whether DNA is available, whether a relative is already diagnosed with a cardiogenetic condition, and whether symptoms were noticed during life, there are different situations possible: 1) sudden death, with clinical observations or DNA testing suggesting a specific diagnosis, and 2) sudden death, with no cause identified. The first situation will be discussed in Section 8.2, the second in Section 8.3 [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref]. ## Investigation of the family: cause identified-cascade testing, clinical and genetic investigations In cascade testing, after the postmortem diagnosis in an index patient by a DNA test, an invitation can be sent to parents, brothers and sisters, and children. [bib_ref] Barriers and facilitating factors for implementation of genetic services: a public health..., Cornel [/bib_ref] If any of the relatives is also diagnosed with the condition, a next circle of firstdegree relatives is invited. If one of the first-degree relatives is not available (either deceased or not wanting to participate), second-degree relatives are invited, for instance, children of a deceased sibling. This systematic approach is very effective in autosomal dominant conditions, since first-degree relatives are at 50% a priori risk to carry the same pathogenic mutation and second-degree relatives at 25% risk. For minors, the age at which treatment starts determines the age before which DNA testing is advised. This may differ between countries and conditions. DNA testing of minors is not advised if the result would have no consequences in childhood. Presymptomatic DNA testing makes it possible to organize preventive measures, such as regular cardiological follow-up, use of medication (eg, beta blockers), lifestyle advice (eg, avoid intensive sports), implantable cardioverter-defibrillators, or reproductive planning. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Active cascade screening in primary inherited arrhythmia syndromes: does it lead to..., Hofman [/bib_ref] [bib_ref] Prenatal molecular diagnosis in hypertrophic cardiomyopathy: report of the first case, Charron [/bib_ref] [bib_ref] The ESHRE PGD Consortium: 10 years of data collection, Harper [/bib_ref] [bib_ref] PGD for inherited cardiac diseases, Kuliev [/bib_ref] [bib_ref] Outcomes of contemporary family screening in hypertrophic cardiomyopathy, Van Velzen [/bib_ref] [bib_ref] Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects..., Domingo [/bib_ref] [bib_ref] Life-threatening arrhythmic presentation in patients with arrhythmogenic cardiomyopathy before and after entering..., Rootwelt-Norberg [/bib_ref] [bib_ref] Family screening for hypertrophic cardiomyopathy: is it time to change practice guidelines?, Lafreniere-Roula [/bib_ref] Presymptomatic DNA testing also puts an end to uncertainty and fear for those family members who test negative. [bib_ref] Outcomes of contemporary family screening in hypertrophic cardiomyopathy, Van Velzen [/bib_ref] For them, follow-up investigations are no longer indicated. In studies describing cascade screening, often the participation of relatives is limited. [bib_ref] Uptake of predictive genetic testing and cardiac evaluation for children at risk..., Christian [/bib_ref] [bib_ref] Practice variation among an international group of genetic counselors on when to..., Christian [/bib_ref] [bib_ref] The uptake of family screening in hypertrophic cardiomyopathy and an online video..., Harris [/bib_ref] [bib_ref] Genetic testing and cascade screening in pediatric long QT syndrome and hypertrophic..., Knight [/bib_ref] [bib_ref] Family relationships associated with communication and testing for inherited cardiac conditions, Shah [/bib_ref] [bib_ref] Patient outcomes from a specialized inherited arrhythmia clinic, Adler [/bib_ref] This implies that many persons carrying pathogenic variants remain undiagnosed [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref] and are at continued risk of sudden death. Increasingly, geneticists and other stakeholders plea for an active approach to cascade testing for conditions where interventions are available. [bib_ref] Postmortem disclosure of genetic information to family members: active or passive?, Boers [/bib_ref] [bib_ref] Returning results to family members: professional duties in genomics research in the..., Fox [/bib_ref] [bib_ref] Stakeholder views on active cascade screening for familial hypercholesterolemia, Van El [/bib_ref] Stakeholders agree on the importance of early diagnosis and informing the family. [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] [bib_ref] Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects..., Domingo [/bib_ref] [bib_ref] Relevance of molecular testing in patients with a family history of sudden..., Kauferstein [/bib_ref] Barriers to cascade screening include outof-pocket expenses for the patient, limited resources for informing relatives, and privacy regulations. [bib_ref] Outcomes of contemporary family screening in hypertrophic cardiomyopathy, Van Velzen [/bib_ref] [bib_ref] Stakeholder views on active cascade screening for familial hypercholesterolemia, Van El [/bib_ref] [bib_ref] The accessibility and utilization of genetic testing for inherited heart rhythm disorders:..., Roston [/bib_ref] [bib_ref] Family communication about genetic risk of hereditary cardiomyopathies and arrhythmias: an integrative..., Shah [/bib_ref] To benefit from predictive, personalized, and preventive medicine, the roles and responsibilities of stakeholders in genetic testing as a preventive strategy need to be carefully aligned. If clinical signs and symptoms suggest an inherited condition but no DNA test has been performed or no pathogenic variant has been identified, then history, examination, and clinical investigations of first-degree relatives are required to identify those at risk for SCD. ## Synopsis A postmortem diagnosis in a victim of SCD implies the possibility of avoiding sudden death in relatives. This requires an active approach to inform parents, siblings, and children of the index case and offer clinical evaluation and potential genetic testing. A multidisciplinary service should support all elements of recognizing an inherited cardiac disorder in a victim (pathologist), identifying pathogenic mutations (geneticist), clinical evaluation and surveillance of carriers of the mutation (cardiologist), and supporting the patients and relatives (psychologist). ## Recommendation-specific supportive text 1. Since undiagnosed cardiogenetic conditions can be lifethreatening and since interventions are available to reduce the risk of sudden death, first-degree relatives who are at 50% risk of carrying the pathogenic variant need to be informed about the possibilities of clinical investigations and genetic testing. [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Genetic testing in the evaluation of unexplained cardiac arrest, Mellor [/bib_ref] [bib_ref] Genetic testing and cascade screening in pediatric long QT syndrome and hypertrophic..., Knight [/bib_ref] [bib_ref] A cost-effectiveness model of genetic testing and periodical clinical screening for the..., Catchpool [/bib_ref] [bib_ref] Sudden arrhythmia death syndrome in young victims: a five-year retrospective review and..., Mak [/bib_ref] Second-degree relatives whose intervening first-degree relative refuses genetic testing (or is not available) should be offered testing due to a 25% risk. 2. Patients often can inform their relatives at risk, but medical professionals increasingly feel ethically responsible to support this process. [bib_ref] Postmortem disclosure of genetic information to family members: active or passive?, Boers [/bib_ref] [bib_ref] Returning results to family members: professional duties in genomics research in the..., Fox [/bib_ref] [bib_ref] Informing relatives at risk of inherited cardiac conditions: experiences and attitudes of..., Van Den Heuvel [/bib_ref] Supplying a letter for the patient to share with relatives is advised. Occasionally, directly contacting relatives may be possible in some jurisdictions. Studies have shown that there is substantial room for improvement of the uptake of family screening. Barriers include reluctance to consent to postmortem investigations, lack of information, and lack of funding for the services. While the services needed should involve many disciplines (pathologist, cardiologist, geneticist), the systematic approaching of family members fits the specialty of clinical genetics well. To achieve a high uptake, a systematic approach is needed. 3. The identification of at-risk individuals leads to the question of whether all require active treatment. Prospective clinical studies are needed to answer this question. To balance pros and cons for survival and for quality of life on treatment, long-term follow-up of persons following the suggested surveillance and interventions is needed. Precision prevention advice should build on this evidence. [bib_ref] HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic..., Towbin [/bib_ref]. In families with genetically affected individuals (with or without clinical findings), detailed prenatal counseling and guidance regarding inheritance patterns, variant penetrance, and risk should be offered, and other options including preimplantation genetic diagnosis should be explored. [bib_ref] Prenatal molecular diagnosis in hypertrophic cardiomyopathy: report of the first case, Charron [/bib_ref] [bib_ref] The ESHRE PGD Consortium: 10 years of data collection, Harper [/bib_ref] [bib_ref] PGD for inherited cardiac diseases, Kuliev [/bib_ref] ## Investigation of the family: cause not identified-clinical and genetic investigations Sudden death in the young is always a tragedy for those lost and the remaining family. When the cause of sudden death is not identified, either because there was no postmortem examination or because the autopsy was negative, significant anxiety in the family focuses on two major questions: why did the subject die suddenly and what risks apply to the remaining family members? An autopsy is typically requested, and in some jurisdictions mandated, but may not be completed because of cultural, family, or logistical limitations. When a postmortem examination establishes a cause of death, diagnosis transitions from SUD to death attributed to autopsy-related findings (see Section 8.2). When no underlying anatomic or toxicologic cause of death is identified with forensic autopsy, the description of the death goes from SUD to sudden arrhythmic death (syndrome)/SAD(S), since death is attributed to a presumed arrhythmia, or autopsy-negative SCD. In the case of 1 C-LD 1. If a pathogenic or likely pathogenic variant that fits with the phenotype has been identified in an SCD proband, first-degree relatives should be offered DNA testing, with ongoing clinical evaluation for those testing positive. 1 B-NR 4. In families affected by SCA, reproductive genetic counseling should be offered to discuss risks and options for future or current pregnancies. ## 336-338 nonspecific findings, follow-up of families should be similar to that with a negative autopsy. [bib_ref] Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous..., Papadakis [/bib_ref] [bib_ref] Insights into sudden cardiac death: exploring the potential relevance of non-diagnostic autopsy..., Raju [/bib_ref] When sudden death is classified as SAD or autopsynegative SCD (ie, SUD), the differential diagnosis includes a breadth of inherited conditions that are predominantly ion channelopathies, with latent cardiomyopathy a consideration based on subtle autopsy findings. Causes include long QT syndrome, CPVT, short QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy. Careful review by a trained cardiac pathologist is recommended to ensure that assigned causes or absent causes are accurate (see Section 6.3). [bib_ref] European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death, Fellmann [/bib_ref] Recent studies have shown that a genetic evaluation of the deceased subject's DNA associated with a clinical evaluation of first-degree relatives of the deceased subject retrospectively identified the cause of death in 20-40% of cases. [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] Cardiac abnormalities in first-degree relatives of unexplained cardiac arrest victims: a report..., Steinberg [/bib_ref] [bib_ref] The diagnostic yield of Brugada syndrome after sudden death with normal autopsy, Papadakis [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] In this situation, the identification of the cause of sudden death provides an explanation to the family and facilitates further cascade screening. In a second step, it will enable prevention measures in the family to limit the risk of a second death. ## Synopsis Screening of first-degree relatives of the SCD victim is informed by findings from the forensic investigation. Though the yield of genetic testing is relatively low, results should be applied to all first-degree relatives in conjunction with clinical assessment. In the absence of genetic results, screening tests should include a medical history, standard and high precordial lead ECG, 24-hour ambulatory monitoring, echocardiography, and exercise test, with select use of pharmacological provocation and advanced imaging. ## Recommendation-specific supportive text 1. Although autopsy is recommended, family screening after sudden death in young patients is effective even when an au-topsy is not conducted. Broad screening of first-degree relatives with systematic testing is warranted. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] Cardiac abnormalities in first-degree relatives of unexplained cardiac arrest victims: a report..., Steinberg [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] Combining molecular autopsy with clinical evaluation in surviving families increases diagnostic yield. [bib_ref] Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome, Lahrouchi [/bib_ref] The value of surveillance testing after negative evaluation is uncertain, though commonly undertaken until age 45 years (range: 40-50 years), with decreasing frequency with age. [bib_ref] Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the..., Van Der Werf [/bib_ref] The context of SCD, the family history, and existing findings should inform the potential merits of ongoing surveillance, including frequency and duration. The age at which and from which onward surveillance is warranted depends on the (suspected) underlying condition. 2. When decedent genetic testing detects a pathogenic or likely pathogenic variant, the result enables identification of all family members at risk of SCD. [bib_ref] Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination..., Tan [/bib_ref] [bib_ref] Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome, Behr [/bib_ref] [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] Cardiac abnormalities in first-degree relatives of unexplained cardiac arrest victims: a report..., Steinberg [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] It is important to combine genetic and clinical evaluation, especially when the pathogenicity of the detected variant is uncertain, to evaluate the correlation between the genetic finding and clinical diagnosis for each family. [bib_ref] Assessment and validation of a phenotype-enhanced variant classification framework to promote or..., Giudicessi [/bib_ref] It is reasonable to screen select postpubertal family members of SUD subjects with pharmacological testing including sodium channel blocker when baseline testing or proband findings increase suspicion of the target diagnosis. [bib_ref] Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the..., Behr [/bib_ref] [bib_ref] The diagnostic yield of Brugada syndrome after sudden death with normal autopsy, Papadakis [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden..., Krahn [/bib_ref] [bib_ref] Familial catecholamine-induced QT prolongation in unexplained sudden cardiac death, Huchet [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] 2b B-NR 6. It may be reasonable to screen first-degree relatives of SUD subjects with pharmacological testing including epinephrine challenge (if exercise testing is impractical) and sodium channel blockade. [bib_ref] The diagnostic yield of Brugada syndrome after sudden death with normal autopsy, Papadakis [/bib_ref] [bib_ref] Low rate of cardiac events in firstdegree relatives of diagnosis-negative young sudden..., Van Der Werf [/bib_ref] [bib_ref] Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden..., Krahn [/bib_ref] [bib_ref] Familial catecholamine-induced QT prolongation in unexplained sudden cardiac death, Huchet [/bib_ref] [bib_ref] Clinical yield of familial screening after sudden death in young subjects: the..., Quenin [/bib_ref] during physical activity suggests the diagnosis of long QT syndrome or CPVT. As Brugada syndrome may be masked or intermittent in some patients, sodium channel blocker challenge may unmask the type 1 pattern and increase the effectiveness of family screening. It should be recognized that there is a potential high rate of false positives, as data on the specificity and sensitivity of the test are not available, and a positive ECG may be induced in 4-5% of normal subjects. [bib_ref] High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant..., Hasdemir [/bib_ref] [bib_ref] Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern, Hasdemir [/bib_ref] In the pediatric age group, a negative test may convert to a positive test after puberty. [bib_ref] Follow-up from childhood to adulthood of individuals with family history of Brugada..., Conte [/bib_ref] Long QT syndrome may also be unmasked by standing, exercise test, epinephrine test, or mental stress test. [bib_ref] The phenomenon of "QT stunning": the abnormal QT prolongation provoked by standing..., Adler [/bib_ref] [bib_ref] The response of the QT interval to the brief tachycardia provoked by..., Viskin [/bib_ref] [bib_ref] Derivation and validation of a simple exercise-based algorithm for prediction of genetic..., Sy [/bib_ref] [bib_ref] Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden..., Krahn [/bib_ref] [bib_ref] Familial catecholamine-induced QT prolongation in unexplained sudden cardiac death, Huchet [/bib_ref] In first-degree relatives of young SUD victims with no manifest abnormalities during the initial examination, the risk of developing manifest inherited cardiac disease or cardiac events during follow-up is low. 205 ## Section 9 future directions Many of the recommendations in this document seem intuitive, obvious, and straightforward; however, much of what is being recommended within this document is seldom routinely performed even in well-resourced countries. Many decedents of SUD never receive an autopsy, and the evaluation of first-degree relatives of an SUD victim or an SCA survivor ranges widely from no evaluation to ordering a multitude of tests that are then repeated regularly and indefinitely. The extensive variability in practice indicates that developing common sense processes and multidisciplinary teams remains a considerable challenge in many areas and guidance is required. Developing these processes and teams involves leaders challenging many medico-political barriers that obstruct and delay best print & web 4C=FPO [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref] Investigation of sudden cardiac arrest survivors. Colors correspond to the Class of Recommendation in [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. AED 5 automated external defibrillator; AF 5 atrial fibrillation; BBR-VT 5 bundle branch re-entry ventricular tachycardia; CIED 5 cardiovascular implantable electronic device; CMR 5 cardiac magnetic resonance imaging; CPVT 5 catecholaminergic polymorphic ventricular tachycardia; ECG 5 electrocardiogram; EP 5 electrophysiological; LQTS 5 long QT syndrome; SCA 5 sudden cardiac arrest; SVT 5 supraventricular tachycardia. medical practice. We hope that this document will empower those who wish to achieve such changes for the better, including efforts for continuous improvement of practice. So, assuming the recommendations in this document are embraced and implemented, what are the next steps and future directions in this field? Firstly, unlike cancer statistics and even SCD in the elderly due to coronary artery disease, the precise prevalence, epidemiology, and etiologies of either SUD or SCA in the young remain obscure in most countries. Only if these conditions become a notifiable event will the true scale and scope ever be captured. Secondly, communities, states/provinces, and countries must advocate for and expect that a true comprehensive autopsy, including postmortem genetic testing (ie, molecular autopsy), occurs whenever an SUD occurs in a young person. The current dismal rate of autopsy must be reversed. Only when this becomes the standard of care will the true epidemiology/etiology of SCD be determined. Thirdly, the basic occurrence and subsequent extent of an evaluation of the living, whether she/he is an SCA survivor or the first-degree relative of an SUD victim or an SCA survivor, must become standard of care. After initial cardiological evaluation (examination, ECGs, stress test, and echocardiogram) has been completed, the true contribution of SCApredisposing genetic heart disease will be exposed. Furthermore, the composition and contribution of advanced investigations ranging from sodium channel drug provocation studies, to MRI, to genetic testing requires further study, as does the recommended interval for a repeat cardiological evaluation of the first-degree relatives when their first evaluation is either normal or inconclusive. Finally, when such investigations are commenced, future studies to minimize the collateral damage from uncertain clinical findings and genetic "variants of uncertain significance" will be needed. While it is recognized that the correct necropsy diagnosis of the SUD decedent and the correct diagnosis of the SCA survivor may give patients and their families some answers and resolution to the event, the premature and erroneous diagnosis due to excessive confidence in or overinterpretation of clinical or genetic findings of uncertain significance can cause remarkable harm. If we are to "first do no harm," the model of multidisciplinary teams with the expertise to correctly evaluate all the investigations and potential (mis)diagnoses should be made accessible to all. print & web 4C=FPO [fig_ref] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death [/fig_ref] Investigation of the family affected by sudden cardiac arrest and/or sudden unexplained death when cause is identified or not identified. Colors correspond to the Class of Recommendation in [fig_ref] Table 1: ACC/AHA recommendation system [/fig_ref]. CMR 5 cardiac magnetic resonance imaging; ECG 5 electrocardiogram; SCA 5 sudden cardiac arrest; SCD 5 sudden cardiac death; SUD 5 sudden unexplained death. [fig] : Representative of the Pediatric and Congenital Electrophysiology Society (PACES) †Representative of the Heart Rhythm Society (HRS) ‡Representative of the European Heart Rhythm Association (EHRA) xRepresentative of the European Society of Human Genetics (ESHG) {Representative of the Asia Pacific Heart Rhythm Society (APHRS) #Representative of the National Society of Genetic Counselors (NSGC) Representative of the Latin American Heart Rhythm Society (LAHRS) † †Representative of the Association for European Cardiovascular Pathology (AECVP) UMember of the European Cardiac Arrhythmia Genetics (ECGen) Focus Group of the European Heart Rhythm Association (EHRA) IIMember of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart DPatient representativê Martin K. Stiles, MBChB, PhD, FHRS, and Arthur A.M. Wilde, MD, PhD, are co-first authors. [/fig] [fig] KEYWORDS: Brugada syndrome; Cardiac arrest; Cardiac genetics; Catecholaminergic polymorphic ventricular tachycardia; Defibrillator; Expert consensus statement; Genetic counseling; Guidelines; Long QT syndrome; Postmortem; Resuscitation; Sudden arrhythmic death syndrome; Sudden cardiac death; Sudden unexplained death; Ventricular arrhythmia ABBREVIATIONS AED 5 automated external defibrillator; CIED 5 cardiovascular implantable electronic device; CMR 5 cardiac magnetic resonance imaging; COR 5 Class of Recommendation; CPR 5 cardiopulmonary resuscitation; CPVT 5 catecholaminergic polymorphic ventricular tachycardia; CT 5 computed tomography; ECG 5 electrocardiogram; EMS 5 emergency medical services; LOE 5 Level of Evidence; MRI 5 magnetic resonance imaging; OH-CA 5 out-of-hospital cardiac arrest; PVC 5 premature ventricular complex; RWI 5 relationship with industry and other entities; SAD(S) 5 sudden arrhythmic death (syndrome); SCA 5 sudden cardiac arrest; SCD 5 sudden cardiac death; SUD 5 sudden unexplained death (Heart Rhythm 2020;-:1-46)Section 8 Investigation of the Family .................... 33 8.1. Background ................................................ 33 8.2. Investigation of the Family: Cause Identified-Cascade Testing, Clinical and Genetic Investigations ................................ 34 8.3. Investigation of the Family: Cause Not Identified-Clinical and Genetic Investigations ............................................. 35 Section 9 Future Directions .................................... 37 [/fig] [fig] Figure 1: Distribution of causes of death among autopsied cases of sudden cardiac death (n 5 753) according to age in persons aged 1-49 years in Denmark (J.T.-H., unpublished data). SADS 5 sudden arrhythmic death syndrome. Coronary artery disease, especially in young persons, may be due to inherited disease (eg, familial hypercholesterolemia). [/fig] [fig] Figure 2: Cumulative overall survival rates, by participating emergency medical services agency-Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005-December 31, 2010. Agencies sorted by total number of out-of-hospital cardiac arrest events in CARES (from low to high; [/fig] [fig] Figure 3: Cumulative Utstein survival rates (patients alive when arriving to hospital) by participating emergency medical services agency-Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005-December 31, 2010. [/fig] [fig] Figure 5, Figure 6, Figure 4: Bystander-witnessed arrest, bystander cardiopulmonary resuscitation (CPR), shockable heart rhythm as first recorded rhythm, and survival on arrival at the hospital, Denmark, 2001-2010. Reprinted with permission from the American Medical Association. 54 print & web 4C=FPO Examples of complimentary bystander cardiopulmonary resuscitation (CPR) programs. Reprinted with permission from Elsevier. 64 print & web 4C=FPO Bystander treatments of patients with out-of-hospital cardiac arrest before emergency medical services arrival among neighborhoods by percentage of black residents. Reprinted with permission from the American Medical Association. 39 AED 5 automated external defibrillator; CPR 5 cardiopulmonary resuscitation. [/fig] [fig] Figure 8: Participants in a cardiac genetic service. "Pathologists" includes forensic pathologists. Modified with permission from Elsevier.69 [/fig] [table] Table 1: ACC/AHA recommendation system: Applying Class of Recommendation and Level of Evidence to clinical strategies, interventions, treatments, and diagnostic testing in patient care* Reprinted with permission from the American College of Cardiology (ACC) and the American Heart Association (AHA). [/table] [table] Table 2: Relevant clinical practice documents European Recommendations Integrating Genetic Testing into Multidisciplinary Management of Sudden Cardiac Death 2 2019 2019 HRS/EHRA/APHRS/LAHRS Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias 3 2019 2019 HRS Expert Consensus Statement on Evaluation, Risk Stratification, and Management of Arrhythmogenic Cardiomyopathy 4 2019 2018 ESC Guidelines for the Diagnosis and Management of Syncope 5 2018 2017 AHA/ACC/HRS Guideline for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes 10 2013 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies 11 [/table]	None	http://www.heartrhythmjournal.com/article/S154752712030953X/pdf	None
79c9d3246fb4010286a15b78d678a44ef42f9870	pubmed	Chemotherapy: United Kingdom National Multidisciplinary Guidelines	Chemotherapy: 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. This paper summarises the role of chemotherapy in head and neck cancer management, recent advances and what the future holds for this modality. # Introduction Chemotherapy alone cannot cure head and neck cancer. It is used in conjunction with other treatments, surgery and radiotherapy (RT), to improve outcomes in terms of local control, organ preservation with continued organ function and to decrease the incidence of subclinical micro-metastatic spread. Chemotherapy is not given routinely for early primary T1/T2 disease without nodal involvement. Chemotherapy is given for its direct tumouricidal effect, at both the local primary and distant metastatic sites. If given with RT it can have a radio sensitising effect, making cancer cells more susceptible to RT and increasing the cancer cell kill. It may be used as induction chemotherapy (ICT), almost always before RT rather than surgery. If ICT is used, further chemotherapy is usually given with subsequent RT, and this is known as sequential chemotherapy. More commonly, chemotherapy is given only concurrently with radiotherapy (combined chemoradiotherapy) with only a minority of patients having induction or sequential regimens. Combined chemoradiotherapy has been shown to improve local control and increase survival where primary surgery has been the definitive treatment in selected populations. ## Induction (neoadjuvant) chemotherapy The response to neoadjuvant chemotherapy could give important prognostic information, as it can act as a surrogate marker for response to later treatment. This latter advantage was used in one of the earliest trials of neoadjuvant chemotherapy for organ preservation, the 'Veterans' trial, 1 where patients were given two cycles of cisplatin and 5-fluorouracil (5-FU), and if there was a response to chemotherapy patients went on to have chemotherapy and RT, but if there was no response, the patients went directly to laryngectomy. Induction chemotherapy is considered beneficial for several reasons. If ICT could shrink primary tumour volumes before the principal treatment of RT or chemoradiotherapy, this might allow better blood flow into the tumour allowing a greater tumouricidal dose of drugs into the tumour and decrease the volume of hypoxic areas which would decrease the radio-resistance that hypoxic cancer cells show. Improved local control would lead to a greater chance of organ preservation and functionality. Since surgery and RT are both locoregional treatments, ICT could theoretically treat distant subclinical metastatic disease. The response to ICT could give important prognostic information, as it can act as a surrogate marker for response to later treatment. One of the main evidence sources for the use of chemotherapy in head and neck cancer is the Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) which was originally published in 2000 and updated in 2007 and 2009. [bib_ref] Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on..., Pignon [/bib_ref] This overview reviewed 87 trials containing data on over 16 000 patients, with overall survival as the primary endpoint. There was no overall survival benefit with the use of ICT when compared with primary surgery or RT alone, although cisplatin and 5-FU delivered as combined chemoradiotherapy did show some benefit. It also suggested that ICT may reduce the incidence of distant metastases more effectively than combined chemoradiotherapy. Debate continues as to whether ICT followed by combined chemoradiotherapy is more beneficial than combined chemoradiotherapy alone. Some large trials, such as the Spanish Head and Cancer Corporative Group trial have shown no benefit, [bib_ref] A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus..., Hitt [/bib_ref] while others, such as a large Italian trial comparing ICT followed by combined chemoradiotherapy to combined chemoradiotherapy alone showed significantly improved overall survival for the former arm.Interest was rekindled in ICT when two trials, one European, and one from North America, TAX 323 5 and TAX 324 6 showed a benefit by including a taxane, such as docetaxel or paclitaxel in the chemotherapy regimen in addition to cisplatin and 5-FU. The evidence suggested that adding a taxane, such as docetaxel or paclitaxel to cisplatin and 5-FU, i.e. docetaxel/cisplatin/5-FU (TPF) vs cisplatin/5-FU (PF) did improve survival in the TPF arm, but at a cost of much higher toxicity. However, these trials have been criticised for not using optimal concurrent chemotherapy schedules. Based on further phase 3 studies (DeCIDE, [bib_ref] Phase III randomized trial of induction chemotherapy in patients with N2 or..., Cohen [/bib_ref] PARADIGM trial and 8 TREMPLIN study [bib_ref] Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the..., Lefebvre [/bib_ref] the evidence to date does not suggest ICT is in general beneficial in head and neck cancer. Usually, induction and sequential regimens are offered to patients with good performance status, fewer comorbidities and those with bulky nodal disease, stage N2b and above, and where surgery is not appropriate. ## Concurrent or concomitant chemotherapy The main advantage of combined chemoradiotherapy, over sequential chemotherapy, is the reduced chance of patients having to stop treatment because of toxicity, and resulting in breaks in RT, which is radiobiologically suboptimal and can be detrimental to treatment outcome. In the MACH-NC trial, 2 the use of combined chemoradiotherapy showed that it gave a survival benefit when added to RT alone, giving a 6.5 per cent decrease in mortality at five years, in absolute terms. This benefit was not seen in patients over 70 years of age. The most commonly used combined chemoradiotherapy regimens are cisplatin 100 mg/m 2 on days 1, 22 and 43 of RT, either alone or with 5-FU, 1 g/day on days 1-4, and then repeated 3 weekly with cisplatin. If 5-FU is added, the cisplatin dose is usually reduced. Although this regimen is commonly used, there are few direct comparisons with other combined chemoradiotherapy within randomised controlled trials. Increased toxicity produced by adding platinum chemotherapy to RT can be considerable. A significant proportion of patients do not receive all three cycles of chemotherapy because of toxicity, but one study has shown no survival difference in patients receiving two cycles of cisplatin rather than three cycles, but the RT given was not identical within the arms of this study. 10 chemotherapy toxicity can also interfere detrimentally with RT delivery causing breaks during treatment which are associated with poorer outcomes. If cisplatin is contraindicated because of renal function status, the presence of neuropathy, tinnitus or deafness, or where there is a danger of fluid overload with the necessary pre-hydration used in cisplatin administration, carboplatin can be considered as it causes less nephrotoxicity, ototoxicity and peripheral neuropathy but is more myelosuppressive. It is not thought to be as tumouricidal as cisplatin and for this reason it has now been largely overtaken by the epidermal growth factor receptor inhibitor, cetuximab in clinical practice when cisplatin is contraindicated. ## Concurrent radio-sensitisers It is known that tumour cell hypoxia induces radioresistance, and there has been renewed interest in giving hypoxic cell radiosensitising drugs during RT. The two most common in use are the antihelminthic drug nimorazol, which is extensively used in some parts of Europe, and tirapazamine, an anticoagulant which is activated in hypoxic environments. Although established in some parts of the world, trials are ongoing with these agents to establish efficacy and with nimorazol, patient tolerability. ## Chemotherapy and human papilloma virus (hpv)-positive tumours Human papilloma virus is known to have an aetiological role in inducing some head and neck cancers, especially in the oropharynx where HPV infection may be linked to 50-80 per cent of tumours. There is evidence from several studies that outcomes are better following treatment in patients with HPV-positive tumours. There is also growing evidence that continuing to smoke negates the outcome benefit associated with HPV positivity. Given the good prognosis, the question arises if HPV-positive cancers are being overtreated with standard head and neck chemoradiotherapy regimens and being given unnecessary morbidity. At present there is not enough evidence to alter chemotherapy or indeed RT treatment regimens depending on the patient's HPV status, outside of the context of a clinical trial. Several trials are now investigating these questions, most using cetuximab comparing with cisplatin (see below). These include the RTOG 1016 in the USA, the De-ESCALATE HPV study in the UK and the Trans-Tasman Radiotherapy Group 12.01 study in Australia. ## Targeted biological agents Targeted therapy in head and neck cancer developed with the recognition that epidermal growth factor receptor (EGFR) is overexpressed in the majority of head and neck cancers, up to 90 per cent in some studies, and is associated with a poorer prognosis. When a growth factor attaches to its receptor on the cell surface, cells are stimulated to divide and consequently tumours grow. If the receptor is abnormal because of a mutation the stimulation to divide may even occur without growth factors interacting with the receptor. Cetuximab is a mouse-human chimaeric monoclonal antibody which binds to the extracellular portion of EGFR and turns this signalling system off. In the initial innovative cetuximab trial by Bonner et al., [bib_ref] Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck, Bonner [/bib_ref] patients with advanced head and neck cancer were randomised to receive radical RT with or without cetuximab. At three years, survival (55 vs 45 per cent) and local control (50 vs 41 per cent) was better in the patient group who had received cetuximab. [bib_ref] Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival..., Bonner [/bib_ref] Although these initial results were encouraging, a major drawback to the study was that, since the study had started, RT alone as used in this study had been overtaken as a standard of care by combined chemoradiotherapy. So, comparing radiation alone vs radiation plus cetuximab was much less relevant in the context of contemporary standard practice. Also in the initial trial patients were not stratified by HPV status. Despite initial hopes that cetuximab would give less toxicity than the standard chemotherapy, and can therefore be given to older patients and those with a poorer performance status, it has been shown to have a different, although not necessarily less toxic, morbidity profile in the form of grade 3 and 4 radiation dermatitis. Patients may also develop an acne-like rash predominantly over the face, neck and trunk with a more eczema-like condition at the fingertips and elbows. In a minority of patients this reaction can be so severe that cetuximab may need to be stopped as these side effects can usually be managed by increasing the treatment interval and supportive care with topical medications. There is some suggestion that patients who develop this rash may also have a better tumour response with improved overall survival. Other targeted EGFR monoclonal antibodies are under investigation such as panitumamab or zalutumumab, but to date with less encouraging results showing no improvement in overall survival. Another potential target further down this biological pathway, offering a different mechanism of action is used by erlotinib, a small molecule inhibitor of EGFR tyrosine kinase. One phase II trial of erlotinib given alone or combined with cisplatin, unfortunately did not show any benefit in outcome for the combination. Despite this other targets in the epidermal growth factor receptor pathway are being investigated. Chemotherapy for recurrent or metastatic head and neck cancer Chemotherapy or targeted biological agents may be indicated for patients with recurrent and/or metastatic disease but prognosis for patients with metastatic disease has a median survival of approximately 6-12 months in most studies. Appropriateness of chemotherapy depends on several factors such as extent and burden of disease; whether symptoms are present or not; whether failure of control has taken place at the primary site only; and whether there is metastatic disease only or both. The most important factor often is the fitness and performance status of the patient and whether they could tolerate the proposed chemotherapy, and how much it would reduce their pre-treatment quality of life, for whatever limited survival period they have. ## Locoregional failure In this group of patients where salvage surgery or retreatment with RT or combined chemoradiotherapy is being considered, it is important to be aware if distant metastatic disease is also present and also to establish that the locoregional recurrent disease is not a second primary head and neck cancer. Discovering that metastatic disease is also present is not an absolute contraindication to salvage treatments at the primary site, as locoregional failure and metastatic disease can be considered as two separate problems in the patient's management plan. If good palliation at the primary site or locoregionally can be achieved relatively easily, by a salvage procedure, the presence of metastatic disease, especially small volume metastatic disease, should not necessarily stop treatment to the primary or locoregional site. The patients who do better with salvage treatment are those with smaller volumes of recurrence, a longer disease-free interval and less comorbidity. Some particular head and neck subsites such as the larynx, also have better outcomes. [bib_ref] Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy..., Spencer [/bib_ref] Distant metastases Chemotherapy is often indicated here, as part of a best supportive care package to improve symptoms, but has not been shown to significantly extend survival. The therapeutic window for giving chemotherapy in this situation would be when the patient still has an appropriate performance status to receive and benefit from chemotherapy, with the trade-off being, an improved symptom state for the inevitable morbidity caused by the chemotherapy. The choice of regimen depends on factors such as performance status, comorbidities, renal function, estimated physiological reserve of the patient and the interval since last chemotherapy. If chemotherapy is to be given for distant metastatic disease then which regimen is most appropriate depends on several factors including performance status, comorbidities present, renal function and the estimated physiological reserve of the patient. Also which regimens the patients had before and the interval since last chemotherapy may be important. The most common regimens used are cisplatin or carboplatin with 5-FU. These give an expected response rate of approximately 30 per cent. Carboplatin is used more in this palliative metastatic setting than with induction or concurrent regimens, because although deemed slightly less effective than cisplatin; its less toxic side-effect profile, can be seen to be more appropriate in the palliative setting. Elderly patients do appear to respond to platinumbased chemotherapy in the metastatic setting, 14 in contrast to a lack of benefit in the elderly when used in primary chemoradiotherapy regimens. Other more toxic chemotherapy regimens have also been investigated using platinum and a taxane (docetaxel or paclitaxel), in combination, but no survival benefit has been demonstrated. Cetuximab added to cisplatin and 5-FU, can increase both response rate and improve short-term survival slightly as shown in the EXTREME trial, 15 but fiveyear follow-up published recently in abstract form shows very low survival for patients in both arms of the study. The EXTREME study did not allow crossover between regimens, so similar results might be achieved by the use of cisplatin and 5-FU followed by cetuximab used sequentially. In patients who have become refractive to cisplatin and 5-FU, cetuximab as a single agent does have a low response rate of approximately 10-15 per cent. [bib_ref] Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity..., Vermorken [/bib_ref] [bib_ref] Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody..., Baselga [/bib_ref] Key points - Concurrent chemoradiotherapy is at present the standard of care for treatment of locally advanced head and neck cancer with a confirmed survival benefit of 6.5 per cent at five years - Single agent cisplatin, which in the past has been shown to be as effective as multiple drug regimes, is now being challenged by the introduction of the use of taxanes - Targeted biological agents, such as cetuximab, have a role to play in both advanced head and neck cancer and recurrent or metastatic disease but those roles are still being established - At present human papilloma virus status does not alter management regimens, although there are multiple studies underway examining if less intense treatment, both with radiotherapy and chemotherapy, could be given to achieve the same outcome but with less toxicity - The potential benefit of neoadjuvant or induction chemotherapy is being re-examined now, but most recent work has not shown a substantial benefit - Elderly patients benefit least in terms of survival advantage with the use of concurrent chemotherapy. © 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/S0022215116000840	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/55E76BCC5FC676588FDF4E92DAABDE6D/S0022215116000840a.pdf/div-class-title-chemotherapy-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. This paper summarises the role of chemotherapy in head and neck cancer management, recent advances and what the future holds for this modality.
30d4b17f3cca5ac092db199cd9fec2aec578df25	pubmed	Antibiotic Prophylaxis in Gynaecologic Procedures	Antibiotic Prophylaxis in Gynaecologic Procedures This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC. # Introduction I nfectious complications following gynaecologic surgical procedures are a significant source of morbidity and potential mortality. They include urinary tract infection, endometritis, wound infection, vaginal cuff cellulitis, 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 gynaecology. 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 betalactamase-producing organisms. Both morbidity and mortality are increased in infections involving 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 treatment and prophylaxis guidelines likely assists in reducing infection and antibiotic resistance. Physician adherence to antibiotic prophylaxis guidelines is variable and frequently 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, all factors that affect infectious risk reduction in our specialty must be reviewed. Sterile surgical fields must be ensured, and ongoing quality assessment of sterilization technique, air ventilation, and postoperative wound care are 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. ## 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 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 in which the incision will be closed in the operating room. Before an agent can be considered for use as a prophylactic, 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 If prophylactic antibiotics are to be given, they should be administered shortly before or at bacterial inoculation. [bib_ref] The timing of prophylactic administration of antibiotics and the risk of surgical-wound..., Classen [/bib_ref] This should be done 15 to 60 minutes before skin incision. The majority of studies suggest that a single dose is effective but that for lengthy procedures (> 3 hours) the dose should be repeated at intervals 1 or 2 times the halflife of the drug. It has also been suggested that with large blood loss (> 1500 mL), a second dose should be given. 8 ## Surgical procedures ## Vaginal hysterectomy A hysterectomy is considered a "class II or cleancontaminated" wound ( There is no meta-analysis or systematic review regarding antibiotic prophylaxis for vaginal hysterectomy. A review by Duff and Park 10 included 20 studies, the majority of which were prospective randomized trials (18/20) and many of which were double-blinded . Without prophylaxis, the incidence of febrile morbidity averaged 40% to 50% but was reduced to 5% to 20% with prophylactic antibiotics. [bib_ref] Antibiotic prophylaxis in vaginal hysterectomy: a review, Duff [/bib_ref] The type, dose, and duration of antibiotics used were highly variable, but a first-generation cephalosporin was used in the majority of studies. A randomized trial comparing amoxicillin-clavulanic acid with cefazolin (n = 178) showed no difference in infection rates. [bib_ref] Antimicrobial prophylaxis in vaginal gynecologic surgery: a prospective randomized study comparing amoxicillin-clavulanic..., Cormio [/bib_ref] Another trial comparing use of cefuroxime, metronidazole, or both showed an increased morbidity when metronidazole was added. [bib_ref] Vaginal hysterectomy: cefuroxime, metronidazole or both?, Kauer [/bib_ref] Treating bacterial vaginosis with metronidazole rectally for at least 4 days prior to vaginal hysterectomy appears to reduce the incidence of vaginal cuff infection (n = 59; 0 vs. 27%) but may be impractical given the possibility of surgery cancellation. [bib_ref] Does pre and postoperative metronidazole lower vaginal cuff infection rate after abdominal..., Larsson [/bib_ref] It is also difficult to comment on the costbenefit of screening all women for BV prior to surgery. ## Abdominal hysterectomy There are 3 meta-analyses exploring the efficacy of antibiotic prophylaxis for abdominal hysterectomy. The most recent, by Tanos and Rojansky in 1994, 14 compared 17 trials (n = 2752) that used single dose or up to 24 hours of intramuscular or intravenous cephalosporins. There was a significant reduction in the incidence of infection in the treatment groups (OR = 0.35; 95% CI 0.3 to 0.4). Febrile morbidity was prevented by first-generation cephalosporins but not by some second-and third-generation choices. The authors concluded that a single dose of a first-or secondgeneration cephalosporin was efficacious and cost-effective. Mittendorf et al. [bib_ref] Avoiding serious infections associated with abdominal hysterectomy: a meta-analysis of antibiotic prophylaxis, Mittendorf [/bib_ref] (1993) meta-analyzed 25 RCTs (n = 3604) with varying antibiotic choice, duration, and routes of administration. They found that serious infections were less common in the treatment groups (9% vs. 21.1%, P = 0.001). Among those who received cefazolin or metronidazole, 11.4% and 6.3% respectively had serious postoperative infections. Lastly, Wttewaall-Evelaar [bib_ref] Meta-analysis of randomized controlled trials of antibiotic prophylaxis in abdominal hysterectomy, Wttewaall-Evelaar [/bib_ref] (1990) examined 17 RCTs, the majority of which (14 of 17) used first-or secondgeneration cephalosporins. Infections were significantly reduced in the treatment groups (P < 0.001). A randomized trial with women undergoing a gynaecologic procedure via laparotomy (which included abdominal hysterectomy) comparing amoxicillin-clavulanic acid with cefazolin (n = 511) showed no difference in infection rates. [bib_ref] Antimicrobial prophylaxis in laparotomic gynecologic surgery: a prospective randomized study comparing amoxicillin-clavulanic..., Cormio [/bib_ref] A randomized trial (n = 321) comparing placebo, ampicillin, and cefazolin, demonstrated significant superiority of cefazolin to reduce postoperative infection. [bib_ref] Placebo-controlled, double-blind, randomized study of prophylactic antibiotics in elective abdominal hysterectomy, Chongsomchai [/bib_ref] A randomized study comparing a single dose versus 24-hour regimen of cefuroxime plus metronidazole, showed no difference. 19 ## Laparoscopic hysterectomy A Cochrane review showed that laparoscopic hysterectomy (laparoscopically assisted vaginal hysterectomy or laparoscopic subtotal hysterectomy) results in fewer wound or abdominal wall infections (OR 0.32; 95% CI 0.12 to 0.85) and fewer unspecified infections or febrile episodes (OR 0.65; 95% CI 0.49 to 0.87) than abdominal hysterectomy. There was no difference in any infections between laparoscopic hysterectomy and vaginal hysterectomy. [bib_ref] Surgical approach to hysterectomy for benign gynaecological disease, Johnson [/bib_ref] There are no trials assessing the use of prophylactic antibiotics for any types of laparoscopic hysterectomy. Given that this is a clean-contaminated procedure with a rate of postoperative infections similar to that of vaginal hysterectomy, it would seem reasonable to treat these patients in a similar fashion. A single dose of cefazolin was determined to be as effective as multiple doses in a study of 310 women who underwent laparoscopically assisted vaginal hysterectomy. 20 ## Laparoscopy not entering the uterus and/or vagina These procedures are considered clean, as the genital tract is not entered. A randomized non-blinded trial of 450 women undergoing laparoscopy for various indications (not hysterectomy), found no difference in infection rates between those who received a single dose of cefazolin and those who did not. 21 [bib_ref] A randomized, double-blind, placebocontrolled comparison of the effect of nitrofurantoin monohydrate macrocrystals..., Rogers [/bib_ref] There are no studies assessing prophylactic antibiotics prior to these surgeries without use of a suprapubic catheter. There are also no studies regarding isolated sub-urethral sling procedures (e.g., transvaginal or transobturator tapes), but given the very poor outcomes associated with mesh infection, administration of a single preoperative dose of a first-generation cephalosporin is common practice. ## Recommendation ## 7. All women undergoing surgery for pelvic organ prolapse and/or stress urinary incontinence should receive a single dose of first-generation cephalosporin. (III-B) ## Hysteroscopic surgery A Cochrane review of prophylactic antibiotics for transcervical intrauterine procedures did not identify any randomized trials that met their criteria. [bib_ref] Prophylactic antibiotics for transcervical intrauterine procedures, Thinkhamrop [/bib_ref] A pseudorandomized study that used centre-specific antibiotic prophylaxis analyzed 631 infertile women who underwent office hysteroscopy. Two hundred sixty-six women received amoxicillin-clavulanate and doxycycline 2 hours pre-procedure. There was no difference in postprocedural infection (1 in the antibiotic group). [bib_ref] Antibiotic prophylaxis for hysteroscopy evaluation of the uterine cavity, Kasius [/bib_ref] A randomized trial of amoxicillin and clavulanate versus placebo for hysteroscopic ablation (n = 116) found a significant difference in the occurrence of bacteremia (16% vs. 2%); however, the authors comment that the majority of organisms were of dubious clinical significance and that contamination could not be excluded in 7 of 10 cases. No significant difference was found for women treated for presumed infection (11.4% vs. 9%), but no objective measures were used. [bib_ref] A prospective randomized study of the effects of prophylactic antibiotics on the..., Bhattacharya [/bib_ref] A case series of 568 women suggests that the infection risk is low (< 1%). [bib_ref] Endometrial ablation: a series of 568 patients treated over an 11-year period, Baggish [/bib_ref] There are no studies addressing prophylactic antibiotics in the setting of hysteroscopic myomectomy. ## Recommendation ## Antibiotic prophylaxis is not recommended for hysteroscopic surgery. (ii-2d) ## Induced (therapeutic) abortion A meta-analysis that included 12 randomized clinical trials, demonstrated that prophylactic antibiotics significantly reduced post-abortal infection (at < 16 weeks), compared with placebo. [bib_ref] Antibiotics at the time of induced abortion: the case for universal prophylaxis..., Sawaya [/bib_ref] The relative risk of upper genital tract infection following surgical abortion was 0.58 (95% CI 0.47 to 0.71) with antibiotics. The benefit was seen in women considered to be at high risk and in those at low risk for infection; thus, the authors conclude that universal prophylaxis should be given and that no more placebocontrolled trials should be performed. The most appropriate antibiotic regimen, however, is yet to be determined, as no comparative or superiority trials have been conducted. The largest trial to date (n = 1074), which had the most statistically significant reduction in postoperative infection rates (RR 0.12; 95% CI 0.08 to 0.38), used doxycycline 100 mg orally before the procedure followed by 200 mg after the procedure. [bib_ref] Prophylactic antibiotics for suction curettage abortion: results of a clinical controlled trial, Lavellois [/bib_ref] Other regimens that have been effective in a randomized trial include metronidazole 400 mg orally 1 hour before the procedure and then repeated 4 and 8 hours after the procedure (RR 0.19; 95% CI 0.10 to 0.83) [bib_ref] Metronidazole prophylaxis in elective first trimester abortion, Heisterberg [/bib_ref] and doxycycline 400 mg orally 10 to 12 hours before the procedure (RR 0.33; 95% CI 0.22 to 0.73) [bib_ref] The prophylactic effect of doxycycline on postoperative infection rate after first-trimester abortion, Darj [/bib_ref] A cost-effectiveness study looking at universal screening for sexually transmitted infections versus prophylactic azithromycin (1 g) showed that prophylactic treatment provided a significant cost savings. [bib_ref] Universal screening or prophylactic treatment for Chlamydia trachomatis infection among women seeking..., Chen [/bib_ref] hours), or if the estimated blood loss is > 1500 mL, an additional dose of the prophylactic antibiotic may be given 3 to 4 hours after the initial dose. (III-C) 6. Antibiotic prophylaxis is not recommended for laparoscopic procedures that involve no direct access from the abdominal cavity to the uterine cavity or vagina. (I-E) flora with those who had BV (RR = 4.2 in untreated group; 95% CI 1.2 to 15.9). [bib_ref] Treatment with 2% clindamycin vaginal cream prior to first trimester surgical abortion..., Larsson [/bib_ref] Another randomized blinded trial found that giving a single 2 g metronidazole suppository preoperatively to women who had confirmed bacterial vaginosis 33 did not make a significant difference (RR = 0.53; P = 0.055). Screening and treating for bacterial vaginosis prior to surgery also may be impractical, and the cost-effectiveness is not known. ## Missed or incomplete abortion There are two randomized placebo-controlled trials that assess the effectiveness of prophylactic antibiotics to reduce infectious morbidity following uterine evacuation for incomplete abortion. One trial involving 240 women used a preoperative intravenous dose of doxycycline or placebo. [bib_ref] A randomized trial of prophylactic doxycycline for curettage in incomplete abortion, Prieto [/bib_ref] Chlamydia and gonorrhea rates were low (3% to 6%) in this population. No difference in postoperative infectious morbidity rates occurred up to 2 weeks postprocedure. A second study of 300 women investigated the use of 200 mg oral doxycycline at 30 to 60 minutes pre-procedure. Again, no significant difference between groups was found. [bib_ref] Prophylactic antibiotics for suction curettage in incomplete abortion, Ramin [/bib_ref] ## Intrauterine device insertion Various authors have demonstrated that the risk of IUD-related infection is limited to the first few weeks to months after insertion. [bib_ref] Type of intrauterine device and the risk of pelvic inflammatory disease, Lee [/bib_ref] [bib_ref] Intraterine devices and pelvic inflammatory disease: an international perspective, Farley [/bib_ref] It is therefore likely related to contamination of the endometrial cavity at the time of insertion, rather than the IUD or strings themselves. [bib_ref] The intrauterine device: a bacteriologic study of the endometrial cavity, Mishell [/bib_ref] A 1999 Cochrane Review that included 4 randomized control trials found no difference in the occurrence of PID after IUD insertion in patients who were given prophylactic doxycycline or azithromycin and in those given placebo (OR 0.89; 95% CI 0.53 to 1.51). Use of these antibiotics also did not affect whether the IUD was removed within 90 days of insertion (OR 1.05; 95% CI 0.68 to 1.63). [bib_ref] Antibiotic prophylaxis for intrauterine contraceptive device insertion, Grimes [/bib_ref] However, if the patient is considered at high risk for sexually transmitted infections, it would be reasonable to consider screening before IUD placement. ## Recommendation ## 11 . Antibiotic prophylaxis is not recommended for insertion of an intrauterine device. (I-E) However, health care professionals could consider screening for sexually transmitted infections in high-risk populations. (III-C) ## Endometrial biopsy There are no studies that assess the use of prophylactic antibiotics given before an endometrial biopsy procedure, and this is not considered standard of care. ## Recommendation ## 12. There is insufficient evidence to support the use of antibiotic prophylaxis for an endometrial biopsy. (III-L) ## Hysterosalpingography There are many options for preventing infection that may occur as a result of HSG: 1. Universal screening for STIs could be carried out, and patients treated as necessary. 2. Only patients at high risk (determined by history) could be screened. 3. All patients could receive prophylactic antibiotics. 4. Antibiotics could be given to patients at high risk (determined by history and/or as indicated by the presence of tubal obstruction at the time of HSG). Many of the patients may already have had screening performed as part of an infertility work-up. If infection is found, treatment should follow the Canadian Guidelines for STIs.There are no prospective studies that investigate any of these options. A retrospective study found that among 278 women who did not receive antibiotics, the incidence of PID after HSG was 1.4% (4/278), and all 4 patients had dilated tubes; 31 other patients with dilated tubes did not develop infection. A second group of patients (n = 326) received a single dose of oral doxycycline before HSG; no patient (including 56 who had dilated tubes) developed PID. This study suggests that the incidence of PID with normal tubes is very low, regardless of prophylactic antibiotics (0/398) and that the highest-risk group of women with dilated tubes at the time of HSG did benefit from prophylactic doxycycline. 42 ## Recommendation 13. The best method to prevent infection after hysterosalpingography is unknown, Women with dilated tubes found at the time of hysterosalpingography are at highest risk, and prophylactic antibiotics (e.g., doxycycline) should be given. (II-3B) ## Urodynamic studies A systematic review in 2008 included 8 RCTs, with 995 patients, most of whom were women. [bib_ref] Prophylactic antibiotics in urodynamics: a systematic review of effectiveness and safety, Latthe [/bib_ref] The prophylactic antibiotics differed in type, dose, and duration and were compared with either placebo or no treatment. The authors noted that most of the trials had poor methodology. They concluded that there was a 40% reduction in the risk of bacteriuria (OR 0.39; 95% CI 0.24 to 0.61), correlating to a number needed to treat of 13. This study assessed only the occurrence of bacteriuria and not that of symptomatic UTI; therefore, the clinical significance is unknown. It has been estimated that only 8% of women develop a symptomatic UTI within 1 week of a diagnosis of asymptomatic bacteriuria. [bib_ref] A prospective study of asymptomatic bacteriuria in sexually active young women, Hooton [/bib_ref] On the basis of the results of a decision-analysis that incorporated reasonable estimates of benefits and adverse events from the published literature, the authors concluded that prophylactic antibiotics after urodynamics in women at low risk should be administered only when the background rate of UTIs after urodynamics without prophylaxis is higher than 10%. 45 ## Recommendation 14. Antibiotic prophylaxis is not recommended for urodynamic studies in women at low risk, unless the incidence of urinary tract infection posturodynamics is > 10%. (1-E) ## Dosage of antibiotic prophylaxis in obese patients Increased BMI is associated with higher rates of surgical infectious complications. Expert opinion recommends twice the normal dose of prophylaxis for morbidly obese patients (BMI > 35 km/m 2 ). [bib_ref] Antibiotic prophylaxis against postoperative wound infections, Gordon [/bib_ref] However, controlled trials assessing the required dosage for antibiotic prophylaxis based on patient BMI have not been assessed in our specialty, and future research is needed. ## Recommendation ## 15. In patients with morbid obesity (BMI > 35 kg/m 2 ), doubling the antibiotic dose may be considered. (III-B) ## Recommendations for penicillin/ cephalosporin allergy Penicillin allergy is self-reported by up to 10% of patients, yet only 10% of those who report themselves as allergic are 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] Penicillin skin testing in patients with a history of betalactam allergy, Del Real [/bib_ref] [bib_ref] Results of the National Institute of Allergy and Infectious Diseases collaborative clinical..., Sogn [/bib_ref] True anaphylactic response to penicillin is rare, occurring in 1 to 4 per 10 000 administrations. 50 Allergic reaction to a cephalosporin occurs at rates of 0.17% to 8.4% in those with a penicillin allergy. [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 cephalosporins in hospitalized patients with a history of..., Fonacier [/bib_ref] Alternative prophylactic antibiotics for those deemed truly penicillin allergic include clindamycin 600 mg IV and erythromycin 500 mg IV. ## Prevention of infective endocarditis The American Heart Assocation guideline published in 2007 [bib_ref] American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care..., Wilson [/bib_ref] found no evidence that genitourinary procedures cause infectious endocarditis or that administration of antibiotics prevents infectious endocarditis following such procedures. The American Heart Assocation therefore does not recommend prophylactic antibiotics for patients undergoing genitourinary procedures; this is a change from the 1997 American Heart Assocation guideline. The 2007 guideline identifies 4 conditions that are at highest risk of adverse outcome [fig_ref] Table 3: Cardiac conditions associated with the highest risk of adverse outcome from endocarditis... [/fig_ref]. For patients with the conditions listed in [fig_ref] Table 3: Cardiac conditions associated with the highest risk of adverse outcome from endocarditis... [/fig_ref] who have an established gastrointestinal or genitourinary infection, or for those who receive antibiotic therapy for another reason (e.g., to prevent wound infection), it may be reasonable that the antibiotic used also be active against enterococci (ampicillin, piperacillin, or vancomycin). The guidelines also suggest that it may be reasonable for patients at high risk of infectious endocarditis who have a known enterococcal urinary tract infection or colonization to receive antibiotic treatment prior to any urinary tract manipulation. A review of this recommendation change has recently been published. 55 ## Recommendation 16. Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary procedure. (III-E) ## Summary For a number of procedures in gynaecology, the use of prophylactic antibiotics has been shown to reduce infectious morbidity in a safe and cost-effective manner [fig_ref] Table 4: Prophylactic antibiotics recommendations for gynaecologic procedures IV [/fig_ref]. There remain a number of procedures for which the utility of prophylactic antibiotics is either unclear or not studied. Appropriate antibiotics used at the correct dose and time and with the appropriate frequency will reduce infectious postoperative complications and minimize the development of antibiotic resistant organisms. [fig] Recommendations 1: All women undergoing an abdominal or vaginal hysterectomy should receive antibiotic prophylaxis. (I-A) 2. All women undergoing laparoscopic hysterectomy or laparoscopically assisted vaginal hysterectomy should receive prophylactic antibiotics. (III-B) [/fig] [fig] Recommendation 9: All women undergoing an induced (therapeutic) surgical abortion should receive prophylactic antibiotics to reduce the risk of post-abortal infection. (I-A) [/fig] [table] Table 1: The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care .56 †Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care .56 [/table] [table] Table 2: Centers for Disease Control and Prevention surgical wound classification Class I/Clean: An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered . In addition, clean wounds are primarily closed and, if necessary, drained with closed drainage . Operative incisional wounds that follow nonpenetrating (blunt) trauma should be included in this category if they meet the criteria . Class II/Clean-Contaminated: An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination . Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major break in technique is encountered . [/table] [table] 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 . Prevention of Infective Endocarditis: Guidelines From the American Heart Association: A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group . Circulation 2007;116:1736-54 . 54 Used with permission of Wolters Kluwer Health . [/table] [table] Table 4: Prophylactic antibiotics recommendations for gynaecologic procedures IV: intravenous *Considering screening for sexually transmitted infections in high risk populations †Evidence for/against screening unknown ‡Canadian guidelines on sexually transmitted infections-2006 edition 43 §In patients at low risk with a background risk of UTI < 10% after urodynamics [/table]	None	None	None
804d4bd67e51390e1f6c99a8539ae7347a12f7eb	pubmed	Mass Critical Care Surge Response During COVID-19	Mass Critical Care Surge Response During COVID-19 BACKGROUND: After the publication of a 2014 consensus statement regarding mass critical care during public health emergencies, much has been learned about surge responses and the care of overwhelming numbers of patients during the COVID-19 pandemic. Gaps in prior pandemic planning were identified and require modification in the midst of severe ongoing surges throughout the world.RESEARCH QUESTION: A subcommittee from The Task Force for Mass Critical Care (TFMCC) investigated the most recent COVID-19 publications coupled with TFMCC members anecdotal experience in order to formulate operational strategies to optimize contingency level care, and prevent crisis care circumstances associated with increased mortality.STUDY DESIGN AND METHODS: TFMCC adopted a modified version of established rapid guideline methodologies from the World Health Organization and the Guidelines International Network-McMaster Guideline Development Checklist. With a consensus development process incorporating expert opinion to define important questions and extract evidence, the TFMCC developed relevant pandemic surge suggestions in a structured manner, incorporating peer-reviewed literature, "gray" evidence from lay media sources, and anecdotal experiential evidence.RESULTS: Ten suggestions were identified regarding staffing, load-balancing, communication, and technology. Staffing models are suggested with resilience strategies to support critical care staff. ICU surge strategies and strain indicators are suggested to enhance ICU prioritization tactics to maintain contingency level care and to avoid crisis triage, with early transfer strategies to further load-balance care. We suggest that intensivists and hospitalists be engaged with the incident command structure to ensure two-way communication, situational awareness, and the use of technology to support critical care delivery and families of patients in ICUs.INTERPRETATION: A subcommittee from the TFMCC offers interim evidence-informed operational strategies to assist hospitals and communities to plan for and respond to surge capacity demands resulting from COVID-19. CHEST 2022; 161(2):429-447 The COVID-19 pandemic confronted hospitals with unprecedented surges of seriously ill patients. [bib_ref] Hospital preparedness for COVID-19: a practical guide from a critical care perspective, Griffin [/bib_ref] [bib_ref] Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in..., Richardson [/bib_ref] In 2014, the Task Force for Mass Critical Care (TFMCC) developed consensus statement suggestions for the provision of care during pandemics in collaboration with the American College of Chest Physicians. [bib_ref] Introduction and executive summary: care of the critically ill and injured during..., Christian [/bib_ref] The concepts of increasing critical care bed numbers and augmenting staff, equipment, supplies, and describe operational strategies to scale up surge staffing effectively and maintain contingency-level medications ("space, stuff, staff") provided an effective framework for hospitals confronted by COVID-19 [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref]. [bib_ref] Surge capacity principles: care of the critically ill and injured during pandemics..., Hick [/bib_ref] [bib_ref] Surge capacity logistics: care of the critically ill and injured during pandemics..., Einav [/bib_ref] It is disappointing that these were not operationalized to the degree necessary to prevent adverse outcomes. [bib_ref] Association of intensive care unit patient load and demand with mortality rates..., Bravata [/bib_ref] [bib_ref] Intensive care unit strain and mortality risk among critically ill patients with..., Rubinson [/bib_ref] As foreseen, supply chain disruptions led to shortages of key medications, consumables, and personal protective equipment. [bib_ref] A California hospital's response to COVID-19: from a ripple to a tsunami..., Bader [/bib_ref] [bib_ref] It takes a village . . . : contending with drug shortages..., Burry [/bib_ref] Hospital space became a premium as critically ill patients overflowed from full ICUs into postanesthesia care units, EDs, operating rooms, intermediate and monitored units, flat-space areas, and even temporary or tent facilities, with up to 25% of COVID-19 deaths attributable to increased hospital surge caseload. [bib_ref] Hospital preparedness for COVID-19: a practical guide from a critical care perspective, Griffin [/bib_ref] [bib_ref] Association between caseload surge and COVID-19 survival in 558, Kadri [/bib_ref] The prolonged course of COVID-19 has led to contingency conditions becoming the norm for months. More than 3,600 US health care workers (HCWs) have died.Contingency responses refer to increasing hospital resources by repurposing equipment and supplies, augmenting the clinical workforce, and expanding care to nontraditional areas of the hospital while maintaining functionally equivalent standards of care. [bib_ref] Surge capacity principles: care of the critically ill and injured during pandemics..., Hick [/bib_ref] [bib_ref] Surge capacity logistics: care of the critically ill and injured during pandemics..., Einav [/bib_ref] demonstrates the transition from contingency to crisis where contingency level care is not sustainable and care is prioritized or limited, leading to substantial risk of adverse outcomes and potential triage of scarce resources. [bib_ref] Introduction and executive summary: care of the critically ill and injured during..., Christian [/bib_ref] [bib_ref] Triage of scarce critical care resources in COVID-19: an implementation guide for..., Maves [/bib_ref] Notably, no so-called bright line exists between risk levels that separates contingency from crisis, and it is imperative that neighboring hospitals adopt similar strategies. Ten new suggestions are presented in this interim report emphasizing specific operational strategies intended to prolong the contingency state, thereby avoiding crisis and the need for triage of scarce resources. These suggestions are based upon data and experiences from COVID-19 surge mitigation that, when implemented, will maintain contingency-level care and will prevent or delay transition to crisis. # Methods The TFMCC is composed of a interdisciplinary group of disaster professionals including physicians, nurses, pharmacists, respiratory therapists, and health system leaders experienced in the management of critically ill patients with COVID-19. The TFMCC adopted a modified version of established rapid guidelines from the World Health Organization [bib_ref] Developing WHO rapid advice guidelines in the setting of a public health..., Garritty [/bib_ref] and Guidelines International Network-McMaster Guideline Development Checklist 14 with our previous methodology. [bib_ref] Methodology: care of the critically ill and injured during pandemics and disasters:..., Ornelas [/bib_ref] Subcommittee members voted on initial suggestions using a five-point Likert scale, derived from the Grading of Recommendations Assessment, Development and Evaluation grid. [bib_ref] Use of GRADE grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref] [bib_ref] Methodologies for the development of CHEST guidelines and expert panel reports, Lewis [/bib_ref] Three distinct areas of surge preparedness and management related to the COVID-19 pandemic were prioritized and include (1) communication and coordination, (2) staffing and resilience, and (3) communications and technology. See e-Appendix 1 for complete methodology. ## Data extraction The TFMCC members believe it is urgent to distribute the most important and relevant information widely based on preliminary work, generating this interim communication. Each subcommittee conducted a literature review of published evidence relevant to their respective area. Studies published since 2020 were prioritized for inclusion due to direct evidence addressing COVID-19. Key narrative statements deemed relevant were extracted and arranged into overarching themes. The TFMCC members also met weekly to share anecdotal evidence from their own experiences managing COVID-19 surge. The statements extracted from the literature review were combined with the anecdotal evidence for each theme, when applicable, to arrive at initial suggestions for each subcommittee. # Results The TFMCC members identified four issues requiring urgent attention to address future surges including staffing, load-balancing, communications, and technology, resulting in 10 suggestions with corresponding operational strategies [fig_ref] TABLE 1 ]: Summary of 10 Suggestions and Operational Strategies [/fig_ref]. ## Staffing suggestions During the COVID-19 pandemic, patients have died from the lack of staffed ICU beds. [bib_ref] Facing Covid-19 in Italy-ethics, logistics, and therapeutics on the epidemic's front line, Rosenbaum [/bib_ref] Rapid bed expansion must balance staff safety and quality of care, impact on providers, and impact outside of ICUs. [bib_ref] Adult ICU triage during the coronavirus disease 2019 pandemic: who will live..., Sprung [/bib_ref] The risks of repurposing and augmenting staff include (1) lower-quality care without adequate training, [bib_ref] Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in..., Richardson [/bib_ref] excessive duty times and workload, (3) moral injury, (4) the costs of training new staff, and (5) the costs of cancelling time-sensitive but nonemergent care with associated potential adverse consequences. chestjournal.org experienced physician) managing up to 24 patients in collaboration with non-ICU skilled physicians and advanced practice providers (including nurse practitioners, physician assistants, and similar professionals), delivering care to more patients than ICU staff could achieve alone [fig_ref] Figure 3 -: Diagram showing critical care adult physician or provider staffing model for expanding... [/fig_ref]. Further staffing can be expanded by use of specialized procedure teams (eg, for central venous catheterization, intubations, and assistance in care activities such as prone positioning) and telemedicine coverage. The suggested nursing model expands the reach of one ICU-trained nurse to four patients by teaming with two nurses focused on the non-ICU aspects of care after a period of focused training . Both models account for staffing up to 100% above normal baseline patient levels, consistent with previous TFMCC suggestions for the upper limit of contingency care, 4 but can be scaled proportionately to the level of surge. Achieving these ratios requires extensive clinical experience and may need to be modified for those with less training. Pediatric ICUs can effectively care for adult patients with consultative support from adult teams, either in person or via telemedicine, mitigating the loss of time for training new staff in the basics of critical care medicine, while expanding system capacity due to lower pediatric ICU use experienced during the pandemic [fig_ref] Figure 5 -: Diagram showing model for staffing and support of PICUs embedded in facilities... [/fig_ref]. [bib_ref] Changes in pediatric ICU utilization and clinical trends during the coronavirus pandemic, Zee-Cheng [/bib_ref] [bib_ref] Critical care for coronavirus disease 2019: perspectives from the PICU to the..., Joyce [/bib_ref] [bib_ref] A hybrid model of pediatric and adult critical care during the coronavirus..., Deep [/bib_ref] Suggestion 2: We suggest limiting overtime to less than 50% above normal for all HCWs to minimize the risk of burn-out and exhaustion. There are limits to how long a clinical team can remain effective in the setting of increased workloads. Experience with deployed military surgical teams found them to be ineffective after 48 continuous hours. [bib_ref] The impact of sleep deprivation in military surgical teams: a systematic review, Parker [/bib_ref] Team effectiveness may be preserved by limiting shift durations to 12 h, mandating rest periods every 24 h, naps, "sleep banking," and consistent schedules to prevent circadian desynchronization. [bib_ref] The impact of sleep deprivation in military surgical teams: a systematic review, Parker [/bib_ref] Staffing plans must also account for surges of weeks to months. Limiting overtime should be an operational strategy to minimize the risk of burnout. Suggestion 3: We suggest that the mental health needs of all HCWs are priorities for maintaining an effective response and staffing capacity. HCWs are secondary victims of the COVID-19 pandemic. [bib_ref] Stress and fear: clinical implications for providers and patients (in the time..., Karnatovskaia [/bib_ref] -Diagram depicting the spectrum of surge from minor through major. The magnitude of surge is illustrated by the alterations in the balance between demand (stick figures) and supply (medication boxes). As surge increases, the demand-supply imbalance worsens. Conventional, contingency, and crisis responses are used to respond to the varying magnitude of surge. Varying response strategies are associated with each level of response. As the magnitude of the surge increases, the strategies used to cope with the response gradually depart from the usual standard of care (default defining the standards of disaster care) until such point that even with crisis care, critical care is no longer able to be provided. (Reprinted with permission from Christian et al. [bib_ref] Introduction and executive summary: care of the critically ill and injured during..., Christian [/bib_ref] burnout (28%), depression (24%), posttraumatic stress disorder (13%), [bib_ref] Impact of viral epidemic outbreaks on mental health of healthcare workers: a..., Serrano-Ripoll [/bib_ref] and suicide. [bib_ref] COVID-19 related suicide among hospital nurses; case study evidence from worldwide media..., Rahman [/bib_ref] Identification of factors that place HCWs at risk of moral injury or exhaustion [fig_ref] TABLE 2 ]: Risk Factors for Health Care Workers Expe-Inadequate access to personal protective equipment... [/fig_ref] should be a central operational priority, with a focus on prevention by leadership, managing expectations, and proactive guidance for changes to clinical care. [bib_ref] Impact of viral epidemic outbreaks on mental health of healthcare workers: a..., Serrano-Ripoll [/bib_ref] [bib_ref] Symptoms of anxiety, depression, and peritraumatic dissociation in critical care clinicians managing..., Azoulay [/bib_ref] [bib_ref] Burnout and psychological distress amongst Australian healthcare workers during the COVID-19 pandemic, Dobson [/bib_ref] [bib_ref] Psychological impact of an epidemic/pandemic on the mental health of healthcare professionals:..., Stuijfzand [/bib_ref] [bib_ref] The relationship between psychological resilience, burnout, stress, and sociodemographic factors with depression..., Yoruk [/bib_ref] [bib_ref] Occupational burnout syndrome and post-traumatic stress among healthcare professionals during the novel..., Raudenska [/bib_ref] Globally, the health care workforce is composed predominantly of women in diverse roles, including critical custodial, food service, laboratory, and Load-balancing 7. We suggest that early transfer of patients before a hospital is overwhelmed promotes the effective conservation of resources and less deviation from routine care standards. Transfer (load-balance) patients early before a hospital is overwhelmed to maintain contingency-level care. Load-balancing 8. We suggest earlier utilization of regional transfer centers for load-balancing during surge for patient transfers and placement. We also suggest having intensivist or hospitalist availability to help prioritize transfers and provide support to bedside clinicians when transfers are delayed. Implement regional transfer centers to improve bed access and assure efficient ICU bed use through active management and load-balancing of admissions across all hospitals in a state or region. On-call intensivist or hospitalist support should be available as a resource. Load-balancing 9. We re-emphasize that designated clinicians who are actively engaged in clinical work (especially intensivists and hospitalists) actively participate in hospital incident command structure; this group should provide updates to clinical staff for improving situational awareness, ensuring bidirectional communication. Establish formal communication structures between incident command and frontline clinicians, such as PCSS or PCCS team to ensure bidirectional communication and situational awareness. Communication 10. We suggest hospitals apply telemedicine technology to augment critical care early and in the broadest sense possible. Use telemedicine technology to support bedside critical care, to connect specialty clinicians to distant sites, and to support visitation needs of families. Technology HCW ¼ health care worker; PCSS ¼ physician clinical support supervisor. chestjournal.org radiographic technicians and direct patient care by nurses, advanced practice providers, and physicians. Of nurses in the United States, 87.4% are women who may find themselves bearing a disproportionate amount of the stresses of both workplace and home during the pandemic.A survey of > 12,000 US nurses reported that workplace strategies that best promoted well-being during the pandemic included talking with colleagues (47%), expressions of gratitude (37%), and accurate information about the virus (34%) [bib_ref] The relationship between critical care work environment and professional quality of life, Monroe [/bib_ref] ; only 5% identified employee assistance programs or formal counseling as helpful.The Healthy Work Environment Standards [fig_ref] TABLE 3 ]: Resilience Letters or cards from community members and local school children show... [/fig_ref]. [bib_ref] The relationship between critical care work environment and professional quality of life, Monroe [/bib_ref] Concerns such as childcare, reduced family contact, significant change in daily life, and work-life balance place individuals at high risk for burnout. [bib_ref] Impact of viral epidemic outbreaks on mental health of healthcare workers: a..., Serrano-Ripoll [/bib_ref] [bib_ref] Symptoms of anxiety, depression, and peritraumatic dissociation in critical care clinicians managing..., Azoulay [/bib_ref] [bib_ref] Burnout and psychological distress amongst Australian healthcare workers during the COVID-19 pandemic, Dobson [/bib_ref] [bib_ref] Psychological impact of an epidemic/pandemic on the mental health of healthcare professionals:..., Stuijfzand [/bib_ref] [bib_ref] The relationship between psychological resilience, burnout, stress, and sociodemographic factors with depression..., Yoruk [/bib_ref] [bib_ref] Occupational burnout syndrome and post-traumatic stress among healthcare professionals during the novel..., Raudenska [/bib_ref] Suggestion 4: During surge, we suggest minimizing redundant clinical documentation requirements to focus on core elements directly relevant to bedside care. The TFMCC believes it is an effective operational strategy to reduce documentation requirements to maximize staff time for bedside care during public health emergencies. Clinician documentation should focus mainly on critical care provided and limitations due to resource challenges and should address issues (3) the presence of telemedicine support. Higher acuity patients (as is typical with patients with COVID-19 in the ICU) may impact capacity negatively by demanding greater resources to maintain contingency-level care. Other clinician team members may include non-ICU skilled physicians and ICU or non-ICU skilled practitioners, or both; training institutions trainees (residents and fellows) also may be team members. Finally, this model is focused on resources for direct patient care only, and sufficient resource needs for overnight staffing and cross-coverage also should be factored and scaled up appropriately with increasing surge. related to diagnoses for billing; templated notes and dictation services are supportive. Nursing documentation changes may include exemptions from repetition of documented care plans or extended time windows for signatures on telephone orders.Streamlining facility-specific documentation and focused patient assessments may further assist in decreasing documentation requirements. Authorities should provide general approvals for streamlined documentation during a public health emergency to help facilities avoid the burden of requesting individual waivers. ## Load-balancing and patient transfers Load-balancing is the process of coordinating emergency response by sharing resources, transferring patients amongst hospitals, or both. [bib_ref] Changes in pediatric ICU utilization and clinical trends during the coronavirus pandemic, Zee-Cheng [/bib_ref] [bib_ref] Critical care for coronavirus disease 2019: perspectives from the PICU to the..., Joyce [/bib_ref] [bib_ref] A hybrid model of pediatric and adult critical care during the coronavirus..., Deep [/bib_ref] Adult RNs, pharmacists, and physicians can provide brief daily and as-needed in-person or teleconsultation for pediatric ICUs of varying sizes providing care for critically ill adults starting with younger patients with less comorbidities, but with upper age of 70 years or older as needed to meet increasing demands. This model is supported most easily in facilities that also routinely care for adults because of existing logistic ("stuff") and system capabilities. PICU ¼ pediatric ICU; RN ¼ registered nurse. chestjournal.org hospital mortality increasing when bed capacity was exceeded. [bib_ref] Association of intensive care unit patient load and demand with mortality rates..., Bravata [/bib_ref] [bib_ref] Intensive care unit strain and mortality risk among critically ill patients with..., Rubinson [/bib_ref] [bib_ref] Broadening the scope of healthcare operations: expanding capacity strain hospital-wide, Kohn [/bib_ref] [bib_ref] Higher ICU capacity strain is associated with increased acute mortality in closed..., Wilcox [/bib_ref] Effective load-balancing first involves knowledgeable ICU strain monitoring and mindful resource management by frontline clinical leaders. It next involves the organized transfer of patients from overburdened to lesser burdened hospitals facilitating a balance, so that no single institution enters crisis and that consistent level of care is provided within and across regions. Patient transfers within a single health care network are helpful, but insufficient. Regional mechanisms to share information and load-balance across facilities may be the most important factor in mitigating crisis care situations.Suggestion 5: We suggest that resource strain level be actively monitored and determined by frontline clinical leaders based upon assessment of available resources and conditions. ICU strain is defined as a discordance between demand for and availability of ICU resources and is assessed with objective criteria. [bib_ref] Hospital preparedness for mass critical care during SARS-CoV-2 pandemic, Wurmb [/bib_ref] [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] [fig_ref] TABLE 4 ]: Strain Indicator Limits Defining Conventional, Contingency, and Crisis Levels of Resources Typically... [/fig_ref] suggests ICU strain indicators that are resources ICU clinicians and leaders assess during routine ICU management and include staffed ICU beds, patient acuity, queuing time to admission, available equipment, supplies, and ICU staff. [bib_ref] Hospital preparedness for COVID-19: a practical guide from a critical care perspective, Griffin [/bib_ref] [bib_ref] Surge capacity principles: care of the critically ill and injured during pandemics..., Hick [/bib_ref] [bib_ref] Surge capacity logistics: care of the critically ill and injured during pandemics..., Einav [/bib_ref] [bib_ref] Refining surge capacity: conventional, contingency, and crisis capacity, Hick [/bib_ref] [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] Strain is defined further based on conventional, contingency, and crisis care surge levels. The TFMCC suggests the criteria for crossing from conventional to contingency threshold be when two or more conventional strain criteria are exceeded and the criteria for crossing form contingency to crisis be when any crisis strain criterion is met [fig_ref] TABLE 4 ]: Strain Indicator Limits Defining Conventional, Contingency, and Crisis Levels of Resources Typically... [/fig_ref]. We suggest strain indicators be updated continuously and available in an electronic database. As an operational strategy, the TFMCC suggests bedside clinician leaders, including ICU directors and service chiefs, be empowered to determine ICU surge level (especially contingency and crisis) based on their real-time assessment and in conjunction with strain indicators [fig_ref] Figure 7 -: Diagram showing an example of a nine-hospital system illustrating daily levels of... [/fig_ref]. Hospital and system leadership may sustain contingency-level care by expanding ICU care areas, supplementing staff, and distributing equipment, transferring patients to load-balance, or a combination thereof. ## Suggestion 6: We suggest there is a transition zone toward the limits of contingency care when increasingly scarce resources are modified beyond routine standards of care to preserve life. This critical clinical prioritization level precedes triage of scarce resources and is a powerful indicator for needed resources to maintain contingency-level care. 54 (Case study [fig_ref] Figure 8 -: Case study of CCP [/fig_ref] Although guidance exists for formal triage, clinicians may encounter situations of severe strain that fall short of this need, where clinical judgement is needed to determine optimal use of available resources. [bib_ref] Triage of scarce critical care resources in COVID-19: an implementation guide for..., Maves [/bib_ref] [bib_ref] Triage: care of the critically ill and injured during pandemics and disasters:..., Christian [/bib_ref] [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] The use of advanced therapies is not strictly binary; resources may be shared in some cases. Continual renal replacement therapy systems can be shared by two or more patients on 6-to 12-h alternating schedules; the choice of ventilator for a given patient can be based on the severity of lung disease; and patients with severe hypoxemia often may be managed with noninvasive respiratory support in an intermediate or ward setting instead of the ICU. These strategies are a form of resource conservation, but border on crisis care and are termed critical clinical prioritization (CCP) ; a case study is illustrative [fig_ref] Figure 8 -: Case study of CCP [/fig_ref].Clinicians should recognize CCP when they are on the verge of transitioning from contingency to crisis and should alert leadership and request urgent support, including more resources (if available) or patient transfers (load-balance) to less-strained facilities. If neither of these are available, health systems are left resorting to triage and allocation processes dynamically based on available resources. Ideally, these strategies should be consistent across a region's hospitals. Operational strategies include educating clinicians in advance to recognize and respond to CCP, preparing decision support for potential crisis scenarios, and prioritizing communication systems for rapid access to ethical, legal, and administrative counsel when the potential need for triage of scarce resources is encountered. Suggestion 7: We suggest that early transfer of patients before a hospital is overwhelmed promotes the effective conservation of resources and less deviation from routine care standards. The mortality of patients rises as pandemic surge increases. Early transfer of patients is an operational strategy to help mitigate proactively the effects of surge and to prevent crisis care conditions. 10,67 Patients awaiting ICU admission have an increased mortality with longer-duration queuing times, and patients in the ED are at great risk [fig_ref] TABLE 5 ]: Risk for Patients Waiting for ICU Admission vs the Risks of Transfer,... [/fig_ref]. [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] [bib_ref] Interhospital transfer: an independent risk factor for mortality in the surgical intensive..., Arthur [/bib_ref] [bib_ref] Patient safety incidents during interhospital transport of patients: a prospective analysis, Lyphout [/bib_ref] [bib_ref] The interhospital medical intensive care unit transfer instrument facilitates early implementation of..., Malpass [/bib_ref] Strategies to mitigate risks during transfer include assuring respiratory and hemodynamic stability and transferring patients with minimal organ failure and at shorter times and distances as possible [fig_ref] TABLE 5 ]: Risk for Patients Waiting for ICU Admission vs the Risks of Transfer,... [/fig_ref]. [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] [bib_ref] Interhospital transfer: an independent risk factor for mortality in the surgical intensive..., Arthur [/bib_ref] [bib_ref] Patient safety incidents during interhospital transport of patients: a prospective analysis, Lyphout [/bib_ref] [bib_ref] The interhospital medical intensive care unit transfer instrument facilitates early implementation of..., Malpass [/bib_ref] We suggest patient transfer be considered when hospitals reach the threshold for contingency care surge level (suggestion 5). Despite transfer risks, load-balancing before a site becomes overwhelmed, including the transfer of convalescent patients to less-acute settings, promotes effective conservation of resources before reaching the limits of contingency care. [bib_ref] Association of intensive care unit patient load and demand with mortality rates..., Bravata [/bib_ref] ## Meaningful recognition Be recognized and recognize others for the value each brings to the work of the organization ## Authentic leadership Fully embrace the imperative of a healthy work environment, authentically live it, and engage others in its achievement. ## Skilled communication Be as proficient in communication skills as you are in clinical skills ## Healthy work environment Resilience Well-Being Suggestion 8: We suggest earlier utilization of regional transfer centers for load-balancing during surge for patient transfers and placement. We also suggest having intensivist or hospitalist availability to help prioritize transfers and provide support to bedside clinicians when transfers are delayed.In the TFMCC 2014 guidance, evacuation of hospitals for surge mitigation was highlighted [bib_ref] Evacuation of the ICU: care of the critically ill and injured during..., King [/bib_ref] ; however, hospitals have been challenged by management of patient transfers during prolonged surges. The COVID-19 pandemic demonstrated increasing mortality associated with increasing surge, 6,10 and load-balancing through large-volume patient transfer centers has been proven both practical and effective. [bib_ref] In Imperial County, medical air teams work around the clock to move..., Vives [/bib_ref] Health systems have developed their own regional placement centers designed to improve access and patient flow through active management techniques. [bib_ref] Use of systems engineering to design a hospital command center, Kane [/bib_ref] [bib_ref] Use of high-reliability principles in the evolution of a hospital command centre, Collins [/bib_ref] Several states rapidly developed pandemic placement centers to transfer patients to any available ICU bed, optimizing statewide access and preventing hospitals from reaching crisis conditions. [bib_ref] Statewide real-time tracking of beds and ventilators during coronavirus disease 2019 and..., Merkel [/bib_ref] The operational strategy of having a command center is to improve Appropriate staffing Ensure sufficient rest between work periods Team staffing with clear delegation of responsibilities Team huddles at shift change and prescribed intervals Identify team leads with strong clinical skills, knowledge of organizational policy, and strong interpersonal skillsEffective decision-making Engage team members in discussion of policies and procedures that impact them True collaboration Use just-in-time strategies for supporting the interdisciplinary team: Using "the pause" after a patient death: pausing for a moment of silence after resuscitation attempt or the expected death of a patient allows team members to reflect and honor the patient, providing a transition before returning to patient care After-shift huddles to review the events of the day, including challenges and wins PPE ¼ personal protective equipment. The transition from conventional to contingency strain is triggered when any two conventional strain indicators are exceeded (any "no" answer in the conventional strain criteria column should be considered to have exceeded that strain criteria's conventional limit). The transition from contingency to crisis strain is triggered when any crisis strain criteria is met. CRRT ¼ continual renal replacement therapy; HD ¼ hemodialysis; HFNC ¼ high flow nasal cannula; NIV ¼ noninvasive ventilation; RN ¼ registered nurse. chestjournal.org access and assure efficient use of beds through active management and load-balancing of admissions across all hospitals to reduce ED boarding and diversion and to prevent extended waiting times for admission. [bib_ref] The positive impact of establishing an internal transfer center, Simmons [/bib_ref] The key elements of success include a call center with appropriate technology and personnel, participation of large health systems with transfer capacity, and agreements by participants to support the transfer center's processes with clear lines of communication between call center directors and state or health system leaders to resolve barriers rapidly [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref]. We also strongly suggest having intensivist or hospitalist assistance to help prioritize transfers and to provide assistance to bedside clinicians. Best practices are under development. Technology from cell phones and paper intake forms should transition to secure electronic forms and telephone platforms. Oregon, [bib_ref] Statewide real-time tracking of beds and ventilators during coronavirus disease 2019 and..., Merkel [/bib_ref] Arizona,and Minnesota 59 use tools including electronic bed boards to report bed availability and calls requesting transfers. The most important success element was frequently updated electronic bed capacity data (even when hand-entered), although collaboration and teamwork among call center, state, and health care organizations is as important. [bib_ref] Statewide real-time tracking of beds and ventilators during coronavirus disease 2019 and..., Merkel [/bib_ref] Communications During Surge Suggestion 9: We re-emphasize that designated clinicians who are actively engaged in clinical work (especially intensivists and hospitalists) actively participate in hospital incident command structure; this group should provide updates to clinical staff for improving situational awareness, ensuring bidirectional communication. As stated in 2014, tight coordination of resource management is a cornerstone of effective hospital incident command systems. [bib_ref] Surge capacity principles: care of the critically ill and injured during pandemics..., Hick [/bib_ref] decision-maker with authority to act quickly, the actions occurring in incident command often are opaque to HCWs tasked with their orders. It is strongly suggested as an operational strategy that formal communication structures be established to ensure bidirectional communication to update clinicians and provide ## Critical clinical prioritization: a case study from nych+h/bellevue hospital The traditional model of supply: demand mismatch describes a progression from conventional to contingency to crisis care, with each transition representing care that deviates further from standard. Several authors (AU, VM, TH) experienced that the transition from contingency to crisis care can potentially be deferred, or fully prevented, through creative and novel methods managing resources. Resource management at this transition was primarily based on clinical decisions for how best to use available resources to sustain the entire population of patients requiring them and is distinct from crisis triage of scarce resources. We term this decision-making at the transition between contingency and crisis care Critical Clinical Prioritization (CCP). To illustrate how CCP was utilized during the surge of critically ill COVID cases, we have provided real-life examples of strategies implemented by the authors. Renal replacement: The high demand for continuous renal replacement therapy (CRRT) overwhelmed the capacity to deliver it in the standard way in many hospitals. A transition to crisis standards would mean choosing individual patients who would receive this therapy continuously over 24 hours while others would be denied. Instead, this standard approach was adjusted based on patient need with intervals adjusted down to 12 or even 6 hours per patient to facilitate rotation of a small number of machines amongst a larger patient pool to provide life sustaining care to all of them. When the limits of this strategy were reached, an emergency peritoneal dialysis (PD) program, which primarily takes place outpatient, was initiated for appropriate patients to further expand the breadth of renal replacement therapies offered inpatient. Mechanical ventilators: When the demand for mechanical ventilation overwhelmed ventilator capacity, a transition to crisis standards would have meant determining which patients would or would not be candidates for a ventilator via committee-based resource triage. Instead, to maximize ventilator allocation, standard ICU ventilators were triaged to the most severe patients while ventilators not typically used for critically ill patients (such as transport, anesthesia, home/portable, and non-invasive ventilators retrofitted to provide invasive mechanical ventilation) were triaged to patients less severely ill. As severely ill patients improved, they were transitioned to the atypical ventilators as appropriate for their needs, making standard ICU ventilators available. ## Space: The demand for ICU care overwhelmed the supply of primary and secondary ICU spaces. Instead of denying ICU care to patients, methods to maximize utilization of space were implemented from retrofitting non-ICU spaces to accommodate critical patients to placing two patients into rooms intended for one, while taking steps to mitigate the risks of doing this. Additionally, if available ICU bed space was identified in other regional hospitals, patients were transferred to load balance between hospitals. ## Staff: The peak of the pandemic pushed ICU staff to their limits with increased patient loads and extended work hours. To prevent a staffing crisis, tasks were offloaded to other non-ICU disciplines. Examples included integrating non-ICU personnel into ICU teams, senior critical care fellows assuming the role of attending physicians, anesthesia and general surgery teams managing procedures from airways to central and arterial line placement, orthopedic surgeons and operating room staff leading prone positioning teams, and ophthalmologists running PD teams. Other strategies included relaxing non-critical documentation requirements for all clinical staff. -Diagram showing critical clinical prioritization. As resource strain approaches crisis levels, ICU clinicians may need to adapt, substitute, conserve, or even initiate rationing of resources. [bib_ref] Refining surge capacity: conventional, contingency, and crisis capacity, Hick [/bib_ref] This transition zone immediately preceding crisis level is termed critical clinical prioritization and is illustrated on the lower panel, "Basis of Clinical Management." [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref] -Diagram showing regional and statewide patient placement centers. Transfer centers interface with all hospital and health systems in a region or state and typically may be engaged after routine referral sources are no longer accepting transfers. Their role is to facilitate patient transfers quickly to an appropriate hospital setting including ICU and medical or surgical beds, while efficiently and effectively using capacity at both larger and smaller hospitals. The ability to pay should never be a criterion regarding transfer, and transfer centers should have policy authority to rotate transfers if required. Transfer distances may require a combination of ground and air transport. Intensivists and hospitalists may help to prioritize transfers based on both the type of (specialized) care needed and urgency of transfer, and they may be able to provide clinical advice to onsite clinicians whose patients may not be able to be transferred immediately. suggests respected clinical leaders are likely most effective. Town hall-type meetings, tiered huddles, and structured e-mails are other important communication vehicles [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref]. ## Technological issues and solutions during surge management Suggestion 10: We suggest hospitals apply telemedicine technology to augment critical care early and in the broadest sense possible. Telemedicine was used to augment surge capacity and to provide family access for communication with hospitalized patients using straightforward and inexpensive technology including computers, electronic tablets, and conferencing software. Health care organizations used this technology to connect intensivists and specialists to distant rural sites and potentially to tele-triage. [bib_ref] Collaboration between tele-ICU programs has the potential to rapidly increase the availability..., Chandra [/bib_ref] [bib_ref] Rapid implementation of telecritical care support during a pandemic: lessons learned during..., Krouss [/bib_ref] Outpatient strategies include monitoring at-risk but stable patients remotely, home care for stable patients (hospital-at-home programs), and outpatient care [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref] , [bib_ref] Hospital surge capacity in a tertiary emergency referral centre during the COVID-19..., Carenzo [/bib_ref] Telemedicine and tele-ICU technology with portable applications can augment both the delivery of clinical expertise to virtually any hospital bedside in support of ICU care and specialty consultation support and can provide families virtually unlimited audiovisual access to their loved ones who are hospitalized patients (right side of diagram). This technology also functions by helping decompress hospital surge by outpatient care reach support for patients at home and preventing disease exposure from unnecessary office visits (left side of diagram). chestjournal.org ones to care and provide decision-making goals, [bib_ref] Paved with good intentions: hospital visitation restrictions in the age of coronavirus..., Andrist [/bib_ref] [bib_ref] Association between visitation restriction during the COVID-19 pandemic and delirium incidence among..., Kandori [/bib_ref] and telemedicine was used to support the needs of families and patients. Operational strategies to facilitate family presence in the ICU includes video conferencing and conventional telephones with regular inclusion of multidisciplinary team members such as psychiatrists, palliative care specialists, social workers, and chaplains. Visitation policies also should include on-site strategies for families with limited access to technology Discussion Before the COVID-19 pandemic, mass critical care guidelines were tested infrequently under contingency or crisis conditions, and thus were underappreciated by planners. The impact of a prolonged public health emergency, leading to a state of chronic contingency care that would fluctuate unpredictably [fig_ref] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the... [/fig_ref] , [bib_ref] Triage of scarce critical care resources in COVID-19: an implementation guide for..., Maves [/bib_ref] has resulted in significant workforce stress. With increasing surge, mortality rises-sometimes dramatically-and it is likely many of our health care systems endured a chronic state of crisis conditions. 2,6,10 ICU clinicians recognized a highly dynamic zone of contingency care and intuitively developed ingenious strategies to identify and extend these boundaries, and the TFMCC focused on greater understanding of this contingency zone. Sustaining a large operational workforce was a top priority. The three staffing strategies incorporate critical care-trained clinicians working with other professionals, combining skill sets and procedure teams and leveraging telemedicine ICU support and adult care in pediatric ICUs in needed proportions to sustain contingency-level care. They are adaptable and expandable based on surge levels. Also essential is supporting HCW resilience over months, including a reasonable ceiling of work hours, responsibly limiting required documentation, and addressing HCW's mental health needs through effective communication, adapting quickly to surge demands and promoting a healthy work environment (Tables 2, 3, [fig_ref] Figure 6 -: Diagram showing the American Association of Critical Care Nurses Healthy Work Environment... [/fig_ref]. Effectively managing surge resources and load-balancing is another priority. ICU pandemic strain was experienced poignantly by ICU clinician leaders, and their understanding of staff, bed, and supply resources in absolute amounts and imminent availability impacts the degree to which resources may be stretched to responsible limits during periods of CCP. The TFMCC strongly suggests clinical leadership be empowered to determine surge level and priorities, with the suggested communication strategies (suggestion 9) pivotal in keeping clinicians and administrative leaders aligned. ICU strain indicators [fig_ref] TABLE 4 ]: Strain Indicator Limits Defining Conventional, Contingency, and Crisis Levels of Resources Typically... [/fig_ref] are suggested as adjuncts for clinician leader assessment in determining surge levels and priorities, are useful under routine conditions, and can be acquired electronically for ongoing use and predictive analysis. At present, ICU queuing time may be the most powerful strain indicator, given its strong correlation with mortality [fig_ref] TABLE 5 ]: Risk for Patients Waiting for ICU Admission vs the Risks of Transfer,... [/fig_ref] , [bib_ref] Intensive care role in disaster management critical care clinics, Hossain [/bib_ref] and among the most compelling reasons for early load-balancing to prevent overcrowding and crisis care during times of severe surge. [bib_ref] Association of intensive care unit patient load and demand with mortality rates..., Bravata [/bib_ref] [bib_ref] Association between caseload surge and COVID-19 survival in 558, Kadri [/bib_ref] Finally, transfer hubs proved an instrumental strategy in load-balancing hospitals at or near crisis to those with remaining capacity and a powerful process for maintaining contingency level care across regions and states, ranging from statewide support for individual centers to massive regional off-loading of specific sites. [bib_ref] In Imperial County, medical air teams work around the clock to move..., Vives [/bib_ref] Successful transfer centers demand relatively unsophisticated technology and software, but as a top priority require regional and statewide commitment, coordination, and above all teamwork among health care systems, professional associations, and health departments. [fig] Figure 1 -: Diagram showing a framework for critical care surge capacity planning outlining the conventional, contingency, and crisis surge responses. PACU ¼ post-anesthesia care unit. (Reprinted with permission from Christian et al. 3 ) [/fig] [fig] Team: Composition, additional required personnel to care for increasing increments of patients ICU experienced physician (ICU-EP)Advanced practice providers, non-ICU trained clinicians, and other clinicians [/fig] [fig] Figure 3 -: Diagram showing critical care adult physician or provider staffing model for expanding surge coverage.[22][23][24][25][26][27][28][29] This model assumes all ICU care teams have at least one intensivist or other skilled ICU physician (red circle-and-diamond figures) to surge while maintaining contingency level care. An intensivist or skilled ICU physician may manage up to 12 patients in a 12-h shift when providing only direct hands-on care, and up to 24 patients when combining hands-on care with support and collaboration for up to four other clinician team members (blue circle-and-diamond figures). The factors that effectively increase an ICU team's capacity to expand coverage while maintaining contingency level care include (banners at the top of graph): (1) team members with more ICU experience, (2) the presence of procedure teams (for placing invasive lines or other procedures, for intubations, for other care such as prone positioning), and [/fig] [fig] Figure 5 -: Diagram showing model for staffing and support of PICUs embedded in facilities that routinely care for adult patients to support adult surge. [/fig] [fig] Figure 6 -: Diagram showing the American Association of Critical Care Nurses Healthy Work Environment Standards.46 The six standards have been shown to correlate with burnout among critical care nurses. The Healthy Work Environment Standards have been demonstrated to apply to the interdisciplinary team and to noncritical care areas. Authentic leadership and meaningful recognition are shown to correlate most strongly with compassion satisfaction, which counteracts compassion fatigue and enhances professional quality of life.46 chestjournal.org numbers of sicker patients quickly when crisis conditions do occur.72 [/fig] [fig] Figure 7 -: Diagram showing an example of a nine-hospital system illustrating daily levels of strain during a severe pandemic surge. Using clinical leaders' assessment and strain criteria each of nine hospitals (left margin, top frame) assesses their daily level of ICU surge for the first 10 days (shown across the top); the levels of daily strain are illustrated in the colored legend below. For health system leadership, the ebb and flow of daily level of strain for each hospital helps to determine where hospital resources need to be directed, where resources are available to transfer patients, or both. PACU ¼ post-anesthesia care unit. [/fig] [fig] Figure 8 -: Case study of CCP. CCP ¼ critical clinical prioritization. [/fig] [fig] Figure 11 -: Diagram showing the role of the PCSS. PCSS ¼ physician clinical support supervisor. [/fig] [fig] Figure 12 -: Diagram showing telemedicine and tele-ICU technology. [/fig] [fig] Figure 13 -: Diagram showing the impact of triage in crisis surge response to balance demand and capacity, demonstrating different levels of triage depending on the degree of demand in relationship to system capacity. LTC ¼ long-term care. (Reprinted with permission from Maves et al.12 ) [/fig] [table] TABLE 1 ]: Summary of 10 Suggestions and Operational Strategies [/table] [table] TABLE 2 ]: Risk Factors for Health Care Workers Expe-Inadequate access to personal protective equipment or essential supplies High perception of personal risk for infection Fear of being infected Fear of spreading the illness to family and friends Inability to care for one's family [/table] [table] TABLE 3 ]: Resilience Letters or cards from community members and local school children show gratitude from the public; family and community support was a significant factor in nurse well-being during the COVID-19 pandemic as surveyed by the American Nurses Foundation 47 [/table] [table] TABLE 4 ]: Strain Indicator Limits Defining Conventional, Contingency, and Crisis Levels of Resources Typically Encountered During the COVID-19 [/table] [table] TABLE 5 ]: Risk for Patients Waiting for ICU Admission vs the Risks of Transfer, and Strategies to Help Mitigate [/table]	None	http://journal.chestnet.org/article/S0012369221038459/pdf	None
16edf9b12be25f9dc6ff20b7c40886bcf1f38298	pubmed	Lessons from the past: pathways to the future	Lessons from the past: pathways to the future # Introduction A famous American surgeon, A. Bruce Gill, once said "Study principles, not methods. A mind that understands principles can devise its own methods." Here I discuss 10 basic principles in the fi eld of spinal deformity treatment that have strong messages from the past and apply equally to the future. ## Principle 1: progressive curves must be stopped by bracing or surgery -there is no excuse for procrastination That spinal curves must be stopped from progressing by bracing or surgery is a very old principle, and we should not even have to mention it in this era, but the problem still exists. Sometimes the problem lies with the general practitioner who does not understand the seriousness of a child with a unilateral unsegmented bar and fails to refer the child promptly to a spine specialist. Only when the curve has progressed severely does the referral come, and then it is too late. This is a problem of educating our medical colleagues. Sometimes the problem is with the spine surgeon who either fails to recognize the serious nature of the problem or fails to measure the fi lms carefully to detect the progression. Sometimes there is simply a reluctance to operate on a 1-year-old child for fear of "stunting the child's growth." Letting a curve progress severely gives far more torso shortening than would early fusion. ## Principle 2: just because it is new does not mean it is good We as medical practitioners have a tendency to jump onto a new treatment idea without giving it adequate thought and especially without looking at it using a true scientifi c approach. This is not as bad a problem as it used to be, but it still exists. The main reason seems to be a reverence for our mentors and teachers. By this I mean that when a distinguished member of our profession states, "I've been using this treatment for some time and it is really good" we accept it blindly and do not test it scientifi cally before using it on our patients. An excellent example is the historical enthusiasm for exercises in the treatment of scoliosis. Exercises were promoted for hundreds of years by "learned" professors but in reality have been proven useless. We are now seeing a resurgence of interest in exercise therapy but again without any scientifi c proof whatsoever. The list of treatments that we have "jumped on" without good evidence is quite long, so I mention only a few. Electrical stimulation of the paraspinal muscles was a hot topic during the early 1990s but proved to be useless. The Halo-pelvic device, fi rst introduced in Hong Kong in 1963 and later in Chicago, was used on hundreds of patients but was a disaster with little benefi t and many complications. Gruca springs were proven useless. The Wenger device (New York, 1961) was equally useless and even more dangerous. Cotrel traction for 2 weeks prior to surgery sounded good but turned out to be useless (preoperative traction for curves is discussed in more detail later). Stapling of the convexity was tried and abandoned during the 1950s but has emerged once again. 1 Principle 3: There is more than one way to correct a scoliosis, and it is the wise surgeon who knows when to use each approach If we can look at a lateral curvature of the spine as an engineer and not be prejudiced by the latest fad of instrumentation, we can see that several corrective mechanisms are available. The fi rst is simple concave distraction. A Harrington distraction rod best illustrates this in the concavity of the curve. Another mechanism is simple convex compression. This is best illustrated by a purely compressive implant for a Scheuermann's kyphosis. Back in the "old" days of cast correction, we used the Risser localizer cast, which used longitudinal distraction, coupled with a convex localizer force, a translation force. This method was introduced during the early 1950s but was done in exactly the same way by Wullstein in Germany during the 1880s. Harrington frequently combined a concave distraction rod with a convex compression rod, using two different forces to achieve correction plus stabilization. The convex compression rod was a form of segmental fi xation. Luque introduced a whole new concept -that of cantilever correction when applied to the convexity of a curve. There was no distraction and no compression. A Luque rod in the concavity corrected the deformity by translation, the wires pulling the apex of the curve to the midline. Cotrel and Dubousset, during the early 1980s, introduced us to correction by rod rotation. This was originally conceived as a "derotation" maneuver but in reality was translation of the apex of the curve toward the midline and out of lordosis by rod rotation. Thus, translation was emphasized rather than distraction. In summary, we can correct by pure distraction, pure compression, cantilever force, pure translation, and various combinations of the above. The introduction of thoracic pedicle screws has added a fi nal maneuver -segmental derotation of the pathological elements. ## Principle 4: correction of thoracic lordosis is best accomplished with sublaminar wires and kyphotically contoured stiff rods Whether a pure lordosis or a lordoscoliosis, the mechanism needed for correction is direct translation of the affected vertebrae out of the lordosis into a normal sagittal alignment. The problem is how do we achieve it? Distraction lessens the lordosis but cannot create kyphosis. Compression worsens the deformity, and cantilever forces cannot be used. For the pediatric or adolescent patient, the best method is the use of sublaminar wires, pulling the spinal elements directly backward. Radical excision of the ligamentum fl avum, necessary for passing wires, is also a major release of the contracted elements. It is coupled with complete excision of the facet capsules. The rods must be stiff, or the rod will be fl attened, defeating the purpose of the procedure. The best rods are "coldrolled" stainless steel, which is stiffer than ordinary spinal steel. Titanium is too soft a metal to accomplish this goal. Dual rods are best with separate sets of wires for each rod. The tightening begins at each end, working toward the center. It usually takes several passes before the apex of the lordosis fi nally reaches the rod. This is one situation where pedicle screws are virtually useless. The patient in illustrates this principle. ## Principle 5: correct the primary curve and let the compensatory curve balance itself Back in 1949, Von Lackum told us that we surgeons must analyze carefully each of the curves as to their magnitude and their fl exibility and that we should not overcorrect the primary curve beyond the ability of the secondary (compensatory) curve to balance the spine. [bib_ref] Critical observations of the results in the operative treatment of scoliosis, Lackum [/bib_ref] This was during the era of cast correction; and now in our era of powerful internal devices, we must be careful not to repeat the same mistake. There are two main areas where this is a problem. The fi rst is the high, left upper thoracic curve above a typical right thoracic scoliosis. This short curve can have various degrees of fl exibility (rigidity), which must be carefully analyzed before surgery. When it is quite stiff, as evidenced by a well-done bending fi lm, it is a double primary curve situation (King-Moe 5, or Lenke 2), and both curves must be included in the fusion. If they are not, a vigorous correction of the right thoracic curve will result in lifting of the left shoulder. If this high left curve is very fl exible, the surgeon can proceed to correct the right thoracic curve without concern for shoulder imbalance. The problem is the high left curve, which has intermediate fl exibility. This is the curve we would like not to fuse, but we must use constraint when correcting the right thoracic curve. The more common problem is the left lumbar curve below the right thoracic curve. When it is just as large and just as stiff as the right thoracic curve, it is a double primary pattern (King-Moe 1, Lenke 3), and both curves must be fused. When this curve is small and very fl exible (King-Moe 3, Lenke 1A), there is no problem; and one can fuse the right thoracic curve without concern. The issue is the common situation of a lumbar curve that is as large or almost as large as the right thoracic curve but is much more fl exible on the bending fi lms (King-Moe 2, Lenke 1C). Because of the size of the curve and the rotation seen on the standing fi lm, many surgeons are tempted to extend the fusion down into the lumbar curve. This is a mistake, as this lumbar curve will spontaneously correct itself to balance the residual thoracic curve. It makes no difference how the thoracic curve was treated (anterior, posterior, hooks, screws, hybrids); the lumbar curve will balance so long as the thoracic curve is not overcorrected. The Lenke 1B curve pattern should be abandoned, as it does not aid in the selection of the fusion area, as not all of these curves need the lumbar curve to be fused. The patient in illustrates this principle During the 1980s, Cotrel advocated the use of 2 weeks of preoperative traction using a head halter and pelvic bands, stating that such traction "softened-up" the curve, allowing greater correction during surgery. This program was widely adopted around the world -with no scientifi c evidence to support its use. When subjected to scientifi c analysis, patients undergoing traction did not have any better correction at surgery than those who did not undergo traction. [bib_ref] Preoperative Cotrel traction in idiopathic scoliosis, Bjerkreim [/bib_ref] This was a classic example of our listening to the "expert" without applying the scientifi c method. What about more vigorous forms of traction, such as halo-femoral traction for very large curves? During the 1960s, Moe began using halo-femoral traction for very large or very stiff curves. This was usually a 2-to 4-week program of gradually increasing weights until no further improvement was seen on periodic radiographs. One patient had her 100° postpoliomyelitis curve corrected in traction to 25° in just 2 weeks. She was scheduled for surgery, but it had to be postponed owing to a viral infection, so she spent another month in traction. Her curve did not improve a single degree in those four additional weeks of traction, which made us begin to doubt the effectiveness of this treatment. We thus set up a small experiment wherein we did the usual standing, supine, and supine bending fi lms. We then put the patient on the Risser/Cotrel casting table and pulled very hard plus adding a localizer strap to the convexity of the primary curve. A radiograph was then obtained, establishing the "true" fl exibility of the curve. This was always a value better than the bending fi lm. We then applied halo-femoral traction for 3 weeks, obtaining a radiograph weekly. After 3 weeks, the curve was always the same as the curve on the casting table fi lm. Pinto, of Sao Paulo, Brazil, analyzed 150 patients placed in halo-femoral traction for very large curves, mostly after poliomyelitis. He found that once a shortradius curve was corrected to a long-radius curve, no further correction occurred. This study was presented to the Scoliosis Research Society in 1974 but was never published. [bib_ref] Halo-femoral traction in the treatment of severe postpoliomyelitis scoliosis, Pinto [/bib_ref] Is halo traction useless? No, because there is a specifi c indication for it that is still valid today -in the patient who presents with a very large thoracic curve and whose pulmonary functions are so bad as to make surgery highly dangerous or impossible. In such situations, halogravity traction can result in such a great improvement ## Principle 7: not all hemivertebrae need excision There is an alarming situation developing in which the surgeon sees a child with congenital scoliosis, and at the apex of the scoliosis is a hemivertebra. Surgery is immediately scheduled for a hemivertebra excision that is to be done through a posterior approach. This is wrong. There are many types of curve that contain one or more hemivertebrae, and even different types of hemivertebrae. One situation is a spontaneously improving curve situation where the treatment is observation alone. We have seen four such patients at our center, and none of the four ever needed surgery. At the other end of the spectrum is the fully segmented hemivertebra at L5. These hemivertebrae are notorious for causing progressive decompensation with a very large secondary curve if left untreated. The optimal treatment is excision at an early age. Hemivertebrae that cause fi xed truncal decompensation require excision as there is no other way to achieve trunk balance. Hemivertebrae at the thoracolumbar junction or in the thoracic spine can be better managed by convex hemiepiphyseodesis/hemiarthrodesis surgery -which is slow to achieve correction but much, much safer. Although we know that "posterior-only" hemivertebra excision can be done, we prefer the safer combined anterior/posterior approach as it also allows us to perform epiphyseodesis surgery above and below the hemivertebra if needed. The patient in illustrates this principle. ## Principle 8: early fusion can be good What do we do with the child born with severe congenital scoliosis that progresses during the fi rst year of life? It is almost always caused by a unilateral unsegmented bar with or without a convex hemivertebra. As shown by McMaster and Ohtsuka and others, these curves progress at a rate of 5°-10° per year. Thus, if a child has a 60° curve at birth, it will be at least 85°-110° by age 5 years. By this time major damage has been done to the lung capacity, and correction is extremely diffi cult. The traditional answer to such a problem was prompt fusion surgery, both anterior and posterior, at about the age of 1 year. Anterior surgery was needed because the growth plates on the convexity, the ones responsible for the progression, are anterior. Epiphyseodesis surgery would not work because there are no growth centers in the concavity to cause progressive improvement. What about the effect of a major fusion of the thoracic spine in a 1-year-old child? Would we not be causing severe shortening of the torso? Would we be A B,C . a This 1-year-old boy had 42° congenital scoliosis due to a hemivertebra at L1. Should it be removed? b At age 14, the curve was 30°. He had received no treatment of any kind. c A photograph at age 14 shows almost no deformity. Of interest is that he is one of identical twins, and his twin brother has no anomaly of the spine causing a major pulmonary problem? These are all good questions but must be answered scientifi cally, not emotionally. Yes, the fused area will not grow vertically. However, preventing a major curve increase results in a short trunk but one that is longer than would have occurred if the fusion had not been done. By early fusion we are preventing progressive loss of lung function and early death due to cor pulmonale. The few cases of such early surgery with follow-up into adult life have shown highly positive results, far better than allowing curve progression. [bib_ref] Congenital thoracic scoliosis with unilateral unsegmented bar and concave fused ribs: rib..., Winter [/bib_ref] [bib_ref] Congenital scoliosis due to unilateral unsegmented bar: posterior spine fusion at age..., Winter [/bib_ref] There is a new procedure, osteotomy of the fused ribs in the concavity of the curve and insertion of a vertical rib distraction device, developed by Campbell and colleagues in Texas. [bib_ref] The characteristics of thoracic insuffi ciency syndrome associated with fused ribs and..., Campbell [/bib_ref] The rib distraction, periodically lengthened, is designed to create a far better concave C D ## A b lung space and to stop curve progression or even alleviate the curve. So far these procedures appear to be doing well, but none of the patients has reached the end of growth. Unfortunately, few pulmonary function tests have been done; only computed tomography scans of the chest volumes are available. ## Principle 9: instrumentation without fusion can be effective Instrumentation without fusion with periodic lengthening has been with us since 1970. It is not something new. It is designed for the young child with a curve too large for brace treatment but a curve fl exible enough to have major improvement with distraction. Because the concept is to maintain curve control while permitting vertical torso growth, there must be viable growth tissue in the concavity of the curve, which rules out most congenital scolioses. Thus, its primary use has been with infantile and juvenile idiopathic scoliosis and syndromic scoliosis. We began doing this procedure in 1975, the fi rst patient being a 4-year-old girl with an 84° curve related to congenital muscular hypotonia. Since then we have performed the surgery in more than 100 patients with mixed results. [bib_ref] Spinal instrumentation without fusion for progressive scoliosis in young children, Klemme [/bib_ref] Our initial patient was fused at age 10 and was followed to the end of growth. Both goals were achieved. Her fi nal curve is 50°, and her torso length is normal. Recent studies have shown that a dual distraction rod system is better than a single rod system, that lengthening is needed on a regular basis (every 6 months), and fusion should be done whenever curve control is lost or no further torso lengthening is being accomplished. [bib_ref] Dual growing rod technique for the treatment of progressive early-onset scoliosis: a..., Akbarnia [/bib_ref] Fusion usually takes place at the pubertal growth spurt as curve control is usually lost then and the curves become so stiff that correction fails. ## Principle 10: the ideal end result of our surgery is a spine balanced in both the frontal and sagittal planes, not the maximum correction As various implant systems have been developed, we as surgeons have become obsessed with "percent correction." When all we had was a Risser localizer cast, the average fi nal correction of typical thoracic idiopathic scoliosis was about 40%. When Harrington instrumentation was introduced, the average correction increased to about 45%. For a 60° curve, this meant a fi nal curve of 36° with a cast, and a 33° curve with the rods, not a signifi cant difference. With Cotrel/Dubousset instrumentation or the many other hook-rod systems, the correction improved to about 55% and with pedicle screw systems to about 65%. This meant a fi nal curve of 27° and 21°, respectively. Thus, the fi nal result is a better Cobb measurement number, but does this mean a healthier, happier patient? [bib_ref] How much correction is enough?, Winter [/bib_ref] When our enthusiasm for more correction of the primary curve results in a decompensated patient, our goals of good patient care have been violated. A long time ago the French philosopher Voltaire said, "The enemy of good is better." More recently, in his Harrington Guest Lecture to the Scoliosis Research Society, Dubousset said, "The maximal correction is not the optimal correction." We must look at the whole patient, and not just at the Cobb X-ray measurement . # Conclusions There are many principles from the past that apply to the future. I have chosen 10 of them that I believe to be important. When I hear doctors discussing exercises for scoliosis, I am discouraged, as this method has long been proven to be useless by many researchers. When I hear surgeons discussing the benefi ts of halo traction for "softening-up" a big curvature, I am discouraged. These surgeons have not researched the earlier literature, nor have they consulted with those "old" surgeons who went through those trials years ago. I plead for not adopting new methods until their value has been proven scientifi cally, especially by someone who is not the inventor. Finally, I plead for us as surgeons not to be seduced by "percent correction" mania. The patients and/or their families were informed that data from any cases would be submitted for publication and gave their consent. [fig] Principle 6: Traction does not "soften up" a curve; it merely shows you the true fl exibility of a large curve [/fig]	None	None	None
557e577197a58c0e3ce63809abd80bd3c57c9651	pubmed	Recommended Practices for Cleaning, Handling, and Processing Anesthesia Equipment	Recommended Practices for Cleaning, Handling, and Processing Anesthesia Equipment ## Recommended practices for Cleaning, Handling, and Processing Anesthesia Equipment he following recommended practices were developed by the AORN Recom-T mended Practices Committee and have been approved by the AORN Board of Directors. They were presented as proposed recommended practices for comment to members and others. These recommended practices are effective Jan 1,2005. These recommended practices are intended as achievable recommendations representing what is believed to be an optimal level of practice. Policies and procedures will reflect variations in practice settings or clinical situations that determine the degree to which the recommended practices can be implemented. AORN recognizes the numerous types of settings in which perioperative nurses practice. These recommended practices are intended to provide guidance for various practice settings, including traditional ORs, ambulatory surgery units, physicians' offices, cardiac catheterization suites, endoscopy suites, radiology departments, and all other areas where operative and other invasive procedures may be performed. PURPOSE. Anesthesia equipment is a potential vector in the transmission of microorganisms. Proper handling and processing of medications, supplies, and equipment can reduce the risk of infection to the patient. These recommended practices provide guidelines for the handling, cleaning, disposal, and reprocessing of anesthesia equipment and instrumentation. Medications should be stored in a clean area. Personnel should perform basic hand hygiene according to the CDC's "Guideline for hand hygiene in health-care settings,"'" before preparing medication. Vial stoppers should be cleaned with alcohol before they are punctured. Single-dose vials should be used for only one patient. Syringes of unused medication should be discarded at the end of the procedure. Propofol should be withdrawn immediately before administration. ing medications, them, ication into multiple syringes, ication between patients, and temperature for the day. Aseptic technique should be used when administering medications. Bacteria from hands can contaminate syringes and their Multidose vials have been found to be contaminated." Syringe contents have been found to contain blood or bloodbome pathogens after one injection or entry into IV Using a common syringe in the IV tubing ports of more than one patient has transmitted infectious Syringes and needles should be used for only one application (eg, one syringe and one needle per entry into a multidose vial). Intravenous tubing ports should be cleaned with alcohol before they are punctured with a needle. ## Recommended p r a c t i c e ## I1 Anesthesia equipment that comes in contact with mucous membranes should be sterilized or undergo high-level disinfection before use. 2. Reusable semicritical items should be cleaned as the first step in reprocessing. Removal of organic material provides optimal conditions for proper exposure of equipment to disinfectants and steril a n t~. ' ,~~,~~ Rgid laryngoscopes should be disassembled and all components cleaned, including handles. Some automated pasteurization equipment has a cleaning step within the pasteurizing cycle. ## 3. Clean, semicritical reusable items should be processed by high-level disinfection, pasteurization, or sterilization with a US Food and Drug Administration (FDA)-approved agent, according to AORN's "Recommended practices for high-level disinfection" or "Recommended practices for sterilization in the practice ~e t t i n g . "~~,~* Written instructions from the manufacturers of reprocessing equipment, chemicals, and instruments should be followed. Items should be rinsed with sterile water after the chemical disinfection process. If sterile water is not used, the item should be rinsed first with water and then with 70% alcohol, and it should be thoroughly dried, along with its lumens and channels?' 6. Disinfected semicritical items should be stored in a clean location in a manner that prevents recontamination or damage. Storing semicritical items in a clean location minimizes the risk of contamination with pathogens before use. Endoscopes should be stored vertically with control valves, caps, and hoods removed." 7. Personnel should be trained in the reprocessing procedures and equipment. Training personnel regarding the complexities of the equipment, chemicals, and processes used minimizes the risk of human error. 8. Quality control of reprocessing procedures should be performed and documentation maintained in accordance with 0 AORN's "Recommended practices for high-level disinfection,"" 0 AORN's "Recommended practices for sterilization in the practice setting,"" and 0 manufacturers' written instructions. Quality control measures provide assurance that mechanical and chemical conditions are optimal for high-level disinfection. Documentation provides a mechanism for process improvement and investigation of adverse events. ## Recommended practice 111 Anesthesia equipment contacting intact skin should be clean at the time of use. 1. Items such as blood pressure cuffs, electrocardiogram (ECG) leads, and oximeter probes that contact only intact skin are con-sidered noncritical. The CDC 0 has determined that the potential for transmission of infectious agents is lower when items contact only intact skin, 0 has classified these items as noncritical, and 0 recommends low-level dismfection.' 2. Reusable items and surfaces contacting intact slun (eg, blood pressure cuffs, ECG leads, s h temperature probes) should be cleaned between use on patients. Cleaning removes organic and inorganic material, whch allows the disinfectant to contact all surfaces.',E,2h 3. Reusable laryngoscope handles should be cleaned and low-level disinfected between patients. Laryngoscope handles become contaminated during airway management. In studies, 40% to 50% of handles tested positive for Cleaning and disinfecting these handles minimizes the risk of transmission of bloodborne pathogens. The disinfectant selected should be registered with the Environmental Protection Agency (EPA) for use as a hospital disinfectant and used according to the manufacturer's written instructions.ffi 4. Reusable noncritical items should be lowlevel disinfected between patients. Low-level disinfection with an EPA-registered hospital disinfectant kills most bacteria and some viruses and fungi but may not kill tubercle bacilli or bacterial spores.' After subjection to low-level disinfection, the device is considered safe to come in contact with intact skin. 5. Surfaces of anesthesia equipment that are touched by personnel while they are providing patient care or handling contaminated items should be cleaned and low-level disinfected between use on patients, according to manufacturers' written instructions. Surfaces of anesthesia equipment become contaminated with oral secretions and blood during surgical procedure^."^-^^ Researchers have found occult or visible blood on 29.5% to 35.5% of anesthesia machines, carts, and monitor~.~~,~* Blood also has been found on ventilator controls, flow meter knobs, vapor controls, ECG leads, oximeter probes, and blood pressure cuffs (ie, 25% to 64.3°h). [bib_ref] The prevalence of visible and/or occult blood on anesthesia and monitoring equipment, S M Perry [/bib_ref] Surfaces of anesthesia carts, drawer handles, touch screens, flow meter knobs, ventilator controls, ECG leads, oximeter probes, and blood pressure cuffs should be cleaned and disinfected between use on patients. Other surfaces known to have been touched during patient care also should be cleaned and disinfected between patients. ## 6. Exterior surfaces of anesthesia equipment (eg, anesthesia cart, machine, monitors) that are not knowingly contaminated during patient care should be terminally low-level disinfected at the end of the day according to manufacturers' written instructions. Contact with blood and body fluids is routinely associated with tasks performed by anesthesia care These surfaces may become contaminated during use, without the knowledge of the provider.Low-level disinfection with an EPA-registered hospital disinfectant renders the surfaces safe to contact intact skin.' Manufacturers recommend specific agents to clean complex electronic equipment. These instructions should be followed. ## Recommended practice i v Single-use items (eg, breathing circuits, endotracheal tubes, filters, needles, some LMAs, stylets, suction catheters, syringes) should be used once and discarded in accordance with local, state, and federal regulations. 1. Single-use items should be used for a single patient and not reused on subsequent patients. Patient care equipment and supplies are potential vectors of microorganisms and can transmit infectious agents. Safe cleaning and reuse of single-use items has not been established. These items should be discarded after use on a single patient. 2. Single-use items should not be reprocessed unless requirements for validation testing can be met. Reuse of items designed for single use creates the potential for injury related to mechanical failure, residual bioburden, and chemical residue from the reprocessing agent. For these reasons, reprocessing of items designed for single use is regulated by the FDA. Under the Federal Food, Drug, and Cosmetic Act, facilities reprocessing single-use devices must meet all regulatory requirements of a device manufacturer, including 0 facility registration and device listing, 0 premarket clearance or approval, 0 labeling, 0 corrections and removals, 0 medical device tracking, 0 medical device reporting, and 0 quality system regulation?' These requirements exceed the capabilities of most perioperative settings. ## Recommended practice v Anesthesia equipment should meet performance and safety criteria established by the practice setting and that is consistent with the manufacturer's written instructions. of the anesthetic circuit was identified as the likely cause of transmission of hepatitis C virus.'5 Currently, there is no consensus about the routine use of bacterial f i l t e r~. 2~,~,~* ,~~,~ For patients with known or suspected tuberculosis, the CDC, ASA, and AANA recommend using a bacterial filter between the patient and breathing circuit.2y,W,58 The Canadian Society of Anesthesiologists also recommends use of bacterial filters for patients with severe acute respiratory syndrome (SARS).'* With the increased prevalence of tuberculosis, increased numbers of immunocompromised patients, and the advent of SARS, it is prudent to consider the routine use of bacterial filters on the inspiratory and expiratory limbs of the anesthesia circuit. Some single-use circuits have a heat and moisture exchanger equipped with these filters. Reusable circuits should be cleaned and undergo high-level disinfection, pasteurization, or sterilization between use on patients. ## Humidifiers should be used and cleaned according to manufacturers' written instructions. The water in humidifiers is heated to temperatures that reduce or eliminate microbial growth.79 Tap water may contain stationary-phase forms of Legionella pneumophila, which are heat resistant.66 Sterile water should be used in h~rnidifier~.~~~'-' Reusable humidifying chambers should undergo sterilization or high-level disinfection between patient U S~S .~"~~ Single-use chambers should be discarded after use on one patient. ## Recommended p r a c t i c e ## Vii Waste must be disposed of in a manner consistent with local, state, and federal regulations. 1. Biohazardous waste should be placed in a biohazardous waste bag. Some anesthetic waste poses a risk of transmission of bloodborne pathogens. Placing it in designated biohazardous containers alerts handlers to this risk. Management of biohazardous waste within the health care facility is regulated by the Occupational Safety and Health Administration (OSHA).8Z State and local laws also apply. Perioperative professionals should be aware of and act in accordance with these laws. 2. Sharps should be handled in a manner that minimizes the risk of percutaneous injury. To minimize the risk of injury from contaminated sharps, OSHA requires that puncture-resistant sharps containers be located at the point of Placing the container next to or on the anesthesia equipment meets this expectation. Sharps should be placed directly into the container. ## 3. Waste that is hazardous upon disposal must be managed in a way that minimizes environmental impact. Some waste poses a risk to the environment (eg, alcohol, bezoin, epinephrine, mercury). This waste is classified by the EPA as hazardous upon disposal and is regulated under the Resource Conservation and Recovery Act.The EPA requires that this waste be placed in hazardous waste containers at the point of use to alert handlers to the need to take precautions upon its disposal.84 State and local laws also may apply. ## Recommended practi ce viii Potential hazards to perioperative personnel that are associated with handling and processing clean and contaminated anesthesia equipment (eg, exposure to infectious organisms, chemicals) should be identified, and practices should be established to reduce the risk of injury. 1. Contaminated sharps must be discarded in a puncture-resistant container at the point of use. Immediate disposal of sharps prevents injuries to people unaware of the location of the sharp and is required by OSHA.*' 2. All personnel involved with cleaning and processing anesthesia equipment should practice according to A0R"s "Recommended practices for standard and transmissionbased precautions.''85 These precautions define general measures for infection control. 3. Anesthesia equipment should be processed using methods that reduce the risk of exposure to pathogens and injury. Manual cleaning methods that minimize splashing, spraying, spattering, and generation of droplets protect personnel from exposure to blood, body fluids, and cleaning agents. 4. Personnel must be apprised of the hazards in the workplace, including chemicals used for reprocessing anesthesia equipment. Knowledge of the hazards in the workplace, preventive measures, and exposure management minimize the risk of injury to employees and are required by OSHA." ## Personal protective equipment (ppe) must be provided to minimize the risk of exposure to bloodbome pathogens and chemicals used in the workplace. Use of barrier protection minimizes the risk of exposure to bloodbome pathogens by personnel performing tasks likely to generate contact with blood. According to OSHA regulations, employers are required to provide PPE (eg, gloves, gown, mask, protective eyewear, face shield) for their employees.K' 6. Personnel should actively participate in the evaluation of engineering devices and work practice controls to minimize the risk of exposure to bloodbome pathogens. Active participation in the selection of PPE and practices provides the best opportunity for designing a safer workplace. According to OSHA regulations, employers are required to solicit nonmanagerial employee input during evaluation of engineering devices and work practice controls to minimize exposures to bloodbome pathogens.67 ## Recommended p r a c t i c e I X Anesthesia equipment should be handled, cleaned, processed, or discarded in the same manner in all areas of the practice setting. 1. Guidelines should be developed and approved by appropriate mechanisms and goveming bodies in the practice setting. Equipment may be located in satellite areas (eg, labor and delivery). Guidelines should be consistent throughout the practice setting because all patients are entitled to the same standard of care.88 ## Recommended p r a c t i c e x Policies and procedures on cleaning and processing anesthesia equipment should be developed, reviewed periodically, and readily available in the practice setting. 1. These recommended practices should be used as guidelines for developing policies and procedures in the practice setting. Policies and procedures establish authority, responsibility, and accountability for cleaning, handling, and processing anesthesia equipment and serve as operational guidelines. Policies and procedures also help in developing performance improvement activities. 2. Policies and procedures for cleaning and processing anesthesia equipment should include, but not be limited to, 0 disposal of single-use items, 0 equipment maintenance programs, 0 equipment quality checks, 0 personal protection, 0 personnel education, 0 processing reusable equipment, and 0 waste disposal. ## Glossary ANESTHESIA EaUIPMENT: Equipment used to provide anesthesia and/or monitor the patient under sedation or anesthesia. CLEANING: A process using friction, detergent, and water to remove organic debris. CRITICAL ITEM: An item that contacts the vascular system or enters sterile tissue, posing the hghest risk of transmission of infection. ## High-level disinfection: A process that uses a government-registered agent that kills vegetative bacteria, tubercle bacilli, some spores, fungi, and lipid and nonlipid viruses, given appropriate concentration, submersion, and contact time. ## Low-level disinfection: A process by which most bacteria, some viruses, and some fungi are killed. This process may not kill resistant organisms, such a s Mycobacteriurn tubercle or bacterial spores. NONCRITICAL m~: An item that comes in contact with intact skin but not with mucous membranes, sterile tissue, or the vascular system. PASTEURIZATION: A process that employs time and hot water (ie, 160" to 170" F [21.7" C to 25" C] for 30 minutes) for high-level disinfection. The intensity of heat and duration of exposure must be determined by the manufacturer of the pasteurization unit and the manufacturer of the product or device to be cleaned. SEMICRITICAL ITEM: An item that comes in contact with mucous membranes or with skin that is not intact. The technique, which uses ultrasound along with a fine needle biopsy, determines reliably whether the lymph nodes are malignant. Traditional means of determining cancer's spread to the axilla (ie, underarm) are sentinel lymph node sampling, in which the first lymph node is identified and assessed for cancerous cells, or axillary Lymph node dissection, in which all lymph nodes in the underarm are removed and examined for cancer. If the sentinel node biopsy shows cancer, then a patient must undergo surgery to have the lymph nodes removed. For some women, chemotherapy may be necessary before surgery. In these cases, physicians must determine whether the lymph nodes are affected before the chemotherapy begins. Rather than performing a sentinel lymph node sampling surgery, physicians can use ultrasound-guided fine needle aspiration to confirm the cancer's spread without surgery. The technique uses ultrasound to identify the axillary lymph nodes and determine if their appearance is normal or abnormal. If they look abnormal, a 22-gauge needle is inserted into the node to extract cells to be evaluated for cancer. The technique requires only local anesthesia and involves no surgical incisions, unlike sentinel lymph node sampling and axillary node dissection, which are full surgical procedures. Researchers used ultrasound to examine 57 women who were recently diagnosed with breast cancer. If the lymph nodes appeared abnormal on uitrasound, the researchers performed a fine needle aspiration, using ultrasound to guide the biopsy. Patients then underwent breast surgery and either sentinel lymph node sampling or axillary node dissection. Pathology reports from surgery were compared to results from the ultrasound-guided fine needle aspiration. Of the women whose ultrasounds showed abnormal lymph nodes, 92.8% had cancerous nodes at surgery. Additionally, all the women with an abnormal ultrasound and a positive biopsy were found to have cancer in their lymph nodes at surgery. Researchers note that the technique is not reliable to rule out the cancer's spread-it only can confirm positive lymph nodes. If a test is negative, therefore, sentinel lymph node sampling still is necessary. New Biopsy Technique Helps Assess Breast Cancer' s Spread (news release, Ann Arbor, Mich: University of Michigan Health Center, Nov [fig] RECOMMENDED: PRACTICE I Anesthesia equipment that comes in contact with the vascular system or sterile body tissue should be sterile at the time of use. 1. Items such as IV catheters, tubing, and stopcocks; syringes and needles; and medication vials and ampules are considered critical items. The Centers for Disease Control and Prevention (CDC) uses Spaulding's criteria to determine the potential for transmission of infectious agents. In this classifi-856 AOKN JOURNAL cation, items contacting the vascular system or sterile tissues pose the greatest risk of infection and are classified as critical.' Using sterile items when contacting the vascular system or sterile tissues minimizes the risk of infection. Aseptic technique should be used when preparing medications. Breaks in aseptic technique have contaminated IV anesthetic agents and medications, resulting in clusters of infections.2" Good practices include 0 performing hand hygiene before prepar-0 cleaning vial stoppers before puncturing 0 using multiple needles to withdraw med-0 not transferring syringes of unused med-0 not storing syringes of propofol at room [/fig] [fig] NOTES 1: W A Rutala, APIC Guidelines Committee, "APIC guideline for selection and use of disinfectants," American Journal uflnfection Control 24 (August 2. Centers for Disease Control and Prevention, "Postsurgical infections associated with an extrinsically contaminated intravenous anesthetic agent-California, Illinois, Maine, and Michigan, 1990," Morbidity and Mortalify Weekly Report 39 (' June 29, 3. M J Daily, J B Dickey, K H Packo, "Endogenous Candida endophthalmitis after intravenous anesthesia with propofol," Archives of Opht\mlmology 109 4. M E Villarino et al, "Postsurgical infectious associated with an extrinsically contaminated intravenous anesthetic agent," program and abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 29 Sept-2 Oct 1991. 5. B Veber et al, "Severe sepsis after contaminated Propofol," Anestkesiology 80 (March 1994) 712-713. 6. K Kidd-Ljunggren et al, "Nosocomial transmission of hepatitis B virus infection through multipledose vials," Journal of Hospital Znfection 43 (September 1999) 57-62. 7 . M J Kuehnert et al, "Staphylococcus aureiis bloodstream infections among patients undergoing electroconvulsive therapy traced to breaks in infection control and possible extrinsic contamination by Propofol," Anesthesia and Analgesia 85 (August 8. M Massari et al, "Transmission of hepatitis C virus in a gynecological surgery setting," Journal of Clinical Microbiology 39 (August 2001) 2860-2863. 9. Centers for Disease Control and Prevention, "Transmission of hepatitis B and C viruses in outpatient settings-New York, Oklahoma, and 1997) 420-425. Nebraska, 2000-2002," Morbidity and Mortality Weekly Report 52 (Sept 26,2003) 901-906. 10. J M Boyce, D Pittet, "Guideline for hand hygiene in health-care settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC /SHEA / APIC/ISAD Hand Hygiene Taskforce," Morbidity and Mortality Weekly Report 51 (Oct 25, 2002) 11. C E Blogg, M A Ramsey, J D Jarvis, "Infection hazard from s ringes," British Journal of Anaesthesia 46 (April 19747260-262. 12. M R Lessard et al, "A microbiological study of the contamination of the syringes used in anaesthesia practice," Canadian Journal of Anaesthesia 35 (November 1988) 567-569. 13, C T Lutz et al, "Allergy testing of multiple patients should no longer be performed with a common syringe," The New England Journal of Medicine 310 (May 17,1984) 1335-1337. 14. J W Koepke, J C Selner, "Allergy testing of multiple patients with a common syringe," The New England Journal Medicine 311 (Nov 1,1984) 1188-1189. 15. D J Shulan et al, "Contamination of intradermal skin test syringes," Journal of Allergy and Clinical bnnzunology 76 (August 1985) 226-227. 16. J W Koepke et al, "Viral contamination of intradermal skin test syringes," Annals of Allergy 55 (December 1985) 776-778. 17. A Carbonne et al, "Patient to patient transmission of hepatitis C in surgery clinic through multidose vials," abstract presented at the 13th annual meeting of the Society for Healthcare Epidemiology of America, Arlington Va, 5-8 April 2003. 18. A Fleming, A C Ogilvie, "Syringe needles and mass inoculation technique," British Medical Journal 1 (March 17,1951) 543-546. 19. R R Hughes, "Post-penicillin jaundice," British Medical Journal2 (Nov 9, 1946) 685-688. 20. R Uren, C Commens, R Howman-Giles, "Intradermal injections: A potential health hazard?" Medical Journal of Australia 161 (August 994) 226. 21. H A Hein et al, "Recapping needles in anesthesia-Is it safe?" Anesthesiology 67 (September 1987) A161. 22. C A Trepanier et al, "Risk of cross-infection related to the multiple use of disposable syringes," Canadian Journal of Anaesthesia 37 (March 1990) 156-159. 23. J L Parlow, "Blood contamination of drug syringes used in anaesthesia," Canadian Journal of Anaesthesia 36 suppl (1989) S61-S62. 24. B Meier, "Reuse of needle at hospital infects 50 with hepatitis C," New York Times, Oct 10,2002. [/fig] [table] 1: Written mformation regarding safety and testing methods, warranties, and a manual for maintenance and inspections should be obtained from the manufacturer for all anesthesia equipment. These manuals help in developing operational, safety, and maintenance guidelines. Recommendations vary by manufacturer and equipment model. Manuals should be maintained for each.2. Anesthesia equipment should be assigned an identification number. Identification numbers allow for documentation of inspections, safety checks, preventive maintenance, repairs, and tracking in the event of a patient or equipment problem.3.Before placing anesthesia equipment into service, the safety features of the equipment should be tested by qualified, trained personnel, according to manufacturers' written instructions. These tests should be specific to the type and model of equipment involved AORN JOURNAL 86 1 and include, but not be limited to, calibrations and alarms. Testing the equipment before initial use minimizes the risk of patient injury resulting from faulty equipment. [/table] [table] 25: Association for the Advancement of Medical Instrumentation, "Safe handling and biological decontamination of reusable medical devices in health care facilities and in nonclinical settings; Anesthesiologists, http://www.asahq.org/Publications 55. B Abraham et al, "Malignant hyperthermia susceftibflity;,Anaesthetic implications and risk strati ication. Ouarterlu lournal of Medicine 90 56. "Medical FAQs," Mali ant Hyperthermia .org/index.cfmlfuseaction/Con ten t. Display/lagePK /Medical€AQs.cfm (accessed 24 Sept 2004). 57. "Reducing mercury use in healthcare: Promoting a healthier environment: A how-to manual." US Environmental Protection Aeencv. htb: Association of the United ! ? tates, http://www.mhaus //wwzu.epa.gov/gInpo/bnsdocs/merchealth~ (acGessid 24 Sevt 2004). 58. Centers for Disease Control and Prevention, "Guidelines for prevention of nosocomial pneumonia, 2003," Morbidity and Mortality Weekly Report 53 (March 26,2004) (RR03) 1-36. 59. G E Dryden, "Risk of contamination from the anesthesia circle absorber: An evaluation," Anesthesia and Analgesia 48 (November/December 60. J R Jenkins, W M Edgar, "Sterilization of anaesthetic equipment," Anaesthesia 19 (April 84. "Identification and listing of hazardous waste," in Electronic Code of Federal Regulations (e-CFR) 40 Protection of Environment, Part 261, http://zmmo .epa.gou/~nhoine/c~40.htm (accessed 25 Sept 2004). 85. "Recommended practices for standard and transmission-based precautions," in Standards, Recornmended Prncticcs, and Gii idelines (Denver: 86. "Hazard communication in the 21st century workplace," US Department of Labor, Occupational Safety and Health Administration, http://zoziw .os~ia.~ou/dsh./h~zco~~i~~in/nisdsr~port./~tni/ (accessed 25 Sept 2004). 87. "Bloodborne pathogens and needlestick prevention," Occupational Safety and Health Administration, Iittp://z~uzii.osha.~ou/S LTChlood-bovize~atho~etis/inde.u.1ztml (accessed 25 Sept 2004). 88. Joint Commission on Accreditation of Health-care Organizations, "Crosswalk of 2003 standards for hospitals to 2004 leadership standards for hos itals," in 2004 Comprehensive Accreditation Manual $r Hospitals: The Official Handbook (Oakbrook Terrace, Ill: Joint Commission on Accreditation of Healthcare Organizations, 2003) LD.3.20. Originally published June 1977, AORN Journal, as A 0 R " s "Recommended practices for cleaning and processing anesthesia equipment." Revised March 1978; July 1982; March 1991. Published as proposed recommended practices September 1994. Revised; published November 1999, AORN Joiirnal. Reformatted July 2000. Revised November 2004; scheduled for pubIication in the AORN Journnl in 2005. New Biopsy Technique Reduces Need for Surgery esearchers have found a new, nonsurgical tech-R nique that can help physicians determine when breast cancer has spread to the lymph nodes, according to a Nov 29, 2004, news release from the University of Michigan Health System, Ann Arbor, Mich. The technique may spare some women an extra trip to the OR. [/table]	None	https://europepmc.org/articles/pmc7111195?pdf=render	None
cd6ca086409fa5944f173b6adb87792552d86c8d	pubmed	SEOM clinical guideline in nasopharynx cancer (2017)	SEOM clinical guideline in nasopharynx cancer (2017) Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. Radiation therapy is an essential component of curative-intent of non-disseminated disease and the association of chemotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum/gemcitabine-based chemotherapy and patients may achieve a long survival time. # Introduction Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. These differences justify a different approach. NPC is an unusual tumor in our country. In Europe, in 2012 the rate of incidence was 0.4 cases/100,000/year (in Spain, 0.5 cases/100,000/year). The incidence of NPC is two to threefold higher in males compared with females. NPC displays a distinct racial and geographic distribution, which is reflective of its multifactorial etiology. In endemic populations, risk appears to be due to an interaction of ## Diagnosis pathological diagnosis A definitive diagnosis is made by endoscope-guided biopsy of the primary tumor. Incisional neck biopsy or nodal dissection should be avoided as this procedure will negatively impact in the subsequent treatment. The pathological diagnosis of NPC should be made according to the World Health Organization (WHO) classification. Basaloid squamous cell carcinoma was added to the WHO classification in 2005; there are few reported cases but these have an aggressive clinical course and poor survival. For nonkeratinizing or undifferentiated histology, consider testing for EBV in tumor and blood. Common means for detecting EBV in pathologic specimens include in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemically staining for latent membrane protein (LMP) . The EBV DNA load within the serum or plasma may be quantified using polymerase chain reaction (PCR) targeting genomic sequences of the EBV DNA such as BamHI-W, EBNA, or LMP; these tests vary in their sensitivity[IIA]. ## Diagnosis and staging The study should include: In pathologic specimens include EBER or LMP [IA]. (g) Nutritional and dental status assessment [bib_ref] Nutrition impact symptoms: Key determinants of reduced dietary intake, weight loss, and..., Kubrak [/bib_ref] [bib_ref] Impact of radiotherapy dose on dentition breakdown in head and neck cancer..., Walker [/bib_ref]. Staging TNM classification has been modified in the 8th edition, 2017. There are two changes in nasopharynx T classifications relating to anatomic markers rather than depth of invasion. The previous T4 criteria ''masticator space'' and ''infratemporal fossa'' were used as synonyms, but their anatomic descriptions differ, sowing confusion among clinicians. These terms will now be replaced by a specific description of soft-tissue involvement to avoid ambiguity. In addition, adjacent muscle involvement (including medial pterygoid, lateral pterygoid, and prevertebral muscles) will now be ''down-staged'' to T2 based on a recent analysis showing them to have a more favorable outcome using current treatment. In the N classification of nasopharynx, the iconic, traditional description of the supraclavicular fossa that was unique to this site will be replaced by contemporary definitions used for other head and neck sites and more suited to axial cross-sectional imaging. In addition, low neck involvement and [ 6 cm size will be merged into a single N3 designation (formerly N3a and N3b), and T4 and N3 will both designate stage IVA (formerly IVA and IVB) in stage grouping [fig_ref] Table 3: TNM staging classification [/fig_ref]. ## Treatment Radiation therapy (RT) is the mainstay of treatment and is an essential component of curative-intent treatment of nondisseminated NPC. Surgery has no role in the initial : tumor confined to the nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal extension T2: tumor with extension to parapharyngeal space and/or infiltration of the medial pterygoid, lateral pterygoid, and/or prevertebral muscles T3: tumor invades bony structures of skull base cervical vertebra, pterygoid structures, and/or paranasal sinuses T4: tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, parotid gland and/or infiltration beyond the lateral surface of the lateral pterygoid muscle Regional lymph nodes (N) NX: regional lymph nodes cannot be assessed N0: no regional lymph nodes metastasis N1: unilateral metastasis, in cervical lymph node(s), and/or unilateral, or bilateral metastasis in retropharyngeal lymph nodes, 6 cm or less, above the caudal border of cricoid cartilage The techniques of 3D planning and intensity-modulated radiation therapy (IMRT) can improve outcomes without worsening toxicity and can offer a better protection of the different organs in the area that usually limit the dose of radiation that can be given (the use of IMRT can reduce the xerostomy frequently seen with the irradiation of the salivary glands) [IIA]. ## Treatment of early stages (i and ii) The treatment for early stage tumors is RT, including both sides of the neck and retropharyngeal nodes. The dose should be 66-70 Gy to the primary tumor and affected lymph nodes areas, and 50 Gy to the uninvolved neck. In patients treated with IMRT alone, 5-year distant-metastases-free survival rate is 92-94% [bib_ref] Evolution of treatment for nasopharyngeal cancer-success and setback in the intensitymodulated radiotherapy..., Lee [/bib_ref] [IA]. Given the significant toxicities of concurrent chemoradiotherapy (CT/RT) and the generally excellent prognosis of stage II nasopharyngeal cancer with IMRT, the role of administering chemotherapy (CT) concurrently with radiation in all stage II patients remains to be clearly defined, although consideration on individual bases should be made based on risk factors such as significant nodal disease, parapharyngeal tumor extension, and plasma EBV level [bib_ref] Improvement of survival after addition of induction chemotherapy to radiotherapy in patients..., Chua [/bib_ref] [IIB]. ## Treatment of locally advanced stage (iii and iv a/b) Concurrent CT/RT is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (with CDDP at 100 mg/m2 every 21 days) substantially improved locoregional control compared with exclusive RT, but distant metastasis is the main source of treatment failure [bib_ref] What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual..., Ribassin-Majed [/bib_ref] [IA]. Additional cycles of CT (with induction or adjuvant chemotherapy) could improve results and increases failurefree survival, overall survival, and distant failure-free survival with acceptable toxicity profile but its role is uncertain . A high rate of toxicity that usually leads to a low percentage of patients that are able to complete the adjuvant treatment and compliance is a significant problem with only about 50-75% of patients who were initially planned for adjuvant chemotherapy receiving the three planned cycles. Induction CT could avoid this problem [bib_ref] Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized..., Al-Sarraf [/bib_ref] [bib_ref] Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally..., Lee [/bib_ref] [IIA]. The use of one or another should be tailored according to the patient's clinical condition (ex, CT induction in highly symptomatic patients, adjuvant therapy to the rest). In patients with good general condition, TPF induction CT should be an option to be considered problem [bib_ref] Improvement of survival after addition of induction chemotherapy to radiotherapy in patients..., Chua [/bib_ref] [bib_ref] Neoadjuvant chemotherapy followed by concurrent chemoradiation for locally advanced nasopharyngeal carcinoma, Kong [/bib_ref] [bib_ref] Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced..., Sun [/bib_ref] [IIB]. When there is persistent cervical disease after standard CT/RT treatment, cervical rescue surgery should be performed. In cases with large cervical disease (N3), irrespective of the response to CT/RT, its systematic use could be considered. This could be especially relevant in cases with WHO type 1 histology WHO. However, the morbidity of this approach can be substantial and it has not been generally accepted. There are no studies to clarify this point definitively . ## Recurrent and metastatic disease treatment (rm-npscc) (iv c) In the setting of local and/or regional relapse, the multidisciplinary team should assess the possibility of salvage local therapy, whether by surgery or re-irradiation, with or without CT. These approaches can rescue a small percentage of cases, albeit at the cost of high toxicity. The election of one or another approach has not been well established [bib_ref] Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC), Chen [/bib_ref]. The best results have been achieved when the previous interval free of disease is longer. If loco-regional relapse of NPSCC occurs, local treatment with surgery and/or chemo-radiotherapy is recommended . When salvage treatment is not feasible or the patient develops a metastatic disease, the treatment of choice is palliative CT. A wide range of chemotherapy drugs has been tested mainly in retrospective and small phase II trials such as: platinum compounds (cisplatin, carboplatin), fluoropirimidines (5-fluorouracil, capecitabine), taxanes (paclitaxel, docetaxel), gemcitabine, anthracyclines, irinotecan and vinorelbine. Traditionally, the most used schedules included platinum-based combinations, mainly with 5-FU, with responses rates between 50 and 70% in retrospective uncontrolled studies [bib_ref] Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx. A review of..., Choo [/bib_ref] [bib_ref] Combined chemotherapy for recurrent and metastatic nasopharyngeal carcinoma, Airoldi [/bib_ref] [bib_ref] Excellent response to cis-platinum-based chemotherapy in patients with recurrent or previously untreated..., Al-Kourainy [/bib_ref]. A recent phase III randomized trial comparing cisplatin-5-FU with cisplatin-gemcitabine in 362 patients, showed a significant advantage in terms of progression-free survival in the gemcitabine-based cohort. Owing to no other phase III trials in this setting, this schedule has become the new standard first line approach in RM-NPC [bib_ref] Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal..., Zhang [/bib_ref]. Cisplatingemcitabine is the first choice as first line palliative CT treatment in RM-NPSCC [IA]. To date, there is not an established standard treatment after the failure of the first line. If the patient has a good performance status, any of the previously reported active drugs could be considered but the inclusion in clinical trials should be encouraged. Follow-up [fig_ref] Table 5: Follow-up of nasopharyngeal carcinoma [/fig_ref] Evaluation of response in the nasopharynx and neck should be performed through clinical, endoscopic examination and imaging studies (18FDG-PET/CT scan or MR). A final assessment of the disease is recommended to be undertaken at 3 months after the end of the treatment to confirm the complete remission. MR is often preferred to evaluate the response to RT or chemo-radiotherapy, especially for T3 and T4 tumors, though distinction between post-irradiation changes and recurrent tumors may be difficult. Sometimes early detection of possible relapses could be managed with salvage treatment. Follow-up of the patients include periodic examination of the nasopharynx, neck, cranial nerve function and evaluation of systemic complaints to identify distant metastasis. Clinical exam and fibroscopy every three to 4 months during the first 2 years, then every 6 months until 5 years, then yearly should be followed. For T3 and T4 tumors, MR might be used on a 6-to 12-month basis to evaluate the nasopharynx and the base of the skull at least for the first few years after treatment. Thyroid function tests (if neck irradiated) and thoracic imaging test should be carried out at least once a year [bib_ref] Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Chan [/bib_ref]. ## Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This article does not contain any studies with human participants performed by any of the authors. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://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. Final assessment (2-3 months after the end of treatment) Local and regional exam plus nasopharyngeal fibroscopy FDG-PET/CT and/or RMI First two years Local and regional exam plus nasopharyngeal fibroscopy (every 3 to 4 months) Chest X-ray, thyroid function test, CT/MRI (yearly) Two to five years Local and regional exam plus nasopharyngeal fibroscopy (every 6 months) Chest X-ray, thyroid function test, CT/MRI (yearly) [fig] -: Cranialcervical computed tomography (CT) scan or magnetic resonance (MR) scan. Chestabdomenpelvis CT scan. Bone scan. Positron emission tomographyCT (PETCT). CT and MR can be complementary in this regard: CT is superior for the study of bony structures and for the presence of cervical lymph nodes, while the MR provides a better assessment of the primary tumor location and of intracranial structures and retropharyngeal spaces. PET scan may assist in the accurate planning of radiotherapy treatment (RT). PETCT scan can replace the traditional workup for detection of distant metastatic disease [4] [IIIA]. (f) Special pathologic studies: Consider EBV/DNA testing [IIIB]. [/fig] [table] Table 1: Strength of recommendation and quality of evidence score [/table] [table] Table 3: TNM staging classification (AJCC Cancer Staging Manual, 8th; 2017) TX primary tumor cannot be assessed T0 no tumor identified, but EBV-positive cervical node(s) involvement [/table] [table] Table 5: Follow-up of nasopharyngeal carcinoma [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-017-1777-0.pdf	None
04d051e8fae185523e84c7942dd840ce713ebbd2	pubmed	Guidelines for personal exposure monitoring of chemicals: Part V	Guidelines for personal exposure monitoring of chemicals: Part V ## Fig. a-24. target workplace (test room) First, a risk assessment supervisor performed basic characterization of the workplace. It was decided that a personal exposure monitoring of toluene should be carried out because toluene was most frequently used. Interviews were conducted with the section manager and engineering staff regarding the organization of the Section, work division, and the contents of work. Observations of the workplace were also conducted. As a result, a similar exposure group (SEG) was divided into the four groups A to D shown in [fig_ref] Table A - 24: [/fig_ref] SEG-A was mainly involved in physical tests of several chemical products and also half-finished products. Exposure (eight-hour exposure) was estimated to be "high" for this group because a significant amount of toluene was used in the testing process. SEG-B principally conducted analyses of chemical substances using a gas chromatograph. The exposure to toluene was estimated to be "medium." Toluene was not directly handled in the SEG-C (in charge of the water quality test). However, as the entire room had a ｌ Risk low and frequency low (interval long) [bib_ref] Comprehensive assessment of gasoline exposure of tank truck drivers, Nishikawa [/bib_ref] Initial (previous) control class 2) Risk due to various factors related to exposure risk High Medium Low -APPENDIX -Guidelines for personal exposure monitoring of chemicals: Part Ⅴ 3 solvent odor, their exposure was still presumed, though estimated to be "low." SEG-D (the administrative staff) was involved in clerical work in a separate room for the majority of the day. Members of this group were limited to entering the workplace on only two or three occasions per day, with a combined time of less than 30 minutes. Their exposure was thus estimated to be "very low"; in fact, far lower than that of SEG-C. Both SEG-A and -B were monitored over a period of two days, collecting five samples from each SEG. To be on the safe side, monitoring was conducted on SEG-C too; in this case a simplified method was used and it took place over just one day. For SEG-C, the number of samples was two. No monitoring was conducted for SEG-D at this time, and it was determined that monitoring would only be performed if exposure of SEG-C turned out to be relatively high. As the result of interviews, it was determined that the contents of the work for each SEG did not change substantially throughout the course of the day and also that there was no work done involving abnormally high short-term exposure. As a result, short-term exposure monitoring was not conducted. On the day of monitoring, the risk-assessment supervisor briefly explained the purpose of his visit and advised on relevant points in the staff meeting. The section chief selected in advance the workers of each SEG to be monitored among those with routine work scheduled for that particular day. Before starting work, the risk-assessment supervisor attached a passive sampler on the chest of each selected worker and handed a work-recording sheet to them. After observing the working conditions for a short period of time, the risk-assessment supervisor left the workplace. Upon completion of the day's work, the section technical staff (who had been briefed and requested in advance by the risk-assessment supervisor) collected the -APPENDIX -Guidelines for personal exposure monitoring of chemicals: Part Ⅴ 5 samplers from the workers. They capped (sealed) the samplers, recorded the sampling completion time, and collected all the work-recording sheets. On the following day, and in a similar manner, the remaining monitoring was conducted for SEG-A and -B. Attachment and collection of samplers were again done by the section technical staff. The risk assessment supervisor submitted the samplers to an external analytical laboratory for analysis. Finally, after reviewing the contents of the work records, the supervisor verified that there had been no abnormal phenomenon present and also that no irregular work had been performed. On the basis of the results of this analysis, the risk-assessment supervisor calculated an eight-hour time weighted average exposure. it was proposed to the section chief and the chief's agreement was obtained to change the procedures in the future to house the containers in the fume hood as much as possible, and also, if possible, to perform all work inside the fume hood. It was also communicated to the section chief to report any changes to the risk assessment supervisor. The risk assessment supervisor submitted a monitoring report to the section chief. In addition, he reported the results of the measurements separately in writing to all the workers monitored. Thereafter, the risk assessment supervisor was invited to attend the section safety meeting. In the meeting, he explained and lectured to the section members regarding the current measurement results and implemented control measures, as well as the SDS for toluene and its toxicity. For the purposes of reassessment and monitoring, in consideration to the fact that this particular monitoring was the first one in this particular workplace, and also that the risk assessment supervisor did not have a good amount of experience, it was determined that reassessment and monitoring of both SEG-A and -B be carried out after a period of six months. If the results are equal to or better, then it would be considered appropriate for the frequency of reassessment and re-monitoring in the future to be reduced. At the moment, SEG-C is scheduled to undergo reassessment and monitoring after a year. However, if the results of SEG-A and -B after six months are sufficient, the instantaneous measurement shall be conducted for SEG-C instead of the regular monitoring. A Working Environment Measurement agency was requested by a painting Company B to conduct personal exposure monitoring. First, a risk assessment supervisor performed basic characterization of the workplace. The workplace was then divided into a preparation workplace and a painting workplace. [fig_ref] Table A - 24: [/fig_ref] -25.1 shows the work contents and the chemical substances used. In the preparation workplace, three workers were employed in cleaning the surface of the objects to be coated by using a cloth soaked in toluene. They then transported the objects to the painting workplace. In the painting workplace, one worker was employed in mixing the paint with thinner, adjusting its viscosity, and pouring it into a painting machine. This worker would then place the objects on a rotating table in front of the washing booth (which contained external local ventilation equipment). Following the completion of the painting process, the worker would place the objects into the drier for heating and remove them after the completion of drying. The organic solvents contained in the paint were toluene and xylene, while the thinner itself only contained toluene. In both of these workplaces, ventilation fans were installed on the walls. Working hours ran from 8 a.m. to 5 p.m. with a noon recess of one hour. In the preparation work, all the toluene in use evaporated into the air. Because local ventilation equipment had not been installed here, it was assumed that exposure was "high" [fig_ref] Table A - 24: [/fig_ref]. In the painting work, a major portion of the toluene and xylene used also evaporated. Although local ventilation equipment had been installed here, because the source of generation was removed a distance away from the hood, exposure was also assumed to be "high" [fig_ref] Table A - 24: [/fig_ref]. Similar exposure groups (SEGs) were formed such that the three preparation workers constituted an SEG-A, and the painting worker, a single individual, constituted an SEG-B. The concentration of toluene exposure was to be monitored for SEG-A, while that of toluene and xylene was to be monitored for SEG-B. Every member of both SEGs was a target and they were monitored for two days [fig_ref] Table A - 24: [/fig_ref]. On the monitoring day, after arriving at the workplace, the risk assessment supervisor verified the regular work to be performed. This supervisor attached a passive sampler (consisting of activated charcoal) to the chest of each worker in order to allow the sampling in the breathing zone. They removed the samplers one hour before the end of the work shift and sealed them. During the noon recess the samplers were also removed and closed with a cap due to the fact that they impeded the workers' movements. The sampling duration of the initial monitoring was basically eight hours, but since it took a certain amount of time to travel back and forth between the Working Environment Measurement agency and this particular workplace, the resultant sampling duration was 330 to 347 minutes (excluding the noon recess). Interview with the plant manager and workers indicated that the work during the time periods before and after sampling was the same as that during the sampling time period. The samplers were then transported back to the agency, and, on the following day, after extraction using carbon dioxide, they were analyzed using a gas chromatograph. Xylene also was assessed using the lower (i.e., 50 ppm) of the TLV-TWA (100 ppm) of ACGIH or the permissible concentration (50 ppm) according to the Japan Society for Occupational Health. [fig_ref] Table A - 24: [/fig_ref] shows the results of the assessment. For SEG-A, the AM of toluene was 18 ppm and X 95 was 75 ppm. The results were classified as control class 2B. For SEG-B, when assessed as a mixed exposure, the AM was 2.5 ppm and X 95 was 7.5 ppm (three times the AM because of two measured values). This resulted in its classification as control class 3. As such, it was decided to prepare an improvement proposal, and also to conduct re-monitoring in order to verify the effectiveness of these after improvements. In the mixing work, powdery stearate was handled. This process produced airborne particulates. Although local exhaust ventilation equipment was installed, it appeared that these particulates did not seem to be adequately removed. Thus, exposure was assumed to be "high" [fig_ref] Table A - 24: [/fig_ref]. In the rolling work, the material mixed by the mixer was kneaded while heated. Initially, this process generated particulates, but with time, and as the viscosity increased, the generation decreased. In this case, exposure was assumed to be "medium" [fig_ref] Table A - 24: [/fig_ref]. In the bagging work, the material was already in a formed pellet type. Exposure here was assumed to be "low" [fig_ref] Table A - 24: [/fig_ref] were also removed since they disturbed the workers' movements. The sampling time in the initial monitoring was basically eight hours, but since it took a certain amount of time to travel back and forth between the Working Environment Measurement agency and this workplace, the actual sampling time was 350 to 360 minutes (excluding the noon recess). Interview with the plant manager and workers showed that the work during the time periods before and after sampling was the same as that during the sampling time period. The filters were then transported back to the agency, and, on the following day, after the lead was eluted with 2.5 M nitric acid, they were analyzed using an atomic absorption photometer. decided to prepare an improvement proposal and also to conduct re-monitoring in order to verify the effectiveness of these after improvements. Short-term personal exposure monitoring was conducted in the Manufacturing Section of the Plant E of Company D. This Section received ethyl t-butyl ether (ETBE) cargoes every two weeks by ships as an additive to petrochemical products. ETBE is an organic solvent with a boiling point of 73 °C and a toxicity similar to that of other general solvents. The following outdoor work was conducted by this section. When a vessel loaded with ETBE arrived at the plant, several workers went onboard and opened the hatch of the hold (an opening and a cover), and then sampled ETBE for quality tests. This is shown in the photograph [fig_ref] Figure A- 27: Sampling work of ETBE [/fig_ref]. First, a risk assessment supervisor performed a basic characterization of the workplace. According to the manager, a certain level of odor emanated during the work. Thus a half-face respirator (with an organic vapor cartridge) was used on a temporary basis while at work. For this reason, it was decided to conduct monitoring without delay. Since workers were exposed to ETBE only during work on this one day, short-term rather than eight-hour monitoring was conducted. Three workers were engaged in the work for approximately 15 minutes or less, and the assumed exposure was "high." [fig_ref] Table A - 24: [/fig_ref] On the day of the monitoring, wind speed was minimal. Thus, the outdoor monitoring was appropriate. Immediately prior to commencement of the work, a passive sampler was attached to each of the three workers to start sampling. The series of tasks consisted of opening the cover of the hatch (the opening seen surrounded by the three workers in the photograph) and inserting a metallic container (held by the worker on the right side in the photograph) into the hatch. Next, they were to draw it up, pour it into another container, and close the hatch cover. Upon completion of the work, the samplers were removed. The risk assessment supervisor conducted observation during the series of tasks. Thus, a value three times the 25 ppm, that is 75 ppm, was used as a short-term occupational exposure limit. The Japan Society for Occupational Health has not set the permissible concentration for ETBE. In this case, the control class turned out to be 2B. Since this work was conducted over a short period of time, its frequency was relatively low, and installation of ventilation equipment onboard was extremely difficult, protective respiratory equipment was required as a risk reduction measure. The protection factor of half-face respirator is 10. Theoretically, this allows for the use of the respirator for a concentration 10 times the reference concentration (occupational exposure limit). Thus the respirator in use was determined to be appropriate. In addition, training was provided on the procedure for the respirator as well as for the periodic maintenance of cartridges. A fit test of the masks (assessment of seal between face and mask) was also conducted. shown in the photograph [fig_ref] Figure A- 28: Loading work of gasoline to a tank truck [/fig_ref]. First, a risk assessment supervisor performed a basic characterization of the workplace. The work included opening the cover of the hatch (the hatch near the worker's feet in the photograph), inserting a gasoline injection pipe (held by the worker in the photograph) into the hatch, and pouring gasoline using a pump. A single injection took about three to four minutes, during which the worker observed the operation while standing at a distance of roughly 1.5 m from the hatch. After the injection, the pipe was pulled out and the hatch was closed. Upon removal of the injection pipe, the pipe was wet with gasoline liquid. As drawing it up, a bucket-type cover was placed on the lower part of the pipe. This was in order to prevent scattering of the liquid. Since one tank truck was loaded with two to six gasoline tanks, the series of work would be completed by repeating this procedure for the number of tanks. The total work time required for the task was 15 to 30 minutes. The worker commented that the odor was detected during the work. Because the work was carried out from the windward side as much as possible, the exposure was estimated to be "medium." This work is carried out daily, and its scale is very large. Since the total number of workers involved throughout Company E is 2,000, ensuring their safety is considered all-important. Thus, a large-scale monitoring plan was prepared [fig_ref] Table A - 24: [/fig_ref]. Since the protocols remained constant regardless of the workers or the workplace, all the drivers of tank trucks were grouped into one SEG (consisting of about 2,000 workers). For six workers in Plant F, short-term exposure monitoring of the work was conducted on a given day. In order to examine seasonal variance, this monitoring was conducted every two months for one year, six times in total. Similar monitoring was also carried out in Plant G. As a result, the planned number of samples came to 72. It was planned to conduct monitoring on a day with wind speeds of 5 m/s or less and no rain. Gasoline and benzene were selected as the substances to be monitored. Gasoline contains about 0.5% benzene, as well as 1% to 10% of toluene, n-hexane, ethyl benzene, and xylene. A past survey had revealed that the health risk of these substances was insignificant when compared to that of gasoline and benzene. This was in consideration of the relationship between the airborne concentrations of these substances and the occupational exposure limits. Thus, no monitoring was performed for these chemicals. The tank trucks were used for loading and unloading of gasoline in the oil refinery for two to three cycles a day. Thus the drivers were subjected to gasoline exposure throughout the day. Eight-hour exposure monitoring had previously been conducted separately for drivers. The result was in an adequately safe zone. Concerning the gasoline-to-truck loading work, it was difficult to identify the specific 15-minute period with the highest exposure during the work. For this reason, it was determined that monitoring was to be conducted throughout the work hours. Immediately before the commencement of the work (before workers got on their tank trucks), the risk assessment supervisor attached an active sampler (activated charcoal and explosion-proof sampling pump) to each worker in order to conduct sampling at a sampling rate of 200 mL/min. Immediately after the workers left their tank trucks, which indicated the completion of the work, the samplers were removed and the sampling was finished. The actual monitoring duration was 15 to 30 minutes. This was the same duration as the work hours. The risk assessment supervisor conducted observation during the entire work. were collected. Since all of the sampling times were 15 minutes or more, the concentration measured at each time weighted average was used to calculate statistical indices, and the control class was determined. The resultant control class for both gasoline and benzene was determined to be 1B. Analysis was conducted on the results in relation to the workplaces and also to the seasons. However, no significant trends were identified. It was considered that the effect of seasons (temperatures) was less likely to be detected since the compositions of gasoline were adjusted depending on them. It was alleged that the workers detected an odor, but the measurement results were lower than expected. It is possibly because the short term occupational exposure limit was considerably high (500 ppm), and the operators were close to the hatch only for a short period of time. From the above results, it was determined that the current work procedure had no issues or problems. For further safety, it was made well known to the tank truck drivers that unless absolutely necessary, during the loading work they should seek to position themselves as far back from the hatch as possible. [fig] Figure A- 23: Conceptual diagram to determine the frequency of reassessment and monitoring Appendix 24: Example of Personal Exposure Monitoring (eight-hour monitoring, test work, organic solvents) [/fig] [fig] Appendix 25: Example of Personal Exposure Monitoring (eight-hour monitoring, painting work, organic solvents) [/fig] [fig] Figure A- 27: Sampling work of ETBE (outdoor, onboard) [/fig] [fig] Figure A- 28: Loading work of gasoline to a tank truck (outdoor) [/fig] [table] Table A -: 24.1. Classification of SEG and assumption of exposure [/table] [table] Table A: Note: Occupational exposure limit of toluene is 20 ppm (ACGIH-TLV-TWA) * SEG; Similar Exposure Group: AM; Arithmetic Mean: [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1539/joh.2018-0060-RA	This Document, “Guidelines for personal exposure monitoring of chemicals” (“this Guideline”), has been prepared by “The Committee for Personal Exposure Monitoring” (“the Committee”) of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a “practical guideline” for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 “Appendices ” are provided in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an “ expert‐centered basic method to reasonably proceed with the assessment and management of risk at workplaces.” It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan.
37afe4dcdeea1adbefe555e16db8d8151de9d1ca	pubmed	The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol	The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol [fig_ref] Figure 1: Handling of specimen by pathologist A [/fig_ref] [bib_ref] The pathology of Wilms' tumour (nephroblastoma): the International Society of Paediatric Oncology..., Vujanic [/bib_ref] ## 5. Open the specimen by a longitudinal incision (bi-valve) to demonstrate the tumour and its relation to the kidney, capsule, and renal sinus (FIG. S1B). [bib_ref] Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to..., Weirich [/bib_ref]. Photograph the tumour, and record the macroscopic appearance. 7. Measure the tumour in all three dimensions, since this will be used for calculating volume. 8. Assess the percentage of necrotic tumour. 9. Take samples required for biology studies (described in the main text). 10. Fix the specimen in formalin (24-48 hours). 11. Samples for histological examination include at least one complete sampled longitudinal slice of tumour and kidney surface, accompanied by a guide block [fig_ref] Figure 1: Handling of specimen by pathologist A [/fig_ref]. If available, use mega-cassettes as it makes histological assessment easier. In addition, sample the following: [formula] a) [/formula] Areas of the tumour that look different macroscopically. It is strongly recommended to state all relevant histological findings with its corresponding block/slide number (for example, 'renal sinus invasion in block A7') as it makes central pathology review easier. It is recommended to make two sets of all sampled blocks at the same time, and send the second set for rapid central pathology review, even if only with a provisional report (final report can be emailed once it is ready). ## Supplementary box 2. histological classification Beckwith and Palmer's criteria for histological sub-typing of Wilms tumours state that one component has to comprise at least 2/3 (66%) of a tumour mass for the tumour to be sub-classified accordingly 1 . Pre-operative chemotherapy results in so-called 'chemotherapy-induced changes' in many Wilms tumours. Therefore, the criteria applicable to sub-classification of primarily operated tumours are modified to take these changes into account and distinguish three different prognostic sub-groups: low, intermediate, and high risk 2,3 . ## Epithelial type wilms tumour The criteria for diagnosing epithelial type Wilms tumour are that the viable part of the tumour must comprise more than 1/3 of the tumour, and of the viable tumour, at least 2/3 consists of epithelial structures ( Stromal type Wilms tumour usually occurs in younger children 5 . However, stromal differentiation may be induced by pre-operative chemotherapy as a stromal type Wilms tumour is far more common in children who have received pre-operative chemotherapy [bib_ref] Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to..., Weirich [/bib_ref]. Stromal type Wilms tumours usually show minimal to moderate chemotherapy-induced changes, since stromal tissue is usually resistant to chemotherapy 5,6 . ## Mixed type wilms tumour The histological criteria for making a diagnosis of mixed type nephroblastoma are: a) the viable part of the tumour comprises more than 1/3 of a tumour mass; b) the viable tumour consists of blastemal and/or epithelial and/or stromal elements, but none of them comprise more than 2/3 of the viable tumour; c) tumours which contain >10% of blastema, even if the predominant components are epithelial or stromal components. ## Regressive type wilms tumour In regressive type Wilms tumour, the previously described chemotherapy-induced changes comprise more than 2/3 of the tumour mass, irrespectively of what the viable part of tumour is (except for diffuse anaplasia). The assessment of the percentage of necrosis/regression is done on both gross and histological examination. Therefore, blocks are taken not only from viable parts of the tumour mass, but also from the parts that show necrotic/regressive changes. ## Wilms tumour with focal anaplasia Wilms tumours which contain one or two foci of anaplasia according to the established criteria (see main text), are still sub-typed and should be reported as, for example, 'Wilms tumour, mixed type with focal anaplasia'. Generally, the size of an anaplastic focus should not exceed 15 mm. However, it is still important to determine the underling sub-type. If the underlying sub-type is blastemal, it is classified as a high risk tumour. ## Blastemal type wilms tumour In blastemal type Wilms tumour, the viable part of the pre-treated tumour must comprise more than 1/3 of the tumour mass, and at least 2/3 of the viable tumour consists of blastema. The blastemal volume is discussed separately as a new item of the pathology protocol in the main text. The blastemal elements are composed of undifferentiated round or elongated cells, which are usually closely packed, and show no evidence of epithelial and/or stromal differentiation. There are several distinctive patterns (e.g. diffuse, serpentine) in which blastemal cells may occur, but they are of no prognostic or therapeutic significance. ## Wilms tumour with diffuse anaplasia Anaplasia occurs in about 5-8% of patients with Wilms tumour 1 . The finding of diffuse anaplasia overrules the diagnosis of any other sub-type of Wilms tumour (for example, it may occur in regressive Wilms tumour), and always upgrades the Wilms tumour to the high risk category. The Wilms tumour with diffuse anaplasia as well as the distinction of focal versus diffuse anaplasia are described in the main article text. [fig] Figure 1: Handling of specimen by pathologist A: Fresh tumour on arrival at the pathology department B: Bi-valved tumour after inking of the surface reveals a multifocal, partly cystic and haemorrhagic tumour that replaces most of the normal kidney parenchyma C and D: examples of a guide block to indicate where each tumour block is sampled Supplementary Box 1. HANDLING OF SPECIMENS BY THE PATHOLOGIST [/fig] [table] 3: The low risk tumours are cystic partially differentiated nephroblastoma (treated by surgery only) and completely necrotic Wilms tumour. The five histological types of Wilms tumours included in the intermediate risk group are regressive type, epithelial type, stromal type, mixed type and focal anaplasia. High risk Wilms tumours are blastemal type and diffuse anaplasia type. All Wilms tumour types are shortly described in the following section. In order to sub-classify and stage Wilms tumour tumour, it is essential to sample tumour according to the UMBRELLA Study protocol, and examine an adequate number of slides. If only a few slides are available, the pathologist should only make the primary diagnosis but should not try to sub-classify tumour.The diagnosis of a completely necrotic Wilms tumour is made when the tumour shows only regressive and/or necrotic changes caused by chemotherapy, in the absence of any viable tumour tissue, especially nests of blastema. The presence of scattered mature tubules, stroma and very small groups of blastemal cells is allowed, as they may represent remnants of nephrogenic rests and is not regarded as viable tumour. The typical histological appearance of pre-treated Wilms tumours is a mixture of necrosis, fibrosis, fibromyxomatous stroma containing lipid-and/or hemosiderin-laden macrophages. Necrosis is most often of coagulative-type. To identify 'ghost' structures a reticulin stain may be useful. Although complete tumour necrosis makes histological diagnosis of any tumour impossible, in many cases 'ghost' tumour structures (mainly blastema, occasionally epithelial elements) can be recognised. In addition, the presence of nephrogenic rests is a very reliable clue that the tumour was a Wilms tumour. Finally, if treated with pre-operative chemotherapy for Wilms tumour, other renal tumours (such as clear cell sarcoma of the kidney, rhabdoid tumour of the kidney, renal cell carcinoma) show only minimal to moderate chemotherapy-induced changes 4 . [/table] [table] TABLE 2: The rest of the tumour can be stromal and blastemal, but only up to 10% of [/table]	None	https://www.nature.com/articles/s41585-018-0100-3.pdf	None
ce5a4d36a0cab53fa9e2722023e1f4b028fcd1e6	pubmed	Development of the Korean Academy of Medical Sciences Guideline for Rating the Impairment in the Brain Injured and Brain Diseased Persons with Motor Dysfunction	Development of the Korean Academy of Medical Sciences Guideline for Rating the Impairment in the Brain Injured and Brain Diseased Persons with Motor Dysfunction To develop an objective and scientific method to evaluate the brain injured and brain diseased persons with motor dysfunction, American Medical Association's Guides to the Evaluation of Permanent Impairment was used as an exemplar. After the motor dysfunction due to brain injury or brain disease was confirmed, active range of motion and muscle strength of affected extremities were measured. Also, the total function of extremities was evaluated through the assessment of activities of daily living, fine coordination of hand, balance and gait. Then, the total score of manual muscle test and functional assessment of impaired upper and lower extremity were added, respectively. Spasticity of upper and lower extremity was used as minus factors. Patients with movement disorder such as Parkinson's disease were assessed based on the degree of dysfunction in response to medication. We develop a new rating system based on the concept of total score. # Introduction The permanent neurologic impairments following traumatic brain injury and brain disease is divided into physical and neuropsychological dysfunction [bib_ref] Rehabilitation after traumatic brain injury, Cifu [/bib_ref]. Physical impairment is further divided into impairment of upper and lower extremity and impairment of cranial nerves. To secure the rights of disabled people due to brain injury and brain disease, an objective assessment of the permanent impairment and its degree is necessary. Current Korean assessment standards for the impairment evaluation is based on over 30 different laws including Welfare Law for the Disabled, Workers' Compensation Law, etc. However, each standard with different levels of impairment or disability leads to a confusion in which an impairment or disability is diagnosed into different levels [bib_ref] The disability evaluation system in U, Lee [/bib_ref] [bib_ref] Problems of assessment of physical impairment and disability evaluation in central nervous..., Lee [/bib_ref]. Also, the compensation of the disability requires different forms of medical certificate for each standards with further inconvenience. In the United States of America, there is a scientific guideline to the evaluation of permanent impairment, established by the American Medical Association (AMA). Likewise, we need a guideline for rating the permanent physical impairment suitable for our cultural and social background. Thus, as a part of developing an objective, scientific systemic standard for the assessment of physical impairment of Korea, this study aims to develop an objective and scientific evaluation tool for motor impairment with brain injury and brain disease, based on AMA Guides for Rating the Permanent Physical Impairment. # Materials and methods A committee of neuro-dysfunction-pain-assessment with neurosurgeon, neurologist, physiatrist, psychiatrist, and anesthesiologist who are experienced at the impairment evaluation of brain injury and brain disease and pain was assembled. This brain injury and brain disease motor dysfunction study team comprise a third party consisting of physiatrists and neurologist. After the analysis of physical impairment assessment standard for central nervous system from Guides to the evaluation of permanent impairment 5th edition of AMAin 2001, we planned to develop a motor impairment assessment tool for physical impairment suitable for Korea, based on the American standard. It was set as a principle that the developing physical impairment assessment tool should include the identification of brain injury and brain disease through clinical symptoms and signs, and diagnostic studies such as brain magnetic resonance imaging, and should only be applied to the dysfunction of upper and lower extremities owing to brain injury and brain disease. In motor dysfunction such as Parkinson's disease, the degree of impairment is assessed in relation to the response to medication. Assessment of upper extremity impairment due to brain injury and brain disease To evaluate the upper extremity impairment due to brain injury and brain disease, manual muscle test (Medical Research Council scale) (7) is used to assess the muscle power. Muscles to evaluate include shoulder flexor, extensor, abductor and adductor, elbow flexor and extensor, forearm pronator and supinator, wrist flexor, extensor, abductor and adductor, second to fifth finger flexors, extensors, abductors and adductors, thumb extensor and oppositor. Each muscle power is graded between zero (complete paralysis) to five (normal) points, total of which is 90 points. In cases where the manual muscle test is not possible due to accompanied contracture or manual muscle test needs to be corrected for the limited range of motion, grading system of active range of motion is used. Measured active range of motion of the involved joint is scored as percentage of normal active range of motion. When normal active range of motion is 100%, maximal active range of motion of the joint is 5 point, and 0% of total ankylosis of the joint is 0 point [bib_ref] Evaluation of clinical results following peripheral nerve suture, Omer [/bib_ref]. With impairment of both upper extremities, the value of both muscle power added and divided by two is used. With motor impairment of an upper ex-tremity, grasp power and fine coordination of hand are evaluated. The total function of an upper extremity is assessed with 18 criteria of activities of daily living (ADL) . The assessment of minute activities of daily living using both arms contains 9 criteria including feeding with spoon while fine coordination of both hand is assessed. Each criterion is assessed with scales of one to five. It is scaled as one (totally dependent or unable to do by oneself) when independent activity is impossible, and as five (totally independent or able to do very well) when capable of independent activity. The degree of spasticity due to brain injury and brain disease is assessed with modified Asthworth scale [bib_ref] Interrater reliability of a modified Ashworth scale of muscle spasticity, Bohannon [/bib_ref] and, when the functional impairment is exacerbated with spasticity, it is applied as a minus factor. Assessment of lower extremity impairment due to brain injury and brain disease To evaluate the lower extremity impairment due to brain injury and brain disease, manual muscle test (Medical Research Council scale) (7) is used to assess the muscle strength. Muscles to evaluate include hip flexor, extensor, abductor, adductor, internal and external rotator, knee flexor and extensor, ankle dorsiflexor, plantar flexor, invertor and evertor, and toe flexors and extensors. Each muscle power is graded between zero to five points, total of which is 70 points. Like the impairment of upper extremity, in cases where the manual muscle test is not possible due to accompanied contracture or manual muscle test needs to be corrected for the limited range of motion, grading system of active range of motion is used. With impairment of both lower extremities, the value of both muscle strength added then divided by two is used. The total functional assessment of lower extremity includes changing position and maintaining balance, walking and moving outside and otherwise [fig_ref] Table 2: Functional mobility tests of the lower extremity in brain injured personsScoring system [/fig_ref]. When orthosis is necessary for gait, the kind of orthosis and the degree of dependency are evaluated. Also, when the muscle spasticity of lower extremity with brain injury and brain disease exacerbates the disability, it is applied as a minus factor. # Results Timing of disability evaluation for the brain injured persons The primary assessment of motor dysfunction due to brain injury and brain disease is performed at least one year postinjury when the functional improvement is not noted even after six or more months of rehabilitation treatment. With severe brain injury, impairment assessed within one year of injury needs to be re-evaluated after two years. For patients with Parkinson's disease or motor dysfunction, drug-on state maintained over 50% of a day with adequate (best) medication is used as the assessment state. Criteria for rating the motor impairments of upper extremities relating to central impairment As a criterion for impairment of upper extremity in brain injury and brain disease, the basic normal score is total 180 points with 90 points of muscle test and 90 points of functional test. With both upper extremities impairment, muscle power for each upper extremity is added and divided into two. Impairment rating is divided into four levels like the standard for AMA. Level one is very severe upper extremity impairment of 18-73 points with 0-34% of normal function remaining and level four is minimal upper extremity impair-ment of 155-178 points with 85-99% of normal function remaining. Impairment rating of dominant hand, non-dominant hand, and both hands impairment in relation to whole body is decided based on the principles of the AMA Guides [fig_ref] Table 3: Criteria for impairment of upper extremities in brain injured persons [/fig_ref] ## 4). Criteria for rating the motor impairments of lower extremities relating to central impairment For impairment of lower extremity with brain injury and brain disease, the basic normal score is total 120 points with 70 points of muscle test and 50 points of functional test. Impairment rating is divided into four levels, ranging from one to four like the standard for AMA. Level one is very severe lower extremity impairment of 10-42 points with 0-29% of normal function remaining, and level four is minimal lower extremity impairment of 98-109 points with 80-99% of normal function remaining. Since the impairment rating for lower extremity due to brain injury and brain disease is lower than other impairments, it was up-regulated than the AMA Guides [fig_ref] Table 5: Criteria for impairment of lower extremities in brain injured persons [/fig_ref]. # Discussion Physical impairment is a state of functional or structural impairment of health in a person. Thus, impairment is a medical concept that needs medical evaluation. Also, the permanent physical impairment means the state in which the symptom and sign are fixed after enough time needed for treatment and any further treatment would be futile in changing the current state of health. This impairment limits a person in activities of daily living, and the degree of functional restraint is expressed as impairment rate (3). In Korea, the compensatory disability rating standard in relation to occupation is the estimation of loss of efficiency. It is well established in McBride's disability evaluationthat it is used as the standard in the fields of law enforcement and insurance-related compensatory work. However, Mc-Bride's disability evaluation was enacted in 1963 that is different from current state of Korea. Also, it is not adequate to be used as the standard for impairment rating for brain injury and brain disease related motor dysfunction [bib_ref] Assessment of physical impairment and disability evaluation in head injury: comparison between..., Lee [/bib_ref]. The Guides to the Evaluation of Permanent Impairment of AMA uses medically established impairment rate with high objective and scientific reliability. In this study, the scientific and rational guideline for impairment rating of AMA is used as an exemplar to evaluate motor dysfunction of the brain injury and brain disease. For more objective evaluation of motor dysfunction, functional assessment tools as well as basic physical examination and neurophysiological assessment are used. The impairment rating of upper extremity after brain injury or brain disease is divided into four levels like that of AMA Guides. The AMA Guides evaluates the functional limitations of upper extremity due to diseases of central nervous system according to its influence on the activities of daily living. It is believed that the basic tasks of everyday living depend on dexterous use of the dominant upper extremity. The impairment rating level is determined from neurological examination of motor strength, coordination, and dexterity. Functional activities such as buttoning a shirt, lacing shoes, writing, and performing a pegboard task can assess abilities needed for daily activities. Also, impairment of lower extremity relating to the injury of central nervous system is assessed as station and gait impairment. In other words, the degree of independent standing, independent gait, walking inside and outside, climbing stairs and station and gait function of legs is evaluated to assess its impairment. However, the problem with criteria for rating impairment of upper and lower extremity relating to central impairment in AMA Guides is that each standard without specific explanation may lead to different conclusion of impairment rate, depending on the eval-uator [bib_ref] The disability evaluation system in U, Lee [/bib_ref] [bib_ref] Assessment of physical impairment and disability evaluation in head injury: comparison between..., Lee [/bib_ref]. This study aims to develop a physical impairment assessment tool to resolve such problems. After thorough evaluation of muscle power, range of motion, spasticity, activities, and whole function of upper and lower extremities in brain injury and brain-diseased people with motor dysfunction, the result labelled as points to determine each impairment level. To further assess the impairment of upper extremity in detail, basic activities of daily living are divided into specific criteria. For the evaluation of fine coordination of hands, several functional assessment tools are included. The total function of lower extremity assessment is based on the specific details of balance and gait function. In addition, with respect to the Korean culture, standing up from floor, using public transportation criteria are added [bib_ref] Functional evaluation of elderly with modified Barthel index and modified Lambeth disability..., Rah [/bib_ref]. Each assessment criteria is given five-point scale according to the performance. National pension impairment assessment provision attached chart #1 (13) is used after considerable change to increase the reliability of criteria in assessing upper and lower extremity function, since it is described as the functional assessment tools of national pension rules of disability judgement attached chart #1 enacted according to the Law of National Pension #58 and its Enforcement Ordinance #41-4. Each of total points of muscle power in upper and lower extremity as well as that of functional assessments is used to decide rating impairment. According to the rules of degree of disability in the Law of Welfare of Disabled People, this grading system is reverse to AMA Guides. Impairment class one is severe impairment with less than 34% of normal function remaining for upper extremity and less than 42% of normal function remaining for lower extremity. Impairment class four indicates minimal impairment with 85-99% of normal function remaining for upper extremity and 80-99% of normal function remaining for lower extremity. The advantage of newly developed physical impairment assessment standard in this study is that more objective and rational determination of rating impairment in motor dysfunction of upper and lower extremity is possible. Also, while the AMA Guides divided impairment into four classes, the newly developed class of impairment is expressed in percentage and can be classified into six to eight levels of impairments. The time of evaluation of impairment due to brain injury and brain disease is when the symptom and sign are fixed after enough treatment. The guides to the evaluation of permanent impairment of AMA states that the maximal medical improvement should be done when the change of impairment rate is less than three percent despite further treatment of one year [bib_ref] Problems of assessment of physical impairment and disability evaluation in central nervous..., Lee [/bib_ref]. By this period, the impairment is assumed to be permanent. Current national pension rules of disability judgement in the Law of Korean National Pensionstates this maximal medical improvement as the recovery date of impairment. This period varies depending on the brain injury and brain disease, however, except for vegetative states, it is to be at least 12 months in most of the cases, after the initial date of medical examination. In the rules of degree of disability in the Law of Welfare of Disabled People (14), the maximal medical improvement is to be more than six months after developing the injury or disease which is shorter than that of AMA Guides. There is a complementation of a re-evaluation after 2 yr so that the possible change after 6 months of injury or disease can be confirmed. It is to give more faster welfare benefit to the disabled people. Nevertheless, it has in reality been the cause of many problems in defining the impairment level. It should be stated in all forms of physical impairment assessment standards that the period of maximal medical improvement should be assessed after 6 months of enough rehabilitation since early rehabilitation and the period of rehabilitation can make difference. In patients with movement disorders including Parkinson's disease, response to medication can be variable. If performance efficiency is more than 50% greater in medication on-state than off-state, physical impairment should be made when the drug response is maximal [bib_ref] Vermeulen M. The AMC Linear Disability Score in patients with newly diagnosed..., Weisscher [/bib_ref]. For one upper extremity impairment due to the dysfunction of central nervous system, dominant and non-dominant upper extremity function is separately assessed to estimate impairment rate in the AMA Guides (6). However, this has problems. First, it is difficult to define a dominant hand after the brain injury. Second, it might work as a factor to decrease the effect of rehabilitation, even though activities of daily living can be improved with enough rehabilitation treatment. But, considering the nature of Korean culture in which using left hand is regarded as a disability and most people tend to use the right hand as the dominant one, the up-regulation of the impairment rate of dominant upper extremity is decided. Limitations to further application of this physical impairment assessment are as follows. First, the effectiveness might be compromised since the time needed to evaluate increases when many fields of assessment are included. Second, it is necessary to educate the disability evaluating specialists for more efficient evaluation of the impairment and/or disability. However, in case of general hospitals with physical and occupational therapists, brain disease and brain injury impairment evaluating specialists can colligate the result after the initial assessment is done by the therapists with minimal problem. Third, verification steps for this assessment tool are required. To resolve these problems, further studies on the correlations between late physical impairment assessment tools and newly developed physical impairment assessment standard and between late impairment level of AMA Guides and new impairment assessment standard would be helpful. [table] Table 2: Functional mobility tests of the lower extremity in brain injured personsScoring system (1-5) is the same as tests of the upper extremity (mimimum 10, maximum 50). [/table] [table] Table 4: Criteria for rating impairments of upper extremities relating to central impairment [/table] [table] Table 5: Criteria for impairment of lower extremities in brain injured persons [/table] [table] Table 3: Criteria for impairment of upper extremities in brain injured persons [/table] [table] Table 6: Criteria for rating impairments of lower extremities relating to central impairment AMA, American Medical Association. [/table]	None	None	To develop an objective and scientific method to evaluate the brain injured and brain diseased persons with motor dysfunction, American Medical Association's Guides to the Evaluation of Permanent Impairment was used as an exemplar. After the motor dysfunction due to brain injury or brain disease was confirmed, active range of motion and muscle strength of affected extremities were measured. Also, the total function of extremities was evaluated through the assessment of activities of daily living, fine coordination of hand, balance and gait. Then, the total score of manual muscle test and functional assessment of impaired upper and lower extremity were added, respectively. Spasticity of upper and lower extremity was used as minus factors. Patients with movement disorder such as Parkinson's disease were assessed based on the degree of dysfunction in response to medication. We develop a new rating system based on the concept of total score.
1c385de6f33aee8064238497ec2c31bf9f6e9b19	pubmed	Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic	Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic # Abstract The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities. # Introduction The outbreak of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan and, despite the drastic safety measures taken by the Chinese government, rapidly evolved into a pandemic. Consequently, healthcare facilities have intensively decreased elective activities both to avoid potential transmission of the virus and to shift human and structural resources to the management of COVID-19. Beyond these general measures, some gastroenterological activities have been triaged according to risk and need, including endoscopic procedures, which result in aerosolisation of the virus. Therefore, several scientific societies have released recommendations to prioritise indications and implement safe working protocols of endoscopic clinical practice during the pandemic.In recent years faecal microbiota transplantation (FMT) has revolutionised the management of recurrent Clostridioides difficile infection (CDI). As CDI continues to be associated with significant morbidity and mortality,FMT should be considered among the non-postponable gastroenterological procedures during the COVID-19 pandemic, at least in high-risk patients with CDI where FMT could be life-saving and the benefits outweigh the risks. FMT has become increasingly standardised and safe, and guidance on the general organisation and the criteria required to establish a stool bank has recently been released.However, this pandemic has raised several issues and concerns regarding the impact and risks of FMT related to SARS-CoV-2, as the risk of a medium-to long-term cohabitation with this pandemic is inevitable. Recently, the FDA has recommended that only FMT products generated from stool donated before 1 December 2019 should be used until proper SARS-CoV-2 testing of donors and/or stool 'as feasible' and screening protocols become available,and some FMT centres have suspended the active recruitment of new donors until FMT protocols are able to screen donors for COVID-19 and specific stool testing is available.Therefore, we aim to provide guidance regarding the reorganisation of FMT services in light of the evolving COVID-19 pandemic to assure the highest level of safety for the patients and healthcare providers who perform FMT. # Methods The main topics of this position paper were proposed by two authors (GI and GC) and reviewed and refined by the working group, who were selected as being internationally acknowledged experts in FMT and stool banking. To update and extend on previously published guidelines in light of the evolving COVID-19 pandemic, the following key topics were identified by GI and GC and approved by all authors: patient selection; donor recruitment and selection; stool manufacturing and supply; FMT procedure and follow-up of treated patients. In addition to pragmatic expert guidance, a literature review was conducted to capture best available current evidence. Recommendations from the major international medical institutions (eg, WHO, European and US Centers for Disease Prevention and Control) and from scientific societies involved in digestive disorders were also reviewed. However, in view of the limited evidence and need for urgent guidance, a formal standard consensus methodology was not followed. The first draft of the paper was primarily written by a small task force (GC, GI, CRK, BHM and ZK), and iterative changes were made via virtual discussion among all experts, including three rounds of revision, until consensus was reached. The final position paper was approved by all experts after further virtual discussion. ## Patient selection recipients of fmt for recurrent/refractory cdi The COVID-19 pandemic is going to affect the placement of FMT within the treatment algorithm for patients with recurrent or refractory CDI (figure 1). CDI is present when it recurs within 8 weeks after the onset of a prior episode, provided that symptoms of the previous episode have been resolved after completion of initial treatment. Refractory disease occurs when CDI is unresponsive to the antimicrobial treatment and there is persistence of diarrhoea with positive C. difficile toxin, or of diarrhoea without toxin in the absence of other plausible causes of diarrhoea.The indication for FMT should be considered on a case-by-case basis, taking into account factors including: number and severity of previous CDI episodes; prior treatment modalities administered and alternative possible strategies; comorbidities; and the safety, feasibility and practicality of FMT administration, given the specific complexities presented by the COVID-19 pandemic. At present, it may be pragmatic to consider treating many 'typical' recurrent CDI patients-who would have received FMT in the pre-COVID-19 era-with other approved therapies, including vancomycin, fidaxomicin and/or bezlotoxumab. Specifically, there may be a role for tapered and pulsed vancomycin regimens or extended fidaxomicin, although there is a paucity of data.This strategy may have the dual benefit of effectively treating a patient with recurrent CDI, while also creating a 'window' of time in which clinical developments may occur which could facilitate safer administration of FMT-for example, improvements in donor screening techniques or adequate organisation of the FMT centre. However, during the COVID-19 pandemic there are still likely to be a number of patients with presumed recurrent/refractory CDI for whom FMT is thought to be the most appropriate therapy-for example, especially those with fulminant CDI who have limited therapeutic alternatives and are felt to not be surgical candidates. In all such cases, careful evaluation of diagnostic certainty of CDI causing symptoms needs to be made prior to considering FMT. Furthermore, it would be appropriate to have a detailed discussion during the consent process with such patients to explain the complexities and uncertainties associated with FMT, and alternative treatment options during the pandemic. A further uncertainty relates to the number of FMTs that may be appropriate in a CDI treatment regimen. Specifically, protocols related to pseudomembranous colitis have reported good outcomes either through repeating FMT every 3 days until pseudomembrane resolutionor, alternatively, giving 5 days of vancomycin in the case of FMT failure before a subsequent FMT.Almost all FMT studies in CDI and clinical guidelines recognise that sequential FMT has higher efficacy than a single infusion, at least in specific situations such as severe CDI or enema infusion. Therefore, when clinicians are committing to FMT as a treatment approach in the time of COVID-19, it seems reasonable that they are prepared to offer at least a second FMT to a patient in the event of initial FMT failure, using, if possible, aliquots from the same donor of the first infusion to reduce the risk for transmission. However, recognising the risks inherent in FMT administration at present, as well as the limited FMT stocks available for the forseeable future, stool banks and/or clinicians should consider on a case-by-case basis whether offering two or more FMTs for a patient with recurrent/refractory CDI is feasible, safe, appropriate and equitable compared with other patients who may also be in need. Other issues at the standard questionnaire? ## Laboratory testing Standard blood and stool exams Nasopharyngeal swab and serology for SARS-CoV2 ## Donation: Potential exposure to, clinical picture suggestive of, or known diagnosis of, Other issues at the standard questionnaire? Rapid stool assay for common pathogens and SARS-CoV-2 (advocated) When FMT is being considered in a COVID-19-positive patient with CDI, an additional consideration to the above should be whether the FMT procedure can be postponed. The treatment for recurrent/refractory CDI should be considered on a case-bycase basis, taking into account all the above discussed factors and also the COVID-19-related clinical picture. In such cases, a thorough multidisciplinary discussion among FMT experts, infectious disease physicians and intensivists/anaesthetists is mandatory. ## Donor recruitment and screening To minimise the risk of COVID-19 infection of donors and recipients, we suggest specific changes in the pathway for donor recruitment and screening, principally including the evaluation of clinical history, laboratory testing and checks on the day of donation. For hospital-based stool banks, donors should also sign an informed consent, or at least be thoroughly informed by the physicians (according to local rules) to accept the potential risk of being infected with COVID-19 when they come to the hospital for testing and donation.The suggestions below are similar to those already released by some regulatory institutions (eg, the US Food and Drug Administrationand the Italian National Transplant Centre 23 ) and differ slightly from those previously released by our group.Such measures should be adapted to local healthcare systems and updated accordingly with further evidence on COVID-19. ## Questionnaire and clinical history Although the initial clinical assessment and questionnaire administration are usually carried out in the FMT centres, in the COVID-19 era they can be generally implemented via telemedicine to avoid unnecessary exposure of potential donors to the hospital. The donor health questionnaire should be sent earlier to the candidate donor electronically, and the interview can be conducted through a video/phone consultation. For hospital-based stool banks, healthcare visits should be kept only on a case-to-case scenario, based on the physician's discretion (eg, clinical issues, technical obstacles, need for a cultural-linguistic mediator) or on donor desire for healthcare visit (eg, impossibility for a confidential interview in a reserved space at home). Additional items should be included in the clinical questionnaire. First, physicians should specifically assess if the donor has been diagnosed with laboratory-confirmed SARS-CoV-2 infection or has been closely exposed to subjects with suspected or proven infection. In addition, potential donors should be clinically assessed for COVID-19 including, as suggested by the Center for Disease Control and Prevention (CDC): fever, cough, dyspnoea, chills, anosmia or ageusia, sore throat, muscle pain not explainable by alternative diagnosis within the previous 30 days.If the potential donor has any symptoms suggestive of COVID-19, he/she should be temporarily excluded from the next stage of the laboratory screening and donation process. Moreover, healthcare workers actively involved in the management of patients should be excluded too. ## Laboratory testing All donors who pass the questionnaire should undergo laboratory examinations.Specific testing for the detection of SARS-CoV-2 must be added to the standard panel of donor laboratory testing,including at least nasopharyngeal swab and reverse transcription polymerase chain reaction (RT-PCR) assay and serology.Where available, validated molecular stool testing should be performed on the donated material (figure 2), and efforts from centres to include it in the donor screening are strongly advocated. All subjects who test positive must be temporarily excluded from donation, and advised of the result and to take precautionary measures against transmission, based on local protocols. Some considerations about COVID-19 testing are necessary. First, there is no diagnostic testing so far that guarantees full accuracy of the diagnosis of COVID-19, nor can a single testing be used for all stages of the disease, so the examinations should be combined at different time points of the donor screening. Moreover, there is only limited evidence on COVID-19 diagnostics, so our suggestions could be updated once more consolidated data are available. These diagnostic limits should be discussed with the recipient. ## Guidelines So far, the nasopharyngeal swab is the most commonly used test for diagnosis of pulmonary COVID-19. Viral RNA in the nasopharyngeal swab is detectable from a few days before start of the symptoms, peaks within the first week of symptom onset, and starts to decline by week 3, becoming subsequently undetectable.Serological diagnosis is especially important to intercept subjects with few or late symptoms where the nasopharyngeal swab could be less sensitive. IgM and IgG ELISA have been found to be positive from day 4 after symptom onset, with a peak after 2-3 weeks from the start of the infection ; specifically, IgM lowers at week 5 and disappears from week 7 of the illness, while IgG persists beyond week 7.Combined nasopharyngeal swab and IgM testing have been shown to increase diagnostic accuracy, so we recommend using them together to screen donors.However, the long-term persistence of antibodies remains unknown. The screening of donor stools through a molecular test for SARS-CoV-2 has been advocated as the safest way forward to prevent the potential risk of viral transmission. 14 However, although there is recent evidence that SARS-CoV-2 can be found in faecesand that it actively infects human gut enterocytes,it is not yet clear if the presence of faecal viral particles indicates infectivity, and if asymptomatic serologically positive individuals can also shed the virus that way. Moreover, several studies report on longer faecal excretion than nasopharyngeal route (table 1). Recently, local protocols for stool SARS-CoV-2 viral quantification have become available, and quantification has yielded promising results.Based on these considerations, positivity of PCR on nasopharyngeal swab/stool and/or IgM serology should be absolute criteria for exclusion from donation for at least 8 weeks; after that time frame, the potential donor could be considered again and re-tested. In case of IgG seroconversion for SARS-CoV-2, a donor should be excluded for 30 days and then re-tested with questionnaire and molecular stool testing; thereafter, if negative for stool testing and symptom-free, the donor should be allowed to donate. Finally, as the COVID-19 diagnostics are still evolving, these suggestions should be updated as soon as further evidence is gained and new tests (eg, those on saliva) are developed. ## Donation workflow and quarantine The donation workflow is summarised in figure 2. Potential donors who pass the questionnaire and laboratory testing described above can start providing faecal material. A dedicated toilet at the stool bank should be reserved for stool collection, and high-touch surface areas should be cleaned after each donation. If not operationally possible, stool should be collected at home with standard recommendations.At each donation, donors should be checked, beyond the standardised questionnaire already suggested, 12 for: diagnosis of SARS-CoV-2 infection; household exposure to subjects with suspected or proven infections; clinical symptoms of COVID-19 (as described above) not explainable by alternative diagnosis, since the last donation. Donors who prove to be positive for one of these items must be excluded from donation and previously donated stool, up to 4 weeks before the occurrence of symptoms/COVID-19 diagnosis, should be discarded as initial evidence suggests that SARS-CoV-2 is able to remain in stools up to 4 weeks after infection.For each donor, donated stools must be either: (1) immediately manufactured into FMT preparations, frozen and stored at −80°C, and finally quarantined until that donor has passed a further donor screening (to be repeated every 8-12 weeks) at the end of a period of donation, and be available for administration to patients only after this further check; or (2) assessed directly with validated molecular stool testing for common pathogens and for SARS-CoV-2. In this case, if direct testing is negative, they can be released for use without the need for quarantine, as recommended in our previous guidelines. 12 ## Stool manufacturing Broadly, there are two models for preparing FMT: patientselected fresh FMT or frozen FMT manufactured by a stool bank from healthy donors. However, due to factors related to safety, access and economics, the frozen FMT model manufactured by stool banks is widely adopted by clinicians. Although rare clinical scenarios may require the use of fresh FMT prior to COVID-19, to date the fresh FMT model should be avoided to facilitate close adherence to recommended safety measures during the COVID-19 pandemic.Although the infectivity of RNA-positive SARS-CoV-2 stool is unknown, preliminary data suggest that viral shedding in the stool takes approximately 2-4 weeks,gastrointestinal symptoms commonly precede respiratory symptoms,and viral shedding in stool may lag behind despite clearance in respiratory samples. These data confirm the need for best practices in the manufacturing of FMT preparations. In our previous consensus report we recommended high-quality microbiology facilities (at least biosafety level 2) with robust standard operating procedures that allow safe processing of human samples by trained staff.Additionally, appropriate documentation, robust quality processes, retention of donor samples for further checks and standards for release of the final product are recommended. Therefore, as high safety measures were already recommended by previous guidelines, 12 no significant changes in the stool manufacturing working protocol are currently needed to deal adequately with COVID-19. ## Fmt procedure and follow-up routes of fmt delivery: which is best during covid-19? Endoscopic FMT routes are most commonly used worldwide. Overall, endoscopic procedures have the potential to facilitate the transmission of virus to healthcare workers and patients (due to the close distance between patients and physicians, exposure to splashes, mucus or saliva during upper endoscopy, potential oral-faecal transmission during lower endoscopy, or by creating aerosol), although early real-world data suggest that the risk of viral transmission through endoscopy may be low. For these reasons it is prudent to create a process by which risks are minimised. Professional societies have released guidelines on gastrointestinal endoscopy and the use of personal protective equiptment (PPE) for these procedures in the setting of COVID-19. When FMT is administered via colonoscopy, it is recommended that the strict procedures to minimise risk before, during and after the procedure be followed (detailed in the section below). The only method of FMT delivery which does not generate aerosol is the ingestion of encapsulated donor stool. This is the preferred method, when available, to minimise transmission risks and usage of PPE which may be in limited supply. However, we acknowledge that capsulised FMT is still not widely available for use at all centres. Delivery by retention enema would be less likely to be aerosol generating and can be performed by a single healthcare provider, minimising their exposure and PPE utilisation, but efficacy appears lower than endoscopic administration 6 and patients may need multiple treatment courses, which would increase their exposure to the healthcare environment. FMT via nasoenteric or colonic transendoscopic enteral tube is used widely in some centres, particularly in elderly hospitalised patients. The otolaryngology literature considers procedures of the head and neck to be high risk in patients with confirmed or suspected COVID-19.The nose and nasopharyx have been shown to be reservoirs of high concentrations of the SARS-CoV-2 virus,and placement of the tube through the nasopharynx could cause particles to become aerosolised. Adequate topical analgesia to make the procedure comfortable for the patient and minimise coughing, gagging and sneezing is recommended. Furthermore, staff numbers present should be minimised. Those present should wear full PPE, including N95 masks and face shields/goggles, gloves, hair nets, and dedicated operating room or procedural areas, ideally with negative pressure, are advised. Generally, it is advisable that FMT centres determine preferred routes of delivery on a case-by-case basis and according to their expertise in one or another route. ## Endoscopic procedures Several scientific societies have issued recommendations for healthcare facilities providing elective procedures. Restrictions will vary based on country or state, and local considerations should be identified and followed. When FMT is being performed in an endoscopy unit, the following procedures are advisable to minimise risk to staff and other patients. Patient triage: Patients scheduled for outpatient elective endoscopic FMT should have temperature checked and be questioned about symptoms including fever, cough, dyspnoea, chills, anosmia or ageusia, sore throat and muscle pain on arrival for the procedure and prior to entering the facility. In patients who are suspected of, or have a known diagnosis of COVID-19, the physician should assess if the procedure is postponable based on the clinical picture of the patient and, in case, he/she should be instructed to perform a nasopharyngeal swab and to resume oral vancomycin to prevent recurrence. The outcome of these checks must be tracked in an appropriate register. Patients who present with symptoms suggestive of COVID-19 should be asked to contact their primary care provider for further evaluation. Patients should be given a cloth or surgical facemask to wear on arrival at the facility and strict social distancing should be maintained in waiting room areas, with chairs at least 2 metres apart. Visitors/family members should be prohibited from remaining on site and can be telephoned afterwards to meet the patient at the door at time of discharge. PPE: It is recommended that all patients, healthcare providers and staff wear surgical facemasks at all times. FMT procedures involving mucous membranes including nasoenteric tube insertion, upper endoscopy or colonoscopy require N95 masks and face shields to be worn by proceduralists and any members of the healthcare team present. Staff should be educated on the proper methods for donning and removing PPE. Recovery room: Patients should ideally recover in the room in which the procedure is conducted, which can then be terminally cleaned before being used for the next patient. If space does not permit, then the patient should be recovered in an area in which social distancing can be maintained (at least 2 metres between patients). There is no sound basis for asking patients to retain donor material for longer than is necessary to recover from sedation. ## Follow-up Patients should be called 24 hours after the procedure to assess any short-term adverse events or procedural complications. Follow-up appointments should be conducted using telemedicine as per institutional protocols, when possible. Follow-up evaluations at different time points (between 1 and 8 weeks) are advisable to discuss post-FMT symptoms, assess for signs of recurrence and enquire about symptoms of infection. Patients should be instructed to contact the provider immediately if symptoms of infection develop or if they are diagnosed with COVID-19 within 28 days of the procedure so that contact tracing and monitoring of exposed staff can be performed, as well as 'look-back' testing of retained donor stool samples. If patients develop diarrhoea suggestive of CDI recurrence, they can be triaged by telephone to determine whether they need to seek care at the hospital or whether they can submit stool for testing and/or start empiric anti-CDI therapy at home. Those whose prior CDI episodes have been severe or who report diarrhoea suggestive of CDI recurrence together with high fevers, severe abdominal pain or vomiting should be evaluated in an Stool donation ► Repeat standard and COVID-19 screening interview (preferably remote assessment prior to access to the clinic) ► Checkpoint at entrance (body temperature, subjects must wear surgical mask, hand wash, company forbidden) ► Direct stool testing for SARS-CoV-2 and/or common pathogens; quarantine approach as potential alternative ## Guidelines Stool handling ► Stool transferred to microbiological laboratory by dedicated health workers ► Retention of stool samples for 'look-back' testing is recommended ► Stool processing conforms to local standard operating procedures and biosafety protocols; at minimum, biosafety level 2 is advised FMT by endoscopic procedure ► Access to the endoscopy service: -Differentiate logistic pathways of patient access according to COVID-19 diagnosis -Outpatients can be accompanied by a caregiver -Checkpoint at entrance (body temperature, patients and caregiver must wear surgical mask, hand wash) ► Management of the endoscopic procedure: -Differentiate endoscopic and recovery room (dedicated rooms for COVID-19 patients) -Dedicated healthcare professionals for COVID-19 -Staff present in the endoscopic room must be protected for drops in air (wear FFP2, protect eyes, wear double gloves, wear shields or hats) -Patients should wear surgical mask ► Discharge of the patient: -Keep differentiated logistic pathways according to COVID-19 diagnosis -Inpatient return to the ward accompanied by dedicated healthcare workers -Outpatient discharged after brief observation, medical and nurse staff report follow-up instructions to caregivers via remote contact ## Follow-up Follow-up visits should preferably take place via remote assessment (medical interview by voice or video call, reports sent by email), outpatient visits should be limited to cases where in-presence assessment is mandatory Research activities ► Ongoing trials should adapt their protocols according to the changing status of COVID-19 ► Upcoming trials should be designed taking into account the same security measures proposed in this document for clinical practice ► Virtual visits (especially those after treatment) should be considered rather than in-person assessments ► Donor recruitment protocols and workflows must follow international guidelines ► The use of multi-donor FMT should only be considered within a FMT trial if there is strict adherence to proposed security measures ► The use of frozen stools is preferred over fresh material, although SARS-CoV-2 can probably survive the storage conditions ► Highly safe environment (at least biosafety level 2) for stool manipulation ► Use of registers, application of the same strict traceability protocols already recommended for clinical practice emergency room or physician's office. If the conditions and indication exist, further treatment with FMT may be considered. ## Research activities The enormous potential impact of COVID-19 on many facets of research (including the undertaking of clinical trials) has already been recognised. This clearly applies to the very active field of FMT clinical trials. Specifically, prior to the COVID-19 pandemic there were >300 trials involving FMT registered on www. clinicaltrials. gov, involving a myriad of indications from autism to ulcerative colitis.In the months leading up to the current pandemic there were two important safety alerts from the USA relating to the possible transfer of pathogens to patients via FMT, resulting in one death and five hospitalisations. Before those undertaking FMT research were able to fully respond to the last alert, the COVID-19 pandemic struck and FMT trial activity has been currently paused in most regions. However, as the most realistic scenario is the medium to longer cohabitation with COVID-19, FMT-related research should take adequate security measures rather than being suspended, despite potential complexity. To guarantee the best possible safety based on current evidence, ongoing trials should adapt their protocols according to the changing status of COVID-19, and upcoming trials should be designed taking into account the same security measures proposed in this document for clinical practice. For specific patient populations, including those with inflammatory bowel disease (IBD) treated with immunosuppressive medication or cancer patients on chemotherapy, exposure to a healthcare facility for FMT administration may be difficult. For example, patients with IBD living in high prevalence areas for COVID-19 have been recommended to 'shield' from public activity by government-mandated advice and professional guidelines to minimise the risk of infection. Additionally, the panel discussed solutions to keep a smooth patient recruitment in FMT clinical trials. To avoid enrolment hurdles and to safely perform follow-up, virtual visits (especially those after treatment) should be considered rather than in-person assessments. Moreover, where possible, potentially eligible candidates should be provided with specific documentation (eg, the ticket of the scheduled visit) to be able to reach the hospital without being stopped by authorities if unnecessary movements are not allowed during the lockdown phase. Furthermore, for FMT trials there should be a pragmatic ongoing dialogue between trial investigators and the ethical, funding and administrative bodies overseeing the study to ensure that studies can still proceed safely and effectively, although with potential adaptations; this may require flexibility in study protocols, review of appropriate and achievable endpoints (eg, length of participant follow-up) and consideration of unblinding if required. To ensure the safety of patients, also taking into account recent FMT-related adverse events in the context of clinical trials,it is recommended that donor recruitment protocols and workflows follow international guidelines.The use of multidonor FMT could potentially increase the risk of COVID-19 transmission and should only be considered within a FMT trial if there is strict adherence to proposed security measures. The development of a reliable stool assay for SARS-CoV2 is also advocated to make the implementation of clinical trials faster and safer and, when available, such diagnostic tools should be included in the screening protocols. As suggested for clinical practice, the use of frozen stools is preferred over fresh material, although SARS-CoV-2 can probably survive the storage conditions. The manipulation of faecal aliquots and the storage of stool samples before and after FMT should be done in a highly safe environment (at least biosafety level 2). Additionally, members of the FMT staff who are in charge of sample handling should undergo, in the COVID-19 era, a more rigorous safety training as there is a potential risk of being exposed to SARS-CoV-2. The use of registers and the application of the same strict traceability protocols that have been recommended for clinical practice are also recommended for research protocols.Finally, these principles for assessing SARS-CoV-2, designed for standard FMT, are also recommended to be applied to trials investigating next-generation microbiome drugs which are directly derived from human faeces (while it is not necessary for synthetically derived ones). # Conclusions The COVID-19 pandemic is challenging the healthcare systems of individual countries worldwide, and it is reasonable to assume that it will be present also in the near future, forcing us to adapt overall clinical-procedural standards. Therefore, we have learnt to rationalise medical care services with criteria dictated first by the emergency and then by reasoned planning, with varying degrees of difficulty in different clinical scenarios. In that context, FMT finds its place as a life-saving procedure for a considerable number of patients with CDI which, despite COVID-19, will continue to be numerous in clinical practice. The general workflow of a FMT service, as recommended before the diffusion of COVID-19, 12 already allows guaranteeing high levels of safety, both for physicians and for patients. Due to their robust organisation, FMT services can adapt to the pandemic-related scenario, and a few feasible security measures, which are described in this position paper (table 2) are advocated to assure a safe cohabitation with COVID-19 in the near future. However, we recognise that certain recommendations here represent expert opinion rather than clear evidence-based practice and that, given the rapid developments occurring in evidence related to COVID-19 pathophysiology, they may need updating in the future to maintain the highest safety levels for FMT services. microbiota transplantation from the Italian Ministry of Health. BHM is the recipient of a National Institute of Health Research (NIHR) Academic Clinical Lectureship. The Division of Digestive Diseases at Imperial College London received financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Contributors GC conceived the idea of the project. GC and GI organised and designed the project, selected the expert panel and established the main topics. GC, GI, CRK, BHM and ZK wrote the initial draft of the manuscript. All panel members read and revised the manuscript for important intellectual content and approved the final manuscript. Funding The project was in part funded by the Catholic University of Rome, Line D-1 research funding. Competing interests AG reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, Sinergie Srl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. BHM reports personal fees from Finch Therapeutics Group. CRK has served as a clinical advisor, with no financial compensation, for OpenBiome since 2013; she is a local principal investigator for the PRISM-3 clinical trial, for which her institution receives some salary support for a research coordinator and compensation from Finch Therapeutics Group for each patient enrolled. FZ reports grants from the non-profit China Microbiota Transplantation System (fmtBank) and has a patent for GenFMTer for separating microbiota issued to FMT medical. GC has received personal fees for acting as advisor for Ferring Therapeutics. GI has received personal fees for acting as speaker from Biocodex, Danone, Metagenics, and for acting as consultant/advisor from Ferring Therapeutics, Giuliani, Metagenics. HS reports personal fees from Danone, Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, BMS, Astellas, MSD, Novartis, Tillotts Pharma, and Biose, and grants from Biocodex, Danone and BiomX, and is a co-founder of Exeliom Biosciences. JJK and EJK report grants from Vedanta Biosciences. JRA reports personal fees from Finch Therapeutics and has a non-financial relationship with OpenBiome as a	None	https://gut.bmj.com/content/gutjnl/69/9/1555.full.pdf	The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities.
e85137c9d296f8834ce2ae95fc93f5987a35f1fa	pubmed	Guidelines for telematic second opinion consultation on headaches in Europe: on behalf of the European Headache Federation (EHF)	Guidelines for telematic second opinion consultation on headaches in Europe: on behalf of the European Headache Federation (EHF) The seeking of a second opinion is the longestablished process whereby a physician or expert from the same or a similar specialty is invited to assess a clinical case in order to confirm or reject a diagnosis or treatment plan. Seeking a second opinion has become more common in recent years, and the trend is associated with significant changes in the patient-doctor relationship. Telemedicine is attractive because it is not only fast but also affordable and thus makes it possible to reach highly qualified centres and experts that would otherwise be inaccessible, being impossible, or too expensive, to reach by any surface transport. In Europe, the European Headache Federation (EHF), being able to draw on a group of headache experts covering all the European languages, is the organisation best placed to provide qualified second-opinion consultation on difficult headache cases and to develop a Headache Medical Opinion Service Centre. The provision of good quality clinical information is crucial to the formulation of a valid, expert second opinion. This preliminary step can be properly accomplished only by the primary health care provider through the furnishing of an appropriate clinical report, together with the results of all available tests, including original films of all imaging studies already performed. On receiving the EHF's proposed standardised data collection form, properly filled in, we may be sure that we have all the relevant data necessary to formulate a valid expert second opinion. This form can be accessed electronically and downloaded from the EHF website. Once finalised, the EHF second opinion project should be treated as a pilot strategy that requires careful monitoring (for the first year at least), so that appropriate changes, as suggested by the retrospective analysis and its quality control, can be implemented. # Introduction The seeking of a second opinion is the long-established process whereby an expert from the same or a similar specialty is invited to assess a clinical case in order to confirm or reject a diagnosis or treatment plan. A second opinion might be requested by the primary physician (primary health care provider, PCP), by the patient, or by the patient's relatives. It serves to reduce uncertainty and thus anxiety, and to promote a better understanding of the disease by the patient and her/his family, as well as better compliance with the treatment plan. When a second opinion confirms the initial diagnosis, it may indeed provide reassurance and help the patient to accept her/his disease. By bridging an important gap between the primary physician's diagnosis and treatment plan and the patient's emotional need for expert opinion, a medical second opinion should thus help to establish a patient's medical needs and contribute to achieving optimal treatment goals. Because traditional second opinion evaluations involve a face-to-face examination, they can be difficult to obtain, rather expensive and involve a delay; as a result, they tend to be carried out in very few or very special cases. However, in recent decades, advances in the field of information technology, and in telecommunications technology in particular, have led to the development of a new model of second opinion and the creation of the concept of telemedicine. Nowadays, with access to the internet so widespread, patients and doctors are directly involved in establishing primary diagnoses and in the treatment decision-making process. Both categories actively use the internet to get information about a disease and about modern treatment options and strategies and will often actively seek second opinions from opinion leaders in the field. Initially, telemedicine (the use of telecommunications technology for medical diagnosis and patient care) was mainly used for getting second opinions on imaging data (e.g. radiological and neuroradiological images, online ECG, USG, etc.). However, this novel concept rapidly spread to other medical specialties: pathology, surgery, cardiology, dermatology, orthopaedics, gynaecology, urology, neurology, including neurosurgery and so on [bib_ref] WebOnCOLL enabled remote cardiology consultation for suspected myocardial infarction, Chronaki [/bib_ref] [bib_ref] Online engineering education: learning anywhere, anytime, Bourne [/bib_ref] [bib_ref] Practice guidelines and healthcare telematics: towards an alliance, Gordon [/bib_ref]. Telemedicine [bib_ref] I2C:a system for the indexing, storage, and retrieval of medical images by..., Orphanoudakis [/bib_ref] has proved attractive because it is not only fast but also affordable and thus makes it possible to reach highly qualified centres and experts that would otherwise be inaccessible (unavailable, impossible or too expensive to reach by any surface transport) [bib_ref] WebOnCOLL enabled remote cardiology consultation for suspected myocardial infarction, Chronaki [/bib_ref] [bib_ref] I2C:a system for the indexing, storage, and retrieval of medical images by..., Orphanoudakis [/bib_ref] [bib_ref] WebOnCOLL: medical collaboration in regional healthcare networks, Chronaki [/bib_ref]. As a result of this trend, which is one of the reasons why second opinion seeking has become more common in recent years, the relationship between patients and doctors has changed radically: the era of the paternalistic relationship, in which patients blindly followed the advice of their doctors, is over. ## The european headache federation project In the field of headache medicine in Europe, the European Headache Federation (EHF), being able to draw upon the expertise of a group headache experts covering all the European languages, is the organisation best placed to provide qualified second opinion consultation on difficult headache cases. Through its development of a Headache Medical Opinion Service Centre, the EHF will provide a valuable and necessary service to the populations and health care providers of all European countries, while also accomplishing the most important of its aims: to promote headache knowledge and care in Europe [bib_ref] Headache in Europe, Gerber [/bib_ref] [bib_ref] Guidelines for the organization of headache education in Europe: the headache school;..., Antonaci [/bib_ref]. The provision of good quality clinical information is crucial to the formulation of a valid, expert second opinion. This preliminary step can be properly accomplished only by the PCP through the furnishing of an appropriate clinical report, together with the results of all available tests, including the original films of all imaging studies already performed. Furthermore, it may be better accomplished if a standard data collection form is provided in advance. To this end, several second opinion software solutions have been developed to facilitate communication and prevent the omission of important, sensitive data, while guaranteeing adequate personal data protection [bib_ref] WebOnCOLL: medical collaboration in regional healthcare networks, Chronaki [/bib_ref]. To the best of our knowledge, no such software programs are available for the requesting and formulation of second opinions on headache patients, even though there is a need for them in order to guarantee optimal results. When assessing a difficult case, there are certain crucial data that must always be collected. First of all, it is important to know the reason for the consultation: whether it is to confirm a diagnosis, for differential diagnosis or diagnostic work-up counselling, or for treatment advice. The need for treatment advice may arise when a patient fails to respond to a therapy or develops side effects, or it may simply stem from a desire to explore all possible and available therapeutic options in order to optimise a patient's treatment. The expert should also know who is requesting the second opinion: whether it is the patient her/himself, family members and/or friends, or a doctor (i.e., the PCP). If it is the PCP, it is important to know his/her name, affiliation and contact details in case he/she needs to be contacted again in order to get more detailed clinical information. The best way to provide the necessary information is through a semi-structured questionnaire. The data collection form (available as Electronic Supplementary Material) must cover a series of important aspects, as detailed in the following steps: It is also important to know the suggested clinical diagnosis (headache type or types), as formulated by the PCP, as well as the patient's other current comorbid medical conditions. Information should be given regarding current headache treatments (prescribed and over-the-counter medications) for acute and for prophylactic therapy (drugs, doses, treatment duration, response and side effects). Use/overuse of OTC drugs and/or other substance use or abuse should be reported, as should treatments used for other comorbidities [bib_ref] Guidelines for the organization of headache education in Europe: the headache school;..., Antonaci [/bib_ref]. On receiving this proposed standardised form, properly completed, we can be sure that all the relevant data have been provided, and a better result, in terms of a valid expert second opinion, may thus be expected [bib_ref] The action workflow approach to workflow management technology, Medina Mores [/bib_ref] [bib_ref] Cardiac event recording yields more diagnoses than 24-hour holter monitoring in patients..., Scalvini [/bib_ref]. The proposed application form can be accessed electronically and downloaded from the EHF website, automatically translated into the user's language, thereby facilitating communication [bib_ref] Guidelines for the organization of headache education in Europe: the headache school;..., Antonaci [/bib_ref] [bib_ref] The action workflow approach to workflow management technology, Medina Mores [/bib_ref] [bib_ref] Cardiac event recording yields more diagnoses than 24-hour holter monitoring in patients..., Scalvini [/bib_ref]. The authors of the present document can be contacted for consultations on behalf of the EHF, but other experts in the field are also welcome to compose a list of opinion leaders on the field (Board of Headache European Consultants) that can provide the requested second opinion, If possible, with the same language of the informer, with quality and safety using appropriate telecommunicating technology [bib_ref] The action workflow approach to workflow management technology, Medina Mores [/bib_ref] (i.e. telecommunication or Skype connection). Through this project, the EHF will open the way for better care for patients with difficult or rare headache conditions, and also for people from remote and/or small places where health care facilities are more restricted and gaining access to a headache expert can be difficult. Through modern telecommunications technology and internet teleconsultation, the EHF might thus be enabled to accomplish, on a global level, its mission to provide strong medical expert support in the field of headache. The objectives the EHF aims to achieve through the implementation of this service are: 1. Secure and fast access to patient information, wherever the patient is located, also making use of on-line dialogue methods (i.e. Skype); 2. better quality diagnosing and treatment; 3. reduced time to treatment; 4. reduced use of OTC drugs; 5. promotion of more efficient use of resources; and 6. promotion of on-line collaboration among health care professionals (across health care organisations and national borders). Once finalised, the programme should be treated as a pilot strategy and be carefully monitored (for the first year at least), so that appropriate changes, as suggested by the retrospective analysis and its quality control, can be implemented. The main problem this project could encounter, in the event of a large volume of requests, is that of the costs involved. It is important to estimate these, i.e., the total cost of implementing the project, as well as the costs per case. It is also essential to establish how these costs will be met (who will pay) and to secure the funds needed. The success of the project will also depend on the availability of a good programme, software and informatics with a broadly available platform. Therefore it is necessary to consider all the possible sources of funding, asking as to whom we should look to for the necessary grants and financial support: the EHF, the WHO, local health authorities, the pharmaceutical industry, or private companies. Since the EHF is a non-profit organisation, which seeks to accomplish a mission and pursues prestige rather than financial gain, this reduces the total costs of the programme and should make it possible to obtain financial support from an external sponsor. A further consideration is the legal question of the liability and responsibility of the consulting experts offering diagnoses and proposing treatments. The expert second opinion they provide should be presented and considered purely as advice, making it quite clear that full responsibility cannot be accepted for advice given on the basis of information provided by a primary health physician. This issue, however, needs further discussion and clarification. Conflict of interest None.	None	https://thejournalofheadacheandpain.biomedcentral.com/track/pdf/10.1007/s10194-010-0211-6	None
76074e30075df69fd3c1addbf69e61fca767340e	pubmed	Evidence-based clinical practice guidelines for inflammatory bowel disease	Evidence-based clinical practice guidelines for inflammatory bowel disease Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn's disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese. # Introduction ## Purpose of the revised guidelines The purpose of these clinical practice guidelines is to improve the patient outcome by providing appropriate clinical indices to health care providers involved in the management of IBD. 2. Revision process 1) Basic principle We adopted the basic concept of GRADE system whenever possible. Clinical indices were based on the summary of evidence by systematic review, and recommendation grades were determined by the consensus of members, not necessarily correlated with level of evidence. 2) Methods for revision Clinical questions (CQ) were completely reexamined. Determination of the level of evidence was in accordance with the method of GRADE system. Initially set to 4 levels of evidence (high/moderate/low/very low) according to study design, necessary downward reset was made after consideration on risk of bias by examining the study method.When the evidence was neither consistent nor available, the statements were made based on the opinion of the members of the group. The grade of recommendation was applied only to the statements concerning the clinical interventions. The appropriateness of each statement was determined by voting of 13 committee members with 9 stage (9 = most appropriate, 1 = most inappropriate) scoring. After Delphi rounds, for those statements with median score 9 or 8, strong recommendation was given (recommended), and weak recommendation (suggested) for median score of 7. Recommendation used for GRADE system was adopted with minor modification. The draft was submitted to the assessment committee draft to the evaluation committee, collected evaluation comments, fed back to the committee members in charge, and necessary modifications made. This process was repeated once more, and the final plan was formulated. 3. Internal review The statements and comments received the public comments by members of the Japanese Gastroenterology, and members of the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour and Welfare of Japan, reviewed for the appropriateness. The final proposal was made after minor revision. [bib_ref] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Jostins [/bib_ref]. Application of guidelines These guidelines are intended for use of clinical practitioners in various settings in the care of patients with IBD. Recommendations are standard or preferred approaches, but should be used flexibly for individual patients. Clinical Practice Guidelines Committee of the Japanese Society of Gastroenterology is responsible for the description contents, but the responsibility for outcomes in practice should be attributed to individual clinical practitioners. In addition, the contents of these guidelines should not be used as a legal basis such as medical lawsuits. [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref]. Future issues With the accumulation of new evidence and the approval of new diagnostic and therapeutic agents, strategies for the management of IBD will change considerably over the next few years. The current guidelines are subject to revision in 4-5 years. ## Clinical features of inflammatory bowel disease CQ1-01. Definitions and pathophysiology of inflammatory bowel disease Statements - Inflammatory bowel disease (IBD) refers to diseases of chronic or remitting/relapsing intestinal inflammation and includes primarily ulcerative colitis (UC) and Crohn's disease (CD). - UC is a diffuse non-specific inflammatory disease of unknown cause that continuously affects the colonic mucosa proximal from the rectum and often forms erosions and/or ulcers. - CD is a chronic inflammatory disease of unknown cause, characterized by discontinuously affected areas with transmural granulomatous inflammation and/or fistula. CD can affect any region in the digestive tract from the mouth to the anus, but is more likely to involve the small and large intestines (especially the ileocecum) and the perianal region. Comments IBD refers to diseases of a chronic or remitting/relapsing intestinal inflammation. This guideline describes UC and CD as the major forms of inflammatory bowel diseases of unknown etiology. Both diseases develop complicated pathology with unknown causes and mainly affect the gastrointestinal tract, resulting in various clinical symptoms. UC is a diffuse non-specific inflammatory disease of unknown cause that continuously affects the colonic mucosa proximal from the rectum and often forms erosions and/or ulcers. It frequently repeats cycles of relapse and remission during its course and may be accompanied by extraintestinal complications. When it extensively affects the large intestine for a long period of time, a risk of developing cancer increases [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref]. CD is a chronic inflammatory disease of unknown cause, characterized by discontinuously affected areas with transmural granulomatous inflammation and/or fistula. It can affect any region in the digestive tract from the mouth to the anus, but is more likely to involve the small and large intestines (especially the ileocecum) and the perianal region [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref]. The cause of IBD has yet to be identified, but it is considered to develop as the result of abnormal intestinal immunity and altered gut microbiota caused by environmental factors such as diet and infection in genetically susceptible individuals. Patients with IBD often experience impaired daily quality of life (QOL) since both diseases develop in young ages, present symptoms such as abdominal pain, diarrhea, and bloody stool, and chronical progression with repeated cycles of relapse and remission. In addition, it may develop extraintestinal complications in systemic organs such as the joints, the skin, and the eyes. The incidence of colorectal cancer (CRC) is significantly increased in UC patients who have extensive lesions for a long period of time, and it is also known that the incidence of cancers in the small and large intestines, especially in the rectum and anal canal region, is high in CD patients. Therefore, an efficient surveillance strategy for cancer development is expected to be established. IBD is not considered to be a disease that significantly affects the patients' life prognosis, although IBD patients have slightly shorter life prognosis compared to normal individuals. UC and CD are collectively referred to as IBD because the two diseases share common or similar features; however, disease location, morphology, and pathophysiology are clearly different between them, and they are considered to be independent diseases. Moreover, it is necessary to classify them because diagnostic procedures, therapeutic interventions, and follow-up observation are somewhat different. Notably, it is called ''IBD unclassified'' when colonic lesions have the features of IBD which cannot be classified as UC or CD. patients are more likely to develop the disease between their late 10s and early 30s. - In Western countries, there tend to be more women among IBD patients, especially CD patients, but there is a male predominance in Japan. - The cause of IBD has not yet been clarified; however, it is considered that inflammation occurs in genetically predisposed individuals as the result of impairment of the regulatory mechanisms of the intestinal mucosal immune system, which is caused by the involvement of various environmental factors. ## Comments In Japan, the number of IBD patients has been increasing year by year; it is estimated by the issued numbers of certificates of recipients of medical service and certificates of registration in 2013 that there are over 160,000 patients with UC (approximately 100 per 100,000) and about 40,000 patients with CD (approximately 27 per 100,000). However, the recent accurate incidence and prevalence of IBD are unknown because a nationwide epidemiological survey has not been conducted since 1991. Both UC and CD develop at relatively young ages; patients are more likely to develop the disease between their late 10s and early 30s. Nevertheless, patients' ages gradually shift to an elderly population and opportunities to see elderly patients with IBD are also increasing in these days because elderly onset IBD is not rare, IBD patients have a relatively good life prognosis and a long disease course, and the general population of elderly has been recently increasing. The incidence and prevalence of IBD in Western countries are different among regions, but higher in most countries compared to Japan; and there tend to be more women in IBD patients in Western countries, especially CD patients; on the other hand, there is a male predominance in Japan. The cause of IBD has not yet been clarified; however, there is an international consensus that inflammation occurs in genetically predisposed individuals as the result of impairment of the regulatory mechanisms of the intestinal mucosal immune system, which is caused by the involvement of various environmental factors. A certain degree of genetic influence is suggested by the slightly higher prevalence of IBD in blood-relations and reports of intra-familial accumulation of IBD. Research on disease susceptibility genes is underway also in Japan, but results consistent with Western countries have not been obtained partly because susceptibility genes of Japanese patients are different from foreign countries. CQ1-03. What are the cause of and risk factors for UC? # Statements - Several loci are reported to be associated with UC (Evidence level: C). - The cause of UC has yet to be identified, but certain kinds of food composition are reported to be associated with UC (Evidence level: C). - It has been reported that smoking is protective against UC, but its causality has not been clear (Evidence level: C). - The use of oral contraceptives is associated with the development of UC; the use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with the development and worsening of IBD (Evidence level: C). ## Comments According to the meta-analysis of 15 genome-wide association studies including about 10,000 patients of UC, [bib_ref] randomized study to evaluate the efficacy and safety of mesalamine suppositories 1..., Lamet [/bib_ref] loci are associated with IBD; of these, 133 loci are associated with UC [bib_ref] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Jostins [/bib_ref]. A Japanese multicenter case-control study showed that an intake of sugar candies is associated with the development of UC; in addition, consumption of vitamin C provides a negative association in the development of UC [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref]. Moreover, a meta-analysis examining the association between smoking and UC suggested that current smokers provided a negative association in the development of UC (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.45-0.75), on the other hand, history of tobacco use was a risk factor for UC (OR 1.79, 95% CI 1.37-2.34) [bib_ref] Smoking and inflammatory bowel disease: a meta-analysis, Mahid [/bib_ref]. Therefore, the causal association between smoking and UC remains undetermined. In addition, it is also necessary to consider that smoking is a risk factor for other diseases than UC. A meta-analysis in 2000 demonstrated that the OR of appendectomy for the development of UC was 0.31 (95% CI 0.25-0.38) [bib_ref] Appendectomy and the development of ulcerative colitis: results of a metaanalysis of..., Koutroubakis [/bib_ref]. A meta-analysis in 2008 reported that the relative risk of oral contraceptives for the development of UC was 1.53 (95% CI 1.21-1.94) [bib_ref] The risk of oral contraceptives in the etiology of inflammatory bowel disease:..., Cornish [/bib_ref]. Additionally, the case-control study including 60 patients with IBD (24 patients of UC, 36 patients of CD) in the United States (US) showed that the OR of NSAIDs for worsening or new development of IBD was 20.3 (95% CI 2.6-159.7) [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref]. CQ1-04. What are the cause of and risk factors for CD? # Statements - Several loci are reported to be associated with CD (Evidence level: C). - The cause of CD has yet to be identified, but certain kinds of food composition are considered to be associated with the cause of CD (Evidence level: C). - Smoking is a risk factor for CD (Evidence level: C). - The use of oral contraceptives is associated with the development of CD; the use of NSAIDs is associated with the worsening and development of IBD (Evidence level: C). ## Comments According to the meta-analysis of genome-wide association studies with inclusion of about 15,000 CD patients, it has been reported that 140 out of 163 loci linked to IBD are associated with CD [bib_ref] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Jostins [/bib_ref]. A multicenter case-control study from Japan showed that an intake of fat, sugar candies, sugar, sweetener, unsaturated fatty acid, and vitamin E were associated with the development of CD [bib_ref] Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in..., Sakamoto [/bib_ref]. A metaanalysis on the association between smoking and CD suggested that the OR of current smokers and past smokers was 1.76 (95% CI 1.4-2.22) and 1.30 (95% CI 0.97-1.76), respectively [bib_ref] Smoking and inflammatory bowel disease: a meta-analysis, Mahid [/bib_ref]. A meta-analysis in 2008 demonstrated that the relative risk for CD after appendectomy is 1.61 (95% CI 1.28-2.02), but the validity of the study is questionable due to the substantial heterogeneity among the studies included in the meta-analysis [bib_ref] The risk of developing Crohn's disease after an appendectomy: a meta-analysis, Kaplan [/bib_ref]. The meta-analysis on oral contraceptives in 2008 demonstrated that the relative risk for CD during the use of oral contraceptives was 1.51 (95% CI 1.17-1.96) [bib_ref] The risk of oral contraceptives in the etiology of inflammatory bowel disease:..., Cornish [/bib_ref]. Additionally, the case-control study including 60 patients of IBD (24 patients of UC, 36 patients of CD) in the US showed that the OR of NSAIDs for worsening and development of IBD was 20.3 (95% CI 2.6-159.7) [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref]. - UC can be divided into two stages: (1) the active stage characterized by the presence of symptoms and endoscopically active mucosal lesions; (2) the remission stage characterized by resolution of symptoms and disappearance of the endoscopically active mucosal findings. - Depending on the disease extent, UC can be divided into proctitis, distal colitis (up to the sigmoid colon), left-sided colitis (up to the splenic flexure), and pancolitis. - The severity of UC can be classified into mild, moderate, and severe, based on clinical symptoms and signs, and blood tests. - Since inflammation of CD tends to develop in the small and large intestines (especially the ileocecum), and the perianal region, CD is divided into the ileal-type, colonic-type, and ileocolonic-type. - The disease patterns of CD are divided into three types: (1) non-stricturing non-penetrating type, (2) penetrating type, and (3) stricturing type. - The Crohn's disease activity index (CDAI), the International Organization for the study of IBD (IOIBD) index, and the Harvey-Bradshaw index have been proposed as indicators of CD activity, but neither of them is commonly used in clinical practice. ## Comments The pathophysiology of IBD is complicated; therefore, it is essential to accurately determine the disease condition to appropriately treat the disease. Selection of the treatment of UC varies depending on the stage, extent, and severity of the disease. In CD, it is essential to determine the location, pattern, activity, and severity of the disease. It is common to divide the stage of UC into ''the active stage'', in which patients complain of bloody stools and endoscopy reveals loss of vascular pattern, friable mucosa, and erosions and/or ulcers, and ''the remission stage'', in which bloody stools resolve and the endoscopic findings of the active disease disappear, and vascular pattern reappears. In addition, UC can be divided into the following types depending on the extent of lesions: proctitis, distal colitis (up to the sigmoid colon), left-sided colitis (up to the splenic flexure), and pancolitis. Since ''pancolitis'' may cause a misunderstanding that the entire colon is affected, a disease with lesions beyond the splenic flexure may be referred to as ''extensive colitis''. The severity of UC is often classified by the definitions developed by the Research Group for Intractable Inflammatory Bowel Disease; the severity is graded as ''mild'' when (1) the frequency of defecation is 4 times/day or less; [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref] bloody stools are slight if exist, and (3) systemic symptoms such as fever, palpitation, and anemia are absent; ''severe'' when (1) the frequency of defecation is 6 times/day or more; (2) apparent bloody stool is present, and (3) systemic symptoms such as fever, palpitation, and anemia are present; ''moderate'' when the clinical features are in-between ''mild'' and ''severe'' [bib_ref] Cortisone in ulcerative colitis; final report on a therapeutic trial, Truelove [/bib_ref] [bib_ref] Inflammatory bowel disease, Hanauer [/bib_ref]. Inflammation of CD tends to develop in the small and large intestines (especially the ileocecum), and the perianal region, and CD is divided into the ileal-type, colonic-type, and ileocolonic-type. Since CD may develop not only the gastrointestinal lesions but also extraintestinal manifestations, it is necessary to evaluate their systemic effects. Treatment plans can vary depending on the affected regions. There is an international consensus that the disease behavior of CD is divided into three types: (1) non-stricturing non-penetrating type, (2) penetrating type, and (3) stricturing type. It is important to determine the disease behavior in order to choose appropriate treatments [bib_ref] A simple classification of Crohn's disease: report of the Working Party for..., Gasche [/bib_ref]. Moreover, it is also necessary to determine the activity of the disease. This is because treatments are different between the remission stage, where patients have mild or no symptoms, and the active stage, where various symptoms may affect patients' QOL. The CDAI was developed to measure the activity of CD in clinical trials [bib_ref] Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study, Best [/bib_ref] , and its validity has been verified; however, it is cumbersome to use in the daily clinical setting. The IOIBD index is a simple indicator which can be used to distinguish between the active stage and the remission stage, but it does not mean that treatments of CD can be chosen based on this index itself. It is confirmed that the Harvey-Bradshaw index which uses only clinical indicators has a relatively favorable correlation with the CDAI [bib_ref] A simple index of Crohn's-disease activity, Harvey [/bib_ref]. In general clinical practice, severity is often comprehensively determined by patients' subjective symptoms, clinical and laboratory findings, etc.; however, the Research Group for Intractable Inflammatory Bowel Disease advocates the severity evaluation criteria that incorporate the CDAI and other indicators ( ## Diagnosis (figs. 1 and 2) CQ2-01. How should IBD be diagnosed? # Statements - A diagnosis of IBD is suspected by medical history, and characteristic findings of physical examinations, and established by typical findings of imaging examinations such as endoscopy. - It is often necessary to differentiate infectious enterocolitis from UC. - The symptoms of the acute stage of CD may resemble those of acute appendicitis or colonic diverticulitis, and it may be difficult to differentiate intestinal tuberculosis or intestinal Behçet's disease from CD before the final diagnosis of CD is established. - Once a diagnosis of IBD has been established, the activity, severity, and disease extent should be evaluated to provide appropriate therapeutic interventions. ## Comments The diagnosis of IBD is usually established by characteristic clinical findings and typical findings of imaging examinations such as endoscopy. However, since there are a number of diseases that are difficult to distinguish even with highly accurate imaging techniques, it is important to first narrow down the differential diagnosis by the appropriate medical history taking and physical examination to obtain an accurate diagnosis and to establish an efficient diagnostic strategy. The first step in establishing a diagnosis is to suspect IBD. When a patient presents with abdominal symptoms such as repeated abdominal pain or diarrhea, IBD should be included in one of the differential diagnosis regardless of age. It is often necessary to distinguish UC from infectious enterocolitis, especially Campylobacter, enteroinvasive Escherichia coli, and amoebic dysentery. Excluding these diseases by bacteriological and parasitological examinations is indispensable to make a diagnosis of UC. The symptoms of the acute stage of CD may resemble those of acute appendicitis or colonic diverticulitis, and it may be difficult to differentiate intestinal tuberculosis or intestinal Behçet's disease from CD before the final diagnosis of CD is established. Once a diagnosis of IBD has been established, the activity, severity, and disease extent should be evaluated to provide the appropriate therapeutic interventions. Endoscopy and various imaging techniques are useful for determining the extent and severity of the disease. Furthermore, clinical evaluation for intestinal and extraintestinal complications is also necessary [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref] [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref]. Refer to CQ2-06 for the diagnostic criteria for UC and CQ2-07 for CD. CQ2-02. What are symptoms/physical findings that should raise suspicion of IBD? # Statements - A diagnosis of UC should be suspected when a patient, especially young, presents with persistent or recurrent bloody diarrhea accompanied with abdominal pain or frequent bowel movements. - A diagnosis of CD should be suspected when a patient, especially young, presents with chronic abdominal pain and diarrhea accompanied with bloody stools, weight loss, fever, or perianal lesions. - Physical findings of UC are not specific, but abdominal tenderness that reflects the extent and/or severity of the disease, and mucous and bloody stools on a digital rectal examination are often seen. - In CD, physical examinations may reveal tenderness or a palpable mass that coincides with the affected areas, and signs of bowel obstruction may be observed. Patients may be diagnosed with the perianal lesions. ## Comments The cardinal symptom of UC is bloody diarrhea, sometimes accompanied with abdominal pain or frequent bowel movements. Therefore, if a patient has persistent or recurrent bloody and/or mucous stools or the history of those symptoms, UC is suspected. It is necessary to take a history of recent foreign travel, medications (especially antimicrobials), and family history. In mild patients, physical examinations often reveal no abnormal findings, but patients with more severe disease demonstrate fever, anemia, weight loss, abdominal tenderness, and fresh blood on a digital rectal examination [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref]. The cardinal symptoms of CD are similar to UC. Patients frequently present with chronic abdominal pain and/or diarrhea, with fewer occurrences of bloody stools compared to UC, and mucous and bloody stools seen in UC are rare. In addition, there is a higher possibility that patients demonstrate weight loss, fever, and perianal lesions than UC. Physical examinations may reveal tenderness and a palpable mass in the area affected by CD, and signs of bowel obstruction may be observed. Patients may often be diagnosed with the perianal lesion [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref]. CQ2-03. What are the useful laboratory examinations for the diagnosis of IBD? # Statements - On a complete blood cell count, the presence and severity of anemia are evaluated, and the severity of inflammation can be presumed by leukocyte count (and differentiation) and platelet count. - Inflammatory markers (CRP, erythrocyte sedimentation rate) are correlated with the activity of the disease. - Albumin is not only an index of nutrition, but also an index of severity of IBD. - Infectious enterocolitis should be excluded by bacteriological and parasitological examinations. - Fecal calprotectin is being introduced as a marker of activity of inflammation. ## Comments When IBD is suspected on clinical findings, laboratory tests of blood and stool, in parallel with imaging investigations, should be conducted. A complete blood cell count is a useful indicator for evaluating the severity of IBD. It can evaluate the presence and severity of anemia, and presume the severity of inflammation by leukocyte count (and differentiation) and platelet count. Inflammatory markers (CRP, erythrocyte sedimentation rate) are correlated with the activity of the disease; however, it should be reminded that normalized values do not necessarily suggest disappearance of inflammation. A decreased albumin level is not only an index of nutrition, but also an index of severity of IBD. Infectious enterocolitis should be excluded by bacteriological and parasitological examinations. Fecal immunological occult blood test (FIT) can be used for monitoring activity of inflammation or assessing of mucosal healing, but its usefulness has not been sufficiently validated [bib_ref] Evaluation of mucosal healing of ulcerative colitis by a quantitative fecal immunochemical..., Nakarai [/bib_ref]. Besides conventional inflammatory markers such as CRP and erythrocyte sedimentation rate, in the near future, fecal calprotectin will be introduced as a marker to assess the activity of inflammation and applied for clinical use [bib_ref] A simple method for assessing intestinal inflammation in Crohn's disease, Tibble [/bib_ref]. ## 1) endoscopy (including biopsy sampling) CQ2-04. How should endoscopy be used for the diagnosis of UC? # Statements - It is recommended that colonoscopy should be conducted to establish a definite diagnosis of UC when it is suspected based on clinical findings (Recommendation grade: 1 (9), Evidence level: D). - Colonoscopy is recommended not only for establishing a definite diagnosis, but also for determining the disease severity and response to treatment, and for surveillance of cancer development (Recommendation grade: 1 (9), Evidence level: D). ## Comments Colonoscopy should be conducted to establish a diagnosis of UC when it is suspected based on clinical findings [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref] [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/bib_ref] [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] European evidencebased Consensus on the diagnosis and management of ulcerative colitis: definitions..., Stange [/bib_ref]. The indications of colonoscopy in UC patients include the establishment of the definite diagnosis, assessment of disease severity, judgment of response to treatment, and surveillance of cancer development. Histological examination of biopsy should be done if deemed necessary. Particularly in patients who are diagnosed with UC for the first time, total colonoscopy should be performed, if possible, in order to determine the appearance, severity, and, extent of colonic lesions, excluding other diseases. However, it is not necessary to perform total colonoscopy early in patients with clinically severe activity because the disease may be worsened by the endoscopic procedure itself or preparation for colonoscopy. Oral bowel cleansing is used as a bowel preparation, but it is often possible to perform colonoscopy without a bowel preparation in patients who have frequent diarrhea and bloody stools in the active stage of UC. Typical endoscopic findings of UC include loss of vascular pattern, granular and easily bleeding mucosa, and ulceration; those findings are observed in a continuous manner. The mucosa is diffusely affected, loses the normal vascular patterns, and presents a coarse or microgranular appearance. Furthermore, the mucosa may become fragile and be accompanied with visible oozing (contact bleeding), bloody mucopurulent secretions may be attached, and multiple erosions, ulcers, and/or pseudopolyposis may be observed. However, the endoscopic diagnosis of UC is not always possible solely on the basis of these findings. These findings serve only as a standard to be referred to by gastroenterologists. One should also pay attention to the limitation that none of those endoscopic findings is specific to make a definite diagnosis of UC. Although histological findings of biopsy specimens in the active phase show diffuse inflammatory cell infiltration in the mucosal layer, crypt abscess, and remarkable goblet cell depletion, these findings are non-specific. Abnormal crypt structures (distortion and branching) and atrophy persist in the remission phase. These findings are usually found continuously extending proximally from the rectum. Histological examination of biopsies is useful to diagnose cytomegalovirus infection complicating UC [bib_ref] Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative..., Fukuchi [/bib_ref]. When the patient lacks endoscopic change in the rectum or the left side of the colon and a definite diagnosis is difficult to be established, histological examination is helpful to determine if a history of inflammation exists. Endoscopic evaluation of the severity of intestinal disease is important to determine treatments of UC. Indices for the assessment of the endoscopic activity of UC include the Mayo endoscopic subscore and the Rachmilewitz index [bib_ref] Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis...., Schroeder [/bib_ref] [bib_ref] Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative..., Rachmilewitz [/bib_ref]. The Mayo endoscopic subscore tends to be used in recent clinical trials; several reports from Western countries defined mucosal healing as score 0 (normal or inactive disease) or score 1 (mild disease: erythema, decreased vascular pattern, mild friability). Endoscopic evaluation of mucosal healing is useful to determine treatments of maintenance of remission and to predict relapse of UC, but there is an argument whether or not a score of 1 should be included in mucosal healing and it is necessary to analyze long-term data on this issue. ## Comments Inflammation of CD develops in any part of the gastrointestinal tract, but is more likely to develop in the colon and the lower ileum. Therefore, both barium contrast radiography and endoscopy are necessary to diagnose CD. Especially when clinical symptoms or laboratory examinations suggest CD, colonoscopy with the observation of the terminal ileum should be promptly conducted in order to establish a diagnosis, determine the extent and severity of the disease, and obtain biopsy specimens for a histological examination [bib_ref] Endoscopy in inflammatory bowel diseases, Hommes [/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]. Besides, when CT suggests inflammation in the small intestine in the pelvis, it is useful to perform not only conventional colonoscopy, but also a combination of endoscopic retrograde ileography in addition to an endoscopic observation of the terminal ileum under the X-ray. It is reported that when IBD is suspected, colonoscopic findings can distinguish CD from UC with an accuracy of 89% [bib_ref] Colonoscopy in inflammatory bowel disease. Diagnostic accuracy and proposal of an endoscopic..., Pera [/bib_ref]. Characteristic colonoscopic findings of CD include discontinuous and regional lesions (so-called skip lesion), cobblestone appearance, longitudinal ulcers, irregular-shaped ulcers, multiple aphthous ulcers, narrowing and stenosis, (internal and external) fistula, and perianal lesions. The Crohn's Disease Endoscopic Index of Severity (CDEIS) is proposed to be used as an index of endoscopic activity for CD; however, it is not suitable for use in daily practice because it is too complicated and time-consuming to calculate the scores. Endoscopy is recently used not only to establish the diagnosis of CD, but also to treat stricture. Upper gastrointestinal lesions are not rare in CD patients and are observed at a high rate (17-75%) regardless of the presence or absence of symptoms. Frequently observed upper gastrointestinal lesions of CD include a bamboo-like appearance in the stomach, gastric erosions/ulcers, duodenal erosions/ulcers, notch-like appearance and longitudinal ulcers in the duodenum. Since the Japanese diagnostic criteria for CD include irregular-shaped ulcer and/or aphtha observed both in the upper and lower gastrointestinal tract as a sub-criterion, upper gastrointestinal endoscopy is useful to assess lesions and obtain biopsy specimens for a histological examination (including the detection of noncaseous epithelioid cell granuloma) in order to establish a diagnosis of CD and exclude other diseases. It is advisable to positively perform upper gastrointestinal endoscopy especially in patients in whom a definite diagnosis cannot be established with colonoscopy or who complain of upper gastrointestinal symptoms [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]. Histological examination of CD focuses on the identification of granuloma, but the detection rate of granuloma in biopsy specimens is only 26-67% [bib_ref] Histology of the lower intestinal tract in Crohn's disease of children and..., Schmitz-Moormann [/bib_ref] [bib_ref] Frequency and clinical correlations of granulomas in children with Crohn disease, De Matos [/bib_ref] [bib_ref] Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult..., Rubio [/bib_ref]. Moreover, it should be noted that granuloma may be observed in intestinal tuberculosis, infectious enterocolitis, and UC. Capsule endoscopic investigation may be useful in patients in whom small intestinal lesions are suspected, but are unable to be detected with other examinations such as small bowel contrast imaging [bib_ref] Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected..., Dionisio [/bib_ref]. Capsule endoscopy (CE) is approved for clinical use in Japan in patients with the definite diagnosis of CD, although it is necessary to confirm the patency of the intestine in advance by a patency capsule. But, diagnostic criteria by CE or its usefulness based on evidence has not yet been established [bib_ref] Role of smallbowel endoscopy in the management of patients with inflammatory bowel..., Bourreille [/bib_ref]. 2) Imaging examinations CQ2-06. How should imaging examinations (except for endoscopy) be used for the diagnosis of UC? # Statements - Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) are recommended to determine the activity before and after treatment or identify complications of UC (Recommendation grade: 1 (8), Evidence level: C). ## Comments Endoscopy is a standard examination to diagnose UC and endoscopic and histological findings are most useful to establish the diagnosis [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] European evidence based consensus for endoscopy in inflammatory bowel disease, Annese [/bib_ref] [bib_ref] Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR..., Panes [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Barium enema examination is useful for determining the extent of UC and its activity in the deeper colon when endoscopy cannot reach there because of a stricture, etc. [bib_ref] European evidence based consensus for endoscopy in inflammatory bowel disease, Annese [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Abdominal US, CT (including colonography), and MRI (including colonography) are also used for the same purpose, and they can provide information on not only luminal status, but also extraluminal lesions [bib_ref] European evidence based consensus for endoscopy in inflammatory bowel disease, Annese [/bib_ref] [bib_ref] Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR..., Panes [/bib_ref]. According to a meta-analysis of prospective studies, it is reported that the sensitivity and specificity for the diagnosis of UC are 89.7%/95.6% by US, 84.3%/95.1% by CT and 93.0%/ 92.8% by MRI [bib_ref] Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: metaanalysis of..., Horsthuis [/bib_ref]. However, the adopted papers included many patients already diagnosed with IBD, therefore the usefulness of these examinations for establishing the definite diagnosis of UC is inconclusive [bib_ref] European evidence based consensus for endoscopy in inflammatory bowel disease, Annese [/bib_ref]. These imaging examinations are not stated in the Japanese diagnostic criteria for UC and are used as supportive examinations, therefore, the use of US, CT, and MRI for establishing the diagnosis of UC is limited. However, they are commonly used and useful for determining the activity of UC before and after treatment. It is necessary to choose optimal imaging modalities for the individual patient considering the characteristics of each examination since it is sometimes difficult to perform endoscopy in severe patients [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] European evidence based consensus for endoscopy in inflammatory bowel disease, Annese [/bib_ref]. CQ2-07. How should imaging examinations (except for endoscopy) be used for the diagnosis of CD? # Statements - Contrast radiography and other imaging examinations are recommended to determine the treatment strategy, disease extent, severity and complications of CD (Recommendation grade: 1 (9), Evidence level: C). - US, CT, and MRI are recommended to be used mainly for evaluation of disease activity before and after treatment and complications of CD (Recommendation grade: 1 (8), Evidence level: C). ## Comments It is extremely important to confirm the major (longitudinal ulcers and cobblestone appearance) and minor findings (irregular or oval ulcers, or aphtha observed in the extensive areas of the digestive tract) described in the Japanese diagnostic criteria for CD by contrast radiography (small bowel contrast imaging, barium enema examination, and endoscopic retrograde ileography) or endoscopy [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref]. In fact, it is reported that 87.4% of patients in Japan were diagnosed based on the major findings; i.e., longitudinal ulcers and cobblestone appearance [bib_ref] Evaluation of diagnostic criteria for Crohn's disease in Japan, Hisabe [/bib_ref]. There is no statement on imaging techniques such as US, MRI, and CT in the Japanese diagnostic criteria for CD [bib_ref] Crohn's disease in Japan: diagnostic criteria and epidemiology, Yao [/bib_ref] and therefore these are used as supportive examinations. Nonetheless, the investigation of the gastrointestinal tract other than the colon including the upper gastrointestinal tract and small intestine is necessary even if the diagnosis of CD has been established based on the findings of colonoscopy or the barium enema examination since CD causes lesions throughout the entire gastrointestinal tract. To determine the therapeutic strategy, it is important to appropriately determine the disease extent (ileal/colonic/ ileocolonic) and behavior (Montreal classification; nonstricturing non-penetrating/stricturing/penetrating). These should be confirmed by combining upper gastrointestinal endoscopy, a small bowel contrast study, a retrograde contrast study of the ileum, abdominal US, CT, and MRI, if necessary [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR..., Panes [/bib_ref] [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. Although CE and balloon-assisted endoscopy (BAE) are being widely used for the evaluation of small intestinal lesions in CD, small bowel contrast imaging is still extremely important since CD frequently develops strictures [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. There is no consensus on which examination should be used to establish the diagnosis of CD, although there are many reports comparing the usefulness of various imaging techniques [bib_ref] Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected..., Dionisio [/bib_ref] [bib_ref] Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: metaanalysis of..., Horsthuis [/bib_ref] [bib_ref] Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging..., Panes [/bib_ref]. A prospective comparative study reported that the sensitivity and specificity for the diagnosis of CD are 83%/53% by CE, 67%/100% by CT (enterography), 67%/100% by ileocolonoscopy, and 50%/100% by small bowel contrast imaging [bib_ref] Small-bowel imaging in Crohn's disease: a prospective, blinded, 4-way comparison trial, Solem [/bib_ref]. It is difficult to examine the small intestinal lesions by a single imaging technique; therefore, it is necessary to combine multiple examinations according to the pathophysiology of individual patients. US, CT, and MRI can evaluate intestinal inflammation by the thickened bowel wall and increased fat density. CT and MRI are useful in examining fistula and abscess formation [bib_ref] Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging..., Panes [/bib_ref]. Enterography/colonography using CT or MRI are non-invasive and useful in evaluating the lesions beyond the strictures that cannot be evaluated by endoscopy, or perianal lesions [bib_ref] Systematic review: MRI enterography for assessment of small bowel involvement in paediatric..., Giles [/bib_ref] [bib_ref] Crohn disease of the small bowel: comparison of CT enterography, MR enterography,..., Lee [/bib_ref]. However, currently, these examinations are not feasible at every institution and there is no established protocol including pre-treatment (and medication) to inflate the bowel. ## General considerations in treatment CQ3-01. Should patients with IBD quit smoking? # Statements - Since smoking cessation is reported to have a negative effect on disease activity in UC patients, it is recommended that when recommending smoking cessation from the viewpoint of comprehensive health benefits, non-smoking policy should be promoted while paying attention to change in disease activity (Recommendation grade: 1 (8), Evidence level: C). - It is recommended that non-smoking policy is promoted in patients with CD (Recommendation grade: 1 (9), Evidence level: C). ## Comments According to the report by Beaugerie et al. [bib_ref] Impact of cessation of smoking on the course of ulcerative colitis, Beaugerie [/bib_ref] that included 32 patients who had stopped smoking after the diagnosis of UC and compared their prognosis between before and after smoking cessation, the periods of time with active disease, hospitalization, steroid use, and immunomodulator use were longer after stopping smoking than before stopping smoking. In addition, the administration period of these immunosuppressive therapies was significantly longer in ex-smokers than in continuing smokers [bib_ref] Impact of cessation of smoking on the course of ulcerative colitis, Beaugerie [/bib_ref]. In CD patients, smokers have a higher risk of surgery, postoperative clinical relapse, and reoperation compared to non-smokers [bib_ref] The effect of smoking after surgery for Crohn's disease: a meta-analysis of..., Reese [/bib_ref] [bib_ref] Smoking in inflammatory bowel disease: impact on disease course and insights into..., Parkes [/bib_ref]. It is reported that in CD patients, smokers are more likely to reduce a response to infliximab (IFX) [bib_ref] Predictors of response to infliximab in patients with Crohn's disease, Parsi [/bib_ref] [bib_ref] An analysis of factors influencing short-term and sustained response to infliximab treatment..., Arnott [/bib_ref]. In CD patients, regarding cigarette consumption, the periods of time with active disease and immunosuppressive therapy were reported to be longer even in light smokers who smoke less than 10 cigarettes per day than non-smoker patients [bib_ref] Effects of light smoking consumption on the clinical course of Crohn's disease, Seksik [/bib_ref]. In the study by Cosnes et al.in which they intervened with CD patients by counseling and nicotine replacement therapy, it is reported that patients who successfully stopped smoking for over a year had less recurrence and less use of corticosteroids and immunomodulators than those who failed to stop smoking, and the risks were equivalent to patients who had never smoked. ## Cq3-02. should patients with ibd quit drinking? # Statements - It is recommended to appropriately advise patients with IBD to refrain from excessive alcohol consumption taking into consideration their medical condition such as disease activity and complications, even though there is no evidence to encourage abstinence from drink (Recommendation grade: 1 (8), Evidence level: D). ## Comments There are few studies on an association between alcohol drinking and disease activity or prognosis in patients with UC and CD. However, it is reported that patients with IBD are more likely to complain about worsening of symptoms by alcohol drinking compared to patients with irritable bowel syndrome [bib_ref] Pattern of alcohol consumption and its effect on gastrointestinal symptoms in inflammatory..., Swanson [/bib_ref]. ## Therapeutic interventions for ibd CQ4-01. What are the risks/benefits and indications of 5-aminosalicyclic acid in the treatment of IBD? # Statements - 5-Aminosalicylic acid (ASA) preparations are effective for induction and maintenance of remission in UC (Evidence level: A). - The efficacy of 5-ASA preparations for CD is generally lower than UC. It is effective in reducing disease activity in active CD, whereas its efficacy for maintenance of remission has not been proven (Evidence level: B). - The efficacy of 5-ASA preparations for preventing UCassociated CRC is inconclusive (Evidence level: B). ## Comments There are many randomized clinical trials (RCT) and systematic reviews evaluating the efficacy and safety of oral and topical 5-ASA preparations for induction and maintenance of remission in UC [bib_ref] Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in..., Ford [/bib_ref] [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref] [bib_ref] Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Feagan [/bib_ref]. Pentasa Ò and Asacol Ò , the oral mesalazine preparations available in Japan, have a difference in the mechanisms of drug delivery to the lesion. Pentasa Ò is a time-dependent slow-releasing medicine, whereas Asacol Ò is pH-dependent slow-releasing medicine. There is a clinical trial directly comparing the efficacy in the treatment of UC between them, but the dose setting in the study was not appropriate to conclude which drug is superior to the other, and there is no clinically apparent difference. Oral salazosulfapyridine (SASP) is as effective as oral mesalazine for induction of remission, but is superior in maintenance of remission [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref] [bib_ref] Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Feagan [/bib_ref]. On the other hand, SASP causes side effects more frequently and patients are less tolerant to it than oral mesalazine when used to induce remission [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref]. Attention must be paid to reversible male infertility by this drug. SASP is a compound in which 5-ASA and sulfapyridine are azo-bonded, and it exerts therapeutic effect after 5-ASA is released by cleavage of the azo bond by the action of intestinal bacteria. The other cleavage product, sulfapyridine, is considered to be responsible for many side effects of SASP, and therefore mesalazine, which is composed only of 5-ASA was developed. There are much smaller numbers of clinical trials studying the efficacy of 5-ASA preparations in CD than UC. There are 2 RCTs in 1970s-1980s demonstrating the efficacy of SASP for induction of remission in CD; however, it is also shown that SASP is inferior to corticosteroids [bib_ref] Aminosalicylates for induction of remission or response in Crohn's disease, Lim [/bib_ref]. The meta-analysis including 3 studies on Pentasa Ò reported that mesalazine is significantly more effective than placebo in reducing CDAI scores [bib_ref] Oral Pentasa in the treatment of active Crohn's disease: a meta-analysis of..., Hanauer [/bib_ref] ; however, it is inconclusive whether or not the effect is clinically significant, and in addition, there was no significant difference in induction of remission compared to placebo [bib_ref] Aminosalicylates for induction of remission or response in Crohn's disease, Lim [/bib_ref]. The lack of efficacy of 5-ASA for maintenance of remission in CD is confirmed by the meta-analysis of placebo-controlled trials with a sufficient sample size [bib_ref] Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease, Akobeng [/bib_ref]. A meta-analysis reported that 5-ASA preparations are effective to a certain degree for preventing postoperative relapse; however, it is not very conclusive since efficacy was not confirmed in 2 trials with a large sample size and there is a possibility of a publication bias [bib_ref] Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease, Gordon [/bib_ref]. There are several meta-analyses on the preventive effect of 5-ASA preparations for carcinogenesis. The results were split to positive [bib_ref] Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic..., Velayos [/bib_ref] [bib_ref] but not sulfasalazine, reduces the risk of colorectal neoplasia in patients with..., O'connor [/bib_ref] or negative [bib_ref] 5-Aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease:..., Nguyen [/bib_ref] conclusions and inconclusive. - Corticosteroids have no efficacy for maintenance of remission and their long-term use can lead to adverse events; therefore, they should not be used for maintenance of remission (Evidence level: C). ## Comments Several RCTs have demonstrated an efficacy of corticosteroids alone for inducing remission in both UC and CD since 1960s in Europe and the US, and a few meta-analyses also showed that corticosteroids are more effective for inducing remission compared to placebo [bib_ref] Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. However, one should keep in mind that the quality of the metaanalyses was not high because most RCTs that the metaanalyses reviewed are old and there is heterogeneity in disease severity, disease extent, the types of steroids, dosing regimens, allocation, etc. Appropriate indications of corticosteroids, including disease severity and type, needs to be determined by further studies since new treatments such as novel forms of 5-ASA preparations and anti-TNF agents have been developed. It has been emphasized repeatedly that corticosteroids are not effective for maintenance of remission. This is proven in CD by a meta-analysis, but there are only two old RCTs that proved the lack of efficacy of corticosteroids for maintenance of remission in UC [bib_ref] Prednisone as maintenance treatment for ulcerative colitis in remission, Misiewicz [/bib_ref] [bib_ref] A controlled trial of alternate day prednisolone as a maintenance treatment for..., Powell-Tuck [/bib_ref]. Long-term or high-dose use of steroids should be avoided and they should not be used to maintain remission because of their various side effects such as immunosuppression, impaired glucose tolerance, a delay in wound healing, and osteoporosis. It is necessary to withdraw and discontinue corticosteroids after determining their efficacy even when they are used for inducing remission, but there is no clear evidence on how to withdraw them. When high-dose or unavoidable long-term administration of corticosteroids is inevitable, attention should be paid to cataract, glaucoma, and adrenal cortical insufficiency, and prophylaxis of pneumocystis pneumonia and prevention of osteoporosis by bisphosphonate are advisable (details in the Guidelines on the Management and Treatment of Glucocorticoid-induced Osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update) [bib_ref] Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese..., Suzuki [/bib_ref]. Budesonide, which has reduced systemic side effects compared to conventional corticosteroids (e.g., prednisolone), is effective for inducing remission in CD, but its efficacy is slightly lower than conventional corticosteroids [bib_ref] Budesonide for induction of remission in Crohn's disease, Rezaie [/bib_ref]. Moreover, its efficacy for maintenance of remission is negative. Besides oral administration, intravenous systemic administration of corticosteroids is used, but there is no clear evidence on it. Furthermore, rectal administration of corticosteroids (enema, suppository) is also effective as a treatment of UC; however, rectal administration should not be chosen as first-line therapy because its efficacy for induction of remission is lower than 5-ASA preparations. ## Cq4-03. what are the risks/benefits and indications of immunomodulators in the treatment of ibd? # Statements - Azathioprine (AZA)/6-mercaptopurine (6-MP) are effective for preventing relapse in UC patients in remission, and therefore are effective for maintenance of remission especially in patients who are steroid-dependent or unable to maintain remission by 5-ASA preparations (Evidence level: A). - AZA/6-MP are effective for maintenance of remission in CD. Administration of AZA/6-MP are effective to avoid surgery, and they are also effective to prevent from postoperative clinical and endoscopic relapse. Their combined use with IFX increases the efficacy for inducing remission compared to IFX alone (Evidence level: A). - Use of AZA/6-MP increases the risk of developing lymphoma. In addition, other side effects include gastrointestinal symptoms such as nausea, myelosuppression, alopecia, and pancreatitis (Evidence level: A). - Tacrolimus (TAC) is effective for inducing remission in active UC; however, there is no sufficient data on the efficacy and safety of its long-term use (Evidence level: C). - Cyclosporine (CyA) is effective as a remission induction treatment in severely active and refractory UC and is as effective as IFX (Evidence level: C). ## Comments The first RCT examining the efficacy of AZA/6-MP for maintenance of remission in UC was published in 1970s; however, there are only 4 placebo-controlled RCTs [bib_ref] Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and..., Khan [/bib_ref] [bib_ref] Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis, Timmer [/bib_ref]. Their efficacy was rather assessed mostly by the long-term experience on their use and retrospective studies about them. There are more data demonstrating the efficacy of AZA/ 6-MP for maintaining remission in CD compared to UC [bib_ref] Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease, Prefontaine [/bib_ref] [bib_ref] The role of thiopurines in reducing the need for surgical resection in..., Chatu [/bib_ref]. Several prospective studies examining their effect on postoperative recurrence have been conducted since the 2000s and demonstrated their efficacy in preventing clinical and endoscopic relapse [bib_ref] Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease:..., Peyrin-Biroulet [/bib_ref]. A review of more than 10 retrospective studies concluded that it is useful in avoiding the first surgery [bib_ref] The role of thiopurines in reducing the need for surgical resection in..., Chatu [/bib_ref]. A prospective placebo-controlled study (SONIC study) demonstrated that a combination treatment of AZA with IFX is superior to IFX alone in terms of the rate of induction of remission in CD [bib_ref] Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease, Chande [/bib_ref]. The increased risk of developing lymphoma by AZA/6-MP has been confirmed by a meta-analysis [bib_ref] Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine..., Kandiel [/bib_ref] , a multicenter large-scale cohort [bib_ref] Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective..., Beaugerie [/bib_ref] , and the US nationwide cohort [bib_ref] Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a..., Khan [/bib_ref]. According to these studies, the risk is reported to increase approximately 4 times, but decreases again after discontinuation of AZA/6-MP. A combined use of AZA/6-MP with IFX is reported to induce the development of fatal hepatosplenic lymphoma, although it is rare. There are 40 reported cases of this type of lymphoma among IBD patients worldwide. Most of the patients are males under the age of 35 years [bib_ref] Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis..., Magro [/bib_ref]. Another important side effect of AZA/6-MP includes myelosuppression and the rate of developing severe myelosuppression in which neutrophil count is less than 1000/ll is reported to be * 1% [bib_ref] Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review, Gisbert [/bib_ref]. There are only 2 RCTs confirming the efficacy of TAC for inducing remission in UC, which are the phase 2 and 3 clinical trials conducted in Japan [bib_ref] Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized..., Ogata [/bib_ref]. There is only 1 small-size placebo-controlled RCT examining the efficacy of CyA for induction of remission in severe steroid-refractory UC [bib_ref] Cyclosporine A for induction of remission in severe ulcerative colitis, Shibolet [/bib_ref]. A recent head-to-head trial indicated that CyA is as effective as IFX in steroid-refractory UC [bib_ref] Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous..., Laharie [/bib_ref]. Both Tac and CyA may induce nephrotoxicity as a side effect. CQ4-04. What are the risks/benefits and indications of antibiotics and probiotics in the treatment of IBD? # Statements - Antibiotics may be effective for induction of remission in CD (Evidence level: C). - Antibiotics can reduce discharge from anal fistula in CD (Evidence level: B). - Antibiotics may be effective for induction of remission in UC, but the type and duration of antibiotics to use are not established (Evidence level: C). - Antibiotics are also effective for pouchitis after colectomy for UC (Evidence level: B). ## Comments Administration of antibiotics, probiotics, and prebiotics have been examined as treatments for IBD because the intestinal microbiota is suggested to be associated with the development of IBD [bib_ref] The gut microbiota in IBD, Manichanh [/bib_ref]. Those treatments are conducted to control the intestinal microbiota as an aggravating factor in IBD and to treat or prevent from bacteremia, abscess, and opportunistic infection. Apart from these effects, it is suggested that particular antibiotics (ex. ciprofloxacin (CPFX), metronidazole (MNZ), macrolide antibiotics) possibly affect IBD as immunomodulators [bib_ref] Modulatory effect of antibiotics on cytokine production by human monocytes in vitro, Morikawa [/bib_ref]. Two meta-analyses reported that monotherapy with CPFX or MNZ, or the combination of the two antibiotics are effective for induction of remission in active CD [bib_ref] Antibiotic therapy in inflammatory bowel disease: a systematic review and metaanalysis, Khan [/bib_ref] [bib_ref] Meta-analysis of broad-spectrum antibiotic therapy in patients with active inflammatory bowel disease, Wang [/bib_ref] ; however, specific indications and administration protocols of these antibiotics have not yet been determined. A meta-analysis showed that administration of CPFX or MNZ decreased discharge from anal fistula in CD patients [bib_ref] Antibiotic therapy in inflammatory bowel disease: a systematic review and metaanalysis, Khan [/bib_ref]. Two meta-analyses reported a low efficacy of antibiotics for UC [bib_ref] Meta-analysis of broad-spectrum antibiotic therapy in patients with active inflammatory bowel disease, Wang [/bib_ref] [bib_ref] A meta-analysis of antibiotic therapy for active ulcerative colitis, Rahimi [/bib_ref] , but types and administration period of antibiotics were different among RCTs, and, therefore, antibiotics are not recommended as remission induction therapy for UC. In the previous therapeutic regimen of high-dose intravenous steroid, short-term empiric administration of broad-spectrum antibiotics was recommended [bib_ref] Intensive intravenous regimen for severe attacks of ulcerative colitis, Truelove [/bib_ref] ; however, the efficacy of antibiotics for severe UC has not been proved, and, therefore, its long-term use should be avoided even when administered on the suspicion of a complication of infection. It is reported from Japan that the combination therapy of three antibiotics (ATM) is effective for UC [bib_ref] Newly developed antibiotic combination therapy for ulcerative colitis: a double-blind placebo-controlled multicenter..., Ohkusa [/bib_ref]. Use of CPFX or MNZ alone or their combination is effective for pouchitis after colectomy for UC and is a standard treatment for it (refer to CQ4-8) [bib_ref] Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative..., Holubar [/bib_ref]. Attention should be paid to peripheral neuropathy as a side effect of MNZ especially when it is administered for a long period and at a high dose. CPFX causes fewer side effects and are more tolerable. Regarding the administration of probiotics for IBD, three meta-analyses on VSL#3 or E coli Nissle 1917 (unreleased in Japan) demonstrated that VSL#3 is effective for induction and maintenance of remission in UC but probiotics did not show efficacy for CD or pouchitis [bib_ref] Probiotics for maintenance of remission in ulcerative colitis, Naidoo [/bib_ref] [bib_ref] Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis,..., Shen [/bib_ref] [bib_ref] Remission induction and maintenance effect of probiotics on ulcerative colitis: a metaanalysis, Sang [/bib_ref]. CQ4-05. How effective are anti-TNF agents in the treatment of IBD? # Statements - Anti-TNF agents are effective for induction of remission in steroid-refractory or steroid-dependent moderate-to-severe UC (Evidence level: A). - Anti-TNF agents are effective for induction and maintenance of remission in patients with CD with active inflammation (Evidence level: A). ## Comments ## Efficacy in uc According to meta-analyses and RCTs, IFX [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] and adalimumab (ADA) [bib_ref] Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis, Sandborn [/bib_ref] are effective for induction of remission in steroid-refractory or -dependent moderate-tosevere UC. It is reported that secondary loss of response may develop in about 60% of the patients who initially respond to anti-TNF agents during approximately 5-year follow-up [bib_ref] Outpatient ulcerative colitis primary anti-TNF responders receiving adalimumab or infliximab maintenance therapy..., Ma [/bib_ref]. ## Efficacy in cd A meta-analysis [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] in 2011 showed that both IFX and ADA were effective for induction of remission in CD patients with active inflammation. Although IFX is effective for preventing relapse of CD patients in remission, the efficacy of ADA for preventing relapse is not confirmed. A multicenter RCT involving a total of 52 institutions in the US, Canada, Belgium, and France demonstrated that ADA, which was administered at the initial dose of 160 mg, followed by the dose of 80 mg after 2 weeks, was effective for inducing remission in moderate-to-severe CD patients who were intolerant to IFX or lost response to IFX [bib_ref] Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized..., Sandborn [/bib_ref]. The RCT enrolling moderate-to-severe CD patients who were steroid-dependent or refractory to high-dose mesalazine or steroids showed that combination therapy with IFX and AZA was significantly superior to IFX alone in the clinical remission rate at 26 weeks [bib_ref] Infliximab, azathioprine, or combination therapy for Crohn's disease, Colombel [/bib_ref]. It is unknown how long anti-TNF therapy should be continued in CD patients who achieved remission with the combination therapy of anti-TNF agents and AZA. However, the prospective cohort study with 115 CD patients in remission in 20 institutions from Belgium and France showed that 50% of the patients relapsed within a year after discontinuation of IFX. Anti-TNF agents were reported to be effective for anal fistula in CD [bib_ref] A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal..., Gecse [/bib_ref]. ## Side effects of anti-tnf agents Reactivation of infections such as tuberculosis and hepatitis B by administering anti-TNF agents has been reported [bib_ref] Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor..., Askling [/bib_ref] [bib_ref] Hepatitis B virus reactivation in rheumatoid arthritis and ankylosing spondylitis patients treated..., Ryu [/bib_ref]. Therefore, it is critical to confirm the absence of latent tuberculosis and hepatitis B virus infection prior to starting anti-TNF therapy. A tuberculin skin test and an interferon-gamma release assay in addition to chest X-ray should be done to exclude latent lung tuberculosis [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref]. Regarding hepatitis B virus infection, tests for HBs-Ag, anti-HBs-Ab, and anti-HBc-Ab should be done. According to a retrospective observational study, skin lesions developed in approximately 30% of patients who were administrated anti-TNF agents [bib_ref] Characteristics of skin lesions associated with anti-tumor necrosis factor therapy in patients..., Cleynen [/bib_ref]. Demyelinating disease and peripheral neuropathy were also reported. Regarding side effects of IFX used for induction of remission of UC, a meta-analysis in 2011 showed no statistically significant differences in the incidence of either abnormal responses to infusion (infusion reaction or injection site reaction), headache, skin lesions, or arthralgia compared with the placebo group [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref]. Furthermore, as for side effects of anti-TNF agents used for induction of remission in active CD patients, there was no statistically significant difference in the incidence of either infection, injection site reaction, headache, abdominal pain, nausea/ vomiting, arthralgia/myalgia, or fever compared with the placebo group. The prospective cohort study including 6000 CD patients in North America reported that IFX was not associated with severe infection (adjusted OR 0.991, 95% CI 0.641-1.535) [bib_ref] Serious infections and mortality in association with therapies for Crohn's disease: TREAT..., Lichtenstein [/bib_ref]. Additionally, the prospective observational study using the same cohort suggested that the adjusted hazard ratio for the development of malignancy by IFX monotherapy was 0.59 (95% CI 0.28-1.22) [bib_ref] Drug therapies and the risk of malignancy in Crohn's disease: results from..., Lichtenstein [/bib_ref] , and IFX monotherapy was not a significant risk factor for malignancy. However, combination therapy with IFX and thiopurine is a risk factor for non-Hodgkin lymphoma [bib_ref] Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy..., Siegel [/bib_ref] and hepatosplenic lymphoma [bib_ref] A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in..., Kotlyar [/bib_ref]. Moreover, the RCT aiming to determine the efficacy of IFX showed that antinuclear antibody and anti-DNA antibody developed more frequently in the IFX group compared with the placebo group [bib_ref] Infliximab for induction and maintenance therapy for ulcerative colitis, Rutgeerts [/bib_ref]. An RCT investigating the efficacy of ADA reported that the incidence of injection site inflammation and leukocytopenia was higher in the ADA group than the placebo group [bib_ref] Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis, Sandborn [/bib_ref]. CQ4-06. What are the risks/benefits and indications of nutrition therapy in the treatment of IBD? # Statements - Efficacy of nutrition therapy alone including enteral nutrition and total parenteral nutrition for inducing remission in UC has not been confirmed; therefore UC patients should not easily be forced to restrict diet and treatment should focus on drug therapy and/or cytapheresis (CAP) (Evidence level: C). - Enteral nutrition therapy is effective for inducing remission in patients with active CD. Enteral nutrition therapy has a good safety profile, but is occasionally difficult for patients to accept (Evidence level: C). - Elemental diet is effective for maintaining remission in CD (Evidence level: B). ## Comments Nutrition therapy (enteral nutrition therapy, total parenteral nutrition, etc.) is not effective for induction of remission in UC patients, unlike CD patients. Although nutritional management is necessary for the acute stage of UC, it is not appropriate to use nutrition therapy for induction of remission [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref]. Unlike CD, there is no evidence showing the efficacy of diet therapy or home nutrition therapy for UC patients in remission. Many UC patients tend to voluntarily have dietary restrictions and avoid dairy products even when they are in remission [bib_ref] Dietary beliefs of people with ulcerative colitis and their effect on relapse..., Jowett [/bib_ref]. However, it is unknown that these restrictions are effective for preventing relapse, on the contrary, it may cause a nutritional deficiency of calcium and so on [bib_ref] Dietary beliefs of people with ulcerative colitis and their effect on relapse..., Jowett [/bib_ref]. UC patients, especially those in remission, should not easily restrict their diet because the restriction may possibly disturb nutritional status and decrease QOL. A meta-analysis showed that the efficacy of enteral nutrition therapy for induction of remission in active CD patients is inferior to corticosteroids (OR 0.3, 95% CI 0.17-0.52). For this reason, in Western countries, nutrition therapy is only used as an alternative to corticosteroids or in order to improve nutritional status in the acute stage in adult CD patients [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref] [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref]. On the other hand, a Japanese study reported that enteral nutrition therapy with elemental diet has a higher rate of induction of remission in CD patients compared with corticosteroids, and especially improves luminal lesions [bib_ref] Controlled trial comparing an elemental diet with prednisolone in the treatment of..., Okada [/bib_ref] , therefore it is chosen as an option of remission induction therapy in CD patients in Japan. Enteral nutrition therapy is superior to drug therapy such as corticosteroids in terms of safety. However, it may be difficult for some patients to continue it due to low tolerability [bib_ref] Defined-formula diets versus steroids in the treatment of active Crohn's disease: a..., Messori [/bib_ref]. Since oligomeric formula is an enteral nutrient formula with amino acids or oligopeptides as nitrogen sources and a little fat content, it is easy to absorb and digest in the bowel. Among oligomeric formulas, an elemental formula utilizes amino acids as a source of nitrogen and contains a very little amount of fat. Polymeric formula is an enteral nutrient formula which contains protein as a nitrogen source and some fat. Polymeric formula is well-balanced in nutrients and easier to ingest orally. There have been many RCTs comparing the efficacy of various nutritional therapies for induction of remission in active CD, but a meta-analysis concluded that there is no significant difference between polymeric and oligomeric formulas in the efficacy for induction of remission. Therefore, in clinical settings in Japan, these treatment options are selected on an individual basis considering acceptability and preference of each patient, although there seems to be no significant difference between these formulas in efficacy for induction of remission. Enteral nutrition therapy is effective not only for induction of remission, but also for maintenance of remission in CD. It is reported that ingestion of half calories of the total calorie intake with elemental diet is more effective for maintenance of remission compared to dietary counseling alone [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref]. However, it has been pointed out that there is a problem in acceptability as therapy despite its proven efficacy [bib_ref] Oral nutritional supplementation is effective in the maintenance of remission in Crohn's..., Verma [/bib_ref]. These 2 trials studying maintenance of remission utilized different evaluation methods although each study demonstrated the efficacy of nutrition therapy [bib_ref] Enteral nutrition for maintenance of remission in Crohn's disease, Akobeng [/bib_ref]. Long-term remission maintenance therapy is necessary for CD patients because there is no cure for CD, but it is not easy to continue enteral nutrition therapy. In clinical practice, nutrient formulas other than oligomeric nutrient formula such as polymeric nutrient formulas are used, considering the acceptability; however, their effects on maintenance of remission have not been well evaluated yet [bib_ref] Indications and options of nutritional treatment for Crohn's disease. A comparison of..., Matsui [/bib_ref]. It is recently expected that enteral nutrition therapy may be more effective when combined with drug therapy, especially anti-TNF agents; however, there are no highquality clinical studies to prove it. - CAP is a useful remission induction therapy for moderate-to-severe UC patients and has a good safety profile. Intensive therapy (two sessions per week) provides more rapid induction of remission with a better remission rate than weekly therapy (Evidence level: C). - In CD patients with active colonic disease, if pharmacotherapy or nutrition therapy is ineffective or unable to adapt, the combination with granulocyte monocyte apheresis (GMA) can be considered (Evidence level: D). ## Comments There are two methods of CAP, GMA (Adacolumn Ò ) and leucocytapheresis (LCAP; Cellsorba Ò ), for UC in Japan (as of 2016). GMA is filled with specially designed cellulose acetate beads as the adsorptive carriers, which selectively adsorb granulocytes and monocytes, while LCAP uses the leukocyte removal filter made of polyester non-woven fabric, which removes leukocytes including lymphocytes and platelets. There is no clear evidence of a difference in efficacy and distinctive use of these two methods. CAP is a treatment covered by insurance in Japan for moderate-to-severe UC patients. A blinded RCT using sham columns conducted in the US and Europe reported that GMA did not demonstrate significant therapeutic efficacy for induction of remission [bib_ref] A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis, Sands [/bib_ref]. On the other hand, there is a meta-analysis examining the efficacy of CAP for induction of remission in moderate-to-severe UC patients, and it reported that CAP was superior to conventional pharmacotherapy in terms of safety and its steroid-sparing effect [bib_ref] The efficacy and safety of selective leukocytapheresis in the treatment of ulcerative..., Zhu [/bib_ref]. It is also reported that CAP produces high efficacy in steroid-naïve patients [bib_ref] Leukocytapheresis for the treatment of IBD, Sigurbjornsson [/bib_ref] and, therefore, it may be applied to patients who are naive to steroids, although there are no controlled trials. An RCT (open label) in Japan reported that intensive GMA (two sessions per week) provides more rapid remission induction and a higher remission rate than weekly GMA (54 vs 71%) [bib_ref] An open-label prospective randomized multicenter study shows very rapid remission of ulcerative..., Sakuraba [/bib_ref]. The usefulness of GMA for active colonic CD has been reported in patients who are refractory to conventional medical and/or nutritional therapies [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref]. It was approved in 2010 for use in the treatment of CD in Japan. CAP is a safe treatment with few side effects; however, sufficient blood flow cannot be secured in patients who are difficult to assure peripheral vascular access (including dehydrated and anemic patients), and CAP may be difficult to conduct in such patients. It is also known in clinical practice that severe patients who demonstrate extensive ulcers tend to show a poor response to CAP. Efficacy of CAP for maintenance of remission in UC has been reported [bib_ref] Adsorptive granulocyte/monocyte apheresis for the maintenance of remission in patients with ulcerative..., Fukunaga [/bib_ref] , although its evidence level is low and its use has not yet been approved for this purpose. There is only one case report suggesting its efficacy for maintaining remission in CD [bib_ref] First successful use of leukocyte apheresis as maintenance therapy for Crohn's disease..., Tate [/bib_ref]. ## Comments In both UC and CD, patients who develop a severe disease refractory to drug therapy or have dysplasia/cancer require surgery to avoid life-threatening conditions (absolute indications) [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Patients who are suffering from the loss of QOL due to IBD symptoms, extraintestinal manifestations, or side effects of drugs should be also indicated for surgery, and improvement of QOL may be expected through the resolution of these symptoms after surgery [bib_ref] Quality of life, health-related quality of life and health status in patients..., Heikens [/bib_ref] [bib_ref] A comparison of the quality of life of ulcerative colitis patients after..., Kuruvilla [/bib_ref] [bib_ref] Clinical outcomes of ileorectal anastomosis for ulcerative colitis, Da Luz Moreira [/bib_ref] [bib_ref] Effect of surgery on health-related quality of life in patients with inflammatory..., Thirlby [/bib_ref] [bib_ref] Health-related quality of life in patients with Crohn's disease: influence of surgical..., Tillinger [/bib_ref]. However, there are risks and disadvantages of surgery, although the postoperative mortality is low in both diseases [bib_ref] Ileal pouch anal anastomosis: analysis of outcome and quality of life in..., Fazio [/bib_ref] [bib_ref] Postoperative complications and mortality following colectomy for ulcerative colitis, De Silva [/bib_ref] [bib_ref] Laparoscopic surgery for Crohn's disease: a meta-analysis, Tan [/bib_ref]. The standard surgical procedure for UC is total restorative proctocolectomy with ileal pouch-anal (canal) anastomosis. It may cause postoperative complications such as anastomotic leak, intestinal obstruction, and pouchrelated complications [bib_ref] Postoperative complications and mortality following colectomy for ulcerative colitis, De Silva [/bib_ref] ; however, the incidence of pouch failure (requiring excision of the ileoanal pouch, formation of a permanent ileostomy) is approximately 5% [bib_ref] A comparison of adverse events and functional outcomes after restorative proctocolectomy for..., Lovegrove [/bib_ref]. There are some reports suggesting a decrease in fertility in females, while the course and outcome of pregnancy are generally normal and defecation function is not worsened by pregnancy. The incidence of postoperative anastomotic leak in CD patients is 2-14% [bib_ref] Side-to-side stapled anastomosis strongly reduces anastomotic leak rates in Crohn's disease surgery, Resegotti [/bib_ref] [bib_ref] Prevention and countermeasures for suture failure in patients with Crohn's disease, Higashi [/bib_ref]. Furthermore, re-surgery due to recurrence of intestinal lesions may lead to small intestinal failure as a result of the shortening of the residual bowel, and total parenteral nutrition may be necessary for such patients [bib_ref] Long-term incidence and characteristics of intestinal failure in Crohn's disease: a multicenter..., Watanabe [/bib_ref]. ## Treatments of uc ## Comments Many RCTs and meta-analyses demonstrated that both topical and oral 5-ASA are effective for induction of remission [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref] [bib_ref] Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis, Ford [/bib_ref]. There are only a few RCTs and meta-analyses comparing the efficacy between oral and topical 5-ASA; some reported that topical therapy is more effective than oral therapy and others reported that there is no significant difference between oral and topical therapies [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] A meta-analysis and overview of the literature on treatment options for left-sided..., Cohen [/bib_ref] [bib_ref] Clinical guidelines for the medical management of left-sided ulcerative colitis and ulcerative..., Regueiro [/bib_ref] [bib_ref] Medical management of left-sided ulcerative colitis and ulcerative proctitis: critical evaluation of..., Regueiro [/bib_ref]. It is necessary to choose the treatment considering factors including mucosal concentrations of 5-ASA and drug adherence of patients; however, many guidelines in the US and Europe recommend topical 5-ASA as first-line therapy [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Oral medications are more likely to be favored in Japan compared to topical medications because topical medications are more timeand effort-consuming to administer than oral medications, which may lead to decreased drug adherence. The Research Group for Intractable Inflammatory Bowel Disease positions oral 5-ASA in parallel with topical 5-ASA. As oral 5-ASA preparations, conventional SASP and two types of mesalazine with different release mechanisms in the intestinal tract are available in Japan; however, according to a meta-analysis, there is no difference in the efficacy between SASP and mesalazine. However, SASP may not be tolerated or may cause side effects, therefore mesalazine tends to be favorably used in Japan; on the other hand, SASP is more recommended especially in the US because of its lower cost. There is no difference in efficacy between the two types of mesalazine preparations. Since there is no significant difference in the efficacy of 5-ASA enema among the daily dose levels of 1, 2, and 4 g, the dose level of 1 g/day is sufficient [bib_ref] A meta-analysis and overview of the literature on treatment options for left-sided..., Cohen [/bib_ref]. A dose-response relationship is observed in oral 5-ASA; dose levels of 2 g/day or more provide a significantly higher rate of induction of remission than dose levels of less than 2 g/day. Although there is no clear evidence on the efficacy of high doses of 4.0 g/day or more because endpoints varied among studies, a higher dose is desirable for moderately active UC patients [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref]. It has been confirmed that the combination of oral and topical 5-ASA therapy significantly improves efficacy compared to using either agent alone [bib_ref] Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in..., Ford [/bib_ref]. Therefore, the combination therapy is recommended for patients showing poor response to monotherapy of either oral or topical 5-ASA or those with severe symptoms. Some guidelines recommend the combination therapy from the beginning, with an expectation of rapid alleviation of the symptoms. It is demonstrated that 5-ASA enema is superior to steroid enema [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] , therefore 5-ASA enema should be used as first-line therapy. When patients show a poor response to 5-ASA enema or combination with oral 5-ASA, steroid enema therapy should be considered. CQ5-02. What are the indications of corticosteroids in the treatment of mildly to moderately active distal UC? # Statements - It is recommended that neither oral or topical steroids should be selected as first-line therapy even though these drugs are effective for induction of remission (Recommendation grade: 1 (9), Evidence level: A). Remission induction treatment for mildly-to-moderately active distal UC - It is recommended not to use steroid enema as first-line therapy because it is comparable or inferior to 5-ASA enema in terms of efficacy (Recommendation grade: 1 (8), Evidence level: A). - In patients who do not respond to oral 5-ASA therapy at an optimal dose combined with topical 5-ASA or steroid therapy, it is recommended that oral prednisolone (PSL) is started at a daily dose of 30-40 mg (Recommendation grade: 1 (9), Evidence level: B). ## Comments Both steroid enema therapy and oral steroid are effective for inducing remission in patients with active distal colitis [bib_ref] Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis, Marshall [/bib_ref]. Budesonide enema and betamethasone dipropionate (BDP) enema, which have a low risk of systemic side effects, are available overseas but not in Japan. There is a meta-analysis showing that steroid enema therapy is comparable to 5-ASA enema therapy in terms of efficacy for mild-to-moderate patients with active distal colitis [bib_ref] Meta-analysis: the efficacy of rectal beclomethasone dipropionate vs. 5-aminosalicylic acid in mild..., Manguso [/bib_ref] ; on the other hand, there is another metaanalysis showing that 5-ASA enema is superior to steroid enema [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis, Marshall [/bib_ref]. The steroid used in the former metaanalysis is BDP, which is not available in Japan. It has been confirmed that the combination of oral 5-ASA and enema therapy is more effective for active distal colitis compared to either agent alone; however, when patients do not respond to oral 5-ASA therapy at an optimal dose combined with topical therapy, oral steroids are indicated. Steroids had been introduced in the treatment of UC long before the quality of clinical trial design was strictly required. Evidence on the efficacy of steroid therapy for active distal colitis is scarce. A meta-analysis examining the efficacy of oral steroids in inducing remission in active UC including extensive colitis demonstrated that oral steroid therapy is superior to placebo [bib_ref] Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref]. UC patients have various physical and nutritional conditions; therefore, it is advisable that the dose of steroids should be adjusted in each patient referring to the dose shown here. Either steroid enema or oral steroids are not effective for maintenance of remission. CQ5-03. What are the indications of miscellaneous treatments in the treatment of mildly to moderately active distal UC? # Statements - It is recommended that use of CAP or IFX/ADA should be considered for UC patients who do not respond to 5-ASA preparations or steroids (Recommendation grade: 1 (9), Evidence level: C). - Antibiotics may be effective for induction of remission but appropriate types of antibiotics, their combinations, and treatment duration have not been determined (Evidence level: C). ## Comments When patients with mildly to moderately active distal colitis do not respond to conventional 5-ASA or steroid therapies, remission induction therapies used for moderateto-severe patients should be considered. Patients are usually outpatients, therefore, anti-TNF agents such as IFX and ADA, or CAP will be the next therapy [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref] (refer to CQ5-10 and CQ5-11 for detail). Evidence has proven the efficacy of these therapies for moderate-to-severe colitis; however, there are few studies where subjects are limited to patients with mildly to moderately active distal colitis. A meta-analysis indicated that antibiotics are effective for induction of remission unless the subjects are limited to distal colitis; however, the type and treatment duration of antibiotics varies among RCTs; therefore, antibiotics have not yet been recommended as remission induction therapy [bib_ref] Antibiotic therapy in inflammatory bowel disease: a systematic review and metaanalysis, Khan [/bib_ref]. The results of an RCT studying the efficacy of a combination of 3 antibiotics have been reported from Japan, but confirmatory studies have not been conducted. It is impossible to evaluate the efficacy of probiotics that are available in Japan because of the absence of sufficient data. Additionally, a meta-analysis failed to demonstrate the efficacy of probiotics for induction of remission [bib_ref] Probiotics for induction of remission in ulcerative colitis, Mallon [/bib_ref]. In contrast, there are some RCTs which showed the efficacy of VSL#3 and E coli Nissle 1917 (unreleased in Japan) for induction of remission. Furthermore, the remission induction effects of miscellaneous treatments such as fish oil, heparin, or nicotine were indicated by RCTs, although meta-analysis did not show the efficacy of these treatments superior to conventional therapies and neither of them are available in Japan [bib_ref] Fish oil for induction of remission in ulcerative colitis, Ley [/bib_ref] [bib_ref] Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis, Chande [/bib_ref] [bib_ref] Transdermal nicotine for induction of remission in ulcerative colitis, Mcgrath [/bib_ref]. CQ5-04. What are the treatments of mildly to moderately active proctitis? # Statements - 5-ASA suppository is recommended for induction of remission in patients with proctitis (Recommendation grade: 1 (8), Evidence level: B). - When patients do not respond to 5-ASA suppository, it is recommended to consider combination therapy with oral 5-ASA or switch to topical steroid therapy (Recommendation grade: 1 (9), Evidence level: B). ## Comments The effectiveness of topical 5-ASA therapy for distal colitis has been established [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] [bib_ref] A meta-analysis and overview of the literature on treatment options for left-sided..., Cohen [/bib_ref] [bib_ref] Clinical guidelines for the medical management of left-sided ulcerative colitis and ulcerative..., Regueiro [/bib_ref] [bib_ref] Medical management of left-sided ulcerative colitis and ulcerative proctitis: critical evaluation of..., Regueiro [/bib_ref] ; however, there is only a little evidence that was demonstrated by metaanalyses when limited to patients with proctitis or the efficacy of 5-ASA suppository. However, an RCT from Japan recently reported that mesalazine suppository was more effective than placebo [bib_ref] Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in..., Watanabe [/bib_ref]. There are only a few comparative studies between enema and suppository, but it is reported in 1980s that the efficacy of these therapies is comparable [bib_ref] 5-Aminosalicylic acid as enemas or suppositories in distal ulcerative colitis?, Campieri [/bib_ref]. Many guidelines recommend the use of mesalazine suppository for patients with proctitis as firstline therapy considering sufficient drug delivery to the affected area and drug adherence of patients [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. In addition to mesalazine suppository, SASP suppository is also available in Japan, but there has been little high-quality evidence for it and it has not been confirmed that SASP suppository is superior to mesalazine suppository in terms of efficacy; therefore, this guideline does not positively recommend the use of SASP suppository. Evidence on enema preparation indicates that the efficacy of topical mesalazine does not increase in a dosedependent manner above 1 g/day [bib_ref] A meta-analysis and overview of the literature on treatment options for left-sided..., Cohen [/bib_ref]. The efficacy of 1 g mesalazine suppository once daily is comparable to that of two doses of 500 mg [bib_ref] randomized study to evaluate the efficacy and safety of mesalamine suppositories 1..., Lamet [/bib_ref] ; therefore, the dose of 1 g once daily is recommended in terms of drug adherence. There is a report that oral 5-ASA alone is less effective than mesalazine suppository [bib_ref] Comparison of oral with rectal mesalazine in the treatment of ulcerative proctitis, Gionchetti [/bib_ref] , and when an oral preparation is used, it is desirable to combine it with a topical preparation or to use a high dose of pH-dependentrelease mesalazine [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref] [bib_ref] Direct comparison of two different mesalamine formulations for the induction of remission..., Ito [/bib_ref]. Treatment options in patients who show an insufficient response to mesalazine suppository is extrapolated from evidence for distal-to-left-sided colitis [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. 5-ASA enema may be an option although there is no evidence for its use in patients who are refractory to mesalazine suppository. Although the efficacy of topical steroid preparations is inferior to that of topical 5-ASA preparations [bib_ref] Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis, Marshall [/bib_ref] , corticosteroid suppository (e.g., betamethasone suppository) may be effective in patients who show an insufficient response to mesalazine suppository. Oral corticosteroids, anti-TNF agents, and/or immunomodulators should be considered as therapeutic options for proctitis resistant to the above treatments while considering the possibility of other pathophysiology such as infections that need to be differentiated from UC [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. 2) Treatment for mildly to moderately active extensive UC [fig_ref] Figure 4: Remission induction treatment for mildly-to-moderately active extensive [/fig_ref] CQ5-05. What are the indications of oral 5-ASA in the treatment of mildly to moderately active extensive UC? # Statements - It is recommended to use oral 5-ASA as first-line therapy (Recommendation grade: 1 (9), Evidence level: A). - It is recommended to use 5-ASA enema for left-sided colitis (Recommendation grade: 1 (8), Evidence level: A). ## Comments First-line therapy for extensive UC with mild-to-moderate activity is oral 5-ASA preparations including SASP. The efficacy of these drugs for inducing remission is confirmed by the Cochrane review [bib_ref] Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis, Feagan [/bib_ref]. The efficacy of 5-ASA preparations is dose-dependent and high-dose (3 g/day or more) is superior to low-dose (2-2.9 g/day) for induction of remission. There is no difference in the efficacy for induction of remission or endoscopic improvement between oral 5-ASA and SASP. However, a safety profile of SASP is inferior to 5-ASA due to the higher incidence of adverse events, although SASP is more cost-effective. Most side effects of SASP are thought to be due to sulfapyridine bound to 5-ASA. Its common side effects are skin rash, headache, epigastric discomfort, and male infertility. There are two different forms of 5-ASA preparations available in Japan, time-dependent (Pentasa Ò ) or pH-dependent-release (Asacol Ò ) mesalazine; however, efficacy and safety do not differ between them if given in the same dose. Furthermore, its efficacy, safety, and acceptability are comparable between different dosing frequencies with once-daily and 2-3 times a day. Regarding the correlation between doses of 5-ASA and therapeutic effect, there are many reports suggesting the efficacy for induction of remission and safety is not dose-dependent if evaluated using the same preparation. However, the RCT of timedependent mesalazine, which is available in Japan, for moderately active UC demonstrated that 4 g/day dosing showed a higher rate of clinical response than 2.25 g/day [bib_ref] Clinical trial: effects of an oral preparation of mesalazine at 4 g/day..., Hiwatashi [/bib_ref]. In addition, the large-scale RCT of pH-dependentrelease mesalazine also suggests that high-dose is more effective than low-dose in patients with moderately active UC with a past history of treatment such as steroids [bib_ref] Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with..., Sandborn [/bib_ref]. It is recommended to start with a high-dose 5-ASA for moderately active UC since most data suggest no correlation between doses of 5-ASA and incidence of side effects. 5-ASA enema is also effective in active left-sided UC and has efficacy for clinical improvement and induction of remission. A meta-analysis of multiple RCTs confirmed the superiority of 5-ASA enema to oral preparations [bib_ref] A meta-analysis and overview of the literature on treatment options for left-sided..., Cohen [/bib_ref]. 5-ASA enema is reported to be superior to steroid enema in both efficacy and safety. ## Comments Efficacy of steroids for UC has been demonstrated by a meta-analysis [bib_ref] Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] , but the quality of evidence is not very high since most studies are old and the doses/types of steroids vary widely among the studies. The optimal dose of steroids for mild-to-moderate UC has not been confirmed yet and therefore 40 mg/day of PSL is widely accepted overseas as a standard dose [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref]. In contrast, 30 mg/day of PSL is frequently used in Japan, but it is unclear whether a dose of 30 mg/day is better than 40 mg/day in terms of risks/benefits. It is demonstrated that 20 mg/day dosing is less effective than 40 mg/day dosing [bib_ref] Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone, Baron [/bib_ref]. There is no report on the optimal dosing period and the optimal tapering method of steroids after achieving remission, and guidelines in other countries just state the empirical rules [bib_ref] Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Kornbluth [/bib_ref] [bib_ref] American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in..., Lichtenstein [/bib_ref]. It is generally recommended to evaluate the response within 1-2 weeks and, after achieving clinical remission, reduce the dose of steroids at 5 mg/ week until 20 mg/day and then at 2.5 mg/week. ## Cq5-07. what are the indications of miscellaneous treatments for the treatment of mildly to moderately active extensive uc? - It is recommended to use CAP for patients who are steroid-refractory, -dependent, or intolerant to steroids (Recommendation grade: 2 (7), Evidence level: B). - It is recommended to consider TAC or anti-TNF agents for patients who are steroid-refractory or -dependent with moderate-to-severe activity (Recommendation grade: 1 (8), Evidence level: C). ## Extensive colitis No response or need immediate treatment ## Left-sided colitis ## Comments The meta-analysis regarding the efficacy of CAP for induction of remission in UC, which includes many publications from Japan, reported its good efficacy and safety [bib_ref] The efficacy and safety of selective leukocytapheresis in the treatment of ulcerative..., Zhu [/bib_ref]. In addition, an RCT conducted in Japan demonstrated that twice-weekly intensive treatment induces remission more rapidly compared with weekly treatment [bib_ref] An open-label prospective randomized multicenter study shows very rapid remission of ulcerative..., Sakuraba [/bib_ref]. It may be effective in steroid-refractory or -dependent patients; moreover, it is reported that the response rate in steroid-naïve patients is even higher despite the lack of comparative studies [bib_ref] Leukocytapheresis for the treatment of IBD, Sigurbjornsson [/bib_ref]. Therefore, use of CAP can be considered for patients who are unable to use steroids for some reason. There are only 2 placebo-controlled RCTs to assess the efficacy of TAC in UC, which were conducted in Japan and included steroid-refractory or -dependent patients [bib_ref] Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized..., Ogata [/bib_ref]. These trials demonstrated high-trough dosing (10-15 ng/ ml) is more effective than low-trough dosing (5-10 ng/ml). The currently recommended protocol is to administer the drug twice daily orally, adjust the trough levels to 10-15 ng/ml during the first 2 weeks, and then reduce the trough levels to 5-10 ng/ml. The efficacy of anti-TNF agents (IFX and ADA) for induction and maintenance of remission until week 52 in refractory UC has been confirmed in placebo-controlled trials [bib_ref] Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis..., Thorlund [/bib_ref] [bib_ref] Biological agents for moderately to severely active ulcerative colitis: a systematic review..., Danese [/bib_ref] , while there is no head-to-head trial directly comparing IFX and ADA. IFX is intravenously administered every 8 weeks following induction dosing at 0, 2, and 6 weeks. ADA is administered subcutaneously at the initial dose of 160 mg, followed by 80 mg at week 2 and then 40 mg every other week. There are a few placebo-controlled trials to examine the efficacy of antibiotics and a meta-analysis also indicated efficacy of antibiotics; however, its reliability as a metaanalysis is to be debated because the types and doses of antibiotics vary across the studies [bib_ref] Antibiotic therapy in inflammatory bowel disease: a systematic review and metaanalysis, Khan [/bib_ref]. Furthermore, it is impossible to discuss the efficacy of the probiotics available in Japan because of the absence of sufficient data, while there are some RCTs confirming the efficacy of VSL#3 and E. coli Nissle 1917 that are commercially available overseas [bib_ref] Probiotics in the treatment of human inflammatory bowel diseases: update, Meijer [/bib_ref]. 3) Treatment for severely active UC [fig_ref] Figure 5: Remission induction treatment for severely active UC [/fig_ref] There is only one study determining the optimal dose of steroids as first-line therapy for severe UC. Oral administration of steroids at 40 mg/day was as effective as 60 mg/day, but had less adverse events compared with 60 mg/day. Therefore, it is necessary to pay attention to side effects (infection, psychological complications, and thrombosis) when the high-dose steroid is used [bib_ref] Review article: the optimal medical management of acute severe ulcerative colitis, Hart [/bib_ref]. The ECCO Guidelines in 2012 stated that the dose of steroids for severe UC is generally 60 mg/day of methylprednisolone (equivalent to 80 mg/day of PSL) or hydrocortisone 100 mg four times daily [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. It is reported that the response to steroids should be determined at least within the first 7 days when high-dose steroid is used for severe UC [bib_ref] Review article: the optimal medical management of acute severe ulcerative colitis, Hart [/bib_ref]. ## Comments CyA blocks the translocation of the transcription factor, nuclear factor of activated T-cells (NFAT), to the nucleus by binding to calcineurin and, thereby, inhibits cytokine production. It is used mostly in acute severe UC and intravenously administered at 2-4 mg/kg continuously under total parenteral nutrition. Van Assche et al. reported that there was no difference between the initial doses of 2 mg/kg and 4 mg/kg in the therapeutic response at day 8 [bib_ref] Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in..., Van Assche [/bib_ref] , suggesting that the optimal dose is 2 mg/kg. When treating with CyA, it is indispensable to monitor drug concentrations in the blood to maintain optimal drug levels and to avoid adverse events. Clinical improvement can be seen within a week or so after the initiation of treatment. The treatment period is usually up to 2 weeks since its long-term use increases the risk of side effects, including hypertension, seizures, sensory disturbance, hand tremor, gingival swelling, hirsutism, abnormal electrolytes, opportunistic infection, and renal dysfunction. The Cochrane review concluded that, although the therapeutic efficacy of CyA is confirmed for severe UC, evidence on it is limited [bib_ref] Cyclosporine A for induction of remission in severe ulcerative colitis, Shibolet [/bib_ref]. TAC also inhibits calcineurin activity and thereby cytokine production. TAC is used for steroid-dependent or -refractory UC. Blood trough levels for induction of remission are recommended to be 10-15 ng/ml [bib_ref] A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory..., Ogata [/bib_ref] [bib_ref] Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis, Yamamoto [/bib_ref]. It is indispensable to monitor blood trough levels of TAC, similar to CyA, to maintain optimal drug levels and to avoid adverse events. Some patients complain of hand tremor and hot flushes during TAC therapy. The severity of headache varies from mild to very severe and may not improve even after lowering blood levels in some severe patients; therefore, attention should be paid. The incidence of renal dysfunction is reported at high blood concentrations but promptly recovers by lowering blood concentrations. It is necessary to establish evidence for the efficacy of TAC in severe UC. In addition, the optimal trough level for severe UC is unknown. However, it is necessary to promptly raise blood trough levels for inducing remission in severe patients. The oral dose of TAC should be increased in a short time considering individual conditions. Attention should be paid to pneumocystis pneumonia and prophylactic use of sulfamethoxazole-trimethoprim should be considered in elderly patients. ## Comments Large multicenter trials overseas indicated that anti-TNF agents are effective for induction and maintenance of remission in moderate-to-severe UC patients who are refractory to conventional treatments [bib_ref] Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis, Sandborn [/bib_ref] [bib_ref] Infliximab for induction and maintenance therapy for ulcerative colitis, Rutgeerts [/bib_ref] [bib_ref] Biological agents for moderately to severely active ulcerative colitis: a systematic review..., Danese [/bib_ref] [bib_ref] Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a..., Jarnerot [/bib_ref] [bib_ref] Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial, Probert [/bib_ref] [bib_ref] Systematic review: infliximab therapy in ulcerative colitis, Gisbert [/bib_ref] [bib_ref] A meta-analysis of the therapeutic effects of tumor necrosis factor-alpha blockers on..., Huang [/bib_ref] [bib_ref] Adalimumab for induction of clinical remission in moderately to severely active ulcerative..., Reinisch [/bib_ref]. The efficacy of IFX and ADA have been demonstrated in the ACT-1/ACT2 studies [bib_ref] Infliximab for induction and maintenance therapy for ulcerative colitis, Rutgeerts [/bib_ref] and the ULTRA-1/ULTRA-2 studies [bib_ref] Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis, Sandborn [/bib_ref] [bib_ref] Adalimumab for induction of clinical remission in moderately to severely active ulcerative..., Reinisch [/bib_ref] , respectively, but comparative studies between each type of anti-TNF agent have not been conducted. Moreover, the CYSIF study reported that IFX is comparable to CyA in terms of efficacy when they are administrated to steroid-refractory moderate-to-severe UC patients [bib_ref] Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous..., Laharie [/bib_ref]. In addition, there are some reports which demonstrated that IFX is effective in avoiding surgery [bib_ref] A meta-analysis of the therapeutic effects of tumor necrosis factor-alpha blockers on..., Huang [/bib_ref]. Since currently available comparative studies between CyA and IFX have variations in target blood levels of CyA, etc., further investigation is required to make a conclusion. Anti-TNF agents are a recommended therapy for UC patients who are refractory to conventional treatments, although more evidence on the efficacy of anti-TNF agents is necessary. ## Cq5-11. what are the indications of cap in the treatment of severely active uc? # Statements - It is recommended that CAP should be considered as one of the treatments of choice to improve the remission rate because its steroid-sparing effect has been demonstrated in severely active UC patients (Recommendation grade: 1 (8), Evidence level: C). - CAP is recommended to be conducted twice-weekly or more to induce more rapid remission [bib_ref] The efficacy and safety of selective leukocytapheresis in the treatment of ulcerative..., Zhu [/bib_ref]. Furthermore, CAP causes severe adverse events less frequently compared to other drug treatments (OR 0.16, 95% CI 0.04-0.60) and is a safe therapeutic option [bib_ref] The efficacy and safety of selective leukocytapheresis in the treatment of ulcerative..., Zhu [/bib_ref]. However, the studies which the meta-analysis analyzed contained only a few RCTs; therefore, highquality evidence that demonstrates the efficacy of CAP is still lacking. A Japanese multicenter prospective RCT, although it was an open-label trial, reported that twice-weekly intensive treatment induced remission more rapidly (28.1 vs 14.9 days, p \ 0.0001) and improved the remission rate (54.0 vs 71.2%, p = 0.029) compared with the weekly treatment [bib_ref] An open-label prospective randomized multicenter study shows very rapid remission of ulcerative..., Sakuraba [/bib_ref]. Monotherapy with CAP is not common in severe UC patients, and CAP should be considered as a treatment of choice in combination with other treatments. [fig_ref] 6: Other gastrointestinal lesions CQ6-09 [/fig_ref] CQ5-12. What are the indications of 5-ASA for UC in remission? ## 4) maintenance treatment for uc in remission # Statements - Oral 5-ASA at a dose of 2 g/day or more is recommended to maintain clinical/endoscopic remission (Recommendation grade: 1 (9), Evidence level: A). ## Remission induced by anti-tnf agents continue anti-tnf agents ## Extensive colitis ## Proctitis / left-sided colitis Maintenance with AZA 6-MP Topical 5-ASA Oral 5-ASA ## Psl dependent relapse Remission induction with or without [fig_ref] 6: Other gastrointestinal lesions CQ6-09 [/fig_ref] Maintenance treatment for UC in remission ## Comments The efficacy of oral 5-ASA for maintenance of remission in UC has been analyzed by the Cochrane review, and it is effective for maintaining clinical as well as endoscopic remission [bib_ref] Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Feagan [/bib_ref]. High-dose 5-ASA is superior to low-dose in maintaining remission; therefore, it is advisable to use 2 g/day or more. In addition, SASP, a form of 5-ASA preparations, is equivalent to, or slightly more effective than 5-ASA for maintenance of remission, and its efficacy is dose-dependent. However, the incidence of its side effects or intolerant symptoms increases in a dose-dependent manner, therefore, a dose of 2-3 g/day is often chosen as a maintenance treatment. There is no clear difference in efficacy for maintenance of remission between a once-daily administration and conventional 2-3 times a day administration [bib_ref] Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Feagan [/bib_ref]. Drug adherence between the two administration methods is also reported to be equivalent; however, this result was obtained in clinical trials. It is reported that multiple split dosing is associated with a lower adherence in daily clinical practice. Lower adherence may lead to higher probability of relapse; therefore, once-daily dosing is more favorable to maximize the remission maintenance effect of this drug. Most of the results of dose comparison studies of individual 5-ASA preparations indicated that a higher dose of 5-ASA is unlikely to result in better maintenance effect; even in the study using time-dependent mesalazine, there was no difference in efficacy between 1.5 and 3.0 g/day [bib_ref] Comparison of the efficacy and safety of 1.5 compared with 3.0 g..., Fockens [/bib_ref]. Efficacy of topical 5-ASA (suppository and enema) in distal UC for maintenance of clinical and endoscopic remission has been confirmed by the Cochrane review and it is as effective as oral 5-ASA [bib_ref] Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis, Marshall [/bib_ref]. There are a few reports demonstrating that dose-increase of topical 5-ASA does not improve its remission maintenance effect. Mesalazine enema approved in Japan is effective and safe at a dose of 1 g once daily. There are a few reports suggesting the efficacy of combination treatment of oral 5-ASA with twice-a-week enema; however, further confirmatory studies are necessary since the number of patients included in these trials is limited [bib_ref] Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in..., Albasio [/bib_ref] [bib_ref] Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative..., Yokoyama [/bib_ref]. It is often difficult for patients to continue topical 5-ASA for a long time as a maintenance therapy; therefore, sufficient consideration should be given to patients' acceptance. ## Comments It is recommended to use immunomodulators (AZA/6-MP) in patients who are dependent on or have difficulty in withdrawing steroids. Many studies demonstrated that continuing AZA after achieving remission provides remission rates of around 50% or higher. It is also known that, based on the results of multiple RCTs, immunomodulators are significantly effective in maintaining remission and tapering steroids [bib_ref] Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis, Timmer [/bib_ref] [bib_ref] Update in medical therapy of ulcerative colitis: a practical approach, Katz [/bib_ref] [bib_ref] Randomised controlled trial of azathioprine withdrawal in ulcerative colitis, Hawthorne [/bib_ref] [bib_ref] Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis, Gisbert [/bib_ref] [bib_ref] A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and..., Mantzaris [/bib_ref]. The recommended doses of immunomodulators are 1.5-2.5 mg/kg/day of AZA and 075-1.5 mg/kg/day of 6-MP; however, Japanese patients are known to be more likely to develop side effects because of their low metabolic capacity. 6-MP is not officially approved in Japan, therefore it is recommended to start with AZA at first and switch to 6-MP if the patient is intolerant to AZA. AZA is generally started at 25 mg/day and careful attention should be paid to both side effects and efficacy. In addition, there is a report suggesting that the effect of AZA monotherapy on maintenance of remission is equivalent to the combination therapy with 5-ASA and AZA, and there is no additive benefit of combined 5-ASA [bib_ref] A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and..., Mantzaris [/bib_ref] ; however, it is still common to use 5-ASA as a maintenance treatment along with AZA because experts' evaluations of this study is not sufficient. It is also common to add AZA/6-MP when the patients cannot maintain remission by high-dose 5-ASA. Caution is required since the combination of 5-ASA and AZA inhibits AZA metabolism and may increase the incidence of side effects such as myelosuppression. Long-term tolerability is relatively good if the patient does not develop side effects in the initial several weeks, and the increase in the risk of malignancy, which was previously of concern, is reported as negative. It is unclear whether or not CyA and Tac are effective for maintaining remission because of the absence of sufficient studies at present; therefore, AZA/6-MP is used as a maintenance therapy after achieving remission by CyA/ TAC [bib_ref] Cyclosporine A for induction of remission in severe ulcerative colitis, Shibolet [/bib_ref]. ## Cq5-14. what are the indications of anti-tnf agents for uc in remission? # Statements - Long-term administration of anti-TNF agents is recommended as remission maintenance therapy for moderate-to-severe UC patients who achieved remission with anti-TNF agents (Recommendation grade: 1 (8), Evidence level: B). - Maintenance of remission with anti-TNF agents provides higher likelihood of avoiding colectomy (Evidence level: B). ## Comments The meta-analysis of 506 clinical trials concluded that anti-TNF agents are effective not only in inducing remission (relative risk (RR) 2.4, 95% CI 1.72-3.47), but also in maintaining remission (RR 2.00, 95% CI 1.52-2.62) in UC patients. The long-term efficacy of maintenance therapy with IFX every 8 weeks for at least up to 52 weeks has been confirmed not only in CD patients, but also in UC patients that have been refractory to conventional therapy and achieve remission with IFX [bib_ref] Infliximab for induction and maintenance therapy for ulcerative colitis, Rutgeerts [/bib_ref]. The probability of colectomy in patients with continued maintenance therapy with IFX is 9.5% within 54 weeks, which is significantly lower than 17% in patients with placebo (p = 0.02) [bib_ref] Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab, Sandborn [/bib_ref] ; therefore, the position statement of the World Organization of Gastroenterology stated that maintenance therapy with IFX should be considered in order to reduce the risk of colectomy [bib_ref] The London Position Statement of the World Congress of Gastroenterology on Biological..., D'haens [/bib_ref]. On the contrary, even in the large-scale trials (ACT1/ ACT2) which demonstrated the usefulness of IFX as a maintenance therapy, placebo-controlled re-randomization in order to examine its efficacy for maintenance of remission was not conducted [bib_ref] Infliximab for induction and maintenance therapy for ulcerative colitis, Rutgeerts [/bib_ref] and, thereby, there is no evidence appropriately confirming its genuine efficacy for maintenance of remission. Therefore, the optimal length of treatment period after induction with IFX or its efficacy as a maintenance therapy after other induction treatments is not clear. The efficacy of long-term maintenance treatment with ADA after successful induction of remission with it is also confirmed as with IFX [bib_ref] Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis, Sandborn [/bib_ref]. ## Comments A meta-analysis failed to demonstrate the non-inferiority of probiotics, which had been expected to have efficacy in maintenance of remission, compared to mesalazine in terms of relapse rates; 40.1% in the probiotic group and 34.1% in the mesalazine group (OR 1.33, 95% CI 0. . It also failed to demonstrate the superiority of probiotics over placebo in terms of relapse rates within a year after induction of remission; 75% in the probiotics group and 92% in the placebo group (OR 0.27, 95% CI 0.03-2.68) [bib_ref] Probiotics for maintenance of remission in ulcerative colitis, Naidoo [/bib_ref]. Long-term use of TAC beyond 3 months for refractory UC patients following TAC-induced remission, and semimonthly CAP following CAP-induced remission are expected as novel remission maintenance treatments; however, there is still no evidence on their efficacy in maintaining remission. 5) Surgical treatment for UC CQ5-16. What are the indications of surgery in UC? # Statements - When patients are suffering from colonic perforation, massive bleeding, toxic megacolon, CRC or high-grade dysplasia, or severe disease which does not respond to medical treatments, surgery is recommended (absolute indications) (Recommendation grade: 1 (9), Evidence level: D). - Surgery is also recommended for patients in whom adequate medical treatment is ineffective, or for patients whose daily life is impaired due to the disease, extraintestinal complications, or side effects of drugs (relative indications) (Recommendation grade: 1 (9), Evidence level: D). ## Comments Because a delay in surgery increases the risk of postoperative complications, it is necessary to avoid a delay in the decision of surgery while monitoring response to medical treatments, side effects of the drugs, and complications, and consulting with specialists or surgeons if necessary [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref]. It is clearly necessary to conduct surgery in patients with life-threatening physiological conditions [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Surgery is absolutely indicated for patients with a severe or fulminant disease who do not respond to sufficient medical therapies such as high-dose intravenous steroid, CAP, intravenous CyA, oral TAC, and anti-TNF agents. Surgery should be considered at an appropriate timing because a delay in surgery increases the incidence of postoperative complications especially in patients with a severe disease or in elderly patients, who have low reserve capacity [bib_ref] Delayed surgery for acute severe colitis is associated with increased risk of..., Randall [/bib_ref] [bib_ref] Prognosis following surgery for ulcerative colitis in elderly patients, Ikeuchi [/bib_ref]. It is difficult to uniformly determine relative indications of surgery because there is a wide variety in patients' disease severity and conditions. A relative indication of surgery is considered in patients who are suspected to have coexisting cancer because of the presence of stricture or low-grade dysplasia, but the surgical indication should be carefully determined in those patients because it is difficult to ascertain the presence of cancer [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Van Assche [/bib_ref]. To determine a surgical indication, gastroenterologists and surgeons should cooperate to fully explain issues associated with surgery to the patient and have enough discussion with the patient while considering his/her physical condition, social background, and preference [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. CQ5-17. What are the surgical procedures for UC? # Statements - It is recommended to perform total proctocolectomy with ileal pouch-anal anastomosis or ileal pouch-anal canal anastomosis as the standard surgical technique of elective surgery (Recommendation grade: 1 (9), Evidence level: D). ## Comments The purpose of surgery is to remove the colon and rectum, the target organs of this disease; therefore, total proctocolectomy or subtotal colectomy is conducted in principle [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Dignass [/bib_ref]. Total colectomy with ileal pouch-anal (canal) anastomosis preserves the anus, providing satisfactory postoperative QOL; therefore, is often chosen as a standard surgical technique of elective surgery. Although the average number of daily bowel movements after surgery is 5-6 times, and patients may develop fecal incontinence, the rate of functional pouch (pouch functioning as a reservoir without ileostomy or resection) is high. Ileal pouch-anal anastomosis is highly curative while ileal pouch-anal canal anastomosis preserves good anal function and causes less fecal incontinence [bib_ref] Quality of life, health-related quality of life and health status in patients..., Heikens [/bib_ref] [bib_ref] Ileal pouch anal anastomosis: analysis of outcome and quality of life in..., Fazio [/bib_ref] [bib_ref] Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis:..., Michelassi [/bib_ref] [bib_ref] Comparison of outcomes after hand-sewn versus stapled ileal pouch-anal anastomosis in 3,109..., Kirat [/bib_ref]. Total (or subtotal) colectomy with ileostomy and mucous fistula of the sigmoid colon or Hartmann surgery may be performed in severe or emergent patients. Total proctocolectomy with (permanent) ileostomy or subtotal proctocolectomy with ileorectal anastomosis may be performed considering anal function, age, and social background. Patients' QOL after these procedures is also satisfactory [bib_ref] A comparison of the quality of life of ulcerative colitis patients after..., Kuruvilla [/bib_ref] [bib_ref] Clinical outcomes of ileorectal anastomosis for ulcerative colitis, Da Luz Moreira [/bib_ref]. After surgical procedures with residual colorectal mucosa, it is necessary to pay attention to the development of cancer/dysplasia. A systematic review overseas reported that laparoscopic surgery is not superior to open surgery in UC patients [bib_ref] Open versus laparoscopic (assisted) ileo pouch anal anastomosis for ulcerative colitis and..., Ali [/bib_ref]. The judgment of surgeons is important in determining the indication of laparoscopic surgery and it is desirable to perform it at specialist centers that have sufficient experience [bib_ref] Guidelines for laparoscopic surgery for inflammatory bowel disease. Practical guidelines for endoscopic..., Jsfe [/bib_ref]. It is necessary for the patient, the surgeon, and the physician to fully discuss to decide a surgical procedure, taking the patient's physical and social conditions into account. ## Comments There is a possibility to develop infectious complications in patients under treatments with strong immunosuppressive effects. As patients who are administered steroids especially have an increased risk of anastomotic leak and infectious complications including wound infection, it is necessary to taper steroids during the preoperative period and be cautious about a choice of surgical procedure, and postoperative management [bib_ref] Guidelines for the management of inflammatory bowel disease in adults, Mowat [/bib_ref]. Pelvic sepsis including anastomotic leak occurs in 4-10% of patients as postoperative complications of total proctocolectomy with ileal pouch-anal anastomosis or ileal pouch-anal canal anastomosis, which is the standard operation for UC [bib_ref] Ileal pouch anal anastomosis: analysis of outcome and quality of life in..., Fazio [/bib_ref] [bib_ref] Update of complications and functional outcome of the ileo-pouch anal anastomosis: overview..., De Zeeuw [/bib_ref]. There are other possible complications such as fistula, anastomotic stricture, pouchrelated complications such as pouchitis [bib_ref] Risk factors for ileoanal J pouch-related septic complications in ulcerative colitis and..., Heuschen [/bib_ref] ; however, the rate of functional pouch (pouch functioning as a reservoir without ileostomy or resection) is approximately 95% at 10 years [bib_ref] Ileal pouch anal anastomosis: analysis of outcome and quality of life in..., Fazio [/bib_ref] [bib_ref] Update of complications and functional outcome of the ileo-pouch anal anastomosis: overview..., De Zeeuw [/bib_ref] [bib_ref] Surgery for ulcerative colitis in 1,000 patients, Ikeuchi [/bib_ref]. The incidence of bowel obstruction is approximately 15% and surgical treatment may be necessary [bib_ref] Ileal pouch anal anastomosis: analysis of outcome and quality of life in..., Fazio [/bib_ref] [bib_ref] A comparison of adverse events and functional outcomes after restorative proctocolectomy for..., Lovegrove [/bib_ref] [bib_ref] Update of complications and functional outcome of the ileo-pouch anal anastomosis: overview..., De Zeeuw [/bib_ref]. The incidence of pouchitis is reported to be approximately 30% in Western countries, which is higher than Japan. MNZ and CPFX are used for treating pouchitis, but the latter causes less side effects [bib_ref] Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative..., Holubar [/bib_ref] [bib_ref] Second European evidence-based consensus on the diagnosis and management of ulcerative colitis..., Van Assche [/bib_ref]. There is no established treatment for patients who do not respond to antibiotics or who have repeated relapses and chronical progression. In female patients, fertility may decrease after proctocolectomy with ileal pouch-anal (canal) anastomosis, but the course of pregnancy is benign until delivery. Defecation function may be affected by pregnancy, but recovers after delivery. ## Treatments of cd 1) Treatment for mildly to moderately active CD [fig_ref] Figure 7: Remission induction treatment for active CD the optimal dose and period of... [/fig_ref] CQ6-01. What is the treatment of choice in mildly to moderately active CD? # Statements - SASP or steroids are suggested for use in mildly to moderately active colonic CD (Recommendation grade: 2 (7), Evidence level: B). - It is recommended to choose enteral nutrition or systemic steroids for the treatment of small intestinal lesions (Recommendation grade: 1 (8), Evidence level: B). - Anti-TNF agents are recommended to be considered for steroid-dependent or -refractory patients (Recommendation grade: 1 (9), Evidence level: A). ## Comments Multiple disease severity classifications of CD have been proposed and, in Japan, the Research Group for Intractable Inflammatory Bowel Disease proposed a severity classification which utilizes the CDAI and other indices (refer to CQ1-05). In daily clinical practice, severity is comprehensively assessed by patients' subjective symptoms, and clinical and laboratory findings. The mild-to-moderate severity referred in this guideline means ''patients who can attend outpatient clinics, can ingest orally, and do not have findings such as dehydration, fever, abdominal tenderness, bowel obstruction, or weight loss of 10% or more''. Efficacy of SASP for mildly to moderately active CD is confirmed by a meta-analysis [bib_ref] Aminosalicylates for induction of remission or response in Crohn's disease, Lim [/bib_ref]. This meta-analysis demonstrated that SASP is effective only for colonic CD and is not as effective as steroids. Efficacy of mesalazine for active CD has been shown in several reports [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: multicenter, open-label,..., Munakata [/bib_ref] [bib_ref] Mesalamine in the treatment of mild to moderate active Crohn's ileitis: results..., Prantera [/bib_ref] , and it is commonly used and may be effective in clinical practice. However, a recent metaanalysis demonstrated that 5-ASA preparations are no more effective than placebo for induction of remission even at a high dose [bib_ref] Aminosalicylates for induction of remission or response in Crohn's disease, Lim [/bib_ref]. Efficacy of steroids for induction of remission has been confirmed by meta-analyses [bib_ref] Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref] , and it was more effective when used longer than 15 weeks [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. However, Side effects were observed more frequently in patients who received steroids compared to low-dose 5-ASA or placebo, but the withdrawal rates from the clinical trials due to side effects were not different from the placebo group or the low-dose 5-ASA group. In Europe and the US, budesonide, a steroid with fewer systemic side effects, is used for ileal and right-sided colonic lesions. A meta-analysis comparing between enteral nutrition and steroids concluded that steroids are superior to enteral nutrition. Anti-TNF agents can be a therapeutic option for moderately active CD patients, especially who are dependent on or refractory to steroids [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Dignass [/bib_ref]. GMA is reported to be effective in patients with colonic CD who do not respond to conventional medical or nutritional treatments [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref]. A meta-analysis studying the efficacy of antibiotics showed that they may be effective in inducing remission. However, many different types and combinations of antibiotics were included in the study; therefore, careful attention should be paid to interpret the data [bib_ref] Antibiotic therapy in inflammatory bowel disease: a systematic review and metaanalysis, Khan [/bib_ref]. 2) Treatment for moderately to severely active CD [fig_ref] Figure 7: Remission induction treatment for active CD the optimal dose and period of... [/fig_ref] CQ6-02. What is the treatment of choice in moderately to severely active CD? # Statements - Administration of oral steroids (PSL & 40 mg/day) is recommended (Recommendation grade: 1 (8), Evidence level: A). - It is suggested to consider enteral nutritional therapy, although its efficacy in induction of remission is comparable or slightly inferior to steroids (Recommendation grade: 2 (7), Evidence level: C). - It is recommended to consider administrating anti-TNF agents to steroid-refractory patients (Recommendation grade: 1 (9), Evidence level: A). - When patients with active colonic disease who do not respond to or intolerant to drug therapy or nutrition therapy, it is suggested to consider GMA (Recommendation grade: 2 (7), Evidence level: C). ## Comments The moderate-to-severe severity referred in this guideline means, as defined overseas, ''patients who have a CDAI score of 250-450 and do not respond to treatments usually administered to mild-to-moderate patients, or those who have a fever, remarkable weight loss, abdominal pain and/ or abdominal tenderness, intermittent nausea/vomiting (without obstruction), or significant anemia'' [bib_ref] Defining disease severity in inflammatory bowel diseases: current and future directions, Peyrin-Biroulet [/bib_ref]. An RCT has demonstrated the efficacy of steroids for induction of remission in CD patients [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. However, steroids are not effective in maintaining remission; therefore, a combination with immunomodulators such as AZA and 6-MP should be considered when the disease recurs during reducing steroids or shortly after steroid withdrawal, or repeatedly relapses after steroid withdrawal. In Western countries, methotrexate is used as an effective option when AZA or 6-MP is not tolerable due to side effects [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]. The efficacy of anti-TNF agents in patients who do not respond to steroids or immunomodulators has been proved in both single-dose administration and scheduled repetitive administration [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor..., Targan [/bib_ref] [bib_ref] Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I..., Hanauer [/bib_ref] [bib_ref] Adalimumab for maintenance of clinical response and remission in patients with Crohn's..., Colombel [/bib_ref] [bib_ref] Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis..., Peyrin-Biroulet [/bib_ref] [bib_ref] A systematic review and economic evaluation of the use of tumour necrosis..., Dretzke [/bib_ref]. The use of GMA in CD patients with active colonic disease who do not respond to conventional drug therapy or nutritional therapy has been approved in 2010 in Japan [bib_ref] Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: an open multicenter..., Fukuda [/bib_ref]. 3) Treatment for severe-to-fulminant active CD [fig_ref] Figure 7: Remission induction treatment for active CD the optimal dose and period of... [/fig_ref] CQ6-03. What is the treatment of choice in severe-tofulminant CD? # Statements - It is recommended that patients should be usually hospitalized, be considered fasting, infusion, and blood transfusion, if necessary, and be administered antibiotics if they have symptoms suggestive of infection (Recommendation grade: 1 (9), Evidence level: D). - It is recommended to administer steroids (PSL 40-60 mg/day) intravenously after excluding infections (Recommendation grade: 1 (8), Evidence level: A). - It is recommended to consider administering anti-TNF agents to steroids-refractory patients (Recommendation grade: 1 (9), Evidence level: A). - It is recommended to consult surgeons early when patients are in poor general condition and do not respond to anti-TNF agents (Recommendation grade: 1 (9), Evidence level: D). ## Comments The severe-to-fulminant severity referred in this guideline means ''patients who have persistent symptoms in spite of oral steroid administration or those who develop a high fever, persistent vomiting, bowel obstruction, rebound tenderness, cachexia, or abscess'' [bib_ref] Management of Crohn's disease in adults, Hanauer [/bib_ref]. Patients with severe-to-fulminant activity should usually be hospitalized and need intensive general care. Intravenous steroid administration should be preceded by oral administration because absorption of oral steroids is not stable and intravenous administration is superior in terms of pharmacokinetics [bib_ref] Absorption of prednisolone in patients with Crohn's disease, Shaffer [/bib_ref]. The efficacy of steroids has been demonstrated by two placebo-controlled trials and six 5-ASA-controlled trials [bib_ref] Traditional corticosteroids for induction of remission in Crohn's disease, Benchimol [/bib_ref]. As many studies have demonstrated the efficacy of anti-TNF agents (IFX and ADA) in severe CD patients, these drugs can be considered as a treatment of choice if infectious complications such as abscess can be excluded or improved if exist [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor..., Targan [/bib_ref] [bib_ref] Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial, Hanauer [/bib_ref] [bib_ref] Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I..., Hanauer [/bib_ref] [bib_ref] Adalimumab for maintenance of clinical response and remission in patients with Crohn's..., Colombel [/bib_ref] [bib_ref] Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis..., Peyrin-Biroulet [/bib_ref] [bib_ref] A systematic review and economic evaluation of the use of tumour necrosis..., Dretzke [/bib_ref]. In addition, anti-TNF agents can be considered as a treatment of choice in fulminant CD patients although evidence on the efficacy of anti-TNF agents in such patients is limited. When treating CD patients who have unstable hemodynamics or peritoneal irritation symptoms, or those who do not respond to anti-TNF agents, it is desirable to consult surgeons for surgical indication early in the course. ## Comments The local pathology of perianal and anal canal diseases accompanying CD should be examined by experienced surgeons or proctologists, and investigation under anesthesia may be necessary [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. Imaging techniques including endoscopy, CT, MRI, and transanal US are useful in examining anal and rectal lesions, and it is important to assess the inflammatory changes in the anus and rectum with these examinations and properly determine the need for surgery [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. A meta-analysis indicated the efficacy of immunomodulators (e.g., AZA) for perianal fistulas [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref]. Antibiotics such as MNZ are used in clinical practice, although there is only limited evidence on their therapeutic efficacy [bib_ref] Healing of perineal Crohn's disease with metronidazole, Bernstein [/bib_ref]. An RCT showed that IFX is effective for induction of remission of fistulas (90% of fistulas in this study were anal fistula) in CD patients [bib_ref] Infliximab for the treatment of fistulas in patients with Crohn's disease, Present [/bib_ref]. Additionally, its efficacy for maintaining remission has also been confirmed [bib_ref] Infliximab maintenance therapy for fistulizing Crohn's disease, Sands [/bib_ref]. A sub-analysis of the maintenance study of ADA demonstrated its efficacy for fistulas [bib_ref] Adalimumab for maintenance of clinical response and remission in patients with Crohn's..., Colombel [/bib_ref]. It is necessary to confirm that infection such as abscess has been controlled before administrating anti-TNF agents. ## Comments CD may be accompanied with internal fistulas such as entero-entero fistulas and external fistulas such as enterocutaneous fistulas. There is still no consensus regarding the necessity of treatments for asymptomatic fistulas. Antibiotics, immunomodulators, and anti-TNF agents are used as medical treatments for fistulas. 1) There are few placebo-controlled studies about antibiotics therapy. However, it can be expected that MNZ or CPFX improves symptoms and closes fistulas [bib_ref] Perianal fistulae in Crohn's disease: current and future approaches to treatment, Keshaw [/bib_ref] [bib_ref] Review article: medical, surgical and radiological management of perianal Crohn's fistulas, Tozer [/bib_ref]. 2) Efficacy of immunomodulators has been proved by a meta-analysis of RCTs overseas (OR 3.09, 95% CI 2.45-3.91) [bib_ref] Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis, Pearson [/bib_ref]. 3) Regarding anti-TNF agents, IFX, ADA, and certolizumab are effective for 50% or more reduction of fistulas in number, or complete closure of fistulas in patients with maintenance therapy with these drugs. However, the efficacy has not been confirmed in a short term (4-18 weeks) [bib_ref] Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis..., Peyrin-Biroulet [/bib_ref]. Moreover, it has been reported that a combination with antibiotics and anti-TNF agents increases the therapeutic efficacy for anal fistula [bib_ref] Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula..., Dewint [/bib_ref]. 4) It is reported that anti-TNF agents are effective in onethird of CD patients with enterocutaneous fistula (in the absence of intestinal stenosis or complex fistula). On the other hand, the efficacy of anti-TNF agents for internal fistula is low. [bib_ref] Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with..., Amiot [/bib_ref]. Surgery should be considered when medical treatments do not improve fistulas. Internal fistulas accompanied with severe malabsorption, repetitive urinary tract infection, an excess leak of enteric juice from cutaneous fistula, perianal pain, or abscess formation are indications for surgery. ## Comments Intestinal strictures include those caused by mucosal edema accompanied with inflammation or those caused by intestinal fibrosis. Strictures that are mainly caused by inflammation may be improved with anti-inflammatory therapy such as steroids. When anti-inflammatory therapy does not improve symptoms, intestinal fibrosis should be suspected, and the indication of endoscopic dilation should be considered based on the length and number of the strictures and the presence of ulcers. The indication of endoscopic dilation should fulfill the following: (1) stricture length is 5 cm or less and its curve is not severe; (2) fistula and abscess related to stricture are absent; (3) deep ulcers are absent in the stricture. Especially when patients do not fulfill (2), surgery should be considered. A meta-analysis has confirmed that therapeutic effects are observed in 58% of CD patients who underwent endoscopic dilatation (average observation period is 33 months). It is reported that surgery can be avoided by endoscopic dilatation in patients who have stricture less than 4 cm in length [bib_ref] Systematic review: endoscopic dilatation in Crohn's disease, Hassan [/bib_ref]. Furthermore, it has been reported in Japan that a combined use of dilation with immunomodulators or biologics may be effective for avoiding surgery in CD patients [bib_ref] Value of concomitant endoscopic balloon dilation for intestinal stricture during long-term infliximab..., Ono [/bib_ref] [bib_ref] Prior use of immunomodulatory drugs improves the clinical outcome of endoscopic balloon..., Honzawa [/bib_ref]. CD causes severe bleeding on rare occasions. Medical therapy including prohibiting food intake and administrating intravenous fluid should be aggressively started and bowel rest should be attempted. There are a few reports suggesting that steroids or IFX were an effective medical therapy for hemostasis [bib_ref] Severe lower gastrointestinal bleeding in Crohn's disease: successful control with infliximab, Belaiche [/bib_ref] [bib_ref] Infliximab stopped severe gastrointestinal bleeding in Crohn's disease, Aniwan [/bib_ref]. In addition, another report indicated that immunomodulators reduced the risk of lower gastrointestinal bleeding [bib_ref] Risk factors and outcome of acute severe lower gastrointestinal bleeding in Crohn's..., Kim [/bib_ref]. If possible, endoscopic hemostasis should be attempted. Angiography with intra-arterial vasopressin or transcatheter arterial embolization was reported to be effective [bib_ref] Acute massive hemorrhage from intestinal Crohn disease, Homan [/bib_ref] [bib_ref] Revisiting the past: intraarterial vasopressin for severe gastrointestinal bleeding in Crohn's disease, Alla [/bib_ref] , but arterial embolization may cause intestinal necrosis. Surgical treatment is necessary if the medical therapy is not effective for hemostasis. It is reported that surgery is required in 20-90% for the first bleeding and 30-35% for the recurrent bleeding after conservative treatment [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]. ## Comments Transmural inflammation of CD may cause abdominal abscesses and its incidence in Japan is reported to be approximately 10% [bib_ref] The clinical characteristics and outcome of intraabdominal abscess in Crohn's disease, Yamaguchi [/bib_ref]. CT, MRI, and US examinations are useful in diagnosing abscess [bib_ref] Ultrasound and magnetic resonance imaging in Crohn's disease: a comparison, Potthast [/bib_ref]. Medical management with fasting and infusion is basically considered. In addition, administration of broad-spectrum antibiotics should be considered and percutaneous drainage, if possible, should be conducted. Draining methods include CTguided or ultrasound-guided percutaneous drainage and surgical drainage with small incision [bib_ref] Percutaneous abscess drainage in Crohn disease: technical success and short-and long-term outcomes..., Gervais [/bib_ref] [bib_ref] Outcome of surgical versus percutaneous drainage of abdominal and pelvic abscesses in..., Gutierrez [/bib_ref]. In patients whose abscess is not improved or recurs after percutaneous drainage, surgery is necessary. In patients who are accompanied with abscesses, it is necessary to identify the intestine responsible for the abscess formation and consider a surgery to resect the affected bowel. The results of ACCENT II indicated that IFX is not associated with recurrence of abscess, and there are case reports suggesting that anti-TNF agents after abscess drainage are effective to prevent recurrence. Therefore, treatment with anti-TNF agents may be considered after appropriate drainage of abscess, although surgery is generally necessary especially for intractable patients with recurring abscess formation. ## Comments Even though evidence on treatment for upper gastrointestinal lesions in CD is scarce, there are some reports suggesting that PPI, steroids, thiopurines [bib_ref] Proximal Crohn's disease: review of the clinicopathologic features and therapy, Van Hogezand [/bib_ref] or IFX [bib_ref] Infliximab for severe gastrointestinal bleeding in Crohn's disease, Ando [/bib_ref] were effective for active upper gastrointestinal lesions. In addition, there is a Japanese report about the efficacy of crushed 5-ASA powder preparation [bib_ref] A case of Crohn's disease that shows the improvement of the gastric..., Nagamata [/bib_ref]. Endoscopic balloon dilation may be effective for a single and short gastric or duodenal stricture [bib_ref] Long-term outcome of endoscopic balloon dilation in obstructive gastroduodenal Crohn's disease, Matsui [/bib_ref]. When endoscopic balloon dilation is difficult to conduct or is ineffective, surgery (gastrojejunostomy, or strictureplasty) should be considered [bib_ref] Proximal Crohn's disease: review of the clinicopathologic features and therapy, Van Hogezand [/bib_ref] [bib_ref] Symptomatic duodenal Crohn's disease: is strictureplasty the right choice?, Tonelli [/bib_ref]. A review based on experts' opinions recommended that PPI is the first choice of treatment for upper gastrointestinal lesions of CD without strictures, and then treatments with steroids, thiopurines, and IFX follow. Endoscopic balloon dilation is recommended as first-line therapy for patients with strictures, and then PPI, steroids, thiopurines, and surgery follow. It has been reported that the presence of upper gastrointestinal lesions of CD is a prognostic factor for disease progression over time [bib_ref] Is it possible to change phenotype progression in Crohn's disease in the..., Magro [/bib_ref]. ## Comments It has been demonstrated that smoking is related to refractoriness or recurrence of CD [bib_ref] Effect of cigarette smoking on recurrence of Crohn's disease, Sutherland [/bib_ref] , and smoking cessation can improve refractoriness and reduce the rate of recurrence. The meta-analysis in 2006 that included 9 studies indicates that the OR of the risk of smoking for worsening CD is 1.76 (95% CI 1.40-2.22) [bib_ref] Smoking and inflammatory bowel disease: a meta-analysis, Mahid [/bib_ref]. Patients with CD should refrain from frequent or excessive drinking because alcohol may affect the function of the intestinal tract. Additionally, it is considered that unbalanced dietary habits can become a risk factor for recurrence of CD because nutrition therapy is effective for CD patients. An association between psychological stress and recurrence of CD has been reported [bib_ref] Psychological stress in IBD: new insights into pathogenic and therapeutic implications, Mawdsley [/bib_ref]. It is important for patients with CD to avoid stress as much as possible or try not to build up stress. As NSAIDs are known to cause gastrointestinal damage as well as become a recurrence or worsening factor of CD, it should be avoided to take NSAIDs as much as possible and, if analgesics or antipyretics are needed, it is desirable to take acetaminophen or COX-2 inhibitors for a short period [bib_ref] Management of Crohn's disease in adults, Lichtenstein [/bib_ref] [bib_ref] Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study, Felder [/bib_ref]. CQ6-11. What is the treatment of choice to prevent recurrence of CD in remission? # Statements - It is recommended to administer thiopurine (AZA/6-MP) to maintain remission (Recommendation grade: 1 (9), Evidence level: B). - Scheduled maintenance administration of anti-TNF agents is recommended when anti-TNF agents induced remission (Recommendation grade: 1 (9), Evidence level: B). - It is recommended that enteral nutrition therapy and 5-ASA should be considered as therapeutic options for maintenance of remission (Recommendation grade: 1 (8), Evidence level: C). ## Comments ## Thiopurine It has been reported that AZA and 6-MP are effective for reduction or discontinuation of steroids during the remission maintenance period, and for long-term maintenance of remission. The optimal dose of AZA is typically 1.0-2.5 mg/kg/day, whereas the dose of 6-MP is approximately half of AZA, but high-dose is considered to be superior to low-dose in terms of efficacy (OR for maintenance of remission with AZA 2.32, 95% CI 1.44-3.49 and OR for maintenance of remission with 6-MP 3.32, 95% CI 1.40-7.87) [bib_ref] Review article: the evidence base for interventions used to maintain remission in..., Akobeng [/bib_ref] [bib_ref] Azathioprine for maintaining remission of Crohn's disease, Pearson [/bib_ref]. However, it is necessary to consider the following: AZA and 6-MP may develop severe side effects; the optimal dose for efficacy or the threshold for side effects varies widely among individuals; as the recommended doses of AZA/6-MP are intended for westerners, even a lower dose of AZA/6-MP may still be effective in Japanese patients but can also cause side effects. A meta-analysis reviewed 3 studies examining the outcome of discontinuation of AZA in 163 patients who maintained remission with thiopurines. The result demonstrated that continuation of AZA is effective to prevent from recurrence of CD [bib_ref] Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease:..., Peyrin-Biroulet [/bib_ref]. Based on the report that showed the efficacy of continuous administration of AZA beyond 2 years, it seems that administrating AZA for 3-4 years is practical as far as patients maintain remission without side effects (RR of relapse with AZA 0.39, 95% CI 0.21-0.74) [bib_ref] Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and..., Khan [/bib_ref]. A meta-analysis in 2009 reported that postoperative administration of thiopurines can reduce endoscopic recurrence [bib_ref] Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease:..., Peyrin-Biroulet [/bib_ref]. ## Remission by anti-tnf agents ## Long-term anti-tnf agents ## Cd in remission ## Anti-tnf agents It has been demonstrated that anti-TNF agents are effective in preventing recurrence in luminal CD patients compared to placebo, according to the meta-analysis in 2011 which included 5 clinical trials (including 1390 CD patients) (RR of relapse 0.71, 95% CI 0.65-0.76) [bib_ref] Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis, Ford [/bib_ref]. Therefore, IFX at a dose of 5 or 10 mg/kg every 8 weeks, ADA at a dose of 40 mg every week (unapproved in Japan) or every other week, and certolizumab at a dose of 400 mg every 4 weeks are effective for maintaining remission in CD patients who have responded to each biological drug. However, data on safety profile related to long-term administration is not yet sufficient. 3. Enteral nutrition therapy Enteral nutrition therapy has a good safety profile as a long-term remission maintenance treatment, but home total enteral nutrition therapy is difficult to continue for a long term because of poor tolerance and low convenience. Partial enteral nutrition therapy can be expected to improve tolerance and convenience, and patients can enjoy eating. There are only two RCTs to compare between enteral nutrition and placebo (no eating restrictions). However, it is reported that when patients intake 30-50% of calories by enteral nutrition, the efficacy for maintaining remission is greater compared to when they only take normal diet [bib_ref] Effectiveness of an 'half elemental diet' as maintenance therapy for Crohn's disease:..., Takagi [/bib_ref] [bib_ref] Enteral nutrition for maintenance of remission in Crohn's disease, Akobeng [/bib_ref] [bib_ref] Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and..., Yamamoto [/bib_ref]. Even though there is no evidence on the efficacy of enteral nutrition that continues beyond a year, if the patient has no problem in tolerability and convenience, it seems to be desirable to continue the therapy as long as possible. 4. 5-ASA preparations A review in 2010 reported that 5-ASA is no more effective for maintaining remission after inducing remission by medical therapy compared to placebo [bib_ref] Review article: the evidence base for interventions used to maintain remission in..., Akobeng [/bib_ref]. On the other hand, the Cochrane review in 2011 that analyzed 9 RCTs indicated that the efficacy of 5-ASA in patients in remission after surgery is slightly superior to placebo in terms of risk reduction of recurrence [bib_ref] Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease, Gordon [/bib_ref]. However, careful interpretation is necessary for the results. 5. Home parenteral nutrition Sufficient digestion and absorption can no longer be expected from the intestinal tract when the residual small intestine becomes 1 m or less due to extensive small intestinal resection because of stricture or perforation in CD patients with small intestinal lesions, or small intestinal resection with frequent surgeries. Therefore, a central venous catheter should be placed in order to provide necessary nutrition and to enable patients or family members to maintain the intravenous management at home [bib_ref] Management of the short bowel syndrome after extensive small bowel resection, Keller [/bib_ref]. ## 8) surgical treatment for cd ## Cq6-12. what are the indications of surgery in cd? # Statements - Surgery is recommended for perforation, massive bleeding, cancer, bowel obstruction refractory to medical therapy, and abscess (absolute indications) (Recommendation grade: 1 (9), Evidence level: D). - Surgery is recommended for refractory stenosis, internal fistula, external fistula, refractoriness to medical treatment, refractory extraintestinal complications (e.g., growth retardation, pyoderma gangrenosum), and refractory perianal lesions (relative indications) (Recommendation grade: 1 (9), Evidence level: D). ## Comments Although there has been no new evidence to revise the statements in this section since the last version of the guideline was published, many physicians and surgeons empirically agree with these statements. Endoscopic balloon dilation may be occasionally chosen for stenosis rather than surgery; however, there are some limitations for the indication of endoscopic balloon dilatation and it should be conducted under backup by surgeons [bib_ref] Endoscopic treatment of strictures in Crohn's disease, Erkelens [/bib_ref]. Although abscess is considered to be eventually an indication for surgery [bib_ref] Current strategies in the management of intra-abdominal abscesses in Crohn's disease, Feagins [/bib_ref] , emergency surgery may be avoided with administration of antibiotics and percutaneous drainage. CQ6-13. What are the surgical procedures for CD? # Statements - For the treatment of stricture or fistula formation, resection of the affected intestine, or strictureplasty for the former, if possible, is recommended (Recommendation grade: 1 (9), Evidence level: D). - Perianal lesions refractory to medical therapy are recommended to be treated by local procedures such as seton drainage, stoma formation, or rectal amputation (Recommendation grade: 1 (9), Evidence level: D). ## Comments Patients with CD often develop postoperative recurrence and may require multiple repeated surgeries. Since the length of the unaffected intestine of the resected margin does not have an impact on the recurrence [bib_ref] Effect of resection margins on the recurrence of Crohn's disease in the..., Fazio [/bib_ref] , resection of the intestine should be limited to the affected lesion that is responsible for symptoms not improved by medical treatment. In addition, surgical management of the healthy intestine and other organs affected by adjacent fistula or inflammation, or drainage of abscess are sometimes required. Strictureplasty such as Heineke-Mikulicz, Finney, and Jabouley methods are performed for strictures. Strictureplasty is utilized for the purpose of preserving as much unaffected intestine as possible because the postoperative recurrence rate is not different from intestinal resection [bib_ref] Safety and efficacy of strictureplasty for Crohn's disease: a systematic review and..., Yamamoto [/bib_ref]. Among different types of anastomoses (end-to-end, endto-side, side-to-side, functional end-to-end), a report demonstrated that functional end-to-end anastomosis has a lower incidence of anastomotic leak and a longer time to recurrence compared with end-to-end anastomosis [bib_ref] A meta-analysis comparing conventional end-to-end anastomosis vs. other anastomotic configurations after resection..., Simillis [/bib_ref] , but another report showed the opposite results [bib_ref] Recurrence of Crohn's disease after ileocolic resection is not affected by anastomotic..., Mcleod [/bib_ref] , and thus no consensus has been made. Laparoscopic surgery has been reported to be superior to or comparable to open surgery in terms of cosmetic outcome, recovery of bowel motility, and the length of hospitalization [bib_ref] National trends and outcomes for the surgical therapy of ileocolonic Crohn's disease:..., Lesperance [/bib_ref] [bib_ref] Laparoscopic versus open surgery for small bowel Crohn's disease, Dasari [/bib_ref]. It is advisable that the indication of laparoscopic surgery for patients who will undergo resurgery or those with abscess or fistula formation should be carefully discussed and the surgery is desirable to be performed at specialist centers [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Dignass [/bib_ref]. Drug therapies such as MNZ or CPFX should be used for intractable perianal lesions in addition to the medical therapy for the intestinal lesions. Perianal fistulas are the most common form of perianal lesions and, if perianal fistulas are refractory to drug therapies, seton drainage is performed. Some patients may further need immunomodulators and/or anti-TNF agents, or surgical procedures such as stoma formation and/or rectal amputation [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. In Japan, there are many reports of anorectal cancer and its incidence is recently increasing; therefore, careful attention should be paid to anorectal cancer when treating anorectal lesions [bib_ref] Crohn's disease and intestinal cancer in Japan, Shinozaki [/bib_ref]. ## Comments Patients in whom residual small intestine becomes less than 150 cm as a result of intestinal resection may be unable to absorb water, electrolytes, and nutrients and may require supplementation by parenteral nutrition or home parenteral nutrition [bib_ref] Long-term incidence and characteristics of intestinal failure in Crohn's disease: a multicenter..., Watanabe [/bib_ref]. Intestinal lesions of CD may recur early after surgery, and the rate of endoscopic recurrence around the ileocolonic anastomosis after ileocecal resection reaches as high as 72% within a year [bib_ref] Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative..., Rutgeerts [/bib_ref]. The re-operation rates are reported to be 16-43% at 5 years and 26-65% at 10 years [bib_ref] Recurrence of Crohn's disease after resection, Williams [/bib_ref] [bib_ref] Analysis of factors for postoperative recurrence of Crohn's disease. Annual reports of, Fukushima [/bib_ref]. The appearance of lesions (morphological recurrence) precedes clinical relapse when post-operative recurrence occurs; therefore, imaging examinations such as endoscopy are useful to diagnose it [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Dignass [/bib_ref]. The Cochrane review states on prevention of postoperative recurrence as follows: MNZ is more effective but causes more side effects than placebo; mesalazine and AZA/6-MP are effective for prevention of clinical recurrence and endoscopic severe recurrence; the rate of endoscopic recurrence is higher in mesalazine than AZA/6-MP, but mesalazine causes fewer side effects; IFX or budesonide does not have sufficient data showing efficacy [bib_ref] Interventions for prevention of post-operative recurrence of Crohn's disease, Doherty [/bib_ref]. As stated above, there is no established standard for prevention of postoperative recurrence, and therefore it is necessary to decide the strategy to prevent postoperative recurrence in consideration of the subject, the start time, medication, side effects, tolerability, cost, etc. ## Comments There are two types of extraintestinal complications of IBD; those associated with the activity of intestinal lesions (a group of peripheral arthritis, erythema nodosum, episcleritis, oral aphtha, etc.) and those unassociated with the activity of intestinal lesions (pyoderma gangrenosum, uveitis, sacrum arthritis, ankylosing spondylitis, PSC, etc.). It is necessary to actively control inflammation of intestinal lesions in either case. 5-ASA preparations such as SASP are first-line therapy for arthritis. NSAIDs should not be used because they may worsen intestinal lesions, but a short-term administration of COX-2 inhibitors is relatively safe [bib_ref] The gastrointestinal safety and effect on disease activity of etoricoxib, a selective..., El Miedany [/bib_ref] [bib_ref] Safety of celecoxib in patients with ulcerative colitis in remission: a randomized,..., Sandborn [/bib_ref]. Local or systemic steroids are used to treat pyoderma gangrenosum [bib_ref] Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based..., Reichrath [/bib_ref] [bib_ref] Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in..., Binus [/bib_ref]. Several case reports indicated that CAP was effective in patients with pyoderma gangrenosum refractory to steroids [bib_ref] Treatment of pyoderma gangrenosum associated with Crohn's disease, Ohmori [/bib_ref] [bib_ref] Leukocytapheresis treatment for pyoderma gangrenosum, Fujimoto [/bib_ref] [bib_ref] A case report of steroid and immunosuppressant-resistant pyoderma gangrenosum successfully treated by..., Okuma [/bib_ref]. Among eye lesions, uveitis may cause blurring of vision; therefore, a consultation of ophthalmologists is warranted when uveitis is suspected [bib_ref] The second European evidence-based consensus on the diagnosis and management of Crohn's..., Van Assche [/bib_ref]. An RCT and a non-RCT that included IBD and non-IBD patients reported that IFX was effective for pyoderma gangrenosum, arthritis, uveitis, ankylosing spondylitis, etc. [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]. PSC is more frequently accompanied with UC than CD, and increases the risk of cholangiocarcinoma and CRC. ## Comments The incidence of CRC in UC patients is significantly higher compared to the general population. According to the meta-analysis including population-based cohort studies, the standardized incidence ratio of CRC among UC patients was 2.39 (95% CI 2.1-2.73) and the standardized incidence ratio of CRC in the patients with extensive colitis was 4.8 (95% CI 3.9-5.9) [bib_ref] Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of..., Jess [/bib_ref]. The American Gastroenterology Association (AGA) technical review on the diagnosis and management of colorectal neoplasia in IBD in 2010 [bib_ref] AGA technical review on the diagnosis and management of colorectal neoplasia in..., Farraye [/bib_ref] recommended that all UC patients should undergo screening colonoscopy 8 years after the disease onset, and, thereafter, patients with left-sided colitis or extensive colitis are recommended to have surveillance colonoscopy annually or biennially. The patients whose disease onset was unclear are recommended to have screening colonoscopy as those with more than eight years' disease duration. Furthermore, when the patient is diagnosed with PSC, surveillance colonoscopy is recommended annually after the diagnosis of PSC. According to crossover studies and the meta-analysis including RCTs, the use of chromoendoscopy with 0.1% of indigo carmine [bib_ref] Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative..., Rutter [/bib_ref] or 0.1% of methylene blue [bib_ref] Image-enhanced, chromo, and cap-assisted colonoscopy for improving adenoma/neoplasia detection rate: a systematic..., Omata [/bib_ref] showed significantly higher intraepithelial neoplasia detection rate than white light endoscopy. In the US, biopsy from the areas with suspected malignant lesion in addition to 4 random biopsies every 10 cm is recommended during surveillance with whitelight colonoscopy in patients with long-standing UC. CQ8-02. How should screening and surveillance colonoscopy for CD-associated cancers be conducted? # Statements - It is proposed that CD patients have screening colonoscopy 8 years after the disease onset, and thereafter the patients whose disease affects more than one-third of the large intestine undergo surveillance colonoscopy annually or biennially (Recommendation grade: 2 (7), Evidence level: D). ## Comments The risk of CRC in CD patients is slightly increased but the risk of small intestinal cancer is substantially high. According to the Minnesota population-based study, the standardized incidence ratio of CRC and small intestinal cancer was 1.9 (95% CI 0.7-4.1), and 41.1 (95% CI 8.5-120), respectively, among CD patients [bib_ref] Risk of intestinal cancer in inflammatory bowel disease: a population-based study from..., Jess [/bib_ref]. The incidence of small intestinal cancer is remarkably higher in CD patients than the general population. On the other hand, a study involving 770 Japanese CD patients showed that the standardized incidence ratio of CRC (including anal canal cancer) is 3.23 (95% CI 1. , which is significantly high [bib_ref] Cancer risk in Japanese Crohn's disease patients: investigation of the standardized incidence..., Yano [/bib_ref]. The AGA technical review in 2010 recommended that all CD patients should undergo screening colonoscopy 8 years after the disease onset, and, thereafter, the patients whose disease affects more than one-third of the large intestine should undergo surveillance colonoscopy annually or biennially [bib_ref] AGA technical review on the diagnosis and management of colorectal neoplasia in..., Farraye [/bib_ref]. The longitudinal study involving 259 CD patients with a disease duration of 8 years or more whose disease affects more than one-third of the large intestine demonstrated that the detection rate of dysplasia or colon cancer at the 4th surveillance colonoscopy (the median time from the index colonoscopy was 7.2 years) was 22%. As a method of screening or surveillance colonoscopy, it remains undetermined whether 4 random biopsies every 10 cm should be obtained in addition to biopsies from the area of suspected neoplastic lesion. On the other hand, in Japan, it is reported that the complication of rectal and anal canal cancers are more prevalent, different from Western countries. Therefore, annual surveillance with a digital rectal examination, endoscopic biopsy, brushing cytology, tumor markers (CEA, CA19-9), and pelvic CT/MRI is recommended for CD patients who have been suffering from rectal and perianal lesions (ulcer, stricture, or fistula) for more than 10 years [bib_ref] Clinical characteristics and prognosis of small intestinal and colorectal cancers associated with..., Sugita [/bib_ref]. ## Ibd in special situations CQ9-01. How should pregnancy and delivery be managed in IBD patients? # Statements - It is recommended to choose treatment during pregnancy or lactation in IBD patients through sufficient discussion between physicians and patients in consideration of risks and benefits of each individual patient (Recommendation grade: 1 (9), Evidence level: C). - It is generally recommended to continue treatment during pregnancy in IBD patients since benefits of treatment exceed risks of drugs in most patients (Recommendation grade: 1 (9), Evidence level: B). ## Comments It is an important issue how to treat IBD patients during pregnancy and lactation in order to achieve safe delivery and lactation because IBD tends to develop among young people. The attending physicians should cooperate with obstetricians and pediatricians to manage IBD patients to make childbirth safely. The attending physicians should understand that pregnancy is a sensitive issue in which complications (spontaneous abortion, congenital anomaly, etc.) can occur with a certain probability, and should explain the risks of the complications to the patients (baseline risks are 15% for spontaneous abortion, 10% for infertility, and 3-5% for congenital anomaly [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref]. Fertility of female IBD patients in remission is the same as healthy individuals. The infertility rate is increased in active CD patients. Although the rate of infertility triples and increases to 48% in female UC patients after total colectomy with ileoanal anastomosis [bib_ref] Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch..., Waljee [/bib_ref] , it is possible for the patients to be pregnant by artificial insemination. Male patients who are taking SASP have reduced fertility, but the ability returns to normal after discontinuing the drug [bib_ref] Reversible male infertility due to sulphasalazine: studies in man and rat, O'morain [/bib_ref]. The risks of giving birth prematurely and having lowbirth-weight infants are slightly increased in pregnancy of patients with active IBD, but patients can generally have a normal pregnancy and safe delivery as long as remission is maintained [bib_ref] Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, Bortoli [/bib_ref] [bib_ref] Congenital abnormalities and other birth outcomes in children born to women with..., Stephansson [/bib_ref] [bib_ref] The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel..., Van Der Woude [/bib_ref] [bib_ref] IBD medications during pregnancy and lactation, Nielsen [/bib_ref] [bib_ref] Systematic review: fertility in non-surgically treated inflammatory bowel disease, Tavernier [/bib_ref] [bib_ref] Conception and pregnancy outcome in women with inflammatory bowel disease: a multicentre..., Naganuma [/bib_ref] [bib_ref] Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis, Ujihara [/bib_ref]. Data on pregnancies of IBD patients have been recently collected overseas. The mainstream opinion on this issue follows: the most serious risk to mothers and fetuses during pregnancy is the disease activity of IBD; therefore patients should continue treatment because the benefits of treatment generally exceed the risks caused by treatment [bib_ref] The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel..., Van Der Woude [/bib_ref] [bib_ref] IBD medications during pregnancy and lactation, Nielsen [/bib_ref] [bib_ref] Systematic review: fertility in non-surgically treated inflammatory bowel disease, Tavernier [/bib_ref]. Although data on Japanese patients are scarce yet, similar outcomes to overseas have been reported [bib_ref] Conception and pregnancy outcome in women with inflammatory bowel disease: a multicentre..., Naganuma [/bib_ref] [bib_ref] Conception outcomes and opinions about pregnancy for men with inflammatory bowel disease, Sato [/bib_ref]. The medical package inserts of most drugs in Japan state that administration should be avoided during pregnancy and lactation; however, none of the standard medications used for IBD in Japan are included in the list of drugs that should be carefully used during pregnancy and lactation described in the guidelines of the Japanese Society of Obstetrics and Gynecology [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref]. 1. Medication for pregnant women Methotrexate must be avoided during pregnancy because there is evidence of its teratogenicity. Care must be taken about over-intake of vitamin A during nutrition therapy(the upper limit of retinol from 3 months before pregnancy to the first 3 months: 3000 lgRE, one packet of Elental Ò : 216 lgRE). SASP has an anti-folic activity and its administration is considered to be a high-risk factor for neural tube defects. Although there is no evidence to prove the preventive effect of folic acid supplementation, administrating folic acid at a daily dose of 4-5 mg before pregnancy beyond the first trimester is advisable (a folic acid 5 mg tablet (Foliamin Ò ) is available in Japan) [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref]. Even though the administration of AZA, CyA or TAC to pregnant women is written as ''contraindicated'' in their data sheets, it has not been proved that they have clinically significant teratogenicity or fetal toxicity [bib_ref] IBD medications during pregnancy and lactation, Nielsen [/bib_ref] [bib_ref] Systematic review and meta-analysis on the effects of thiopurines on birth outcomes..., Akbari [/bib_ref]. When female patients receiving these drugs become pregnant, it is important to re-evaluate whether or not the treatment is necessary at this point; the treatment is discontinued if it is judged it can be discontinued; the treatment should be continued after explaining the fetal risk if it is desirable to continue [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref]. Since IFX and ADA actively cross the placenta and transfer to the fetus from the late second trimester, discontinuing these drugs should be considered during the second trimester if possible [bib_ref] The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel..., Van Der Woude [/bib_ref] [bib_ref] Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory..., Gisbert [/bib_ref]. 2. Administration during lactation Breastfeeding should not be stopped based on misinformation since it reduces the risks of infection and mortality in infants [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref]. 5-ASA, SASP, PSL, and anti-TNF agents are safe during lactation although most drugs are secreted into breast milk, to some extent [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref] [bib_ref] Drug therapy for breast-feeding women, Ito [/bib_ref] [bib_ref] Case report: Fatal case of disseminated BCG infection in an infant born..., Cheent [/bib_ref]. MNZ, CPFX, CyA, TAC, and methotrexate are transferred from milk to infants, therefore they should be avoided during lactation as much as possible [bib_ref] Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology..., Minakami [/bib_ref] [bib_ref] IBD medications during pregnancy and lactation, Nielsen [/bib_ref] [bib_ref] Drug therapy for breast-feeding women, Ito [/bib_ref]. Infants born to mother receiving IFX or ADA are in an immunosuppressed state. BGC and live vaccine should be avoided until 6 months old [bib_ref] Case report: Fatal case of disseminated BCG infection in an infant born..., Cheent [/bib_ref]. There is no evidence of absolute safety of drug administration during pregnancy and lactation, and new information is always being added; therefore, the attending doctor should make an effort to access the latest information, collaborating with the obstetrician. Data in Japan Drug Information Institute in Pregnancy provided by National Center for Child Health and Development (http:// www.ncchd.go.jp/kusuri/index.html) are most updated and useful. Patients can also have an access to the data. CQ9-02. How should elderly IBD patients be managed? # Statements - Treatments for elderly IBD patients are mostly the same as those for non-elderly patients; however, it is recommended to determine the appropriate timing of surgery in elderly patients with severe activity, keeping in mind that a delay in diagnosis and/or surgery may result in the life-threatening prognosis (Recommendation grade: 1 (9), Evidence level: C). - When treating elderly patients who are refractory to one or more immunosuppressive therapies, it is recommended to consult specialists without delay (Recommendation grade: 1 (9), Evidence level: C). ## Comments Many reports demonstrated that there is no significant difference between elderly and young patients in terms of severity and clinical course of the disease, therefore treatment strategy in elderly patients is mostly the same as young patients [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref] [bib_ref] Old-age inflammatory bowel disease onset: a different problem?, Del Val [/bib_ref]. However, attention should be paid to side effects and drug-drug interactions because elderly patients have poor organ reserve capacity and comorbidities, and receive multiple medications [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. Since there are many diseases that must be ruled out such as infectious enteritis including intestinal tuberculosis, drug-induced enteritis, and ischemic enteritis in elderly IBD patients, the diagnosis is sometimes delayed [bib_ref] Change of clinical characteristics of ulcerative colitis in Japan: analysis of 844..., Fujimoto [/bib_ref]. Elderly patients are more prone to deterioration of nutritional status, or reduced activities of daily living due to restriction of daily living compared to young patients [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. Complications such as venous thrombosis and infection may especially affect the life prognosis [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. Infectious diseases caused by immunosuppressive therapies (cytomegalovirus infectious disease and pneumocystis pneumonia), steroid-induced side effects including reduction of bone mineral density, hyperglycemia, adrenal insufficiency, and psychological symptoms, nephropathy caused by calcineurin inhibitors, and cardiac failure caused by anti-TNF agents are more likely to occur in the elderly compared to the young [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. The indication of anti-TNF agents for elderly IBD patients is similar to that for young IBD patients, but there is a report that the response to the therapy is lower and the risk of serious infection and death is higher in elderly patients than young patients [bib_ref] Advanced age is an independent risk factor for severe infections and mortality..., Cottone [/bib_ref]. In addition, sufficient examinations are necessary before starting anti-TNF agents because the risk of latent tuberculosis is also higher in the elderly patients [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. Elderly IBD patients are more likely to develop complications such as massive bleeding and toxic megacolon due to a delay in surgery. Moreover, it has been reported that the rate of perioperative death was high due to postoperative complications such as pneumonia [bib_ref] Prognosis following emergency surgery for ulcerative colitis in elderly patients, Ikeuchi [/bib_ref]. Therefore, if one immunosuppressive therapy is insufficiently effective for elderly IBD patients, it is recommended to consult specialists considering the early indication of surgery [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. The surgical procedure for elderly UC patients should be performed in the same way as young patients as far as the anal sphincter muscle function is preserved since ilealpouch anal (canal) anastomosis is not contraindicated even in elderly patients. However, permanent stoma formation may be selected considering patient's anal sphincter muscle function or ileorectal anastomosis may be selected considering patient's QOL [bib_ref] Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients..., Gisbert [/bib_ref]. ## Compliance with ethical standards Conflict of interest Any financial relationship with enterprises, businesses, or academic institutions in the subject matter or materials discussed in the manuscript are listed as follows: (1) those from which the authors have received individually any income, honoraria or any other types of remuneration; Abbvie Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., IGAKU-SHOIN Ltd, Yakult Honsha Co., Ltd, Mitsubishi Tanabe Pharma Corporation; and (2) those from which the academic institutions of the authors received support (commercial/academic cooperation); Asahi Kasei Medical Co., Ltd., Astellas Pharma Inc., AstraZeneca K.K., Abbvie Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., Eidia Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., JIMRO Co., Ltd., Zeria Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Biofermin Seiyaku Co., Ltd., Pfizer Inc. Bristol-Myers Squibb Company, Merck Serono Co., Ltd. Mochida Pharmaceutical Co., Ltd. Yakult Honsha Co., Ltd., Janssen Pharmaceutical K.K. 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: Diagnostic [/fig] [fig] CQ2- 05: How should endoscopy be used for the diagnosis of CD? Statements • Colonoscopy (including observation of the terminal ileum) and histological evaluation of biopsies are recommended when a diagnosis of CD is suspected based on clinical findings (Recommendation grade: 1 (9), Evidence level: D). • Upper gastrointestinal endoscopy had better be performed when a diagnosis of CD is suspected. Upper gastrointestinal endoscopy is recommended especially when lower gastrointestinal endoscopy fails to establish a definite diagnosis of CD, or patients complain of upper gastrointestinal symptoms (Recommendation grade: 1 (9), Evidence level: D). [/fig] [fig] CQ4- 2: What are the risks/benefits and indications of corticosteroids in the treatment of IBD? Statements • Corticosteroids have potent anti-inflammatory property and are effective for induction of remission in UC and CD (Evidence level: B). [/fig] [fig] CQ 4 - 07: What are the risks/benefits and indications of CAP in the treatment of IBD? Statements [/fig] [fig] CQ4- 08: What are the risks/benefits of surgery in the treatment of IBD? Statements • Surgery can improve the life prognosis of patients with severe disease or co-existing dysplasia/cancer. In addition, it may also provide a better QOL for patients who are suffering from medically refractory IBD symptoms, side effects of drugs, or extraintestinal manifestations (Evidence level: D). • Surgical procedures may cause postoperative complications such as anastomotic leak, intestinal obstruction, pouchitis in UC patients, and small intestinal failure in CD patients (Evidence level: D). [/fig] [fig] 1: Treatment for mildly to moderately active distal UC (Fig. 3) CQ5-01. What are the indications of 5-ASA in the treatment of mildly to moderately active distal UC? Statements • It is suggested to use 5-ASA enema as first-line therapy for induction of remission (Recommendation grade: 2 (7), Evidence level: B). • Oral 5-ASA alone is also effective and is recommended for induction of remission (Recommendation grade: 1 (9), Evidence level: A). • Combination of oral and topical 5-ASA is recommended for patients requiring more potent treatment than oral or topical 5-ASA alone (Recommendation grade: 1 (9), Evidence level: B). • 5-ASA enema is recommended as a first choice of topical treatment because it is at least comparable to or superior to steroid enema therapy in terms of efficacy (Recommendation grade: 1 (8), Evidence level: B). [/fig] [fig] CQ5- 06: What are the indications of corticosteroids in the treatment of mildly to moderately active extensive UC?Statements• It is recommended to use 30-40 mg/day of PSL when the patient does not respond to the sufficient dose of 5-ASA (Recommendation grade: 1 (9), Evidence level: C). • It is recommended to consider withdrawal of the steroid when a clinical response is observed and avoid its longterm use (Recommendation grade: 1 (9), Evidence level: D). [/fig] [fig] Figure 4: Remission induction treatment for mildly-to-moderately active extensive (including left-sided [/fig] [fig] Figure 5: Remission induction treatment for severely active UC [/fig] [fig] CQ5- 09: What are the indications of immunomodulators in the treatment of severely active UC?Statements• It is recommended to consider intravenous CyA for steroid-refractory severe UC (Recommendation grade: 2 (7), Evidence level: C). • It is recommended to consider TAC for steroidrefractory severe UC (Recommendation grade: 1 (8), Evidence level: C). [/fig] [fig] • 5 -: ASA enema is recommended for maintenance of remission in distal colitis (Recommendation grade: 1 (8), Evidence level: A). [/fig] [fig] Figure 7: Remission induction treatment for active CD the optimal dose and period of treatment are undetermined. [/fig] [fig] •: It is recommended to determine a surgical indication for perianal lesions properly based on an examination by experienced surgeons or proctologists and imaging investigations (Recommendation grade: 1 (9), Evidence level: D). It is suggested to use immunomodulators as a medical treatment for anal fistula (Recommendation grade: 2 (7), Evidence level: C). It is recommended to consider anti-TNF agents as a medical treatment for anal fistula if abscess is under control (Recommendation grade: 1 (8), Evidence level: A). [/fig] [fig] CQ6- 06: Intestinal complications of CD (2): what is the treatment of choice for strictures? Statements • Short-term steroid administration or anti-TNF agents are recommended for inflammatory strictures (Recommendation grade: 1 (8), Evidence level: D). • Endoscopic dilation or surgery is recommended when the obstructive symptoms do not improve by drug therapy alone (Recommendation grade: 1 (8), Evidence level: C). [/fig] [fig] CQ6- 07: Intestinal complications of CD (3): what is the treatment of choice for bleeding? Statements • Attempt to hemostasis by endoscopy or interventional radiology is recommended, along with general care (Recommendation grade: 1 (8), Evidence level: D). of surgery should be considered for each clinical situaƟon [/fig] [fig] Figure 8: Treatment [/fig] [fig] CQ6- 08: Intestinal complications of CD (4): what is the treatment of choice for abscess? Statements • Antibiotics administration, cutaneous drainage, and/or incision drainage are recommended after imaging examinations such as CT, US, and MRI (Recommendation grade: 1 (9), Evidence level: D). • Administration of anti-TNF agents after treating abscess reduces the risk of recurrence of abscess (Evidence level: D). [/fig] [fig] 6: Other gastrointestinal lesions CQ6-09. What is the treatment of choice for upper gastrointestinal involvements in CD? Statements • Although evidence is scarce, it is suggested to consider proton pump inhibitors (PPI), steroids, thiopurines, and IFX as treatments for active upper gastrointestinal tract lesions (Recommendation grade: 2 (7), Evidence level: D). • It is recommended to administer steroids and/or thiopurine for edematous stenosis, and consider endoscopic balloon dilation or surgery (gastrojejunostomy, or strictureplasty) for fibrous strictures (Recommendation grade: 1 (8), Evidence level: D). [/fig] [fig] 7: Maintenance treatment for CD in remission (Fig. 9) CQ6-10. What are the things to do in daily life to help prevent recurrence of CD in remission? Statements • It is recommended to instruct smokers to quit smoking (Recommendation grade: 1 (9), Evidence level: B). • It is recommended to avoid prolonged use of NSAIDs (Recommendation grade: 1 (8), Evidence level: C). [/fig] [table] Table 2: [18]. [/table] [table] 8: Cancer surveillance CQ8-01. How should screening and surveillance for UC-associated cancers be conducted? Statements • Screening colonoscopy is recommended 8 years after the disease onset (Recommendation grade: 1 (8), Evidence level: C). • Patients with left-sided colitis or extensive colitis are recommended to undergo surveillance colonoscopy annually or biennially after the screening colonoscopy (Recommendation grade: 1 (8), Evidence level: C). • Target biopsy with chromoendoscopy is recommended rather than random biopsy during colonoscopy (Recommendation grade: 1 (8), Evidence level: B). [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs00535-018-1439-1.pdf	None
ca45a8810c44cf5f7e5293938e4e3cf195858fe1	pubmed	Follow-up of patients with curatively resected colorectal cancer: a practice guideline	Follow-up of patients with curatively resected colorectal cancer: a practice guideline Background: A systematic review was conducted to evaluate the literature regarding the impact of follow-up on colorectal cancer patient survival and, in a second phase, recommendations were developed.Methods:The MEDLINE, CANCERLIT, and Cochrane Library databases, and abstracts published in the 1997 to 2002 proceedings of the annual meeting of the American Society of Clinical Oncology were systematically searched for evidence. Study selection was limited to randomized trials and meta-analyses that examined different programs of follow-up after curative resection of colorectal cancer where five-year overall survival was reported. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the practice guideline report was obtained from the Practice Guidelines Coordinating Committee.Results: Six randomized trials and two published meta-analyses of follow-up were obtained. Of six randomized trials comparing one follow-up program to a more intense program, only two individual trials detected a statistically significant survival benefit favouring the more intense followup program. Pooling of all six randomized trials demonstrated a significant improvement in survival favouring more intense follow-up (Relative Risk Ratio 0.80 (95%CI, 0.70 to 0.91; p = 0.0008). Although the rate of recurrence was similar in both of the follow-up groups compared, asymptomatic recurrences and re-operations for cure of recurrences were more common in patients with more intensive follow-up. Trials including CEA monitoring and liver imaging also had significant results, whereas trials not including these tests did not.Conclusion: Follow-up programs for patients with curatively resected colorectal cancer do improve survival. These follow-up programs include frequent visits and performance of blood CEA, chest x-rays, liver imaging and colonoscopy, however, it is not clear which tests or frequency of visits is optimal. There is a suggestion that improved survival is due to diagnosis of recurrence at an earlier, asymptomatic stage which allows for more curative resection of recurrence. Based on this evidence and consideration of the biology of colorectal cancer and present practices, a guideline was developed. Patients should be made aware of the risk of disease recurrence or second bowel cancer, the potential benefits of follow-up and the uncertainties requiring further clinical trials. For patients at high-risk of recurrence (stages IIb and III) clinical assessment is recommended when symptoms occur or at least every 6 months the first 3 years and yearly for at least 5 years. At the time of those visits, patients may have blood CEA, chest x-ray and liver imaging. For patients at lower risk of recurrence (stages I and Ia) or those with co-morbidities impairing future surgery, only visits yearly or when symptoms occur. All patients should have a colonoscopy before or within 6 months of initial surgery, and repeated yearly if villous or tubular adenomas >1 cm are found; otherwise repeat every 3 to 5 years. All patients having recurrences should be assessed by a multidisciplinary team in a cancer centre. # Background Colorectal cancer is one of the most common malignancies with an estimated age-adjusted annual incidence in North America of 75 cases per 100,000 population [bib_ref] Predictors of survival after curative resection of carcinoma of the colon and..., Griffin [/bib_ref] [bib_ref] Carcinoma of the colon and rectum in a defined population, Berge [/bib_ref] [bib_ref] Colorectal cancer: total provincial experience with survival analysis, Weinerman [/bib_ref]. About 75% of newly diagnosed cases have the tumour confined to a portion of the bowel and regional lymph nodes. Complete removal of the tumour en-bloc with a portion of normal bowel along with mesenteric and regional lymph nodes is considered a curative resection. In spite of this curative resection approximately half the patients develop recurrent disease and their median survival does not exceed two years [bib_ref] Predictors of survival after curative resection of carcinoma of the colon and..., Griffin [/bib_ref] [bib_ref] Carcinoma of the colon and rectum in a defined population, Berge [/bib_ref] [bib_ref] Colorectal cancer: total provincial experience with survival analysis, Weinerman [/bib_ref] [bib_ref] Patterns of recurrence after curative resection of carcinoma of the colon and..., Galandiuk [/bib_ref]. Most of these recurrences occur in patients who, at initial staging, had a tumour invading across the bowel wall causing perforation of the bowel, adhesion, invasion of neighbouring organs (stage IIb disease), or had lymph node metastases (stage III disease). Beside disease recurrence, patients with colorectal cancer are considered to be at a higher risk for developing a second or metachronous bowel cancer [bib_ref] The risk of subsequent primary malignant diseases after cancers of the colon..., Enblad [/bib_ref] [bib_ref] Metachronous colorectal carcinoma, Bulow [/bib_ref] [bib_ref] Cumulative incidence of metachronous colorectal cancer, Cali [/bib_ref] [bib_ref] The risk of subsequent primary cancers after colorectal cancer in southeast England, Evans [/bib_ref] [bib_ref] Effect of age on risk of second primary colorectal cancer, Shureiqi [/bib_ref] [bib_ref] Surveillance for second primary colorectal cancer after adjuvant chemotherapy: an analysis of..., Green [/bib_ref] , particularly if they are 60 years of age or younger [bib_ref] The risk of subsequent primary cancers after colorectal cancer in southeast England, Evans [/bib_ref] [bib_ref] Effect of age on risk of second primary colorectal cancer, Shureiqi [/bib_ref]. The principal aim of follow-up programs after curative resection of colorectal cancer is to improve survival. To achieve this goal, patients are screened for early recurrent disease and second colorectal cancer with the intent of a second curative surgery. Common sites of recurrence and the screening tests used to detect early disease in those sites are shown in [fig_ref] Table 1: Sites of recurrent disease and screening tests for colorectal cancer [/fig_ref]. As no single screening test is best for all sites of recurrent disease and second colorectal cancer, a combination or package of tests is commonly used. The screening tests are directed to areas of potential disease and conducted at pre-established intervals. Since the incidence of recurrent disease occurs at an exponential rate over the first three to four years after surgery but then plateaus [bib_ref] Predictors of survival after curative resection of carcinoma of the colon and..., Griffin [/bib_ref] [bib_ref] Carcinoma of the colon and rectum in a defined population, Berge [/bib_ref] [bib_ref] Colorectal cancer: total provincial experience with survival analysis, Weinerman [/bib_ref] , the screening tests for recurrent disease are conducted frequently during the first three years and infre-quently afterwards. Screening tests for second colorectal cancer, on the other hand, must be done at equally spaced intervals for life because the incidence of second colorectal cancer occurs at a constant cumulative rate of 3% every six years [bib_ref] Metachronous colorectal carcinoma, Bulow [/bib_ref] [bib_ref] Effect of age on risk of second primary colorectal cancer, Shureiqi [/bib_ref]. An example of this strategy is noted in a 1994 survey of members of the American Society of Colon and Rectal Surgeons [bib_ref] Current follow-up strategies after resection of colon cancer. Results of a survey..., Vernava [/bib_ref] ; it showed that most patients are assessed every three months for three years, and every six to twelve months thereafter. During those visits patients have clinical assessment, blood tests including CEA (carcinoembryonic antigen), x-rays of the chest and abdomen, and colorectal endoscopy. A debate has developed as to the effectiveness and expense of intensive follow-up programs. A program of colorectal cancer follow-up similar to those described by Vernava et al [bib_ref] Current follow-up strategies after resection of colon cancer. Results of a survey..., Vernava [/bib_ref] , and using U.S. costs per test given by Nelson [bib_ref] Postoperative evaluation of patients with colorectal cancer, Nelson [/bib_ref] , would have an approximate five-year cost per patient of $10,000, half of it being due to colonoscopy. This cost does not include surgical procedures ($8,000 per operation) for asymptomatic disease, most of which cannot be curatively resected. Several other investigators have also emphasized these high economic costs [bib_ref] Colorectal cancer follow-up: perspectives for future studies, Audisio [/bib_ref] [bib_ref] Cost-effectiveness analysis of colorectal cancer treatment, Van Der Hout [/bib_ref]. Similar costs will occur in the Canadian context. There is also the added potential for possible harms that may result from such intensive follow-up programs [bib_ref] Is follow-up of colorectal cancer patients worthwhile?, Safi [/bib_ref] [bib_ref] Does methodic long-term follow-up affect survival after curative resection of colorectal carcinoma?, Bohm [/bib_ref] [bib_ref] Optimal follow-up in colorectal cancer patients: what tests, how often?, Kronborg [/bib_ref] [bib_ref] Preoperative evaluation and postoperative surveillance for patients with colorectal carcinoma, Vignati [/bib_ref]. This debate has resulted from the varied and likely biased results of non-randomized studies [bib_ref] Value of a follow-up study of recurrent carcinoma of the colon and..., Ekman [/bib_ref] [bib_ref] The value of intensive follow-up after curative resection for colorectal carcinoma, Tornqvist [/bib_ref] [bib_ref] Significato e limiti del follow up intensivo dopo intervento radicale per cancro..., Fucini [/bib_ref] [bib_ref] Follow-up of patients operated on for colorectal carcinoma, Ovaska [/bib_ref] [bib_ref] Routine compared with nonscheduled follow-up of patients with "curative" surgery for colorectal..., Bergamaschi [/bib_ref] [bib_ref] Is intensive follow-up really able to improve prognosis of patients with local..., Secco [/bib_ref] [bib_ref] Outcome of follow-up programs in patients previously resected for colorectal cancer, Pugliese [/bib_ref] [bib_ref] Improved survival in patients complying with a postoperative endoscopic surveillance program, Eckardt [/bib_ref] [bib_ref] Value of postoperative surveillance after radical surgery for colorectal cancer: results of..., Castells [/bib_ref] and meta-analyses based mostly on these studies [bib_ref] Follow-up of patients with colorectal cancer. A meta-analysis, Bruinvels [/bib_ref] [bib_ref] Followup of colorectal cancer. A meta-analysis, Rosen [/bib_ref]. The purpose of the present systematic overview is to critically evaluate the results of available randomized trials and corresponding meta-analyses to obtain more definitive evidence regarding the impact of colorectal cancer follow-up on patient survival. Further, we investigate attitudes of Ontario physicians regarding follow-up practices to develop appropriate recommendations. # Methods This practice guideline report was developed by the Practice Guidelines Initiative (PGI), using the methodology of the Practice Guidelines Development Cycle. The practice guideline report is a convenient and up-to-date source of the best available evidence on follow-up of patients with curatively resected colorectal cancer, developed through systematic reviews, evidence synthesis, and input from practitioners in Ontario. The report is intended to enable evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. Evidence was selected and reviewed by one member of the PGI's Gastrointestinal Cancer Disease Site Group (DSG) and methodologists. Members of the Gastrointestinal Cancer DSG disclosed potential conflict of interest information, reviewed the analysis of the evidence and prepared draft recommendations. External review was obtained from a random sample of a registered list of Ontario practitioners involved in cancer patient care. The mailed survey consisted of items that addressed the quality of the draft practice guideline report and recommendations, and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report modified by practitioners' feedback was obtained from the Practice Guidelines Coordinating Committee (PGCC). The PGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. ## Examination of the evidence Literature Search Strategy , CANCERLIT (1983 to May 2003) and the Cochrane Library (2003, issue 1) were searched with no language restrictions. "Colonic neoplasms" (Medical subject heading [MeSH]), "rectal neoplasms" (MeSH) and "colorectal neoplasms" (MeSH) were combined with "recurrence" (MeSH), "prognosis" (MeSH), "compliance" (MeSH), "survival analysis" (MeSH) and the following phrases used as text words: "follow-up" and "surveillance." These terms were then combined with the search terms for the following study designs or publication types: randomized controlled trials, systematic reviews or meta-analyses, and clinical guidelines. Details of the literature search strategy appear in Appendix 3 -see Additional file: 3. In addition, investigators personal files and reference lists from retrieved papers were searched for additional trials. ## Study selection criteria Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of: 1. Randomized trials comparing groups of patients receiving different follow-up programs after curative resection of colorectal cancer, and overall patient survival was reported. 2. Meta-analyses of these randomized trials. Excluded were non-randomized studies or randomized trials without at least 5-year survival data. Although survival was the main outcome of interest, results of trials were also searched for recurrence rates, time to recurrence, asymptomatic recurrences, re-operation rates for recurrences, complications, and compliance with follow-up programs. It was planned, a priori, to conduct a subgroup analysis to examine the pooled results of studies using or not using blood CEA testing and liver imaging. This was based on the premise that these screening tests were widely used, and was therefore considered important for analysis. ## Synthesizing the evidence Survival rates from the randomized trials were pooled and the results were used to develop recommendations for follow-up programs. # Results # Literature search results The combined results of randomized with non-randomized patients. Therefore, these two trials are excluded from the analysis. The remaining six randomized trials were classified according to the intensity of follow-up programs compared and use of blood CEA testing and liver imaging [fig_ref] Table 2: Classification of randomized trials of colorectal cancer follow-up [/fig_ref]. ## Quality of trial reporting Study evaluation with the Detsky instrument [32] detected significant deficits in the reporting of trial design and performance. Although all trials randomized patients after surgery, the description of the randomization process and stratification for prognostic factors was rarely mentioned . It was impossible to assess bias in assignment except for the trial by Schoemaker et al . Criteria for patient inclusion and exclusion were described but comorbidity was not mentioned. Criteria to measure outcomes were described and seemed objective but blind assessment was mentioned in only the trial by ## Population investigated In all randomized trials, the study population was patients who underwent curative resection for colorectal cancer. There were 1679 patients, with a male to female ratio of 1.17, a median age in the mid-sixties and an age range of 30 to 87 years; one trial had a cut-off age of 76. Tumours involved the colon (n = 837) and rectum (n = 505 [fig_ref] Table 2: Classification of randomized trials of colorectal cancer follow-up [/fig_ref]. The follow-up programs for each of the trials are shown in [fig_ref] Table 3: Description of randomized trials of follow-up of colorectal cancer after resection [/fig_ref]. Results of individual trials are presented in [fig_ref] Table 4: Results of randomized trials of follow-up after resection of colorectal cancer [/fig_ref]. Overall survival is significantly improved for patients in the more intensive programs of follow-up. This improvement amounts to a risk difference of 7% (95%CI, 3% to 12%; p = 0.002) in five year survival. The number of all recurrences was similar in programs of more and less intense follow. The incidence of asymptomatic recurrences was, however, significantly more common on patients on the more intense follow-up. The latter may explain the more common re-operation for cure of recurrences in the group of patients undergoing the more intense follow-up. Overall survival was also investigated for the group of trials according to the use of CEA and liver imaging screening. Trials using blood CEA screening demonstrate a significant impact on survival whereas those not using CEA do not . A similar finding is that whereas trials using liver imaging show a significant improvement in survival, and trials not using liver imaging do not . Pooled results of all randomized trials revealed no statistically significant heterogeneity (X 2 = 3.95; p > 0.10). Pooled results of randomized trials: overall mortality at five years Pooled results of randomized trials: overall mortality at five years. Overall relative risk ratio = 0.80 (95% CI, 0.70 to 0.91; p = 0.0008) There was no evidence of publication bias as the relative risk ratios of the individual trials distributed symmetrically about the pooled risk ratio. The finding of decreased mortality with more intensive follow-up does not permit us to recommend a specific program of follow-up. To be more specific, we investigated the role of CEA monitoring and use of liver imaging. Our results demonstrate that only trials including CEA testing and/or liver imaging give significant improvements in survival . It must be stressed that all studies including liver imaging also used blood CEA monitoring. CEA testing alone was investigated in a randomized trial by Lennon et al but unfortunately other screening tests were not controlled. Patients were randomized only after a period of follow-up and when the CEA level was significantly elevated over several weeks and then to either an aggressive surgical approach to search and resect recurrence or a more conventional approach. Preliminary results indicate no difference in post-randomization survival. The lack of survival benefit of an aggressive surgical approach to CEA elevation may be due to several causes: 1) More than 60% of patients with elevated CEA had symptoms suggestive of disease. 2) There was no control for other tests which may render the CEA screening ineffective. ## Meta-analyses 3) The criteria for CEA elevation required two values over 20 ng/ml or two values over 10 ng/ml but with a rise of greater than seven units. This conservative estimate of elevated CEA will decrease the diagnostic sensitivity of the test and may delay the diagnosis by two or three months, which may have an impact on patient survival. 4) This trial required an "aggressive" pursuit of the diagnosis of recurrent disease that might include a second-look laparotomy. This "aggressive" approach may cause some harm, reducing the benefit of CEA monitoring. Therefore, the negative results of this trial do not negate a potential benefit for CEA testing. Our finding of a CEA effect may simply represent confounding factors. CEA testing has been combined with chest and abdominal imaging and endoscopic examination. These factors as well as CEA testing may have an impact on survival results. Imaging of the chest by plain radiographs has been included in all intensive follow-up programs. Lung metastases occur in 25% of patients with resected colorectal cancer [fig_ref] Table 1: Sites of recurrent disease and screening tests for colorectal cancer [/fig_ref] ; localized lesions are less common but resection led to 30% long-term survival . In a large cohort study of 1247 patients with resected colon cancer [51], recurrences occurred in 548 after a median follow-up of 7 years. There were 22 patients with resectable lung metastases, all detected by plain chest radiographs, and 6 were long-term survivors. In the same study, only 49 patients had hepatic resections and 32% survived more than 5 years. Thus, although plain radiographs detect very few patients with localized lung metastases, the situation is very similar to that of liver metastases. Computerized tomography of the chest has not been used as a screening test in colorectal cancer. In regard to the incidence of second bowel cancer, no definite comments can be made based on the evidence reviewed. Only three randomized trials reported on the incidence of such tumors and the rates were similar for both follow-ups. Most studies had median observation periods around five years. Therefore, the expected number of metachronous cancers in these patients is <3% [bib_ref] Metachronous colorectal carcinoma, Bulow [/bib_ref] [bib_ref] Cumulative incidence of metachronous colorectal cancer, Cali [/bib_ref]. Patient compliance with the follow-up plans is described in three trials [37,39,41]. Overall, it appears that patients are quite willing to undergo frequent visits and tests. The improvement in patient survival receiving intensive follow-up programs is achieved at the cost of frequent visits, extensive testing, earlier knowledge of disease recurrence, and increased number of further testing and surgical interventions. Harmful consequences of such extra testing and intervention have rarely been measured in randomized trials. One trial noted two perforations and two episodes of bleeding after polypectomy in 731 colonoscopies, a complication rate of 0 . Quality of life (Nottingham Health Profiles) and patient attitudes toward follow-up were investigated on 350 of 597 patients who were alive after closure of the rand-omized trial. Patients were mailed the questionnaires to complete at home. Ninety-one percent of patients returned completed questionnaires. Quality of life measures and attitudes were almost the same for patients on the minimal and intensive follow-up indicating the extra tests or inconveniences were balanced by the more frequent reassurance of health. These results are also consistent with those of one of the randomized trials in resected breast cancer follow-up where there was no impact of follow-up on the patients' quality of life, even after knowing that the follow-up program had not improved their survival [bib_ref] Impact of follow-up testing on survival and health-related quality of life in..., The [/bib_ref]. In summary, follow-up programs for patients with curatively resected colorectal cancer do improve survival. These follow-up programs include frequent visits and performance of blood CEA, chest x-rays, liver imaging and colonoscopy. It is not clear which tests or frequency of visits is optimal. There is a suggestion that improved survival is due to diagnosis of recurrence at an early and asymptomatic stage which allows for more curative resection of recurrence. There is almost no data on complications from testing and therapies. Patients' quality of life does not appear to be affected. ## Development of the clinical practice guideline gastrointestinal cancer disease site group consensus Intense debate occurred during several sessions around the interpretation of the presented evidence as well as the consideration of common practices and our role in guiding other physicians as to what is an acceptable follow-up program. Further, there are other goals for follow-up than to increase survival, including psychosocial support, documentation of disease course and close contact with patients to test new therapies. The evidence presented clearly demonstrates a survival benefit for patients receiving programs of more intense follow-up. The evidence for the schedule of visits and screening tests to detect disease recurrence is soft or non-existent. The evidence for the use of colonoscopy to detect second colorectal cancer and its precursors must derive from other investigations such as the Polyp Surveillance Study in the United States [bib_ref] Shike M and the National Polp Study Workgroup: Randomized comparison of surveillance..., Winawer [/bib_ref]. 6. Approval of the recommendation as a practice guideline: 73% ## Summary of main findings Written comments provided by practitioners varied. One practitioner believed that liver and lung imaging should be included in the recommendations, since the only positive study included liver ultrasound. Another practitioner thought that the lack of specificity of CEA testing, its cost, and the poor results with resection of intraperitoneal recurrences argued against its routine use. Based on the studies that were reviewed, it is not clear how CEA testing every four months was recommended, and this practitioner suggested adding the following recommendation: "If a patient would not be considered fit for resection of liver, lung, or intraperitoneal metastases, there is no value to CEA monitoring." Another practitioner thought that clinical exam every four months would not be effective as no resectable disease can be diagnosed on exam. Another practitioner thought that if several randomized controlled studies showed survival benefits for yearly colonoscopy on an intensive follow-up program, then routine annual colonoscopy should be recommended as suggested by the literature review, but that the lack of evidence for the schedule of visits should be emphasized. ## Gastrointestinal cancer disease site group modifications and actions Although 80% of the respondents were favourable to the draft recommendations, 20% were not in full agreement and wrote specific comments. Major concerns were low sensitivity of clinical assessment and blood CEA, and the more specific value in detecting resectable solitary metastases by liver and chest imaging. These concerns are reflected in a recent survey of Canadian oncologists regarding frequency of visits and tests performed in the follow-up of curatively resected colorectal cancer: Of oncologists surveyed, 35% recommend liver ultrasound and 50% recommend chest x-rays (Grunfeld et al, unpublished results). In the randomized trials reviewed, the more intensive follow-up programs which showed an increase in survival did indeed use liver and chest imaging. Therefore, we suggested the use of chest radiographs and liver imaging with CT or US. Although CT is more sensitive than US, availability and cost of CT are significant problems. Similarly, modifications were made to address the importance of an optimal decision regarding treatment of disease recurrence. In regard to colonoscopy, we advise the recent American Gastroenterology Association Guidelines recommendations [bib_ref] American Gastroenterological Association: Colorectal Cancer Screening and Surveillance: Clinical Guidelines and Rationale, Winawer [/bib_ref]. Other comments were also considered, including colonoscopy for patients with stage I disease and more intense follow-up of patients who are fit and willing to undergo investigations and potential intervention for recurrence, regardless of age. An Information Sheet to be given to the patient at the start of the follow-up (Appendix 1 -see Additional file: 1) was added. Several recent practice guidelines for surveillance after colorectal cancer resection were reviewed [bib_ref] Recommended colorectal cancer surveillance guidelines by the, Desch [/bib_ref] [bib_ref] Surveillance after colorectal resection, Berman [/bib_ref] [bib_ref] Follow-up of stage B and C colorectal cancer in the United States..., O'dwyer [/bib_ref] [bib_ref] Guidelines for follow-up after resection of colorectal cancer, Scholefield [/bib_ref]. Two of these practice guidelines discussed levels of evidence for the recommendations [bib_ref] Recommended colorectal cancer surveillance guidelines by the, Desch [/bib_ref] [bib_ref] Surveillance after colorectal resection, Berman [/bib_ref] but only one or two of the RCTs analyzed in this paper were considered. The recommendations are not consistent between practice guidelines, partly because of the use of biased data from cohort and non-randomized studies. Clearly, even after considering only randomized studies neither of the overviews provided definite answers to the tests required, and further research with support from sources other than those dedicated to patient care is required [bib_ref] Postoperative evaluation of patients with colorectal cancer, Nelson [/bib_ref] [bib_ref] Preoperative evaluation and postoperative surveillance for patients with colorectal carcinoma, Vignati [/bib_ref]. Patients should be made aware of the importance of these research trials, and should be encouraged to participate in them. These clinical studies should be randomized to pre-vent biases and should be directed to homogeneous groups of patients stratified according to risks. Patients should be randomized to specific screening procedures (i.e., abdominal ultrasound or CT, PET scanning), and should measure quality of life and survival. Sufficiently long observation periods will be important to achieve reliable differential rates of risk, and sufficiently large sample sizes are necessary to obtain conclusive results. In planning such trials, a cost-benefit analysis must be performed to assess the economic costs of potential improvements in survival and quality of life [bib_ref] Colorectal cancer follow-up: perspectives for future studies, Audisio [/bib_ref] [bib_ref] Cost-effectiveness analysis of colorectal cancer treatment, Van Der Hout [/bib_ref]. Several such trials are under way . # Conclusions ## Practice guideline This practice guideline applies to adult patients with curatively resected colorectal cancer, defined as patients who have had all apparent disease removed by surgery. - Patients should be alerted to the future risks of disease recurrence, which is related to tumour stage, and to the development of a second colorectal cancer. - There is evidence from six randomized trials and two meta-analyses of a small but significant survival benefit with more intensive follow-up compared to less intensive follow-up. This benefit is due to the early diagnosis and resection of limited recurrent disease in the liver, lungs, or local sites. It seems that this diagnosis of resectable recurrences is due to early assessment of symptoms and the use of screening tests (blood carcinoembryonic antigen, chest x-ray, liver imaging, or colonoscopy). There is insufficient evidence on which to base a recommendation for specific screening tests and frequency of visits. - In light of the uncertainty of the schedule of visits and screening tests to be recommended, and based on the rate of recurrent disease and second neoplasms and on current practices, we advise: 1. In patients who are at high risk of relapse (stages IIb and III disease) and are fit and willing to undergo investigations and treatment of recurrence: -Prompt assessment for symptoms of potential disease relapse (see Appendix 1); -Clinical assessment at least every six months for three years, and then annually for an additional three years; -During those visits patients may have blood CEA, chest x-rays, and liver ultrasound or CT; -When recurrences of disease are detected, patients should be assessed by a multi-disciplinary oncology team including surgical, radiation, and medical oncologists to determine the best treatment options. 2. In patients at high risk of relapse but who have co-morbidities which may interfere with prescribed tests or potential treatment for recurrence, or who are unwilling to undergo prescribed tests or potential treatment for recurrence: -Clinical assessments yearly or for suggestive symptoms of relapse. 3. In all patients with resected colorectal cancer (stages I, II, and III) and based on the American Gastroenterological Association recent guideline: Colonoscopy postoperatively if not yet done; -if high-risk polyps (villous or tubular >1 cm) are present, excise as they are potential precursors of colorectal cancer; and repeat colonoscopy yearly as long as polyps are found. -If there are low-risk or no polyps, repeat colonoscopy in three to five years. 4. Patients should be encouraged to participate in clinical trials investigating screening tests added on to their clinical assessment. These trials of follow-up need to target patients with resectable recurrent disease and who are fit for required surgery. ## List of abbreviations In order of appearance: CEA, carcinoembryonic antigen; PGI, Practice Guidelines Initiative; DSG, Disease Site Group; PGCC, Practice Guidelines Coordinating Committee; MeSH, medical subject heading; RR, relative risk ratio; CI, confidence interval; CT, computerized tomography; PET, positron emission tomography. ## Note Mean return rate for Gastrointestinal Cancer DSG Practice Guidelines = 60.2%; Range = 51% -84% Additional material [table] Table 1: Sites of recurrent disease and screening tests for colorectal cancer. [/table] [table] Table 2: Classification of randomized trials of colorectal cancer follow-up [/table] [table] Table 3: Description of randomized trials of follow-up of colorectal cancer after resection.Regular (n = 54): Clinical assessment, blood counts and CEA, chest x-ray, and fecal occult blood (FOB) every 3 months for 2 years, then every 6 months for next 3 years; rigid sigmoidoscopy for rectosigmoid tumours at each visit, and yearly barium enema for all patients.Intensive (n = 52): Clinical assessment, blood counts and CEA, chest x-ray and FOB as in regular follow-up program. In addition, colonoscopy at 3 months if not performed preoperatively and then yearly thereafter on all patients, flexible sigmoidoscopy for rectosigmoid tumors every 3 months, liver ultrasound every 6 months, and yearly CT of liver and site of operation.Minimal (n = 307): Clinical assessment, blood hemoglobin, sedimentation rate and liver enzymes, chest x-ray, FOB, and colonoscopy (if incomplete, double contrast barium enema) at 5, 10, and 15 years. Regular (n = 290): Same tests as minimal follow-up program, but tests were conducted every 6 months for 3 years, and then at 4, 5, 7.5, 10, 12.5, and 15 years. Regular (n = 167): Clinical assessment, blood counts, CEA, liver function tests and FOB as in regular follow-up program. In addition, chest x-rays, liver CT scan and colonoscopy annually. [/table] [table] Table 4: Results of randomized trials of follow-up after resection of colorectal cancer. [/table]	None	https://bmccancer.biomedcentral.com/track/pdf/10.1186/1471-2407-3-26	None
2ac52a107b265209a6a395ac32f7869004056a32	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 13 - Resistant Arterial Hypertension	7th Brazilian Guideline of Arterial Hypertension: Chapter 13 - Resistant Arterial Hypertension [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large,..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Apparent and true resistant hypertension: definition, prevalence and outcomes, Judd [/bib_ref] [bib_ref] Measuring, analyzing, and managing drug adherence in resistant hypertension, Burnier [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] ## Complementary tests Blood biochemistry, urinalysis and ECG should be requested at the time of diagnosis, and repeated at least once a year. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] Echocardiogram and retinal exam, when available, should be repeated every 2 to 3 years. ## Secondary causes Secondary causes are common in RAH, 6 OSAHS being the most prevalent (80%, and 50% with moderate-severe apnea), [bib_ref] Prevalence and associated factors of obstructive sleep apnea in patients with resistant..., Muxfeldt [/bib_ref] followed by hyperaldosteronism (20%, mainly adrenal hyperplasia) [bib_ref] Hyperaldosteronism as a common cause of resistant hypertension, Calhoun [/bib_ref] and renal artery stenosis (2.5%). Other secondary causes should only be investigated in the presence of suggestive clinical findings. 6 ## Abpm and hbpm Although the diagnosis of RAH is based on office BP measurement, 1 BP assessment by using ABPM or HBPM is mandatory for the initial diagnosis and clinical follow-up. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Is home blood pressure monitoring useful in the management of patients with..., Muxfeldt [/bib_ref] It is estimated that 30-50% of resistant hypertensive individuals have normal outside-the-office BP levels. 9,12,16 The diagnosis obtained on ABPM defines diagnostic and therapeutic management (Chart 1). [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] Resistant hypertension: a practical clinical approach, Muxfeldt [/bib_ref] In true or masked RAH, the medication should be progressively adjustedwith the introduction of nocturnal doses of antihypertensive drugs. [bib_ref] Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients..., Hermida [/bib_ref] Patients with controlled BP on ABPM should have their therapy maintained, regardless of the office BP levels. In white-coat RAH, confirmatory ABPM needs to be performed after 3 months, and repeated every six months (if wakefulness SBP ≥ 115 mm Hg) or annually (if wakefulness SBP < 115 mm Hg). [bib_ref] Appropriate time interval to repeat ambulatory blood pressure monitoring in patients with..., Muxfeldt [/bib_ref] When ABPM is not available, HBPM is a good complementary method. Although it does not assess the nocturnal period and overestimates BP levels, HBPM reaches moderate agreement on the diagnosis, [bib_ref] Home versus ambulatory blood pressure monitoring in the diagnosis of clinic resistant..., Nasothimiou [/bib_ref] with high specificity and low sensitivity (Chart 2). 17 ## Treatment non-pharmacological treatment The NPT is aimed at: Encouraging lifestyle changes: reduction in salt intake (up to 2.0 g of sodium/day); DASH diet; body weight loss (BMI < 25 kg/m 2 ); physical activity; smoking cessation; and moderate alcohol intake; [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] [bib_ref] First Brazilian position on resistant hypertension, Alessi [/bib_ref] [bib_ref] Effects of dietary sodium reduction on blood pressure in subjects with resistant..., Pimenta [/bib_ref] [bib_ref] Heated water-based exercise training reduces 24-hour ambulatory blood pressure levels in resistant..., Guimaraes [/bib_ref] Suspending substances that raise BP. [bib_ref] Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American..., Calhoun [/bib_ref] ## Pharmacological treatment The basic principle of the pharmacological treatment is the association of antihypertensive drugs that block most pathophysiological mechanisms of BP elevation. Ideally, the following should be prescribed at full-tolerated dose and at proper intervals: a DIU, a RAAS inhibitor, and a dihydropyridine CCB. In certain situations, such as CAD, CHF and tachyarrhythmias, a BB can replace a CCB in the initial therapeutic regimen with 3 medications. The correct use of DIUs to ensure control of volemic expansion is essential, and more than half of the patients can meet the BP target with DIU optimization. [bib_ref] Resistant hypertension revisited: a comparison of two university based cohorts, Garg [/bib_ref] Chlorthalidone is superior to hydrochlorothiazide. [bib_ref] Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood..., Ernst [/bib_ref] For stage 4 or 5 CKD patients, loop DIUs should be used and administered at least twice a day. Spironolactone, an aldosterone antagonist, is the choice for the fourth drug in patients with true RAH, enabling a mean reduction of 15-20 mm Hg in SBP, and of 7-10 mm Hg in DBP, at doses of 25-50 mg/day. [bib_ref] Effect of aldosterone antagonists on blood pressure in patients with resistant hypertension:..., Liu [/bib_ref] However, up to 20-30% of the patients might not tolerate its use, because of renal function worsening, hyperpotassemia, gynecomastia or mastalgia. In such cases, amiloride can be used (5-10 mg/ day), but with an apparently lower BP response. [bib_ref] Amiloride 10 mg is less effective than spironolactone 25 mg in patients..., Lane [/bib_ref] The use of clonidine as the fourth drug is being assessed in the Brazilian ReHOT study, considering the sympathetic and RAAS activity measurements as possible predictors of the best therapeutic response to clonidine and spironolactone, respectively. [bib_ref] ReHOT Investigators. Resistant hypertension optimal treatment trial: a randomized controlled trial, Krieger [/bib_ref] In patients not reaching BP control on ABPM after the addition of spironolactone, BBs (mainly those with vasodilating effect) are the fifth drugs, if not contraindicated. Central alpha-agonists (clonidine and alpha methyldopa), direct vasodilators (hydralazine and minoxidil), or central agonists of imidazoline receptors are usually used as the sixth and seventh drugs. In addition, associations of multiple DIUs (thiazide DIUs, loop DIUs and spironolactone), especially in the presence of edema, or dihydropyridine and non-dihydropyridine CCBs can be used in the most critically ill patients. Chronotherapy guided by ABPM, with the nocturnal administration of at least one antihypertensive drug, could improve BP control and reverse the unfavorable nondipping pattern in those patients, in addition to reducing CV morbidity and mortality (Chart 3). [bib_ref] Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients..., Hermida [/bib_ref] ## New therapeutic strategies New strategies are being developed, but are still experimental. Although safe, they are not better than the conventional treatment, and should only be used in truly resistant patients (Chart 4). ## Direct and chronic stimulation of carotid sinus baroreceptors The Rheos system is a programable device, like a pacemaker, surgically implanted, consisting in a generator of impulses that activate the carotid baroreceptors via radiofrequency. The Rheos Pivotal Trial has not detected significant long-term benefits. [bib_ref] Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results..., Bakris [/bib_ref] ## Renal sympathetic denervation Percutaneous transluminal renal sympathetic denervation through a catheter has been mainly assessed in the SYMPLICITY studies conducted in RAH patients. Recent meta-analyses [bib_ref] Metaanalysis of five prospective and randomized trials of renal sympathetic denervation on..., Elmula [/bib_ref] have not confirmed the initially promising results. ## Use of cpap The antihypertensive effect of CPAP is controversial. However, as an auxiliary treatment in patients with OSAHS, mainly those who tolerate its use for more than 4 hours/ night, there is evidence that it can help to reestablish the dipping pattern. 29 ## Chart 2 -diagnostic investigation of rah ## Central iliac arteriovenous anastomosis The ROX Control HTN study 30 has shown promising results with significant reductions in BP levels and in hypertensive complications of patients with central iliac arteriovenous anastomosis with the coupler device. ## Prognosis A retrospective cohort study performed from a North American registry indicates that, after beginning the antihypertensive treatment, the apparent RAH incidence (uncontrolled BP with 3 medications) is 0.7/100/patients-year, and those patients' relative risk for CV events is 1.47 (95% confidence interval: 1.33-1.62). [bib_ref] Incidence and prognosis of resistant hypertension in hypertensive patients, Daugherty [/bib_ref] A prospective study with 556 resistant hypertensives (follow-up of 4.8 years) has shown that uncontrolled ABPM and lack of nocturnal dipping are important markers of CV risk. [bib_ref] Prognostic factors in resistant hypertension: implications for cardiovascular risk stratification and therapeutic..., De Souza [/bib_ref] The apparent RAH condition is considered of independent risk for the occurrence of CV events. (GR: IIa; LE: C). Performing ABPM is recommended to establish the prognosis of hypertensives with true RAH. (GR: IIa; LE: C). Central arteriovenous anastomosis (coupler device)IIb B [table] , 3: Chart 1 -Classification of RAH based on ABPM [/table]	None	None	Resistant AH (RAH) is defined as uncontrolled office BP despite the use of at least three antihypertensive drugs at appropriate doses, including preferably one DIU, or as controlled BP using at least four drugs.1-3 Because it does not include the systematic assessment of therapy and adherence, that situation is better defined as apparent RAH (pseudoresistance). Identification of true RAH is fundamental to establish specific approaches.2 Population-based studies have estimated a 12% prevalence in the hypertensive population.2 In Brazil, the ReHOT study assesses prevalence and therapeutic choice.4 Refractory hypertension is defined as uncontrolled BP using at least five antihypertensive drugs,5 and corresponds to 3.6% of resistant hypertensive individuals. To diagnose RAH, ABPM is required, as well as systematic assessment of adherence. (GR: I; LE: C).
d3632877d04ab1b0c7d7c579236a2fb31acd5ac8	pubmed	Executive Summary of the II Brazilian Guidelines for Atrial Fibrillation	Executive Summary of the II Brazilian Guidelines for Atrial Fibrillation # Introduction Since 2009, when the Brazilian Society of Cardiology released the Brazilian Guidelines for Atrial Fibrillation, 1 important studies on the subject have been published, particularly on new oral anticoagulants (NOACs). At least three of these drugs (dabigatran, rivaroxaban and apixaban) are currently approved for clinical use in Brazil. In addition to pharmacological treatment, new data related to non-pharmacological treatment, notably the radiofrequency ablation (RA) procedure, have expanded the indication of this therapeutic approach. For this reason, an update of the guidelines is justified. ## Epidemiological changes in atrial fibrillation In the last two decades, atrial fibrillation (AF) has become a public health problem, with high consumption of health resources. AF is the most frequent sustained arrhythmia in the clinical practice, with a prevalence of 0.5% -1.0% in the general population. According to more recent studies, however, AF prevalence is almost two times higher than that in the last decade, ranging from 1.9% in Italy to 2.9% in Sweden, possibly associated with age increase . [bib_ref] Epidemiology of atrial fibrillation: European perspective, Zoni-Berisso [/bib_ref] However, in addition to ageing, other potential factors may explain the increment in AF prevalence, including advances in the treatment of chronic heart diseases, leading to greater number of patients susceptible to AF. Furthermore, besides the classical risk factors for AF -hypertension, diabetes mellitus, heart valve disease, heart infarction and heart failure (HF) 3,4 -new potential ones, including obstructive sleep apnea, 5 obesity, [bib_ref] Overweight and obesity as risk factors for atrial fibrillation or flutter: the..., Frost [/bib_ref] alcohol consumption, 7 physical exercise, [bib_ref] Work related physical activity and risk of a hospital discharge diagnosis of..., Frost [/bib_ref] family history and genetic factors, [bib_ref] Association between familial atrial fibrillation and risk of new-onset atrial fibrillation, Lubitz [/bib_ref] contribute to the increase in AF prevalence. The most used AF classification in the clinical practice is based on its form of presentation. "Paroxysmal AF" is defined as an episode of AF that terminates spontaneously or with medical intervention within seven days of onset. The term "permanent AF" refers to AF episodes longer than seven days, and "long-term persistent AF" is used by some authors to refer to cases longer than one year. Finally, the term "permanent AF" is used when attempts to convert to sinus rhythm have been abandoned. The prognosis of AF is related to its close association with increased risk of ischemic and hemorrhagic stroke, and mortality. Other important consequences of AF include cognitive changes and socioeconomic implications ## Prevention of thromboembolic phenomena Patients with AF are more likely to have blood clots, which is an inherent risk of arrhythmia. Those at very low risk do not need anticoagulation, and should be identified and considered as non-eligible for this therapy. The score used for this purpose is the CHA2DS2-VASc (initials for congestive HF, hypertension, age, diabetes mellitus, stroke, vascular disease, age, sex category). [bib_ref] Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation..., Lip [/bib_ref] Patients with a score of zero do not need anticoagulation, for the risk of thrombotic complications is very low. A CHA2DS2-VASc of 1 is considered a low risk (1.3% per year); in this case, anticoagulation is optional, depending on the risk of bleeding or patient's decision. All other patients have a definite indication for anticoagulation. HAS BLED (initials for hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio -INR, elderly, drugs or alcohol use) is the most used score to estimate bleeding risk. A score > 3 indicates increased risk of bleeding by OACs. It is worth mentioning, however, that the score does not contraindicate the use of OACs, but rather gives direction on special measures aimed to make the treatment safer. There are four NOACs available for prevention of thromboembolic events: the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the direct fator IIa inhibitor dabigatran. Dabigatran was the first NOAC available at the market and validated by the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate.This is a prospective, randomized, phase III study that compared two doses of dabigatran (110 mg and 150 mg) twice a day with adjusted doses of warfarin. The primary outcomes were stroke and systemic embolism. Warfarin 150 mg showed better safety outcomes, including major bleeding, without statistical significance. The dose of 110mg was non-inferior to warfarin, showing a reduction of 20% in bleeding rate. The ROCKET-AF (Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) study introduced rivaroxaban in clinical practice to prevent thromboembolic phenomena in patients with nonvalvular . With respect to safety outcomes, there was a significant decrease in the incidence of hemorrhagic stroke and intracranial hemorrhage, with no effect on mortality rate. The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) was the main study on evaluation of apixaban in patients with nonvalvular AF.This randomized, double-blind study evaluated apixaban, given in 5mg doses twice a day or in adjusted dose of 2.5 mg, twice a day, in patients with at least two of the three following factors: age older than 80 years, body weight lower than 60 kg, and a serum creatinine level greater than or equal to 1.5 mg/dL . Warfarin was used as control. As compared with warfarin, apixaban significantly reduced the risk of the efficacy outcomes (stroke and systemic embolism) by 21%, major bleeding by 31%, and all-cause mortality by 11%. Edoxaban was assessed in the ENGAGE -AF (Edoxaban versus Warfarin in Patients with Atrial Fibrillation) study. 14 This was a three-arm, randomized, double-blind study on the use of warfarin and two regimens (low dose and high dose) of edoxaban. Both high-dose (60 mg once a day) and low-dose (30 mg once a day) edoxaban was non-inferior to warfarin. In patients assigned to receive edoxaban, the dose established at randomization was halved if any of the characteristics was present: creatinine clearance lower than 50 mL/minute, a body weight lower than 60 kg, or the concomitant use of a potent P-glycoprotein inhibitor (verapamil). High-dose edoxaban significantly reduced the rate of ischemic and hemorrhagic stroke, whereas a significant increase in ischemic stroke rate was observed in patients that received a low-dose of the drug. Therefore, the best efficacy-safety ratio was obtained from high-dose regimen. While the low-dose regimen of edoxaban provides higher safety in terms of the risk of major bleeding and hemorrhagic stroke, it tends to lose in efficacy. Recommendations for prevention of thromboembolic phenomena in nonvalvular AF are described in Chart 1. The NOACs have caused a drastic change in the therapeutic approach to nonvalvular FA, in terms of prevention of thromboembolic events. However, drug-related hemorrhagic complications may represent a limitation. NOACs have short half-life, and hence a low-degree bleeding may be controlled by discontinuation of the drug. Different NOACs have distinct pharmacokinetic characteristics, which may influence the therapy. Dabigatran, for example, binds weakly to plasma proteins, and are potentially removed by hemodialysis. On the other hand, both riaroxaban and apixaban are not dialyzable, due to strong plasma protein binding. Activated charcoal could be used in case of anticoagulant ingestion within two hours of a hemorrhagic event, although its use is contraindicated in gastrointestinal bleeding. Activated charcoal is available in powder and may be diluted in water or juice for administration in awake patients or by nasogastric tube, at 1g/kg body weight. Despite not currently available in Brazil, there have been advances in medications that can reverse the effect of NOACs. Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with higher affinity than to thrombin. The effect of idarucizumab as an anticoagulant reversal agent has been evaluated by intravenous administration; based on the results, the drug has been recently approved for clinical use in the United States. Andexanet is an inactive recombinant protein that reverses the anticoagulant effect by binding to activated factor X inhibitors (rivaroxaban, apixaban and edoxaban). The effect of its intravenous administration has been also evaluated, with satisfactory rates of reversal. It is expected that the use of andexanet in clinical practice will be approved soon. Administration of supplemental clotting factors via frozen plasma may also be an option of anticoagulant reversal. However, the concentrations of these factors are lower than in prothrombin complex concentrates (PCC), which, in turn, may be indicated for severe hemorrhage. [bib_ref] The role of prothrombin complex concentrates in reversal of target specific anticoagulants, Babilonia [/bib_ref] Although the OACs continue to be the main treatment option to prevent embolic phenomena in patients with AF, the use of anticoagulants is associated with risks, especially hemorrhagic stroke and other potentially severe bleeding, such as gastrointestinal bleeding. This therapeutic limitation, associated with the severity of AF-related embolic events, has motivated the development of new strategies aimed to reduce the incidence of thromboembolic phenomena. In this context, left atrial appendage closure (LAAC) emerged as an alternative approach. The main recommendations for this treatment strategy are described in Chart 2. ## Antiarrhythmic drugs in the clinical management of atrial fibrillation When evaluating an AF patient, the patient may be allocated to a rhythm control or to a heart rate control strategy, depending on echocardiographic features and the progress in previous therapies. In this regard, the use of antiarrhythmic (AA) agents has a relevant role in both strategies. An initial assessment should identify the presence of structural heart disease, as well as to evaluate whether the cause is reversible. There are a limited number of medications for the maintenance of sinus rhythm in Brazil. The available drugs are propaphenone, sotalol and amiodarone, and neither dofetilide nor droneadrone is available in the country. Propaphenone is useful for acute reversal and maintenance of sinus rhythm. It is a safe medication to be administered in patients with normal heart structure, but should be avoided in structural heart disease because of the risk of ventricular arrhythmia. [bib_ref] Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the..., Freemantle [/bib_ref] Sotalol has shown no significant result in reversing arrhythmia acutely, but was effective in maintaining sinus rhythm in up to 72% of some groups of patients within 6 months, and thus may be useful in recurrence prevention. In addition, sotalol reduce the occurrence of symptoms by decreasing the ventricular response of the episodes due to its beta-blocker effect. The most common side effects are related to the beta-blocker effect, including tiredness and fatigue. Nevertheless, the most important symptom is prolongation of QT interval and development of torsade de pointes. Sotalol cannot be used in patients with congestive HF. [bib_ref] Sotalol versus quinidine for the maintenance of sinus rhythm after direct current..., Jull-Moller [/bib_ref] Amiodarone is effective in reversing and maintaining sinus rhythm. Some studies have shown superiority of this drug over the others; however, in addition to the proarrhythmic risk, amiodarone may produce important side effects in many organs. Currently, it is the available drug for patients with congestive HF. [bib_ref] Amiodarone to prevent recurrence of atrial fibrillation, Roy [/bib_ref] Another strategy is the control of heart rate, which is important for both prevention of symptoms (e.g . palpitations, tiredness and reduced capacity for exercise), reduction of disease-related morbidity, and specially prevention of tachycardiomyopathy, which has an impact of patients' quality of life. However, the optimal heart rate in AF is still controversial. Many drugs have been tested and shown to be effective in the control of heart rate, including beta-blockers, non-dihydropyridine calcium channel blockers, and some antiarrhythmics, such as amiodarone and sotalol. To choose the most suitable drug, one must consider the severity of patients' symptoms, hemodynamic state, ventricular function, precipitating factors of AF and the risk for adverse events. Beta-blockers are the most commonly used medications for the control of heart rate in AF. [bib_ref] The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to..., Olshansky [/bib_ref] The main action is the blockade of adrenergic tone by competitive inhibition of the binding of cathecolamines to beta-receptors. This class of drugs mitigates the reduction in spontaneous depolarization (phase 4 of action potential), particularly in sinus node and atrioventricular (AV) node cells (reduces AV node conduction), and increases refractoriness of the His-Purkinje system. Non-dihydropyridine calcium channel blockers such as verapamil and diltiazem block L-type calcium channels especially in the AV node of cardiac conduction system. These drugs are effective in the control of heart rate in acute or permanent AF 20 via intravenous or oral administration. Digoxin is commonly used in the control of heart rate in AF, although it is not considered a first line agent for this purpose. It has a direct action on the membrane of atrial cells, ventricular cells and conduction system, by increasing vagal tone, and consequently reducing sinus node automacity and AV node conduction. Recommendations for the use of antiarrhythmic drugs in AF are described in Chart 3. ## Catheter ablation for atrial fibrillation Intensive therapy by catheter ablation may be considered for rhythm control in AF. ## Heart rate control In patients resistant or intolerant to medications for heart rate control, AV junction ablation (induction of complete AV block) with pacemaker implantation may be indicated. [bib_ref] Longterm survival after ablation of the atrioventricular node and implantation of a..., Ozcan [/bib_ref]. This is a simple intervention with high success rate and low risk of complications, improving the quality of life of patients and reducing hospitalizations and HF incidence as compared with pharmacological treatments. Pacemaker implantation should be performed 4-6 weeks before the AV junction ablation for adequate maturation of electrode leads, since these patients are dependent on the pacemaker. ## Rhythm control There is solid evidence that AF ablation (pulmonary vein isolation) is more effective than AA drugs in rhythm control, [bib_ref] Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic..., Calkins [/bib_ref] [bib_ref] Pulmonary vein isolation for the maintenance of sinus rhythm in patients with..., Piccini [/bib_ref] [bib_ref] Systematic review: comparative effectiveness of radiofrequency catheter ablation for atrial fibrillation, Terasawa [/bib_ref] which has gradually increased the use of interventional therapy for AF. In recent international guidelines, 26-28 ablation is recommended (Class I) in case of failure of an AA drug and also as the first choice (Class IIa) in patients with paroxysmal AF, without structural disease. Both patients with structural heart disease and patients with paroxysmal AF may be considered for ablation as the initial therapy, in case of suspicion of tachycardiomyopathy and patient's desire for this therapy. Data confirming the benefits of AF ablation in very old patients, patients with long-standing persistent AF, or advanced HF are still missing. [bib_ref] AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary:..., January [/bib_ref] Its indication for asymptomatic patients has not been established yet, and is still a matter of controversy. [bib_ref] Guidelines for the management of atrial fibrillation: the Task Force for the..., Camm [/bib_ref] [bib_ref] HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial..., Calkins [/bib_ref] [bib_ref] AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary:..., January [/bib_ref] There is still no evidence that AF ablation is a better intervention as compared with AA drugs with respect to reduction of hard outcomes, such as mortality, HF and stroke. These issues are being addressed by ongoing studies. [bib_ref] Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation: results of the..., Packer [/bib_ref] The main objective of AF ablation is the electrical isolation of pulmonary veins. Among the available techniques, the most widely used is the conventional point-by-point radiofrequency (RF) ablation, guided by electroanatomical mapping and/or intracardiac electrocardiogram. [bib_ref] Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with..., Wilber [/bib_ref] [bib_ref] Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation..., Morillo [/bib_ref] [bib_ref] The use of intracardiac echocardiography and other intracardiac imaging tools to guide..., Kim [/bib_ref] The use of cryoablation balloon for circumferential ablation of pulmonary veins is an equally validated, alternative technique. [bib_ref] AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary:..., January [/bib_ref] [bib_ref] Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of..., Packer [/bib_ref] [bib_ref] Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review..., Andrade [/bib_ref] Also, the use of circular multipolar catheters (that perform simultaneous delivery of energy through all electrodes) [bib_ref] TTOP-AF Investigators. Phased RF ablation in persistent atrial fibrillation, Hummel [/bib_ref] and laser balloon catheters [bib_ref] Pulmonary vein isolation using a visually guided laser balloon catheter: the first..., Dukkipati [/bib_ref] to create RF lesions has also increased. Despite its proven efficacy, AF ablation is a highcomplexity procedure that involves a nearly 4.5% risk for major complications. [bib_ref] AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary:..., January [/bib_ref] [bib_ref] Updated worldwide survey on the methods, efficacy, and safety of catheter ablation..., Cappato [/bib_ref] [bib_ref] ESC-EURObservational Research Programme: the Atrial Fibrillation Ablation Pilot Study, conducted by the..., Arbelo [/bib_ref] [bib_ref] Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation, Shah [/bib_ref] In addition, AF ablation is not a curative procedure. Recurrence is common, particularly following pulmonary vein reconnections or atrial substrate progression. [bib_ref] Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a..., Ouyang [/bib_ref] In these cases, a new ablation procedure may be needed, [bib_ref] Progression of atrial fibrillation after a failed initial ablation procedure in patients..., Pokushalov [/bib_ref] and after ablation, all patients should be anticoagulated for a 2-3 month-period . [bib_ref] Guidelines for the management of atrial fibrillation: the Task Force for the..., Camm [/bib_ref] [bib_ref] HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial..., Calkins [/bib_ref] [bib_ref] AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary:..., January [/bib_ref] At the end of this period, the anticoagulants may be suspended in patients with low risk of thromboembolic phenomena. [bib_ref] The risk of thromboembolism and need for oral anticoagulation after successful atrial..., Themistoclakis [/bib_ref] [bib_ref] Very low risk of thromboembolic events in patients undergoing successful catheter ablation..., Saad [/bib_ref] Since late and asymptomatic recurrences of AF may also occur after ablation, [bib_ref] Long-term outcome of atrial fibrillation ablation: impact and predictors of very late..., Wokhlu [/bib_ref] [bib_ref] Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before..., Verma [/bib_ref] patients should be monitored for a long period to ensure the control of arrhythmia. Indications for AF are listed in Chart 3. ## New mapping and ablation technologies Three-dimensional mapping of AF is nowadays considered the standard therapy for this condition worldwide. Aiming to visually guide the examiner in the analysis of left atrial anatomy and catheter localization, the technique allowed the reduction of radiation exposure for patients and staff. ## Three-dimensional mapping systems The three-dimensional mapping systems allow a 3-D reconstruction of the left atrium and pulmonary veins by mobilization of a catheter positioned in heart chamber and in direct contact with the left atrial wall, with reduced X-ray exposition. [bib_ref] Reduction of fluoroscopy exposure and procedure duration during ablation of atrial fibrillation..., Rotter [/bib_ref] There is a consensus among Brazilian experts that the use of treedimensional mapping increases the safety of ablation procedure. ## Chart 3 -recommendations for catheter ablation of atrial fibrillation for maintenance of sinus rhythm ## Intracardiac echocardiography In intracardiac echocardiography, the catheter is placed inside the right atrium, corresponding to an optimal adjuvant strategy in ablation procedures. ## Rotational angiography Rotational angiography is a x-ray method used for image acquisition of the left atrium in the electrophysiology laboratory using a basic hemodynamic system. [bib_ref] 3D ultrasound imaging using a forward-looking CMUT ring array for intravascular/intracardiac applications, Yeh [/bib_ref] [bib_ref] Image integration using intracardiac ultrasound to guide catheter ablation of atrial fibrillation, Singh [/bib_ref] The disadvantage of this method, as compared with the above described three-dimensional mapping technique, is the requirement of an ionic contrast media and a large amount of radiation. ## Ablation catheter technologies Nowadays, nearly all procedures are performed using irrigated ablation catheters. [bib_ref] Comparison of the change in the dimension of the pulmonary vein ostia..., Yamamoto [/bib_ref] [bib_ref] Low incidence of permanent complications during catheter ablation for atrial fibrillation using..., Stabile [/bib_ref] More recently, irrigated ablation catheters with contact force sensor have become available, which measure the intensity of the interaction between the catheter and the myocardium, and may increase the efficacy of the lesion by reduction of complications. [bib_ref] A systematical analysis of in vivo contact forces on virtual catheter tip/tissue..., Okumura [/bib_ref] [bib_ref] Novel contact force sensor incorporated in irrigated radiofrequency ablation catheter predicts lesion..., Yokoyama [/bib_ref] [bib_ref] Toccata multicenter clinical study using irrigated ablation catheter with integrated contact force..., Schmidt [/bib_ref] [bib_ref] Paroxysmal AF catheter ablation with a contact force sensing catheter: results of..., Natale [/bib_ref] With respect to new energy sources, three types of sources are currently available -ultrasound, laser and cryotherapy. ## Special article ## Cintra & figueiredo guidelines for atrial fibrillation Arq Bras Cardiol. 2016; 107(6):501-508 ## Robotic navigation technologies Robotic navigation has emerged based on the high radiation exposure present in most AF catheter ablation modalities. [bib_ref] Atrial fibrillation ablation using a robotic catheter remote control system: initial human..., Saliba [/bib_ref] [bib_ref] Robotic magnetic navigation for atrial fibrillation ablation, Pappone [/bib_ref] [bib_ref] Remote magnetic navigation: human experience in pulmonary vein ablation, Biase [/bib_ref] However, studies demonstrating higher success or decreased complication rates with these technologies are not available yet, and their high cost is also a barrier to be overcome. ## Surgical treatment for atrial fibrillation Many surgical procedures for the treatment of AF have been developed since the 80's. [bib_ref] Intraoperative salineirrigated radiofrequency modified Maze procedure for atrial fibrillation, Guden [/bib_ref] [bib_ref] Combined sinoatrial node atrioventricular node isolation: a surgical alternative to his bundle..., Guiraudon [/bib_ref] [bib_ref] The surgical treatment of atrial fibrillation. III. Development of a definitive surgical..., Cox [/bib_ref] [bib_ref] Modification of the Maze procedure for atrial flutter and atrial fibrillation. I...., Cox [/bib_ref] [bib_ref] Cardiac surgery for arrhythmias, Cox [/bib_ref] The Cox-Maze III procedure, or labyrinth surgery, is the gold standard for surgical treatment of AF. The key components in this procedure and in most of the new surgical techniques for AF are also pulmonary vein isolation and atrial appendage resection. Although the Maze surgery may be performed by a minimally invasive approach, involving a small chest incision, the technique requires 45-60 minutes of extracorporeal circulation (when performed by experienced hands) and cardioplegia. [bib_ref] Cosgrove D 3 rd . The Cox-Maze procedure: the Cleveland Clinic experience, Mccarthy [/bib_ref] [bib_ref] Cox-Maze procedure for atrial fibrillation: Mayo Clinic experience, Schaff [/bib_ref] [bib_ref] Current status of the Maze procedure for the treatment of atrial fibrillation, Cox [/bib_ref] Furthermore, although this procedure may be performed alone, the surgery is commonly indicated for patients that require surgical interventions for other conditions, such as valvular and ischemic heart diseases. Today, few patients are referred to surgery for AF alone. Even in those undergoing a surgical approach for other reasons, surgeons are reluctant to perform the Maze surgery, due to its complexity and magnitude. ## Hybrid treatment of atrial fibrillation The so called "hybrid procedures" combine the minimally invasive epicardial surgery with electrophysiological mapping techniques and endocardial catheter ablation. This mixed approach is aimed to patients with persistent AF or longstanding persistent AF, to whom the use of one of these techniques alone would be unsatisfactory. [bib_ref] Surgical techniques used for the treatment of atrial fibrillation, Robertson [/bib_ref] [bib_ref] Hybrid thoracoscopic and transvenous catheter ablation of atrial fibrillation, Gelsomino [/bib_ref] [bib_ref] Initial experience of sequential surgical epicardial catheter endocardial ablation for persistent and..., Mahapatra [/bib_ref] [bib_ref] Durable staged hybrid ablation with thoracoscopic and percutaneous approach for treatment of..., Muneretto [/bib_ref] [bib_ref] Hybrid approach for the treatment of long-standing persistent atrial fibrillation: electrophysiological findings..., Bisleri [/bib_ref] [bib_ref] Surgical options for treatment of atrial fibrillation, Meir [/bib_ref] [bib_ref] Minimally invasive surgical treatment of lone atrial fibrillation: early results of hybrid..., Meir [/bib_ref] [bib_ref] Two-staged hybrid treatment of persistent atrial fibrillation: short-term single centre results, Kurfirst [/bib_ref] In general, the initial results of hybrid procedures have been encouraging, especially considering the complexity of the treated population (persistent, long-standing AF). However, these results have been obtained from small samples. It is expected that the use of hybrid procedures expands as improvements in these techniques are made. [fig] Chart 1 -: Recommendations for prevention of thromboembolic phenomena in nonvalvular atrial fibrillationRecommendationsClass Level of evidenceThe CHA 2 DS 2 -VASc should be used in all patients I B Patients at low risk, with a CHA 2 DS 2 -VASc of zero, have no indication of antithrombotic therapy I B In patients with CHA 2 DS 2 -VASc of 1, the antithrombotic therapy may be indicated, taking into consideration the risk of bleeding and patients preferences IIa C Patients with CHA 2 DS 2 -VASc ≥ 2 have an indication for antithrombotic therapy I A [/fig] [table] Table 1 -: (A) CHA2DS2-VASc score used to evaluate the risk of thromboembolic phenomena in patients with atrial fibrillation. (B) Adjusted annual event rate by score [/table]	None	None	Since 2009, when the Brazilian Society of Cardiology released the Brazilian Guidelines for Atrial Fibrillation,1 important studies on the subject have been published, particularly on new oral anticoagulants (NOACs). At least three of these drugs (dabigatran, rivaroxaban and apixaban) are currently approved for clinical use in Brazil. In addition to pharmacological treatment, new data related to non-pharmacological treatment, notably the radiofrequency ablation (RA) procedure, have expanded the indication of this therapeutic approach. For this reason, an update of the guidelines is justified. Epidemiological changes in atrial fibrillation In the last two decades, atrial fibrillation (AF) has become a public health problem, with high consumption of health resources. AF is the most frequent sustained arrhythmia in the clinical practice, with a prevalence of 0.5% - 1.0% in the general population. According to more recent studies, however, AF prevalence is almost two times higher than that in the last decade, ranging from 1.9% in Italy to 2.9% in Sweden, possibly associated with age increase.2 However, in addition to ageing, other potential factors may explain the increment in AF prevalence, including advances in the treatment of chronic heart diseases, leading to greater number of patients susceptible to AF. Furthermore, besides the classical risk factors for AF - hypertension, diabetes mellitus, heart valve disease, heart infarction and heart failure (HF)3,4 -new potential ones, including obstructive sleep apnea,5 obesity,6 alcohol consumption,7 physical exercise,8 family history and genetic factors,9 contribute to the increase in AF prevalence. The most used AF classification in the clinical practice is based on its form of presentation. "Paroxysmal AF" is defined as an episode of AF that terminates spontaneously or with medical intervention within seven days of onset. The term "permanent AF" refers to AF episodes longer than seven days, and "long-term persistent AF" is used by some authors to refer to cases longer than one year. Finally, the term "permanent AF" is used when attempts to convert to sinus rhythm have been abandoned. The prognosis of AF is related to its close association with increased risk of ischemic and hemorrhagic stroke, and mortality. Other important consequences of AF include cognitive changes and socioeconomic implications
79ab1dd2b4b7a91a81008fc2de1c2a91780c305e	pubmed	Aetiology and risk factors for head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Aetiology and risk factors for head and neck cancer: United Kingdom National Multidisciplinary Guidelines This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the aetiology and risk factors for head and neck cancer and the recommended interventions appropriate for each risk factor.Recommendations- Recent evidence synthesis from National Institute for Health and Care Excellence suggests that the following brief interventions for smoking cessation work should be used: ○ Ask smokers how interested they are in quitting (R) ○ If they want to stop, refer them to an intensive support service such as National Health Service Stop Smoking Services (R) ○ If they are unwilling or unable to accept a referral, offer a stop smoking aid, e.g. pharmacotherapy. (R) - Brief interventions are effective for hazardous and harmful drinking. (R) - Specialist interventions are effective in people with alcohol dependence. (R) - Most people with alcohol dependence can undergo medically assisted withdrawal safely at home, after risk assessment. (R) - Management of leukoplakia is not informed by high-level evidence but consensus supports targeted use of biopsy and histopathological assessment. (R) - The management of biopsy proven dysplastic lesions favours: ○ advice to reduce known environmental carcinogens such as tobacco and alcohol (R) ○ surgical excision when the size of the lesions and the patient's function allows (R) ○ long-term surveillance. (R) - Fanconi anaemia patients should: ○ be followed up in a multidisciplinary specialist Fanconi anaemia clinic (G) ○ have quarterly screening for head and neck squamous cell carcinoma and an aggressive biopsy policy (G) ○ receive prophylactic vaccination against high risk human papilloma virus (G) ○ receive treatment for head and neck squamous cell carcinoma with surgery alone where possible. (G) # Introduction The major risk factors for head and neck cancer in the UK are tobacco smoking and alcohol consumption and withdrawal of these environmental carcinogens remains the focus for primary and secondary prevention. Additionally the role of human papilloma virus (HPV) is being increasingly recognised, but as the natural history and transmission of oral and oropharyngeal HPV infection are incompletely understood, the opportunities for reducing this risk are not yet clear. Some patients have recognised local or systemic pre-malignant conditions which are also discussed. ## Smoking Smoking is an independent risk factor for head and neck cancer. [bib_ref] Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer:..., Maasland [/bib_ref] Patients who continue to smoke during radiotherapy are more likely to develop osteoradionecrosis and to require hospitalisation during treatment. Continued smoking through radiotherapy was thought to have an adverse effect on local control (hazard ratio 1.5) and survival (hazard ratio 1.7), but more recent evidence would suggest baseline smoking status is more important. [bib_ref] Complications of radiotherapy in laryngopharyngeal cancer: effects of a prospective smoking cessation..., Zevallos [/bib_ref] Smoking cessation before surgery is desirable to reduce the risk of anaesthetic related complications and improve wound healing, particularly after reconstructive surgery. [bib_ref] A surgeon led smoking cessation intervention in a head and neck cancer..., Tang [/bib_ref] Quitting tobacco smoking for a short period of time (one to four years) results in a head and neck cancer risk reduction of about 30 per cent compared with current smoking, reduces the risk of laryngeal cancer by 60 per cent after 10-15 years and after 20 years can reduce the risk of developing oral cavity cancer to the level of a never smoker. 5 ## Recommendations ## Alcohol Alcohol is the other major independent risk factor for head and neck cancer. Patients who continue to drink heavily after treatment for head and neck cancer have a significantly worse quality of life [bib_ref] Continued alcohol use in patients with head and neck cancer, Potash [/bib_ref] and continued drinking has a negative impact on survival (hazard ratio 1.28). [bib_ref] Alcohol and tobacco use prediagnosis and postdiagnosis, and survival in a cohort..., Mayne [/bib_ref] [bib_ref] Influence of smoking and alcohol drinking behaviors on treatment outcomes of patients..., Fortin [/bib_ref] The beneficial effects of quitting alcohol, on the risk of developing head and neck cancer, are only observed after more than 20 years, when the level of risk reaches that of non-drinkers. [bib_ref] Cessation of alcohol drinking, tobacco smoking and the reversal of head and..., Marron [/bib_ref] Cessation of alcohol on admission for surgery can present a significant problem in heavy drinkers. A review in the British Medical Journal suggests that we should screen all patients for excessive alcohol consumption with a validated questionnaire such as Fast Alcohol Screening Test. 9 [bib_ref] Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancersystematic..., Mehanna [/bib_ref] The prevalence of HPV-16 chronic infection in oropharyngeal mucosa of the general population is currently unclear. ## Recommendations Without a clinically identifiable premalignant lesion, any future (primary or secondary) screening approach would rely on molecular biomarkers. Oral HPV infection increases with numbers of recent oral sex partners and isolated cases of transmission of HPV-16 between partners leading to the possible 'transmission' of cancer have been reported. [bib_ref] Case-control study of human papillomavirus and oropharyngeal cancer, D'souza [/bib_ref] Evidence seems currently insufficient to counsel avoidance of specific sexual activities, over and above guidance that informs the prevention of other sexually transmitted diseases. It is awaited with interest as to whether the current programme of vaccination against high risk HPV (strains 16 and 18) offered to 12-13-year-old girls will in the future reduce the incidence of head and neck squamous cell carcinoma (HNSCC). ## Premalignant lesions Leukoplakia and erythroplakia are common premalignant lesions; however, most HNSCC cases have no history of such antecedent lesions. Biopsy-proven epithelial dysplasia is demonstrated in 25 per cent of biopsies of leukoplakia but most erythroplakia; however, HPV-16 is very rarely a factor in these conditions. The significant clinical predictors of malignant transformation in oral dysplastic lesions are non-smoking status, sub-site (e.g., high risk in lateral tongue and low risk in floor of mouth), non-homogeneous appearance, size of lesion greater than 200 mm and higher histological grade (severe vs mild/moderate). A recent systematic review of oral dysplasia (992 patients) showed malignant transformation in 12.1 per cent after mean 4.3 years following biopsy. [bib_ref] Treatment and follow-up of oral dysplasia -a systematic review and meta-analysis, Mehanna [/bib_ref] Severity of dysplasia predicted for malignant transformation ( p = 0.008). Lesions that were not excised demonstrated considerably higher transformation rate than those that were excised ( p = 0.003). [bib_ref] Outcomes of oral squamous cell carcinoma arising from oral epithelial dysplasia: rationale..., Ho [/bib_ref] A binary histological grading into the high and low risks has been suggested based on good predictive power that has been independently verified in other series. A systematic review of laryngeal dysplastic lesions (942 patients) showed transformation in 14 per cent after a mean interval of 5.8 years, again severity of dysplasia correlated with risk of transformation. 14 Importantly, these data only reflect patients already referred for a specialist opinion and with biopsyproven dysplasia. In population-based studies of oral leukoplakia without histological inclusion criteria the risks are much lower; 40-50 per cent regress spontaneously and less than 1 per cent transform. [bib_ref] A long-term follow-up study on the natural course of oral leukoplakia in..., Roosaar [/bib_ref] [bib_ref] Interventions for treating oral leukoplakia, Lodi [/bib_ref] There is insufficient evidence to justify screening in the general population to prevent oral cancer. [bib_ref] Screening programmes for the early detection and prevention of oral cancer, Brocklehurst [/bib_ref] The premalignant potential of oral lichen planus (OLP) is controversial; however, rigorously conducted retrospective series have confirmed the risk in classic inflammatory OLP with histological confirmation is low, at about 1 per cent. Oral lichenoid lesions which harbour features of OLP, but also epithelial dysplasia do present a modest risk for malignant transformation, and in some series this subset reflect the only cancer cases arising, interestingly with a predisposition to lateral tongue. Proliferative verrucous leukoplakia is a rare condition presenting with exophytic widespread progressive leukoplakia, somewhat refractory to intervention and with very high (50-80 per cent) transformation rates and hence, poor overall prognosis. ## Recommendations - Management of leukoplakia is not informed by high-level evidence, but consensus supports targeted use of biopsy and histopathological assessment (R) - The management of biopsy proven dysplastic lesions favours: [formula] ○ [/formula] ## Acquired immunodeficiency Patients who are immunosuppressed due to poor nutrition, advanced age, immunosuppressive therapy after transplant or acquired immunodeficiency syndrome (AIDS) are at greater risk of developing malignancy. The most commonly reported AIDS-related neoplasms of the head and neck region include Kaposi's sarcoma and non-Hodgkin's lymphoma. There is also an increased risk of oropharyngeal squamous cell carcinoma. Although HPV-related HNSCC has been seen in immunosuppressed patients, further clinical studies are needed to determine the safety and effectiveness of HPV vaccines in this setting. ## Key points - Smoking is an independent risk factor for head and neck cancer, is associated with post treatment complications and has an adverse effect on oncological outcomes - Alcohol is an independent risk factor for head and neck cancer and continued drinking has a negative impact on survival - High risk human papilloma viruses (HPV 16 and 18) are recognised causative agents for oropharyngeal squamous cell carcinoma - Malignant transformation of oral dysplasia and laryngeal dysplasia occurs in 12 per cent (mean 4.3 years) and in 14 percent (mean 5.8 years) respectively.	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/2CA4E52ABA23716D3A4A0AF4C694761D/S0022215116000360a.pdf/div-class-title-aetiology-and-risk-factors-for-head-and-neck-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It discusses the aetiology and risk factors for head and neck cancer and the recommended interventions appropriate for each risk factor. Recommendations • Recent evidence synthesis from National Institute for Health and Care Excellence suggests that the following brief interventions for smoking cessation work should be used: ○ Ask smokers how interested they are in quitting (R) ○ If they want to stop, refer them to an intensive support service such as National Health Service Stop Smoking Services (R) ○ If they are unwilling or unable to accept a referral, offer a stop smoking aid, e.g. pharmacotherapy. (R) • Brief interventions are effective for hazardous and harmful drinking. (R) • Specialist interventions are effective in people with alcohol dependence. (R) • Most people with alcohol dependence can undergo medically assisted withdrawal safely at home, after risk assessment. (R) • Management of leukoplakia is not informed by high-level evidence but consensus supports targeted use of biopsy and histopathological assessment. (R) • The management of biopsy proven dysplastic lesions favours: ○ advice to reduce known environmental carcinogens such as tobacco and alcohol (R) ○ surgical excision when the size of the lesions and the patient's function allows (R) ○ long-term surveillance. (R) • Fanconi anaemia patients should: ○ be followed up in a multidisciplinary specialist Fanconi anaemia clinic (G) ○ have quarterly screening for head and neck squamous cell carcinoma and an aggressive biopsy policy (G) ○ receive prophylactic vaccination against high risk human papilloma virus (G) ○ receive treatment for head and neck squamous cell carcinoma with surgery alone where possible. (G)
4a9a417e4ef879ca9267e3873d853e158c01275d	pubmed	Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices	Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices Vaccine providers include anyone who provides or administers vaccines: primary care physicians, specialists, physician assistants, nurse practitioners, registered nurses, and pharmacists. - § Affirmed (13:1) PCV13 would remain available to patients who want this added protection Abbreviations: CSF = cerebrospinal fluid; PCV13 = 13-valent pneumococcal conjugate vaccine; PPSV23 = 23-valent pneumococcal polysaccharide vaccine.* Policy options listed in the order they were presented to ACIP for a vote. † Includes adults with chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies. § No content for this cell. # Introduction Two pneumococcal vaccines are currently licensed for use in adults in the United States: a 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Pfizer, Inc.]) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax 23, Merck and Co., Inc.]). In 2014, the Advisory Committee on Immunization Practices (ACIP)* recommended routine use of PCV13 in series with PPSV23 for all adults aged ≥65 years based on demonstrated PCV13 safety and efficacy against PCV13-type pneumonia among adults aged ≥65 years [bib_ref] Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among..., Tomczyk [/bib_ref]. At that time, ACIP recognized that there would be a need to reevaluate this recommendation because it was anticipated that PCV13 use in children would continue to reduce disease burden among adults through reduced carriage and transmission of vaccine serotypes from vaccinated children (i.e., PCV13 indirect effects). On June 26, 2019, after having reviewed the evidence accrued during the preceding 3 years (https://www. cdc.gov/vaccines/acip/recs/grade/PCV13.html), ACIP voted to remove the recommendation for routine PCV13 use among adults aged ≥65 years and to recommend administration of PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition, † cerebrospinal fluid (CSF) leak, or cochlear implant, and who have not previously received PCV13. ACIP recognized that some adults aged ≥65 years are potentially at increased risk for exposure to PCV13 serotypes, such as persons residing in nursing homes or other long-term care facilities and persons residing in settings with low pediatric PCV13 uptake * Recommendations for use of vaccines in children, adolescents, and adults are developed by the Advisory Committee on Immunization Practices (ACIP). ACIP is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of the CDC on use of vaccines and related agents for the control of vaccine-preventable diseases in the civilian population of the United States. or traveling to settings with no pediatric PCV13 program, and might attain higher than average benefit from PCV13 vaccination. When patients and vaccine providers § engage in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for a particular person, considerations might include both the person's risk for exposure to PCV13 serotypes and their risk for developing pneumococcal disease as a result of underlying medical conditions. All adults aged ≥65 years should continue to receive 1 dose of PPSV23. If the decision is made to administer PCV13, it should be given at least 1 year before PPSV23. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years with an immunocompromising condition, CSF leak, or cochlear implant (2). # Background Streptococcus pneumoniae (pneumococcus) can cause serious illness, including sepsis, meningitis, and pneumonia with bacteremia (invasive) or without bacteremia (noninvasive). Since the early 1980s, PPSV23 has been recommended for persons aged ≥2 years with certain underlying medical conditions, and all adults aged ≥65 years (3). 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine pediatric immunization schedule in 2000 and was replaced by PCV13 in 2010 (4). In 2012, PCV13 was recommended in series with PPSV23 for adults aged ≥19 years with immunocompromising conditions, CSF leaks, or cochlear implants. In 2014, PCV13 was recommended for all adults aged ≥65 years. Widespread use of PCV7 and PCV13 in children has led to sharp declines in pneumococcal disease among unvaccinated children and adults by preventing carriage, and thereby transmission, of vaccine-type strains . In 2014, ACIP recognized that, while in the short-term, routine PCV13 use among adults aged ≥65 years was warranted, in the long-term, continued indirect effects from PCV13 use in children might limit the utility of this recommendation. In addition, models predicted limited public health benefits in the long-term, given the relatively low remaining PCV13-type disease burden [bib_ref] Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among..., Tomczyk [/bib_ref]. Therefore, ACIP proposed that the recommendation for routine PCV13 use among adults aged ≥65 years be evaluated 4 years after implementation of the 2014 recommendation. US Department of Health and Human Services/Centers for Disease Control and Prevention * Serotype 6C showed cross-protection from 6A antigen in PCV13 and was grouped with PCV13 serotypes for IPD. # Methods During 2016-2019, using the Evidence to Recommendations Framework, (https://www.cdc.gov/vaccines/acip/recs/grade/ PCV13-etr.html) the ACIP Pneumococcal Vaccines Work Group reviewed relevant scientific evidence regarding the benefits and harms of PCV13 use among adults aged ≥65 years without an immunocompromising condition, CSF leak, or cochlear implant, in the context of >5 years of pediatric PCV13 use. The Work Group evaluated the quality of evidence for PCV13 efficacy, effectiveness, safety, and population-level impact on pneumococcal-related disease using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html). A systematic review of scientific literature published from January 1, 2014, to July 3, 2018, was conducted to identify studies evaluating direct and indirect effects of vaccination with PCV13 on invasive pneumococcal disease (IPD), pneumonia (PCV13-type, ¶ all pneumococcal, and all-cause), and mortality (pneumococcal or all-cause). In addition, PCV13 safety was evaluated by looking for severe adverse events, including death, occurring after receipt of PCV13 in adults aged ≥65 years. Title and abstract screening yielded 364 studies for in-depth review. Of these, 344 did not use PCV13 or did not include an outcome or population of interest. Observational studies with <20% adult PCV13 coverage and studies conducted in settings with low pediatric PCV13 coverage were excluded, as were studies evaluating PCV13 safety if PCV13 was administered with another vaccine, because severe adverse events could not be attributed to PCV13. The remaining 20 studies were included in the GRADE tables. The policy question considered was whether PCV13 should be administered routinely to all immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV use experienced to date. ## Summary of evidence PCV13 effectiveness and safety (individual-level benefits and harms). Before the 2014 recommendation, a randomized placebo-controlled Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) conducted in the Netherlands demonstrated 75% (95% confidence interval [CI] = 41%-91%) efficacy against PCV13-type IPD and 45% (CI = 14%-65%) efficacy against noninvasive PCV13-type pneumonia among adults aged ≥65 years [bib_ref] Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults, Bonten [/bib_ref]. Postlicensure studies included in the GRADE tables in 2019 (https://www. cdc.gov/vaccines/acip/recs/grade/PCV13.html) demonstrated PCV13 effectiveness against PCV13-type IPD (47%-59%) [bib_ref] Effectiveness of pneumococcal vaccines against invasive pneumococcal disease (IPD) among adults >65..., Pilishvili [/bib_ref] , noninvasive PCV13-type pneumonia (38%-70%) [bib_ref] Effectiveness of the 13-valent pneumococcal conjugate vaccine against adult pneumonia in Italy:..., Prato [/bib_ref] , and all-cause pneumonia (6%-11%) [bib_ref] A public health evaluation of 13-valent pneumococcal conjugate vaccine impact on adult..., Gessner [/bib_ref] [bib_ref] Effectiveness of PCV13 in adults hospitalized with pneumonia using Centers for Medicare..., Lessa [/bib_ref]. PCV13 efficacy was not demonstrated against PCV13-type or allcause mortality [bib_ref] Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults, Bonten [/bib_ref] ; no studies evaluating PCV13 effectiveness against mortality were identified. Three randomized controlled trials [bib_ref] Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine formulations with and without..., Juergens [/bib_ref] [bib_ref] Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine compared to the..., Shiramoto [/bib_ref] and six observational studies [bib_ref] Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly, Durando [/bib_ref] [bib_ref] Post-licensure surveillance of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥19..., Haber [/bib_ref] [bib_ref] Randomized clinical trial of a single versus a double dose of 13-valent..., Jackson [/bib_ref] [bib_ref] Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine when administered to healthy..., Shiramoto [/bib_ref] [bib_ref] Open-label trial of immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine..., Tinoco [/bib_ref] [bib_ref] Pneumococcal conjugate vaccine safety in elderly adults, Tseng [/bib_ref] that assessed harms were evaluated (https://www.cdc.gov/ vaccines/acip/recs/grade/PCV13.html). The rates of severe adverse events were similar among participants vaccinated with PCV13 versus placebo or PPSV23 (https://www.cdc.gov/ vaccines/acip/recs/grade/PCV13.html). Common reported PCV13-associated adverse reactions included pain, redness, and swelling at the injection site, limitation of movement of the arm in which the injection was given, fatigue, headache, chills, decreased appetite, generalized muscle pain, and joint pain. Overall, PCV13 was assessed to be safe and effective in preventing PCV13-type IPD and noninvasive pneumonia. PCV13 population-level impact (indirect and direct effects) on disease among adults aged ≥65 years. The U.S. pediatric PCV program has been successful in preventing disease among young children through direct protection of vaccinated children as well as in unvaccinated populations through indirect effects . The incidence of PCV13type IPD among adults aged ≥65 years declined ninefold during 2000-2014, before the adult PCV13 program was implemented [bib_ref] Changes in invasive pneumococcal disease (IPD) among adults following 6 years of..., Pilishvili [/bib_ref]. During the same period, indirect effects of similar magnitude were observed among adults aged ≥65 years at increased risk for IPD because of either older age (≥85 years) Immunocompetent defined in discussion as adults without an immunocompromising condition (chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies), CSF leak, or cochlear implant. ## Summary What is already known about this topic? In 2014, the Advisory Committee on Immunization Practices (ACIP) recommended 13-valent pneumococcal conjugate vaccine (PCV13) in series with 23-valent polysaccharide vaccine (PPSV23) for all adults aged ≥65 years. What is added by this report? PCV13 use in children has led to sharp declines in pneumococcal disease among adults and children. Based on a review of accrued evidence ACIP changed the recommendation for PCV13 use in adults. What are the implications for public health practice? ACIP recommends a routine single dose of PPSV23 for adults aged ≥65 years. Shared clinical decision-making is recommended regarding administration of PCV13 to persons aged ≥65 years who do not have an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant and who have not previously received PCV13. If a decision to administer PCV13 is made, PCV13 should be administered first, followed by PPSV23 at least 1 year later. [bib_ref] Changes in invasive pneumococcal disease (IPD) among adults following 6 years of..., Pilishvili [/bib_ref] or presence of underlying chronic medical conditions [bib_ref] Early impact of 13-valent pneumococcal conjugate vaccine use on invasive pneumococcal disease..., Ahmed [/bib_ref]. Indirect effects on PCV13-type and all-cause pneumonia among adults have also been demonstrated since 2000 [bib_ref] Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia, Rodrigo [/bib_ref] [bib_ref] Indirect (herd) protection, following pneumococcal conjugated vaccines introduction: a systematic review of..., Tsaban [/bib_ref] [bib_ref] Impact of introduction of infant vaccination with 13-valent pneumococcal conjugate vaccine (PCV13)..., Lessa [/bib_ref]. In 2014, additional reductions in disease incidence among adults aged ≥65 years were expected to occur as a result of ongoing indirect effects of the pediatric PCV13 program, as well as through direct effects of PCV13 use among adults. PCV13 uptake among adults aged ≥65 years increased rapidly, with coverage in 2018 estimated at 47%; coverage with any pneumococcal vaccine was 62%, with PPSV23 was 45%, and with both PCV13 and PPSV23 was 30% (23). However, from 2014-2017, no further reduction in PCV13-type IPD incidence was observed among adults aged ≥65 years, with the incidence stable at five of 100,000 population (20% of all IPD) [bib_ref] Changes in invasive pneumococcal disease (IPD) among adults following 6 years of..., Pilishvili [/bib_ref]. Similarly, since 2014, no impact on PCV13type IPD incidence has been observed among adults aged 19-64 years, a population only experiencing indirect PCV13 effects during this period. During 2014-2016, no reduction in the incidence of noninvasive pneumococcal pneumonia (all serotypes combined) was observed among adults. One recent unpublished cohort study found a 31.5% reduction in PCV13-type pneumonia and a 13.8% reduction in allcause pneumonia between 2014-2015 and 2015-2016. In this study, PCV13-types contributed to 4% of all-cause pneumonia among adults aged ≥65 years during 2015-2016 (29) compared with the estimated 10% in 2014 (1). Overall, since the 2014 recommendation for PCV13 use among adults, minimal changes in the incidence of pneumococcal disease among adults at the population-level were observed, through both direct PCV13 effects from vaccinating older adults and continued indirect effects from PCV13 use in children. Economic analyses. Two independent economic models evaluated the expected public health impact and cost effectiveness of continued PCV13 use in series with PPSV23 versus use of PPSV23 alone. These models estimated that, over the lifetime of a single cohort of 2.7 million adults aged 65 years, an expected 76-175 cases of PCV13-type IPD and 4,000-11,000 cases of PCV13-type pneumonia would be averted through continued PCV13 use in series with PPSV23, compared with PPSV23 alone. Applying the total costs to quality adjusted life years (QALY), the estimated cost effectiveness ratios were $200,000 to $560,000 per QALY. In 2014, the estimated cost per QALY for PCV13 use in series with PPSV23 was $65,000 [bib_ref] Incremental cost-effectiveness of 13-valent pneumococcal conjugate vaccine for adults age 50 years..., Stoecker [/bib_ref]. Considering the range of values for sensitivity analyses for key inputs in these models, the results of the economic analyses were less favorable toward continued PCV13 use for all adults aged ≥65 years compared with PPSV23 alone. ## Rationale Incidence of PCV13-type disease has been reduced to historically low levels among adults aged ≥65 years through indirect effects from pediatric PCV13 use. Implementation of a PCV13 recommendation for all adults aged ≥65 years in 2014 has had minimal impact on PCV13-type disease at the population level in this age group. However, PCV13 is a safe and effective vaccine that can reduce the risk for PCV13-type IPD and noninvasive pneumonia among persons aged ≥65 years. Balancing this evidence and considering acceptability and feasibility concerns, in June 2019 ACIP voted to no longer routinely recommend PCV13 for all adults aged ≥65 years and instead, to recommend PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition, CSF leak, or cochlear implant [fig_ref] TABLE 1: Recommendations for 13-valent pneumococcal conjugate vaccine [/fig_ref]. No additional doses of PPSV23 should be administered following the dose administered at age ≥65 years. † Recommendations that changed in 2019. § Includes congestive heart failure and cardiomyopathies. ¶ Includes chronic obstructive pulmonary disease, emphysema, and asthma. ** Includes B-(humoral) or T-lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease). † † Diseases requiring treatment with immunosuppressive drugs, including long-term systemic corticosteroids and radiation therapy. ## New pneumococcal vaccine recommendations for adults aged ≥65 years old PCV13. PCV13 vaccination is no longer routinely recommended for all adults aged ≥65 years. Instead, shared clinical decision-making for PCV13 use is recommended for persons aged ≥65 years who do not have an immunocompromising condition, CSF leak, or cochlear implant and who have not previously received PCV13 [fig_ref] TABLE 1: Recommendations for 13-valent pneumococcal conjugate vaccine [/fig_ref]. CDC guidance for shared clinical decision-making. When patients and vaccine providers engage in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for the specific individual aged ≥65 years, considerations may include the individual patient's risk for exposure to PCV13 serotypes and the risk for pneumococcal disease for that person as a result of underlying medical conditions (Box). If a decision to administer PCV13 is made, it should be administered before PPSV23. The recommended intervals between pneumococcal vaccines remain unchanged for adults without an immunocompromising condition, CSF leak, or cochlear implant (≥1 year between pneumococcal vaccines, regardless of the order in which they were received) (5). PCV13 and PPSV23 should not be coadministered. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years (including those aged ≥65 years) with immunocompromising conditions, CSF leaks, or cochlear implants [fig_ref] TABLE 1: Recommendations for 13-valent pneumococcal conjugate vaccine [/fig_ref]. PPSV23 for adults aged ≥65 years. ACIP continues to recommend that all adults aged ≥65 years receive 1 dose of PPSV23. A single dose of PPSV23 is recommended for routine use among all adults aged ≥65 years (1). PPSV23 contains 12 serotypes in common with PCV13 and an additional 11 serotypes for which there are no indirect effects from PCV13 use in children. The additional 11 serotypes account for 32%-37% of IPD among adults aged ≥65 years [bib_ref] Changes in invasive pneumococcal disease (IPD) among adults following 6 years of..., Pilishvili [/bib_ref]. Adults aged ≥65 years who received ≥1 dose of PPSV23 before age 65 years should receive 1 additional dose of PPSV23 at age ≥65 years (2), at least 5 years after the previous PPSV23 dose [fig_ref] TABLE 1: Recommendations for 13-valent pneumococcal conjugate vaccine [/fig_ref] (5). ## Future research and monitoring priorities CDC will continue to assess the safety, implementation and the impact of shared clinical decision-making regarding administration of PCV13 to adults aged ≥65 years; the indirect effect of pediatric PCV13 vaccination on disease burden among older adults; and the emergence of nonvaccine serotypes, to inform - PCV13 is a safe and effective vaccine for older adults. The risk for PCV13-type disease among adults aged ≥65 years is much lower than it was before the pediatric program was implemented, as a result of indirect PCV13 effects (by preventing carriage and, thereby, transmission of PCV13-type strains). The remaining risk is a function of each individual patient's risk for exposure to PCV13 serotypes and the influence of underlying medical conditions on the patient's risk for developing pneumococcal disease if exposure occurs. - The following adults aged ≥65 years are potentially at increased risk for exposure to PCV13 serotypes and might attain higher than average benefit from PCV13 vaccination, and providers/practices caring for many patients in these groups may consider regularly offering PCV13 to their patients aged ≥65 years who have not previously received PCV13: ű Persons residing in nursing homes or other longterm care facilities ű Persons residing in settings with low pediatric PCV13 uptake ű Persons traveling to settings with no pediatric PCV13 program - Incidence of PCV13-type invasive pneumococcal disease and pneumonia increases with increasing age and is higher among persons with chronic heart, lung, or liver disease, diabetes, or alcoholism, and those who smoke cigarettes or who have more than one chronic medical condition.* Although indirect effects from pediatric PCV13 use were documented for these groups of adults and were comparable to those observed among healthy adults, the residual PCV13type disease burden remains higher in these groups. Providers/practices caring for patients with these medical conditions may consider offering PCV13 to such patients who are aged ≥65 years and who have not previously received PCV13. policy decisions for higher valency conjugate vaccines currently in development. ACIP will continue to review relevant data as they become available and update pneumococcal vaccination policy as appropriate. Before administering PCV13 or PPSV23, health care providers should consult the relevant package insertsregarding precautions, warnings, and contraindications. Adverse events occurring after administration of any vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). Reports can be submitted to VAERS online, by facsimile, or by mail. More information about VAERS is available at https://vaers.hhs.gov/. [fig] FIGURE.: Invasive pneumococcal disease (IPD) incidence among adults aged ≥65 years, by pneumococcal serotype* -United States, 1998Active Bacterial Core Surveillance, unpublished data, 2019. Abbreviations: PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F); PCV13 = 13 valent PCV (PCV7 serotypes plus 1, 3, 5, 6A, 19A and 7F). [/fig] [fig] : Ahmed SS, Pondo T, Xing W, et al. Early impact of 13-valent pneumococcal conjugate vaccine use on invasive pneumococcal disease among adults with and without underlying medical conditions-United States. Clin Infect Dis 2019. Epub August 12, 2019. [/fig] [table] TABLE 1: Recommendations for 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) among adults aged ≥19 years [/table] [table] TABLE 2: Policy options for use of pneumococcal vaccines in adults aged ≥65 years presented for a vote and considerations by the Advisory Committee on Immunization Practices (ACIP), June 2019Changing the recommendation could negatively impact the perceived importance of adult pneumococcal vaccine recommendationsPopulation-level impact from PCV13 use among older adults observed to date has been minimal Universal recommendations are easier for clinicians to understand and implement than the recommendation based on shared clinical decision-making Universal PCV13 recommendation for older adults are not a judicious use of resources ACIP no longer recommends PCV13 for adults aged ≥65 years who do not have an immunocompromising condition, † CSF leak, or cochlear implant. All adults aged ≥65 years should receive a dose of PPSV23 ACIP recommends PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition, † CSF leak, or cochlear implant and who have not previously received PCV13.All adults aged ≥65 years should receive a dose of PPSV23 Balances the minimal population-level impact of a routine recommendation with the potential for individual-level protection BOX. Considerations for shared clinical decision-making regarding use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥65 years [/table]	None	https://www.cdc.gov/mmwr/volumes/68/wr/pdfs/mm6846a5-H.pdf	Two pneumococcal vaccines are currently licensed for use in adults in the United States: a 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Pfizer, Inc.]) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax 23, Merck and Co., Inc.]). In 2014, the Advisory Committee on Immunization Practices (ACIP)* recommended routine use of PCV13 in series with PPSV23 for all adults aged ≥65 years based on demonstrated PCV13 safety and efficacy against PCV13-type pneumonia among adults aged ≥65 years (1). At that time, ACIP recognized that there would be a need to reevaluate this recommendation because it was anticipated that PCV13 use in children would continue to reduce disease burden among adults through reduced carriage and transmission of vaccine serotypes from vaccinated children (i.e., PCV13 indirect effects). On June 26, 2019, after having reviewed the evidence accrued during the preceding 3 years (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html), ACIP voted to remove the recommendation for routine PCV13 use among adults aged ≥65 years and to recommend administration of PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition,† cerebrospinal fluid (CSF) leak, or cochlear implant, and who have not previously received PCV13. ACIP recognized that some adults aged ≥65 years are potentially at increased risk for exposure to PCV13 serotypes, such as persons residing in nursing homes or other long-term care facilities and persons residing in settings with low pediatric PCV13 uptake or traveling to settings with no pediatric PCV13 program, and might attain higher than average benefit from PCV13 vaccination. When patients and vaccine providers§ engage in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for a particular person, considerations might include both the person's risk for exposure to PCV13 serotypes and their risk for developing pneumococcal disease as a result of underlying medical conditions. All adults aged ≥65 years should continue to receive 1 dose of PPSV23. If the decision is made to administer PCV13, it should be given at least 1 year before PPSV23. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years with an immunocompromising condition, CSF leak, or cochlear implant (2).
383f0593059a121f1bf86e968223f671828c180e	pubmed	Pre-treatment clinical assessment in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Pre-treatment clinical assessment 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. This paper provides recommendations on the pre-treatment clinical assessment of patients presenting with head and neck cancer.GUIDELINE ## Recommendations - Comorbidity data should be collected as it is important in the analysis of survival, quality of life and functional outcomes after treatment as well as for comparing results of different treatment regimens and different centres. (R) - Patients with hypertension of over 180/110 or associated target organ damage, should have antihypertensive medication started pre-operatively as per British Hypertension Society guidelines. (R) - Rapidly correcting pre-operative hypertension with beta blockade appears to cause higher mortality due to stroke and hypotension and should not be used. (R) - Patients with poorly controlled or unstable ischaemic heart disease should be referred for cardiology assessment pre-operatively. (G) - Patients within one year of drug eluting stents should be discussed with the cardiologist who was responsible for their percutaneous coronary intervention pre-operatively with regard to cessation of antiplatelet medication due to risk of stent thrombosis. (G) - Patients with multiple recent stents should be managed in a centre with access to interventional cardiology. (G) - Surgery after myocardial infarction should be delayed if possible to reduce mortality risk. (R) - Patients with critical aortic stenosis (AS) should be considered for pre-operative intervention. (G) - Clopidogrel should be discontinued 7 days pre-operatively; warfarin should be discontinued 5 days pre-operatively. (R) - Patients with thromboembolic disease or artificial heart valves require heparin therapy to bridge peri-operative warfarin cessation, this should start 2 days after last warfarin dose. (R) - Cardiac drugs other than angotensin-converting enzyme inhibitors and angiotensin II antagonists should be continued including on the day of surgery. (R) - Angotensin-converting enzyme inhibitors and angiotensin II antagonists should be withheld on the day of surgery unless they are for the treatment of heart failure. (R) - Post-operative care in a critical care area should be considered for patients with heart failure or significant diastolic dysfunction. (R) - Patients with respiratory disease should have their peri-operative respiratory failure risk assessed and critical care booked accordingly. (G) - Patients with severe lung disease should be assessed for right heart disease pre-operatively. (G) - Patients with pulmonary hypertension and right heart failure will be at extraordinarily high risk and should have the need for surgery re-evaluated. (G) - Perioperative glucose readings should be kept within 4-12 mmol/l. (R) - Patients with a high HbA1C facing urgent surgery should have their diabetes management assessed by a diabetes specialist. (G) - Insulin-dependent diabetic patients must not omit insulin for more than one missed meal and will therefore require an insulin replacement regime. (R) - Patients taking more than 5 mg of prednisolone daily should have steroid replacement in the peri-operative period. (R) The Journal of Laryngology & Otology (2016), 130 (Suppl. S2), S13-S22. # Introduction This section deals with the topics of patient assessment and optimisation prior to treatment for head and neck cancer (HNC). The importance of collaborative teamwork, structured pre-operative assessment, grading and analysing comorbidity, and prophylaxis against infection and venous thromboembolism (VTE) are summarised in the section below. ## Comorbidity: outcomes and data collection The presence of illnesses unrelated to the tumour significantly affects prognosis in HNC patients, and is contributed to by tobacco, alcohol and substance misuse. The Adult Comorbidity Evaluation 27 (ACE 27) and the Charlson Index are the most commonly used indices to quantify comorbidity. The National Cancer Intelligence Network (NCIN) recommends that collection of an ACE 27 comorbidity score be mandated for all adult cancer patients. This facilitates surgical oncology research with the objective of improving cancer care through improved patient counselling and treatment planning. Information should be extracted from notes rather than relying on self-reporting. Comorbidity scoring captures the impact of coexisting diseases, but not the disease of interest. [bib_ref] Co-Morbidity and performance status as independent prognostic factors in head and neck..., Wang [/bib_ref] [bib_ref] Comorbidity in head and neck cancer: a critical appraisal and recommendations for..., Paleri [/bib_ref] Performance status assesses the effect of all illnesses on the patients' functional ability. Performance status is not a reliable substitute for comorbidity status as a prognostic measure, as they can each independently lead to poor tolerance of treatment. There is good evidence that integrating comorbidity with staging systems produces better prognostic instruments. The development of 'prognostigrams' relating to tumour-node-metastasis (TNM) stage, comorbidity and performance status require the accurate collection of these variables in large numbers as suggested by NCIN. The effects of increased pre-treatment comorbid burden include: - Adverse impact on short-term mortality of patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC) - Reduced overall survival in HNSCC and possible predictor for distant metastases - Adverse influence on disease-specific survival, probably due to the advanced stage at presentation and the likelihood of such patients undergoing less aggressive treatment i.e. treatment selection - Higher incidence of and more severe complications - Adverse impact on quality of life (QoL) - Adverse impact on functional outcomes - Increased cost of treatment. The relationship between performance status and survival is much less well-defined. ## Recommendation - Comorbidity data should be collected as it is important in the analysis of survival, QoL and functional outcomes after treatment as well as for comparing results of different treatment regimens and different centres. (R) Pre-operative assessment A good pre-operative assessment system will provide an appropriately informed, consented and prepared patient on the day of surgery, avoiding late cancellation and preventable risk. It is imperative that referral for pre-operative assessment takes place as early as possible within the patient pathway. Measures of the effectiveness of a pre-operative assessment service should be regularly audited. These include: - Avoiding delay in listing and admission for surgery - Avoiding unnecessary or duplicate investigations - High proportion of same day admissions for surgery - No cancellations as a result of inadequate investigation or workup - Length of hospital stay. The role of the anaesthetist in pre-operative assessment includes: - Identification of the difficult airway - Risk stratification and discussion - Optimisation of comorbidities within the limited timeframe prior to surgery - Formulation of a plan for peri-operative care with appropriate allocation to critical care resources. Guidance for the use of pre-operative testing is available from National Institute for Health and Care Excellence (NICE), The Clinical Audit and Practice Advisory Group of ENT UK and the British Association of Day Surgery and Royal College of Anaesthetists. [bib_ref] ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task..., Kristensen [/bib_ref] Individual department guidelines should be developed, including the use of general and dynamic testing. There should be a clinical lead in each anaesthetic department for pre-operative assessment and for head and neck anaesthesia with established links to related specialities. ## Identification of the difficult airway In head and neck practice, the surgeon and anaesthetist have an important role in identifying the difficult airway (Box I). A collaborative approach and communication greatly reduces the risk associated with a difficult airway. Suspected cases should be discussed between surgeon and anaesthetist prior to the day of surgery ideally with nasolaryngoscopy and scans to aid decision making. Airway assessment is imperfect in predicting problems and an airway strategy that encompasses emergency options should be formulated for both induction and the end of surgery. This strategy must be communicated clearly to the entire team working in theatre on the day and human factors considered. ## Risk stratification and optimisation of comorbidities Assessment of risk. In recent years, there has been an increasing focus on risk prediction in patients undergoing major surgical procedures. In terms of risk stratification, head and neck surgery is classed as intermediate-risk surgery. The POSSUM (Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity) score is a useful aid to predicting morbidity but despite being a well-validated tool, it has not demonstrated effective prediction of mortality in head and neck surgery. The extensively validated Revised (Lee) Cardiac Risk Index (Box II) is a six point index score derived from patients over the age of 49; it is used to assess the risk of major cardiac event associated with noncardiac surgery. This and other scoring systems were predominantly validated in the general and vascular surgical populations, but evidence suggests that it is a useful predictor of cardiovascular morbidity perioperatively in head and neck surgery, particularly when combined with age over 70 as an additional variable. The assessment of dynamic function or aerobic fitness is extremely important to aid quantification of risk and allocation of critical care resources. Simple subjective methods include the estimate of metabolic equivalents (METs), where one MET equates to the oxygen consumption of a 70 kg man at rest, four METs equate to walking up one flight of stairs; failure to achieve this is associated with increased risk. Dynamic testing of functional capacity may include the use of shuttle walk testing, 6 minutes walk testing, treadmill cardiac testing and cardiopulmonary exercise testing (CPET). CPET is currently the most reliable and objective assessment of functional capacity; the anaerobic threshold and peak oxygen consumption are proven to be well correlated with morbidity and mortality in the peri-operative period in major surgery; its application to head and neck surgery is still being evaluated. The following sections will concentrate on identification of significant comorbidities and therapies which require specific pre-operative management, using a system-based approach. Cardiovascular system. Between 40 and 50 per cent of patients will have cardiovascular disease. [bib_ref] Incidence and prediction of major cardiovascular complications in head and neck surgery, Datema [/bib_ref] All patients over 55 years and those with diabetes or other cardiac risk should have an electrocardiogram (ECG) as a minimum pre-operative investigation. Hypertension. Hypertension is the commonest cardiovascular comorbidity. There is evidence that hypertension with target organ damage is associated with a small increased incidence of major cardiovascular events. The diagnosis of hypertension should be made in primary care. A patient with a blood pressure of greater than 180/110 mm Hg has severe hypertension and should not proceed to non-urgent surgery until the blood pressure is controlled to below 160/100. Patients with more moderate hypertension with associated target organ damage are also at higher risk. Where surgery must proceed patients should be made aware of the increased risk. Patients with hypertension demonstrate a more labile haemodynamic response to induction, airway instrumentation, surgical stimulus and post-operative pain. The practice of rapidly correcting pre-operative hypertension with beta blockade appears to cause higher mortality due to stroke and hypotension as per the PeriOperative ISchaemic Evaluation (POISE) study. Patients with hypertension pre-operatively should be managed by their primary care doctor with introduction of antihypertensive agents as per the British Hypertension Society (BHS) guidelines.Ischaemic heart disease. Patients with poorly controlled ischaemic heart disease (IHD) should be referred for cardiology assessment. There is no evidence that pre-operative percutaneous coronary intervention (PCI) improves outcome, peri-operative nor long term, in patients with stable coronary artery disease; however, it is justifiable when it is likely to improve the patient's long-term prognosis, such as due to the presence of left main stem stenosis, three-vessel disease or left ventricular (LV) dysfunction. Referral to a cardiologist for patients with recent unstable coronary symptoms should precede surgery. If PCI is performed prior to major surgery bare metal stents are preferred, as these require only four to six weeks of dual antiplatelet therapy, which otherwise markedly increases peri-operative bleeding. Patients with poorly controlled IHD (including recent myocardial infarction (MI)) or who have had recent intervention should undergo surgery in a centre with access to interventional cardiology. ## S16 Dobutamine stress echocardiography can provide a useful dynamic assessment if IHD is suspected and CPET is not possible. Patients with severe valvular disease have an increased risk of surgery. Aortic stenosis can progress rapidly in the elderly population, and those with critical aortic stenosis may need to be considered for pre-operative intervention. Arrhythmias and pacing. Atrial fibrillation and other arrhythmias are frequently found at pre-operative assessment; these may be known or new. Management should focus on the rate control, appropriate anticoagulation and identification of associated risks such as structural heart disease or indication for pre-operative pacing. Cardiac pacemakers should have a recent battery and threshold check within one year. Patients with implantable defibrillators require organisation with a cardiology technician so that they can be deactivated in the anaesthetic room and external pads placed; this is due to the risk of inappropriate discharge due to anaesthetic drugs (suxamethonium) or movement. In both cases, theatre alerts should be placed to remind staff about diathermy risk and bipolar used. Cardiac and anticoagulant drugs. Clopidogrel should normally be discontinued 7 days pre-operatively; aspirin should be continued without interruption. Patients taking warfarin for uncomplicated atrial fibrillation can discontinue it 5 days pre-operatively, restarting post-operatively when enteral function returns and the risk of bleeding is low. Patients with thromboembolic disease or artificial heart valves require heparin therapy to bridge peri-operative warfarin cessation. This will normally be with therapeutic dose low molecular weight heparin (LMWH) and can be managed in the community either with self-injection or district nurse involvement. Last dose should be 24 hours before the start of surgery. Patients with severe renal impairment will require adjusted dosing or occasionally unfractionated heparin infusion. LMWH or heparin infusion will need to be continued postoperatively until the INR is within the therapeutic range. Newer oral anticoagulants (e.g. Dabigatran and Apixaban) have variable elimination times depending on renal and liver function; these are non-reversible agents and if there are no locally agreed policies, advice should be sought from a haematologist. There is increasing evidence that statin therapy should be continued without interruption to prevent peri-operative coronary syndromes due to its plaque stabilising properties. Provision should be made for enteral administration of cardiac drugs as early as possible post-operatively, and patients should continue the majority of these medicines up to admission. Angotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists are a source of debate; the majority of anaesthetists will choose to omit these drugs on the morning of surgery, particularly if it is purely for hypertension control. ## Recommendations - Patients with hypertension of >180/110 or associated target organ damage, should have antihypertensive medication started preoperatively as per BHS guidelines (R) - Rapidly correcting pre-operative hypertension with beta blockade appears to cause higher mortality due to stroke and hypotension and should not be used (R) - Patients with poorly controlled or unstable IHD should be referred for cardiology assessment pre-operatively (G) - Patients within one year of drug eluting stents should be discussed with the cardiologist who was responsible for their PCI pre-operatively with regard to cessation of antiplatelet medication due to risk of stent thrombosis (G) - Patients with multiple recent stents should be managed in a centre with access to interventional cardiology (G) - Surgery after MI should be delayed if possible to reduce mortality risk (R) - Patients with critical AS should be considered for pre-operative intervention (G) - Clopidogrel should be discontinued 7 days pre-operatively; warfarin should be discontinued 5 days pre-operatively (R) - Patients with thromboembolic disease or artificial heart valves require heparin therapy to bridge peri-operative warfarin cessation; this should start 2 days after last warfarin dose (R) - Cardiac drugs other than ACE inhibitors and angiotensin II antagonists should be continued including on the day of surgery (R) - Angotensin-converting enzyme inhibitors and angiotensin II antagonists should be withheld on the day of surgery unless they are for the treatment of heart failure (R) - Post-operative care in a critical care area should be considered for patients with heart failure or significant diastolic dysfunction (R) Heart failure and diastolic dysfunction. Heart failure is a considerably greater peri-operative risk factor than angina or previous MI alone. New or poorly controlled heart failure should be referred to cardiology for optimisation, with early commencement and uptitration of an ACE inhibitor, unless contraindicated, whilst that assessment is pending. Heart failure carries a 50 per cent four-year mortality from diagnosis if the underlying cause cannot be treated; 50 per cent of patients with severe heart failure (symptomatic and frequent presentations) will die within one year. Post-operative care in a critical care area should be considered for patients with heart failure or significant diastolic dysfunction. Right heart failure carries a very high peri-operative risk, much more than LV failure, and there is little available treatment. Right heart failure associated with pulmonary hypertension carries extraordinary risk and is discussed in the respiratory section. Respiratory system. Significant respiratory disease occurs in 20-30 per cent of patients and respiratory morbidity is the most frequent medical complication of major surgery and cause of intensive care unit stay. Preoperative respiratory disease should be optimised wherever possible and right heart disease and pulmonary hypertension considered in those with significant hypoxia (oxygen saturations <93 per cent) or exercise limitation. Respiratory investigations. Chest radiographs are not required routinely from a fitness perspective; the functional capacity of the patient is paramount here. Cardiopulmonary exercise testing may be useful to assess dynamic function and can demonstrate whether respiratory disease is the main contributing factor to generalised debility. Intensive care must be planned for patients with significant pulmonary hypertension. Lung disease should be quantified with spirometry and in severe cases arterial blood gas sampling. An FEV1 of less than 25 per cent predicted poses a markedly increased risk of post-operative ventilatory support, especially when accompanied by hypoxia, hypercarbia or cor pulmonale. The risk of respiratory mortality alone may outweigh any benefit from major surgery. The following actions will optimise a patient's condition for surgery: - Optimise bronchodilator therapy - Trial of steroid responsiveness in moderate and severe disease - Smoking cessation - Peri-operative nebuliser therapy - Treatment of inter-current chest infection, possibly delaying surgery - Sputum sampling to enable 'best guess' treatment of chest infection. Patients with significant hypoxia (oxygen saturations greater than 93 per cent) arterial blood gas estimation should be performed to look for CO 2 retention. Such patients should be considered for an echocardiogram. Obstructive sleep apnoea. It is useful to know the degree of obstructive sleep apnoea (OSA) pre-operatively to allow post-operative care planning and to consider the need to exclude pulmonary hypertension and right heart failure, which may occur if there has been an extended period of untreated OSA. Mask fitting should be optimised and any change to anatomy that could compromise use of the mask should be considered and managed appropriately. Patients with proven or suspected OSA and no continuous positive airway pressure (e.g. not tolerated), will require critical care for at least the first post-operative night. ## Recommendations - Patients with respiratory disease should have their peri-operative respiratory failure risk assessed and critical care booked accordingly (G) - Patients with severe lung disease should be assessed for right heart disease preoperatively (G) - Patients with pulmonary hypertension and right heart failure will be at extraordinarily high risk and should have the need for surgery re-evaluated (G) Endocrine system Diabetes. Poor glycaemic control is associated with increased wound infections, post-operative morbidity, intensive care requirements and hospital mortality. Peri-operative glucose readings should be kept within the target range of 6-10 mmol/l or the acceptable range of 4-12 mmol/l in order to reduce risk. HbA1C is a useful indicator of diabetic control within the preceding three months and patients with an HbA1C greater than 69 should be considered as higher risk of peri-operative poor glucose control. If time allows, these patients should be referred to a diabetes specialist as important changes can be made to glucose control within two to three weeks of surgery. Clear and accessible peri-operative diabetes guidelines should be available in every hospital; National Health Service (NHS) guidelines are available for the management of adults with diabetes undergoing surgery.Insulin-dependent diabetic patients must not omit insulin for more than one missed meal and will therefore require an insulin replacement regime, such as a variable rate intra-venous insulin infusion (VRIII) or a glucose potassium insulin infusion (GKI) for major surgery. Many of the longer acting insulins regimes should be continued at reduced dose alongside the insulin replacement regime. Oral hypoglycaemic agents should be omitted on the day of surgery and restarted when normal diet is resumed. Many of these patients will also require a VRIII or GKI. This can still be managed with day of surgery admission in the well-controlled diabetic patient, provided that sufficient protocols are in place. Many patients with HNC will have an adjusted diet postoperatively and input from diabetic specialists is important to successfully manage medication requirements. Steroids. Steroid replacement is essential for those with adrenal suppression from primary or secondary causes to prevent potentially fatal adrenal crises; 60 per cent of patients taking 5 mg of prednisolone daily fail a short Synacthen test and are therefore at risk of relative post-operative adrenal failure. Guidelines agreed and awaiting publication by the AAGBI and agreed by the Clinical Advisory Panel to the Addison's Disease Self-Help Group, recommend the use of peri-operative steroid cover for all patients taking more than 5 mg prednisolone daily, or the equivalent doses of hydrocortisone 20 mg or dexamethasone 1 mg. Patients using inhaled, intra-nasal or topical steroids may also be at risk. Hydrocortisone is only therapeutic for 2-3 hours after intra-venous bolus, so the more traditional QDS bolusing can leave patients sub-therapeutic for several hours before the next dose. The recommended steroid replacement regime is as follows: 100 mg IM hydrocortisone at induction followed 4 hours later by 200 mg by intra-venous infusion over 24 hours; this may be commenced intra-operatively. This infusion should be continued until oral steroids can be used. Oral dosing should be doubled for at least 48 hours for major surgery and then rapidly tapered back to normal dosing. If intra-venous infusion is impossible, a secondary option is IM 50 mg hydrocortisone QDS. National Institute for Health and Care Excellence guidelines regarding oral corticosteroids note a higher risk of gastrointestinal bleeding and dyspepsia if steroid use is associated with advanced cancer, older age, concomitant non-steroidal anti-inflammatory medications or anticoagulants, previous gastrointestinal ulcer, bleed or perforation. These patients should be considered for proton pump therapy. ## Recommendations - Peri-operative glucose readings should be kept within 4-12 mmol/l (R) - Patients with a high HbA1C facing urgent surgery should have their diabetes management assessed by a diabetes specialist (G) - Insulin-dependent diabetic patients must not omit insulin for more than one missed meal and will therefore require an insulin replacement regime (R) - Patients taking more than 5 mg of prednisolone daily should have steroid replacement in the peri-operative period (R) - Consider proton pump therapy for patients taking steroids in the peri-operative phase if they fit higher risk criteria (R) ## Neurological system Stroke. Peri-operative stroke occurs in approximately 1 in 1000 patients with no prior history of stroke. The comparative odds ratios increase markedly in the presence of prior stroke. [bib_ref] Time elapsed after ischemic stroke and risk of adverse cardiovascular events and..., Jørgensen [/bib_ref] Where surgery cannot be delayed, attention must be paid to cardiovascular stability with avoidance of significant hypotension and head positioning to avoid compression or distortion of the neck vessels, which may impede cerebral perfusion pressure. Carotid dopplers are appropriate for stroke within 12 months. Rheumatoid arthritis related neck instability. Patients with rheumatoid arthritis are at risk of atlanto-axial subluxation and subsequent cord injury and extreme caution should be used at intubation and head positioning. [bib_ref] Anaesthesia for adult patients with rheumatoid arthritis, Fombon [/bib_ref] There are no clear guidelines on the use of cervical spine radiographs pre-operatively. Symptoms suggesting a higher risk of atlanto-axial instability include hesitation on neck movement, pain on movement radiating to the occiput, paraesthesia to the shoulder blades on head movement, or sensory loss in the hands. Up to 20 per cent of patients with rheumatoid arthritis can demonstrate abnormalities on radiographs and in view of the movement often required at surgery for head and neck disease it is advisable that these patients should have cervical spine stability assessed radiologically. Flexion and extension views of the cervical spine are required and should be interpreted by a senior radiologist. ## Recommendations - Surgery within three months of stroke carries high risk of further stroke and should be delayed if possible (R) - Patients with rheumatoid arthritis should have flexion/extension views assessed by a senior radiologist pre-operatively (R) - Patients at risk of POCD and delirium should be highlighted at pre-operative assessment (G) - Patients with Parkinson's disease (PD) must have enteral access so drugs can be given intra-operatively. Liaison with a specialist in PD is essential (R) Post-operative cognitive dysfunction (POCD) and postoperative delirium. Post-operative cognitive dysfunction is new cognitive impairment arising after a surgical procedure, which may be permanent. The incidence of POCD in non cardiac surgery is in the region of 20 per cent at one week and 10 per cent at three months, rising with age. The incidence of delirium (temporary acute confusional state) is higher. Every effort should be made to highlight these risk factors at pre-operative assessment so the anaesthetic and post-operative care can be tailored accordingly (Box IV). This may include the use of short acting anaesthetic agents, close monitoring for infection and ensuring adequate pain relief; but also includes ensuring the patient has all necessary aids such as for hearing and sight. [formula] BOX IV RISK FACTORS FOR POCD OR DELIRIUM INCLUDE - Age > 70 - Preoperative cognitive impairment or dementia - Depression - Preoperative alcohol misuse - Visual impairment - Renal dysfunction - Tobacco use - Previous delirium [/formula] Haematological system. The commonest haematological abnormality is anaemia, usually due to iron deficiency. It is essential that haematinic evaluation is completed to look for the specific deficiency, which may be associated with nutritional failure. A source of iron deficiency anaemia should be always sought (occult malignancy, ulcer disease). Treatment should be based on the active replacement of the haematinics, whether B 12 , folate or iron. Iron replacement can be oral or intravenous; oral therapy will only be effective if absorption is likely and there is at least six weeks before surgery. Intravenous iron is increasingly used and can cause a meaningful rise in haemoglobin levels within two to three weeks. Erythropoietin should be considered on advice from a haematologist or nephrologist for patients with anaemia due to renal disease or anaemia related to chronic disease. ## Recommendations - Intravenous iron should be considered for anaemia in the urgent HNC patient (G) - Preoperative blood transfusion should be avoided where possible (R) - Where pre-operative transfusion is essential it should be completed 24-48 hours preoperatively (R) Preoperative transfusion should be avoided wherever possible and considered on a case by case basis rather than a target haemoglobin level. There is no evidence to support a cut off transfusion point and there is significant risk independently associated with peri-operative blood transfusion. Where pre-operative transfusion cannot be avoided, it should be completed at least 24-48 hours pre-operatively in order to allow time for regeneration of 2,3-diphosphoglycerate in stored red cells, which ensures optimum oxygen delivery by the haemoglobin. ## Alcohol and smoking Alcohol misuse. There is an increased rate of high alcohol intake in patients with HNCs. General postoperative complication rates are approximately 50 per cent higher for patients who drink 5-6 units of alcohol per day compared with those who drink 0-3 units. If untreated, 6 per cent of alcohol-dependent patients will develop clinically relevant symptoms of withdrawal, and up to 10 per cent of these will experience delirium tremens. Acute alcohol withdrawal in the context of major surgery can cause significant morbidity and a peri-operative mortality of up to 10 per cent. An accurate alcohol assessment should include details of intake and level of dependency as well as impact on general health. Alcohol withdrawal should be considered in any patient who has hazardous drinking levels defined as more than 5 units per day for men, 3 units per day for women. Information about appropriate alcohol counselling and support should be provided to patients considered at risk. Identification of alcohol dependency at pre-operative assessment enables further investigation for associated conditions. It also allows planning for pre-operative detoxification, prophylactic intervention, and a higher level of vigilance during admission for the early signs of alcohol withdrawal. Patients considered to have a high level of dependency should be considered for active in-patient withdrawal at least 48 hours pre-operatively in liaison with relevant specialists. Thiamine deficiency is common in patients with alcohol dependency and oral absorption can be poor. Parenteral B vitamins (Pabrinex) should be used before surgery to prevent Wernicke-Korsakoff syndrome in those patients with high levels of alcohol intake. Tobacco use. Smoking tobacco before diagnosis in patients with HNC has a negative correlation with survival. A significant proportion of patients attending cancer diagnostic clinics are smokers. Continued tobacco use in the period leading up to surgery is associated with higher morbidity and mortality in general. Smokers have a considerably increased risk of both intra-operative and post-operative complications, including a 3 to 6-fold increase of peri-operative pulmonary complications. Patients requiring flap reconstructions have higher flap failure rates and greater wound infection rates. Continued smoking during radiotherapy treatment increases complications in patients with laryngopharyngeal cancer and increases the risk of treatment failure. Smoking shortens overall survival and increases both the risk of recurrence and of developing a second primary tumour. Ideally patients should be supported to stop smoking from the time of their initial clinic visit. Stopping for 24-48 hours pre-operatively normalises the amount of carbon monoxide in the blood, which may be as high as 15 per cent in smokers, allowing better oxygen carrying capacity of the blood to the heart and surgical wounds. Stopping for four to six weeks will allow the immune system recovery. Stopping for six to eight weeks allows recovery of respiratory tract cilia function. Nicotine withdrawal should be treated both pre-and post-operatively. The Nutritional failure Nutritional failure impacts negatively on mortality, infection and wound healing. Detailed nutritional assessment and support should be instituted pre-operatively for all patients facing major head and neck surgery as a matter of routine. Dietician-led nutritional support intervention should be provided to any at-risk patients as part of their multidisciplinary management. ## Antibiotic prophylaxis The rationale for considering surgical antibiotic prophylaxis is based on reducing major morbidity, reducing patient length of stay, reducing hospital costs and decreasing overall consumption of antibiotics. Antibiotic use is not without risk and careful adherence to local antibiotic policies is essential to account for local resistance patterns. Risk factors affecting the incidence of surgical site infection can be both patient and operation associated. Head and neck cancer patients who smoke, are obese (over 20 per cent of ideal body weight), diabetic and immunosuppressed, and have advanced disease or require free flap reconstruction have the greatest risk of surgical wound infection. Operative factors include duration of surgery, antimicrobial prophylaxis and surgical technique (haemostasis, appropriate use of drains, tissue handling and wound closure). The risks of infection can be minimised by: - Day of surgery admission where possible - Advising patients to shower or bathe on the day before or the day of surgery - Methycillin-resistant Staphylococcus aureus screening and use of topical agents to reduce carriage if required - Use of antibiotic prophylaxis, where indicated - Aseptic surgical technique and careful tissue handling - Minimising post-operative stay. The Scottish Intercollegiate Guidelines Network has published a review of the role of antibiotic prophylaxis in surgery, updated in April 2014. Whilst the guidelines are for surgery in general, the search criteria and conclusions include evidence and specific conclusions for head and neck surgery. It must be remembered that antibiotic use is not without risk and reducing inappropriate prescribing is one of the aims of rationalising surgical antibiotic prophylaxis. In the setting of clean head and neck surgery for benign disease, antibiotic prophylaxis is not recommended. For surgery with malignant disease that is clean (e.g. neck dissection) antibiotic prophylaxis can be considered. For contaminated and clean-contaminated surgery antibiotic prophylaxis is recommended. In this setting, a single dose of antibiotic with a long enough half-life to achieve activity throughout the operation is recommended. The duration of prophylactic antibiotics should not be more than 24 hours. The choice of antibiotic should ensure broad-spectrum cover for aerobic and anaerobic organisms. ## Recommendations - Antibiotics are necessary for cleancontaminated head and neck surgery, but unnecessary for clean surgery (R) - Antibiotics should be administered up to 60 minutes before skin incision, as close to the time of incision as possible (R) - Antibiotic regimes longer than 24 hours have no additional benefit in clean-contaminated head and neck surgery (R) - Repeat intra-operative antibiotic dosing should be considered for longer surgeries or where there is major blood loss (R) - Local antibiotic policies should be developed and adhered to due to local resistance patterns (G) The timing of the administration of prophylactic antibiotics is important. Intravenous antibiotic should be given up to 60 minutes before the skin is incised. There is some evidence which suggests this dose should be as close to incision as possible. Repeat dosing should be considered when the operation is significantly longer than the half-life of the antibiotic given. In the event of major intra-operative blood loss (>1500 ml), additional prophylactic antibiotic dosage should be considered after fluid replacement to maintain serum concentrations. ## Thromboembolic disease prophylaxis The stated incidence of clinically significant venous thromboembolism (VTE) varies from 0 to 13 per cent in HNC operations. [bib_ref] Safety of thromboprophylaxis after oncologic head and neck surgery. Study of 1018..., Gavriel [/bib_ref] Variation may relate to extent of surgery, and non-pharmacological mechanical interventions, with most series showing an incidence of less than 1 per cent. Early mobilisation and adequate hydration status are essential therapeutic interventions. Current NICE guidance on VTE and Scottish Intercollegiate Guidelines Network guidelines cover all surgical patients without specific reference to head and neck cases. Individual assessment for risk of VTE and bleeding should occur on admission and be repeated at least every 48 hours throughout admission. All patients with one or more of the risk factors (Box V) should receive mechanical prophylaxis from admission (anti-embolism stockings to knee or thigh, or foot impulse devices or intermittent pneumatic compression devices) unless contraindicated. Do not offer anti-embolism stockings to patients with cardiac failure, peripheral arterial disease or neuropathy or local tissue damage. Patients should be encouraged to mobilise and remain well hydrated. If the surgical procedure is associated with a low risk of major bleeding and taking into account individual risk factors, prophylactic LMWH, or unfractionated heparin for those with severe renal impairment, may be added until mobility is restored. From the risk factors detailed above it can be seen that the majority of head and neck patients are likely to be appropriate for combined pharmacological and mechanical prophylaxis regimes. ## Recommendations - Individual assessment for VTE risk and bleeding risk should occur on admission and be reassessed throughout the patient's stay (G) - Mechanical prophylaxis for VTE is recommended for all patients with one or more risk factors for VTE (R) - Patients with additional risk factors of VTE and low bleeding risk should have LMWH at prophylactic dose or unfractionated heparin if they have severe renal impairment (R) [fig] •: Consider proton pump therapy for patients taking steroids in the peri-operative phase if they fit higher risk criteria. (R) Surgery within three months of stroke carries high risk of further stroke and should be delayed if possible. (R) Patients with rheumatoid arthritis should have flexion/extension views assessed by a senior radiologist pre-operatively. (R) Patients at risk of post-operative cognitive dysfunction and delirium should be highlighted at pre-operative assessment. (G) Patients with Parkinson's disease (PD) must have enteral access so drugs can be given intra-operatively. Liaison with a specialist in PD is essential. (R) Intravenous iron should be considered for anaemia in the urgent head and neck cancer patient. (G) Preoperative blood transfusion should be avoided where possible. (R) Where pre-operative transfusion is essential it should be completed 24-48 hours pre-operatively. (R) An accurate alcohol intake assessment should be completed for all patients. (G) Patients considered to have a high level of alcohol dependency should be considered for active in-patient withdrawal at least 48 hours pre-operatively in liaison with relevant specialists. (R) Parenteral B vitamins should be given routinely on admission to alcohol-dependent patients. (R) Smoking cessation, commenced preferably six weeks before surgery, decreases the incidence of post-operative complications. (R) Antibiotics are necessary for clean-contaminated head and neck surgery, but unnecessary for clean surgery. (R) Antibiotics should be administered up to 60 minutes before skin incision, as close to the time of incision as possible. (R) Antibiotic regimes longer than 24 hours have no additional benefit in clean-contaminated head and neck surgery. (R) Repeat intra-operative antibiotic dosing should be considered for longer surgeries or where there is major blood loss. (R) Local antibiotic policies should be developed and adhered to due to local resistance patterns. (G) [/fig]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/BA4B25B3C4C17F5F41403D8CF0A792FD/S0022215116000372a.pdf/div-class-title-pre-treatment-clinical-assessment-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. This paper provides recommendations on the pre-treatment clinical assessment of patients presenting with head and neck cancer. Recommendations • Comorbidity data should be collected as it is important in the analysis of survival, quality of life and functional outcomes after treatment as well as for comparing results of different treatment regimens and different centres. (R) • Patients with hypertension of over 180/110 or associated target organ damage, should have antihypertensive medication started pre-operatively as per British Hypertension Society guidelines. (R) • Rapidly correcting pre-operative hypertension with beta blockade appears to cause higher mortality due to stroke and hypotension and should not be used. (R) • Patients with poorly controlled or unstable ischaemic heart disease should be referred for cardiology assessment pre-operatively. (G) • Patients within one year of drug eluting stents should be discussed with the cardiologist who was responsible for their percutaneous coronary intervention pre-operatively with regard to cessation of antiplatelet medication due to risk of stent thrombosis. (G) • Patients with multiple recent stents should be managed in a centre with access to interventional cardiology. (G) • Surgery after myocardial infarction should be delayed if possible to reduce mortality risk. (R) • Patients with critical aortic stenosis (AS) should be considered for pre-operative intervention. (G) • Clopidogrel should be discontinued 7 days pre-operatively; warfarin should be discontinued 5 days pre-operatively. (R) • Patients with thromboembolic disease or artificial heart valves require heparin therapy to bridge peri-operative warfarin cessation, this should start 2 days after last warfarin dose. (R) • Cardiac drugs other than angotensin-converting enzyme inhibitors and angiotensin II antagonists should be continued including on the day of surgery. (R) • Angotensin-converting enzyme inhibitors and angiotensin II antagonists should be withheld on the day of surgery unless they are for the treatment of heart failure. (R) • Post-operative care in a critical care area should be considered for patients with heart failure or significant diastolic dysfunction. (R) • Patients with respiratory disease should have their peri-operative respiratory failure risk assessed and critical care booked accordingly. (G) • Patients with severe lung disease should be assessed for right heart disease pre-operatively. (G) • Patients with pulmonary hypertension and right heart failure will be at extraordinarily high risk and should have the need for surgery re-evaluated. (G) • Perioperative glucose readings should be kept within 4–12 mmol/l. (R) • Patients with a high HbA1C facing urgent surgery should have their diabetes management assessed by a diabetes specialist. (G) • Insulin-dependent diabetic patients must not omit insulin for more than one missed meal and will therefore require an insulin replacement regime. (R) • Patients taking more than 5 mg of prednisolone daily should have steroid replacement in the peri-operative period. (R) • Consider proton pump therapy for patients taking steroids in the peri-operative phase if they fit higher risk criteria. (R) • Surgery within three months of stroke carries high risk of further stroke and should be delayed if possible. (R) • Patients with rheumatoid arthritis should have flexion/extension views assessed by a senior radiologist pre-operatively. (R) • Patients at risk of post-operative cognitive dysfunction and delirium should be highlighted at pre-operative assessment. (G) • Patients with Parkinson's disease (PD) must have enteral access so drugs can be given intra-operatively. Liaison with a specialist in PD is essential. (R) • Intravenous iron should be considered for anaemia in the urgent head and neck cancer patient. (G) • Preoperative blood transfusion should be avoided where possible. (R) • Where pre-operative transfusion is essential it should be completed 24–48 hours pre-operatively. (R) • An accurate alcohol intake assessment should be completed for all patients. (G) • Patients considered to have a high level of alcohol dependency should be considered for active in-patient withdrawal at least 48 hours pre-operatively in liaison with relevant specialists. (R) • Parenteral B vitamins should be given routinely on admission to alcohol-dependent patients. (R) • Smoking cessation, commenced preferably six weeks before surgery, decreases the incidence of post-operative complications. (R) • Antibiotics are necessary for clean-contaminated head and neck surgery, but unnecessary for clean surgery. (R) • Antibiotics should be administered up to 60 minutes before skin incision, as close to the time of incision as possible. (R) • Antibiotic regimes longer than 24 hours have no additional benefit in clean-contaminated head and neck surgery. (R) • Repeat intra-operative antibiotic dosing should be considered for longer surgeries or where there is major blood loss. (R) • Local antibiotic policies should be developed and adhered to due to local resistance patterns. (G) • Individual assessment for venous thromboembolism (VTE) risk and bleeding risk should occur on admission and be reassessed throughout the patients' stay. (G) • Mechanical prophylaxis for VTE is recommended for all patients with one or more risk factors for VTE. (R) • Patients with additional risk factors of VTE and low bleeding risk should have low molecular weight heparin at prophylactic dose or unfractionated heparin if they have severe renal impairment. (R)
0ee9a36edbf985f77545de3b6e4bb0423f739457	pubmed	SEOM clinical guidelines for the treatment of renal cell carcinoma	SEOM clinical guidelines for the treatment of renal cell carcinoma The purpose of this article was to provide updated recommendations for the diagnosis and treatment of renal cell carcinoma. Pathological confirmation is mandatory before treatment with ablative or focal therapies before any type of systemic therapy. Renal cell cancer should be staged according to the TNM classification system. A laparoscopic nephron-sparing surgery should be the approach for tumors \4 cm if technically feasible. Otherwise, radical (or partial in selected cases) nephrectomy is the treatment of choice, with lymph node dissection only performed in patients with clinically detected lymph node involvement. Some retrospective evidence for a cytoreductive nephrectomy in the postimmunotherapy era suggests a benefit in patients with good or intermediate risk or for patients with a symptomatic primary lesion. Adjuvant treatment with chemotherapy or with targeted agents is not recommended and studies are ongoing today. Patients with metastatic disease should be staged by computed tomography scans of the chest, abdomen and pelvis. The efficacy of sunitinib, bevacizumab plus interferon-a, and pazopanib is well established in patients with good and intermediate risk as well for temsirolimus in poor-risk patients. These four agents are considered standard of care in first-line treatment. Sorafenib, axitinib and everolimus are standard of care in second line in different settings based on their benefit in PFS. Besides some benefit described for IL-2 in highly selected patients in first line, there is a promising and emerging role for the new immunotherapeutic approaches in metastatic renal cell carcinoma.Keywords Renal cell carcinoma Á SEOM Á GuidelinesIncidence and survival ratesRenal cancer is the 12th most common malignancy worldwide (338,000 new cases diagnosed in 2012) with 6,474 new cases diagnosed in 2012 in Spain[1]. It occurs more often in men than in woman (age-standardized ratios for both incidence and mortality are 50 % higher in man compared with woman). Worldwide incidence of all stages has increased in recent years, 2 % yearly, and was responsible for over 143,469 deaths in 2012 [2].Risk factorsApproximately 75 % of renal cancers are diagnosed over the age of 60, with a plateau reached around 70-75 years of age[2]. Smoking is a well-established risk factor for renal cancer with a meta-analysis reporting a clear difference between smokers and non-smokers and also a dosedependent risk in number of cigarettes smoked [bib_ref] Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies, Hunt [/bib_ref]. Smoking cessation for more than 10 years may reduce the risk of RCC [bib_ref] Smoking cessation and renal cell carcinoma, Parker [/bib_ref]. Obesity has also been established as a risk factor for RCC. A meta-analysis provided evidence for an association between body mass index and risk of RCC [bib_ref] Body-mass index and incidence of cancer: a systematic review and meta-analysis of..., Renehan [/bib_ref]. Several studies have demonstrated an inverse relationship between physical activity and RCC risk. Several cohort studies have reported an association with long-term hypertension and risk of RCC [bib_ref] Blood pressure and risk of renal cell carcinoma in the European prospective..., Weikert [/bib_ref]. Approximately 2-3 % of RCCs are familial or hereditary [bib_ref] Familial and hereditary renal cancer syndromes, Coleman [/bib_ref] with a twofold increase incidence in a first-degree relative. Each histological subtype has a corresponding hereditary component caused by distinct genetic alteration. The most common hereditary syndrome for clear cell RCC is the von Hippel-Lindau (VHL) syndrome. Hereditary papillary RCC is associated exclusively with type 1 papillary RCC and does not present with manifestations in other organs. The familial leiomyomatosis and RCC syndrome have been correlated with mutations in the fumarate hydratase gene (FH) and patients present with type 2 papillary RCC. Lastly, in the Birt-Hogg-Dubé (BHD) syndrome, germ line mutations in the homonymous tumor suppressor folliculin gene are characteristic and patients present typically with chromophobe RCC, oncocytomas or hybrid tumors. ## Pathological diagnosis/molecular biology More than 50 % of RCCs are currently detected incidentally when imaging is being performed for some other reasons. However, still a large number of patients with RCC present with symptoms, such as flank pain, gross hematuria and palpable abdominal mass. This is considered the ''classical triad'' for diagnosis, nowadays infrequently seen together. Metastatic symptoms such as bone pain, dyspnea, cough or paraneoplastic syndromes such as hypercalcemia, unexplained fever, erythrocytosis or wasting syndromes are occasionally seen, being this the reason the name RCC as ''the internist tumor''. A core biopsy can provide the confirmation of malignancy with the specific histological type with high sensitivity and specificity. Biopsy is mandatory especially before the treatment with ablative or focal therapies . It is also mandatory in patients with metastatic disease before starting any type of systemic treatment . The final histopathological diagnosis, classification, grading and evaluation of prognostic factors are based on the nephrectomy specimen when available. Different histological subtypes with specific genetic alterations have been identified with similar genetic alterations seen in the familial forms. ## Clear cell renal cell carcinoma Clear cell RCC (ccRCC) is the most common subtype of renal cancer, accounting for 75 % of all primary kidney tumors. These tumors have clear cytoplasm secondary to deposition of lipids and glycogen. Clear cell tumors are commonly hypervascular and can show coagulative tumor necrosis. The most characteristic feature seen in ccRCC is the inactivation of von Hippel-Lindau (VHL) tumor suppressor gene [bib_ref] Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors, Nickerson [/bib_ref] reported in up to 75 %. Other commonly observed cytogenetic alterations in ccRCC include losses at 3p (90 %) 14q, 8p and 9p and gains at 12q and 5q [bib_ref] Comprehensive molecular characterization of clear cell renal cell carcinoma, Network [/bib_ref]. Inactivation of several histone-modifying genes has been described, such as SETD2 (10-12 %), PBRM1 (40 %) and BAP1 (10 %) with suggested prognostic implications [bib_ref] Molecular genetics of clear-cell renal cell carcinoma, Brugarolas [/bib_ref]. ## Papillary renal cell carcinoma Papillary RCC types occur in 10-15 % of cases. Multifocal and synchronous bilateral cases are observed in 10 % of papillary RCC. Two subtypes are described: papillary type 1 and type 2. Germ line met proto-oncogene (MET) and FH alterations are observed in the hereditary form of papillary 1 and in the hereditary leiomyomatosis (type 2), respectively. However, these genetic abnormalities are not frequently observed in the sporadic forms. Cytogenetic alterations in papillary RCC type 1 include gains of chromosomes 7, 8q, 12q, 16p, 17, 20 and loss of 9p. Papillary type 2 tumors gain 8q, lose 1p and 9p [bib_ref] Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary..., Klatte [/bib_ref]. There are conflicting data on the differences/similarities in clinical behavior between papillary RCC type 1 and type 2. Nevertheless, the former appears to be associated with fewer aggressive features than the latter, including a lower stage and grade, as well as longer 5-year survival (*89-94 % versus 55-74 %) [bib_ref] Targeted therapies and the treatment of non-clear cell renal cell carcinoma, Bellmunt [/bib_ref]. Chromophobe renal cell carcinoma Chromophobe RCC occurs in 5 % of cases. This subtype has a less aggressive phenotype when compared with the other histological subtypes. Whether or not patients with chromophobe RCC have a better survival outcome than those with other histological subtypes is unclear. Chromophobe histology is present in 30 % of renal tumors seen in the hereditary Birt-Hogg-Dubé (BHD) syndrome [bib_ref] Renal tumors in the Birt-Hogg-Dubé syndrome, Pavlovich [/bib_ref]. This disease is associated with mutations in the BHD gene whose product is folliculin. Chromophobe tumors frequently have copy number alterations at chromosome 1, 2, 6, 10, 13 and 17. Strong staining for cell membrane-bound KIT protein has consistently been shown in chromophobe RCC tumors. ## Sarcomatoid transformation Sarcomatoid transformation is present in 5 % of RCC. Sarcomatoid components can occur in all histological subtypes of RCC and do not in themselves represent a distinct histological entity. It has been suggested that a cutoff of 30 % sarcomatoid features in the primary tumor may be useful in predicting systemic sarcomatoid histology. TP53 alterations occur in this dedifferentiation process [bib_ref] Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current..., Shuch [/bib_ref]. Collecting duct renal cell carcinoma Collecting duct RCCs account for less than 0.5 % of RCC. These tumors arise from the medullary distal nephron or Bellini ducts. Bellini ducts tumors are an aggressive histological subtype, and most patients have metastases at presentation. Cytogenetic abnormalities include losses at 1p, 8p, 9p and 16p and gains at 13q [bib_ref] Collecting duct carcinomas represent a unique tumor entity based on genetic alterations, Becker [/bib_ref]. ## Other types Other less common subtypes include renal translocation carcinomas. This rare entity of renal translocation carcinomas was first observed in children and young adults but has also been reported in adults. This tumor is characterized by the translocation of Xp11.2, with the gene fusions involving the TFE3 transcription factor gene or TFEB. More than 10 additional histological subtypes have been defined which occur rarely. These include the unclassified RCC, medullary, multilocular cystic RCC, mucinous tubular and spindle cell carcinoma and carcinoma associated with end-stage renal disease. The last WHO classification should be used to classify histology in RCC. ## Staging of rcc: prognostic models for risk assessment ## Staging of rcc The staging of renal cell carcinoma (RCC) should be done according to the TNM classification system (version 2009) [bib_ref] Validation of the 2009 TNM version in a large multi-institutional cohort of..., Novara [/bib_ref] [fig_ref] Table 1: AJCC TNM staging for RCC [/fig_ref]. ## Evaluation of local disease ## Computed tomography (ct) scan The abdominal CT scan represents the gold standard in the staging of RCC and must be performed with and without intravenous [3, A] contrast and including images from the nephrographic phase. A change in 15 or more Hounsfield units before and after the contrast administration will be diagnostic of enhancement and suggesting malignancy. Abdominal CT imaging will provide relevant information for staging including: (1) degree of extension of primary tumor; (2) involvement of vasculature; (3) regional lymph nodes status; (4) adrenal gland and liver involvement; and (5) morphology and function of the contralateral kidney. ## Magnetic resonance imaging (mri) Abdominal MRI is not performed routinely in the staging of RCC. Indications of staging using MRI include: (1) allergy to CT iv contrast or pregnancy; (2) indeterminate results of CT regarding enhancement of complex renal masses; and (3) investigation of venous involvement when poor definition of inferior vena cava tumor thrombus in CT scan or investigation of locally advanced disease. 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]. ## Other imaging tests Vascular imaging studies Studies such as arteriography/ venacavography will be utilized only in selected cases. Radioisotope renography Renal function evaluation studies should be considered when contemplating nephronsparing strategies or if any sign of impaired renal function is present pre-surgery. Positron emission tomography (PET) There is no defined role for PET in diagnosis or follow-up of RCC. It should be considered investigational . ## Evaluation of advanced disease ## Chest imaging evaluation In addition to the abdominal CT, the most accurate imaging test for chest staging is the chest CT that should be considered at initial staging . An alternative is the chest X-ray [bib_ref] Imaging approach to staging of renal cell carcinoma, Bechtold [/bib_ref]. ## Bone or brain studies Outside a clinical trial, imaging studies of bone or brain should be performed only in the presence of symptoms or specific laboratory abnormalities [3, A] [bib_ref] Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma, Marshall [/bib_ref]. ## Risk assessment Different variables including anatomical factors (i.e., size of the tumor, renal capsule invasion, venous invasion, adrenal and lymph node involvement), histological factors (i.e., RCC subtype, tumor necrosis and Fuhrman grade) and clinical factors (i.e., PS, cachexia, anemia, platelet count or local symptoms) are incorporated in prognostic models both in localized and metastatic disease. The UISS, SSIGN and the postoperative Karakiewicz's nomogram are the most widely used prognostic models in localized disease [bib_ref] Improved prognostication of renal cell carcinoma using an integrated staging system, Zisman [/bib_ref] [bib_ref] An outcome prediction model for patients with clear cell renal cell carcinoma..., Frank [/bib_ref] [bib_ref] Multi-institutional validation of a new renal cancer-specific survival nomogram, Karakiewicz [/bib_ref]. In the advanced setting, the MSKCC and the Heng classification are the two most spread prognostic models although others have also been developed [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref] [bib_ref] Interferon-alfa as a comparative treatment for clinical trials of new therapies against..., Motzer [/bib_ref] (see [fig_ref] Table 3: MSKCC or Heng risk criteria MSKCC risk criteria [/fig_ref]. While the MSKCC or Heng criteria should be routinely utilized in the treatment decision process of the patient with advanced RCC, the prognostic models in the localized setting remain investigational until data of prospective ongoing adjuvant studies are available. ## Management of localized/resectable disease ## Local disease Surgery (nephrectomy) is the best approach with curative intention for localized RCC. Different techniques can be performed based on the extension of the resection (nephron sparing or radical [RN]) or the approach (open vs. laparoscopic). For RCC tumors \4 cm, RN has been associated with increased mortality when compared with NSS. Therefore, RN is not recommended in this context unless a NSS is not technically feasible [bib_ref] Radical nephrectomy for pT1a renal masses may be associated with decreased overall..., Thompson [/bib_ref]. These outcomes have not been replicated in RCC tumors of 4-7 cm where partial and radical nephrectomy achieved similar cancer-specific survival and overall survival [bib_ref] Laparoscopic radical versus partial nephrectomy for tumors [4 cm: intermediate-term oncologic and..., Simmons [/bib_ref]. Regarding the approach, when compared with radical open surgery (ROS), radical laparoscopic nephrectomy (RLN) seems to have less surgical related complications although no differences in oncological outcomes have been demonstrated. Therefore, when a radical approach is recommended, RLN should be prioritized [bib_ref] Laparoscopic versus open radical nephrectomy for large renal tumors: a long-term prospective..., Hemal [/bib_ref]. When analyzed by stage, RCC tumors stage 1 (T1) should be treated with a laparoscopic NSS if technically feasible. Stage 2 (T2) tumors should be handled with RLN. Stage III (T3, T4) tumors should be treated with open radical nephrectomy. Neither extended lymph node dissection nor adrenalectomy has shown added survival benefit and should not be performed routinely unless there is radiological or intraoperatory evidence of node involvement [bib_ref] Management of the adrenal gland during partial nephrectomy, Lane [/bib_ref] [bib_ref] Radical nephrectomy with and without lymph-node dissection: final results of European Organization..., Blom [/bib_ref]. Active surveillance (AS) (described as an initial watching of tumor size by successive abdominal imaging tests with deferred intervention reserved for those tumors that show clinical progression during follow-up) is an acceptable option in elderly and comorbid patients with small renal masses (\4 cm) detected incidentally as these masses tend to have a relatively low RCC-specific mortality [bib_ref] Active treatment of localized renal tumors may not impact overall survival in..., Lane [/bib_ref]. Adjuvant treatment is not recommended in patients at high risk of relapse. Adjuvant trials with targeted therapies are ongoing or have completed accrual, and results are not yet available. Neo-adjuvant approaches are investigational and are not recommended in daily practice. ## Management of advanced metastatic disease: first-line, second-line and therapeutic sequences--therapeutic algorithm ## Role of surgery In the era of cytokines, cytoreductive nephrectomy before systemic therapy was shown to provide a survival benefit in patients with good PS [I, A]. In the era of targeted therapies, we have retrospective evidence that cytoreductive nephrectomy can be of benefit in patients with good or intermediate risk or for patients with a symptomatic primary lesion . Prospective trials are ongoing. Metastasectomy can be considered in selected patients with solitary or limited number (B4) of lung metastases and in solitary resectable metastases in other locations with long metachronous disease-free interval. It can also be considered in selected patients with stable responses to targeted therapies [bib_ref] Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma, Karam [/bib_ref]. ## First-line treatment The efficacy of sunitinib, bevacizumab plus interferon [fig_ref] Recommendations 1: After progression to first-line therapy with a TKI, sequential administration of alternative... [/fig_ref] , pazopanib and temsirolimus as first-line therapy was compared with either IFN-a or placebo in separate randomized phase III trials [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] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref]. Results showed that each of these targeted agents was superior to IFN-a in prolonging progression-free survival or overall survival times, or both. The majority of the patients in the sunitinib, pazopanib and bevacizumab plus IFN-a trials were in the favorable or intermediate MSKCC risk groups, and benefits relative to IFN-a were observed across groups. In the temsirolimus trial, all patients were classified by similar criteria as having a poor prognosis, which was equivalent to 74 % of patients being classified in the MSKCC poor-risk group and 26 % of patients being classified in the MSKCC intermediaterisk group. The results of these trials prompted many changes in first-line therapy recommendations. Although Interferon plus bevacizumab have demonstrated similar impact than oral agents as a first-line therapy for metastatic RCC, oral monotherapy with a TK inhibitor has become the ''de facto'' standard of care in this situation. Sunitinib has been the first agent showing high activity in first line. To date, three phase III trials have compared two different TKIs. After the phase III and the non-inferiority COMPARZ trials (median PFS 8.4 vs. 9.5 months with pazopanib and sunitinib, respectively), pazopanib has become an alternative option to sunitinib with some differences in toxicity profile, as first-line therapy for advanced or metastatic RCC [bib_ref] Pazopanib versus sunitinib in metastatic renal-cell carcinoma, Motzer [/bib_ref]. In addition, two randomized trials have recently compared sorafenib with either tivozanib or axitinib. Tivozanib has become the first TKI that showed a benefit in terms of PFS in a phase III trial over another TKI, but was not approved because of its lack of impact in survival [bib_ref] Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal..., Motzer [/bib_ref]. On the other hand, axitinib did not reach the pre-established target of the study, and the trial was prematurely discontinued [bib_ref] Axitinib versus sorafenib as first-line therapy in patients with metastatic renalcell carcinoma:..., Hutson [/bib_ref]. ## Recommendations (clear cell histology) 1. Sunitinib and pazopanib are best first-line treatment alternatives in metastatic RCC patients with good and intermediate risk (level of evidence: I; grade of recommendation: A and B, respectively). 2. Bevacizumab combined with interferon is also an option, although it has been less used in favor of more convenient use of oral therapies (level of evidence: I; grade of recommendation: A). 3. In patients with poor risk features, temsirolimus constitutes the first-line therapy (level of evidence: I; grade of recommendation: A), although sunitinib may also be an option for these patients (level of evidence: II; grade of recommendation: B). 4. At this moment, first-line treatment with immunotherapy should not be recommended for patients with metastatic RCC (level of evidence: I; grade of recommendation: A). 5. In highly selected fit patient population, high dose IL-2 could be considered (level of evidence: I; grade of recommendation: D). ## Second-line treatment and therapeutic sequences Based on a phase III study, the TKI sorafenib is approved for patients with advanced RCC, in whom cytokine therapy has failed or was not indicated [I, A] [bib_ref] Sorafenib in advanced clear-cell renal-cell carcinoma, Escudier [/bib_ref]. Sorafenib almost doubled PFS in second-line therapy compared to placebo (2.8 vs. 5.5 months). With axitinib, a second TKI has recently become available for the second-line therapy of patients after failure of first-line therapy with sunitinib or a cytokine [I, A]. In the AXIS study [bib_ref] Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS):..., Rini [/bib_ref] , PFS was increased by 2 months (6.7 vs. 4.7 months) with axitinib compared to sorafenib as reference . Moreover, in second-line therapy, with everolimus an mTOR inhibitor can be used to treat these patients [II, A]. In the phase III RECORD-1 study, this agent was compared with placebo in patients after failure of at least 1 anti-VEGF therapy and increased median PFS (1.9 vs. 4.9 months) [bib_ref] Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled..., Motzer [/bib_ref]. A phase III trial comparing an mTOR inhibitor, temsirolimus, with a second TKI, sorafenib, following progression on first-line sunitinib has been reported [bib_ref] Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after..., Hutson [/bib_ref]. No differences in PFS were found (4.2 vs. 3.9 months). However, a significant advantage in OS in favor of sorafenib was observed (16.6 vs. 12.2 months; p = 0.014). The results of this study could be related to subsequent treatments administered, but unfortunately, these data are lacking. However, this finding and other retrospective studies [bib_ref] Sequential targeted therapy after pazopanib therapy in patients with metastatic renal cell..., Bellmunt [/bib_ref] give more support to the sequence TKI after TKI. Nevertheless, mTOR inhibitors are also active after a second TKI and could be a good alternative in patients with severe toxicity on a previous TKI. Recently, a randomized phase II study that compared the sequence of first-line sunitinib followed by second-line everolimus with the reverse sequence showed a superiority in terms of PFS and OS favoring the sunitinib--everolimus sequence [bib_ref] Controversies in renal cell carcinoma: treatment choice after progression on vascular endothelial..., Calvo [/bib_ref] , suggesting that the order of administration of the agents is not irrelevant. ## Treatment of metastatic non-clear cell histology Some studies suggest now that patients with non-clear cell histology may benefit from treatment with sunitinib, sorafenib or temsirolimus [III, B]. The recent communication of ESPN trial (Tannir, N ASCO 2014) confirms that everolimus is not considered today the first option for therapy and still the optimal therapy remains unclear and warrants further study [bib_ref] Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and..., Vera-Badillo [/bib_ref] [fig_ref] Table 4: Treatment algorithm 12 weeks with CT chest-abdomen-pelvis as the method of choice [/fig_ref]. ## Response evaluation and follow-up ## Response evaluation Currently, response evaluation in patients with advanced RCC is generally accepted to be performed every [bib_ref] Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic..., Thian [/bib_ref] [bib_ref] Recommendations for the clinical and radiological evaluation of response to treatment in..., León [/bib_ref]. ## Follow-up After definitive local treatment of RCC, there is no consensus about the best follow-up protocol. The most widely accepted approach is stratifying patients based on Fuhrman Grade, TNM Stage, ECOG and type of local treatment, in risk groups. Those patients considered with intermediate or high risk of relapse should be followed more intensively (3 versus 6 months imaging). CT of the chest-abdomen and pelvis is the imaging test of choice although no clear data about the proper timing and/or number of test per year is available [fig_ref] Table 5: Levels of evidence and grades of recommendation [/fig_ref]. Conflict of interest J.B. Consultant for Pfizer, Novartis and GSK. 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. [fig] Recommendations 1: After progression to first-line therapy with a TKI, sequential administration of alternative targeting agents should be considered (level of evidence: I; grade of recommendation: A). In this setting, both sequences either administering a second TKI or mTOR inhibitor are active therapeutic alternatives (level of evidence: I, B for everolimus and I, B for axitinib).2. Axitinib has been shown to be superior to sorafenib in second-line treatment (level of evidence: I; grade of recommendation: A), but sorafenib could be even consider an active option (level of evidence: IV; grade of recommendation: B). 3. Sequential therapy with mTOR inhibitors should be considered in patients who progress after a second TKI (level of evidence: III; grade of recommendation: B) or in those patients who experienced poor tolerance to a first-line TKI (level of evidence: IV; grade of recommendation: B). [/fig] [table] Table 1: AJCC TNM staging for RCC (7th ed.) [/table] [table] Table 2: Stage grouping for RCC Based on AJCC TNM stage and survival [/table] [table] Table 3: MSKCC or Heng risk criteria MSKCC risk criteria (prognostic factors for poor OS) [/table] [table] Table 4: Treatment algorithm 12 weeks with CT chest-abdomen-pelvis as the method of choice. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting but still remains the standard. Other imaging changes such as those integrated in the modified Choi criteria could be more accurate in correlating with clinical outcomes when using tyrosine kinase inhibitors. Special caution is needed when interpreting moderate size changes with density variations and no new lesions to avoid misinterpretation of progression in patients with advanced RCC [/table] [table] Table 5: Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System) Levels of evidence I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or metaanalyses of well-conducted randomised trials without heterogeneity II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or metaanalyses of such trials or of trials with demonstrated heterogeneity III Prospective cohort studies IV Retrospective cohort studies or case-control studies V Studies without control group, case reports, experts' opinions Grades of recommendation A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional D Moderate evidence against efficacy or for adverse outcome, generally not recommended E Strong evidence against efficacy or for adverse outcome, never recommended [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12094-014-1219-1.pdf	None
2814603e61a4962035751c24e2553d2fff7702c1	pubmed	European Antibiotic Awareness Day 2017: training the next generation of health care professionals in antibiotic stewardship	European Antibiotic Awareness Day 2017: training the next generation of health care professionals in antibiotic stewardship Antimicrobial stewardship (AMS) aims to optimise treatment, minimise the risk of adverse effects and reduce health care costs. In addition, it is recognised as a key component to stop the current spread of antimicrobial resistance in Europe. Educational programmes are particularly important for the successful implementation of AMS. Training should start during medical school, continue during clinical training and be reinforced throughout postgraduate training. National core curricula for paediatric training should include passive and active training of competencies needed for AMS and future paediatricians should be skilled in taking leadership roles in AMS initiatives. Other core members of the paediatric AMS team should also receive training focused on the unique medical needs of the paediatric patient.Conclusion: Ideally, all communities, hospitals and health regions in Europe should have AMS that serve all patient types, including children. We all have the responsibility to ensure that existing antibiotics remain effective. # Introduction Antimicrobial resistance (AMR) poses a serious and increasing threat to public health as infections caused by bacteria that are resistant to antimicrobials lead to approximately 25,000 deaths in the European Union every year. In children, a significant increase in the prevalence of multidrug-resistant bacterial infections has occurred during the past couple of decades [bib_ref] Antimicrobial-resistant pathogens: an emerging pediatric threat, Elliot [/bib_ref]. Over the last few years, there have been significant shortages in the development and availability of new antibiotics, and the number of targeted studies on antibiotics in children remains strikingly low [bib_ref] Antimicrobial stewardship in paediatrics, Principi [/bib_ref]. Therefore, the implementation of strategies to preserve the efficacy of existing antibiotics is an urgent public health priority, both in hospital and community settings. Antimicrobial stewardship (AMS) aims to appropriately and safely prescribe antibiotics to patients, while reducing unnecessary or suboptimal use of antibiotics, thus maximising outcomes for the patient [bib_ref] Effect of antibiotic stewardship on the incidence of infection and colonisation with..., Baur [/bib_ref]. AMS is recognised as a key component to stop the current spread of AMR in Europe. AMS programmes have the ultimate goal of minimising selective pressure on the emergence of drug-resistant strains. Successful AMS programmes are characterised by the ability to break down activities into specific interventions that can be more easily implemented, monitored and evaluated [bib_ref] Antimicrobial stewardship for neonates and children: a global approach, Bielicki [/bib_ref]. Successfully implemented AMS programmes have a significant impact on reducing antimicrobial use in paediatric patients, costs and prescribing errors without negative impacts on patient safety, and actually resulting in improved patient outcomes [bib_ref] Antimicrobial stewardship programs in freestanding children's hospitals, Hersh [/bib_ref] [bib_ref] Antimicrobial stewardship in paediatrics, Principi [/bib_ref] [bib_ref] Inpatient antimicrobial stewardship in pediatrics: a systematic review, Smith [/bib_ref]. The identification of paediatric conditions with both frequent and variable antimicrobial use could guide the prioritisation of high-impact targets for AMS interventions [bib_ref] Identifying targets for antimicrobial stewardship in children's hospitals, Gerber [/bib_ref]. Paediatric AMS should not be limited to the hospital setting and collaboration among hospital and outpatient health care facilities is of paramount importance [bib_ref] New horizons for pediatric antibiotic stewardship, Goldman [/bib_ref] [bib_ref] Antimicrobial stewardship in pediatrics: how every pediatrician can be a steward, Hyun [/bib_ref]. Indeed, AMS can be effective in reducing antibiotic misuse in community settings [bib_ref] Impact of a 16-community trial to promote judicious antibiotic use in Massachusetts, Finkelstein [/bib_ref] [bib_ref] Effect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by..., Gerber [/bib_ref] , and potential strategies to promote these programmes in community-based settings have been published [bib_ref] Antimicrobial stewardship in pediatrics: how every pediatrician can be a steward, Hyun [/bib_ref]. ## Training in antimicrobial stewardship As active participation of clinical professionals at all levels of care is required for AMS to succeed, educational programmes are particularly important for the successful implementation of AMS. Education of health care providers on appropriate antibiotic prescribing has been shown to enhance other antimicrobial stewardship interventions [bib_ref] Health care provider education as a tool to enhance antibiotic stewardship practices, Ohl [/bib_ref]. Therefore, the European Academy of Paediatrics (EAP) Curriculum for Common Trunk Training in Paediatricsincludes specific knowledge and skills related to AMR and the European Society for Paediatric Infectious Diseases (ESPID) and other national (paediatric) infectious diseases groups run specific courses on AMR [fig_ref] Table 2: Available e-learning tools AMS [/fig_ref]. The syllabus for Core Training sets out a European road map for common paediatric training. It is intended as a guide for national paediatric societies to help them understand the principles of core training. The EAP recognises that in many countries in Europe, training does not conform to these recommendations, but as such differences gradually diminish, quality, content and assessment of training, including training related to the principles AMR, will become more uniform across Europe. At the same time, it is recognised that differences in regional epidemiology and healthcare infrastructure require a tailor-made approach, also for AMS. Recently, recommendations were published for key points to be included in clinical curricula, in order to develop the necessary skills to participate in AMS [bib_ref] The intersection of antimicrobial stewardship and microbiology: educating the next generation of..., O'donnell [/bib_ref] [bib_ref] Health care provider education as a tool to enhance antibiotic stewardship practices, Ohl [/bib_ref]. These are summarised in [fig_ref] Table 1: Key points to include in clinical AMS curricula [adapted from[20,22] [/fig_ref]. It is important that assimilation of knowledge about AMS starts already during medical school, is continued during clinical training and is reinforced throughout postgraduate training. Passive educational techniques like large and small group presentations are modestly effective for increasing knowledge. However, interactive or dynamic techniques influence prescribing behaviour. This includes education associated with specific episodes of patient care. Interactive small group sessions, e-learning, educational outreach, periodic retrospective audit and feedback and one-on-one patient-directed education have been shown to be moderately to highly effective in optimising antibiotic use and patient outcomes [bib_ref] Health care provider education as a tool to enhance antibiotic stewardship practices, Ohl [/bib_ref]. In particular, internet-based education shows encouraging results [bib_ref] Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections:..., Little [/bib_ref] [bib_ref] Antibiotic Awareness Day 2012: general practitioners encouraged to TARGET antibiotics through guidance,..., Mcnulty [/bib_ref] [bib_ref] Scottish Antimicrobial Prescribing Group (SAPG): development and impact of the Scottish National..., Nathwani [/bib_ref]. The advantages of e-learning include improved access to education in rural or low-resource areas and the potential to develop an interactive platform. Several examples of e-learning tools are listed in [fig_ref] Table 2: Available e-learning tools AMS [/fig_ref]. In addition, AMS was recently taught during the EAP MasterCourse 2017 and is included in the upcoming European Academy of Paediatric Societies congress in Paris, 2018. In addition, AMS is always covered during the annual residential ESPID-Oxford Course. Although many of the overarching principles of AMS apply to children and adults alike, many factors related to paediatric AMS are unique to children. Children have high rates of infection and frequently present with non-specific symptoms adding to diagnostic uncertainty. Patterns of infection The participant learns how to de-escalate antibiotic use in order to more effectively treat an infection while limiting exposure to broad-spectrum antimicrobials Determine and verify antibiotic allergies Consider local antibiotic susceptibility Specify expected duration of therapy based on evidence and national and hospital guidelines Ensure appropriate administration (intravenous versus oral) Give antibiotics at the right dose and interval and resistance vary significantly by age, thus age-specific antibiotic panels for antibiograms should preferably be used to guide antibiotic choices for selected infections. Children are more prone to infection with resistant organisms due to a future lifetime of antibiotic exposure. In addition, considerations related to age-appropriate dosing and formulations pose challenges to the prescription of antibiotics in children [bib_ref] Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics, Downes [/bib_ref]. Children may respond differently to antibiotics compared to adults. Finally, immunisation initiatives should be included in AMS programmes as a preventive strategy in both in-and outpatient paediatric settings, in order to decrease the likelihood of serious illness and to decrease AMR. Therefore, other core members of the paediatric AMS team, like the microbiologist, paediatric infectious disease specialist and clinical pharmacist, should receive training focused on the unique medical needs of the paediatric patient [bib_ref] Making a case for pediatric antimicrobial stewardship programs, Magsarili [/bib_ref] [bib_ref] Advocacy Committee for the Pediatric Pharmacy Advocacy Group (2017) Pediatric antimicrobial stewardship..., Nichols [/bib_ref]. In addition, future paediatricians should be skilled in taking leadership roles in AMS initiatives and develop practical solutions rooted in the general principles of AMS, as it is important to further expand AMS activities from the hospital to paediatric offices and communities [bib_ref] Antimicrobial stewardship in pediatrics: how every pediatrician can be a steward, Hyun [/bib_ref]. ## Keep antibiotics working Limiting the further spread of AMR is one of EAP's child health priorities for 2017-2018. We will work together with the European Centre for Disease Prevention and Control to raise awareness about the relevance and benefits of costeffective AMS policies [bib_ref] Antimicrobial stewardship initiatives throughout Europe: proven value for money, Oberjé [/bib_ref] and training in child health and to advocate for sustained implementation of these across Europe. Europe would greatly benefit from a uniform adoption of AMR and infection prevention best practice across countries. This includes harmonisation and simplification of the various treatment guidelines that currently exist across Europe. Moreover, there is an urgent need to conduct research on new antibiotic (classes) for critical multi-drug-resistant pathogens and on the effects of AMS programmes in lowincome countries in which emerging resistance are particularly alarming [bib_ref] The role of antimicrobial stewardship programmes in children: a systematic review, Araujo Da Silva [/bib_ref]. In addition, limited access to high-quality antibiotics is particularly of concern in these countries. Continuous education and training of health care professionals on appropriate antibiotic use is crucial. We therefore welcome the new European Action Plan, which was launched this summer. The European Commission intends, among others, to develop training programmes on AMR for health professionals through the ECDC and the EU health programme. # Conclusion Prevention of AMR needs rigorous actions in the community, at practice, ward, institutional, national and international levels. Best practices should be applied cross-border and healthcare institutions and communities should collaborate regionally and internationally, in order to fight AMR successfully. Effective Europe-wide implementation and sustained use of cost-effective antimicrobial policies can consequently lead to improved safety and quality of care while contributing to more sustainable healthcare. Ideally, all communities, hospitals and health regions in Europe should have AMS programmes that serve all patient types, including children. This includes adult academic and community hospitals and outpatient care centres that primarily care for children. Therefore, the EAP is interested to discuss interdisciplinary approaches of education with other stakeholders. Prudent use of antibiotics is very important to address the global challenges posed by AMR. We all have the responsibility to ensure that existing antibiotics remain effective. Authors' contributions Lenneke Schrier initiated the EAP statement (together with HJD), wrote the draft and agrees on its final wording. Adamos Hadjipanayis commented on the draft and agrees on its final wording. Stefano del Torso commented on the draft and agrees on its final wording. Tom Stiris commented on the draft and agrees on its final wording. Marieke Emonts commented on the draft and agrees on its final wording. Hans Juergen Dornbusch initiated the EAP statement (together with LS), commented on the draft and agrees on its final wording. ## 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 or animals performed by any of the authors and therefore neither ethical approval nor informed consent applies. Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. [table] Table 1: Key points to include in clinical AMS curricula [adapted from[20,22] [/table] [table] Table 2: Available e-learning tools AMS (general) Collection of AMS online courses made by the European Centre for Disease Prevention and Control: https://ecdc.europa.eu/en/publications-data/directory-guidance-prevention-and-control/training-antimicrobial-stewardship Massive Open Online Course on Antimicrobial Stewardship (University of Dundee, UK): https://www.futurelearn.com/courses/antimicrobial-stewardship Antimicrobial Stewardship Online CME Courses (Stanford University School of Medicine, USA): https://med.stanford.edu/cme/learning-opportunities/antimicrobialstewardship.html Paediatric AMS European Society for Paediatric Infectious Diseases (ESPID) online course on paediatric AMS: http://www.espid.org/content.aspx?Page=ESPID%20Online%20Antibiotic%20Management%20Course [/table]	None	https://link.springer.com/content/pdf/10.1007/s00431-017-3055-0.pdf	None
4c1d1706cd7c84a3a9ebd00ed2cc4d49aae961b2	pubmed	Acute abdomen in the immunocompromised patient: WSES, SIS-E, WSIS, AAST, and GAIS guidelines	Acute abdomen in the immunocompromised patient: WSES, SIS-E, WSIS, AAST, and GAIS guidelines # Introduction Emergency surgery admissions carry a substantial risk of in-hospital death of 3.04%and a chance of postoperative complication of 21%. That is further increased with an immunocompromised state. Immunocompromised patients (IP) are a heterogeneous and diffuse category of patients frequently presenting to the emergency department (ED) with acute surgical diseases. Diagnosis and treatment in IP are often challenging and must be multidisciplinary. Misdiagnosing of acute surgical disease in an IP may be followed by increased morbidity and mortality. IP not only seek later medical assistance because their symptoms are often undefined, but they have some unique surgical problems that do not affect the general population. There have been a few attempts to stratify these patients in the last 30 years, especially since a universally accepted definition of an immunocompromised state does not exist. Revision of all those conditions and diseases causing immunocompromission (IC) may lead to patient categorization into two groups: one with mild-moderate IC and another with severe IC. Precise indications deriving from the literature are scarce. The present paper represents the World Society of Emergency Surgery (WSES), Surgical Infection Society Europe (SIS-E), World Surgical Infection Society (WSIS), American Association for the Surgery of Trauma (AAST), and Global Alliance for Infection in Surgery (GAIS) joined guidelines about the management of acute abdomen in immunocompromised patients. # Material and methods ## Research strategy The bibliographer conducted a computerized search in different databanks (MEDLINE, PubMed, Scopus, Web of Science, EMBASE). Citations were included for the period between January 1990 and March 2020 using the primary search strategy: emergency surgery, general, immunocompromised, immunosuppressed, abdominal sepsis, infection, with AND/OR. As the definition of immunocompromission is quite variable, the search also included terms as "HIV", "AIDS", "transplanted", and "chronic steroid therapy" with synonyms and MeSH terms. No language restriction was imposed. Duplicates and animal studies were removed. The dates were selected to allow comprehensive published abstracts of clinical trials, consensus conferences, comparative studies, congresses, guidelines, government publication, multicenter studies, systematic reviews, meta-analysis, large case series, original articles, and randomized controlled trials. Narrative review articles were also analyzed to identify other studies. Abstracts were screened, and not relevant studies were removed; then, a full-text assessment of the articles was performed. Case reports were excluded. In case of disagreement between the two reviewers (FC, MI), the consensus was reached by discussion. If there was no consensus, a third reviewer was sought (FCa). Prisma flowchart of the systematic review is reported in. Level of evidence (LoE) graded in high, moderate, low, and very low and the grade of recommendation (GoR) graded as strong, moderate, and weak were calculated according to the WSES rules for guidelines update, keeping into consideration the GRADE model. An international expert panel in a modified Delphi process discussed the different issues in subsequent rounds. At each round, the manuscript was revised and improved. The final version about which agreement was reached resulted in the present manuscript. Statements are summarized in. ## Definitions ## Definition of the immunocompromised patient An immunocompromised host is a patient presenting an impaired or weakened immune system; this does not allow a normal response to infections. Immunocompromised patients are defined as follows: 1. Congenital conditions (T-or B-cell defects, macrophage dysfunctions, often in newborns and children but even in the adult population) Clinical classification of patients with immune deficiency 2. Acquired conditions a. Infected by human immunodeficiency virus (HIV) who developed acquired immunodeficiency syndrome (AIDS) b. Hematologic malignancy c. Patients affected by intrinsic immune conditions considered immunodeficiency along with one between "solid malignancy or solid organ transplanted patients or inflammatory disease/ rheumatologic disease" plus the concurrent assumption of immunomodulatory drugs or chemotherapy d. Patients in a physiologic or pathologic condition that is accompanied by any degree of immunodeficiencyClassification of immunodeficiency state shows the conditions causing immunodeficiency, ranging from mild to severe. Notes on the use of the guideline The guidelines are evidence-based, with the grade of recommendation based on the evidence. The guideline presents the diagnostic and therapeutic methods for optimal management of acute abdomen in the immunocompromised patient. The practice indications promulgated in this work do not represent a standard of practice. These are suggested plans of care based on the best available evidence and experts' consensus, but they do not exclude other approaches as being within the standard of practice. For example, they should not be used to compel adherence to a given medical management method, which method should be finally determined after taking account of the conditions at the relevant medical institution (staff levels, experience, equipment, etc.) and the characteristics of the individual patient. However, the treatment results' responsibility rests with those directly engaged and not with the consensus group. ## Diagnosis Diagnosis and treatment in immunocompromised patients must be multidisciplinary (GoR moderate based on low LoE). High clinical suspicion must be kept in the presence of an immunocompromised patient presenting with signs ## Specific acute abdominal infections in immunocompromised patient Neutropenic enterocolitis -Neutropenic enteritis and typhlitis have a high mortality rate if misdiagnosed or underestimated; accurate differential diagnosis is mandatory (GoR moderate based on low LoE). -Treatment of neutropenic enteritis and typhlitis should be nonoperative, including broad-spectrum antibiotics and bowel rest. Emergency surgery must be reserved only for those patients presenting with signs of perforation or ischemia (GoR moderate based on low LoE). -A damage control approach in complicated neutropenic enteritis and typhlitis should be adopted in severely sick patients with physiological derangement (GoR moderate based on low LoE). ## Cytomegalovirus colitis -Cytomegalovirus colitis has a high mortality rate if misdiagnosed or underestimated. Accurate differential diagnosis is of paramount importance (GoR moderate based on low LoE). -Treatment of cytomegalovirus colitis should be nonoperative, including antiviral therapy, broad-spectrum antibiotics, and bowel rest. Emergency surgery must be reserved only for those patients presenting with signs of toxic megacolon, fulminant colitis, perforation, or ischemia (GoR moderate based on low LoE). ## Clostridioides difficile colitis -A damage control approach in complicated cytomegalovirus colitis should be adopted in severely sick patients with physiological derangement (GoR moderate based on low LoE ## Common acute abdominal infections in transplanted patients In transplanted patients, the epidemiology of acute surgical diseases varies, with gallbladder disease being one of the most common problems after heart and/or lung transplantation and intestinal perforation due to diverticulitis being the most common disease following kidney and liver transplants (GoR moderate based on intermediate LoE Immunocompromised patients usually do not present specific signs and symptoms. A reliable diagnosis may be reached only by combining signs, symptoms, patient history, and imaging evaluation (GoR moderate based on low LoE). Clinical signs may not be reliable in immunocompromised patients; the more the immunocompromission, the less the reliability (GoR moderate based on low LoE). Laboratory tests may not accurately reflect the severity of the clinical condition of the patient immunocompromised (GoR moderate based on low LoE). Plain radiographs and ultrasound are often not sufficiently sensitive and specific to allow for a definitive diagnosis in immunocompromised patients (GoR moderate based on low LoE). Contrast-enhanced CT scan, whenever feasible, is the most reliable exam to diagnose intrabdominal disease in immunocompromised patients (GoR moderate based on low LoE). In the event of diarrhea, with or without acute abdomen, a specific test for Clostridioides difficile and its toxin should be performed (GoR moderate based on low LoE). Additional microbiologic tests for a specific disease should be performed only if clinically congruent (GoR moderate based on low LoE). Diagnostic workup for acute abdomen in patients with HIV infection should always consider surgical diseases specifically associated with HIV (i.e., Abdominal tuberculosis, Mycobacterium avium complex infections) (GoR moderate based on low LoE). IC patients' status at presentation may vary from reasonably functional and able to carry on daily activities, to extreme physical debilitation, with inadequate nutrition, considerable pain, and other significant comorbidities. Along with a thorough history and physical examination, further laboratory evaluations and tests include, but are not limited to, a complete blood count, serum electrolytes, liver function tests, and coagulation studies. C-reactive protein (CRP) may become fundamental in differential diagnosis. Depending on the degree of cardiac involvement and type of surgery planned, a 12-lead ECG and echocardiogram may be advisable. A chest radiograph should be considered to screen for tuberculosis, metastatic intrathoracic disease, pleural effusions, or other pulmonary disease processes that may have perioperative consequences. Fever, leukocytosis, and peritonitis may be mild or absent, especially in patients with severe IC. A first-level radiological evaluation with US and X-ray may not be sufficiently effective in obtaining a definitive diagnosis. Since IP mortality is higher if a diagnosis of surgical disease is missed, liberal use of contrastenhanced CT scan is advocated for this population. ## Specific acute abdominal infections in immunocompromised patient ## Neutropenic enterocolitis Statements are as follows: Neutropenic enteritis and typhlitis have a high mortality rate if misdiagnosed or underestimated; accurate differential diagnosis is mandatory (GoR moderate based on low LoE). Treatment of neutropenic enteritis and typhlitis should be nonoperative, including broad-spectrum antibiotics and bowel rest. Emergency surgery must be reserved only for those patients presenting with signs of perforation or ischemia (GoR moderate based on low LoE). A damage control approach in complicated neutropenic enteritis and typhlitis should be adopted in severely sick patients with physiological derangement (GoR moderate based on low LoE). Neutropenic enterocolitis (ileocecal syndrome or typhlitis) is the commonest cause of acute abdominal pain in neutropenic cancer patients. Typically, it occurs 1 or 2 weeks after chemotherapy is initiatedand is more common in leukemic patients or patients after high-dose chemotherapy for solid organ cancer. Almost 1% of all cancer patients admitted to the emergency department yearly had neutropenia at the admission [7] and 6.5% of neutropenic patients for myelosuppressive therapy have neutropenic enterocolitis. Four percent of cancer patients admitted to emergency departments had neutropenic fever. Up to 7% of cancer-related ICU admissions are for neutropenic patients. The real incidence of neutropenic enteritis ranges from 0.8 to 26%. Neutropenic enterocolitis generally presents with neutropenia associated with one or more of the following signs and symptoms: fever, bowel wall thickening, diarrhea, and abdominal pain. US signs that increase the risk of complications are fluid-filled bowel, ascites, free fluid between bowel loops, and hyperechoic septa floating inside the bowel's lumen (that correspond to bowel necrotic mucosa). Half of the patients with signs and symptoms of neutropenic enteritis have an ultrasound positive for bowel wall thickening (> 5 mm), confirming the diagnosis. Up to 70% of patients with a positive US have a full recovery after a mean of 8 days; 100% of the patients without identified bowel wall thickening have a full recovery after an average of 4 days. Patients with US scan positive for bowel thickening > 10 mm had a higher death rate. Mortality in patients with US or CT scan positive for suggestive signs of neutropenic enteritis or typhlitis reaches 29.5%. Therefore, a high index of suspicion in patients undergoing conservative treatment with positive radiologic signs is mandatory (see diagnosis paragraph for high-risk radiological signs). CT scan detection of right colon wall thickening is the best indicator of the diagnosis and a good predictor for the prognosis. Patients with bowel wall > 10 mm had a 60% risk of death compared to 4.2% if < 10 mm. Once the diagnosis is confirmed, immediate broadspectrum antibiotic therapy must be initiated. The disease should be treated with empiric antimicrobial therapy according to the IDSA guidelines for "fever with neutropenia". They suggest monotherapy with an anti-pseudomonas B-lactam agent or a carbapenem or piperacillin-tazobactam as the first choice. The addition of other antimicrobials may be suggested if no clinical improvement is observed and/or if a specific infection focus is suspected and/or in case of complications. No indications for the immediate administration of empirical antifungal therapy exist. Adjunct antifungal therapy may be added if fever failed to improve after empiric antibiotic therapy. Resolution is obtained in up to 86% of patients with conservative antibiotic treatment in a median of 6-8 days. Interestingly, a rise in the neutrophil count after nadir would directly correlate with the resolution of symptoms. Treatment of neutropenic enteritis or typhlitis is nonoperative with antibiotics and bowel rest. Surgery must be reserved only for those presenting with signs of perforation or ischemia. No studies investigated surgical vs. conservative management of patients with neutropenic enteritis, but it is widely accepted that conservative management should be preferred. Cancer patients developing neutropenic enteritis, usually after high-dose chemotherapy, are poor candidates for surgery, especially if unplanned. Neutropenic enteritis generally develops during the secondthird week of chemotherapy (the period of the mucosal damage induced by drugs). After chemotherapy, in a spot of 30 days, it has been shown that planned elective surgery does not carry excessively higher risk. Conversely, on chemotherapy, the reported mortality rate is up to 81%. Patients with leukemia who underwent emergency surgery and had chemotherapy in the previous 30 days presented a 57% mortality rate, with leukopenia being an adverse prognostic factor. Comparing patients who had chemotherapy in the previous 30 days undergoing emergency surgery to those who had not, mortality and complication rates were higher in the chemotherapy group (22.4% vs. 10.3% and 44% vs. 39.2%, respectively). Leukopenia (WBC count < 4500 × 10 3 /mm 3 ) was associated with a higher risk of mortality and morbidity (24.4% vs. 10.8% and 45.4% vs..9%, respectively). Concerns may exist in admitting patients to the ICU with ongoing cancer progression or recurrence after emergency surgical intervention. Indication for ICU admission should be defined on a case-by-case basis, considering all the clinical, organizational, and even economic aspects. A large multicenter study on 717 cancer patients admitted to 28 different ICUs reported a rate of in-hospital mortality for emergency surgery of 37%. In contrast, ICU mortality for the same category was 23%. Mortality was related to the need for mechanical ventilation and performance status and not directly to cancer-related characteristics. ## Cytomegalovirus colitis Statements are as follows: Cytomegalovirus colitis has a high mortality rate if misdiagnosed or underestimated. Accurate differential diagnosis is of paramount importance (GoR moderate based on low LoE). Treatment of cytomegalovirus colitis should be nonoperative, including antiviral therapy, broadspectrum antibiotics, and bowel rest. Emergency surgery must be reserved only for those patients presenting with signs of toxic megacolon, fulminant colitis, perforation, or ischemia (GoR moderate based on low LoE). A damage control approach in complicated cytomegalovirus colitis should be adopted in severely sick patients with physiological derangement (GoR moderate based on low LoE). No sufficient data exist to indicate whether to perform subtotal or segmental colectomy resecting only the involved colon segment. Cytomegalovirus (CMV) infection accounts for up to 34% of severe acute colitis in IC. Liver transplant recipients have been described to have a 4.9% 10-year cumulative incidence of post-transplantation CMV end-organ disease (colitis, hepatitis, pneumonia). After allogeneic hematopoietic stem cell transplantation, the incidence of CMV end-organ disease is 15-25%. Even HIV-positive patients with or without AIDS, kidney transplant recipients, and patients with malignancies may present with severe CMV infections. In pediatric patients, the most common cause is acute lymphoblastic leukemia. CMV colonic localization is the most common and causes vasculitis that ultimately leads to bowel wall necrosis. CMV colitis symptoms are nonspecific, encompassing all mild-to-severe colitis symptoms like diarrhea, rectal bleeding, fever, abdominal pain, weight loss, and up to colonic perforation. Patients with CMV colitis usually do not present classical CMV viremia symptoms (pharyngitis, lymphadenopathy, splenomegaly). In diagnosing CMV colitis, blood serology has no diagnostic value. The CMV seroprevalence analysis in adults showed at least 70% of seropositivity. At the endoscopy, the only factor that may suggest the diagnosis is the presence of ulcerations with a well-defined, punched-out appearance present in up to 80% of patients. Some studies proposed a typical cecum ulcer involving the ileocecal valve as a specific finding in CMV colitis in patients with graftversus-host disease. A biopsy is always required when colonoscopy is performed in IP, specifically considering CMV infection. In hematoxylin-eosin-stained tissue sections, the "owl eye" appearance inclusions and are highly specific for CMV. The "gold standard" for diagnosing CMV colitis is the CMV-specific immunohistochemistry in tissue biopsies. Contrast-enhanced CT scan is helpful for the diagnosis. Bowel thickening is almost always present, but pancolic appearance is rare and may help in differential diagnosis with CDc together with the presence of small bowel thickening (present in up to 40% of CMV infections and absent in CDc). In-hospital mortality of immunocompetent severely ill patients with CMV colitis is almost 70% despite treatment. Results in immunocompromised patients are even worst. The possible association between inflammatory bowel disease (IBD) and CMV colitis should be kept into consideration. In fact, patients affected by IBD presenting even a CMV colitis may experience up to seven times higher in-hospital mortality. There are insufficient publications with good quality to determine if treating CMV colitis with antiviral agents will improve patient outcomes regarding colectomy and mortality rate. However, untreated CMV disease in immunodeficient patients is associated with higher morbidity and mortality. The drug of choice for initial therapy in adults is intravenous ganciclovir (5 mg/kg twice daily). After 3-5 days of intravenous ganciclovir, a transition can be made to oral valganciclovir (900 mg/ twice daily) for the remainder of the 2-3-week course. In pediatric patients, 14-21 days of parenteral ganciclovir is recommended. Early switch to oral treatment in children may promote CMV reactivation. Large spectrum antibiotic therapy is indicated. A subtotal or partial colectomy is indicated in severe conditions characterized by toxic megacolon, fulminant colitis, perforation, or ischemia. No definitive data exist in defining the superiority of segmental colectomy over subtotal colonic resection. ## Clostridioides difficile colitis Statements are as follows: Clostridioides difficile colitis (CDc) ranges from 6 to 33% in hematology-oncology population with most cases occurring in the first month post-transplantation. In transplanted patient incidence ranged from 0.77 to 11.3% in kidney transplant (KT) up to 0.63 to 19% in liver transplant (LT) and 1.93 to 22.9% in lung transplant. In HIV-infected patients, incidence is 7.1-8.3 cases 1000 patients/year. Common risk factors are generally the use of high-risk antibiotics such as antipseudomonal penicillin, fourth generation cephalosporins, carbapenems, fluoroquinolones, and clindamycin. Other risk factors included CD4 count ≤ 50 cells/μLgrade ≥ 2 mucositis, higher dose of chemotherapy, reactivation of cytomegalovirus, and reactivation of other Herpesviridae. Acute abdomen is rarely the first manifestation, but it may occur in combination with diarrhea, leukocytosis and fever. Radiological findings are various in CDc with normal X-ray of the abdomen in up to 68%. Free fluid detected with ultrasound is present in CDc (77%). Contrast-enhanced CT scan has the best diagnostic power in detecting signs of CDc. It may be available before toxin stool testing and represents the gold standard if associated with signs and symptoms. Up to 84% of patients with CDc show at CT scan colonic wall thickening with 50% being pancolic. CDc infection is mainly a medical disease. Optimal timing for emergent surgical intervention remains controversial. Surgical management should be performed when the clinical conditions worsen or do not improve with maximal medical and supportive therapy. Patients with fulminant colitis progressing to systemic toxicity require emergent surgical intervention. The mortality rate of emergency surgery performed in patients with CDc is 35%and higher survival rates are observed in patients managed in dedicated surgical units. Predictors of mortality include age > 70 years, severe leukocytosis or leukopenia (white blood cell count, ≥ 35,000/μL or < 4000/μL) or bandemia (neutrophil bands, ≥ 10%), cardiorespiratory failure, thrombocytopenia (platelet count < 150 × 100/mm 3 ), coagulopathy (international normalized ratio > 2.0), and renal insufficiency (blood urea nitrogen > 40 mg/dL). The effects of a short period of medical optimization before colectomy in improving outcomes are debated. At present, no clinical and/or laboratory findings exist able to predict neither who will improve with medical therapy nor who needs surgery. The timing of surgical intervention is the most important factor influencing survival. Subtotal colectomy is the intervention of choice and is superior to partial or segmental colectomy or other surgical procedures. Diverting loop ileostomy with antegrade colonic lavage with vancomycin may be a colon-preserving alternative to subtotal colectomy with good results regarding morbidity and mortality. Intestinal tuberculosis (TB) is one of the most common abdominal diseases in IP, especially in low resource settings. Its diagnosis is generally difficult and may be based on local epidemiology. It may affect almost any intracavitary organ and has nonspecific symptoms in the majority of cases. Presentation symptoms and signs are generally aspecific: fever (75%), abdominal pain (65%), and weight loss (36%) had a higher prevalence than the other ones. The most frequent imaging findings are lymph-nodal disease (23%), gastrointestinal tract (19%), and solid organs (10%) involvement. In the gastrointestinal tract, the terminal ileum and the ileocecal region are the most affected (50%). Liver and spleen show greater involvement among solid organs (70%). Peritoneal tuberculosis is the most common form of abdominal tuberculosis and includes the peritoneal cavity, the mesentery, and the omentum. Free or loculated ascites can be present in 30-100% of cases and tomographic density is variable , depending on the stage of the disease. Only 3% of patients have the dry type of tuberculosis peritonitis. Multiple mesenteric lymph nodes with peripheric enhancement and central hypodensity can be seen and aid in the diagnosis. The presence of lipohydric level, in association with necrotic lymph nodes, is highly specific for tuberculous ascites. Abdominal TB is generally characterized by three main presentations associated with several less specific symptoms: the ascitic, the plastic (which causes intestinal obstruction), and the glandular presentation (which involves the mesenteric nodules). Less commonly, it may be possible to observe tuberculous strictures, nodules, fistulae, or an interconnected association of these manifestations. Generally, CT scan is not sufficiently sensible or specific. Test for purified protein derivative is usually negative in IP. Additionally, up to 85% of patients with abdominal TB will not have any form of pulmonary involvement. Differential diagnosis is fundamental in defining the presence of abdominal TB in IC. Treatment of intestinal TB is mainly medical. In case of complication as perforation, the treatment of choice seem to be resection and anastomosis more than direct suture of the perforation. ## Common acute abdominal infections in transplanted patients In transplanted patients, the epidemiology of acute surgical diseases varies, with gallbladder disease being one of the most common problems after heart and/or lung transplantation and intestinal perforation due to diverticulitis being the most common disease following kidney and liver transplants (GoR moderate based on intermediate LoE). Up to 30 % of transplanted patients frequently present to the ED with abdominal pain as the first complaint, but only 10% of them will require emergency surgery. It is essential to consider the time from initiation of immunosuppressant therapy with the onset of abdominal pain. In fact, the longer the time from initiation of immunosuppressant therapy, the milder the signs and symptoms of the abdominal disease may be. Several common medical conditions may be responsible for infectious diseases in transplanted patients mimicking acute abdomen. The timeline from the transplantation and consequent initiation of immunosuppressive therapy may help in narrowing the differential diagnosi s. During the first month after transplantation, suspicion should be highest for nosocomial infections related to the hospital stay and surgery. Incision cellulitis, intraabdominal abscess, fungal infection, urinary tract infection, hospital-acquired/ventilator-associated pneumonia, Clostridioides difficile, or bacteremia secondary to central line placement should be ruled out. During months 1 to 6 after transplantation, generally, the patient undergoes the greatest immunosuppression, and this timeframe is at the highest risk for opportunistic infections. Acute viral infections, such as CMV and bacterial infections similar to those discussed below for HIV-related acute abdominal conditions, may all be present in post-transplant patients during this time. After six months from the transplantation, variability in the immune response is observed in this group of patients. For those requiring low-dose antirejection therapy, the risk of infection presenting as abdominal pain is similar to immunocompetent patients. Patients requiring a more intensive antirejection regimen continue to have a higher risk for opportunistic infections. In general, abdominal pain and fever were the most common presentation. Conversely, leukocytosis was absent in 65% of these patients than 33% of immunocompetent ones. ## Acute cholecystitis Statements are as follows: Laparoscopic cholecystectomy is feasible and should be Acute cholecystitis (AC) clinical signs such as pain in the right upper quadrant, temperature > 38°C, and elevation in bilirubin levels have been reported up to 65%, 26%, and 10% of patients, respectively. Ultrasound signs of AC are present in up to 87% of patients. Acalculous AC accounts for up to 40% of cases, with a higher percentage concerning the general population. White blood cell count alteration occurred in almost 55% of patients, with C-reactive protein elevation in nearly 68% of cases. AC frequently occurs after heart, lung, and kidney transplantation. The incidence is up to 72.2% after heart transplant and up to 30% after kidney transplant. A large study evaluated 1687 heart transplant recipients undergoing cholecystectomy. 72.2% of patients had AC and were admitted urgently/emergently in the 60.9% of cases. Overall postoperative mortality was 2.2%. Open cholecystectomy was associated to higher morbidity and mortality compared to laparoscopic (6.2% vs. 0.9%; P = 0.009) as well urgent/emergent cases compared to elective cases (3.6% vs. 0%; P = 0.04). Acute posttransplantation urgent operation for acute complications of the biliary tract are associated to a mortality rate up to 29%. Among 1595 renal transplant patients, 31 underwent laparoscopic cholecystectomy for AC with a conversion rate of 32.3%. Severe cholecystitis (empyema, phlegmon, or gangrene) was pathologically confirmed in 15 patients (48.4%). Acalculous AC was observed in 13 cases (41.9%). Overall morbidity was 19.4%. Surgical complications occurred in 12.9% of cases, with the need for reoperation in 2 patients (6.5%). There was no compromise of kidney function postoperatively. One graft was lost due to postoperative sequelae. Prophylactic cholecystectomy before subsequent KT showed a mortality and morbidity rate of 0% and 12.5%, respectively. Patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) are susceptible to infections, leading to increased morbidity and mortality. Acute cholecystitis is very common. Acute cholecystitis diagnosis is often delayed in the HSCT population because transplant patients are prone to multiple hepatobiliary complications with similar clinical presentations. The typical signs of infection may be masked by immune and marrow suppression. In the HSCT population, cholecystitis development was associated with an increased 1year overall mortality rate (62.5% versus 19.8%, P < .001). Twenty cases of acute cholecystitis (62.5%) were treated with cholecystectom y. ## Acute appendicitis ## Statements are as follows: There is no data to recommend conservative treatment of acute appendicitis in transplanted patients. Given the high rate of complicated appendicitis and the good clinical outcomes observed after surgical intervention, operative management may be considered safer (GoR weak based on low LoE). Transplanted patients with acute appendicitis should undergo appendectomy as soon as possible and usually within 24 h from the diagnosis (GoR moderate based on intermediate LoE). Laparoscopic appendectomy should be preferred whenever feasible and not contraindicated (GoR moderate based on intermediate LoE). The majority of patients had clinical symptoms and a suggestive CT scan, but only 25% of them showed leukocytosis. 8.2% of patients had complicated AA with perforation. IC patients with AA may show symptoms similar to the immunocompetent population, such as nausea/vomiting and fever along with right lower quadrant (RLQ) pain, but different laboratory pattern. Fortythree percent up to 76% of transplanted patients with AA had leukocytosis, fever, or migrating pain, but all patients had elevated CRP. Sarici et al.conducted a case-control matched analysis confirming the incongruence in laboratory findings among transplanted patients with AA compared with nonimmunocompromised patients. They found that LT patients with AA had median WBC count of 7.500 cells/ mm 3 vs. 12.500 in non-transplanted patients (p = 0.002) while CRP was 6.1 mg/dl vs. 0.8 (p = 0.009). In liver transplanted patients, cumulative incidence of AA ranges from 0.09 to 0.54%demonstrating the rarity of this pathology in LT. In a recent meta-analysis, AA accounted only for 2% of all emergency surgery in transplanted patients. Jamtani et al. showed as early surgical intervention is mandatory in this population. No differences in outcome exist comparing laparoscopic to the open approach suggesting that laparoscopic appendectomy is feasible. Some series of post-transplantation AA showed a very low rate of perforated appendicitis at the specimen in those patients operated within 24 h from the insurgence of the symptoms. On the other hand, all the patients with perforated AA were operated after a median time of 72 h. Patients who underwent surgical procedures showed a rate of complication ranging around 25%. In kidney transplanted patients, the incidence of AA is low. Leukocytosis is rare in KT patients developing AA, but CRP result generally elevated. Fifty percent of KT patients operated for AA had perforated AA and then resulted in a longer hospital stay. Those who had complicated AA experienced generally a longer time from diagnosis to surgical intervention than patients who had acute non-complicated appendicitis (overall time to surgery 69 h vs. 25 h p < 0.05). ## Acute diverticulitis Statements are as follows: Acute left side colonic diverticulitis is associated with increased mortality in immunocompromised patients. Accurate diagnosis and follow-up are mandatory in this cohort of patients (GoR moderate based on intermediate LoE). Kidney and liver transplanted patients, as well as patients on immunosuppressant drugs (chronic steroid/ immunosuppressant therapy), have higher incidence and higher severity of acute colonic diverticulitis compared to the general population (GoR moderate based on intermediate LoE The incidence of acute colonic diverticulitis (AD) in transplanted ranges around 1-2%. It is wrongly thought to be even higher in patients with adult polycystic kidney disease (ADPKD), where colonic diverticula are often present and could be in a non-conventional location (e.g., 39% of colonic diverticula in ADPKD were located in the right colon). Transplant patients have a 22-fold higher risk of experience complicate AD compared to the overall populationand generally develop it at a younger age (54 vs. 61 years p = 0.02). Patients with a known diverticular disease before transplantation have a 16% risk of developing AD after transplantation and the start of immunosuppression. Usually, diverticulitis episodes in transplanted patients occur early after transplantation, the most of them within 2 years. The rate of surgical intervention for AD in the general population ranges from 14 to 39%, in transplanted patients, is up to 94% of patients admitted for AD. Reported overall morbidity and mortality rates after emergency surgery for AD in the general population are up to 24% and 5.7%, while in transplanted patients are up to 51% and 23% respectively. Among IC admitted for left colonic AD and divided according to the cause of immunosuppression (steroids, transplant, cancer, etc.), the highest rate of immediate emergency surgery was observed in patients on chronic steroid therapy. In general, patients rarely present with generalized peritoneal irritation signs; patients with free peritoneal perforation can manifest little or no abdominal symptoms and less severe leukocytosis. Up to 61% of TP needing admission for AD present complicated disease (45% for perforation and 16% colo-vesical or colo-vaginal fistula). General population with complicated AD varies from 14 to 19%. In transplanted patients, elective sigmoidectomy may be considered after the first episode of AD, given the high morbidity and mortality rate when emergency surgery is required. Biondo et al., in a series of 931 patients with AD, found that 22.9% of them underwent emergency surgery ad first admission. IC patients had a more severe presentation (48.2% vs. 37.3% p < 0.009) compared with non-IC and resulted in a higher rate of upfront surgical treatment (31% vs. 21% p = 0.004). Of the 239 patients who underwent emergency surgery, 48 died, 33% in the IC group vs 15.9% (P = 0.004); fatality rate for patient treated conservatively was 3.5% vs. 1% (p = 0.03). Klarenbeek et al. evaluated 291 patients to differentiate those who may benefit from elective surgery after nonoperative management of an AD episode. Eightyeight patients (30.2%) experienced recurrence after the first episode of AD. The mortality rate was 13%, with patients with perforation accounting for 80% of the deaths. Perforation was more common among those on immunosuppressant therapy (95% were on steroids), chronic renal failure, and collagen vascular disease. For this reason, elective sigmoidectomy in this population should be considered. The need for elective sigmoidectomy after a successfully treated episode of acute uncomplicated diverticulitis in IC patients ranges between 20.7 and 30.2% of patientsAD recurrence rate varies from in 21.5 to 27.8% in IC patients and 13 to 20.5% of non-IC. When recurrence occurred, it was more severe in the IC group (46% of IC vs. 15% in non-IC group). However, most cases (66.7%) were mild, and 7.1% of recurrence needed emergency surgery, similarly to the general population. Elective sigmoidectomy (IC and non-IC) showed a mortality and morbidity of 0% and 17% respectively with no differences between the two groups. Among kidney transplant (KT) patients, Catena et al. analyzed 1611 patients in 31 years and found 47 gastrointestinal perforations (prevalence 2.9%); 21 were colonic, and 90% of these occurred in ADPKD patients. In general, half of all perforations happened within the first year after KT, when immunosuppressant drug doses are higher. The association of immunosuppressants and corticosteroids increases the risk of developing complicated AD. Hospital mortality for KT patients who experience AD can be very high, ranging from 19 to 100%. Mortality is influenced by the timing of intervention with patients operated on < 24 h from symptoms beginning showing better outcomes. A series of 1137 kidney transplant patients reported complicated AD in 46% of ADPKD patients with a rate of emergency surgical intervention of 52.9%. The rate of complicated AD was higher in ADPK D compared with non-PKD patients (5.6% vs. 0.68%). Opposite results were also published. Elective sigmoidectomy in patients with ADPKD before kidney transplant should consider the incidence of AD, which ranges between 0.9 and 1.25%. In some studies, the mortality rate of kidney transplant patients operated on for AD is 0%therefore, the "on-demand" strategy seems to be safer. Lastly, patients who are candidates for living donor kidney transplants have never been assessed for this topic. The choice between Hartmann's procedure (HP) and resection and primary anastomosis (RPA) with or without protective loop ileostomy is debated even in non-IC patients. However, some recent evidence favors RPA over HP in hemodynamically stable patients. Dalla Valle et al. reported resection and primary anastomosis for two KT patients with AD experienced uneventful recovery; they had a 12.5% rate of mortality in a patient who underwent Hartmann procedure (HP). Scotti et al., on the other hand, had 0% mortality, and every patient that needed surgical intervention had a Hartmann procedure. Biondo et al. reported that IC patients operated on during the first AD episode underwent an anastomosis less frequently than those considered immunocompetent (27 vs. 64% p < 0.001). This could be explained by a higher number of Hinchey III/IV patients in the IC group (65 % vs. 40% p ≤ .001). # Other transplant-related diseases Small bowel lymphoma may occur in up to 46% of patients with AIDS or transplanted patients on a high dose of immunosuppressant drugs and may cause gastrointestinal perforation or bleeding. Moreover, Kaposi sarcoma (KS) or intestinal lymphoma may lead to intussusception, abdominal obstruction, and acute abdomen. When KS presents as intra-abdominal disease, usually there are also skin manifestations. Bright contrast enhancement of lymph nodes at CT can help diagnose KS; the presence of this sign has a positive predictive value of 79%. Up to 50% of intestinal perforation in patients with a kidney transplant occurs in the first three months from the transplant. Graft-versus-host disease (GVHD) more frequently develops in patients after allogeneic bone marrow transplantation; up to 20% of patients with GVHD will develop a gastrointestinal emergency such as perforation or hemorrhage. Abdominal pain as the presenting symptom is atypical. The skin and gastrointestinal tract are the most commonly affected areas. Generally, within 2 to 6 weeks after the transplant, skin rash with diarrhea or less frequently associated with abdominal pain should raise suspicions. In the last decade, the medical literature has been unclear if the high mortality observed in patients with HIV infection or AIDS derives from the inability of this susceptible population to tolerate emergent surgical interventions or whether the natural course of the disease leads to higher mortality rates. For this reason, knowing the HIV status of emergency surgery patients is essential, and testing should be rapidly available. The initial data on mortality and morbidity of HIV/AIDS patients undergoing surgical intervention was obtained mixing HIV-infected and AIDS patients, leading to a misperception and wrong approaches to surgical intervention in HIV patients. More recent evidence shows that HIV patients with early infection or in early stages (e.g., CD4 > 500 and absence of AIDSdefining infections) have the same operative risk as HIV-negative patients and should therefore be treated accordingly. ## Patients with hiv/aids Patients affected by AIDS admitted to ED for acute abdominal pain are a diagnostic challenge with a large spectrum of possible diagnoses. Surgeons must discriminate between HIV-infected patients with an unrelated surgical disease and abdominal conditions primarily related to HIV/AIDS. Abdominal tuberculosis is frequently seen as a co-infection. In general, the presence of an AIDS-related disease requiring surgical exploration increases morbidity, and the mortality risk for emergency surgery rises from 15 to 45%. Owotade et al.showed that up to 25% of HIV patients would require some form of surgical intervention, either elective or emergent. It could be even more significant in a country where HIV is endemic: in a single center in Durban, South Africa, the seropositivity rate for HIV on 350 patients admitted to the surgical ward was 39%. Anyway, when surgery or invasive procedures are needed, one must consider the elevated rate of postoperative complications that are more frequent in patients with low CD4 count or high viral load. Deneve et al., in a study on 77 patients with HIV/AIDS, found that 55% had at least one postoperative complication. There was a 30% mortality rate; patients with lower CD4 count (< 200 cells/mm 3 ) had a higher risk for emergency surgical intervention and experienced higher morbidity and mortality rates. Grubert et al.compared a cohort of HIVinfected women with their un-infected matched respective undergoing an abdominal surgical procedure to assess postoperative complication rates. They found that HIV-infected cases are more prone to experience infectious postoperative complications (fever > 48 h requiring antibiotic treatment (12% vs. 1.7%, OR 8.1 p < 0.001)). Morrison et al.compared two cohorts, one of more than 1300 patients with HIV and another of HIVnegative patients, both admitted for trauma. The death rate was higher in HIV patients than HIV-negative but without reaching significance (5.6% vs. 4.6% p = 0.84). After stratifying for age and ISS, it appears that HIV status did not affect mortality in any subclass except for patients older than 65 years (mortality in HIV+ 15.6% versus 8.5% in HIV− p = 0.001). Unfortunately, this work did not consider HIV infection severity, AIDS status or CD4 count, and viral load. In patients undergoing antiretroviral therapy (ART), the mortality and morbidity rate after surgical intervention is lower than observed in HIV+ patients not undergoing ART. It is mainly influenced by the efficacy of the therapy that affects CD4 count. King Jr. et al. demonstrated comparable morbidity and mortality rate after surgical intervention in patients undergoing ART and with a CD4 count > 200 cells/mm 3. Sandler et al. analyzed a large series of patients undergoing emergency surgery. Their propensity score analysis compared HIV-positive patients without AIDS, AIDS patients, and HIV-negative patients. HIV-positive patients without AIDS had the same outcomes as HIVnegative patients. AIDS is the only factor influencing the prognosis. Mortality rates were 4.4%, 0.5%, and 1.6% for AIDS patients, HIV-infected patients, and HIV-negative patients. HIV-positive patients without AIDS showed lower mortality because they are usually younger without other comorbidities. HIV-negative patients undergoing emergency surgery in this cohort were older, with more comorbidities. The PRO-HIV study confirmed these results. They reported an overall "adverse surgical outcome" identified by death or major infective complication of 6.6% in HIV-positive patients (mostly on ART therapy at the time of surgery). Urinary tract infections, pneumonia, and surgical site infections were the most frequent infective complications. Thirteen percent of blood cultures resulted positive in patients with postoperative fever. Highly active antiretroviral therapy (HAART), along with current therapeutic options, improved the outcome of HIV patients after surgery. However, ART administration is per osand patients undergoing emergency surgery are often in a nihil per os state, and pathology affecting the GI tract can impair intestinal absorption of ART drugs. For these reasons, it was argued if the absence of ART administration could increase the viral load, decrease CD4 count, and increase postoperative complications in HIV patients. Intravenous Albuvirtide may be an alternative in patients candidates for emergency surgery in which ART therapy cannot be initiated postoperatively. ## Perioperative steroid management Statements are as follows: In patients currently on steroid therapy or that have been in steroid therapy for the last year, there is no evidence regarding the necessity of the administration of a push-dose steroid in the event of a surgical intervention (GoR moderate based on intermediate LoE). No sufficient data exist to suggest the suspension of steroid medication before emergency surgery. Patients on steroids should remain on their usual regimen, and the treating physician should be aware of a higher rate of surgical complications when planning the intervention (GoR moderate based on low LoE). In the event of an inexplicable and fluid unresponsive hypotensive event immediately prior/after/during surgery, adrenal insufficiency should be part of the differential diagnosis and an i.v. push dose of 100 mg hydrocortisone should be administered (GoR moderate based on low LoE). Chronic steroid therapy (CST) is considered 20 mg/ day prednisone or equivalent for at least 3 weeks. High corticosteroid doses have been routinely administered perioperatively as "push dose" (or stress dose) to patients on long-term steroid therapy. No evidence exist supporting this practice. Recent reports concluded that "push-dose steroids" are not needed as long as the patient on high-dose chronic steroid therapy continues to assume their usual dosage. Perioperative stress steroid dose, however, is frequently used by anesthesiologists to reduce and prevent such dramatic effects in the postoperative period. The most followed practical recommendation is to administer 200 to 300 mg of hydrocortisone during surgery. Evidence supporting this practice is insufficient. Friedman et al.demonstrated the capability to increase endogenous steroid production in response to surgical stress patients on high doses of chronic steroids before orthopedic procedures. The recent approach is not to administer a push dose of steroid perioperatively in patients with a low probability of hypothalamic-pituitary-adrenal axis (HPA) suppression. In case of hypotension related to the adrenal crisis in the perioperative period (or during surgery), a push dose of 100 mg hydrocortisone is administered, followed by a continued supplement of 50 mg hydrocortisone q6h. At present, in some centers, for patients with documented or presumed (from high dosage chronic therapy) HPA suppression, perioperative stress-dose steroid administration is still utilized even in the absence of high-quality evidence since it appears to carry minimal risk compared to the risk of adrenal crisis. It has to be noted that although testing of the HPA can reveal an adrenal insufficiency, it does not directly predict the possibility of perioperative hypotension or clinical manifestation and therefore should not guide treatment. Zaghiyan et al.randomly assigned patients on chronic steroids or treated with steroids during the previous year who were going to major surgery. No differences in postural hypotension or adrenal insufficiency were seen between those receiving high-dose glucocorticoids (hydrocortisone 100 mg intravenously three times daily) and low-dose glucocorticoids (the equivalent of their preoperative dose given intravenously). Steroid therapy is a well-known cause of augmented morbidity and mortality among surgical patients. In some cases, complications could be severe, such as an anastomotic leak or dehiscence. The rate of anastomotic leak in patients on chronic steroid therapy is up to 6.2%, versus 3.3% observed in elective colonic surgery. In patients with ulcerative colitis undergoing complex reconstructive procedures, the use of diverting ileostomy in patients taking a preoperatively high dose of steroids is broadly accepted. Chouairi et al.in a multicenter retrospective analysis with more than 180,000 patients on CST comparedwith a propensity score-matched analysisoutcomes of surgical patients with and without CST. The CST population showed a longer hospital stay and a higher complication, reintervention, readmission, and mortality rate. Ritter et al.analyzed 686 patients affected by ulcerative colitis undergoing complex reconstructive procedures. 4.2% had an anastomotic leak. In the "leak" group, 34% of patients had oral steroid taper after surgery vs. 14% in the "non-leak" group (p = 0.003). No effect on complication was noted when analyzing preoperative steroid therapy or IV taper immediately after surgery. Slieker et al. in a prospective cohort study of 259 patients on steroids undergoing left-sided colorectal anastomosis, had a 7-fold increase in the risk of developing an anastomotic leak, with a 15% mortality if steroid therapy is ongoing, independently from the presence of a diverting stoma. Intraoperative hypotension that cannot be adequately managed by conservative means (e.g., decreasing depth of anesthesia, fluid resuscitation, vasopressor administration, and managing metabolic abnormalities) should raise suspicion for adrenal crisis, and a rescue dose of 100 mg of hydrocortisone IV should be administered, followed by continued supplementation of 50 mg of hydrocortisone IV every 6 h. Often, there is no time to consider preoperative testing to determine HPAA integrity. Clinical judgment is required whether to administer stress-dose steroids based on the patient's perioperative condition (e.g., degree of hemodynamic stability) and surgical risk. It is reasonable, for example, to withhold glucocorticoids if the patient is otherwise healthy and stable preoperatively without signs or symptoms of Cushing disease, with a low threshold for administration of a rescue dose of steroids in the event of unexplained intra-or postoperative hypotension. Hydrocortisone is the drug of choice for stress and rescue dose steroid coverage. Growing body of data suggests administration of dexamethasone instead, having no mineralocorticoid activity and probably the same protective effect in short course. ## Perioperative and anesthesiologic management Immunocompromised patients should be considered "frail". They are exposed to an increased risk of complications. Perioperative care of IC patients requires a deep understanding of immune system function and pharmacological implications. Multidisciplinary management is crucial. No definitive data exist about anesthetic drugs' effect on the immune system. However, anesthesiologists and ICU physicians must be aware of the immunosuppressive effects of the different drugs and procedures as listed in. In HIV-positive patients under general anesthesia, pharmacokinetic interactions of antiretroviral therapy with cytochrome 450 enzyme should be considered. Drugs like etomidate, atracurium, remifentanil, and desflurane can be safely used as their metabolism is independent of the cytochrome 450 enzyme. In the group of non-depolarizing drugs, it is preferable to use agents independent of kidney and liver function (cisatracurium, atracurium) or with a reversal medication (sugammadex). Patients receiving cyclosporine as immunosuppressive therapy may require a smaller dose of non-depolarizing muscle relaxant, and the recovery time may be prolonged. Strict precautions on infection prevention should be applied. Whenever possible, Cytomegalovirus status should be checked. Even in the case of emergent procedures, a complete preoperative assessment including cardiopulmonary status, glomerular filtration rate, liver function, blood gas analyses, bleeding risk assessment, and electrocardiography monitoring throughout the whole surgical procedure is strongly suggested. Patients should be promptly covered and actively warmed upon arrival in the operating room; even mild hypothermia has been shown to disrupt clotting and increase postoperative infection rates. Specific attention must be posed on patients with primary immunodeficiency syndromes as Ig infusion must be considered. The dose of immunosuppressive drugs in transplanted patients should be continued postoperatively. Daily monitoring of the steady-state blood level is recommended. # Conclusions The management of immunocompromised patients with acute abdomen must be multidisciplinary. Appropriate recognition and stratification of this particular cohort of patients with its proper risks and clinical peculiarities allow setting the correct diagnostic and therapeutic pathways as management should be individualized.	None	https://wjes.biomedcentral.com/counter/pdf/10.1186/s13017-021-00380-1	None
1c1ce5ffff3a42dd324c4564881d3a3e3694ec0e	pubmed	Guidelines for laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal Hernia [International Endohernia Society (IEHS)]	Guidelines for laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal Hernia [International Endohernia Society (IEHS)] # Introduction Governments and health insurers increasingly demand transparent quality-control mechanisms. A new type of reimbursement, ''pay for performance,'' is being discussed. Therefore, the development and implementation of guidelines constitutes an important step toward the introduction of optimal diagnostic and therapeutic concepts with the goal of improving the quality of treatment. Guidelines should define standards to help the surgeon in his or her daily work by finding the best surgical strategy for his patient. The Guidelines are essentially evidence-based (Evidence-Based Medicine, EBM) but also allow use of ''eminence''-based statements in a critical way. Already 200 years ago, P.Ch.A. Louis postulated: ''Thus, a therapeutic agent cannot be employed with any discrimination or probability of success in a given case, unless its general efficacy, in analogous cases, has been previously ascertained; therefore I conceive that without the aid of statistics nothing like real medicine is possible.'' Opponents of EBM argue that, in view of the uniqueness of the patient, clinical studies are of little value. However, despite these criticisms, it is generally accepted today that classifications, rules, laws, and scientific theories cannot be developed without identifying the common features of large patient populations or diseases; variety in itself warrants statistical methods. To answer specific questions in a particular case, the surgeon should be able to draw from pertinent, high-quality, well-documented biometric studies to choose the most appropriate therapy for his patient. However, because the studies often suffer from methodical flaws, especially from the heterogeneity of data, it needs caution and deep clinical experience when applying results of EBM to an individual case, even if elaborate meta-analytic techniques have been developed to allow for a differential evaluation of the study results. The authors of the following guidelines are aware of these problems and are conscious of the responsibility that they undertake when describing the scientific state-of-theart in laparoscopic/endoscopic inguinal hernia repair according to the best external evidence available and when making recommendations for the individual case. Inguinal hernia repair is the most frequent operation in general and visceral surgery worldwide. In the western countries, including the United States, more than 1.5 millions procedures are performed every year. Thus, hernia repair not only affects the individual patient but also has a significant socioeconomic relevance and an important impact on the costs for the health care system. During the third meeting of the network International Endohernia Society (IEHS) held in Stuttgart, January 2008, live demonstrations of hernia repair performed by ten surgeons from four continents showed that guidelines for standardization of operative technique, especially regarding teaching, are urgently needed. This prompted a discussion about this challenge, which was pursued during the meeting of AHS in Scottsdale/Arizona, 2008, with the attendance of R. Fitzgibbons, M. Arregui, F. Köckerling, and P. Chowbey. The need for guidelines was unanimously acknowledged but with a focus on technique and special problems in transabdominal preperitoneal patch plasty (TAPP) and total extraperitoneal patch plasty (TEP). The authors were aware that some overlapping or interference with the EHS Guidelines was not completely avoidable but should be limited as far as possible. Regarding this problem, the authors appreciate the valuable contributions that M. Miserez gave during the past year. We started the guideline development process in June 2008 by collecting the most important questions and assembling the most qualified experts in laparoscopic hernia repair. An inviting letter was sent to all well-known laparoscopic hernia specialists who have made outstanding contributions to hernia surgery published in peer-review journals to participate in a Consensus Conference organized for February 2009 in Delhi by P. Chowbey. The following questions were asked: 1. Are you willing to participate? 2. Are you interested in an active participation? In your opinion what are the most important questions in endoscopic hernia surgery? (e.g., TAPP or TEP, to fix or not to fix, etc.). 4. Are you (you can create a working group) ready to answer one of these questions according to the literature and your own data? Thus, you are able to give a recommendation at the conference. 5. If yes, please inform us about the topic you want to look for. On the basis of the answers received, 14 topics were identified as most important and 14 surgeons declared their willingness to draft the respective guideline. In a second step, the experts were asked to: (1) search the literature regarding the topic at hand, and (2) graduation of the papers according to the Oxford hierarchy of evidence (following the advice of Dr. S. Sauerland) as outlined below consisting of the following five levels: However, there often is a need to upgrade or downgrade a recommendation, because the outcome is so important or the clinical preference is so strong. This is possible but needs to be explained in the commentary text, and (4) Prepare a paper to present at the Consensus Conference in Delhi. In Delhi (Consensus Conference and fourth meeting of the International Endohernia Society (IEHS), February , the papers were discussed first in the round of experts and one day later during the plenary session attended by several hundreds of participants. During the following months, the authors drafted the first version of their specific chapter, including all the suggestions they had received during the conference. These first versions had been sent to our biometric advisor, Dr. S. Sauerland, for review and then were distributed to all the other experts for critics, remarks, and supplements. During these weeks, countless mails and revisions of papers were exchanged to achieve definitive guidelines that all experts could agree upon. In addition, two meetings that brought together most of the authors and the steering committee took place in September 2009 during the AHS/EHS/APHS meeting in Berlin and in December 2009 in Stuttgart respectively. The guidelines focus on technique and perioperative management of laparoscopic/endoscopic inguinal hernia repair. They are not intended as competing alternatives to the EHS guidelines, although there is some overlap, especially regarding risk factors for pain and selection of mesh. The advantages of the guidelines presented here are: (1) Papers published until 01.02.2009 could be included, therefore, literature used here is more up to date; (2) The authors come from Europe, America, and Asia; therefore, the guidelines are, effectively, global; (3) The authors use the Oxford hierarchy of evidence comprising five levels; thus, big case series could be included, all together giving a more realistic representation of generally used practice. Steering Committee Prof. Reinhard Bittner, MD. Professor of Surgery, Dr.h.c. mult., FRCS; visceral surgeon, em. Director, ## Antibiotic prophylaxis Antibiotic prophylaxis in inguinal hernia surgery is controversial. The overall infection rate is low, with a mean value of 1-4% . An infectious rate\2% is regarded as a clean operation. Repair for inguinal hernia is a highvolume operation. Antibiotic prophylaxis may reduce wound infection rates with an impact on patients' satisfaction, wound care, and sick leave, but it also involves risks of toxic, allergic side effects, bacterial resistance, and higher costs. There also has been a discussion on risk factors used to select the best candidates for antibiotic prophylaxis. Age [75 years, obesity, and urinary catheter were heavy risk factors for global infectious complications in one study . Other known risk factors for infectious complications are hernia recurrence, diabetes, immunosuppressant, corticosteroid usage, and malignancy. RCT studies as well as systematic reviews and metaanalyses on antibiotic prophylaxis versus placebo were identified. To analyze the wound infection rate in a large population, the Swedish National Hernia register was searched for the years 1992-2006 . The five largest RCTs between open and laparoscopic hernia repair, having wound infection as a secondary endpoint, also were analyzed , as well as large case series reporting on antibiotic prophylaxis and infectious complications. A total of five systematic reviews or meta-analyses comparing antibiotic prophylaxis versus placebo were identified. Sanchez-Manuel and Seco-Gil reported in the Cochrane Database system in 2004 and updated the results in 2007 . Three different systematic reviews and meta-analyses were performed in 2005, 2006, and 2007 . Almost the same studies are referred to in these publications adding some new references each time. A total of 12 randomized studies are presented in the latest Cochrane Publication , involving only open surgery. Until now, a total of 14 RCTs comparing antibiotic prophylaxis versus placebo in inguinal hernia surgery were identified, of which there was only 1 about laparoscopic repair and the remaining were about open repair [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref]. The endoscopic RCT by Schwetling and Bärlehner has an incorrect randomization, lacks a definition of wound infection, and is heavily underpowered with only 40 patients in each arm. It does not allow any conclusions to be made and is not included in the Cochrane review. In the remaining studies on open hernia repair, a total of 4,128 patients are included in the latest report from the Cochrane database by Sanchez-Manuel and Seco-Gil . The wound infection rate was 2.9% in the prophylaxis group and 3.9% in the nonprophylaxis group with no statistical difference. There is a huge variation in infection rate between the studies both in the prophylaxis group (0-8.8%) and nonprophylaxis group (0-8.9%). A subgroup analysis between no mesh and mesh was performed. In the no-mesh group, an infection rate of 3.5% was seen in the prophylaxis and 4.9% in the placebo with no statistical difference. In the mesh group, the infection rate was 1.4% in the prophylaxis and 2.9% in the placebo, also with no statistical difference. Only one further randomized, controlled study on open hernia surgery has been presented after the latest Cochrane report [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref]. Wound infection is registered as a secondary endpoint in large RCTs on laparoscopic versus There is insufficient evidence for routine antibiotic prophylaxis in laparoscopic hernia surgery. Level 5 There is insufficient evidence for routine thromboembolic prophylaxis in laparoscopic hernia surgery. Grade D Antibiotic prophylaxis for elective laparoscopic inguinal hernia repair cannot be universally recommended. Grade D It is recommended that antibiotic prophylaxis should be considered in the presence of risk factors for wound and mesh infection based on patient (advanced age, corticosteroid usage, immunosuppressive conditions and therapy, obesity, diabetes, and malignancy) or surgical complications (contamination, long operation time, drainage, urinary catheter). Grade D It is recommended that thromboembolic prophylaxis is given according to usual routines in patients with risk factors. open operation, but only two of five mention antibiotic prophylaxis [fig_ref] Table 2: Details of visceral and vascular injuries from non-randomized studies of TAPP and... [/fig_ref]. The infection rate varies between 0-2.8% in the laparoscopic group and 0. in the open group. There are significantly more infections reported in the open group in one study, whereas all other studies show no difference between groups, including the two studies that report the administration of antibiotics. Five TAPP case series, including more than 1,000 patients each, reported on wound and/or mesh infections . Four studies are from the same institution. Antibiotic prophylaxis was given to all patients and commented about in only one study . No large TEP series was identified. Schmedt et al. reported 0.07% infections in 4188 unilateral TAPP procedures and 0% in 1,336 bilateral procedures. Kapiris et al. reported 0.11% mesh infections in 3,017 patients, and Leibl et al. reported 3 cases (0.001%) in 2,700 patients. Bittner et al. reported 0.1% mesh infections and 0% wound infections in 8,050 TAPP procedures in a total of 6,479 patients. The Swedish National Inguinal Hernia Register recorded the wound infections between 1992 and 2006. The incidence was 1.4% in 28,220 patients recorded to have received antibiotic prophylaxis. The infection rate also was 1.4% in the nonprophylactic group, consisting of 104,354 patients . There is no specific analysis on the laparoscopic patients representing approximately 8% of the patients who underwent surgery. Pessaux et al. has converted predictive risk factors for infection, such as age older than 75 years, obesity, and urinary catheter, into a global infection complication score. Low-risk patients had an infection rate of 2.7% and highrisk patients of 14.3% (p \ 0.001) . ## Thromboembolic prophylaxis Because thromboembolic complications have been very rarely reported after inguinal hernia surgery, there has been a heated debate about whether thromboembolic prophylaxis is needed at all in the absence of risk factors. Moreover, the laparoscopic techniques might involve risks from altered venous flow due to pneumoperitoneum and the Trendelenburg position. No RCT or case-controlled studies about laparoscopic versus open hernia repair or case series were identified on thromboembolic prophylaxis. To analyze the current practice in thromboembolic prophylaxis for inguinal hernias in the United Kingdom, 200 questionnaires were sent to endoscopic surgeons of Great Britain with a respondent's rate of 72%. Risk stratification was 10% for laparoscopic and 14% for open procedures . In one case-controlled study on laparoscopic cholecystectomy in 569 patients where only 18 patients received DVT prophylaxis, a postoperative clinical control showed no symptoms of DVT or pulmonary embolism . An expert opinion discussing pros and cons for thromboembolic prophylaxis also has been published . References (in parentheses graduation of evidence) # Introduction The learning curve of TAPP groin hernia repair is longer than in open procedures. To facilitate teaching and learning, it is necessary to analyze and structure the procedure and emphasize the importance of various surgical steps for the success of the treatment. The standardization of specific steps, which are supported by evidence-based principles or by positive experience reports, should help to reproduce the best achievable results. Several RCTs and prospective clinical studies have demonstrated that TAPP repair has a strong potential for achieving patient-oriented positive outcomes . However, other studies have shown that, despite using a ''similar'' technique, the expected results could not be reached . The reason for the obvious differences of published results seems to be the individual interpretation of the surgical technique and its performance. Therefore, strict standardization of the technique according to the best available evidence is recommended. # Results EBM data on technical key points of TAPP repair per se are not available and are not expected due to the complexity of the whole procedure (heterogeneity and importance of the particular technical steps). Therefore, the TAPP procedure was divided into several parts (phases), and each is evaluated separately. ## Preparation of the patient Is preoperative bladder emptying of importance? When is the urinary bladder catheter recommended? Statements ## Recommendations Full urinary bladder can increase substantially the technical difficulty of TAPP repair . To diminish the risk of bladder injury, the bladder should be emptied before surgery. Predisposing factors for an injury are a full bladder or a previous exposure of the retropubic space particularly after prostate interventions, irradiation, or TAPP (see . An early stage of the learning curve in endoscopic hernia repair might be another reason . With adequate experience, TAPP is a safe procedure even after radical prostatectomy . The incidence of urinary retention was 0.37% (33/8,991 patients) with local anaesthesia, 2.42% (150/6,191 patients) with regional anaesthesia, and 3.0% (344/11,471 patients) with general anesthesia . The inhibitory effect of general anaesthesia on bladder function would explain the increased incidence of postoperative urinary retention. The volume of intravenous postoperative fluid administered is a significant risk factor for urinary retention . Urinary retention prolongs hospitalization and predisposes the patient to urinary tract infection. Atony of the bladder results from unrecognized overdistension of the bladder and consequent damage to the detrusor muscle. With increasing emphasis on cost-effectiveness and early discharge of patients, the avoidance of urinary retention is of utmost importance (see . Preperitoneal placement of mesh with the TEP technique was found not to cause urinary retention by outflow obstruction or alteration of the bladder contractility . In a report of 8,050 TAPP repairs from Bittner et al., the incidence of urinary retention is very low at 0.5% . This may be due to the patient being imperatively ordered to evacuate his/her urinary bladder just before being brought to the operating room, short operating times, and very restrictive fluid administration by anesthesiologists. Perioperative catheterisation of urinary bladder is very rarely necessary. Grade D It is recommended that the patient empty his/her bladder before the operation. Grade D Restrictive per-and postoperative intravenous fluid administration reduces the risk of postoperative urinary retention. Grade D If you expect technical difficulties (e.g., after prostatic surgery, scrotal hernia) or an extended operating time, consider using a urinary catheter during the intervention. Does preoperative hair removal increase the risk of surgical site infection (SSIs)? Statements ## Recommendations Specific studies in hernia surgery are not available, but studies in general surgery have demonstrated no difference in SSIs among patients who have had hair removed before surgery and those who have not . Clipping results in fewer SSIs than razor shaving using a razor. Three trials involving 3,193 people compared shaving with clipping and found that there were statistically significantly more SSIs when hair is shaved rather than clipped (relative risk (RR), 2.02; 95% confidence interval (CI), 1.21-3.36) . There is insufficient evidence regarding depilatory cream compared with razor shaving. Three trials involving 625 people compared hair removal using depilatory cream or razors with no hair removal and found no statistically significant difference between the groups in terms of surgical site infections. Seven trials involving 1,420 people compared shaving with removing hair using a depilatory cream but found no statistically significant difference between the two groups in SSI rates . There is no difference in SSIs when hair is shaved or clipped 1 day before surgery or on the day of surgery . A significant drawback of these studies is that the evidence does not derive from studies in laparoscopic hernia repair. Information before surgery Statements ## Recommendations The informed consent of the patient is an important part of any surgical act. The patient must be provided with information not only on the details of the procedure or on the different operative methods but also be informed of the possibility of a negative outcome . Correct information helps to prevent unfulfilled expectations. Unexpected bilaterality is reported in 10-25% . Up to 28.6% of these patients will progress to a symptomatic hernia within 1 year . ## Establishing pneumoperitoneum Which is the safest and most effective method of establishing pneumoperitoneum and obtaining access to the abdominal cavity? Statements ## Recommendations To create pneumoperitoneum to gain access to the abdominal cavity has a risk of injury. The safest and most efficient method of access is still controversial. There are four ways to obtain access to the abdominal cavity: (1) Open access (Hasson); (2) Veress needle to create pneumoperitoneum and trocar insertion without visual control; (3) Direct trocar insertion (without previous pneumoperitoneum); and (4) Visual entry with or without previous gas insufflation. ## Level 2b Chronic pain may develop after inguinal hernia repair. In a significant number of cases, unsuspected hernias are found on the contralateral side at surgery. Grade 1A There is no evidence for a difference in surgical site infections SSI between hair removal or no removal before surgery. Grade 1A Shaving causes significantly more SSIs than hair clipping. Grade 1A There is no difference in SSIs when hair is shaved or clipped 1 day before surgery or on the day of surgery. Among general surgeons and gynecologists, the most popular method is the Veress needle . To increase the safety and minimize the morbidity of this method, several safety tests were proposed by Semm . The literature does not always support the use of these tests because they provide very little useful information on the placement of the needle . The intraperitoneal pressure initially induced by the gas insufflations seems to be more important to control the correct placement of the Veress needle . If the pressure is initially higher than 2-3 mmHg, then the needle is not placed correctly. Therefore, it might not be necessary to perform various safety checks when inserting the Veress needle, but their routine use may still remind the surgeon of the risk of injury involved in this procedure; however, waggling of the Veress needle from side to side must be avoided, because this can enlarge a 1.6-mm puncture injury to an injury of up to 1 cm in viscera or blood vessels . The angle of the Veress needle insertion should vary according to the BMI of the patient: from 45 degrees in nonobese to 90 degrees in obese patients. Although the open approach seems to be the safest, it does not eliminate the entire risk of injury (Level 2C). In 12,919 cases, its morbidity was in 12,919 cases: Hasson 0.09%, Veress ? first trocar 0.18% and optical trocar 0.29%. When using open approach palpation through the peritoneal aperture, to exclude adhesions is mandatory before inserting a blunt canula . There is no evidence that the open entry technique is superior or inferior to the other entry techniques currently available. One RCT recommends open access as a standard for laparoscopic operations, but the number of only randomized 50 patients is too small to allow definite conclusions . There is an upcoming trend to direct trocar insertion without previous gas insufflation . The benefit, it is argued, is to diminish the potential morbidity of the Veress needle and to create pneumoperitoneum faster. The new designs of blunt tip trocars promise to decrease the number of minor injuries (subcutaneous, preperitoneal gas insufflation, needle tip injuries intra-and retroperitoneally) while maintaining the incidence of major injuries equally low as the Veress needle. Direct insertion of the trocar is associated with less insufflation-related complications, such as gas embolism, and faster than the Veress needle technique. The visual entry trocars may offer an advantage over traditional trocars, because they allow a clear optical entry, but this advantage has not been fully explored. They also minimize the size of the entry wound and reduce the force necessary for insertion, but they are not superior to other trocars because they do not avoid visceral and vascular injury. The 2002 EAES clinical practice guideline on the pneumoperitoneum did not make any strong recommendation favoring one technique over the other ; however, the use of either technique may have advantages in specific patient subgroups (Recommendation B). A systematic review of the safety and effectiveness of methods used to establish pneumoperitoneum in laparoscopic surgery (2003) could not demonstrate any significant difference to support one method of choice . The method of approach has to be adapted to patient's condition in case of expected increased risk of injury (BMI, previous surgery, position of scars, suspicion of adhesions, etc.). Implementation of the available evidence should optimize the decision-making process in choosing a particular technique to enter the abdomen during laparoscopy . After an unsuccessful attempt in the umbilical region, preferably with safety tests or having a high intraperitoneal pressure when starting gas insufflations , ''Palmer's'' point in left hypochondrium can be chosen . If in any doubt, the Hasson approach is recommended. The use of visual entry trocars outside of potential danger areas may increase the safety of trocar insertion. Trocar choice, placement and positioning What kind of trocars should be used? Is there any relation between trocar type and risk of injury and/or trocar hernias? Statements ## Recommendations # Discussion Instrumentation has improved to the point that the principles of minimally invasive surgery can be put into practice. The design of dilating instead of cutting trocars contributed significantly to decrease the risk of port-site bleeding and development of port-site hernias [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref]. Bittner et al. found significant differences in incidence of trocarrelated parietal hemorrhage (cutting trocar 1.76 vs. 0.056% conical trocar, p [ 0.0001) and incidence of trocar hernias (cutting trocar 1.27 vs. 0.037% conical trocar, p [ 0.0001) . The equal effect on incisional pain of both trocar types found in patients after laparoscopic cholecystectomy is no reason to continue to cutting trocars . In TAPP, three trocars are usually placed at the umbilical level (optic and two working ports); all working ports are inserted under direct vision. The parietal, intraabdominal, and retroperitoneal vascular injuries are preventable Level 1B The radially dilating trocars cause less acute injuries (bleeding at trocar site) and less chronic tissue damage (trocar hernias). Level 2B Visual entry trocars are not superior to other trocars, because they do not avoid visceral and vascular injury. Level 2B The visual entry cannula trocars have the advantage of minimizing the size of the entry wound and reducing the force necessary for insertion under visual control. Grade A Cutting trocars should be avoided. with good anatomical orientation and cautious pressurecontrolled trocar insertion. The optimal trocar positioning respects the rules of triangulation to facilitate and improve the workflow ergonomics. Consider the proximity of bony structures as potential inhibitors of instrumentation freedom. Assessment of defect, contralateral site, exploration of abdominal cavity Is clinical examination of hernias efficient enough? What is the role of TAPP and other techniques in reliable assessment? # Statements ## Recommendations The accuracy of a clinical groin examination is limited. The incidence of occult contralateral hernia found at the time of unilateral hernia repair using TAPP or TEP is up to 25% . For definitive proof of the presence of a hernia, the sensitivity of ultrasound is clearly higher than a mere physical examination. The final and definitive classification of hernias can only be made intraoperatively; at best, the results of an ultrasound examination can help to orientate the surgeon. The TAPP enables rapid assessment . In conventional hernia surgery or with the total extraperitoneal (TEP) method, this kind of evaluation is impossible or at least problematic. In case of a missing hernia sac, most cord lipomas can be visualized when external pressure is applied over the groin. When no hernia is found in patients with strong hernia suspicion (positive clinical examination, positive ultrasound finding), the preperitoneal exploration is still indicated to rule out other pathologies of inguinal canal or preperitoneal lipomas in the femoral canal. A significant proportion of incidental defects will progress to a symptomatic hernia if left untreated (28% within 15 months). Therefore, incidental hernias should be simultaneously repaired if the patient has agreed ; 11% of clinically unrecognized hernias were repaired at the time of surgery. TAPP herniorrhaphy is beneficial to avoid unnecessary explorations and allow timely repairs in patients with occult inguinal hernias [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref]. Although the reported incidence of chronic pain after TAPP repair is very low, the simultaneous repair of the healthy contralateral groin ''in advance'' is not justified unless a ''significant collagen deficiency'' is suspected. Anatomical landmarks, peritoneal incision, extent of dissection Statements ## Recommendations In the majority of cases, the anatomical points of primary orientation are visible or demonstrable by external palpation: the medial umbilical ligament (MUL), the lower epigastric vessels (the lateral umbilical ligament), the deep (inner) inguinal ring, the anterior superior iliac spine (ASIS), and the spermatic structures (vas deferens and spermatic vessels) or the round ligament. The other important structures (secondary orientation) become visible during the preperitoneal dissection: the ileopubic tract, the symphysis pubis, Cooper's ligament, and the femoral canal. In case of local omental or intestinal adhesions to the peritoneum of the groin, it is not recommended to perform adhesiolysis in general, unless it obstructs the overview. In sliding hernias or even irreducible hernias, neither adhesiolysis nor reduction is mandatory, but the straightforward preperitoneal dissection should be performed. This facilitates the mobilization of hernia content within the sac and helps to avoid intestinal injury. In strangulated hernias, the preperitoneal dissection allows to visualize the safe position of a relaxing incision of the hernia ring if necessary . ## Surgical strategy No studies have compared different positions of the patient and the operating table or the positioning of the surgeons. However, there is a general agreement that the patient is kept in the supine position on the operating table, which is in head-down position during the operation and slightly (approximately 15°) turned toward the surgeon . The operating surgeon and the camera assistant stay on opposite sides of the hernia. 1. The peritoneal incision is placed 3-4 cm above all possible defects from ASIS to MUL (not vice versa ER, PE), which does not have to be transected. If more space is needed, a cranial extension of the peritoneal incision parallel to MUL may be helpful. 2. A complete anatomical dissection of the whole pelvic floor is necessary for a flat and wrinkle-free placement of the mesh. 3. The extent of dissection reaches medially 1-2 cm beyond the symphysis pubis to the contralateral side, cranially 3-4 cm above the transversalis arch or any direct defect, laterally to ASIS, and caudally minimally 4-5 cm below the ileopubic tract at the level of psoas muscle and 2-3 cm below the Cooper's ligament at the level of superior arch of the pubic bone. 4. The resulting preperitoneal space has to accommodate a mesh of adequate size (at least 10 9 15 cm 2 ) (PE). 5. The level of the dissection plane within the avascular ''spin-web'' space between the internal and external layer of peritoneum is crucial. The objective is to retract all peritoneal sack and corresponding pre-, extra-, and retroperitoneal fat tissue from the hernia orifices down to the middle of psoas muscle (=parietalization) . The preservation of the spermatic fascia and of the lumbar fascia protects the fragile parietal structures (vas deferens, vessels and the nerves) [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref]. # Indirect hernias statements ## Recommendations Large and/or deep indirect sacs may prolong the operating time, but complete retraction is possible in almost every case. Delicate dissection and ongoing control of hemostasis do not increase the incidence of scrotal hematoseromas [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] but eliminate the formation of chronic seroma/pseudo-hydrocele. The transection of a difficult indirect sac was suggested to prevent possible damage to the spermatic cord and decrease the incidence of scrotal hematomas. Bittner et al. reported low rates of orchitis (0.1%) and testicular atrophy (0.05%) despite nearly always complete reduction of the sack. In difficult conditions, in the presence of large and deep sacs, after temporary strangulations or in complicated recurrences, the following strategy is recommended: identify the spermatic vessels far latero-caudally first before starting the dissection along the vessels towards the inguinal canal and to the top of the indirect sac. In this manner, damage to the spermatic vessels can be safely prevented . Quite often, substantial funicular lipomas or pre-/or retroperitoneal fat prolapse into the enlarged hernia orifices ring [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref] [bib_ref] Sportsman's hernia, Moeller [/bib_ref] [bib_ref] Groin injuries in athletes, Morelli [/bib_ref] [bib_ref] Athletic pubalgia and ''sports hernia'': optimal MR imaging technique and findings, Omar [/bib_ref]. They should be retracted and eventually resected, because they may become symptomatic or mimic a recurrent hernia [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref]. An overlooked lipoma is one of the known reasons for ''recurrence'' [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref]. Although the published data provide low evidence, the search for and exclusion of such masses is integral part of the endoscopic hernia repair [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref]. # Direct hernias statements Recommendations A prospective nonrandomized study demonstrates significantly lower incidence of postoperative seromas in the group of patients with direct hernias and transversalis fascia inversion, without increase of postoperative pain despite the use of invasive fixation with tacks to the Level 2C Cord lipomas or lipomas in the femoral canal may imitate primary hernia, hernia recurrence, or become symptomatic in later course. Complete reduction of the hernia sac does not increase the incidence of sero-hematomas if careful dissection and control of hemostasis are done. Level 5 Complete reduction of the hernia sac may eliminate the occurrence of chronic seroma/''pseudo-hydrocele.'' Grade B Lipomas of spermatic cord/round ligament and the preperitoneal lipomas of direct and femoral sacs should be removed. Grade D In case of unclear anatomy, first identify spermatic vessels. Level 2B The incidence of seromas in direct hernias can be significantly reduced when the lax transversalis fascia is inverted. Level 2C Seroma is a common early postoperative minor complication in endoscopic preperitoneal hernia repair. ## Grade b In voluminous direct hernias, the extended transversalis fascia should be inverted. Grade D If dense adhesions to the cord structures are present in a long hernia sac, the sac may be exceptionally transected at the level of inner inguinal ring to prevent injury. Cooper's ligament [bib_ref] Groin injuries: a true challenge in orthopaedic sports medicine, Renstroem [/bib_ref]. In some expert reports, fixation with sutures is recommended as a less expensive alternative. A cautious use of superficial electrocoagulation to obliterate blood, and lymphatic vessels, also has been suggested to reduce seroma formation . Mesh choice, mesh size, mesh slit, mesh fixation The mesh issues (type, size, slited/nonslited, and fixation) are technical key points of paramount importance. The details will be analyzed and discussed in another chapter. # Peritoneal closure statements ## Recommendations The bowel obstruction can develop due to adhesions between omentum or epiploic appendices and suture line, between the mesh and the intestines, e.g., by inadequate closure of a peritoneal lesion [bib_ref] Adductor-related groin pain in competitive athletes. Role of adductor enthesis, magnetic resonance..., Schilders [/bib_ref] [bib_ref] Long-term followup of laparoscopic preperitoneal hernia repair in professional athletes, Srinivasan [/bib_ref] [bib_ref] Surgery for posterior inguinal wall deficiency in athletes, Steele [/bib_ref]. The peritoneal opening must be thoroughly closed to prevent contact of viscera with the prosthetic mesh material and to reduce the risk of bowel obstruction. The closure can be achieved with staples, tacks, running suture, or glue. These last two methods are more time-consuming but less painful (see Chap. 9). Rare cases of bowel obstruction in port-site hernias also have been described, especially after TAPP. The reduction of intra-abdominal pressure (e.g., 8 mmHg or less) facilitates the peritoneal closure during the running suture, especially in difficult cases . Several anecdotic reports on small-bowel obstruction both in TAPP and TEP repairs have been published [bib_ref] Laparoscopic repair of ''sportsman's hernia'' in soccer players as treatment of chronic..., Susmallian [/bib_ref] [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. The data from Swedish National Inguinal Hernia Register show higher incidence of late postoperative bowel obstruction after TAPP than after TEP [bib_ref] Adductor-related groin pain in competitive athletes. Role of adductor enthesis, magnetic resonance..., Schilders [/bib_ref]. Theoretically, the deep indirect sacs could cause internal hernia. Therefore, the author closes the internal orifice of the sac to eliminate the incarceration risk (author's personal experience). # Port-site closure statements Recommendations Port-site hernia is a late postoperative complication predominantly reported in TAPP repair. Although, according to general opinion, only 10 mm and bigger trocar site defects should be closed, the development of incisional hernia with consequences was described even with 3-5-mm trocars [bib_ref] Abdominal musculature abnormalities as a cause of groin pain in athletes. Inguinal..., Taylor [/bib_ref] [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref] [bib_ref] Outcome of conservative management of athletic chronic groin injury diagnosed as pubic..., Verrall [/bib_ref] [bib_ref] Incidence of pubic bone marrow oedema in Australian rules football players: relation..., Verrall [/bib_ref] [bib_ref] Groin pain in athletes from Southern Sweden, Westlin [/bib_ref] [bib_ref] The value of herniography in football players with obscure groin pain, Yilmazlar [/bib_ref] [bib_ref] Transabdominal preperitoneal laparoscopic approach for the treatment of sportsman's hernia, Ziprin [/bib_ref]. A review of 63 reports (24 case reports, 27 original articles, 7 technical notes, and 5 review articles) was published in 2004 [bib_ref] ) any question, costs are an important issue. Several studies attempted to..., Ziprin [/bib_ref]. The evidence level of these reports varies from 1 to 3. Recommendation B concerns the closure of trocars of 10 mm or bigger. A difference should be made between the periumbilical closure and the closure of the working ports. Again, it should be differentiated according the defects through the rectus muscle and through the weaker oblique abdominal wall. A pre-existent umbilical hernia/weakness must be treated like a primary hernia (author's personal experience). It is the author's opinion that it is important to close the peritoneum in lateral working ports C10 mm, because trocar hernias do not occur in TEP (peritoneum under working ports remains intact) (PE). # Pain control statements Recommendations Efficient pain control after hernia repair is a pillar of success. A significant reduction of postoperative pain through preemptive use of Bupivacaine was described in TEP . Such effect was not reported in TAPP yet, although routine infiltration of the wound after hernia repair provides extra pain control and limits the use of analgesics. Additional use of local anesthetics positively influences postoperative pain in TAPP. Infiltration of trocar wounds with long-acting local anesthetic in TAPP Incomplete peritoneal closure or its breakdown in endoscopic preperitoneal hernia repair increases the risk of bowel obstruction. Level 3 TAPP procedure presents a higher statistical risk of small-bowel obstruction than TEP. Level 5 The most appropriate peritoneal closure is achieved by running absorbable suture. Level 5 Running suture seems to cause less pain compared with clip/tack closure. Level 5 The closure of entrance of indirect sacs may reduce the risk of internal hernia with consecutive incarceration, strangulation, or small-bowel obstruction. Grade C A thorough closure of peritoneal incision or peritoneal tears should be done. ## Grade d The peritoneal closure can be accomplished by running suture. Level 3 Use of 10-mm trocars or larger may predispose to hernias, especially in the umbilical region or in the oblique abdominal wall. Grade C Trocar sites with fascial defects of 10 mm or larger can be closed. Level 5 Additional use of local anaesthetic positively influences postoperative pain in TEP and TAPP. Infiltration of trocar wounds with long-acting local anaesthetic in TAPP improves patient's well-being and accelerates return to ambulation. Grade D To improve postoperative pain control, trocar wounds can be infiltrated by local anesthetics. improves patient's well-being and accelerates return to ambulation (PE). ## Conclusion on technical key points in tapp repair The multitude of data published on this subject presents different levels of evidence, but particular technical key points are well investigated . Some expert opinions lack supporting data, but some steps of the TAPP technique are clearly supported by strong levels of evidence. The grade of recommendations varies from A to D. The proven technical key points should become the pillars of the standardized TAPP repair, transferred to the wide surgical community and emphasized in the teaching and learning environment to guarantee the best possible outcomes. References (in parentheses graduation of evidence) , and References 1-7. ## Positioning of patient and surgeons recommendation No studies have compared different positions of the patient and the operating table or the positioning of the surgeons. However, there is a general agreement that the patient is kept in the supine position on the operating table, which is in head-down position during the operation and slightly (approximately 15°) turned toward the surgeon. The operating surgeon and the camera assistant stay on opposite sides of the hernias . ## Preperitoneal access What is the most popular mode of accessing the preperitoneal space? # Statements ## Recommendations Direct access with Hassan trocar has been popularized by many and is used by Ferzli et al. , McKernan and Laws , Chowbey , Garg et al. , and Köckerling . The suprapubic Veress needle technique requires the placement of Veress needle in the space of Retzius followed by carbon dioxide insufflation and direct trocar placement. In this method, it is difficult to place the Veress needle correctly and the working space is initially narrow. The transperitoneal visualization technique of Philip requires creation of pneumoperitoneum and subsequently a preperitoneal blister is raised using 0.5% Bupivacaine followed by direct trocar placement in the preperitoneal space. This also has been used by Arregui and Young . The disadvantage of this technique is the addition of complications inherent to a transperitoneal approach, such as bowel injury and port site hernia. The presence of pneumoperitoneum may compromise the extraperitoneal space. ## Space creation Which technique of space creation best achieves the required extraperitoneal space? Statements ## Recommendations Balloon dissection is the most commonly used method to create extraperitoneal space . There are commercially available balloons as well as low-cost indigenous balloons, such as the ones used by Chowbey in which two cut fingers stalls of an 8-size glove are applied over a suction-irrigation cannula and tied with silk. Similar techniques and minor variations thereof have been used by different authors . A randomized, prospective, multicenter study showed that a dissection balloon made the dissection of preperitoneal space easier and safer, thus reducing operative time, conversion rate, and number of complications . Blunt probe dissection under vision with a 10-mm zerodegree operative scope with a 5-mm working channel was described by . Direct telescopic dissection has been described by McKernan and used in many centers across the globe . Modifications to the technique of balloon dissection are needed for patients with previous lower abdominal surgery. The balloon is distended much less than in those without previous surgery and away from the scar site to prevent tearing of scar tissues and thereby decreasing the potential for tearing of bowel, bladder, or peritoneum . Furthermore, balloon dissection has a major disadvantage in patients who have a linea alba that extends to the pubic symphysis. In these patients, the balloon will dissect one The patient is kept in the supine position. Level 5 The operating surgeon and the camera assistant stay on opposite sides of the hernias. Level 4 Direct open access is a simple and reproducible technique for accessing the preperitoneal space. Access by transperitoneal visualization is an alternative but is associated with the risks of entering the peritoneal cavity. Suprapubic Veress needle technique also is used by few surgeons. Grade D Direct access with the Hasson trocar via a 1-2-cm subumbilical incision on the side of hernia and opening of the rectus sheath, enlargement of the space between the rectus muscle and the posterior sheath. Level 1B Balloon dissection is associated with significantly reduced postoperative pain at 6 h, scrotal edema, and seroma formation compared with telescopic dissection. At 3 months follow-up, balloon dissection did not offer significant advantage over direct telescopic dissection. The use of a dissection balloon in TEP reduces the conversion rate and may be especially beneficial early in the learning curve. The technique of balloon dissection provides adequate extraperitoneal space creation and is evolving as a method of choice; indigenous balloons contribute to cost-effectiveness. Dissection with the telescope is another frequently used method. Anatomical delineation of inguinal area and dissection in the extraperitoneal space in TEP repair was equally satisfactory in both the balloon dissection and the telescope dissection group. Grade A Balloon dissection should be considered for extraperitoneal space creation, especially during the learning period, when it is difficult to find the correct plane in the preperitoneal space. Surg Endosc (2011) 25:2773-2843 2791 side of the preperitoneal space posterior to the epigastric vessels and may cause bleeding . ## The role of needlescopic tep statements ## Recommendations In the past, needlescopic TEP was difficult because the instruments were not strong enough to allow sufficient dissection of the hernia sac, especially of the indirect sac; however, new technical developments have eliminated this problem . ## Ports How does port positioning contribute to the technique of TEP repair? Statements ## Recommendations Three ports are required, of which the camera port is constant and is a 10-mm subumbilical port. The two working ports are variable. Both of them may be in the midline as far cephalad as possible from the pubic symphysis. Another option is one midline port below the camera and one lateral port near the anterior superior iliac spine . This port placement gives a better trocar triangulation and makes complete dissection of large lateral hernia sacs easier. Along with the three midline ports, additional ports if required can be placed lateral to the rectus muscle below the linea semicircularis . Caution should be exercised to avoid injury to inferior epigastric vessels during introduction of the lateral trocar . ## Dissection of preperitoneal space What are the limits of dissection and the landmarks to be visualized? Statements ## Recommendations Before any dissection is performed, the pubic tubercle, the iliopubic tract, and Cooper's ligaments must be clearly identified. The complete space medial to the inferior epigastric vessels (Retzius) must be visible, and then the transversus abdominis muscle lateral to the epigastric vessels to the level of anterior superior iliac spine has to be exposed . Wide exposure of preperitoneal space is the key to a good TEP repair . What are the techniques of management of a peritoneal tear during TEP? How can peritoneal tears be prevented and treated? Statements Level 2 B Needlescopic TEP is a safe technique for the repair of inguinal hernia. Postoperative recovery after needlescopic and conventional TEP was similar. Needlescopic TEP conferred a significantly lower pain score upon coughing on the first day after operation. Grade C In patients with a low pain threshold, a needlescopic TEP can be performed. ## Level 5 The midline ports have the advantage of accessing both sides with equal ease and minimal risk of injuries to the inferior epigastric vessels. All three ports made in the midline at the commencement of the procedure enable bimanual dissection right from the start. Another technique of a 10-mm port at the umbilicus, a 5-mm port a few centimeters lower, and another 5-mm trocar laterally near the anterior-superior iliac spine is the next alternative. Overlapping mesh in the midline is thought to be easier with this technique. Lateral ports, two in number, just lateral to the rectus muscle, used along with a midline camera port are an option. Grade D Two alternatives for the trocar placement: two 5-mm working ports in the midline, and in the midway between the camera port and the pubic symphysis. Alternatively, the second working trocar (5 or 10 mm) can be placed after lateral dissection approximately 3-4 cm superior and 1-2 cm anterior to the anterosuperior iliac spine. Lateral working trocars are favored when mesh overlap over the midline is perceived to be difficult. Level 3 The dissection should extend superiorly up to the subumbilical area, inferiorly to the space of Retzius, inferolaterally to the psoas muscle and Bogros space until spina iliaca anterior superior is reached, and medially beyond the midline. The landmarks to be visualized are the pubic bone, Cooper's ligament, inferior epigastric vessels, cord structures, the myopectineal orifice boundaries, and the fascia over psoas muscle. Posteriorly, the peritoneum is reflected to the point of which the vas turns medially. Level 4 Extensive preperitoneal dissection with complete exposure of the myopectineal orifice of Fruchaud is critical to the success of the laparoscopic inguinal hernia repair. Grade B Complete parietalization of the vas deferens and the testicular vessels needs to be performed. Complete dissection of the whole pelvic floor (anatomical) should be done for flat placement of the mesh to cover the entire myopectineal orifice and prevent its folding. Level 3 The incidence of peritoneal tear is 47%. Techniques for the closure of a peritoneal opening include pretied suture, loop ligation, endoscopic stapling, and endoscopic suturing. To decrease the potential for peritoneal tear, the balloon dissection is modified. Less volume of saline is used for inflation; the balloon is sited away from the scar. Careful dissection in close proximity to the vas deferens and adhesions, in addition to cautious use of traction and counter traction, associated with prudent application of sharp dissection with endo-scissors to divide adhesions can help to prevent peritoneal laceration. ## Recommendations Peritoneal tear is the most common reason for conversion and predisposes patients to small-bowel adhesions and internal herniation. The mesh is no longer securely buttressed between the abdominal wall and retroperitoneum by intra-abdominal pressure and becomes susceptible to migration when not stapled. Hence, closure of the defect is preferred . Difficulty in reaching the pubis by the balloon dissector is associated with an increased risk of peritoneal tear . In a randomized multicentric trial, a 24% incidence of peritoneal tears was found, but loss of pneumopreperitoneum occurred only in 7%, which required switching to another technique . In a study of 107 consecutive TEP repairs , it was found that no peritoneal tear was noticed in two patients with previous laparotomy scars and 17 patients with previous hernia repair scars after balloon dissection of preperitoneal space. However, minor peritoneal tears resulted in a few cases during dissection and retraction of the hernial sac. None of the peritoneal defects in these few cases were closed. Shpitz et al. found no perioperative or postoperative complications related to these tears . In a prospective study of 400 patients with a total of 588 inguinal hernias, tiny peritoneal defects occurred in 13% of the hernias, which were closed in most cases with a running endoclip suture. Various methods of closure include loop ligation, pretied suture, endoscopic stapling, and endoscopic suturing . How best can injury to the urinary bladder and epigastric vessels be avoided? Urinary bladder injury (see Chap. 11, Fitzgibbons) Statements ## Recommendations Injury to the bladder was seen in 8 of 3,868 patients who underwent surgery during a 7.5-year period, the majority of whom had previously undergone suprapubic catheterization . ## Inferior epigastric artery injury statements ## Recommendations Correct plane of dissection is important to prevent inferior epigastric vessel injury . Bleeding is usually controlled endoscopically . Dissection of hernia sacs Direct sac How should a large direct sac be handled? Statements ## Recommendations The direct hernial sac is the first structure to be reduced starting from midline laterally, medial to the inferior epigastric vessels. The fundus was separated from the redundant fascia transversalis, which gives the appearance of a reverse sac and then pulled down . The defect may be enlarged or a releasing incision given when the hernia is incarcerated . A prospective, nonrandomized study demonstrates significantly lower incidence of postoperative seromas in the Grade D It is recommended that peritoneal tears be closed whenever feasible to prevent adhesions. ## Level 3 In patients who have previously undergone lower abdominal surgery or suprapubic catheterization, injury to the bladder is the most common major complication of TEP (0.06-0.3%). Recognized intraoperatively bladder injuries may be managed endoscopically. Grade C Utmost caution to prevent a bladder injury is necessary in a patient with previous lower abdominal surgery and a high index of suspicion to recognize one intraoperatively and manage if it were to occur. Level 3 Plane should be developed with inferior epigastric vessels anteriorly and the cord structures posteriorly. In 2.75%, bleeding from epigastric branches, vessels on the pubic bone or testicular vessels can occur. Level 4 Inferior epigastric vessels were ligated in 3%, because they blocked the view of the surgeon. Inferior epigastric vessel injury occurred in 0.4% of patients during trocar insertion. Grade C Dissection should be performed in the plane posterior to the inferior epigastric vessels, because they are prone to injury when they drop down and also obstruct the view of the surgeon. Level 2B In large direct hernias, inversion and fixation of the extended fascia transversalis to Cooper's ligament may reduce the frequency of occurrence of serohematoma. Level 3 Direct Hernias are already largely reduced by inflation of the balloon, through the wall of which the whitish enlarged fascia transversalis can be seen overlapping the Cooper's ligament. Seroma formation seems to be more common after repair of direct hernia with significantly enlarged transversalis fascia. In an incarcerated hernia, the opening of the defect may be enlarged to allow safe dissection of its contents. A releasing incision is made of the anteromedial aspect of the defect to avoid injury to epigastric or iliac vessels. Grade B The direct sac should be inverted and anchored to Cooper's ligament to decrease the risk of seroma and external hematoma formation. Grade D In incarcerated direct hernias, the opening of the defect may be enlarged or an anteromedial releasing incision may be used. group of patients with direct hernias and transversalis fascia inversion, without increase of postoperative pain despite the use of invasive fixation with tacks to the Cooper's ligament . In some expert reports, fixation with sutures is recommended as a less expensive alternative. Indirect sac How should a large indirect sac be handled? Statements ## Recommendations In a case of indirect hernia, lateral to the inferior epigastric vessels, the peritoneal sac is dissected away from the cord structures, both medially and laterally until it is separated completely and then dealt with appropriately . At times, a long indirect sac cannot be completely reduced from the deep inguinal ring and is divided, the peritoneal side being ligated with a laparoscopic suture (see Chap. . Femoral hernia Should occult femoral hernia be looked for and treated? Statements ## Recommendations The high frequency of femoral recurrence after inguinal herniorrhaphy in women argues for the use of endoscopic repair covering both inguinal and femoral orifices simultaneously . Contralateral dissection: how far? Should occult contralateral hernias always be looked for? Statements ## Recommendations Hertz and Holcomb performed a laparoscopic transabdominal exploration before performing a TEP inguinal hernia repair and reported an incidence of incipient contralateral hernias as high as 20%. Laparoscopic TAPP repair allows easy identification of the hernia sacs without any need to dissect the spermatic cord. However, it is accompanied by the risk of visceral adhesions to the mesh and the peritoneal dissection site. TEP eliminates the need to penetrate the abdominal cavity. Skeletonization of the cord to detect an asymptomatic hernia is not necessary and avoiding excessive dissection limits the potential for injuries to vas deferens and spermatic vessel . Tenting of the peritoneum toward the internal ring and inability to visualize the vas warrants further dissection of the cord. The advantage of contralateral exploration is that an unsuspected contralateral inguinal hernia can be diagnosed at the time of initial surgery, and if treated, the patient can avoid reoperation, exposure to a second anesthesia, another period of work loss, and containment of costs to the healthcare system. The disadvantages would be the violation of a virgin space, difficulty in the event of a requirement for surgery at a later date, and the additional time and morbidity associated with the procedure. In the light of this observation, another question arises ''once dissected, is there a need or advantage in placing a contralateral mesh?'' Should a drain be used after a TEP repair? Should seromas be aspirated? Statements ## Recommendations Level 4 Dissection of the indirect hernial sac, for the most part blunt, is performed under exposure of the spermatic cord/ round ligament and all inguino-femoral hernial orifices. Complete dissection of large indirect sacs may carry the risk of an injury of the cord structures or may disturb blood circulation to the testis. Grade C A large indirect sac may be ligated proximally and divided distally. ## Level 2c Women have a higher risk of recurrence after an open inguinal hernia repair operation due to a higher occurrence of overlooked femoral hernia at primary operation. Grade D A preperitoneal endoscopic approach should be considered in female hernia repair. Level 3 The incidence of incipient unsuspected contralateral hernia is 11.2-20%. Laparoscopic hernia repair (TAPP) has a major advantage of allowing the surgeon to explore the site contralateral to the clinically diagnosed hernia without any additional dissection steps. In TEP, the contralateral medial space can be explored easily, but the exploration of the deep inguinal ring may be difficult. ## Grade d The systematic exploration of the contralateral side using the TEP technique is controversial. Further studies are needed. Level 1A Patients who receive anticoagulant are prone to afterbleed. The most frequent early complications are hematomas and seromas (8-22%). The incidence of hematomas is lower for endoscopic (4.2-13.1%) techniques than for open repair (5.6-16%). The risk of seroma formation is higher for endoscopic techniques than for open repairs. Level 1B The use of Fibrin sealant for mesh fixation during bilateral TEP leads to a significant reduction of analgesic consumption but is associated with an increased incidence of postoperative seroma. Level 3 Most seromas disappear spontaneously within 6-8 weeks. Infection after aspiration of seromas is described. Level 5 Perioperative drainage to prevent seromas is contradictory. Grade B It is recommended that wound drains be used only when specifically indicated (large blood loss, coagulopathies). Anticoagulants should be stopped before surgery. Seromas are best not aspirated. Grade D If indicated, a closed suction drain is kept as per the assessed requirements. Incidence of seromas and hematomas are described in various studies . In a study, the author recommends routine use of drain, because release of carbon dioxide pressure is followed by bleeding from tiny capillaries, resulting in unpredictable amount of blood collecting in the preperitoneal space. Avoidance of postoperative hematomas is important to the achievement of a low mesh infection rate and prevention of potential mesh displacement by the collection fluid. Furthermore, drainage also ensures complete deflation and readaptation of the tissue layer . In a multi-institutional retrospective analysis, it was found that local complications, such as hematoma, seroma, and emphysema, were seen most commonly after TEP repair. Fifty-six local complications were found in 457 TEP repairs compared with a total 95 local complications in 1,514 repairs by various endoscopic techniques; the important local complications are hematoma and seroma . In a study of 400 patients who had undergone TEP repair, one patient who received anticoagulant treatment had to undergo endoscopic revision of an afterbleed . ## Preparation and introduction of mesh recommendations No data allow any relevant recommendations. Under absolutely sterile conditions just before introduction, the mesh is prepared to facilitate its introduction into the preperitoneal space and its placement over the myopectineal orifice. The techniques of Felix , Philip , and Chowbey et al. are subtle variations in the preparations of the flat polypropylene mesh. Chowbey recommended cutting the mesh to a size of 15 9 13 cm, rolled superiorinferiorly for approximately two-thirds of its length and fixed with two sutures. This ensures ease of introduction and placement, following which the stitches are cut and the mesh unrolled. Golash rolls the mesh from both the medial and lateral edges. Lal et al. also rolls up the mesh and secures it with two Vicryl ties to introduce it into the preperitoneal space via the 10-mm telescope. Should one or two meshes be used for bilateral hernias? Statements ## Recommendations In a prospective, randomized, controlled trial of 100 patients comparing totally preperitoneal laparoscopic approach and Stoppa procedure (open), the author suggests the use of a large prosthesis rather than two small ones for bilateral hernias to minimize recurrence . Another RCT concurs due to the presence of a weak zone in the midline . A retrospective study [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref] could not find a significant difference between the use one large or two small meshes in the totally extraperitoneal repair for bilateral inguinal hernias. Mesh placement-how much overlap? Is there any scientific basis? Are there cases for fixation? Statements ## Recommendations The scientific basis of mesh overlap has been explained by Hollinsky . The required mesh overlap over the hernial opening is calculated based on the distribution of adhesive force and load on the mesh. In a randomized, controlled trial, a medial overlap of mesh by some 4 cm is advised in direct unilateral hernias to prevent recurrence . How to avoid uprolling of the mesh during desufflation of pneumopreperitoneum? Statements Grade C The mesh should be taken out of its packaging just before introduction under absolutely sterile conditions. Level 1B To treat bilateral hernias, implantation of two meshes overlapping by 1-2 cm in the midline above the pubic symphysis or one large mesh are options. Level 2B The issue stills remain unresolved as to whether two different meshes of adequate size with overlap in the midline or a single large mesh be used to treat bilateral inguinal hernias. After implantation of two meshes, the recurrences detected (direct and bilateral) suggest the presence of a weak zone in themidlinedespitethetwomeshesoverlappinginthemidline. ## Level 3 Implantation of one large mesh seems to be technically more difficult than that of two meshes. Grade C In bilateral hernias, a sufficiently large mesh should be used or two different meshes (e.g., 15 9 13 cm on both sides). ## Level 4/5 Mesh overlapping of less than 2-3 cm may lead to a protrusion of the mesh into the hernia opening. The larger the hernia opening the more overlapping there should be. In large direct defect, danger for protrusion of mesh into the opening is increased. Grade C The minimum distance between the margin of the prosthesis and that of the hernial opening should be equal to the diameter of the opening in hernias of size 2 cm or larger. For smaller lesions (\1-2 cm), a minimum mesh overlap of 2 cm is required. For hernias C4 cm, the prosthesis should be fixed to prevent recurrence. In direct hernia, medial overlapping should be [4 cm. Grade D The mesh should cover without wrinkles all the facial defects in the groin, including Hesselbach's triangle, the indirect ring, the femoral ring, and the obturator ring. ## Level 3 Uprolling of mesh is one main cause for recurrence. Insufficient preperitoneal dissection (parietalization) is the main cause for uprolling of mesh. ## Recommendations With adequate preperitoneal dissection, the mesh is spread out completely and steadied before desufflation [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref]. References (in parentheses graduation of evidence) TEP is more suitable for regional anesthesia. Unsuspected hernias on the contralateral side are easier to detect with TAPP. # Introduction Two revolutions in the inguinal hernia surgery have occurred during the past two decades. The first was the introduction of tension-free open mesh repair (OMR) by Lichtenstein et al. in 1989, which significantly reduced the recurrence rates. The second revolution was the application of laparoscopic surgery in the treatment of inguinal hernia during the early 1990s, which led to decrease in postoperative pain and faster recovery along with low recurrence rates . Ger et al. reported first laparoscopic inguinal hernia repair (LIHR). Schultz et al. were the first to report the use of prosthetic material during laparoscopic inguinal hernia repair. # Discussion There is only one RCT done by Schrenk et al. who compared TAPP and TEP inguinal hernia repairs. The authors found less early postoperative pain after TAPP (p \ 0.02) and a shorter hospital stay than after TEP (p = 0.03), but the number of patients randomized to the two techniques is very small (EBM IIb). The Cochrane database review 2005 concluded that there are insufficient data to draw any significant conclusions regarding what is better TAPP or TEP. Anesthesia consideration LIHR requires general anesthesia and thus cannot be considered if the patient is unfit for this type of anesthesia. Few reports expressed their concern that general anesthesia is too much a procedure for uncomplicated unilateral inguinal hernia in a young patient and advocated OMR under local anesthesia . LIHR should be offered to patients with bilateral and recurrent hernias. We feel that to pass on the advantages of LIHR to patients with bilateral and recurrent hernias, one should be doing LIHR even in uncomplicated unilateral inguinal hernia routinely to overcome the steep learning curve. Sumpf et al. reported another issue related to CO 2 absorption during LIHR which can influence anesthetic management and perioperative morbidity. They observed that TEP group required more minute ventilation (range 9-22.6) than TAPP group (range 7.7-11.5) to maintain normocapnia and concluded that more CO 2 absorption during TEP repair puts the patient with chronic lung disease at risk who might be unable to eliminate excess CO 2 . There are many reports published with variable experiences of TEP repairs performed under regional (1,724 repairs under spinal and 82 under epidural anesthesia. All of the studies concluded that laparoscopic TEP repair under spinal/epidural anesthesia appears to be safe, technically feasible, and an acceptable alternative in patients who are at high risk or unfit for general anesthesia, but the same is not possible for TAPP (EBM IV and V). Results of comparative studies and case series in primary, bilateral/recurrent/incarcerated inguinal hernia: laparoscopic repair (EBM III, IV, V) Comparative studies and large case series [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref] show an overall very low rate of potentially serious adverse events independent of the technique used. Regarding vascular injuries, there is a slight advantage in favor of TAPP series [TAPP 0.25% (35/13,475): TEP 0.42% ]. Conversion rates are lower in TAPP studies. On the other hand, occurrence of visceral injuries, deep mesh infection, and port site hernias rates are in favor of TEP. Most vascular complications were injuries to inferior epigastric vessels and more often in TEP series. Most of the visceral complications were in the form of small bowel and urinary bladder injuries and were slightly more after TAPP repair [fig_ref] Table 2: Details of visceral and vascular injuries from non-randomized studies of TAPP and... [/fig_ref]. We compared overall complication and recurrence rates after TAPP and TEP repairs during the first decade showed acceptable complication and recurrence rates after TEP repair in 3,100 patients. During TAPP repair, there is an advantage of diagnosing and repairing unexpected contralateral hernias in patients with unilateral hernias, which has been reported to occur in 25-50% of patients [bib_ref] Groin injuries in athletes, Morelli [/bib_ref] [bib_ref] Athletic pubalgia and ''sports hernia'': optimal MR imaging technique and findings, Omar [/bib_ref]. The results of our systematic review are to be discussed with caution due to relevant inconsistencies of most of the studies published. Grade B Both techniques are acceptable treatment options for inguinal hernia repair, but there is insufficient data to allow conclusions to be mde about relative effectiveness of TAPP compared with TEP. Grade D In selected patients having a contraindication for general anesthesia, TEP in regional anesthesia can be done. ## Learning curve (ebm iv) McCormack et al. [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref] showed, in an analysis regarding learning of TAPP and TEP for inexperienced surgeons (\20 repairs), an operating time of 70 min for TAPP but 95 min for TEP, and for experienced surgeons (30-100 repairs), 40 min for TAPP and 55 min for TEP respectively, thus indicating that TAPP might be easier to perform, although there is no level 1 evidence to support this belief. ## Cost One of main issues in LIHR is to justify its cost-effectiveness. Greenberg et al. [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] concluded after a systemic review of laparoscopic and open repair of inguinal hernia that a shorter recovery time and shorter off work period after laparoscopic hernia repair could compensate for the increased hospital expenditures. Kapiris et al. reported that the operation expenses can be reduced by eliminating the need for a fixation device. They advocated that fixation of mesh is not required in TAPP repair and advocated suturing of peritoneal flaps with absorbable sutures. They also concluded that hospital cost can be further reduced by doing laparoscopic hernia repair as day-care procedure. Beattie et al. [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] also reported that fixation of mesh is not required in TEP repair and not associated with increased risk of hernia recurrence. Farinas et al. [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] suggested that cost can be significantly reduced by performing TEP repair without balloon dissection using reusable cannulas and other instruments. Misra et al. [bib_ref] Groin injuries: a true challenge in orthopaedic sports medicine, Renstroem [/bib_ref] advocated the use of low-cost indigenous balloon to reduce the cost of TEP repair. In the recently completed RCT (unpublished; clinical trial identifier NCT 00687375), we did not fix the mesh in both the TAPP and the TEP repair. There was no difference in the cost of procedure. No recurrence was noted at mean follow-up of 17 months. [formula] 0 (0/733) 0 (0/382) 0.4 (3/733) 0 (0/382) 0 (0/733) 0 (0/382) 0.8 (6/733) 0 (0/382) 0 (0/733) 1.8 (7/382) Khoury (1995) [16] 0 (0/60) 3 (2/60) 0 (0/60) 0 (0/60) 0 (0/60) 0 (0/60) 1.7 (1/60) 0 (0/60) 0 (0/60) 0 (0/60) [/formula] # Conclusions There are two standardized techniques for laparoscopic groin hernia repair (LIHR): (1) Trans-Abdominal Pre-Peritoneal (TAPP) and (2) Totally Extra-Peritoneal (TEP) repair. There is a paucity of published data with level 1 evidence comparing TAPP versus TEP. There are advantages and disadvantages of both TAPP and TEP procedures. There is no statistically significant difference regarding postoperative complications, particularly recur- ## Recommendations Laparoscopic repair of the scrotal hernia is a controversial subject in laparoscopy, because it implies a large abdominal wall defect and great difficulty in dissecting the extensive hernia sac. Literature on the subject is scant. Ferzli first described laparoscopy for scrotal hernia in 17 patients in 1996. He utilized the TEP method and had no recurrences. In 1999, Leibl addressed the subject of TAPP for the scrotal hernia. He and his colleagues analyzed the results of 191 prospectively studied TAPP repairs for scrotal hernias. They only rarely transected the sac. Operative times were slightly increased compared with normal TAPP repair. Total minor complication rate was 12% for the scrotal repair versus 5% for the normal TAPP repair, with the most common complication being seroma. Major complications were 1.6% for scrotal versus 0.6% for the normal repair. The recurrence rate was 1% . Bittner followed up this data with analysis of 440 scrotal hernias in their large, single-center series of 8,050 TAPP repairs. Overall recurrence for the series was 0.7% but 2.7% for scrotal hernias . Detailed clinical analysis and experimental studies (Hollinsky) show that the higher recurrence rate in some cases of scrotal hernias having a large defect may be due to inadequate overlapping. Other causes for recurrence in these cases may be the use of meshes with less flexural stiffness and insufficient fixation (Hollinsky) . Bittner's overall morbidity was 3.2% and decreased with experience. The scrotal subgroup had a significantly increased rate of sero-hematoma (12.5%), which mandated drainage . Palanivelu also presented a small series of patients using TAPP to repair irreducible scrotal hernias with good results. ## Tapp for incarcerated and strangulated inguinal hernia statements ## Recommendations In 2001, Leibl et al. published the results of 220 prospectively studied acutely (strangulated) and chronically incarcerated inguinal hernia repairs; 194 of these repairs were accomplished via TAPP. There was no difference in operative time comparing laparoscopic and conventional repair; however, the time of operation was significantly longer compared with elective TAPP repair. Recurrence rate for TAPP repairs of incarcerated hernias were low (0.5%) and was similar to conventional open repair of incarcerated hernias. Other complications, including bleeding, mesh infection (0.1%), organ injury, and death, were similarly low or lower. The authors noted that one advantage of the TAPP technique is that it allows assessment of the viability of the bowel. The time needed for hernia repair allows time for the congested bowel to return to normal or not. A comparison to the prelaparoscopic era shows less frequent bowel resections when performing TAPP. Resection can be performed, if needed, after repair of the hernia. Leibl's group has extensive experience with TAPP repair of routine hernia, and he cautions that surgeons must be comfortable with this technique in routine hernias before attempting it on a complex incarcerated hernia. Other smaller case series and case reports have shown the viability of the TAPP technique for incarcerated hernias . The key step to the operation is the reduction of the sac and its contents. The hernia ring can be enlarged (while preventing injury to the femoral or epigastric vessels) through a ventromedial incision in the case of direct hernias and through a ventrolateral incision in the case of reported no recurrences, a single mesh infection that resolved with continuous irrigation, and a midline wound infection after bowel resection. In 2003, Tamme et al. showed the results of a large series of TEP repairs of inguinal hernias. In this group, he includes, but does not detail, repairs performed on strangulated hernias. His overall results demonstrated low rates of recurrence and complications. Among his conclusions is that TEP is particularly advantageous for the treatment of bilateral, recurrent, and strangulated hernias versus open and TAPP repairs. He cites a reduction in postoperative neuralgia versus open repair and a reduction in bowel injury and port site hernia versus TAPP. Saggar and Sarang retrospectively looked at 34 patients (of 286 elective TEP hernia repairs) who underwent repair of chronically incarcerated inguinal hernia using TEP. Recurrence rate was higher for incarcerated versus nonincarcerated hernias (5.8 vs. 0.35%). The recurrences in the incarcerated group (n = 2) occurred during the immediate postoperative period and 2 months postoperatively. Scrotal hematoma and cord induration also were significantly higher in the incarcerated group. He converted the umbilical port to an intraperitoneal port to inspect the bowel when its viability was in question. ## Tapp and tep for incarcerated femoral hernia statements ## Recommendations There are currently no major reports on the use of laparoscopy for the treatment of femoral hernia although case series exist . Watson first reported the use of TAPP for an incarcerated femoral hernia in a 1993 case report. He used a plug and patch and resected the compromised bowel extracorporeally . Yau et al. describe a cohort of eight patients with incarcerated femoral hernias that were repaired laparoscopically by the TAPP technique. The hernia was reduced with atraumatic forceps and, if needed, the lacunar ligament was incised. After opening the preperitoneal space, a Prolene mesh was inserted into the femoral canal and the peritoneum was reapproximated over the repair. The authors opted not to lay mesh over the entire pectineal orifice in the case of an isolated femoral hernia . Rebuffat et al. describes 7 TAPP repairs of strangulated femoral hernias in his series of 28 TAPP repairs for strangulated hernias. Comman et al. wrote a case report of a single patient with an incarcerated femoral Littre's (herniation of a Meckel's diverticulum), which was treated successfully by TAPP repair. The literature on the use of TEP for incarcerated femoral hernia is even sparser than for that of TAPP. Ferzli et al. report one case in his series of TEP for incarcerated inguinal hernias. Laparoscopic inguinal hernia repair in the setting of peritonitis and bowel necrosis Statements ## Recommendations Laparoscopic (TAPP or TEP) repair of an incarcerated hernia should be avoided in the setting of frank peritonitis or if an infected abdominal wall is encountered in association with necrotic bowel during laparoscopic evaluation. Standard surgical principles still dictate that the risks of mesh The conversion rate in the acute setting is high. Recurrence and complication rates are higher than in the nonincarcerated hernia. Level 5 A drawback to the TEP vs. TAPP approach for the strangulated inguinal hernia is that TEP does not allow inspection of the bowel without laparoscopy. Grade C TEP may be used for repair of both incarcerated and strangulated inguinal hernias; however, the data on the subject are scant. Grade D The umbilical port can be converted from a preperitoneal port to an intraperitoneal port to assess bowel viability when it is in question. ## Level 5 There are only few reports of successful treatment of incarcerated femoral hernia. Reduction of hernia contents requires incision of the lacunar ligament. Grade D Incarcerated femoral hernia may be safely repaired via the TAPP or TEP; however, in TEP additional laparoscopy for inspection of the incarcerated hernia content is necessary. Although in some cases a plug repair was done, the general opinion is that a flat mesh having usual size should be inserted. infection and its associated complications (recurrence, draining sinus, and enterocutaneous fistula) are too great and a myofascial repair should be performed . ## Tapp and tep for recurrent inguinal hernia Recurrence of inguinal hernia is a common problem that vexes all general surgeons. Large database studies from Denmark and Sweden demonstrate that reoperation rates after first repair that range from 3.1 to 17% . The re-recurrence rate of inguinal hernia after a repair for recurrence is even higher. Some reports state a re-recurrence rate as high as 33% . The higher re-recurrence rate of inguinal hernia after a prior recurrence results from distortion of the normal anatomy and from the replacement of the fascial strength layer with weaker scar tissue. The potential for reduction of re-recurrence after laparoscopic hernia repair stems from the use of mesh, which, as Lichtenstein demonstrated, reduces tension along the repair, thereby, reducing the rate of recurrence . Just as importantly, the posterior approach of the laparoscopic inguinal hernia repair not only provides the mechanical advantage of an underlay repair but also provides the technical advantage of operating through virgin tissue when performed after prior anterior repair. ## Tapp for recurrent inguinal hernia statements ## Recommendations Review of the literature from 1996 to present on the use of TAPP for repair of recurrent hernia demonstrates overall that TAPP is equal to or has a significantly better profile compared with the Lichtenstein and other open repairs in terms of re-recurrence. This is especially true for the use of TAPP after prior anterior (open) repair. These data include smaller prospective randomized trials, small and large nonrandomized prospective cohorts, and reviews of large, prospective national hernia databases. Several smaller, single-institution studies (Sandbilcher, Felix, Memon) demonstrate good re-recurrence rates for TAPP for recurrence (0.5, 0.6, and 3%, respectively). Ramshaw's large single institution review demonstrated a 2% rerecurrence rate after TAPP for recurrence. Bittner's rerecurrence rate (1.1%) in his large series was no different than his rate of recurrence for primary unilateral or bilateral hernia. The same was true for operation time, complication rate, and time of sick leave. Bisgaard's large prospective study from the Danish national hernia database shows a re-recurrence rate of 1.3% for TAPP repair of recurrent inguinal hernia versus 11.3% for Lichtenstein repair of recurrent inguinal hernia. Dedemadi and Eklund demonstrated improved and equivalent re-recurrence results, respectively, for TAPP versus Lichtenstein. Furthermore, Mahon, Dedemadi, and Eklund found significantly less pain during the early postoperative period. In addition, Mahon reported significantly less chronic pain compared with open mesh repair. These and multiple other studies (most notably, Neumayer) are consistent in the finding that a significant learning curve is associated with the TAPP repair and that TAPP for recurrent hernia should only be attempted by surgeons who are very familiar with the technique [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref]. ## Tep for recurrent inguinal hernia statements recommendations A number of studies have demonstrated that TEP repair of recurrent inguinal hernia is a viable technique that can be done with low re-recurrence and low morbidity. These studies range from case series to data prospectively collected from multicenter and large national hernia databases. They also include one prospective, randomized study with a subset analysis of laparoscopy for recurrent hernia and a prospective, controlled, nonrandomized study looking at TEP versus open repair for recurrence . Conversion rates to open were comparable to conversion rates of repairs for primary hernias. Re-recurrence rates after recurrent repair by TEP ranged from 0 to 20%, but most studies show a comparable or improved recurrence rate compared with the open re-repair [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref] [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref]. Ramshaw's large single institution study had a re-recurrence rate of 0.3% after TEP . The study by Bay-Nielson et al. showed a reoperation of 1.3% after TEP for recurrence versus 3.2 and 6.7% respectively for the Lichtenstein and muscle repair for recurrence. These results were later reconfirmed when his group looked at all laparoscopy for recurrence . One drawback to the technique, as Ferzli and Sayad point out, is that sutures or scarring from the prior repair may result in inadvertent pneumoperitoneum. This results in a technical obstacle to repair, but the challenge can be overcome with experience [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref]. Again, most authors emphasize the importance of the steep learning curve with this technique and caution that only surgeons who are well trained in the TEP technique utilize it for recurrent hernia [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref] [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref] [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref] [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref] [bib_ref] Sportsman's hernia, Moeller [/bib_ref] [bib_ref] Groin injuries in athletes, Morelli [/bib_ref] [bib_ref] Athletic pubalgia and ''sports hernia'': optimal MR imaging technique and findings, Omar [/bib_ref] [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref] [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] [bib_ref] Groin injuries: a true challenge in orthopaedic sports medicine, Renstroem [/bib_ref] [bib_ref] Adductor-related groin pain in competitive athletes. Role of adductor enthesis, magnetic resonance..., Schilders [/bib_ref]. Pain score and return to regular activity after TAPP and TEP for recurrent inguinal hernia Statements ## Recommendations The long skin incision and myofascial dissection of an open inguinal hernia repair create significant postoperative pain, resulting in prolonged recuperation and in delayed return to normal activity and return to work. TAPP has been directly compared in a number of retrospective and small, randomized, prospective studies to open repair for recurrent hernia and has been shown to be associated with significantly decreased postoperative pain and earlier return to work and activity. The incidence of wound and mesh infections also has been demonstrated to be lower . TAPP and TEP seem to be similarly effective, although there is a scarcity of data comparing both techniques directly [bib_ref] Surgery for posterior inguinal wall deficiency in athletes, Steele [/bib_ref]. ## Tapp inguinal hernia repair after failed tapp/tep statements ## Recommendations According to EHS Guidelines, it is generally agreed that an anterior approach seems to be the best choice after failed posterior repair. Yet, a number of studies have looked at TAPP repair for recurrence after TAPP as the primary repair modality (TAPP after TAPP). Most show excellent results. Bisgaard's review from the Danish hernia registry is the exception. The recurrence rate of 7.1% for TAPP vs. 2.7% for Lichtenstein repair may stem from the fact that this is a national study and includes all comers (expert and novice laparoscopic surgeons alike). Bisgaard's review highlights the need for a high level of experience and comfort in the basic TAPP technique before attempting its use for TAPP after TAPP. Indeed, the largest series of TAPP after TAPP, Bittner (n = 135), demonstrates a significant learning curve, but with a low overall re-recurrence rate of 0.74% [bib_ref] Abdominal musculature abnormalities as a cause of groin pain in athletes. Inguinal..., Taylor [/bib_ref] [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref] [bib_ref] Outcome of conservative management of athletic chronic groin injury diagnosed as pubic..., Verrall [/bib_ref]. TAPP and TEP repair in patient after previous transabdominal radical prostatectomy Statements ## Recommendations It is generally accepted that an anterior approach seems to be the best choice after previous preperitoneal surgery. Only two studies report the results of TAPP (Wauschkuhn et al. [bib_ref] Incidence of pubic bone marrow oedema in Australian rules football players: relation..., Verrall [/bib_ref] and TEP (Dulucq et al. [bib_ref] Groin pain in athletes from Southern Sweden, Westlin [/bib_ref] in hernia patients after previous transabdominal radical prostatectomy. During a 1-year period, Dulucq operated on a total of 10 patients after prostatectomy with TEP. Operation time was longer than in uncomplicated repairs and two patients were converted to TAPP, but overall complication rate and outcome were similar. Wauschkuhn et al. report approximately 264 patients who underwent surgery during a 10-year period. They found a longer operation time and a higher morbidity (5.7 vs. 2.8), but time of slick leave and recurrence rates were similar. Analysis of subgroups with respect to the time period during which they were operated on showed a steep learning curve [bib_ref] Incidence of pubic bone marrow oedema in Australian rules football players: relation..., Verrall [/bib_ref] [bib_ref] Groin pain in athletes from Southern Sweden, Westlin [/bib_ref]. ## Pitfalls of tapp and tep repair for recurrent inguinal hernia statements ## Level ib Compared with open repair, TAPP and TEP have a better profile in terms of level of pain and return to regular activity. ## Incidence of wound and mesh infection is lower compared with open hernia surgery. level iv Effectiveness of TAPP versus TEP is similar. Grade A Both techniques TAPP and TEP are recommended after an anterior approach, providing the surgeon is sufficiently experienced in the specific procedure. Level III Re-TAPP is possible. Operation time is longer and morbidity higher compared with repair of primary hernia, but time of sick leave and re-recurrence rate are similar. There is a steep learning curve. Level IV/V TAPP is superior to TEP. Grade C TAPP repair of recurrent inguinal hernia after prior TAPP or TEP may be performed; however, it should only be attempted by experts in TAPP inguinal hernia repair. ## Level 3 tapp and tep are possible treatment options. Operation time is longer and morbidity higher compared with repair of primary hernia, but time of sick leave and re-recurrence rate are similar. There is a steep learning curve. In TEP, there is a significant conversion rate to TAPP. Level 5 TAPP seems to be easier to perform. Grade D TAPP or TEP repair may be performed, but it should only be attempted by experts in TAPP or TEP inguinal hernia repair. Level 4 The presence of two or more meshes in the inguinal region does not seem to enhance the frequency of chronic pain. Removal of a previously implanted preperitoneal mesh may increase the risk for lesion of urinary bladder, bleeding complications, and substantial defects of the peritoneum. ## Recommendations The presence of old mesh in the prior hernia repair presents a technical challenge for TAPP or TEP repairs of recurrence. The mesh from a prior Lichtenstein repair should not affect the field of a posterior approach. However, the mesh plug technique poses a unique problem for laparoscopic repair of recurrence. The old plug creates an obstacle to placing the mesh and replacing the peritoneum over the mesh. Removal of the plug is not simple and cannot be easily accomplished with endo-shears. We find that electrocautery more effectively cuts the protruding aspect of the plug, thus allowing posterior mesh placement and replacement and repair of the peritoneum. The best approach to a mesh placed from prior laparoscopic repairs may be to leave it in place and avoid risk of injury to the iliac vein or to the bladder. The new mesh can be laid on top of the old to correct any technical failure of a slipped or misplaced prior mesh. TAPP and TEP repair and the occult synchronous hernias. Statements ## Recommendations One problem associated with the repair of the recurrent inguinal hernia repair is the missed synchronous hernia [bib_ref] The value of herniography in football players with obscure groin pain, Yilmazlar [/bib_ref]. Felix et al. found an occult femoral hernia incidence of 9% in his 1996 series of laparoscopic repair of recurrent inguinal hernia. Mikkelsen et al. found the risk of femoral hernia to be 15 times higher after inguinal hernia repair than in the general population, and Chan believes prior inguinal hernia repair may precipitate femoral hernia [bib_ref] Transabdominal preperitoneal laparoscopic approach for the treatment of sportsman's hernia, Ziprin [/bib_ref] [bib_ref] ) any question, costs are an important issue. Several studies attempted to..., Ziprin [/bib_ref]. He found that 50.9% of his series of 225 femoral hernia repairs had concurrent inguinal hernia and 18.2% had prior groin hernia repair. Laparoscopic inguinal hernia repair provides the benefit of a panoramic view of the all the potential hernia spaces: direct and indirect, femoral, and obturator hernias. TAPP and TEP therefore address the missed femoral and concomitant ipsilateral hernias. Furthermore, TAPP enables rapid evaluation of contralateral hernias (see Chap. 2, Kukleta). The laparoscopic approach obliterates these associated occult synchronous or potential hernias utilizing a single repair without any particular modification to the technique. There has been a general agreement that in every case of hernia repair a careful complete dissection of the whole ipsilateral pelvic floor is mandatory. References (in parentheses graduation of evidence) Laparoscopic trans-peritoneal hernioplasty (TAPP) for the acute management of strangulated inguino-Grade D Old mesh from prior preperitoneal hernia repair should be left in place. The re-repair should be defect-adapted. When an old plug is encountered that does not allow placement of a flat mesh, the protruding part of the plug may be best cut away with the use of electrocautery. Level 4 TAPP and TEP repair of inguinal hernia allow easy identification of the occult ipsilateral femoral or obturator hernia. TEP allows easy identification of concomitant contralateral direct hernias. TAPP allows easy identification of concomitant contralateral direct and indirect hernias. The laparoscopic approach obliterates these associated occult synchronous or potential hernias utilizing a single repair without any particular modification to the technique. Mesh size may have a greater impact on recurrence than surgical technique . A small mesh has been shown to be an independent risk factor for recurrence compared with a large one, irrespective of the type of mesh, i.e., light or heavyweight . We found no randomized trials that specifically compared mesh sizes, but several studies on surgical techniques used different sizes of mesh. Data extracted from a recent meta-analysis of open versus laparoscopic hernia repairs provide some information about this issue . A significant trend toward reduced recurrence rates with increasing mesh size was noted (a ''large'' mesh was most often 10 9 15 cm 2 size). Indeed, use of a small mesh almost doubled the risk for recurrence . A large, retrospective series that included 3,017 patients who underwent TAPP inguinal herniorrhaphies showed a 5% recurrence rate using an 11 9 6 cm 2 mesh in 325 repairs and a 0.16% recurrence rate using a 15 9 10 cm 2 mesh in 3,205 repairs . There are two large randomized studies from Sweden; one compared TAPP with Shouldice with a 5-year followup of 920 patients and showed a recurrence rate of 6.6% when using a mesh size of 7 9 12 cm 2 , and the other compared TEP with Lichtenstein with 5-year clinical examination of 1,370 patients when using a mesh size of 12 9 15 cm 2 and showed a recurrence rate of 3-5% . Animal data have suggested that a minimum of 3-cm mesh overlap is essential to prevent mesh protrusion through the hernia defect resulting in recurrence . To summarize, the use of a large mesh for laparoscopic inguinal hernia repair is supported by the literature, albeit with a low level of evidence, which makes it impossible to recommend an optimal size. However, it seems reasonable to suggest that the mesh should overlap the hernia defect by at least 3 cm in all directions. It should be emphasized that dissection of the preperitoneal space has to be adequate for the size of mesh to ensure that the mesh lies flat against the abdominal wall . ## Comprehensive comments As recurrence factor, mesh size is much more important than the prosthetic material used. In daily clinical practice, we use a mesh of 10 9 15 cm 2 size, even in ''small'' patients. If the patient is big or has a large hernia defect, it is advisable to use a larger mesh. However, for logistic reasons, we have decided to use only 10 9 15 cm 2 meshes in our departments, and if we encounter a patient who requires a larger mesh, we simply implant two meshes instead of one with sufficient overlap. Some surgeons routinely cut the mesh making it curved, i.e., rounding the edges. This is not necessary. Instead, the dissection should be thorough with a complete parietalization and a wide exposure of the entire preperitoneal space to ensure a flat positioning of the mesh. # Introduction The common approach in hernia surgery is the tensionfree technique with alloplastic materials to strengthen the connective tissue or partial connective tissue replacement in large fascia defects. Modern implants have to fulfill increasingly stringent requirements concerning their mechanical and biological qualities. A large number of investigations deal with the improvement of the biocompatibility of implants. In this respect, the definition of biocompatibility moves away from the concept of a biochemical inert material to an application-oriented definition. In the past, a variety of experimental studies were performed to improve the implants to prevent undesirable effects, such as chronic groin pain or movement-dependent discomfort, and allow quicker return to work and daily activities. Against this background, the light mesh concept has established itself over the years. An analysis of prospective, randomized, double blind studies that compared the theoretical effect of weight reduction to clinical outcome should result in a recommendation of the choice of mesh in TAPP and TEP technique based on the strength of the evidence. # Materials and methods The clinical studies analyzed were conducted between January 2000 and February 2009, because no comparable studies are available before this period. We conducted a search of Pubmed, Medline, and Cochrane Library using the terms: TAPP/TEP and mesh, biocompatibility and mesh, groin and mesh. We analyzed each article. The classification in degrees of evidence followed the Oxford hierarchy of evidence starting from Level 1A (systematic review of RCTs with consistent results from individual studies) up to level 5 (expert opinion, animal, or lab experiments). # Results tapp In total, 374 hits were found from January 2000 to February 2009. Excluding 48 review articles, 326 publications were classified according to the evidence criteria. The result was three articles [1-3; Study design Figs. 1-3] (0.92%) based on a prospective study design, of which only two performed randomization (0.6%). Early results (3 months) are described in one article , medium-term results (12-month follow-up) likewise in one article , and 5-year long-term results in one study . ## Tep The TEP search resulted in 359 articles. Excluding 42 review articles, 317 articles were (peer) reviewed. Three of 317 (0.94%) publications were prospective, controlled, randomized studies [4-6; Study design Figs. . Two articles described early results (2 months) and one medium-term results. Long-term results were not available. Apart from the article by Horstmann et al., only five articles seem to be comparable [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref]. This prospective, longitudinal study continues to be taken Level 1A In the long-term comparison, lighter meshes with larger pores do not lead to improvements of the quality of life or a reduction of discomfort that are of statistical significance. They offer advantages in terms of convalescence during the first few postoperative weeks. Grade B The hernia repair in the TAPP/TEP technique with a so-called material-reduced mesh (less amount of material, bigger pores, some elasticity) decreases the rate of mesh-related complaints, at least within the first 3 months. Grade D 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. into consideration despite the insufficiently standardized methodology; however, it is critically discussed in the overall analysis and separately assessed (Level 2B). The five analysed RCT studies (Level 1B) agree that postsurgical advantages last for up to 3 months. These advantages are partly very subtle and not always corroborated by the VAS and SF score [fig_ref] 1: Ferzli GS, Kiel T [/fig_ref]. Only one study (TAPP) has a survey of 5 years and could not detect any difference of statistical significance. Noteworthy, this long-term study reported on 5% of patients complaining about discomfort, similarly for three different mesh materials tested (smooth heavyweight, rigid ultra heavyweight, lightweight). There was no significant difference in the hernia recurrence rate in the long-term comparison between HM and LM. # Discussion It is hardly possible to make a best treatment recommendation because the clinical studies do not accurately assess the value of medical devices. To this effect, we have to consider a huge variety of modifications (advantages of some slight changes, e.g., thinner filaments may be demonstrable only in nonclinical settings), a long delay of some device-related complications (e.g., infection, migration), the variable individual response with increased risk in yet insufficiently defined subgroups (e.g., collagen formation, intra-abdominal adhesions), and not least many confounders that make it difficult to associate clearly an outcome with a device. In view of to these limitations of clinical studies and RCTs, any recommendation has to consider experimental results as basic evidence (see author's comment). Therefore, when comparing medical devices, the absence of any statistically significant differences in RCTs (Levels A-B) does not mean that a proper selection of a device will not be beneficial, but a negative result in a study rather expresses the principally limited power of clinical studies. ## Authors' comment Even if experimental studies and experts' opinions are to be allocated an evidence Level 5, their results cannot be and at unilateral recurrent hernias ignored. The summarized findings of these articles are listed consecutively and taken into account in the following recommendation: 1. The older generation of polypropylene mesh is oversized with regard to the mechanical properties. 2. Bigger pore size improves the integration into the tissue and also preserves a high degree of elasticity and stability in the implant matrix. 3. Monofilament meshes have a lower infection potential. The authors' recommendations are based on three textile design construction parameters [fig_ref] Table 3: Complications and recurrence rates after TAPP hernia repair in various series from... [/fig_ref]. The implant weight parameter alone is unsuitable and, hence, is modified by the structural parameter: pore size. Usual meshes with small pores \1 mm are ''heavy'' weight ([60 g/m 2 ), whereas those with large pores are ''low'' weight. However, there are no precisely defined limits, there are some meshes with low weight but small pores (e.g., Mersilene), and some heavyweight polymers despite large pores (e.g., made of PVDF). Because porosity is more difficult to measure than weight, the term most often used by manufacturers is ''weight,'' and therefore, this is used in this text too. The hernia repair in the TAPP/TEP technique using 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) [16 N/cm appears to be most advantageous, summarizing personal and published clinical and experimental experiences [fig_ref] 1: Ferzli GS, Kiel T [/fig_ref] We identified one randomized trial . In this threearmed study, including 360 patients, a TAPP procedure was performed. In group A, the mesh was implanted through a central incision, creating a deep inguinal ring by overlapping the two incised sides. In groups B and C, a non-incised mesh was used, which was fixed with staples in group B and with nonresorbable sutures in group C. The authors reported no significant differences between the groups regarding operation times, postoperative complaints, and need for pain killers. Furthermore, they found only one recurrence in group C (no recurrences in groups A and B). Moreover, we found one comparative study with historical controls , including 2,700 TAPP procedures from a single institution. After a median follow-up time of 26 months, there were 28 recurrences, 9 (0.3%) of which were due to insufficient closure of the mesh slit. From the same institution, a later prospective study involving 8,050 procedures without slit in the mesh reported an overall recurrence rate of 0.4% . Thus, there is no evidence to support use of a 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 at all. ## Comprehensive comments Routinely, we do not cut a slit in the mesh, because it does not bring any technical advantage for the surgeon or better clinical results for the patient. Recurrence after surgery for primary inguinal hernia occurs after approximately 2% of both open and endoscopic procedures at specialized centres . Several recurrence factors have been identified, such as mesh or no mesh, mesh size, hernia type, and surgeon's volume of procedures . Most studies on this issue were performed in patients who underwent open surgery. Acute and chronic pain, defined as pain lasting for 3 months or more , after inguinal hernia surgery has We recommend not to cut a slit in the mesh. ## Level 3 Cutting a slit in the mesh to allow the structures of the funicle to pass through the mesh may be a risk factor for recurrence after laparoscopic inguinal hernia repair. Level 1B An intact mesh does not produce more postoperative complications or higher risk of recurrences compared with a cut mesh. Level 1B Fixation and nonfixation of the mesh are associated with equally low recurrence rates in both TAPP and TEP; however, in most studies the hernia opening was small (\3 cm) or not measured. Staple fixation is associated with a higher risk of acute and chronic pain compared with nonfixation. Fixation is more expensive than nonfixation. Fibrin glue is associated with low recurrence rates. Fibrin glue is associated with less acute and chronic pain than stapling. Level 5 Fibrin glue is less expensive than most stapling devices. emerged as a key issue in the literature. Reported chronic pain rates after groin hernia repair vary from 0 to 75.5% . Overall, moderate to severe pain was experienced by 10-12% of the patients. In this respect, operations performed endoscopically seem to be more favorable than both nonmesh and mesh open technique operations . Apparently, the use of mesh reduces the risk of chronic pain . After the introduction of the endoscopic hernia surgery, mesh fixation was thought to be mandatory to avoid dislocation of the mesh and recurrences. Permanent fixation with tacks, staples, or sutures was used. The perplexing problem of chronic pain after endoscopic hernia surgery raised the question of whether fixation is really necessary. Nerve entrapment and pain caused by shrinkage of the mesh due to scar tissue formation have been suggested as possible causes. The technique of nonfixation or temporary fixation using glue is increasingly used to solve the pain problem. It is unclear whether nonfixation increases recurrence rates, especially in large defects, or decreases chronic pain. When fixation may be indicated, it is not clear which method of fixation should be recommended. Indications for fixation may be different for totally extraperitoneal (TEP) repair and transabdominal preperitoneal (TAPP) repair or for direct and indirect hernias. A total of 33 studies, described in 34 different articles , were included in this review. The number of patients included in each study varied widely. In most of the studies comparing fixation to nonfixation, a TEP repair was performed. ## Fixation or nonfixation of the mesh Permanent fixation using tacks, staplers, or anchors is compared with no fixation at all in terms of recurrence, acute pain, chronic pain, and costs. There are no studies comparing nonfixation with fibrin fixation for open or endoscopic hernia repair. A total of 16 studies were identified. Case series where fixation was used in all patients were not included. ## Recurrence Recurrences after fixation versus nonfixation are reported in [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref]. Five randomized, controlled trials (RCTs) , four case-controlled studies comparing fixation versus nonfixation , and five case series on nonfixation [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref] [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref] [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref] were identified. Only one study with a 1b evidence level compared fixation versus nonfixation in TAPP repair and found no significant differences in the incidence of recurrence between fixated and nonfixated repairs. However, the majority of hernia defects in this trial were smaller than 2 cm. In total, seven studies have compared fixation versus nonfixation in TEP, of which only two have 1b evidence level. They did not discover any difference in the incidence of recurrence between fixated versus nonfixated mesh . Three of the case series used selective mesh fixation. Saggar and Sarangi retrospectively analyzed 822 TEP reconstructions and demonstrated a 0.7% recurrence rate. The mesh was fixated in only 28 hernias with large defects. Kapiris et al. demonstrated 1% recurrences in 104 TAPP reconstructions. The mesh was fixated in only nine hernias with large defects in this study. In total, 12,114 hernia repairs were performed without fixation in all studies combined. The recurrence rate was 61 (0.5%), which is comparable to the recurrence rate of 7 of 936 (0.7%) after fixation. ## Acute and chronic pain There are only one small RCT (N = 20) and one cohort study (N = 509), both with a 2b evidence level, that compare acute pain after stapler fixation versus nonfixation [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref]. Significantly more acute pain is found after stapling compared with nonfixation in the cohort study, whereas the RCT shows no differences between fixation and nonfixation with respect to acute pain. Chronic pain after fixation versus nonfixation is reported in [fig_ref] Table 2: Details of visceral and vascular injuries from non-randomized studies of TAPP and... [/fig_ref]. Four RCTs included data on chronic pain after fixation versus nonfixation . A total of 1,072 patients were involved in these studies, which all used 8 different scales for pain scoring. A significant difference was demonstrated only in one large study, in which fixation was associated with a significant increase in chronic pain . ## Costs Costs are analyzed in three RCTs. In only one study, Moreno-Egea et al. performed a cost-analysis, which included not only the costs for endoscopic equipment but also for hospitalization and surgery (including anaesthesia, time spent in the operating room, and materials). For fixation of the mesh, they found a mean increase in costs of $517, mainly due to the costs of a stapling device. Ferzli et al. reported a net saving of $120 when the operation was performed without fixation and Taylor et al. a net saving of $245. Type of fixation The following methods for fixation were used in the included studies: different types of permanent fixation devices (tacks, staples, and anchors), sutures, I-clips, fibrin glue, and autologous fibrin. Altogether, 17 studies were identified: 4 RCTs, 5 case-controlled studies, and 8 case series. Two small studies have been published on the use of autologous fibrin: a small RCT in 22 patients that compared staples to autologous fibrin and one case series that included 10 patients . No reliable conclusions can be made based on these small studies. One case series focused on the use of I-Clips (resorbable clips) to secure the mesh and another on the use of sutures . Additional studies are needed before any conclusions can be drawn regarding the use of these fixation techniques. ## Staples versus fibrin glue recurrence Recurrences after fixation with staples versus fixation with fibrin glue are reported in [fig_ref] Table 3: Complications and recurrence rates after TAPP hernia repair in various series from... [/fig_ref]. Three RCTs and five case-control studies were found, including a total of 2,327 patients . The recurrence rate was 0.6% in the stapled group and 0.4% in the fibrin glue group. One of the RCTs compared different types of stapling devices, e.g., spiral tacks, conventional staples, anchor-shaped devices, and fibrin glue . Five case series were found , including a total of 460 hernia operations with fibrin glue fixation. Only one recurrence is reported with a minimum follow-up of 1 year. Three of the studies were performed on TAPP, one on TEP, and one on an intraperitoneal onlay mesh (IPOM). ## Acute and chronic pain Acute pain after fixation with staples versus fixation with fibrin glue is reported in [fig_ref] Table 4: Complications and recurrence rates after TEP hernia repair in various series from... [/fig_ref]. Three studies described acute postoperative pain. In the study by Boldo , autologous fibrin glue was used. Two of three studies reported significantly less acute pain after fibrin glue compared with stapled fixation. Chronic pain after fixation with staples versus fixation with fibrin glue is reported in [fig_ref] Table 5: Chronic pain after fixation with staples versus fixation with fibrin glue [/fig_ref]. Six of the studies comparing staples and fibrin glue for fixation reported chronic pain [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref]. Four of six studies found significantly less chronic pain in patients in whom the mesh was fixated with fibrin glue compared with patients in whom the mesh was fixated using staples [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref]. ## Costs We did not find any publication that addressed this specific issue. Most studies agreed that stapling devices are more costly than fibrin glue, depending on the amount of fibrin glue used. References (in parentheses graduation of evidence) Endosc # Introduction It is well established that surgical injury can lead to chronic pain, which is defined as pain lasting for 3 months or more by the International Association for the Study of Pain (IASP) . In the literature, chronic pain rates after groin hernia repair vary between 0% and 75.5% . Overall, moderate-to-severe pain was experienced by 10-12% of patients. The use of mesh seems to reduce the risk of chronic pain . After a mesh-based inguinal hernia repair, 11% of the patients suffer from chronic pain, more than a quarter of these report moderate-to-severe pain . # Methods The conclusions and recommendations for risk factors and prevention of acute and chronic pain after endoscopic hernia repair are based on a systematic review of the literature and a consensus conference for the development of technical guidelines in endohernia surgery, which was held in February 2009 in New Delhi, India, during the fourth meeting of the International Endohernia Society (IEHS). Search terms: Pubmed, Medline, Embase, British Journal of Surgery database, Science Citation Index, and the Cochrane database were searched for studies on acute and chronic pain after endoscopic hernia repair. Search terms were ''TEP'' and ''pain''; ''TAPP'' and ''pain''; ''groin hernia'' and ''pain''; ''inguinal hernia'' and ''pain.'' Additionally experts in the field of endoscopic hernia repair were contacted. The levels of evidence and grades of the recommendation are based on the Oxford evidence-based medicine criteria . Surgery-related risk factors have to be differentiated from those not related to surgery. Risk factors for acute and chronic pain after endoscopic groin hernia repair and recommendations for its prevention: Statements ## Recommendations pain and sensory disturbances after endoscopic and open groin hernia repair According to Aasvang et al. , the overall incidence of chronic pain after open groin hernia repair is 18% (range, 0-75.5%) and 6% after endoscopic repair (range, 1-16%; p \ 0.01) Eight systematic reviews published between 2001 and 2008 of which 7 included only prospective, randomized and quasirandomized trials concluded that endoscopic hernia repair is associated with less acute and chronic pain, less numbness, and a faster return to usual activities . Four of these meta-analyses revealed statistically highly significant lower chronic pain rates (p \ 0.001 to p \ 0.00001), lower rates of numbness (p \ 0.001 to p \ 0.00001), and a highly significant faster return to normal activities (p \ 0.001 to p \ 0.00001) after endoscopic hernia repair . Only 2 of 58 controlled, randomized trials report more pain after endoscopic hernia repair. In a randomized, multicentric study of 390 patients comparing endoscopic and open groin hernia repair, Millat found significantly more testicular pain 30 days after TEP and TAPP. However, after a median follow-up of 2.5 years, there was no difference in chronic pain. In a prospective, randomized, controlled trial on 163 patients with a medium follow-up of 7.3 years, Hallen et al. reported significantly more testicular pain (p \ 0.003) after TEP versus open mesh repair. The analysis of quality adjusted life years favors endoscopic groin hernia repair . A retrospective analysis by Hindmarsh et al. showed that the attendance at a pain clinic with severe chronic pain was significantly more frequent after open inguinal hernia repairs. ## Level 1a The risk of acute and chronic pain is lower after endoscopic groin hernia repair compared with open surgery with or without mesh. The risk of sensory disturbances of the groin is lower after endoscopic groin hernia repair compared with open surgery with or without mesh. Level 1B There is no difference of acute and chronic pain after TEP and TAPP. Preoperative pain is a risk factor for chronic pain. The risk of acute and chronic pain after staple mesh fixation is higher compared with fibrin fixation or nonfixation (see Chapter ''fixation''). Bilateral TAPP and TEP repairs are not associated with more acute and chronic pain compared with unilateral repair. The risk of acute and chronic is lower after endoscopic recurrent groin hernia repair compared with open surgery with or without mesh (see Chapter ''Complicated hernia'') Level 2A There is no difference in chronic pain after endoscopic hernia repair with heavy or lightweight meshes (see Chapter ''Mesh''). The use of light-weight meshes seems to reduce acute postoperative pain and discomfort compared with the use of traditional heavy-weight meshes (see Chapter ''mesh''). ## Level 2b History of other pain syndromes is a risk factor for chronic pain. Severe acute postoperative pain is a risk factor for chronic pain. Endoscopic recurrent groin hernia surgery is a risk factor for chronic pain. Age younger than 65 years is a risk factor for acute pain. Age below median (40-50 years) is a risk factor for chronic pain. Women suffer more often from acute and chronic pain. Level 3B Surgical complications (seroma, hematoma, wound infection, bowel or bladder injury, and bowel obstruction) are a risk factor for chronic pain. Surgery-related sensory disturbance of the groin is a risk factor for chronic pain. Day-case surgery may be a risk factor for acute pain. Employment status may be a risk factor for chronic pain. Grade B To reduce acute pain, the use of weight reduced macroporous (pore size [1 mm) monofilament meshes should be considered (see Chapter ''Mesh''). Regarding frequency of chronic pain, the use of light and heavyweight meshes can be considered (see Chapter ''Mesh''). To reduce the risk of acute and chronic pain and discomfort, nonfixation of the mesh or fibrin glue fixation should be preferred to staples fixation (see Chapter ''Fixation''). Endoscopic groin hernia repair should be considered in patients with risk factors for acute and chronic pain if expertise is present. Bilateral TAPP and TEP repair can be recommended without a higher risk of acute and chronic pain. Grade D Every endoscopic groin hernia surgeon has to be familiar with the anatomy of the inguinal nerves. The use of penetrating fixation devices in the ''trapezoid of pain'' and ''triangle of doom'' is prohibited. The nerves should not be exposed, leaving the protecting nerve fascia intact. Electrocautery has to be used with care. ## Acute and chronic pain after tapp and tep repair Only two prospective, randomized trials with small patient numbers comparing both procedures have been published . Although Schrenk et al. found less pain after TAPP on the operation day and day 1 after surgery (p \ 0.02) without any difference later, Dedemadi et al. reported no difference in pain at any time after surgery. A retrospective, multicentric comparison of 1,972 TAPP and TEP hernia repairs using polyester meshes found no difference in chronic pain with rates of 0.6 and 0.7% after TAPP and TEP respectively . A systematic review of Wake et al. comparing TAPP and TEP showed no difference in early and chronic pain. According to the present literature, there is no difference in acute and chronic pain after TAPP and TEP hernia repair. ## Preoperative pain and chronic pain Two review papers on chronic pain, which included publications on open and endoscopic repair , reported that preoperative pain in the groin is a risk factor for chronic pain. In one controlled, randomized trial of 300 patients comparing laparoscopic and open groin hernia repair with a 5-year follow-up , preoperative pain was a significant risk factor for chronic pain (p \ 0.001). A recent, prospective, nonrandomized trial on chronic pain after laparoscopic groin hernia repair , which included 881 patients with 1,029 hernias, found preoperative pain significantly associated with chronic pain (p \ 0.001). Two other large, prospective, nonrandomized trials on long-term pain with a follow-up of 81 and 72%, respectively, which included 4,877 patients, the majority of whom had had an open hernia repair, showed that preoperative pain was significantly linked to long-term chronic groin pain (p \ 0.001). In a retrospective, comparative study by Dennis and O'Riordan on 24 patients with severe chronic pain after groin hernia repair, preoperative pain was a risk factor for chronic pain (p \ 0.005). Acute, chronic pain and discomfort and type of mesh: see Chapter ''Selection of mesh material for TAPP and TEP'' Acute and chronic pain after nonfixation, glue, or stapler mesh fixation: see Chapter ''Mesh fixation modalities in endoscopic inguinal hernia repair'' A history of nongroin hernia-related pain syndromes and chronic pain Other preoperative chronic pain conditions not related to the groin are a risk factor for chronic postoperative groin pain. In one controlled, randomized trial comparing open and endoscopic hernia repair with a 5-year follow-up, other previous pain syndromes were a significant risk factor for chronic pain (p \ 0.01) . Two retrospective studies of patients with severe chronic postoperative groin pain mostly after open groin hernia repair are in accordance with these findings . Severe early postoperative pain and chronic pain Whereas several publications have reported that severe early postoperative pain after groin hernia repair is significantly associated with chronic pain , only a few publications are available on high acute pain rates and chronic pain after endoscopic hernia repair. In a randomized, controlled trial, Berndsen et al. found that severe early postoperative pain was a risk factor for chronic pain after Shouldice repair but not after TAPP repair. However, two prospective, nonrandomized studies of 313 and 123 patients, respectively, reported that severe early postoperative pain was a significant risk factor for chronic pain after endoscopic hernia repair (p \ 0.05 and p \ 0.03, respectively). ## Recurrent groin hernia surgery and chronic pain Surgery for a recurrent hernia might be a risk factor for chronic pain. In a review, Poobalan et al. found that surgery for a recurrent hernia was a risk factor for chronic pain. The exact number of endoscopic recurrent hernia repairs was not mentioned. A randomized, controlled trial by Liem et al. did not confirm this finding. Four, large, prospective, nonrandomized trials are available on this issue , but only two of these report exclusively on endoscopic recurrent hernia repair. Dickinson et al. found significantly more chronic pain after a recurrence compared with primary endoscopic hernia repair (p \ 0.02), Tantia et al. reported no difference between primary and recurrent TAPP and TEP repair. ## Age and acute and chronic pain One prospective, nonrandomized study reported more acute pain after TEP repair in patients younger than age 65 years . Nine studies identified age below median as a risk factor for chronic pain after groin hernia repair: one randomized controlled trial , five large prospective nonrandomized trials including the data of the Swedish and Danish hernia database , and three retrospective trials [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref]. However, most of these trials include mainly patients after open hernia repair. Only one prospective, nonrandomized trial found that age younger than 50 years is a risk factor for chronic pain after endoscopic hernia repair (p \ 0.001) . Acute and chronic pain after endoscopic hernia surgery in women The prospective, nonrandomized trial by Lau et al. found significantly more acute pain in women after TEP repair. Two large prospective, nonrandomized trials by Bay-Nielsen et al. [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref] and Kalliomäki et al. of the Danish and Swedish hernia database identified female gender as a risk factor for chronic pain, but only a small fraction of the patient population had an endoscopic hernia repair. This finding was confirmed by a retrospective study by Sondenna et al. [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref]. ## Surgical complications after groin hernia surgery and chronic pain Two large, prospective, nonrandomized trials of the Danish and Swedish hernia database , which included only a small number of endoscopic hernia repairs, identified surgical complications, such as seroma, wound infection, bowel or bladder injury, and bowel obstruction, as risk factors for chronic pain. Surgery-related sensory disturbances of the groin and chronic pain Chronic postoperative numbness and other sensory disorders of the groin were identified as risk factors for chronic pain in one retrospective trial (p \ 0.001) . ## Employment status and chronic pain In one case control study [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] and one retrospective cohort study [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref] , patients who received workers' compensation and employed patients suffered significantly more often from chronic pain. ## Day-case surgery and acute pain In one prospective, nonrandomized trial, day-case surgery was identified as a risk factor for acute postoperative pain . Bilateral endoscopic groin hernia surgery and acute and chronic pain According to one systematic review by Pfeffer et al. [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref] , bilateral endoscopic groin hernia repair is not associated with more acute and chronic groin pain compared with a unilateral approach. History of lower abdominal surgery and direct defect closure and chronic pain A history of lower abdominal surgery was not identified as a risk factor for chronic pain after endoscopic groin hernia repair in a prospective nonrandomized trial by Elshof et al. [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. In another prospective nonrandomized trial, Reddy et al. [bib_ref] Groin injuries in athletes, Morelli [/bib_ref] reported that the inversion of the fascia transversalis for the closure of big direct defects is not associated with chronic pain. Body weight, hernia defect size, hernia defect location, and mesh size are not related to acute and chronic pain. In the current literature on endoscopic groin hernia repair, insufficient or no data are available about the relationship between pain and the management of strangulated and incarcerated hernias, port defects, scrotal hernias, and cord lipomas. Although several publications have reported on pain and nerve management in open groin hernia surgery [bib_ref] Athletic pubalgia and ''sports hernia'': optimal MR imaging technique and findings, Omar [/bib_ref] [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref] [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] [bib_ref] Groin injuries: a true challenge in orthopaedic sports medicine, Renstroem [/bib_ref] , no data are available on nerve manipulation and pain in endoscopic hernia repair. ## Recommendations Laparoscopic peritoneal access or secondary suprapubic trocar placement can result in a bladder perforation, usually the result of failure to decompress a distended bladder. Less commonly, injury is associated with a congenital bladder abnormality. It should be suspected if urine is withdrawn into a syringe after Veress needle insertion or blood and gas are noticed in the urine drainage bag if the patient is catheterized. In questionable cases, methylene blue dye may be instilled into the bladder to look for leakage. Bladder injury recognized during laparoscopy should be repaired laparoscopically providing the experience of the surgeon is sufficient. This should be followed by bladder drainage for 7-10 days. Bladder injury may present in a delayed fashion with hematuria and lower abdominal discomfort. Contrastenhanced computerized tomography, cystography, or cystoscopy are the primary imaging techniques used to evaluate patients for a suspected injury . Small defects may be managed with postoperative decompression via an indwelling catheter for urinary drainage, whereas larger defects necessitate repair. The bladder is especially prone to injury during LIH when the preperitoneal space has previously been dissected, e.g., previous preperitoneal hernia repair or prostatectomy . ## Mesh erosion into the bladder statements Mesh erosion into the bladder after LIH is rare; only eight cases have been reported since 1994 . Therefore, Grade D The bladder should be decompressed either by having the patient void immediately preoperatively (preferred method) or by the use of an indwelling catheter Grade A Consider referral of patients in need of a preperitoneal inguinal hernia repair who had a previous preperitoneal dissection, e.g., prostatectomy or failed previous hernia repair to a specialty center. Level 4 Bladder injury can be the result of careless use of a Veress needle or a trocar. The bladder is especially prone to injury during LIH if the preperitoneal space has previously been dissected. Level 4 Polypropylene and expanded polytetrafluoroethylene will erode into the bladder in a small number of patients in whom it is implanted. The reason is not known. the exact incidence is not known. Both polypropylene and expanded polytetrafluoroethylene have been incriminated . Probable causes are unrecognized injury to the bladder wall at the time of the LIH and improper placement of mesh and fixation material. Repeated urinary tract infections, hematuria, or the development of bladder stones can all be presenting signs . # Urinary retention statements Recommendations Urinary retention is less common after inguinal herniorrhaphies performed under local anesthesia compared with general or regional . Urinary retention is not unusual after a LIH, because the most common associated factor, the use of general anesthesia, is almost always used . The incidence varies widely from as low as 0.2% in a singleauthor study from France to as high as 22.2% of patients undergoing laparoscopic inguinal hernia repair in a study from the Mayo clinic in Rochester, Minnesota . More commonly, it is reported to occur in the 2-7% range . Although reports in the literature conflict somewhat, in general older age, prostatic symptoms, postoperative use of narcotics, and the administration of postoperative intravenous fluid [500 cc have been found to be predictive . Type of procedure (TEP vs. TAPP), surgical time, anesthesia time, intraoperative fluid restriction, or the development of other complications do not appear to be significant risk factors. Intermittent catheterization or temporary placement of an indwelling urinary catheter is usually adequate therapy. # Urinary infection statements ## Recommendations ## Miscellaneous cord and testicular problems statements Scrotal hematomas can be prevented after LIH if complete hemostasis is assured before completing the procedure. Conservative treatment (ice, scrotal support, pain management, and observation) is sufficient for most, but large hematomas may require surgical drainage. Patients with bleeding disorders are especially prone to this complication . Hydroceles can develop but the cause is not known. Whereas urological literature suggests that this is due to the practice of leaving the distal sac in situ, most experienced hernia surgeons do not accept this theory. The treatment is the same as for any other hydrocele. It is important to differentiate a hydrocele from a seroma because the later is almost always self-limiting and will resolve without treatment . ## Ischemic orchitis/testicular atrophy statements ## Recommendations Orchitis is defined as postoperative inflammation of the testicle occurring within 1-5 days after surgery. It is felt to be due to acute thrombosis of the delicate venous pampiniform plexus rather than an arterial injury . It is most common after an inguinal scrotal herniorrhaphy when extensive dissection of the spermatic cord has been performed. The presenting symptoms are a lowgrade fever with a painful, enlarged, firm testicle. The differential diagnosis includes scrotal hematoma and testicular torsion. Management is supportive with scrotal support and anti-inflammatory agents. Duplex ultrasound scanning is useful when infarction is suspected. Ischemic orchitis may result in testicular necrosis within days or have a slower course resulting in testicular atrophy during a period of several months. Fortunately most patients recover from ischemic orchitis uneventfully without Grade C Intra-and postoperative intraveneous fluid administration should be restricted to no more than 500 cc. Level 1a Urinary retention is higher after LIH than a conventional inguinal hernia performed under local anesthesia because of the need for general anesthesia for LIH Level 1a Testicular complications occur after both open and endoscopic hernia surgery. No significant difference in incidence between open and laparoscopic techniques was found in a large comparative trial and a Cochrane analysis did not show any difference between TEP and TAPP . Grade B Antibiotic prophylaxis should be considered in patients at risk for infection .Urinary catheterization should be avoided if at all possible. Level 2B Incidence is highest in patients older than aged 74 years or who have a urinary catheter placed. Grade B In herniorrhaphies where there is a question that damage to the cord structures could occur with complete excision (e.g., large inguinal-scrotal hernias, sacs extending all the way to the testicle, densely adherent sacs), the surgeon should consider dividing the sac at a convenient point distal to the internal inguinal ring, leaving the distal sac in situ. The proximal sac should then be ligated. Level IA Unequivocal evidence that LIH will decrease the incidence of orchitis/testicular atrophy is not available. Level III In most cases, complete dissection and reduction of the hernia sac is possible without serious risk of orchitis or testicular atrophy. testicular atrophy. Interestingly, most patients who develop testicular atrophy do not give a history of orchitis. It is not yet known whether laparoscopy will have an advantage over conventional surgery because of the more proximal dissection in the preperitoneal space. However, in one large analysis of a prospectively maintained database containing of 8,050 TAPP laparoscopic hernia repairs, orchitis and testicular atrophy was reported to be extremely low at 0.1 and 0.05% respectively. Interestingly, this group removes all indirect sacs despite the size except in rare circumstances of excessive inflammation . Nevertheless, based primarily of the extensive writings of the late George Wantz, undue dissection of the cord and testicle to remove an indirect inguinal hernia sac completely is not recommended . The hernia sac can be divided at a convenient point in the inguinal canal with the distal aspect left open. The proximal sac is then dissected from the cord structures and ligated. ## Sexual dysfunction Postherniorrhaphy impairment of sexual activity to a moderate or severe degree occurs in a small percentage of men after groin hernia repair, primarily inguinal scrotal or ejaculatory pain. In a Danish study, the incidence of substantial pain during sexual activity was higher with laparoscopic inguinal hernia repair compared with a Lichtenstein TFR (12.7 vs. 6.5%), but this may have been related to the greater use of LIH for recurrent hernias . 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 . Recommendations ## Infertility Injury to the vas deferens can occur during LIH, and if bilateral will lead to certain infertility. The vas deferens may be injured during dissection and mobilization or during fixation of the mesh. Unilateral injury to the vas can lead to the exposure of spermatozoa to the immune system and the formation of antisperm antibodies, causing secondary infertility . Bilateral testicular atrophy (discussed earlier) is another cause. A recent study that detailed 14 patients whose infertility was apparently the result of damage to the spermatic cord caused by the normal fibroplastic response to polypropylene mesh resulting in obstruction of the of the vas deferens included 10 open procedures, 2 laparoscopic, and 2 where laparoscopy was used on one side and open on the other . However, the explanation for their findings might be a more traditional injury mechanism at the time of surgery, such as ligation, division, or cauterization followed by scarring to the moist convenient adjacent structure, which in this case would be the mesh . Inguinal herniorrhaphy has been evolving since it was first described by Bassini. Lichtenstein popularized tension-free repair with mesh. Laparoscopy arrived on the scene in late 1980s and has further revolutionized the surgical techniques. It is well accepted that laparoscopic transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) repairs have comparable recurrence rates and acceptable morbidity and mortality. Both techniques are challenging and have steep learning curves. The IPOM technique was first introduced in 1991 as a way to reduce or eliminate the difficulty and potential complications of preperitoneal dissection and still maintain the tension free concept . It also is perceived to be faster and easier to perform and teach. The simplicity and reduced operative times are the main attraction of this technique. Unfortunately, there are not many prospective randomized studies with long-term results. There are three randomized trial (1B) and one nonrandomized feasibility study to evaluate IPOM technique. There also are 16 Level 4 case series . A study by Vogt et al. initially showed very good results at 8 months. The recurrence rate for IPOM was 3% compared with 7% for open suture repair. Long-term data were then published by Kingsley et al. . The recurrence rate at 41 months was 43% for IPOM and 15% for open suture repair! This really stresses the importance of longterm follow-up. The IPOM technique was performed with ePTFE mesh (10 9 15 cm 2 ) fenestrated to 1:1.5. Cooper's ligament was exposed through a small opening and mesh was secured to Cooper's, the iliopubic tract, and transversus abdominus with EMS Ethicon hernia stapler. The operative times were 62.5 min for IPOM and 80.9 min for the open group. Another study compared TAPP to IPOM in a prospective, randomized fashion (1B). A total of 76 patients underwent TAPP and 72 underwent IPOM; 10 9 7 cm 2 ePTFE was used for IPOM and 15 9 12 cm 2 polypropylene mesh was used for TAPP. There were no recurrences in TAPP at 32 months compared with an 11.1% recurrence rate for IPOM. The mesh was tacked with a hernia stapler in both techniques. Neuralgia was noted with 3 TAPP and 11 IPOM patients (p \ 0.05). The IPOM technique was faster (53 vs. 71 min, p \ 0.001). The strength of this study was that only two surgeons performed all of the operations with reasonable follow-up. The size of the mesh, however, was not standardized! The last Level 1B study compared IPOM to open tension free repair. Catani randomized 26 patients to IPOM and 24 to open. The IPOM technique used ''Gore-Tex DualMesh Plus biomaterial with holes Corduroy'' and the open approach utilized Marlex plug and patch. Analgesic requirements were less for IPOM (p \ 0.001) and resumption to normal activity was faster with IPOM (8 vs. 17 days, p \ 0.001). There were no recurrences with either approach at 12 months. The follow-up is not long enough to draw any strong conclusions from this study. A multicenter feasibility trial was performed by Fitzgibbons et al. . There were 562 patients in TAPP group, 217 patients in IPOM group, and 87 patients in the TEP group. The recurrence rate was 5% for TAPP and IPOM compared with 0% for TEP at an average of 23 months. Polypropylene mesh was used with ''appropriate size.'' This was tacked using a hernia stapler ''like TAPP,'' and the sack was left in situ. IPOM had the highest rate of neuralgia. One patient had to have the mesh removed due to inflammatory mass next to the cecum. No fistula was noted, and there was no mention of bowel resection. The investigators concluded that ''IPOM should be considered investigation.'' Of the 16 Level 4 case series, 10 favored the IPOM technique due to less operative time and acceptable recurrence rate . Four of them were against IPOM due to higher recurrence rates or complications , and two were neutral . Most of the studies had a short and inadequate follow-up. Some of the studies only used a questionnaire rather than physical examinations. More recent studies by Cantani and Fixation may play a significant role. Leaving the sac in situ may lead to higher recurrence. had blood in stool 1 year later and defecated one of the GoreTex mesh. Four years later, he had hematuria and actually urinated four tacks! He had to undergo surgery to remove the GorTex from his bladder. We feel that the IPOM technique is inferior, because mesh is not secured to any substantial fascia. The tacks usually do not penetrate deep into the tissue and there is no posterior fascia. These tacks also can become a source of chronic pain. The hernia sac is left in place and others have noted migration of the mesh into the hernia sac over time (Grade 5). There is a deviation from standard technique of trying to reduce the hernia sac for faster operation. Faster is not always better (Grade 5). There have been case reports of mesh-related bowel and bladder fistulae, which further complicates patient management. We feel that such complications are under-reported. Two Level 1A studies concluded that endoscopic repairs do have advantages in terms of local complications, painassociated parameters, and faster return to normal activities; however, ''Well structured trials with improved standardization of hernia type, operative technique, and surgeons' experience are necessary'' . Both of these studies were reviewed by the Database of Abstracts of Reviews of Effects in 2008. It was concluded that ''overall methodological quality of the studies was poor and limited the conclusions that could be drawn.'' However, laparoscopic hernia repairs did have less postoperative pain and faster return to normal activities. The five Level 1B studies have been outlined in [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref] and overall are in favor of laparoscopic approaches due to less pain and faster return to normal activity . Champault et al. compared 51 patients with TEP to 49 patients with Stoppa. They noted a 6% recurrence rate with TEP and 2% with Stoppa repair, although the mesh used for TEP was smaller (11 9 6 vs. 12 9 15 cm 2 ). Morbidity was only 4% with TEP compared with 30% with Stoppa (p = 0.01). TEP also had less pain and a faster recovery with statistical significance. Beets et al. compared TAPP with GPRVS (great prosthetic replacement of the visceral sac). There was a difference in size of the mesh but not far from what is utilized now (10 9 15 vs. Johansson et al. compared TAPP to open preperitoneal (split incision) to conventional (suture only). Follow-up was 1 year and most of the TAPP recurred in 6 months, indicating technical failure. Also, the open approach used sutures compared with tacks for TAPP. Simmermacher et al. studied TEP compared with the Grid-Iron approach. The open approach was faster. There were no differences in pain and return back to work. However, the major limitation of this study is that there was no follow-up period and no recurrence rate mentioned. There studied only Kugel (five times more expensive than regular mesh) but with 3.5% persistent pain; Reddy et al. were in favor of Kugel but with 2.8% dull ache at 1 year without treatment; Kurzer et al. studied the Stoppa or Wantz repair for recurrent hernias with 5% RR at 4 years. The ten Level 4 studies showed nine for open approach and one against open preperitoneal approach . The majority of these studies had short follow-up, and there was much heterogeneity. The sports hernia is one of the least understood, poorly defined, and under-researched maladies to affect the human body and is a leading cause of athletes' retirement from competitive sports [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref]. It is more common in highlevel athletes . It is an obscure condition of uncertain etiology commonly seen in soccer, football, rugby, and ice hockey players [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. It reflects a compilation of diagnoses grouped together with a wide range of other pathologies that need to be excluded before this should be considered as a diagnosis . The etiology, onset, anatomy involved, and terminology used to define it vary widely in the literature [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. The precise sequence of events that lead to its development is not well known, but the combination of abdominal and hip adductor muscle strength, endurance and coordination imbalances, lumbopelvic and hip rotation range of motion deficits, poor tissue extensibility, and intense or high-repetition hip adductor muscle shearing forces through their pelvic attachments may be the primary factors [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] [bib_ref] Outcome of conservative management of athletic chronic groin injury diagnosed as pubic..., Verrall [/bib_ref]. Some authors emphasize inguinal nerve compression (entrapment) as a cause of chronic pain in athletes produced by direct trauma or overzealous training and hypertrophy of abdominal musculature [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref] [bib_ref] Groin injuries: a true challenge in orthopaedic sports medicine, Renstroem [/bib_ref] [bib_ref] Groin pain in athletes from Southern Sweden, Westlin [/bib_ref]. The phrase ''groin disruption'' was popularized by Gilmore for sport injuries followed by chronic pain in the groin and abdominal muscles area with no findings of hernia, but inguinal wall and superficial inguinal ring disorders caused by injuries to the internal oblique aponeurosis, conjoined tendon-pubic tubercle attachment and dehiscence between the tendoninguinal ligament. He successfully advised a surgical technique for treatment based on modifications of the historic Bassini operation . Gilmore, as well as others, found that the pain is caused by posterior wall deficiency (PWD) as a result of trauma to the tranversalis fascia or conjoint tendon, which is formed by the medial portion of internal oblique and transversus abdominis muscle [bib_ref] Groin injuries in athletes, Morelli [/bib_ref]. Nevertheless, many uncertainties remain, not the least due to the existence of other pathologies around the symphysis pubis, which were in some way easier to diagnose. Diagnostic imaging is useful to exclude other conditions but does not generally reveal a sports hernia. With time, especially after the introduction of laparoscopy, the Level 3A Chronic pain (longstanding groin pain-LSGP) is a leading cause of athletes' retirement from competitive sports. Chronic pain in athletes is an obscure condition of uncertain etiology commonly seen in soccer, football, rugby, and ice hockey players. At a high level of play, teams have significantly higher risk of injury than teams at a lower level. Physical examination reveals no detectable inguinal hernia. The differential diagnosis is difficult to make from physical examination and is thus largely established only at the time of surgery. Although there are several reports of chronic pain in women, it is almost exclusively found in men. Chronic pain is a challenging problem among not only athletes but also the general population. In the majority of athletic maneuvers, a tremendous amount of torque or twisting occurs in the midportion of the body, and the front or anterior portion of the pelvis accounts for the majority of the force. The main muscles inserting at or near the pubis are the rectus abdominis muscle, which combines with the transversus abdominis. Across from these muscles, and directly opposing their forces, is the abductor longus. The opposing forces of the muscles at their insertion site on the pubis cause a disruption of the muscle/ tendon, causing chronic pain related to the fact that forces are excessive and imbalanced, leading to an increase of the weakness of the posterior wall of the groin or to a pubic bone stress injury (PBSI), which may lead to degenerative arthropathy of the pubic symphysis in advanced stages. Chronic groin pain in athletes is mainly caused by two different pathologic entities: the sportsman hernia (SH) or the athletes pubalgia due to a pubic bone stress injury (PBSI). PBSI include entities, such us tendon enthesitis, pubic osteitis, or avulsion fractures. In SH, the likely causative factor is a posterior wall deficiency (PWD). Entrapment of inguinal nerves may create symptoms that resemble those of a sports hernia. understanding of the different pathologies and pathogenetic mechanisms has improved. Today, posterior inguinal wall insufficiency that creates an occult hernia that is not apparent on physical examination is recognized as the most common surgical finding . For this reason, the pathological definition of PWD was accepted as equivalent to the pathology of SH, and confirmed by multiple studies [bib_ref] Groin injuries in athletes, Morelli [/bib_ref] [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. From an anatomical point of view, the definition and the name of this entity should be reviewed. Confusion related to ''sportsmen hernia'' often arises from the complex anatomy and biomechanics of the symphysis region, from the large number of potential sources of groin pain, and from the similarity of symptoms in athletes with different sites of injuries. There are different anatomic areas to be considered when we talk about this entity, including ligaments, tendons, nerves, muscles, and bones. In the majority of athletic maneuvers, a tremendous amount of torque or twisting occurs in the midportion of the body, and the front or anterior portion of the pelvis accounts for the majority of the force. The main muscles inserting at or near the pubis are the rectus abdominis muscle, which combines with the transversus abdominis. Across from these muscles, and directly opposing their forces, is the abductor longus. These opposing forces cause a disruption of the muscle/tendon at their insertion site on the pubis, so the problem could be related to the fact that forces are excessive and imbalanced, and a weak area at the groin could be increased due to the forces produced by the muscles. The forces produced by these muscles may be imbalanced and could produce a disruption of the muscle/tendon at their insertion site on the pubis or/and a weak area may be increased due to the forces produced by the muscles; just this last possibility could be defined as sportsmen hernia. On the other hand, this disruption of the muscle/tendon at their insertion site could be defined as a PBSI (pubic bone stress injury), which affects not only the pubic bone itself but also the muscles and their tendons on both sides of the symphysis pubis [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref]. (In the past, it was mistakenly referred to as osteitis pubis.) For that reason, this term could include different entities, such as tendon enthesitis, pubic osteitis, or avulsion fractures. In conclusion, this global entity could be considered an imbalance of the muscles (abductor and abdominal) at the pubis, which leads to an increase of the weakness of the posterior wall of the groin and produces a tendon enthesitis. Once a true origin is not detected, because, for example, a hernia is a hernia or a nerve entrapment is a nerve entrapment, etc., that may lead to a degenerative arthropathy of the pubic symphyses in the advanced stages. Based on this, this entity could be renamed, ''syndrome of muscle imbalance of the groin,'' and the sportsmen hernia could be considered an entity included in this syndrome [fig_ref] Table 1: RCT comparing prophylaxis versus nonprophylaxis antibiotics in inguinal hernia surgery RCT comparing... [/fig_ref]. Groin pain starts during extreme sport activity, usually with no proper buildup of durability, acceleration, deceleration, and rotation. Pain responds to conservative treatment, anti-inflammatory drugs, and rest. Pain typically recurs at the resumption of sport activity. ## History # Statements # Diagnostic procedures statements ## Recommendations Diagnosis of chronic groin pain is difficult, but early diagnosis is very important because morbidity will be reduced. These groin injuries are some of the most challenging injuries in the field of sports medicine, and the literature provides no consensus on definitions of diagnostic criteria for groin pain in athletes . The combination of complex anatomy , variability of presentation, and the nonspecific nature of the signs and symptoms make the diagnostic process problematical. Therefore, management of groin injuries can be challenging, and diagnosis can be difficult because of the degree of overlap of symptoms between the different problems . This clinical setting demands the recruitment of a team with experience of different aspects of groin pain. Ekberg et al. have established a multidisciplinary investigation to reveal the underlying cause. These examinations included general surgeons for detection of inguinal hernia and neuralgia, orthopedic surgeons for detection of adductor tenoperiostitis and symphysitis, urologist for detection of prostatitis, radiologist for performing different imaging tests, and nuclear medicine for isotope studies. For these reasons, the so-called SH is largely a clinical diagnosis of exclusion [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. SH must be distinguished from the more common osteitis pubis and musculotendinous injuries . The first step is to determine the differential diagnosis of hip and groin pain with respect to the high frequency of referred pain from the lumbar spine, lower abdomen, and pelvis , which is very difficult in some cases. A systematic approach to the hip and groin area is important to identify the origin of pain. Both the history and quality of symptoms and the physical examination are the basics of the diagnostic algorithm. In some cases, the diagnostic workup with roentgenograms and possibly an injection with a local anesthetic to the suspected origin of pain are completed . There are clinical signs for the diagnosis of nerve pathologies, such us obturator neuropathies. These patients usually have clinical symptoms and signs of postexercise groin, lower abdominal or medial tight pain, and adductor muscles weakness and paresthesia in cutaneous distribution of medial thigh. Except clinical signs in the diagnosis of obturator neuropathy diagnostic local anesthetic block and electromyography have been used . History of chronic groin pain that is nonresponsive to treatment should raise suspicion of SH ; however, physical examination findings are subtle and most diagnostic tests do not definitively confirm the diagnosis [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. Traditional physiotherapy of isometric active weight-bearing exercise will result in complete healing of almost all athletes [bib_ref] Groin injuries in athletes, Morelli [/bib_ref]. It is important to highlight that adductor strain is a possible part of this pathological syndrome and therefore tenotomy should not be performed under any circumstances . Finally, in selected cases, correct diagnosis is only possible with diagnostic laparoscopy [bib_ref] Laparoscopic repair of ''sportsman's hernia'' in soccer players as treatment of chronic..., Susmallian [/bib_ref]. ## Level 2b In patients with chronic groin pain and clinically uncertain herniations, magnetic resonance imaging (MRI) and ultrasound (US) are valid diagnostic tools. Level 3B Ultrasound is a useful adjunct diagnostic tool, not only to evaluate the groin for hernias, with high overall accuracy, but also in SH to identify inguinal canal posterior wall deficiency in young men with no clinical signs of hernia with chronic groin pain. Level 4 The management of groin injuries demands the recruitment of a team with experience with different aspects of groin pain. Both the history and quality of symptoms and the physical examination may help to differentiate between SH and TE. History of chronic groin pain that is nonresponsive to conservative treatment should raise suspicion of SH. MRI appears to have excellent diagnostic potential for assessing various causes of long-standing groin pain (LSGP) in athletes. MRI may not be a useful tool for deciding between operative or conservative treatment. MRI is a valuable tool to monitor the alterations with reference to their response to conservative treatment, which alos may help the athletes to return to their activities. Dynamic ultrasound shows promising results in accurately diagnosing SH. In selected cases, laparoscopic inguinal exploration may be helpful. Essentially, it is a diagnosis that can only be confirmed at surgery. Grade 3A Comprehensive physical examination that requires excluding numerous other musculoskeletal and nonmuscoloskeletal conditions is mandatory. Plain radiography, ultrasonography, and scintigraphy should be the first-line investigations to supplement clinical investigation. The cost of computed tomography and magnetic resonance imaging are such that their routine use for assessment of patients with groin pain cannot be justified. They may, however, be employed in difficult cases to help define the anatomical extent of a groin injury. Dynamic ultrasound may be able to replace historical inguinal herniography. In unclear cases with some suspicion of posterior wall deficiency, surgical exploration should be performed. Gradual physical therapy combined with pharmacotherapy should be effective in most cases and should be part of the diagnosis process. ## Physical examination Physical examination is the first step in the diagnosis of groin pain, although symptoms often are vague and diffuse . When active, sportsmen start to feel a dull pain in the groin region. A deep palpation above the inguinal canal will find the area to be sensitive and the external inguinal ring dilated . In a digital examination of the canal, a soft bulge can be felt against the tip of the finger and extreme sensitivity to pressure applied with the tip of the finger against the floor of the canal where the genito-femoral nerve passes. With this syndrome, the nerve is entrapped under the IPT (ileo-pubic tract) in the internal inguinal ring area [bib_ref] Nerve entrapment syndromes as a cause of pain in the hip, groin..., Mccrory [/bib_ref]. In addition, all of the symptoms increase during coughing. The clinical assessment of groin pain in athletes is difficult; the lack of specific clinical tests is in part responsible. The examinations could include evaluation of adductor muscle-related pain and strength, iliopsoas muscle-related pain, strength, and flexibility, abdominal muscle-related pain, and strength and pain at the symphysis joint, but the only test without acceptable interobserver reliability was the strength test for iliopsoas muscle . Gradual physical therapy combined with pharmacotherapy should be effective in most cases and should be part of the diagnosis process. This process includes nonsteroid antiinflammatory drugs and muscle relaxants. A physical therapy program usually involves stretching and strengthening of adductor muscles, abdominal wall muscles, iliopsoas muscle, quadriceps, and hamstrings. If physical therapy and pharmacotherapy fail, different tests should be performed. ## Ultrasound Ultrasound is a useful adjunct to evaluate the groin for hernia. The overall accuracy in finding a hernia of any kind by ultrasound is 92%. On the other hand, this imaging test identifies the pathology in a groin without a palpable bulge at an accuracy of 75% . Ultrasound, which enables a dynamic assessment, is particularly useful in these patients [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref]. Dynamic ultrasound examination is able to detect inguinal canal posterior wall deficiency in young men with no clinical signs of hernia with chronic groin pain. As the patient actively strains during the investigation, a real-time convex anterior bulge and ballooning of the inguinal canal can be observed at the superficial inguinal ring. This examination has been proposed to be performed with the patient in the supine and erect positions, in a relaxed state, as well as during coughing and during Valsalva maneuver [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref]. Orchard et al. [bib_ref] Groin pain associated with ultrasound finding of inguinal canal posterior wall deficiency..., Orchard [/bib_ref] have shown a correlation between bilateral deficiency of the posterior wall and groin pain, although the temporal relationship between the clinical and ultrasound findings was not established by this study. Depasquale et al. also have shown that ultrasound is a useful tool for identifying hernias, and therefore, aids surgical management; 39% (n = 94) of the patients examined who had groin pain were positive for hernias. Only four false-positive were found of the 62 who underwent surgery, giving a positive predictive value of 94% in operated patients. Not seldom, a preperitoneal lipoma herniating into the inner inguinal ring and canal or the obturator canal can be demonstrated by ultrasound. Evidence of genito-femoral nerve entrapment can be shown by edema behind the IPT on the level of internal inguinal ring. In some cases, tears and strain of the conjoint tendon in its insertion to the pubis can be seen. Even though some authors still advocate herniography for identifying impalpable herniations causing pain in athletes [bib_ref] The value of herniography in football players with obscure groin pain, Yilmazlar [/bib_ref] , today dynamic ultrasound should be the diagnostic tool of first choice. ## Ct scan and mri CT scan and MRI have been proposed as diagnostic tests for chronic groin pain, but the costs are such that their routine use for assessment of patients with groin pain cannot be justified . Furthermore, MRI is not a useful tool for deciding between operative and conservative treatment . Bone scan, plain radiography, and ultrasound has been used for diagnosing these entities, but MRI appears to be superior [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref] [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref] [bib_ref] Outcome of conservative management of athletic chronic groin injury diagnosed as pubic..., Verrall [/bib_ref] [bib_ref] Incidence of pubic bone marrow oedema in Australian rules football players: relation..., Verrall [/bib_ref]. A clinical and imaging diagnosis is crucial, because in PBSI there is no need for surgical intervention. The use of CT scans could help to identify posterior inguinal wall deficiencies and hernias in some cases [bib_ref] Surgery for posterior inguinal wall deficiency in athletes, Steele [/bib_ref] and may be employed in difficult cases to help define the anatomical extent of a groin injury . On the other hand, MRI provided an accurate depiction of pubic bone alterations and of adjacent myotendinous structures [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] and also was very useful to determine the presence of inguinal hernias , because allows the direct visualization of the hernial sac within the inguinal canal. Athletes with groin pain and tenderness of the pubic symphysis and/or superior pubic ramus have clinical features consistent with the diagnosis of osteitis pubis. The increased signal intensity seen on MRI is due to pubic bone marrow edema. A stress injury to the pubic bone is the most likely explanation for these MRI findings. MRI can permit an accurate and early diagnosis of the different sport-related pubic conditions and also is a valuable tool for monitoring the alterations with reference to their response to treatment, which may help the athletes return to their activities. It should be considered that abnormal magnetic resonance imaging findings are common in asymptomatic athletes, which decreases the value of magnetic resonance imaging in surgical decision-making [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref]. ## Indication for surgery # Statements ## Recommendations Type of surgical procedure Statements ## Recommendations # Postsurgical rehabilitation statements Recommendations Chronic groin pain in athletes is a difficult problem that requires a multidisciplinary approach not only to diagnosis but also for treatment planning [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. Based on previous definitions, if this imbalance of the groin causes a disruption of the muscle/tendon at their insertion site on the pubis, treatment should be based on rest, anti-inflammatory medication, and a proper training program followed by reevaluation. For that reason, conservative treatment is tried first , but there is no evidence-based consensus available to guide decision-making [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. If a weak area has been found at the groin due to the forces produced by the muscles, patients should undergo surgical repair of the groin reinforcing the posterior wall with mesh, because if a conjoined tendon is adequately supported by mesh, abductor discomfort almost uniformly resolves with postoperative rehabilitation. Rarely will the abductor require an operative release, tenotomy, or perforation on the pubis. Level 1B An active physical therapy program designed to strengthen the muscles to stabilize the hip and pelvis has positive effects and leads to earlier return to sports at the same level, and it is superior to a physiotherapy treatment without active training. Level 3A Until now, there has been no evidence-based consensus available to guide decision-making. The methodological quality of the studies available or analysis is low. A single entheseal pubic cleft injection can be expected to afford at least 1 year of relief from adductor-related groin pain in a competitive athlete with normal findings on a magnetic resonance imaging scan. Surgery seems to be more effective than conservative treatment for SH. Good results can be obtained with surgery when posterior inguinal wall deficiency is the sole diagnosis. Information on specific conservative interventions is poorly presented, and well-designed studies are lacking. In PBSI, conservative management results more likely in an excellent outcome. In SH, the results of surgical repair to the posterior inguinal wall are excellent. Grade B A multidisciplinary approach to groin pain should be adopted. Generally, conservative measures should be tried first, consisting of an initial period of rest or restricted activities, followed by physical therapy designed to stabilize the pelvis and hip. When conservative management has failed, surgical intervention should be done. Grade D Athletes with chronic groin pain and PWD who are unable to compete in active sports should be considered for routine inguinal hernia repair if no other pathology is evident after clinical examination and investigation. Level 3A Both open and laparoscopic surgical approaches have been reported to eliminate symptoms effectively and enable patients to return to previous sporting activity levels. The success rates are very good and comparable between open (92.8%) and laparoscopic (96%) repairs based solely on the criterion of return to sports activity. A wide variety of open repair techniques are described with or without mesh, including repair of a presumed ''thin'' or damaged insertion of the tendon of the rectus abdominis onto the pubic crest, but there are no data allowing a comparison between these techniques. There is no scientific evidence that an adductor tenotomy is of any additional value. In open repair, ilioinguinal nerve resection seems to be beneficial. Laparoscopic approach may provide better posterior inguinal wall exposure, enabling easier bilateral reinforcement. Two variations of laparoscopic surgery are applied: the transabdominal preperitoneal patch plasty (TAPP) and the total extraperitoneal patch plasty (TEP); however, no study shows the superiority of one compared with the other. ## Level 3a A detailed description of postsurgical rehabilitation programs is generally lacking. Level 4 For patients who underwent open repair, overall postsurgical recovery time (based on return to sports activity) was found to be 17.7 weeks compared with 6.1 weeks for laparoscopic repairs. Grade C Regarding time of recovery and return to preinjury sports activity levels, laparoscopic surgery-either TAPP or TEP-should be the treatment of choice. Well-designed prospective, randomized, controlled studies are greatly needed to establish the true efficacy of these different surgical approaches. Grade 3A Early, sharp, sudden movements after surgery should be avoided, and core and leg musculoskeletal inflexibility, weakness, poor endurance, or poor coordination should be identified and corrected. ## Grade 4 A gradually progressive 6-week rehabilitation program should be undertaken after both open and laparoscopic repair. Grade 5 Well-designed studies are greatly needed. ## Conservative treatment Much groin pain due to problems related to the musculoskeletal system are a self-limiting disease that can take several months to resolve, and corticosteroid injection can sometimes hasten this rehabilitation process . Traditional conservative treatment has low success rates [bib_ref] Groin injuries in athletes, Morelli [/bib_ref]. Only one RCT could demonstrate that an active physical training program designed to strengthen the muscles to stabilize the hip and pelvis is of advantage for the patient compared with passive measures . Most studies agree that surgical therapy seems to be superior to nonsurgical treatment , but there is only one randomized comparison of poor quality . On the other hand, Schilders et al. [bib_ref] Adductor-related groin pain in competitive athletes. Role of adductor enthesis, magnetic resonance..., Schilders [/bib_ref] has shown the efficiency of a single entheseal pubic cleft injection. This treatment can be expected to afford at least 1 year of relief of adductor-related groin pain in a competitive athlete with normal findings on a magnetic resonance imaging scan; however, it should be employed only as a diagnostic test or short-term treatment for a competitive athlete with evidence of enthesopathy on magnetic resonance imaging. ## Surgery Conservative treatment of this entity often does not result in resolution of symptoms [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. In some series, the athletes have received different conservative treatments without success, and the surgical procedures performed in these cases have offered a definitive resolution to this problem . Several surgical approaches are available for the repair of inguinal hernias, but without knowing the true natural history of this disorder, the problem is that it is difficult to know when it is appropriate to have a hernia repaired [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref]. Operating is recommended only if conservative therapy, with prolonged rest, fails . It is important to establish that precise diagnose is always preferable before performing a hernia repair in a patient with chronic groin pain. Steele et al. [bib_ref] Surgery for posterior inguinal wall deficiency in athletes, Steele [/bib_ref] showed no significant difference in outcome between subjects who had an abnormal ultrasound scan on the symptomatic side and those who had a normal scan. There was a significant difference in outcome between patients who had a bone scan with increased uptake at the symptomatic pubic tubercle and those who did not (p \ 0.04). This study supports other research that shows that good results can be obtained with surgery when posterior inguinal wall deficiency is the sole diagnosis. Surgical intervention of hernia repair for chronic groin pain results in pain-free return of full activities in a majority of cases [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. No consensus view supports any particular surgical procedure for sportsman's hernia . Various types of operations, based on the variable theories regarding the pathophysiological process, have been developed for the treatment of this syndrome. Some surgeons focus on the external elements of the inguinal canal and repair the external oblique fascia or enforce the groin with the rectus abdominis. Other surgeons perform an inguinal hernia repair procedure, either with sutures or synthetic mesh, performed by an open approach or laparoscopically. Some researchers believe that the problem is in the lower abdominal muscles, or is caused by nerve entrapment, and treat it accordingly. Recent authors compared an open technique (Bassini) and neurotomy of the ileoinguinal nerve applied to patients with a positive herniogram and/or positive nerve block test with athletes who were treated conservatively . Some authors recommend that, in cases where PWD or tear of the posterior inguinal wall are clearly diagnosed, routine inguinal hernia repair should be done without unnecessary delay [bib_ref] Inguinal surgery in athletes with chronic groin pain: the 'sportsman's' hernia, Malycha [/bib_ref] [bib_ref] Sportsman's hernia, Moeller [/bib_ref]. Basically, a number of reports have been published that describe different repairs of the posterior inguinal wall deficiency as the main approach for sportman's hernias with excellent results . During the operation, the inguinal canal should be thoroughly explored to find the different entities that could be detected during surgery, such us a true inguinal hernia, wide internal ring and peritoneal dimple [bib_ref] Laparoscopic repair of ''sportsman's hernia'' in soccer players as treatment of chronic..., Susmallian [/bib_ref] , hernia femoralis , preperitoneal lipoma [bib_ref] Abdominal musculature abnormalities as a cause of groin pain in athletes. Inguinal..., Taylor [/bib_ref] , hernia obturatoria , prevascular hernia , obvious musculotendinous tear [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] , muscle asymmetry [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] , or a significant bulge in the posterior wall [bib_ref] Laparoscopic repair of recurrent groin hernia: results of a prospective study, Tantia [/bib_ref]. Even if no clear pathology is identified, reinforcement of the wall using a mesh offers good clinical results for athletes with idiopathic groin pain [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref] , although other authors have recommended not using the mesh in these cases . The most common finding in athletes with chronic groin pain was a deficiency of the posterior wall of the inguinal canal [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref]. Some authors believe that ilioinguinal nerve resection may be beneficial for patients [bib_ref] Inguinal surgery for debilitating chronic groin pain in athletes, Polglase [/bib_ref] [bib_ref] ) any question, costs are an important issue. Several studies attempted to..., Ziprin [/bib_ref] , but the overall quality of most of the studies is low . When the surgical option is selected, either the open or the laparoscopic approach can provide good results . The endoscopic preperitoneal approach the technique was used more during the past year [bib_ref] Pubic magnetic resonance imaging findings in surgically and conservatively treated athletes with..., Paajanen [/bib_ref] [bib_ref] Long-term followup of laparoscopic preperitoneal hernia repair in professional athletes, Srinivasan [/bib_ref] [bib_ref] Laparoscopic repair of ''sportsman's hernia'' in soccer players as treatment of chronic..., Susmallian [/bib_ref] [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref] , although other authors consider an open hernia repair using mesh, performed as an outpatient procedure with local anesthesia and sedation as the optimal treatment . Ingoldby performed a comparative nonrandomized study that compared the open and the laparoscopic approach, which showed that the endoscopic repair permits an early return to activity. A wide variety of open repair techniques are described with mesh [bib_ref] Surgery for posterior inguinal wall deficiency in athletes, Steele [/bib_ref] [bib_ref] Abdominal musculature abnormalities as a cause of groin pain in athletes. Inguinal..., Taylor [/bib_ref] or without , including repair of a ''thin'' or damaged insertion of the tendon of the rectus abdominis onto the pubic crest [bib_ref] Management of severe lower abdominal or inguinal pain in high-performance athletes. Performing..., Meyers [/bib_ref] [bib_ref] Experience with ''sports hernia'' spanning two decades, Meyers [/bib_ref] , but there are no data allowing a comparison between these techniques . One author reported good preliminary results for using fibrin glue to secure the mesh and achieve tension-free open inguinal hernia repair in soccer athletes with chronic pain . The laparoscopic approach may provide better posterior inguinal wall exposure, enabling easier bilateral reinforcement and allow a quicker recovery time than open surgery [bib_ref] The athletic hernia: a systematic review, Swan [/bib_ref]. Two types of laparoscopic surgery are successfully applied: the transabdominal preperitoneal patch plasty (TAPP) [bib_ref] Transabdominal preperitoneal laparoscopic approach for the treatment of sportsman's hernia, Ziprin [/bib_ref] , and the total extraperitoneal preperitoneal patch plasty [bib_ref] Totally extraperitoneal endoscopic (TEP) treatment of sportsman's hernia, Paajanen [/bib_ref] [bib_ref] Long-term followup of laparoscopic preperitoneal hernia repair in professional athletes, Srinivasan [/bib_ref] [bib_ref] Laparoscopic repair of ''sportsman's hernia'' in soccer players as treatment of chronic..., Susmallian [/bib_ref] [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref]. No studies have shown the true efficacy of these different techniques, thus a recommendation for one or the other method cannot be given and depends on the skill and personal preference of the surgeon involved. Well-designed prospective, randomized, controlled studies are greatly needed for more clarity and more reliable recommendations. The same is true with respect to postsurgical rehabilitation programs. Until now, there has been no general agreement about the best postoperative physical training programme to enable the athletes to return to full sports activity in the shortest time [bib_ref] Successful endoscopic treatment of chronic groin pain in athletes, Van Veen [/bib_ref]. Valuable studies that have a high level of evidence are urgently needed. [fig] 1: Ferzli GS, Kiel T (1997) The role of the endoscopic extraperitoneal approach in large inguinal scrotal hernias. Surg Endosc 11:299-302. (4) 2. Leibl BJ, Schmedt CG, Kraft K, Ulrich M, Bittner R (2000) Scrotal hernias: a contraindication for an endoscopic procedure? Results of a single-institution experience in transabdominal preperitoneal repair. Surg Endosc 14:289-292. (4) 3. Bittner R, Schmedt CG, Schwarz J, Kraft K, Leibl BJ (2002) Laparoscopic transperitoneal procedure for routine repair of groin hernia. Br J Surg 89:1062-1066. (4) 4. Hollinsky C, Sandberg S, Koch T, Seidler S (2008) Biomechanical properties of lightweight versus heavyweight meshes for laparoscopic inguinal hernia repair and their impact on recurrence rates. Surg Endosc 22:2679-2685. (5) 5. Hollinsky C, Hollinsky K (1999) Static calculations for mesh fixation by intraabdominal pressure in laparoscopic extraperitoneal herniorrhaphy. Surg Laparosc Endosc Percutan Tech 9:106-109. (5) 6. Palanivelu C, Rangarajan M, John SJ (2007) Modified technique of laparoscopic intraperitoneal hernioplasty for irreducible scrotal hernias (omentoceles): how to remove the hernial contents. World J Surg 31:1889-1891. (4) 7. Leibl BJ, Schmedt CG, Kraft K, Kraft B, Bittner R (2001) Laparoscopic transperitoneal hernia repair of incarcerated hernias: Is it feasible? Results of a prospective study. Surg Endosc 15:1179-1183. (4) 8. Rebuffat C, Galli A, Scalambra MS, Balsamo F (2006) Laparoscopic repair of strangulated hernias. Surg Endosc 20:131-134. (4) 9. Ishihara T, Kubota K, Eda N, Ishibashi S, Haraguchiy (1996) Laparoscopic approach to incarcerated inguinal hernia. Surg Endosc 10:1111-1113. (4) 10. Legnani GL, Rasini M, Pastori S, Sarli D (2008) [/fig] [table] 5: The level of evidence for the different technical key points is very heterogeneous. Level 5 The supposed consensus on the technical requirements for TAPP is not well supported by the literature. [/table] [table] Table 2: Details of visceral and vascular injuries from non-randomized studies of TAPP and TEP [/table] [table] Table 3: Complications and recurrence rates after TAPP hernia repair in various series from 1990 to 1998 rence rates and chronic groin pain. It is generally believed that TAPP is easier to teach and learn, although there is no level 1 evidence in the literature to support this belief. We need to generate more data comparing TAPP and TEP by conducting randomized, controlled trials. A laparoscopic hernia surgeon must be familiar with open techniques, because there are instances where the procedure needs conversion. A TEP procedure can be easily converted to TAPP rather than to open procedure. References (in parentheses graduation of evidence) 1. Lichtenstein IL, Shulman AG, Amid PK, Montllor MM (1989) The tension-free hernioplasty. Am J Surg 157:188-193. (4) [/table] [table] Table 4: Complications and recurrence rates after TEP hernia repair in various series from 1990 to 1998 [/table] [table] 9: 26 cm 2 ). The open operation was faster (56 vs. 79 min; p = 0.001). There were no wound infections in TAPP compared with four with the open (p = 0.04). The recurrence rate was higher for TAPP (12.5 vs. 1.9%), but there was ''variable degree of experience with the TAPP approach, and all surgeons had performed less than 50 cases. The TAPP group was able to be discharged same day in 93% of the cases compared with 77% with open. Interestingly, the cost of surgery was comparable in both goups ($1,179 for TAPP and $1,150 for open).Aitola et al.[5] compared TAPP with open preperitoneal approach (opening the transversalis fascia from internal ring to pubic tubercle and suturing 6 9 12 cm 2 Marlex mesh to Cooper's, rectus, and Transversalis fascia). There were 24 patients in TAPP and 25 in the open group. Interestingly, there were twice as many patients with recurrent hernia in TAPP group. The open group was faster (55 vs. 66 min, p \ 0.01), but pain was less in TAPP group (p \ 0.01). The recurrence rate was 13% with TAPP and 8% with open. They concluded that open is better due to less cost and lower recurrence rate. The size of the mesh was small in this series and the method chosen to secure the mesh was different (sutures vs. staples). The staples do not go as deep as the sutures are able. [/table]	None	https://link.springer.com/content/pdf/10.1007/s00464-011-1799-6.pdf	None
b5ba8312ccc4487251bcafb8918e00c8298d67a0	pubmed	Recommendations of the Brazilian Society of Cardiac Arrhythmias for Holter Monitoring Services	Recommendations of the Brazilian Society of Cardiac Arrhythmias for Holter Monitoring Services Background: There are innumerous indicators to assure the quality of a service. However, medical competence and the proper performance of a procedure determine its final quality. The Brazilian Society of Cardiac Arrhythmias recommends minimum parameters necessary to guarantee the excellence of ambulatory electrocardiographic monitoring services.Objective: To recommend minimum medical competences and the information required to issue a Holter monitoring report.Methods: This study was grounded in the concept of evidence-based medicine and, when evidence was not available, the opinion of a writing committee was used to formulate the recommendation. That committee consisted of professionals with experience on the difficulties of the method and management in providing services in that area.Results: The professional responsible for the Holter monitoring analysis should know cardiovascular pathologies and have consistent formation on electrocardiography, including cardiac arrhythmias and their differential diagnoses. The report should be written in a clear and objective way. The minimum parameters that comprise a Holter report should include statistics of the exam, as well as quantification and analysis of the rhythm disorders observed during monitoring.Conclusion: Ambulatory electrocardiographic monitoring should be performed by professionals knowledgeable about electrocardiographic analysis, whose report should comprise the minimum parameters mentioned in this document. (Arq Bras Cardiol. 2013;101(2):101-105) Keywords: Arrhythmias, Cardiac / diagnosis; Electrocardiography, Evidence-Based Mediate Ambulatory. by the patient under special conditions, such as the presence of a symptom.A good quality electrocardiographic recording is fundamental to the usefulness and reliability of the examination proposed, providing the necessary information. When that quality decreases, the amount of information also decreases, while the time for necessary edition increases enormously.Special ArticleLorga Filho et al. Since the 1980s, with the evolution of electronic storage, those devices evolved from real-time analysis to storage of digitalized data. Such conditions allowed a large increment in recording reliability, minimizing not only the distortions that can occur in tape recordings, but also the imperfections generated by the mechanical factors inherent in the mechanisms responsible for the rotation of the system. Data analysis has gained in accuracy and details. The 200-Hz frequencies are adequate for the analysis of ST-segment deviations and rhythm disorders. To obtain signal-averaged ECG, 1000-Hz frequencies are required. Recently, digital recorders were made available with the option of 12-lead data acquisition, by use of a cable with either ten electrodes or only five electrodes when the orthogonal leads (X, Y, and Z) of vectocardiography are associated. The software generates the electrocardiographic recording with the conventional 12 leads, at any point of the analysis. # Introduction Ambulatory electrocardiographic monitoring, simply named Holter or 24-hour Holter, is a non-invasive method widely used to assess electrocardiographic abnormalities of patients with various cardiac or non-cardiac diseases, as well as healthy individuals under special conditions or situations. Developed in the 1960s, it underwent great technological advance in recent years. Currently, the recording and storing system used (Holter recorder) is digital, having usually three channels. The device is small (approximately 8.5 x 5.3 x 2.0 cm) and lightweight (45 to 90 grams), being powered by battery, either alkaline or regular. Additional protection against fluid immersion is recommended. Recording is performed with three-channel bipolar electrodes (leads). To mark events, the recorder should have a button, which can be activated Clinical application and types of ambulatory electrocardiographic monitoring Typically, ambulatory electrocardiographic monitoring is classified according to the monitoring category into continuous and intermittent recordings. Continuous recordings usually occur for 24 hours to 48 hours, while intermittent recordings occur for longer periods of time. The device for intermittent recording, named event recorder, has a memory loop that saves random recordings or those motivated by any clinical symptom. Although there is no clinical study assessing the profile of patients who better benefit from continuous or intermittent recordings, the frequency of the symptoms is the parameter used to choose between both methods. Thus, for patients with sporadic symptoms, the use of the event recorder might be more appropriate, especially for assessing near syncope, syncope and sporadic palpitations 1 . ## Special article The implantable event recorder is available in the market to document infrequent symptoms. It is a small device implanted under the skin of the infraclavicular region, which can maintain circular electrocardiographic monitoring for long periods. The use of digital 3-channel 24-hour Holter in clinical practice is aimed at characterizing and diagnosing the occurrence of abnormal electrical cardiac behavior during daily activities (sleep, work, physical exercise, emotional stress, rest). It is mainly, but not exclusively, used for symptomatic or asymptomatic cardiac arrhythmias. However, Holter analysis can also provide the following: ST-segment assessment with or without associated arrhythmias (such as intermittent preexcitation, Brugada-type abnormalities, silent or non-silent ischemia, short or long QT, transient or non-transient abnormality); and autonomous nervous system analysis via heart rate variability 2 . In addition to diagnostic assessment, Holter monitoring can be used to evaluate the efficacy of therapy, both pharmacologic and invasive, for cardiac rhythm disorders and to stratify the risk for sudden death (Box 1). The pattern of beat-to-beat heart rate variability, at baseline or in response to a certain standardized stimulus, can be an objective and non-invasive measure to quantify the autonomic status under physiological and pathological conditions 3 . The analysis techniques most frequently used to determine heart rate variability are obtained in the time and frequency domains. Measures in the time domain are usually taken during 24 hours. In such recordings, the QRS complexes are detected, artifacts and ectopic beats being excluded to avoid hindering statistical analyses. The frequency cycles between the QRS complexes are determined and the statistical distributions of all cycles are calculated as mean and standard deviation. The frequency domain analyzes heart rate variability in another way, its principle residing in the fact that every NN interval can be broken into a series of oscillatory components with different frequencies and amplitudes. Box 2 shows the major cardiac arrhythmias that can be diagnosed by use of digital 3-channel 24-hour Holter. ## Technical aspects of the method Although electrode placement may seem to have little significance for Holter monitoring, it is fundamental to a successful procedure. The skin should be properly cleansed with alcohol to remove grease, and then dried before placing the electrodes, which should be pressed in the periphery of their adhesive areas, and not in their centers, to avoid displacing the gel. A good quality electrode is cost-effective, because it guarantees a better tracing quality and less skin irritation. Box 3 shows the technical recommendations for 24-h Holter monitoring. Holter should be performed with at least three bipolar channels. If on the one hand an increase in the number of electrodes increases patient's discomfort, on the other, the origin of some arrhythmias can be located with a greater number of leads. Although the cases should be individually considered, in clinical practice, the use of three leads seems to meet the requirement in most situations. The choice of the leads should be standardized to allow maximum information regarding morphology and should have good amplitude to avoid failure in heart beat capture. The electrocardiographic channels usually used in Holter monitoring are the modified bipolar leads: V5, V3 and inferior lead 4 . The recommended maximum density of artifacts during monitoring is 5%. Greater figures should be analyzed considering the need to repeat the recording. In some cases with spiked T wave, it can be misdetected as a beat, and thus the complex needs to be excluded, causing an overestimated artifact rate that does not interfere with the overall analysis. Day-to-day variability in the distribution of arrhythmias is a reality [bib_ref] Use of ambulatory electrocardiographic (Holter) monitoring, Dimarco [/bib_ref] [bib_ref] Spontaneous variability of ventricular arrhythmias in patients References at increased risk for..., Pratt [/bib_ref] [bib_ref] Variability of ventricular arrhythmias in hypertrophic cardiomyopathy and implications for treatment, Mulrow [/bib_ref]. Most clinical studies on arrhythmias uses 24-hour monitoring; however, more prolonged periods or repetition of the monitoring can increase the accuracy of the exam [bib_ref] The duration of Holter monitoring in patients with syncope: is 24 hours..., Bass [/bib_ref]. The Brazilian Society of Cardiac Arrhythmias recommends monitoring for at least 18 hours, including wakefulness and asleep periods, for the analysis and report of ambulatory electrocardiographic monitoring. Minimum knowledge and training required to analyze electrocardiographic monitoring tracings The professional responsible for analyzing the Holter monitoring , in addition to knowing cardiovascular pathologies, should have a consistent and specific formation in electrocardiography, including cardiac arrhythmias and their differential diagnoses. The correct interpretation of STsegment deviations, cardiac ischemia and heart rate variability also constitutes a necessary attribute for issuing a Holter report. Box 4 summarizes the major points of medical knowledge required to assess ambulatory electrocardiographic monitoring. ## Proof of competence A s s e s s i n g a n d i n t e r p r e t i n g t h e a m b u l a t o r y electrocardiographic tracing is a medical act to be performed exclusively by physicians registered in the Regional Board of Medicine, who are apt to professional practice. The Brazilian Society of Cardiac Arrhythmias (Sobrac) recommends that professionals have the specialist title in clinical arrhythmia or electrophysiology with a minimum supervised experience of analyzing 150 tracings 9 , in addition to competence regarding the necessary medical knowledge listed in Box 4. ## Role of the holter technician The performance of a Holter technician at a certain service depends on the preference of the physician in charge. Box 5 lists the technician's assignments. It is worth noting that the technician is forbidden to act alone without the supervision of a knowledgeable physician according to the recommendations of Box 4. The Holter technician should be trained at official institutions or with an acknowledged professional in the field with a minimum experience of analyzing 1,000 tracings. ## Minimum report in ambulatory electrocardiographic monitoring The report should be written in a clear and objective way. The report digital file should be saved for at least five years, preferentially for ten years. The report should comprise the parameters listed in Box 6. - To know cardiac arrhythmias, their diagnoses and meaning in healthy individuals and cardiac patients. - To know the wide variability of arrhythmias that can occur in ambulatory patients during a day cycle and the influence of the autonomous nervous system on cardiac rhythm. ## Complete list of authors: - To know the electrocardiographic changes that can result from exercises, hyperventilation, conduction disorders, electrolytic changes, drugs, food, temperature, Valsalva's maneuver, sympathetic and vagal influence, respiratory disorders of sleep, position variation, ischemia, and transient phenomena of repolarization related to a variety of cardiac diseases and their treatment. - To know the drugs used in cardiology and how they can affect conduction and repolarization on the electrocardiogram, particularly in suspected proarrhythmia phenomena. - To know the diagnostic sensitivity, specificity and accuracy of ambulatory electrocardiography in several age and population groups, particularly regarding changes in the ST segment, and the application of Bayes theorem. - To know the ST-segment deviations most accepted as criteria for ischemia. - To identify on ambulatory electrocardiogram the evidence of loss of capture, loss of sensing, and loss of pacing of pacemakers and cardioverter/defibrillators. - To identify on ambulatory electrocardiogram the evidence to diagnose appropriate or inappropriate therapy with antitachycardia stimulation or defibrillation in patients with implantable cardiac defibrillator. - To have basic understanding of the advantages and disadvantages of the equipment used for continuous and intermittent ambulatory electrocardiography recording and the possible causes of false-positivity and false-negativity of tests due to limitations inherent in the equipment or in signal processing. - To know the particularities of the ambulatory electrocardiographic monitoring equipment. - To appreciate the competences required for the technician to interact with the ambulatory electrocardiographic monitoring equipment in the final computer edition and the need to have that technician's competence assured. ## Box 5 -attributions of the holter technician at ambulatory electrocardiographic monitoring services -Import and export of tracings in computerized systems -Diagnostic assessment and elimination of artifacts -Selection of significant tracings for the Holter report -Selection of symptom-related tracings Box 6 -Minimum requirements for issuing a report in ambulatory electrocardiographic monitoring - Baseline cardiac rhythm during monitoring with mean, minimum and maximum heart rate. - To quantify and qualify the rhythm disorders of atrial origin. - To quantify and qualify the rhythm disorders of ventricular origin. - To assess the presence of pauses and to quantify their duration and relationship with wakefulness and asleep periods. - To assess the presence and type of AV conduction disorders. - To assess the presence and type of IV conduction disorders. - To assess the presence of ventricular repolarization disorders, such as QT-interval duration. - To assess the Holter diary and correlate symptoms with concomitant electrocardiographic findings. - To assess the medications used in the 24-hour period and correlate them with electrocardiographic findings. - To report the technical quality of the recording when applicable. - To provide a statistical summary of events. - To provide a timetable with heart rate behavior and distribution of arrhythmic events. - To provide a graph with the ST-T segment behavior in the presence of a change. - To provide an electrocardiographic recording of the major events identified at the speed of 25 mm/s and gain of 1 mm/mVolt. - To provide an electrocardiographic recording at the beginning and end, at the speed of 25 mm/s and gain of 1 mm/mVolt. - To provide an electrocardiographic recording of the maximum and minimum heart rate at the speed of 25 mm/s and gain of 1 mm/mVolt. - To provide condensed recordings that can be used to exemplify more prolonged arrhythmias or their occurrence in a wider context. - To provide the electrocardiographic tracings that validate the findings described in the report. - To provide a summary of heart rate variability when applicable. - To record at least 8 tracings per exam. - To provide readable name, signature and inscription number in the Regional Board of Medicine of the physician in charge. To provide a digital signature for reports sent over the internet. Note: AV: atrioventricular. IV: interventricular. [fig] Box 1 -: Analyses available on ambulatory electrocardiographic monitoring I -Assessment of symptoms that might be related to cardiac rhythm disorders II -Assessment of myocardial ischemia III -Assessment of the risk for future cardiac events -cardiac arrhythmia -heart rate variability -myocardial ischemia -microvolt T-wave alternans (TWA) -QT-interval variations IV -Therapeutic assessment -drugs -surgery -catheter ablation -implantable pacemakers and defibrillators V -Special situations -atrial fibrillation -syncope VI -Assessment of pacemaker [/fig]	None	None	Background There are innumerous indicators to assure the quality of a service. However, medical competence and the proper performance of a procedure determine its final quality. The Brazilian Society of Cardiac Arrhythmias recommends minimum parameters necessary to guarantee the excellence of ambulatory electrocardiographic monitoring services. Objective To recommend minimum medical competences and the information required to issue a Holter monitoring report. Methods This study was grounded in the concept of evidence-based medicine and, when evidence was not available, the opinion of a writing committee was used to formulate the recommendation. That committee consisted of professionals with experience on the difficulties of the method and management in providing services in that area. Results The professional responsible for the Holter monitoring analysis should know cardiovascular pathologies and have consistent formation on electrocardiography, including cardiac arrhythmias and their differential diagnoses. The report should be written in a clear and objective way. The minimum parameters that comprise a Holter report should include statistics of the exam, as well as quantification and analysis of the rhythm disorders observed during monitoring. Conclusion Ambulatory electrocardiographic monitoring should be performed by professionals knowledgeable about electrocardiographic analysis, whose report should comprise the minimum parameters mentioned in this document.
93d2952e7d7e5db3cc7aa2015ae0830d6d8e73a4	pubmed	Revision and update on clinical practice guideline for liver cirrhosis	Revision and update on clinical practice guideline for liver cirrhosis # Introduction Liver cirrhosis (LC) is a disease with a high rate of prevalence and one of the most common causes of mortality in the Republic of Korea (hereafter "Korea"). In Korea, the main etiologies of LC have been found to be chronic hepatitis B (CHB), alcohol, and chronic hepatitis C (CHC). In patients with complications such as ascites, variceal bleeding, and encephalopathy, the 5-year survival rates were 32%, 21%, and 40%, respectively, reflecting the poor (moderate-quality evidence), and C (low-quality evidence). The strength of recommendation has been classified into 2 categories: strong and weak [fig_ref] 1: What are the precipitating factors of hepatic encephalopathy? -Precipitating factors of hepatic... [/fig_ref] ## 1-3. pathological diagnosis of liver cirrhosis The gold standard for confirming the diagnosis of LC is liver biopsy, but it is invasive and susceptible to a sampling error and inter-observer discrepancy. Therefore, liver biopsy has not been widely used in clinical practice. Liver biopsy can be carried out selectively for evaluating activity of the underlying disease and fibrosis. Particularly, when cirrhosis is diagnosed by clinical findings and imaging studies, but not compatible with laboratory data, a liver biopsy is especially helpful for diagnosing LC. 11 ## 1-4. others The serum markers for liver fibrosis directly or indirectly reflect extracellular matrix metabolism. However, their clinical utility in the diagnosis of LC has not been verified. [bib_ref] Noninvasive measures of liver fibrosis, Rockey [/bib_ref] FibroScan has been introduced to measure liver elasticity noninvasively and is an objective diagnostic tool for the diagnosis of LC. However, there is no exact guideline on how to apply it clinically, and there is some variation in its diagnostic accuracy for the diagnosis of LC. Therefore, the practical use of FibroScan is limited. ## 2-1. chronic hepatitis b Antiviral therapy that regulates inflammation via the inhibition of viral proliferation is recommended for improving liver fibrosis. [bib_ref] Histological outcome during long-term lamivudine therapy, Dienstag [/bib_ref] [bib_ref] Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B..., Yokosuka [/bib_ref] [bib_ref] Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis..., Marcellin [/bib_ref] [bib_ref] Efficacy and safety of entecavir in patients with chronic hepatitis B and..., Schiff [/bib_ref] [bib_ref] Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up..., Hadziyannis [/bib_ref] [bib_ref] Analogs and fibrosis regression in hepatitis B, Bourlière [/bib_ref] There were no significant differences in the degree of improvement in fibrosis according to antiviral drugs. [bib_ref] A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B, Chang [/bib_ref] [bib_ref] Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B, Lai [/bib_ref] [bib_ref] Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B, Marcellin [/bib_ref] As liver fibrosis progresses, the rate of improvement by antiviral treatment increases. [bib_ref] Efficacy and safety of entecavir in patients with chronic hepatitis B and..., Schiff [/bib_ref] ## 2-3. alcohol Abstinence is the most important treatment of alcoholic liver disease. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Abstinence not only improves fibrosis in hepatic tissue but also reduces portal pressure and inhibits progression to LC. Ultimately, the survival rate of patients in all stages of alcoholic liver disease increases following abstinence, with improvements being observed in up to 66% of patients. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Sustained drinking increases the risk of variceal bleeding by portal hypertension and is closely related with mortality. In severe alcoholic hepatitis, steroid and pentoxifylline therapy have been recommended by several studies. However, the effect of these drugs on fibrosis has not been confirmed; therefore, these medications are not recommended in the treatment of fibrosis as anti-fibrotic therapy. ## 2-4. nonalcoholic fatty liver Treatment of nonalcoholic fatty liver comprises improving insulin resistance, removing risk factors of metabolic syndrome, lifestyle modifications, drug therapy, and operative treatment. [bib_ref] Effects of weight loss on nonalcoholic fatty liver disease, Rafiq [/bib_ref] [bib_ref] Effect of body weight and lifestyle changes on long-term course of nonalcoholic..., Kim [/bib_ref] [bib_ref] Independent effects of physical activity in patients with nonalcoholic fatty liver disease, St George [/bib_ref] [bib_ref] Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without..., Johnson [/bib_ref] [bib_ref] Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children:..., Socha [/bib_ref] [bib_ref] A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis, Belfort [/bib_ref] [bib_ref] Randomized, placebo-controlledtrial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis, Aithal [/bib_ref] [bib_ref] Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand..., Neuschwander-Tetri [/bib_ref] [bib_ref] Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] A pilot study of vitamin E versus vitamin E and pioglitazone for..., Sanyal [/bib_ref] [bib_ref] Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic..., Harrison [/bib_ref] [bib_ref] Safety of oral intake of vitamin E, Bendich [/bib_ref] [bib_ref] Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality, Miller Er 3rd [/bib_ref] [bib_ref] Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial, Lindor [/bib_ref] [bib_ref] High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebocontrolled trial, Leuschner [/bib_ref] [bib_ref] Metformin in non-alcoholic steatohepatitis, Marchesini [/bib_ref] [bib_ref] Lactic acidosis in patients with diabetes treated with metformin, Misbin [/bib_ref] Weight loss appears to help in liver steatosis as well as relieves hepatic inflammation and fibrosis. [bib_ref] Effects of weight loss on nonalcoholic fatty liver disease, Rafiq [/bib_ref] [bib_ref] Effect of body weight and lifestyle changes on long-term course of nonalcoholic..., Kim [/bib_ref] [bib_ref] Independent effects of physical activity in patients with nonalcoholic fatty liver disease, St George [/bib_ref] [bib_ref] Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without..., Johnson [/bib_ref] Therefore, the first choice of therapy in nonalcoholic fatty liver disease is weight loss through diet therapy and lifestyle ## 2-5. primary biliary cirrhosis Ursodeoxycholic acid has been proven to improve primary biliary cirrhosis and is the only drug recognized for its treatment. [bib_ref] Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response..., Parés [/bib_ref] [bib_ref] A multicenter, controlled trial of ursodiol for the treatment of primary biliary..., Poupon [/bib_ref] [bib_ref] Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study..., Poupon [/bib_ref] [bib_ref] Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary..., Poupon [/bib_ref] Ursodeoxycholic acid reduces serum bilirubin levels, which is an important prognostic factor, and delays the progression and deterioration of fibrosis [bib_ref] Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study..., Poupon [/bib_ref] [bib_ref] Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary..., Poupon [/bib_ref] 13-15 mg/kg/day is the most effective dose in terms of biological effect and cost-effectiveness. Improvements of liver function tests appear within 6-9 months of therapy in more than 90% of patients. [bib_ref] Effect of cholestyramine on bile acid pattern and synthesis during administration of..., Rust [/bib_ref] Ursodeoxycholic acid treatment is not known to improve fatigue, itching, bone diseases, or autoimmune reactions associated with primary biliary cirrhosis. [bib_ref] Effect of cholestyramine on bile acid pattern and synthesis during administration of..., Rust [/bib_ref] ## Variceal bleeding Esophageal variceal bleeding is found in approximately 40% of patients with Child-Pugh A class LC, and in approximately 80% of patients with Child-Pugh C class LC. [bib_ref] Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results..., Giannini [/bib_ref] The risk of variceal bleeding depends on the size of varices, red color sign, and the Child-Pugh classification. Variceal bleeding due to portal hypertension can be prevented when the value of hepatic venous pressure gradient is lower than 12 mmHg or when it is decreased to lower than 20% of the baseline measurement. [bib_ref] Variceal bleeding: pharmacological therapy, Bosch [/bib_ref] ## 3-1. diagnosis It is recommended that all patients undergo endoscopy ## 3-2. acute esophageal variceal bleeding ## 3-2-1. definition and diagnosis Acute variceal bleeding is defined as hematemesis within last 24 hours of presentation, and/or ongoing melena, with the last melenic stool within last 24 hours before the hospital visit in a known or suspected case of portal hypertension. ## 3-2-2. treatment The first line of therapy includes vasoconstrictors such as terlipressin and somatostatin. [bib_ref] Somatostatin and analogues in portal hypertension, Abraldes [/bib_ref] Antibiotics are recommended for patients admitted in the hospital. [bib_ref] Management of varices and variceal hemorrhage in cirrhosis, Garcia-Tsao [/bib_ref] Antibiotic therapy is recommended for 5-7 days to prevent sepsis and rebleeding following endoscopy [fig_ref] Table 2: Drugs for acute esophageal variceal bleeding [/fig_ref]. [bib_ref] Antibiotic prophylaxis for the prevention ofbacterial infections in cirrhotic patients with gastrointestinal..., Bernard [/bib_ref] Medication and endoscopic therapy are recommended in patients with acute variceal bleeding for the first time. [bib_ref] Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a..., Bañares [/bib_ref] If active bleeding is present, banding of the culprit vessel or that just below the ooze should be performed endoscopically. Nonselective beta-blockers do not lower the incidence of bleeding in patients with small esophageal varices. [bib_ref] Pharmacological treatment of portal hypertension: an evidence-based approach, D'amico [/bib_ref] However, patients with a high risk of bleeding (Child-Pugh class B/C or endoscopic red color sign), are considered for nonselective beta-blocker therapy.The dose of nonselective beta-blockers is adjusted for a reduction in the resting heart rate by 25%, to 55 beats/minute, or until the occurrence of side effects. In Koreans, the mean adjusted dose of propranolol is 160 mg/day. [bib_ref] Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop..., De Franchis [/bib_ref] with lesser side effects as compared with EVL. However, additional research is needed before they can be routinely used. [bib_ref] Management of varices and variceal hemorrhage in cirrhosis, Garcia-Tsao [/bib_ref] [bib_ref] Randomized controlled trial of carvedilol versus variceal band ligation for the prevention..., Tripathi [/bib_ref] Combination therapy with EVL and nonselective beta-blockers for the prevention of first bleeding has shown no differences as compared with monotherapy. [bib_ref] Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary..., Sarin [/bib_ref] ## 3-4. prevention of variceal rebleeding ## 3-4-1. definition and diagnosis Variceal rebleeding is defined as bleeding after 5 days of recovery from acute variceal bleeding.It is diagnosed similar to acute variceal bleeding. ## 3-4-2. prevention Nonselective beta-blockers alone or combination therapy with isosorbide mononitrate are known to be effective in the prevention of rebleeding. [bib_ref] Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of..., Gournay [/bib_ref] EVL shows better outcomes than endoscopic injection sclerotherapy in endoscopic therapy for prevention of rebleeding. [bib_ref] Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A..., Laine [/bib_ref] Rebleeding has been reported in 32% of patients after EVL. Combination therapy of EVL and nonselective beta-blockers has been shown to have better outcomes than EVL alone. [bib_ref] Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for..., Lo [/bib_ref] [bib_ref] Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding:..., De La Peña [/bib_ref] TIPS shows a significantly low rebleeding rate as compared with endoscopic therapy. However, it shows a significantly high incidence of hepatic encephalopathy. TIPS is not recommended as a first-line therapy for esophageal variceal bleeding and is recommended only as a rescue therapy when combination therapy fails.Liver transplantation should be considered for patients who meet indications for liver transplantation. [bib_ref] Salvage therapies for refractory variceal hemorrhage, Henderson [/bib_ref] [bib_ref] Current management of portal hypertension, Wright [/bib_ref] If the hepatic venous pressure gradient is reduced to less than 12 mmHg or to more than 20% reduction in baseline levels by medical therapy, the incidence rate of rebleeding is low (10%). [bib_ref] Prevention of variceal rebleeding, Thalheimer [/bib_ref] In such cases, further endoscopic therapy may not be required. ## 3-5. gastric varices ## 3-5-1. definition and diagnosis Gastric varices are enlarged submucosal veins of the stomach that cause critical upper gastrointestinal bleeding. Gastric varices occur in approximately 20% of patients with portal hypertension, and the bleeding rate in 2 years is known to be 25%. [bib_ref] Prevalence, classification and natural history of gastric varices: a long-term follow-up study..., Sarin [/bib_ref] Diagnosis is performed by endoscopy. Endoscopic ultrasound can also be helpful. [bib_ref] Prevalence of paraesophageal varices and gastric varices in patients achieving variceal obliteration..., Lo [/bib_ref] 3 and any other regions, i.e., stomach or duodenum (IGV2). [bib_ref] Prevalence, classification and natural history of gastric varices: a long-term follow-up study..., Sarin [/bib_ref] ## 3-5-3. treatment and prevention EVL is recommended for the treatment of GOV1. Endoscopic variceal obturation (EVO) can be an alternative. [bib_ref] Gastric variceal ligation: a new technique, Shiha [/bib_ref] ## Ascites Ascites is the most common complication in LC, occurring in 60% of the patients with compensated LC within 10 years. [bib_ref] Compensated cirrhosis: natural history and prognostic factors, Ginés [/bib_ref] Ascites appears in 2/3 of the patients who required admission due to LC, [bib_ref] The change of the etiology, complications and cause of death of the..., Han [/bib_ref] and 60% of the patients requiring paracentesis is because of LC. [bib_ref] Etiologic and laboratory analyses of ascites in patients who underwent diagnostic paracentesis, Hwangbo [/bib_ref] ## 4-1. diagnosis Abdominal ultrasound can diagnose ascites with only 100 mL. [bib_ref] Review article: Management of ascites and associated complications in patients with cirrhosis, Kuiper [/bib_ref] Ascites is classified by the amount of fluid as follows: Furthermore, paracentesis should be performed in cirrhotic patients with fever, abdominal pain, bleeding, encephalopathy, hypotension, or kidney dysfunction to assess for spontaneous bacterial peritonitis (SBP), since 10-27% of the patients with ascites have SBP. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] The main purpose of paracentesis is to discriminate the cause of ascites. Therefore, screening tests should include total cell count and differential, albumin, and total protein. Blood cell count is the most useful test for diagnosing SBP. For differential diagnosis of ascites, a serum-ascites albumin gradient can be calculated. If the serum-ascites albumin gradient is is greater than of equal to 1.1 g/dL, ascites is ascribed to portal hypertension with an accuracy of 97%. ## 4-2. treatment Although controversial, 118 a low salt diet is considered effective for controlling ascites and shortening hospitalization. Less than 5 g/day of salt (sodium for 2 g, 88 mEq) is recommended. When plasma sodium is lower than 120-125 mEq/L, water intake should be restricted to 1-1.5 L/day. ## 4-2-1. medications If severe ascites is present, diuretic therapy should be used for negative sodium balance.When peripheral edema is present, the rate of weight loss should be no greater than 1 kg/day. For patients without edema, 0.5 kg/day of weight loss is ideal.If there is no weight loss even with 5 g/day of salt intake, the diet and diuretic dose should be evaluated by examining the amount of urinary sodium excretion per day. [bib_ref] Management of adult patients with ascites due to cirrhosis: an update, Runyon [/bib_ref] Patients with low salt intake should not excrete more than 78 mEq of urinal sodium in 24 hours. In such patients, if urinary sodium excretion is more than 78 mEq, low salt intake is judged not to be followed. When the excretion is less than 78 mEq, the diuretic is considered to be inadequate and the dose needs to be increased. Spot urine Na/K ratio of more than 1 represents 24 hours urine sodium excretion more than 78 mEq. [bib_ref] Detection of diuretic-resistace or diuretic-sensitivity by the spot urine Na/K ratio in..., Stiehm [/bib_ref] It is important to check the weight loss, vital sign, changes in consciousness level, and the level of plasma sodium, potassium, and creatinine during diuretic administration. When plasma sodium is more than 126 mEq/L, diuretics can be used without the restriction of water intake. However, when plasma sodium is less than 125 mEq/L, the physician should consider cessation or reduction in the dose of the diuretic and restriction of water intake. If plasma sodium is less than 120 mEq/L, the diuretic and water intake should be stopped and a plasma expander such as albumin should be administered. If plasma sodium is less than 125 mEq/L with kidney dysfunction, the diuretic should be stopped and a plasma expander should be administered. [bib_ref] Guidelines on the management of ascites in cirrhosis, Moore [/bib_ref] If plasma potassium is less than 3.5 mEq/L, the dose of loop diuretic should be reduced or stopped. If plasma potassium is more than 5.5 mEq/L, the dose of aldosterone antagonist should be reduced. And if plasma potassium is more than 6.0 mEq/L, the aldosterone antagonist should be ceased. ## 4-2-2. therapeutic paracentesis (reference to intractable ascites section) Therapeutic paracentesis is an effective treatment for tension-type ascites, because it relieves the symptoms more quickly than diuretics and shortens hospitalization [fig_ref] Table 3: Treatment of ascites depending on the grade Grade 1, a small amount... [/fig_ref]. with refractory ascites die within 6 months and the median survival period is also less than 1 year, they should be considered for liver transplantation. [bib_ref] Persistent ascites and low serum sodium identify patients with cirrhosis and low..., Heuman [/bib_ref] ## 4-3-2. hyponatremia The diagnostic criterion for hyponatremia is less than 130 mEq/L.A hypervolemic state can be corrected to normal by a negative water balance. Eventually, dilutional hyponatremia can be improved. [bib_ref] Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis in patients with portal hypertension, Kim [/bib_ref] Restriction of water intake can prevent a decrease in the serum sodium level.Hypertonic sodium injection can worsen ascites and edema. [bib_ref] Pathogenesis and treatment of dilutional hyponatremia in cirrhosis, Cardenas [/bib_ref] Plasma expanders can be useful in the treatment of hyponatremia.Vaptan, [bib_ref] Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management, Ginès [/bib_ref]. New International Ascites Club's diagnostic criteria of hepatorenal syndrome 1) Cirrhosis with ascites 2) Serum creatinine >133 mmol/L (1.5 mg/dL) 3) No improvement of serum creatinine (decrease to a level of 133 mmol/L) after at least 2 days with diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day 4) Absence of shock 5) No current or recent treatment with nephrotoxic drugs 6) Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells/high-power field), and/or abnormal renal ultrasound. solute-free water. This agent can be used in the treatment of hyponatremia caused by inappropriate antidiuretic hormone secretion, heart failure, or liver cirrhosis. In the United States and Europe, tolvaptan and conivaptan are approved for the treatment of severe hyponatremia (<125 mEq/L). ## 4-4. hepatorenal syndrome ## 4-4-1. definition and diagnosis Renal failure in LC occurs in 2 forms. First, type 1 hepatorenal syndrome is a rapid progressive acute renal dysfunction which occurs due to the strong contraction of the renal vasculature. Type 2 hepatorenal syndrome is a relatively slow process with a rather moderate renal dysfunction. The most important mechanism involved in the occurrence of hepatorenal syndrome is decreased effective blood volume due to the dilation of the splanchnic and peripheral circulation. This situation activates the sympathetic nervous system as well as the renin-angiotensin system and causes functional renal disorder. [bib_ref] Circulatory function and hepatorenal syndrome in cirrhosis, Ruiz-Del-Arbol [/bib_ref] [bib_ref] Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial..., Ruiz-Del-Arbol [/bib_ref] [bib_ref] Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current..., Arroyo [/bib_ref] In 1994, the International Ascites Club announced the diagnostic criteria for hepatorenal syndrome; in 2007, they revised these criteria to providing clearer diagnostic methods and including infectious diseases . After administration of terlipressin, hepatic venous pressure gradient is known to decrease while the renal blood flow increases. [bib_ref] Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with..., Narahara [/bib_ref] [bib_ref] Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a..., Baik [/bib_ref] Therefore, it can also be used for treatment in patients with secondary renal insufficiency due to variceal bleeding. [bib_ref] Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results..., Ortega [/bib_ref] [bib_ref] Renal failure in cirrhotic patients: role of terlipressin in clinical approach to..., Alessandria [/bib_ref] [bib_ref] Long-term outcome of patients treated with terlipressin for types 1 and 2..., Testro [/bib_ref] Although TIPS [bib_ref] Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type..., Wong [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and..., Guevara [/bib_ref] [bib_ref] Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with..., Brensing [/bib_ref] reduces the serum creatinine levels in most patients with hepatorenal syndrome, the effect is slower than the combined use of terlipressin and albumin. In a group that used molecular adsorbent recirculating system [bib_ref] Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a..., Mitzner [/bib_ref] imaging study such as a CT should be performed (A1), and additional examinations such as those for total protein, LDH, glucose, or gram staining can be performed. (B1) -If the patient has a history of SBP, gastrointestinal bleeding, or protein in ascites less than 1.5 g/dL, although there is no gastrointestinal bleeding, prophylactic antibiotics should be considered because the chance of SBP is high. (B1) ## 4-4-3. prevention Hepatorenal syndrome can be prevented by inhibiting the decrease of plasma volume. Diuretics and lactulose should be used carefully to prevent excessive fluid loss. [bib_ref] Midodrine versus albumin in the prevention of paracentesisinduced circulatory dysfunction in cirrhotics:..., Singh [/bib_ref] [bib_ref] Noradrenaline and albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized pilot..., Singh [/bib_ref] [bib_ref] Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory..., Sola-Vera [/bib_ref] [bib_ref] Terlipressin versus albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized study, Singh [/bib_ref] In patients with SBP, the use of albumin and antibiotics reduce the incidence of hepatorenal syndrome. [bib_ref] Effect of intravenous albumin on renal impairment and mortality in patients with..., Sort [/bib_ref] [bib_ref] Restricted use of albumin for spontaneous bacterial peritonitis, Sigal [/bib_ref] The use of oral norfloxacin has been shown to reduce the occurrence of hepatorenal syndrome and increase 3-month survival rates in patients with low serum protein (<1.5 g/dL) or renal insufficiency (creatinine ≥1.2 mg/dL, or blood urea nitrogen ≥25 mg/dL, or serum Na ≤130 mEq/L). [bib_ref] Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival..., Fernández [/bib_ref] ## Hepatic encephalopathy ## 5-1. definition Hepatic encephalopathy is a neuropsychiatric syndrome that follows liver dysfunction. Patients with hepatic encephalopathy can show various neurological illnesses [fig_ref] Table 7: West-Haven criteria for hepatic encephalopathy183 MHE, minimal hepatic encephalopathy [/fig_ref]. [bib_ref] Practice Parameters Committee of the American College of Gastroenterology. Hepatic Encephalopathy, Blei [/bib_ref] Venous levels of ammonia are not helpful because they are not proportional to the severity of hepatic encephalopathy and some patients with sever hepatic encephalopathy have normal venous ammonia levels. [bib_ref] Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and..., Stahl [/bib_ref] Brain MRI is considered better than brain CT in the diagnosis of brain edema accompanying hepatic failure, but this is not true for hepatic encephalopathy. Brain CT is useful when differentiating between organic causes of neuropsychiatric disorders such as intracranial hemorrhage. [bib_ref] Manganese and chronic hepatic encephalopathy, Krieger [/bib_ref] ## 5-3. treatment The goal of treatment is to prevent secondary damage caused by decreased consciousness, normalize the patient's state of consciousness, prevent recurrence, and to improve the prognosis and quality of life by eliminating the social and economic restrictions caused by hepatic encephalopathy. The precipitating factor can be identified in more than 80% of patients with hepatic encephalopathy. [bib_ref] An analysis of the causes and prevention of hepatic coma, Fessel [/bib_ref] The currently known precipitating factors of hepatic encephalopathy and the corresponding tests and treatments are shown in ## 5-3-2. liver transplantation Liver transplantation is indicated in patients with severe hepatic encephalopathy, who do not respond to the above treatments. Patient with acute liver failure who shows hepatic encephalopathy are also considered for liver transplantation because of the poor prognosis. [bib_ref] Hepatic encephalopathy as a predictor of survival in patients with end-stage liver..., Stewart [/bib_ref] ## 5-3-3. prevention of relapse Because the recurrence rate of hepatic encephalopathy is 50-70%, [bib_ref] Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose..., Sharma [/bib_ref] [bib_ref] Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients, Bajaj [/bib_ref] [bib_ref] Rifaximin treatment in hepatic encephalopathy, Bass [/bib_ref] therapy for the prevention of recurrence should be considered. Lactulose 189 or rifaximin [bib_ref] Rifaximin treatment in hepatic encephalopathy, Bass [/bib_ref] have been used for the prevention of recurrence. ## 5-4. minimal hepatic encephalopathy ## 5-4-1. definition and diagnosis Minimal hepatic encephalopathy is a mild form of hepatic encephalopathy that is defined as a cognitive dysfunction presenting a abnormal psychometric tests without clinical ## 5-4-2. treatment Cognition and health-related quality of life improve significantly in the treatment group compared to placebo group. [bib_ref] Lactulose improves cognitive functions and health-related quality of life in patients with..., Prasad [/bib_ref] It has been reported that microviral agents (e.g., probiotics, synbiotics, etc.) improve minimal encephalopathy by changing intestinal normal flora and suppressing the production of ammonia. [bib_ref] Probiotic yogurt for the treatment of minimal hepatic encephalopathy, Bajaj [/bib_ref] Even though reports are displayed that LOLA [bib_ref] Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy:..., Kircheis [/bib_ref] and acetyl L-carnitine 205 improved minimal encephalopathy, there is no evidence regarding its effectiveness. [fig] 1: Diagnosis of LC LC is a pathologically defined disease, and is clinically classified as compensated and decompensated LC. Decompensated LC includes cases with ascites, variceal bleeding, hepatic encephalopathy, or jaundice. Image studies for diagnosing LC are CT, abdominal ultrasound, and MRI. Typical findings of these images are nodular liver surface, splenomegaly, and the presence of intra-abdominal collateral vessels, which mean increasing portal venous pressure. Although there are not established criteria for the diagnosis of compensated LC, imaging studies may be helpful for the diagnosis of LC b y integrating laboratory findings such as albumin, bilirubin, or prothrombin time and platelet values. [/fig] [table] Table 2: Drugs for acute esophageal variceal bleeding [/table] [table] Table 3: Treatment of ascites depending on the grade Grade 1, a small amount of ascites detected in the ultrasound test; Grade 2, ascites of the amount which distends abdomen symmetrically; Grade 3, ascites of the large volume which distends abdomen; •, major treatment; ○, recommended. [/table] [table] Table 4: Definition and diagnosis of refractory ascites [/table] [table] Table 6: Classification of hepatic encephalopathy180 [/table] [table] Table 7: West-Haven criteria for hepatic encephalopathy183 MHE, minimal hepatic encephalopathy.such as cognition and orientation disorders. Hepatic encephalopathy is classified into 3 groups according to the causative liver disease(Table 6). 180,1815-2. DiagnosisHepatic encephalopathy is generally accompanied by advanced liver disease; therefore, muscle weakness, jaundice, ascites, palmar erythema, edema, spider telangiectasias, and fetor hepaticus can be noted on physical examination.Clinicians should check for gastrointestinal hemorrhage, uremia, use of anti-psychotics or diuretics, protein hyperingestion, infection, constipation, dehydration, electrolyte imbalance, etc. 182 Common symptoms include concentration disorders, sleep disorders, and movement disorders, including lethargy or coma. The severity of hepatic encephalopathy can be evaluated using the West Haven criteria [/table] [table] Table 8: Precipitating factors, tests, and treatment of hepatic encephalopathy The primary treatment of hepatic encephalopathy is nonabsorbable disaccharides such as lactulose (β-galactosidofructose) or lactitiol (β-galctoside sorbitol). These treatments lead to the recovery of 70-90% of patients with hepatic encephalopathy. Although nonabsorbable disaccharides have been reported to have no significant effect on hepatic encephalopathy, 187 randomized controlled studies have indicated a positive effect of lactulose in the treatment and prevention of hepatic encephalopathy. 188,189 Enema with nonabsorbable disaccharides can be used until the consciousness is recovered. After consciousness is restored, nonabsorbable disaccharides (15-45 mL, orally 2-4 times/day) should be recommended for loose stool defecation 2-3 times a day.Antibiotics such as neomycin, metronidazole, and rifaximin that are not absorbed by the intestine, affect urea-producing bacteria and reduce the generation of ammonia, thereby improving hepatic encephalopathy. [/table]	None	None	Liver cirrhosis (LC) is a disease with a high rate of prevalence and one of the most common causes of mortality in the Republic of Korea (hereafter "Korea"). In Korea, the main etiologies of LC have been found to be chronic hepatitis B (CHB), alcohol, and chronic hepatitis C (CHC). In patients with complications such as ascites, variceal bleeding, and encephalopathy, the 5-year survival rates were 32%, 21%, and 40%, respectively, reflecting the poor prognosis of patients with LC. Consequently, a clinical practice guideline appropriate for the medical milieu of Korea is important for both patients and clinicians. In 2005, the Korean Association for the Study of the Liver established a guideline for the treatment of LC that is now widely used. However, it is currently necessary to revise and update the clinical practice guideline based on new evidence over the past 6 years regarding the diagnosis, treatment, and prevention of LC. Therefore, the Korean Association for the Study of the Liver undertook a revision and update of the clinical practice guideline co-organized by the Liver Cirrhosis Clinical Research Center. This guideline was based on an interdisciplinary (hepatology, radiology, pathology, and preventive medicine) approach. A panel of experts selected by the Korean Association for the Study of the Liver and Liver Cirrhosis Clinical Research Center met several times to discuss and write this guideline during 2005-2011. This guideline was written in light of published studies retrieved from MEDLINE, EMBASE, and Cochrane Library. The panel aimed to address 5 subjects: diagnosis of LC, anti-fibrotic therapy for LC, variceal bleeding, ascites, and hepatic encephalopathy. The evidence and recommendations made in this guideline have been graded according to the GRADE (Grading of Recommendations Assessment Development and Evaluation) system. The strength of evidence has been classified into 3 levels: A (high-quality evidence), B (moderate-quality evidence), and C (low-quality evidence). The strength of recommendation has been classified into 2 categories: strong and weak (Table 1). Where there was no clear evidence, the recommendations were based on the consensus expert opinion(s) in literature and that of the writing committee. Table 1 Grading evidence and recommendations 1. Diagnosis of LC LC is a pathologically defined disease, and is clinically classified as compensated and decompensated LC. Decompensated LC includes cases with ascites, variceal bleeding, hepatic encephalopathy, or jaundice. Image studies for diagnosing LC are CT, abdominal ultrasound, and MRI. Typical findings of these images are nodular liver surface, splenomegaly, and the presence of intra-abdominal collateral vessels, which mean increasing portal venous pressure. Although there are not established criteria for the diagnosis of compensated LC, imaging studies may be helpful for the diagnosis of LC b y integrating laboratory findings such as albumin, bilirubin, or prothrombin time and platelet values. 1-1. Diagnostic approach-patient history, physical examination, and laboratory tests When dealing with patients with LC, evaluation of the cause, severity, and stage is the first step. In patients with chronic liver disease, history taking (drug use, blood transfusion, or alcohol use), physical examination (jaundice, ascites, spider angioma, hepatomegaly, or splenomegaly), and symptom such as fatigue from hepatitis should be assessed. In patients with LC, a whole blood test including platelet count, liver function test (albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase), prothrombin time, abdominal ultrasound, abdominal CT, and endoscopy should be carried out to confirm the presence or absence of cirrhosis. In addition, laboratory tests for hepatitis B or C virus infection are needed for the evaluation of its cause. Generally, the Child-Pugh score is used to assess the severity of LC. In clinical practice for the diagnosis of LC, findings of portal hypertension such as ascites, hepatic encephalopathy, or varices, imaging findings, and laboratory findings are common diagnostic tools. Recently, it was found that nodularity of the liver surface, a platelet count of less than 100,000/mm3, albumin less than 3.5 g/dL, and an international normalized ratio of 1.3 or more are related to the presence of LC. Presence of one condition of these findings showed a specificity of 90.42% and a sensitivity of 61.11%.1
093d37e000b01aa982a344cdb60d4869dec95e57	pubmed	What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 1)	What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 1) Description: The widespread availability of SARS-CoV-2 antibody tests raises important questions for clinicians, patients, and public health professionals related to the appropriate use and interpretation of these tests. The Scientific Medical Policy Committee (SMPC) of the American College of Physicians developed these rapid, living practice points to summarize the current and best available evidence on the antibody response to SARS-CoV-2 infection, antibody durability after initial infection with SARS-CoV-2, and antibody protection against reinfection with SARS-CoV-2.Methods: The SMPC developed these rapid, living practice points based on a rapid and living systematic evidence review done by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. Ongoing literature surveillance is planned through December 2021. When new studies are identified and a full update of the evidence review is published, the SMPC will assess the new evidence and any effect on the practice points.Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. # Background The widespread availability of SARS-CoV-2 antibody tests raises important questions for clinicians, patients, and public health professionals related to the appropriate use and interpretation of these tests. However, currently little is known about the relationship between SARS-CoV-2 antibodies and natural immunity. The potential for natural immunity to SARS-CoV-2 infection stems from the activation of B lymphocytes (humoral or antibody-mediated immunity) and T lymphocytes (cellular immunity). However, like with other viruses, the relationship between antibodies and natural immunity may vary on the basis of differences in the level and duration of antibodies produced as well as viral mutations of the infection. When persons are infected with SARS-CoV-2, uncertainty exists about whether the antibodies produced (IgM, IgG, IgA, or neutralizing) are protective against reinfection, and if so, for how long what levels of antibodies are needed for such protection. In addition, because antibodies to other coronaviruses have been shown to decline over time, how long such protection against reinfection may last also needs to be determined [bib_ref] The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential..., Kellam [/bib_ref]. As a step toward better understanding the immune response to SARS-CoV-2, the Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these practice points on the basis of key questions related to the antibody-mediated natural immunity after SARS-CoV-2 infection. This article does not evaluate cellular immunity or artificial immunity conferred by vaccines, both of which are important areas of research. The SMPC developed these rapid, living practice points [fig_ref] Table 1: available at Annals [/fig_ref] on the basis of a rapid and living systematic evidence review done by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality . The details of our process can be found in the Appendix (available at Annals.org). This version of the practice points is based on an initial search to 4 August 2020 that was subsequently revised and updated through 15 December 2020. It was approved by ACP's Executive Committee of the Board of Regents on behalf of the Board of Regents on 22 February 2021 and submitted to Annals of Internal Medicine on 22 February 2021. Ongoing literature surveillance is planned through December 2021. The target audience for these practice points includes clinicians, patients, the public, and public health officials. The target patient population includes adults who have been previously infected with SARS-CoV-2. presents clinical considerations, the Figure and [fig_ref] Table 3: Evidence Summary for Patients With PCR-Confirmed SARS-CoV-2 Infection [/fig_ref] identifies additional evidence gaps. The Appendix Evidence is emerging about the antibody response to SARS-CoV-2 and its durability after initial infection with SARS-CoV-2 as well as protection against future reinfection with SARS-CoV-2. The following practice points are based on current, best available evidence: Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. Practice Point 2: Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection. Practice Point 3: Current evidence is uncertain to predict presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection (after SARS-CoV-2 infection). ## Table 2. clinical considerations In the face of uncertainty, patients with SARS-CoV-2 infection, those with a history of SARS-CoV-2 infection, and the public should follow infection prevention and control procedures to slow and reduce the transmission of SARS-CoV-2 (maintain physical distance; wear face coverings, such as surgical or cloth masks, in settings where physical distancing is not possible; use masks appropriately; self-isolate; quarantine; practice frequent hand hygiene [use soap and water or alcohol-based hand rub]; cover cough and sneezes using a bent elbow or paper tissue; refrain from touching the face; and regularly disinfect frequently touched surfaces). The relationship between the development of antibodies after SARS-CoV-2 infection and the risk for reinfection has not been established . Although SARS-CoV-2 serologic tests detect IgM, IgG, and IgA immunoglobulins, the tests may also give a positive result due to cross-reactivity with antibodies to other coronaviruses . Evidence considers serologic tests that were approved and for which emergency use authorization had not been revoked by the U.S. Food and Drug Administration as of 5 August 2020 . SARS-CoV-2 serologic tests vary in accuracy, and there is insufficient evidence on the association between the use of different tests and the presence of detectable antibodies. These practice points evaluate only the antibody-mediated natural immunity response and do not address the role of other important natural immune responses, such cell-mediated immunity or artificial immunity conferred by vaccines. ## Clinical guideline Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Practice Point 2: Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection. Studies included in the evidence review focused on evaluating the trends in types of antibodies and their levels after symptom onset or confirmation of SARS-CoV-2 infection with a positive RT-PCR test result. Evidence from studies evaluating community prevalence in antibody response showed that patients develop an immune response after SARS-CoV-2 infection. This is evidenced by detectable IgA antibodies in most patients (low certainty), IgM in most patients (moderate certainty), IgG in nearly all patients (moderate certainty), and neutralizing antibodies in nearly all patients (low certainty). The antibody prevalence and levels may vary over time by certain patient characteristics (for example, age, sex, and race/ethnicity) and disease factors (for example, presence of symptoms and severity) (low certainty). The timing from symptom onset or PCR-confirmed infection of when antibodies first become detectable and the level at which they remain detectable vary depending on the type of antibody. At or around peak level, IgM, IgG, IgA, and neutralizing antibodies are estimated to be detectable in approximately 80%, 95%, 83%, and 99% of patients, respectively, after symptom onset or PCRconfirmed infection. Despite variation, each of these antibody types has its peak level on average between 20 and 31 days after symptom onset or PCR-confirmed infection. Evidence shows that antibodies may persist over time; IgM antibodies were detected up to 115 days (moderate certainty), IgG antibodies were detected up to 120 days (moderate certainty), IgA antibodies were detected up to 140 days (low certainty), and neutralizing antibodies were detected up to 152 days (low certainty). Given that not all patients develop detectable antibodies early in the course of the infection and that the presence and levels may vary by patient and disease characteristics, antibody tests should not be used for the diagnosis of SARS-CoV-2 infection. It is also important for clinicians and patients to keep in mind that SARS-CoV-2 antibody test results may be falsely positive due to cross-reactivity with antibodies of other coronaviruses (74, 75). Furthermore, although a complete assessment of diagnostic accuracy of various antibody tests was beyond the scope of the evidence review, characteristics (for example, sensitivity, specificity, and accuracy) varied substantially among the antibody tests used in included studies . Such variation can contribute to false-negative and false-positive test results and ultimately wrong conclusions (76, 77). However, for the purposes of estimating community prevalence of SARS-CoV-2 infection, antibody testing is a feasible option, keeping in mind that antibody levels peak roughly 3 to 5 weeks after symptom onset or PCR * Insufficient certainty of evidence: confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its effect on a health outcome. Low certainty of evidence: confidence in the effect is limited because the true effect may be substantially different from the estimated effect. Moderate certainty of evidence: confidence in the effect is moderate because the true effect is likely close to the estimated effect, but there is a sizable possibility that it is substantially different. High certainty of evidence: confidence that the true effect is close to the estimated effect. Assessments regarding antibody prevalence were focused on results from seroprevalence, cross-sectional, and cohort studies, rather than on results from immunoassay validation studies (which provide less reliable estimates). For all other outcomes of interest, results from all studies were incorporated into strength of evidence assessments . † "Nearly all" refers to greater than 90% of the participants across studies, "most" refers to more than half of the participants across studies, and "some" refers to less than half of the participations across studies. ## Clinical guideline Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 diagnosis. Also, the usability and interpretation of SARS-CoV-2 antibodies will need to be evaluated in persons vaccinated against COVID-19, as vaccination will also affect the development of SARS-CoV-2 antibodies. ## Reinfection among patients with sars-cov-2 antibodies and unintended consequences of antibody testing Practice Point 3: Current evidence is uncertain to predict presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection (after SARS-CoV-2 infection). Current evidence is limited about natural immunity conferred by SARS-CoV-2 antibodies. As discussed earlier, asymptomatic or symptomatic patients may develop an antibody response consistent with natural immunity after having SARS-CoV-2 infection, but key individuallevel differences depend on such variables as COVID-19 disease severity, patient factors, types of antibodies and amount developed, and how long the antibodies last. This is an area of rapidly emerging new evidence. No identified evidence directly evaluates the association between antibodies and natural immunity, although 2 studies are in progress [bib_ref] Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery..., Lumley [/bib_ref]. In the evidence review, a study [bib_ref] A comparative study of the laboratory features of COVID-19 and other viral..., Zhao [/bib_ref] of hospitalized patients with COVID-19 (n = 47) reported a potential case of reinfection during the "convalescence stage" of the disease in 1 patient who did not have detectable IgM or IgG antibodies at 4-week followup. However, the study was not designed to determine whether antibodies confer immunity. Evidence does show that there are detectable levels of IgA antibodies in most patients (low certainty), IgM in most patients (moderate certainty), IgG in nearly all patients (moderate certainty), and neutralizing antibodies in nearly all patients (low certainty). Evidence also shows that IgG antibodies probably remain detectable for at least 120 days (moderate certainty) and neutralizing antibodies may remain detectable for at least 152 days (low certainty). The antibody prevalence and levels over time may vary by certain patient characteristics (for example, age, sex, and race/ethnicity) and disease factors (for example, presence of symptoms and severity) (low certainty). The evidence review also identified 3 longitudinal studies (indirect evidence) that used serologic rather than RT-PCR testing as the index test and, thus, did not meet the inclusion criteria. These studies suggest that antibody presence may be associated with natural immunity [bib_ref] Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery..., Lumley [/bib_ref] [bib_ref] The duration, dynamics and determinants of SARS-CoV-2 antibody responses in individual healthcare..., Lumley [/bib_ref] ; however, the evidence review has not critically appraised them. Given that there is no direct evidence to inform the question of reinfection, we will consider modifying future searches to formally incorporate additional sources of indirect evidence, including these studies. Evidence is uncertain (insufficient) about the unintended consequences of antibody testing. Given limited knowledge about the association between antibody levels and natural immunity, patients with SARS-CoV-2 infection and those with a history of SARS-CoV-2 infection should follow recommended infection prevention and control procedures to slow and reduce the transmission of SARS-CoV-2 (5, 6). Note: The practice points are developed by the SMPC of the ACP. The practice points are guides only and may not apply to all patients and all clinical situations. All practice points are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued. Financial Statement: Financial support for the development of the Practice Points comes exclusively from the ACP operating budget. Disclosures: All financial and intellectual disclosures of interest were declared, and potential conflicts were discussed and managed. Dr. Jokela participated in discussion of the practice points but was recused from authorship and voting due to a moderate-level conflict of interest (authored recent relevant publications). Dr. Marcucci participated in the discussion of the practice points but was recused from authorship and voting due to a moderate-level conflict of interest (author of relevant systematic review [forthcoming]). A record of disclosures of interest and management of conflicts is kept for each SMPC meeting and conference call and can be viewed at www .acponline.org/about-acp/who-we-are/leadership/boards-committees -councils/scientific-medical-policy-committee/disclosure-of-interests -and-conflict-of-interest-management-summary-for-scientific-medical -policy. Disclosures can also be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M20-7569. and includes members with expertise in epidemiology, evidence synthesis, health policy, and guideline development. In addition to contributing clinical, scientific, and methodological expertise, Clinical Policy staff provided administrative support and liaised among the SMPC, the evidence review funding entity and evidence team, and the journal. Clinical Policy staff and the SMPC reviewed and prioritized potential topic suggestions from ACP members, SMPC members, and ACP governance. A committee subgroup, including the SMPC chair, worked with staff to draft the key questions and led the development of the practice points. Clinical Policy staff worked with the subgroup and an independent evidence review team to refine the key questions and determine appropriate evidence synthesis methods for each key question. Via conference calls and e-mail, Clinical Policy staff worked with the committee subgroup to draft the practice points on the basis of the results of the rapid and living systematic evidence review. The full SMPC reviewed and approved the final practice points. Before journal submission, ACP's Executive Committee of the Board of Regents also reviewed and approved the practice points on behalf of the ACP Board of Regents. The evidence review team is planning ongoing literature surveillance at least through December 2021. When no new studies are identified, the SMPC will publish a comment on the most recent version of the practice points that indicates the date of the last search and that no new studies were identified. When new studies are identified but previous conclusions remain unchanged, the SMPC will publish an update alert letter that briefly summarizes the new evidence and updates the rationale and evidence tables for the practice points. When new studies are identified and a full update of the evidence review is published, the SMPC will assess the new evidence and reaffirm (via update alert letter) or revise and modify (via new version) the practice points. The SMPC will continually evaluate the priority level of each living topic and may decide to retire a topic early from living status if it determines that the topic is no longer considered a priority for decision making, if there is confidence that the conclusions are not likely to change with the emergence of new evidence or affect practice, or when it is unlikely that new evidence will emerge (82). [fig] Figure.: Evidence description. [/fig] [fig] From: American College of Physicians, Philadelphia, Pennsylvania (A.Q., I.E.); American College of Physicians, Philadelphia, and Villanova University, Villanova, Pennsylvania (J.Y.); Penn Medicine, Philadelphia, Pennsylvania (M.A.F., M.C.M.); University of Massachusetts Medical School and Saint Vincent Hospital, Worcester, Massachusetts (G.M.A.); and Portland Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon (A.J.O., L.L.H.). [/fig] [fig] Web Reference 82: Akl EA, Meerpohl JJ, Elliott J, et al; Living Systematic Review Network. Living systematic reviews: 4. Living guideline recommendations. J Clin Epidemiol. 2017;91:47-53. [PMID: 28911999] doi:10.1016/j .jclinepi.2017.08.009 [/fig] [table] Table 1: available at Annals.org) presents the data estimates supporting the practice points.PRACTICE POINTS AND RATIONALE Prevalence, Level, and Durability of Antibodies Among Patients Infected With or Recovered From SARS-CoV-2 InfectionPractice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. Practice Points [/table] [table] Table 3: Evidence Summary for Patients With PCR-Confirmed SARS-CoV-2 Infection [/table]	None	https://europepmc.org/articles/pmc8803138?pdf=render	Antibody tests for SARS-CoV-2, the virus that causes COVID-19, are widely available. These practice points help clinicians, patients, and public health professionals understand how to use and interpret these results on the basis of the available evidence. The practice points will be updated as more evidence becomes available.
03d16326e1f4888317bbce45769f1ece136c7cb1	pubmed	Ergonomics in the anaesthetic workplace	Ergonomics in the anaesthetic workplace # Introduction For the purposes of this guideline, we define ergonomics as the scientific study of the interaction between anaesthetists and their workspace environment to promote safety, performance and well-being. Musculoskeletal problems, such as back pain, account for 40% of sickness absence among NHS staff and cost approximately £400 million per year. Legally, employers are obliged to provide a safe working environment for their staff. Under the Manual Handling Operations Regulations 1992 (as amended), employers are required to avoid the need for hazardous manual handling, so far as is reasonably practicable; assess the risk of injury from any hazardous manual handling that cannot be avoided; and reduce the risk of injury from hazardous manual handling, so far as is reasonably practicable. It requires employees to follow appropriate systems of work laid down for their safety; make proper use of equipment provided for their safety; co-operate with their employer on health and safety matters; inform the employer if they identify hazardous handling activities; and take care to ensure their activities do not put others at risk. The foundation for avoiding pain or discomfort at work is to adopt and maintain a good posture. What isand monitoring as recommended by the Association [bib_ref] Recommendations for standards of monitoring during anaesthesia and recovery 2021, Klein [/bib_ref]. Temperature, humidity, noise, lighting and electrical safety Temperature and humidity are controlled by the ventilation system, while noise, lighting and electrical safety are separate aspects. Ergonomists can provide specialist help with the effects of the physical environment on anaesthetists. Guidelines on the provision of anaesthetic services have been published by the Royal College of Anaesthetists; this includes guidelines for the environment. Building regulations require that all enclosed workspaces be ventilated by either natural or mechanical means. ## Temperature Employers are required to make a suitable assessment of the risks to the health and safety of their employees and take action where necessary and where reasonably practicable. While there is no absolute legal requirement for a specific temperature in the workplace, the minimum temperature in the operating theatre should be at least 21°C. A meaningful figure cannot be given for a maximum temperature due to the high temperatures found in some workplaces. Vertical air temperature difference between head and ankle levels should be < 3°C. ## Thermal comfort The temperature of the ambient air alone is not a valid or accurate indicator of an individual person's thermal comfort. It should always be considered in relation to other factors. These comprise environmental factors (air temperature, radiant temperature, air velocity and humidity) and personal factors (clothing insulation, including personal protective equipment, work rate and metabolic heat). In particular, thermal radiation is the heat that radiates from warm objects. Radiant heat may be present if there are sources of heat in the operating theatre such as some types of equipment. For air velocity, as the design of operating theatres should incorporate appropriate ventilation systems for the control of infection, this will affect the flow of air within the room and hence the thermal comfort of personnel. Clothing can be used to control thermal comfort but can also be a cause of thermal discomfort. A person's physical characteristics should always be taken into account when considering their thermal comfort, as factors such as their size and weight, age, fitness level and sex can all have an impact on how they feel, even if all other factors such as air temperature, humidity and air velocity are constant. There are differences between men and women in terms of thermal comfort and temperature preference [bib_ref] Thermal comfort and gender: a literature review, Karjalainen [/bib_ref]. The stability of the temperature (and humidity) in the operating theatre can be disrupted by opening doors and movement of people and equipment [bib_ref] Real-time measurements of relative humidity and temperature in hospital operating room, Wong [/bib_ref]. ## Humidity There are two aspects to humidity: absolute humiditythe amount of water vapour present in a particular volume of air, usually expressed in units of g.m -3 ; and relative humiditythe amount of water vapour in the air relative to the maximum amount that can be contained in the air at a particular temperature, expressed as a proportion. Generally, relative humidity rather than absolute humidity is important when discussing thermal comfort. In the UK, levels of relative humidity in the range of 40-70% are recommended for the workplace environment. ## Clothing, including personal protective equipment Three properties of clothing material to consider are thermal resistance, water-vapour resistance and air permeability. Results from tests carried out according to standards can help a purchaser make an informed choice of appropriate clothing (including personal protective equipment) for use in the operating theatre. ## Noise Any unwanted sound is a noise and this may disturb patients and staff. Noise in the operating room arises from various sources, including staff activities; conversations and communications; ventilation; surgical equipment; and alarms and music [bib_ref] Noise in the operating room, Katz [/bib_ref]. Surgical procedures may need to be undertaken in a noise-free environment. It is, therefore, important that there is no transfer of noise between adjacent theatres. Three parameters are important in assessing the level of noise in operating theatres. Two are in relation to external noise; that is, noise emanating from outside the operating theatre. The third is related to the noise level from mechanical and electrical services within the operating theatre itself. There are noise rating curves, a set of curves based on the sensitivity of the human ear and used to give a single figure for noise levels at a range of frequencies. Typically, noise rating curves are determined between 63 Hz and 4 kHz. In operating theatres, noise rating should be 40 dB, or 50 dB for ultra-clean laminar-flow operating theatres. ## Music Music is commonly played in operating theatres [bib_ref] Music and communication in the operating theatre, Weldon [/bib_ref]. The appropriate use of music in the operating theatre can reduce stress and improve the performance of some staff [bib_ref] Patient safety in the cardiac operating room: human factors and teamwork, Wahr [/bib_ref]. However, music can impair communication [bib_ref] Music and communication in the operating theatre, Weldon [/bib_ref]. Music that is pleasing and helpful to one practitioner might be distracting to other operating theatre personnel. ## Conversation and communication Non-essential conversation and communication can be distracting, leading to errors. The sterile cockpit concept was introduced into aviation to reduce the effect of distractions during the critical phases of flight, normally below 10,000 feet, effectively take-off and landing. This requires pilots to refrain from all non-essential conversation and activity during these critical phases. In anaesthesia, induction and emergence can be considered analogous to take-off and landing. During these phases, it has been suggested that the concept of a 'sterile cockpit' should apply [bib_ref] Critical phase distractions in anaesthesia and the sterile cockpit concept, Broom [/bib_ref]. However, each team in the operating theatre has a different cognitive work-load at different times during a case [bib_ref] Is the "sterile cockpit" concept applicable to cardiovascular surgery critical intervals or..., Wadhera [/bib_ref]. This potentially leads to a casual conversation just when another team member needs absolute quiet. Anaesthetists should politely and firmly make clear that they are not going to discuss any non-emergency matters during drug preparation, with the aim of reducing medication errors [bib_ref] Who is distracting whom?, Moppett [/bib_ref]. ## Audible alarms Alarms generated by anaesthetic equipment can be grouped into three types: high, medium and low priority. Priority levels are determined by the combination of the potential results of failure to respond to the cause of the alarm condition (death or irreversible injury, reversible injury or minor injury or discomfort) and the onset of potential harm (immediate, prompt or delayed). Alarm systems can be an issue for patient safety if they fail to warn of hazards effectively or adversely affect the performance of the operator [bib_ref] Alarms are still a problem!, Edworthy [/bib_ref]. A high false alarm rate may lead to desensitisation and neglect [bib_ref] The effect of audible alarms on anaesthesiologists' response times to adverse events..., De Man [/bib_ref]. This can lead to inappropriate muting of audible alarms and cause anaesthetists to ignore those alarms that are indicating an urgent response. Appropriate setting of alarm trigger levels is therefore important. ## Lighting Lighting should be sufficient to enable people to work and use facilities without experiencing eyestrain. Minimum values for illumination are 200 lx for work requiring perception of detail. Greater levels of illumination are required in particular healthcare settings. In the anaesthetic room this is 1000 lx at the head of the trolley 1 m from the light source. However, in the operating theatre itself, the luminaire should provide between 15,000 and 30,000 lx at the operating table 1 m from the light source. ## Lighting related to anaesthetic equipment Brightness and contrast controls on the screen of the anaesthetic workstation should be adjusted to suit lighting conditions in the operating theatre. When selecting laryngoscopes, the brightness, direction and quality of light are important factors to consider. Illumination provided by laryngoscopes should be at least 500 lx. This level of illumination should be Information (Appendix S1). ## Anaesthetic workstations The anaesthetist, or a trained nominated person, is responsible for ensuring that the anaesthetic machine is plugged in, switched on and that the battery back-up is charged as part of the Association checklist for anaesthetic equipment. Most medical equipment is designed for right-handed people. In a study that looked at 2437 Korean men and women, 6% were left-handed, 8% were ambidextrous and the rest, right-handed. The right-handed and ambidextrous used their right hands for tasks that required accuracy rather than force. The left-handed used the left hand for tasks that required a certain amount of force rather than accuracy. This implies that, in all participants, the right hand was used for tasks that required accuracy [bib_ref] Hand dominance and hand use behaviour reported in a survey of 2437..., Jung [/bib_ref]. It has been shown that the performance of the nondominant hand is detrimental and may affect outcome in critical task performance [bib_ref] Hand dominance and implications for left-handed operation of controls, Garonzik [/bib_ref]. Anaesthetists must make workplace adjustments to optimise their performance with their dominant hands. Ideally equipment should be designed that is essentially neutral and may serve both groups effectively, for example, by placing the reservoir bag and common gas outlets at the centre of the machine. ## Patient monitors Monitoring, as recommended by the Association, is ## Lateral transfer This occurs when the patient needs to be moved from a trolley or bed to the operating table (and back again) and can finish with the patient in the supine or prone position. ## Supine to supine lateral transfer If the patient is conscious and able to mobilise themselves then this should be encouraged, with staff available to ensure safety throughout the transfer. If the patient is anaesthetised, the number of staff required to safely position the patient will depend on the patient's size. For a patient who weighs 70 kg, this is the anaesthetist and three staff members, using a lateral transfer device. There is a range of each of the different types of lateral transfer devices on the market and staff should be familiar with the equipment used in their place of work . It is important to ensure the bed is at a suitable height for the transferring staff with a pull point (i.e. the starting position of the staff member's hands) between their waist and nipple line. ## Supine to prone lateral transfer The patient is likely to be anaesthetised when positioning the patient in the prone position, therefore the anaesthetist controls the head, neck and airway. An additional four members of staff are required to facilitate the transfer. If a mechanical assist device is available, this should be utilised. ## Positioning the patient on the operating table Once the patient has been transferred on to the operating table, they may need to be moved into another position to facilitate the planned procedure. ## Lateral position In order to safely position the patient in this position, a minimum of three members of staff plus the anaesthetist is required for patients weighing > 50 kg. ## Lithotomy position Putting the patient safely into this position depends on the patient's weight. If the patient is not excessively overweight this can usually be done with one person per leg. It is important to move both legs simultaneously to prevent damage to the patient's pelvis [bib_ref] Positioning the surgical patient, Macdonald [/bib_ref]. ## Positions achievable using mechanical theatre tables There are a number of other positions that can be achieved using modern mechanical theatre tables (e.g. the beach chair and Trendelenburg positions). This protects operating theatre staff from musculoskeletal injury, but puts patients at risk, therefore knowledge and training in how to operate the theatre table is essential. ## Special circumstances Certain patients, such as those with proven or suspected unstable vertebral fractures, require extra precautions in order to position them safely. This will often involve specialist pieces of equipment and staff members trained in their use. ## Intra-operative phase The operating theatre should be 55 m 2and have a recommended 20 air changes per hour. Anaesthetists often remain seated during maintenance of anaesthesia and should follow the same advice that is advocated for staff that spend time at a desk working at a ## Box 1 rules of manual handling - Do not lift or handle unnecessarily. If there is a means to execute the movement without manually handling the patient, or another load, then it should be used. - If a load is being moved across a distance, avoid carrying it and use a trolley. - Co-ordinate a lift with team members who will be involved in the movement of a patient. If the patient's weight is a concern, take further action such as having additional handlers or hoists on stand-by. ## Postoperative phase Once the patient is stable and ready for transfer to the postanaesthesia care unit, the same principles of safe patient transfer should be employed. ## Regional anaesthesia The practice of regional anaesthesia has increased in recent years, mainly due to the widespread availability of ultrasound equipment. The provision of regional anaesthesia is not limited to anaesthetists alone, and colleagues in pre-hospital medicine, emergency medicine and intensive care are also providing some of these techniques [bib_ref] Regional anesthesia by nonanesthesiologists, Pawa [/bib_ref]. The successful practice of regional anaesthesia relies heavily on optimisation of ergonomics, and lack of attention to detail in this area is associated with block failure or suboptimal performance [bib_ref] Characterizing novice behavior associated with learning ultrasound-guided peripheral regional anesthesia, Sites [/bib_ref]. Additionally, lack of attention to ergonomics can result in the development of musculoskeletal disorders in the practitioner [bib_ref] Upper limb disorders in anaesthetists -a survey of Association of Anaesthetists members, Leifer [/bib_ref]. The interaction between the anaesthetist, the patient, the equipment used and the environment where the procedure is performed are all important factors in the successful deployment of regional anaesthesia , see also Supporting Information, [fig_ref] Figure S2: Equipment trolley placed on the dominant side for left-and right-handed operators, respectively [/fig_ref]. The anaesthetist should be able to perform the procedure while maintaining asepsis without leaning on, or over, the patient and without exerting excessive thoracolumbar flexion [bib_ref] An ergonomic task analysis of spinal anaesthesia, Ajmal [/bib_ref]. Examples of lateral transfer devices. ## Friction-reducing sheet Inserted under the patient to reduce the frictional force required to be overcome when transferring the patient. Often used in combination with a slider board. Various designs available such as boards with vinyl coverings and rollers, or simple boards that are used in combination with a friction reducing sheet. It is important that the patient's weight does not exceed the manufacturer's safe working load. ## Slider board ## Air-assisted transfer device These devices float patients on a layer of air from one surface to another, reducing the frictional forces required for transfer. Use of this type of device should be considered for heavier patients. study assessing spinal anaesthesia, performed while the anaesthetist was in the standing position, the optimal needle entry angle and anaesthetist comfort level was when the spinal table was raised to the level of the nipple or xiphoid process of the anaesthetist (see also Supporting Information, [fig_ref] Figure S3: Operating table at two different heights during insertion of spinal anaesthesia [/fig_ref] [bib_ref] Higher operating table for optimal needle-entry angle and less discomfort during spinal..., Sohn [/bib_ref]. Ultrasound-guided regional anaesthesia for peripheral nerve blocks Modern regional anaesthesia utilises ultrasound imaging technology. This introduces further ergonomic considerations in addition to general principles. There are well-described industry standards for prevention of musculoskeletal disorders for sonographers. While these do not specifically relate to ultrasound for regional anaesthesia, many principles are relevant. ## Ultrasound machine The machine should be fully adjustable and suitable for use The act of performing an ultrasound-guided regional nerve block consists of a number of phases, each with potential ergonomic challenges [bib_ref] Characterizing novice behavior associated with learning ultrasound-guided peripheral regional anesthesia, Sites [/bib_ref] (Box 3). If any of these steps are not successfully adopted, the likelihood of achieving a successful nerve block is reduced. Turning the trunk, turning the head 45°or more and non-dominant hand Box 3 Phases for performing regional blocks [bib_ref] An ergonomic task analysis of spinal anaesthesia, Ajmal [/bib_ref] - Ergonomic principles for performing procedures. ## Environment There should be sufficient space to perform the procedure The area should be quiet and free from distraction The ambient temperature should be at least 21°C Lighting should be adjustable, preferably with a dimmer switch ## Patient The patient should be comfortable on a trolley, bed or operating table The patient should be positioned in a stable and secure manner, with attention to pressure areas. Access to the patient should be unobstructed and there should be no objects impeding access to the patient (e.g. table attachments) The level of the patient relative to the anaesthetist should be adjusted in order that the neck of the anaesthetist is not flexed > 60°E If in the standing position, optimal heights recommended are within 5 cm above to 10 cm below the elbow needling are associated with fatigue and suboptimal block performance [bib_ref] Monitor position and the accuracy and speed of ultrasound-guided nerve blocks, Langford [/bib_ref]. ## Needle insertion The needle can be advanced towards the target structure either perpendicular to the ultrasound beamout-of-plane, In-plane needling can be achieved by placing the hands and long axis of the ultrasound probe in two orientations (see also Supporting Information, [fig_ref] Figure S4: In-plane needling variations [/fig_ref] : ACROSS the visual axiswith the needle insertion perpendicular to the visual axis or ALONG the visual axiswith the needle insertion parallel to the visual axis. Speed and accuracy of in-plane needling is improved when the in-plane needling ALONG the visual axis is employed [bib_ref] In-plane ultrasound-guided needle insertion ALONG or ACROSS the visual axis hand positions, Wilson [/bib_ref]. Although these studies were performed in phantoms, the principles hold true for ultrasound-guided regional anaesthesia in actual patients and are recommended for novice practitioners. ## Hand dominance There is a range of opinions regarding dominant-hand needling vs learning to be ambidextrous to achieve ergonomic advantage. Although bench top studies have shown that visual-spatial aptitude is more relevant than hand dominance in learning ultrasound skills [bib_ref] Looking into learning: visuospatial and psychomotor predictors of ultrasound-guided procedural performance, Smith [/bib_ref] , there are significant differences in the way that novices will perform a nerve block compared with an expert [bib_ref] Ergonomic task analysis of ultrasound-guided femoral nerve block: a pilot study, Ajmal [/bib_ref]. Therefore dominant-hand needling is recommended for novices. ## Procedures When performing procedures, such as arterial cannulation or central venous access, similar principles to performing regional nerve blocks apply . ## Intensive care unit ## Supporting information Additional supporting information may be found online via the journal website. Appendix S1. Ergonomics during the COVID-19 pandemic. [fig] Recommendations 1: Musculoskeletal injuries are common in anaesthetists and they should aim to make their posture as natural and neutral as possible at all times 2 Wherever possible, patients should position themselves on the operating trolley or table and remain there for their procedure and first-stage recovery 3 All purchased equipment should be assessed using ergonomic principles to ensure it is acceptable for its intended use and that it is adjustable to maintain comfort for the anaesthetist, including those who are pregnant or have disabilities 4 All staff should receive regular teaching in manual handling as part of their mandatory training 5 Room temperature should be at least 21°C, the relative humidity should be in the range of 40-70%, there should be adequate and adjustable lighting and noise should be no louder than 80 dB and for short periods only 6 Good ergonomic practice is one where the patient is at a height that approximates to the level of the umbilicus, T10 dermatome or waist of the anaesthetist 7 If the anaesthetised patient is lying on an operating table or trolley for tracheal intubation, the table height should be adjusted until the patient's forehead is at the level of the anaesthetist's xiphoid process or nipple 8 Tasks such as regional anaesthetic nerve blocks, central venous cannulation and siting of arterial lines should be performed with the preparation trolley on the side of the dominant hand, the ultrasound machine directly opposite the operator's view and the monitor at eye level. [/fig] [fig] •: If the load, such as a patient, is on a heightadjustable surface, raise it upwards before the movement in order that all handlers remain upright during the move. Stand as close to the object being moved as possible as this will limit any reaching. Handling the load at arm's length results in five times the amount of stress than is the case if the load remains very close to the trunk when it is handled. Stand with feet apart and with one foot in front of the other when moving a load. This stance will offer stability to the handler. The floor area around or under the object being moved should be kept clear of cables, hoses or other pieces of equipment. Lower the upper body by flexing the knees. This is less stressful for the lower back than simply bending forward at the waist, which results in the weight of the upper body being added to the overall lift. Raise the head before lifting commences. This will assist in reducing any forward bending. Use the feet to move with the load, where possible, rather than reaching forward when putting the load down. Avoid placing anything at low levels that might encourage bending. computer screen. The anaesthetist must monitor the patient, administer medications and perform other interventions that require frequent changes in posture. The anaesthetist should remain outside the immediate surgical area for purposes of infection prevention and control. There should be ergonomic seating and a desk for documentation (Box 2). Tracheal extubation During tracheal extubation, the anaesthetist should be positioned correctly in order to manage the airway, administer drugs and monitor the patient. This presents more ergonomic challenges than during anaesthetic induction, which is usually performed in a calmer, more predictable scenario than tracheal extubation. The machine, patient and anaesthetist should be in the triangle, with each of them within 45°from the sagittal plane within the arc of movement. The assistant plays an important role by providing equipment, such as suction, and should be positioned appropriately in order to aid the anaesthetist. [/fig] [fig] Figure S1: Tracheal intubation performed with the operator positioned facing the patient and behind the supine or semi-recumbent patient. [/fig] [fig] Figure S2: Equipment trolley placed on the dominant side for left-and right-handed operators, respectively. [/fig] [fig] Figure S3: Operating table at two different heights during insertion of spinal anaesthesia. [/fig] [fig] Figure S4: In-plane needling variations. [/fig]	None	None	Ergonomics in relation to anaesthesia is the scientific study of the interaction between anaesthetists and their workspace environment in order to promote safety, performance and well‐being. The foundation for avoiding pain or discomfort at work is to adopt and maintain a good posture, whether sitting or standing. Anaesthetists should aim to keep their posture as natural and neutral as possible. The successful practice of anaesthesia relies on optimisation of ergonomics and lack of attention to detail in this area is associated with impaired performance. The anaesthetic team should wear comfortable clothing, including appropriately‐sized personal protective equipment where necessary. Temperature, humidity and light should be adequate at all times. The team should comply with infection prevention and control guidelines and monitoring as recommended by the Association of Anaesthetists. Any equipment or machinery that is mobile should be positioned where it is easy to view or reach without having to change the body or head position significantly when interacting with it. Patients who are supine should, whenever possible, be raised upwards to limit the need to lean towards them. Any item required during a procedure should be positioned on trays or trolleys that are close to the dominant hand. Pregnancy affects the requirements for standing, manually handling, applying force when operating equipment or moving machines and the period over which the individual might have to work without a break. Employers have a duty to make reasonable adjustments to accommodate disability in the workplace. Any member of staff with a physical impairment needs to be accommodated and this includes making provision for a wheelchair user who needs to enter the operating theatre and perform their work.
8d2a28f3c5f1bd4fb63ed72a1c868f5c572b76c3	pubmed	Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Men with Possible Zika Virus Exposure — United States, August 2018	Update: Interim Guidance for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus for Men with Possible Zika Virus Exposure — United States, August 2018 [bib_ref] Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians, Moore [/bib_ref] [bib_ref] Update: interim guidance for preconception counseling and prevention of sexual transmission of..., Petersen [/bib_ref] ## Review of evidence Primarily transmitted through the bite of an infected Aedes aegypti mosquito, Zika virus can also be transmitted through unprotected sex (i.e., without correct and consistent use of a condom) with an infected partner. As of July 3, 2018, 52 cases of confirmed sexual transmission of Zika virus infection have been reported in the United States since 2015 (https://www.cdc.gov/zika/reporting/case-counts.html). Most documented reports of sexual transmission have involved transmission from a man to a woman (4); however, transmission also has been reported from a man to another man [bib_ref] Male-to-male sexual transmission of Zika virus-Texas, Deckard [/bib_ref] and from a woman to a man [bib_ref] Suspected female-to-male sexual transmission of Zika virus, Davidson [/bib_ref]. Despite their limited generalizability to humans, preliminary data from animal studies suggest that sexual transmission of Zika virus during pregnancy might pose a higher risk to the fetus than mosquitoborne transmission. In female rhesus macaques, vaginal inoculation (as a model for sexual transmission) of Zika virus appeared to enhance viral dissemination to the female reproductive tract, compared with subcutaneous inoculation [bib_ref] Zika virus preferentially replicates in the female reproductive tract after vaginal inoculation..., Carroll [/bib_ref]. In an immunodeficient mouse model, poorer maternal outcomes and higher fetal viral titers were observed when exposure was through sexual transmission rather than subcutaneous or intravaginal infection [bib_ref] Sexual transmission of Zika virus enhances in utero transmission in a mouse..., Duggal [/bib_ref]. Prevention of sexual transmission of Zika virus during pregnancy can reduce the risk for maternal infection and the potential for congenital Zika syndrome. The risk for congenital Zika syndrome associated with maternal Zika virus infection during the periconceptional period is not known. Maternal infection with other viruses (e.g., rubella) during the periconceptional period have been associated with infection in the fetus and adverse pregnancy outcomes; although in some cases, the timing of infection relative to conception was uncertain [bib_ref] Outcome of confirmed periconceptional maternal rubella, Enders [/bib_ref] [bib_ref] A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome, Picone [/bib_ref] [bib_ref] Diagnosis and outcome of preconceptional and periconceptional primary human cytomegalovirus infections, Revello [/bib_ref] [bib_ref] Human fetal infection with parvovirus B19: maternal infection time in gestation, viral..., Nunoue [/bib_ref]. To date, there are no published data definitively linking Zika virus infection around the time of conception to adverse pregnancy outcomes. Since the last update of this guidance on October 7, 2016 (3), additional evidence relevant to the assessment of risk for sexual transmission of Zika virus infection has been reported. A literature search of PubMed was performed to identify new human studies and data published in English since October 2016. ## Summary What is already known about this topic? Zika virus infection during pregnancy is a cause of serious birth defects. CDC previously released interim guidance on preconception counseling and prevention of sexual transmission of Zika virus in October 2016. What is added by this report? CDC now recommends that men with possible Zika virus exposure who are planning to conceive with their partner wait at least 3 months after symptom onset or their last possible Zika virus exposure before engaging in unprotected sex. This updated timeframe also applies to prevent sexual transmission of Zika virus. What are the implications for public health practice? These recommendations provide couples planning pregnancy with updated timeframes expected to reduce the risk for fetal Zika virus infection. References for included articles were also screened. Specific search terms used included "sexual transmission" or "semen" or "seminal fluid" and "Zika." The search yielded 15 publications, including case reports, case series, and nine cohort studies, which were reviewed for new, primary data. Among the currently available reports of sexual transmission of Zika virus, the longest period from symptom onset in the index case to potential sexual transmission to a partner was between 32-41 days (14); most reports indicate much shorter intervals (4). The longest period after symptom onset at which replication-competent (i.e., potentially infectious) virus has been detected in semen by culture or cytopathic effect was 69 days [bib_ref] Probable sexual transmission of Zika virus from a vasectomised man, Arsuaga [/bib_ref]. No other studies reported potentially infectious Zika virus in semen specimens obtained ≥40 days after symptom onset [bib_ref] Presence and persistence of Zika virus RNA in semen, Atkinson [/bib_ref] [bib_ref] Virus and antibody dynamics in travelers with acute Zika virus infection, Barzon [/bib_ref] [bib_ref] Infection dynamics in a traveller with persistent shedding of Zika virus RNA..., Barzon [/bib_ref] [bib_ref] Evidence of sexual transmission of Zika virus, D'ortenzio [/bib_ref] [bib_ref] Sexual transmission of Zika virus in Germany, Frank [/bib_ref] [bib_ref] Persistent Zika virus detection in semen in a traveler returning to the..., Gaskell [/bib_ref] [bib_ref] Sexual transmission of Zika virus and persistence in semen, Harrower [/bib_ref] [bib_ref] Zika virus in semen: a prospective cohort study of symptomatic travellers returning..., Huits [/bib_ref] [bib_ref] First imported case of Zika virus infection into Korea, Jang [/bib_ref] [bib_ref] Effect of acute Zika virus infection on sperm and virus clearance in..., Joguet [/bib_ref] [bib_ref] Long-lasting persistence of Zika virus in semen, Matheron [/bib_ref] [bib_ref] Zika virus: high infectious viral load in semen, a new sexually transmitted..., Mansuy [/bib_ref] [bib_ref] Zika virus shedding in semen of symptomatic infected men, Mead [/bib_ref] [bib_ref] Duration of infectious Zika virus in semen and serum, Medina [/bib_ref] [bib_ref] Potential sexual transmission of Zika virus, Musso [/bib_ref] [bib_ref] Persistence of Zika virus in body fluids-preliminary report, Paz-Bailey [/bib_ref] [bib_ref] Longitudinal follow-up of Zika virus RNA in semen of a traveller returning..., Reusken [/bib_ref]. Numerous publications have reported on the detection of Zika virus RNA in semen [bib_ref] Sexually acquired Zika virus: a systematic review, Moreira [/bib_ref] , although this might not indicate the presence of infectious virus at the time of sampling or correlate with the potential for sexual transmission of infectious virus. In the largest published cohort study to date, involving 184 men with confirmed symptomatic Zika virus infection from whom a baseline specimen and serial semen specimens were collected at 2-week intervals, Zika virus RNA shedding in semen declined during the 3 months after symptom onset [bib_ref] Zika virus shedding in semen of symptomatic infected men, Mead [/bib_ref]. Overall, Zika virus RNA was detected in semen in 61% (22 of 36); 43% (48 of 112); and 21% (28 of 131) of participants from whom specimens were collected within 30, 31-60, and 61-90 days of illness onset, respectively. At >90 days after illness onset, semen of ≤7% of participants had detectable Zika virus RNA. The estimated mean time to clearance of Zika virus RNA from semen was 54 days [bib_ref] Zika virus shedding in semen of symptomatic infected men, Mead [/bib_ref]. Another large cohort study conducted in Puerto Rico followed 117 men, 89 of whom provided semen specimens and reported similar results: at >90 days after illness onset 11% (8 of 74) of men had detectable RNA in semen (Gabriela Paz-Bailey, Division of Vectorborne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC; personal communication, 2018) [bib_ref] Persistence of Zika virus in body fluids-preliminary report, Paz-Bailey [/bib_ref]. Similar findings have been observed in smaller cohort studies [bib_ref] Presence and persistence of Zika virus RNA in semen, Atkinson [/bib_ref] [bib_ref] Virus and antibody dynamics in travelers with acute Zika virus infection, Barzon [/bib_ref] [bib_ref] Zika virus in semen: a prospective cohort study of symptomatic travellers returning..., Huits [/bib_ref] [bib_ref] Effect of acute Zika virus infection on sperm and virus clearance in..., Joguet [/bib_ref] [bib_ref] Duration of infectious Zika virus in semen and serum, Medina [/bib_ref] [bib_ref] Zika virus dynamics in body fluids and risk of sexual transmission in..., Sánchez-Montalvá [/bib_ref] [bib_ref] Kinetics of Zika viral load in semen, De Laval [/bib_ref]. Zika virus RNA has been detected in semen for as long as 370 days after symptom onset [bib_ref] Virus and antibody dynamics in travelers with acute Zika virus infection, Barzon [/bib_ref] ; however, detection for long periods is rare. Limited data suggest the incidence of Zika virus RNA shedding in semen and its persistence after infection are likely similar for symptomatic and asymptomatic men infected with Zika virus [bib_ref] Sexual transmission of Zika virus in an entirely asymptomatic couple returning from..., Fréour [/bib_ref] [bib_ref] Recipient Epidemiology and Donor Evaluation Study (REDS-III) ZIKV Study Group. Detection of..., Musso [/bib_ref] [bib_ref] Likely sexual transmission of Zika virus from a man with no symptoms..., Brooks [/bib_ref]. ## Guidance for preconception counseling and prevention of sexual transmission CDC's last interim guidance released in October 2016 was based on the maximum duration of detection of Zika virus RNA in semen. In the last interim guidance, CDC recommended that men with possible Zika virus exposure wait at least 6 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) before trying to conceive with their partner [bib_ref] Update: interim guidance for preconception counseling and prevention of sexual transmission of..., Petersen [/bib_ref]. New data published since then support an update to that interim guidance. CDC now recommends that men with possible Zika virus exposure who are planning to conceive with their partner wait for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) before engaging in unprotected sex. CDC now also recommends that for couples who are not trying to conceive, men can consider using condoms or abstaining from sex for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) to minimize their risk for sexual transmission of Zika virus. Recommendations for men with possible Zika virus exposure whose partner is pregnant remain unchanged; these couples should be advised to consistently and correctly use condoms during sex or abstain from sex for the duration of the pregnancy . CDC continues to recommend shared patient-provider decision making, in which couples and health care providers work together to make decisions about timeframes to wait before trying to conceive after possible Zika virus exposure. Some couples might choose to wait shorter or longer periods after possible Zika virus exposure, based on individual circumstances (e.g., age, fertility, or details of possible exposure), clinical judgment, and a balanced assessment of risks and expected outcomes. Other guidance for preconception counseling and prevention of sexual transmission of Zika virus after possible Zika virus exposure remains unchanged (3). The couple should use condoms or abstain from sex for the duration of the pregnancy. [table] TABLE: CDC recommendations for preconception counseling and prevention of sexual transmission of Zika virus among persons with possible Zika virus exposure -United States, August 2018 The couple should talk with their health care provider about their plans for pregnancy, their risk for Zika virus infection, the possible health effects of Zika virus infection on a baby, and ways to protect themselves from Zika. If either partner develops symptoms of Zika virus infection or tests positive for Zika virus infection, the couple should follow the suggested timeframes listed above before trying to conceive. (No change in recommendation)* [/table]	None	https://www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6731e2-H.pdf	Zika virus infection can occur as a result of mosquitoborne or sexual transmission of the virus. Infection during pregnancy is a cause of fetal brain abnormalities and other serious birth defects (1,2). CDC has updated the interim guidance for men with possible Zika virus exposure who 1) are planning to conceive with their partner, or 2) want to prevent sexual transmission of Zika virus at any time (3). CDC now recommends that men with possible Zika virus exposure who are planning to conceive with their partner wait for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) before engaging in unprotected sex. CDC now also recommends that for couples who are not trying to conceive, men can consider using condoms or abstaining from sex for at least 3 months after symptom onset (if symptomatic) or their last possible Zika virus exposure (if asymptomatic) to minimize their risk for sexual transmission of Zika virus. All other guidance for Zika virus remains unchanged. The definition of possible Zika virus exposure remains unchanged and includes travel to or residence in an area with risk for Zika virus transmission (https://wwwnc.cdc.gov/travel/page/world-map-areas-with-zika) or sex without a condom with a partner who traveled to or lives in an area with risk for Zika virus transmission. CDC will continue to update recommendations as new information becomes available.
3dedb92f5b548633319d3237edfe620a2d745ba1	pubmed	Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines	Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines with severe (grade III) acute cholecystitis, multiorgan support is a critical part of management. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy and/or drainage. Delayed elective cholecystectomy may be performed after initial treatment with gallbladder drainage and improvement of the patient's general medical condition. # Introduction Acute biliary infl ammation/infection is classifi ed as either acute cholangitis or acute cholecystitis, and ranges from mild forms that improve with medical treatment to severe forms that require intensive care and urgent intervention. The medical condition of a patient with biliary infl ammation/infection is likely to deteriorate rapidly and the condition can become life-threatening. Early diagnosis should be made based on clinical signs/ symptoms and laboratory fi ndings. The type and timing of treatment should be based on the grade of severity of the disease. # Abstract Diagnostic and therapeutic strategies for acute biliary infl ammation/infection (acute cholangitis and acute cholecystitis), according to severity grade, have not yet been established in the world. Therefore we formulated fl owcharts for the management of acute biliary infl ammation/infection in accordance with severity grade. For mild (grade I) acute cholangitis, medical treatment may be suffi cient/appropriate. For moderate (grade II) acute cholangitis, early biliary drainage should be performed. For severe (grade III) acute cholangitis, appropriate organ support such as ventilatory/circulatory management is required. After hemodynamic stabilization is achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. For patients with acute cholangitis of any grade of severity, treatment for the underlying etiology, including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has improved. For patients with mild Although endoscopic and laparoscopic techniques have advanced recently (level 1b-2b), 1,2 the treatment of severe acute biliary infl ammation/infection still results in fatalities and increased hospital costs. To our knowledge, there are no defi nite diagnostic and therapeutic guidelines for acute biliary infl ammation/infection according to the grade of severity of the disease. This article describes the management strategy for biliary infl ammation/infection in accordance with the severity of the biliary disease. Guidelines were developed, based on best clinical evidence and discussions at the International Consensus Meeting held in Tokyo on April 1-2, 2006. ## General guidance for the management of acute biliary infl ammation/infection A fl owchart showing general guidance for the management of acute biliary infl ammation/infection is presented in . ## Clinical presentation Clinical fi ndings associated with acute cholangitis include abdominal pain, jaundice, fever (Charcot's triad), and rigor. The triad was already reported as an indicator of hepatic fever by Charcot in 1877, [bib_ref] De la fi evre hepatique symptomatique Comparison avec la fi evre uroseptique, Charcot [/bib_ref] and has been, historically, used as the generally accepted clinical fi ndings of acute cholangitis. About 50%-70% of patients with acute cholangitis develop all three symptoms (level 2b-4). 4-7 Reynolds' pentad (Charcot's triad plus shock and a decreased level of consciousness) was presented in 1959, when Reynolds and Dargan 8 defi ned acute obstructive cholangitis. The pentad is often used to indicate severe (grade III) cholangitis, but shock and a decreased level of consciousness are observed in only 30% or fewer patients with acute cholangitis (level 2b-4). 4-7 A history of biliary disease, such as gallstones, previous biliary procedures, or the placement of a biliary stent are factors that are very helpful to suggest a diagnosis of acute cholangitis. Clinical symptoms of acute cholecystitis include abdominal pain (right upper abdominal pain), nausea, vomiting, and fever (level 2b-4). [bib_ref] Diagnostic approaches in acute cholecystitis; a prospective study of 1333 patients with..., Eskelinen [/bib_ref] [bib_ref] Clinical presentation of acute abdomen: study of 600 patients, Staniland [/bib_ref] [bib_ref] Does this patient have acute cholecystitis?, Trowbridge [/bib_ref] The most typical symptom is right epigastric pain. Tenderness in the right upper abdomen, a palpable gallbladder, and Murphy's sign are the characteristic fi ndings of acute cholecystitis. A positive Murphy's sign has a specifi city of 79%-96% (level 2b-3b) 9,11 for acute cholecystitis. ## Blood tests The diagnosis of acute cholangitis requires a white blood cell count; measurement of the C-reactive protein level; and liver function tests, including alkaline phosphatase, gamma-glutamyltranspeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Assessment of the severity of the illness requires knowledge of the platelet count, blood urea nitrogen, creatinine, and prothrombin time (PT). Blood cultures are also helpful for severity assessment, as well as for the selection of antimicrobial drugs. Hyperamylasemia is a useful parameter to identify complications such as choledocholithiasis causing biliary pancreatitis (level 1a). [bib_ref] Predictors of common bile duct stones prior to cholecystectomy: a meta-analysis, Abboud [/bib_ref] There is no specifi c blood test for acute cholecystitis; however, the white blood cell count and the measurement of C-reactive protein is very useful in confi rming an infl ammatory process. Bilirubin, blood urea nitrogen, creatinine, and PT are very useful in assessing the disease severity status of the patient. ## Diagnostic imaging Abdominal ultrasound (US) and abdominal computerized tomography (CT) with intravenous contrast are very helpful studies in evaluating patients with acute [bib_ref] Ultrasonography by emergency physicians in patients with suspected cholecystitis, Rosen [/bib_ref] [bib_ref] Performance and interpretation of focused right upper quadrant ultrasound by emergency physicians, Kendall [/bib_ref] The role of diagnostic imaging in acute cholangitis is to determine the presence/absence of biliary obstruction, the level of the obstruction, and the cause of the obstruction, such as gallstones and/or biliary strictures. Assessment should include both US and CT. These studies complement each other and CT may better demonstrate dilatation of the bile duct and pneumobilia. Some of the characteristic fi nding of acute cholecystitis include an enlarged gallbladder, thickened gallbladder wall, gallbladder stones and/or debris in the gallbladder, sonographic Murphy's sign, pericholecystic fl uid, and pericholecystic abscess. Sonographic Murphy's sign is a very reliable fi nding of acute cholecystitis, with a specifi city exceeding 90% (level 3b,4). 15,16 CT scan or even plain X-ray may demonstrate free air, pneumobilia, and ileus. ## Differential diagnosis Diseases which should be differentiated from acute cholangitis are acute cholecystitis, gastric and duodenal ulcer, acute pancreatitis, acute hepatitis, and septicemia of other origins. Diseases which should be differentiated from acute cholecystitis are gastric and duodenal ulcer, hepatitis, pancreatitis, gallbladder cancer, hepatic abscess, Fitz-Hugh-Curtis syndrome, right lower lobar pneumonia, angina pectoris, myocardial infarction, and urinary infection. ## Flowchart for the management of acute cholangitis A fl owchart for the management of acute cholangitis is shown in [fig_ref] Figure 2: Flowchart for the management of acute cholangitis drainage should be considered [/fig_ref]. The treatment of acute cholangitis should be guided by the grade of severity of the disease. Biliary drainage and antibiotics are the two most important elements of treatment. When a diagnosis of acute cholangitis is suspected, medical treatment, including nil per os (NPO) and the use of intravenous fl uids, antibiotics, and analgesia, together with close monitoring of blood pressure, pulse, and urinary output should be initiated. Simultaneously, a severity assessment of the cholangitis should be documented, even if it is mild. Frequent reassessment is important, and patients may need to be reclassifi ed as having mild (grade I), moderate (grade II), or severe (grade III) disease, based on the response to medical treatment. Appropriate treatment should be performed in accordance with the severity grade. Patients with concomitant diseases such as acute pancreatitis or malignant tumor, and elderly patients are likely to progress to a severe level; therefore, such patients should be monitored frequently. ## Mild (grade i) acute cholangitis Medical treatment may be suffi cient. Biliary drainage is not required in most cases. However, for nonresponders to medical treatment, the necessity of biliary ## Moderate (grade ii) acute cholangitis Patients with acute cholangitis who do not respond to medical treatment have moderate (grade II) acute cholangitis. In these patients, early endoscopic or percutaneous drainage or even emergent operative drain-age with a T-tube should be performed. A defi nitive procedure should be performed to remove the cause of the obstruction once the patient is in a stable condition. ## Severe (grade iii) acute cholangitis Patients with acute cholangitis and organ failure are classifi ed as having severe (grade III) acute cholangitis. These patients require organ support, such as ventilatory/circulatory management (e.g., endotracheal intubation, artifi cial respiration management, and the use of vasopressin), and treatment for disseminated ## Results of the tokyo international consensus meeting At the International Consensus Meeting, responses to the fl owcharts for the management of the different grades of acute cholangitis were elicited and a consensus was reached . ## Flowchart for the management of acute cholecystitis A fl owchart for the management of acute cholecystitis is shown in . Early cholecystectomy is recommended for most patients, with laparoscopic cholecystectomy as the preferred method. Among high-risk patients, percutaneous gallbladder drainage is an alternative therapy for those patients who cannot safely undergo urgent/ early cholecystectomy (level 4). [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] [bib_ref] Treatment of acute cholecystitis in non-critically ill patients at high surgical risk:..., Chopra [/bib_ref] When a diagnosis of acute cholecystitis is suspected, medical treatment, including NPO, intravenous fl uids, antibiotics, and analgesia, together with close monitoring of blood pressure, pulse, and urinary output should be initiated. Simultaneously, the grade of severity needs to be established. Appropriate treatment should be performed in accordance with the severity grade. The assessment of operative risk should also be evaluated based on the severity grade. After the acute infl ammation has been resolved by medical treatment and gallbladder drainage, it is desirable to perform a cholecystectomy to prevent recurrence. In surgically high-risk patients with cholecystolithasis, medical support after percutaneous cholecystolithotomy should be considered (level 4). [bib_ref] Nonsurgical treatment of cholecystolithiasis with percutaneous transhepatic cholecystoscopy, Inui [/bib_ref] [bib_ref] Gallstones in critically ill patients with acute calculous cholecystitis treated by percutaneous..., Boland [/bib_ref] [bib_ref] Gallstone removal with a modifi ed cholecystoscope: an alternative to cholecystectomy in..., Majeed [/bib_ref] For patients with acalculous cholecystitis, cholecystectomy is not required, because recurrence of acute acalculous cholecystitis after gallbladder drainage is rare (level 4). [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] [bib_ref] Percutaneous transhepatic cholecystostomy for acute acalculous cholecystitis, Shirai [/bib_ref] ## Mild (grade i) acute cholecystitis Early laparoscopic cholecystectomy is the preferred treatment. Elective cholecystectomy may be selected (if early cholecystectomy is not performed) in order to improve other medical problems. ## Moderate (grade ii) acute cholecystitis Early laparoscopic or open cholecystectomy is preferred. If a patient has serious local infl ammation making early cholecystectomy diffi cult, then percutaneous or operative drainage of the gallbladder is recommended. Elective cholecystectomy can be performed after improvement of the acute infl ammatory process. ## Severe (grade iii) acute cholecystitis Severe (grade III) acute cholecystitis is accompanied by organ dysfunction and/or severe local infl ammation. Appropriate organ support in addition to medical treatment is necessary for patients with organ dysfunction. Management of severe local infl ammation by percutaneous gallbladder drainage and/or cholecystectomy is needed. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy ## Results of the tokyo international consensus meeting At the International Consensus Meeting, fl owcharts for the management of mild (grade I) and severe (grade III) acute cholecystitis were agreed upon by almost all of the participants; however, the fl owchart for moderate (grade II) acute cholecystitis was agreed upon by fewer than 90% of the participants . We also truly appreciate the panelists who cooperated with and contributed signifi cantly to the International Consensus Meeting held in Tokyo on April 1 and 2, 2006. repeated after the initiation of treatment for acute cholangitis. ## Flowchart for the management of acute cholecystitis There were several controversies over the treatment of acute cholecystitis. Early cholecystectomy is indicated for most patients with acute cholecystitis, and laparoscopic cholecystectomy is preferred for experienced surgeons. Several randomized controlled trials comparing early and delayed operation conducted in the 1970s to 1980s found that early surgery had the advantages of less blood loss, shorter operation time, a lower complication rate, and a shorter hospital stay. Some Japanese doctors advocated that early cholecystectomy should not be recommended because early cholecystectomy was not prevalent in Japan. Steven M. Strasberg mentioned: "We have to be willing to accept the fact that we may need to change our practice based upon the evidence". Results of randomized controlled trials comparing early laparoscopic cholecystectomy with delayed laparoscopic cholecystectomy have also shown that early laparoscopic surgery is superior to delayed surgery in terms of the conversion rate to open surgery, complication rate, and total hospital stay. Toshihiko Mayumi (Japan) mentioned that because laparoscopic cholecystectomy by inexperienced surgeons resulted in more frequent intraoperative complications than open cholecystectomy, the laparoscopic procedure should not be overemphasized. There was more discussion to determine the treatment strategy for acute moderate (grade II) cholecysti-tis. Before the start of the international symposium it was considered that urgent/early cholecystectomy should be performed for these patients. Steven M. Strasberg mentioned: "For patients with acute moderate cholecystitis (patients who have a white [cell] count over 18 000; patients who have cholecystitis for more than 72 h; patients who have a palpable infl ammatory mass), early cholecystectomy is going to be maybe very diffi cult. Therefore do we really want to say to the general surgeon in a small hospital that we recommend that when the white [cell] count is over 18 000 that he takes the patient to the operating room? I do not think so." After the statement of his opinion, delayed elective cholecystectomy was recommended for acute moderate (grade II) cholecystitis with severe local infl ammation. On the other hand, Eduardo de Santibanes (Argentina) advocated that early laparoscopic cholecystectomy could be performed for patients with acute moderate cholecystitis. The treatment courses for mild (grade I) and severe (grade III) cholecystitis were accepted without major adverse opinions. The recommendation of early laparoscopic cholecystectomy for mild (grade I) cases and gallbladder drainage for severe (grade III) cases obtained consensus. Some Japanese doctors suggested that endoscopic gallbladder drainage as well as per cutaneous gallbladder drainage should be recommended. However, Jacques Belghiti rejected this suggestion, because there was poor evidence for effi cacy, and because endoscopic gallbladder drainage needed a special technique. Thomas R. Gadacz added surgical cholecystostomy to one of the methods for gallbladder drainage. [fig] Figure 2: Flowchart for the management of acute cholangitis drainage should be considered. Treatment options such as endoscopic, percutaneous, or operative intervention may be required, depending on the etiology. Some patients, such as those who develop postoperative cholangitis, may only require antibiotics and generally do not require intervention. [/fig]	None	https://link.springer.com/content/pdf/10.1007/s00534-006-1153-x.pdf	None
7bd1326afa6903d8724730f4d9afd5432c27352f	pubmed	First trimester diagnosis and screening for fetal aneuploidy	First trimester diagnosis and screening for fetal aneuploidy [bib_ref] First-trimester or second-trimester screening, or both, for Down's syndrome, Malone [/bib_ref] [bib_ref] A screening program for trisomy 21 at 10 -14 weeks using fetal..., Spencer [/bib_ref] [bib_ref] SURUSS in perspective, Wald [/bib_ref] ## Diagnosis of fetal aneuploidy Although there is exciting research and innovation in the field of noninvasive testing for fetal aneuploidy, at present there are two tests, both invasive, which are used in a routine manner to determine the presence of fetal aneuploidychorionic villus sampling (CVS) and amniocentesis. CVS is performed in the first trimester from 10 through 13 weeks' gestation, whereas amniocentesis can be performed starting at 15 weeks' gestation. More recent literature suggests that the risk of pregnancy loss from sonographically directed amniocentesis is 1 in 300 -600, 5,6 with one study suggesting that there may be no significant increase over the background miscarriage risk. [bib_ref] Pregnancy loss rates after midtrimester amniocentesis, Eddleman [/bib_ref] Likewise, the risk of pregnancy loss with CVS is also low, particularly for transabdominal procedures. [bib_ref] Amniocentesis and chorionic villus sampling for prenatal diagnosis, Alfirevic [/bib_ref] Transcervical CVS loss rates are slightly increased. Based on the relative safety of these diagnostic procedures, and in deference to patient preference and autonomy, the American College of Ob-stetricians and Gynecologists recently recommended that all pregnant women regardless of maternal age should have the option of having an invasive diagnostic test to definitively identify not only DS, but all major fetal aneuploidies. Such diagnostic testing should be made available if requested after appropriate counseling including risks and benefits. Likewise, women who do not want any further information regarding chromosomal status of their fetus should not be required to undergo any further testing or screening. Screening provides such an option for those women who would like to further refine their risk before deciding whether or not to undergo invasive testing. ## First trimester screening serum markers Presently, the two markers currently in clinical practice with demonstrated utility are pregnancy-associated plasma protein A (PAPP-A), which is typically reduced and human chorionic gonadotrophin (hCG), which is elevated in DS. The overall data suggest that free beta hCG is likely superior. [bib_ref] Aneuploidy screening in the first trimester, Spencer [/bib_ref] However, access to free beta hCG has been limited and, therefore, many programs in the United States use intact hCG. ## Ultrasound The big breakthrough in first trimester screening was the advent of the nuchal translucency (NT) measurement. Between 11 and 14 weeks, a clearly demarcated fluid-filled space can be seen behind the fetal neck. This space is present in all fetuses. An increased NT measurement is significantly associated with fetal DS and other aneuploidies. The detection rate for DS is approximately 70% with a 5% false-positive rate. Other sonographic findings are being investigated as potential markers for DS. Absence of the nasal bone is associated with DS but its value as a screening test in the general population is controversial. As with the NT measurement, standardization of the technique and quality assessment programs are essential. [bib_ref] First trimester ultrasonography in screening and detection of fetal anomalies, Sonek [/bib_ref] Some programs have incorporated nasal bone assessment into their first trimester screening protocol. [bib_ref] Nasal bone in first-trimester screening for trisomy 21, Cicero [/bib_ref] Now there is also substantial evidence that congenital heart defects may present with increased NT measurement. [bib_ref] Nuchal translucency and fetal cardiac defects: a pooled analysis of major fetal..., Makrydimas [/bib_ref] Other findings associated with increased NT measurements include diaphragmatic hernias, skeletal dysplasias, and a variety of genetic syndromes. [bib_ref] First trimester ultrasonography in screening and detection of fetal anomalies, Sonek [/bib_ref] Based on the current scientific evidence, the American College of Obstetricians and Gynecologists recommends that patients with a fetal NT measurement of 3.5 mm or higher be offered a targeted ultrasound, echocardiogram, or both. ## Combined ultrasound and serum markers Multiple studies have demonstrated that the most effective DS screening approach in the first trimester is the combination of maternal age, NT measurement, and serum markers. The DS detection rates in four major studies range from 79 to 90% with a 5% false-positive rate. A consistent finding across all studies is the necessity for standardization and rigorous quality control both in the laboratory assays and NT measurements. Combined algorithms are also available for Trisomy 18. [bib_ref] First-trimester screening for trisomies 21 and 18, Wapner [/bib_ref] It is acknowledged that combined ultrasound and serum screening for multifetal gestations remains less sensitive than in singleton pregnancies. There are insufficient prospective studies to determine actual detection rates so that laboratories that do provide risk results are using mathematical models. There is also the ongoing concern that serum marker levels reflective of both pregnancies are actually averaged, which is a problem across all trimesters. NT measurement alone is useful in screening multiple gestations for DS but is associated with a higher positive screening rate. ## Screening in both first and second trimesters There have been several different approaches to improve screening rates based on combining first and second trimester screening. These include integrated testing, where NT measurement and PAPP-A in the first trimester are combined with the second trimester screening that includes alphafetoprotein, hCG, unconjugated estriol, and dimeric inhibin-A; however, with this approach results are not available until the second trimester. 14 Sequential screening takes advantage of the higher detection rates achieved with an integrated approach but discloses the first trimester results, which allows a patient the option of CVS and earlier termination in the event of an affected fetus. Independent assessment of DS risk by both first and second trimester screening is discouraged because of the high false-positive rates associated with this approach. [bib_ref] Sequential pathways of testing after first-trimester screening for trisomy 21, Platt [/bib_ref] Most recently, contingency screening has been proposed whereby only those women with a result in a predefined intermediate range undergo testing in the second trimester. [bib_ref] Practical strategies in contingent sequential screening for Down syndrome, Benn [/bib_ref] These various combinations offer detection rates of over 90% with reduced falsepositive rates. ## Recommendations The American College of Medical Genetics recommends the following: - All women should have the option of invasive diagnostic testing for fetal aneuploidy by CVS, if available, or amniocentesis. Benefits include diagnosis of all major aneuploidies and large chromosomal rearrangements. - For women who do not want any information regarding fetal aneuploidy status, following appropriate documentation, no other testing or screening is required. - First trimester screening (NT, PAPP-A, and hCG) is an acceptable, cost effective approach for DS risk screening for women if they present early in pregnancy (before 14 weeks' gestation). - Incorporation of the nasal bone assessment into the first trimester screening protocol is optional and should be limited to clinicians who have specific training and participate in an ongoing quality assurance program. ## First trimester screening - Women presenting in the second trimester should be offered multiple marker screening as described in the ACMG policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004) (www.acmg.net). - Approaches that use first and second trimester screening have improved detection rates and lower false-positive rates. However, providers and centers must be prepared to ensure that there is adequate follow-up and nondisclosure is acceptable to the patient if they choose to offer integrated screening. Sequential or contingency screening with disclosure of the first trimester results may be preferable for some providers and patients. - Women should be informed of the adjusted risk for DS and allowed to make decisions based on this number, because individuals will weigh risk/benefits differently and are capable of such decision-making. Because age is no longer used as a cutoff to offer invasive testing, it is no longer logical to use predetermined cutoffs based on age risk for screening programs. - First trimester screening can be used in multifetal pregnancies; however, women should be made aware of the limitations of screening in this setting. - An NT measurement of 3.5 mm or greater, even in the setting of a low risk for aneuploidy screen result or normal fetal karyotype should prompt a detailed anatomic ultrasound, echocardiogram, or both. - Women who have elected to have first trimester screening and/or CVS should be offered MSAFP screening and/or an anatomic survey, optimally between 16 and 20 weeks' gestation for the detection of neural tube defects. - First trimester screening requires adherence to strict standards and maintenance of quality, both in the laboratory and ultrasound units. Sonographers must be appropri-ately trained in the proper technique of NT measurement and have appropriate certification through available organizations. January 2008 ⅐ Vol. 10 ⅐ No. 1	None	http://www.gimjournal.org/article/S1098360021028872/pdf	Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. Benefits of first trimester screening include earlier identification of the pregnancy at risk for fetal aneuploidy and anatomic defects, in particular, cardiac anomalies, and the option of earlier diagnosis by chorionic villus sampling, if available. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004) and complements the sections of American College of Medical Genetic's Standards and Guidelines for Clinical Genetics Laboratories entitled “Prenatal screening for Down syndrome that includes first trimester biochemistry and/or ultrasound measurements.”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.
ae77c4f12a9c0e28967e0c141c617b7c8a3c7e65	pubmed	Vascular Surgery Practice Guidelines during COVID-19 Pandemic in a Setting of High Work Volume Against Limited Resources: Perspective of a Developing Country	Vascular Surgery Practice Guidelines during COVID-19 Pandemic in a Setting of High Work Volume Against Limited Resources: Perspective of a Developing Country # Introduction We are living in an unprecedented time. An outbreak of the novel coronavirus disease 2019 (COVID-19; also dubbed as SARS-CoV-2) has dramatically changed the landscape of human behavior all over the world. This highly contagious disease has come to challenge the capability of the most advanced health care systems of the world. Starting from the city of Wuhan, China, in December 2019, the novel coronavirus infection has literally swept across Europe and America where thousands of lives have been lost.To this point in time, more than 13 million people have been infected by the virus globally and more than 580,000 have succumbed to it, most of them in Europe and the Americas.The World Health Organization has correctly labeled this disease a pandemic that has now spread in every major country and region of the world 4 with shifting epicenters. Although the wave of infection seems to have waned in Europe, it continues to rise in other parts of the world including South America and the Indian subcontinent. Medical and surgical patient care has dramatically changed in the time of COVID-19. Developed nations have adopted policies of rendering only the essential services postponing all nonessential issues. The idea behind such a policy is to reduce burden on the health care system and conserve resources to ensure continuity of essential services in the long term. In line with such policy, different professional bodies of the world including the surgical associations have laid down working guidelines for their respective specialty. ## Situation of covid-19 pandemic in bangladesh In Bangladesh, the first case of COVID-19 was detected on March 8, 2020. Since then, the country has seen a steady increase in the number of infections with a rapid surge in the recent few weeks.Known infection is now nearly 200,000 with official mortality figures close to 2,500 making it one of the worst hit countries in Asia. Even with the limited number of tests being performed (10,000e15,000/day), new infections in 24 hr are now consistently exceeding 3,000. Test versus case ratio has steadily increased since April 2020, which now ranges between 21% and 25%.The rate of infection is also increasing in neighboring India, which has a population of over 1,350 million. Given the current trend of infection, it may not be too farfetched to think that the Indian subcontinent may be the next epicenter of COVID-19 pandemic. Although the case fatality rate (about 1.28%) is still somewhat low in Bangladesh,the number of moderate to severely ill patients requiring hospital-based care is increasing. ## Covid-19 management strategy in bangladesh Bangladesh being a developing country with limited resources is facing a challenge of unknown proportion in the fight against COVID-19 pandemic. Here, the strategy for the fight against COVID-19 has been quite unique. The government had initially set aside a number of COVID-designated hospitals, where only the confirmed cases were being housed and cared. These were mainly smaller facilities and not the main large volume public hospitals of the country, which remained non-COVID hospitals, and were meant to be out of bounds for proven patients with COVID-19. Privately owned hospitals were also not allowed to treat known patients with COVID-19 in the initial period. The idea behind such a strategy was to limit spread of infection in the community. However, infection continues to increase for a variety of reasons that include the socioeconomic ones. Health care workers (HCWs), as expected, are in the forefront of the fight against COVID-19 all over the world. They have shown tremendous courage and resilience in facing the crisis head on. It should not come as a surprise that physicians and nurses are contracting the infection at a disproportionately higher rate and are even dying in significant numbers while providing care to the patients with COVID-19. [bib_ref] Coronavirus disease 2019 (COVID-2019) infection among health care workers and Implications for..., Lai [/bib_ref] In Bangladesh, infection among HCWs has also been rising steadily threatening the continuity of essential health care services. More than 2,000 physicians have become COVID-19 positive by the end of June, and there have already been more than 80 casualties. Therefore, protecting HCWs has become a priority in the health care system of Bangladesh as it is all over the world. National Institute of Cardiovascular Diseases and Hospital (NICVD), Dhaka, is the largest tertiary care cardiovascular center in Bangladesh. It is also the only government-funded referral center for emergency vascular care. At the Department of Vascular Surgery of NICVD, we perform about 2,500 vascular operations and endovascular procedures a year, more than 60% of which are vascular emergencies. We also perform more than 3,000 Duplex imaging at our vascular laboratory and provide outdoor consultation to more than 10,000 patients/year. However, the aforementioned vascular care services rendered in ordinary times cannot continue in the COVID-19 crisis for obvious reasons. Rather, we need to adapt to the changing situation. To this end, we on behalf of the Vascular Surgery Department of NICVD have formulated a working guideline for our vascular surgeons to adhere to. The purpose of the guideline is 2fold: to safeguard working manpower against COVID-19, and to continue essential vascular services over a long period of time. The strategic mainstay of this guideline is deferral of the elective procedures and nonessential vascular services to focus only on emergency vascular care. To protect HCWs, we have instituted a protocol of duty roster using minimum manpower in such a way that allows for a sufficiently long period of isolation in between duties. There have been confusions regarding the selection of vascular procedures to be judged for different urgency levels. The present guideline formulated on the principles being followed worldwide and also taking into consideration the health care structure and available resources of Bangladesh is expected to eliminate such confusions and make vascular patient care relatively seamless during the ongoing COVID-19 pandemic. ## Vascular services: working definitions of different ur-gency levels At NICVD, Dhaka, we have categorized vascular diseases that require one or more procedures for evaluation and management into different priority levels mentioned below and assigned one or more recommendations to every one of them [fig_ref] Table I: Working guidelines for vascular procedures and other servicesTable I [/fig_ref]. The basic recommendations are as follows: # Discussion Bangladesh is a small Southeast Asian country, which has drawn international attention in the recent times for giving shelter to more than 1 million Rohingya refugees driven out from neighboring Myanmar. Despite all the adversities, Bangladesh has made significant strides in key socioeconomic indicators over the last decade to get rid of the status of least developed country and is now officially acknowledged as a developing country. Its present population is 164.5 million with an average population density 8 of 1,265/km 2 making it one of the most densely populated countries in the world. Dhaka, the capital of Bangladesh, is one of the most densely populated megacities of the world. As apprehended, the city has been hit very hard by COVID-19 infection with more than half of the country's total infection recorded here.Bangladesh initially pursued a strategy of managing patients with COVID-19 only in specific facilities. A system of triage along with clear demarcation of red, orange, yellow, and green areas is still mostly lacking in the major hospitals. A lack of quick screening for COVID-19 also stands in the way of efficient handling of patients, particularly those requiring emergency surgical procedures. The previously mentioned strategy is fundamentally different from that pursued in the developed countries. [bib_ref] Vascular surgery in the COVID-19 pandemic, Unal [/bib_ref] [bib_ref] Experience from a Singapore tertiary hospital with restructuring a vascular surgery practice..., Ng [/bib_ref] Realizing the pitfalls of this strategy, the government of Bangladesh has now changed its policy to accommodate patients both with COVID-19 and without COVID-19 in the same facility.However, it is still not clear how effective this will be in delivering patient care without compromising safety. As number of infection continues to rise in Bangladesh, the situation will likely become worse. A constraint of resources can be predicted in the coming months. At this point, the COVID-19 treatment facilities all over the country, both public and private, are full to their capacity. With a very limited number of intensive care unit (ICU) beds and ventilators, there may be a need for makeshift ICUs. Operating theaters (OTs) may also need to be repurposed and used as ICU. Similar constraints can also be foreseen for HCWs. At NICVD, the number of HCWs infected with COVID-19 has now exceeded 150, 30 of whom are physicians. The number of dedicated vascular surgeons in Bangladesh is only about 30, which is clearly inadequate for the large population of the country. About one-third of these professionals work at the NICVD. Therefore, it is imperative that vascular surgeons of Bangladesh be protected while rendering essential vascular care services. We strongly believe that the proposed working guideline can greatly facilitate the execution of this policy. Vascular surgical bodies all over the world have put in place such guidelines and adjustments for their members to follow. A large cardiovascular center in Turkey has recently published its own guideline, where different vascular procedures have been assigned a certain level of priority. [bib_ref] Vascular surgery in the COVID-19 pandemic, Unal [/bib_ref] The American College of Surgeons has also published a similar working guideline for the vascular surgeons.Melo and Pedro 14 from Portugal reported their departmental adjustments in the time of COVID-19. Similar COVID-19edriven practice restructuring has been reported from a tertiary hospital in Singapore. [bib_ref] Experience from a Singapore tertiary hospital with restructuring a vascular surgery practice..., Ng [/bib_ref] The present guideline although fundamentally in line with these previously published principles is based on the unique situation in Bangladesh. We have taken into account the availability of not only vascular surgeons but also the supporting staff including anesthesiologists and those who have access to the OT and catheterization laboratories. The guideline also foresees the issues of affordability in addition to availability of surgical materials and hardware for endovascular procedures, which will be inevitable in the near future as a consequence of the COVID-19erelated economic downturn. To this end, we have included in this guideline an additional recommendation of ''consider aggressive medical management instead,'' which if judiciously applied could help further reduce procedural burden at this time of crisis. It is to be noted that since the implementation of the countrywide lockdown from early April, routine outdoor patient pool had dried, which is yet to return to normal despite the easing of lockdown. However, the pattern of vascular emergency cases has remained essentially the same. Vascular trauma resulting from violence or road traffic accidents is being encountered regularly. Complications related to ALI and dialysis access have remained more or less similar in number. Vascular surgeons have the moral and professional responsibility to serve these patients irrespective of their COVID-19 status, which places them at a high risk of contracting the infection. Our roster-based emergency services involving minimum number of HCWs minimize risk of exposure. To further minimize this risk, we have brought in a few adjustments in our anesthetic practices. Regional or locoregional anesthesia is being preferred over general anesthesia with endotracheal intubation whenever possible to reduce aerosol generation in the OT. Availability of personal protective equipment (PPE) has become a key issue for HCWs worldwide. In Bangladesh, quality PPE and masks, as well as proper donning and doffing practices, has been a matter of great concern. Physicians have been infected even when donning PPE and masks. We believe that accountability of the health administrators and training for HCWs can greatly improve the situation. The early outcome of our proposed guideline has been satisfactory in the sense that emergency vascular care services continue to be provided without significant negative impact on safety of the caregivers. Results of ALI and chronic limb-threatening ischemia treatment during pandemic have also been comparable with the preeCOVID-19 months. The slightly higher number of limb loss in the COVID-19 months may be explained by late presentation largely because of the countrywide lockdown. # Conclusions We propose a working guideline for the vascular practices in Bangladesh during the COVID-19 pandemic. The guideline is basically in line with those being practiced elsewhere. However, it is unique in the sense that it takes into account the different reality of a developing country with significant constraint of resources in the face of a rapidly worsening crisis. [table] Table I: Working guidelines for vascular procedures and other servicesTable I. [/table]	None	http://www.annalsofvascularsurgery.com/article/S0890509620307950/pdf	None
dce6444474157a1545080a92a044d860e9210f4e	pubmed	SOFFCO-MM guidelines for the resumption of bariatric and metabolic surgery during and after the Covid-19 pandemic	SOFFCO-MM guidelines for the resumption of bariatric and metabolic surgery during and after the Covid-19 pandemic Bariatric/metabolic surgery was paused during the Covid-19 pandemic. The impact of social confinement and the interruption of this surgery on the population with obesity has been underestimated, with weight gain and worsened comorbidities. Some candidates for this surgery are exposed to a high risk of mortality linked to the pandemic. Obesity and diabetes are two major risk factors for severe forms of Covid-19. The only currently effective treatment for obesity is metabolic surgery, which confers prompt, lasting benefits. It is thus necessary to resume such surgery. To ensure that this resumption is both gradual and well-founded, we have devised a priority ranking plan. The flow charts we propose will help centres to identify priority patients according to a benefit/risk assessment. Diabetes holds a central place in the decision tree. Resumption patterns will vary from one centre to another according to human, physical and medical resources, and will need adjustment as the epidemic unfolds. Specific informed consent will be required. Screening of patients with obesity should be considered, based on available knowledge. If Covid-19 is suspected, surgery must be postponed. Emphasis must be placed on infection control measures to protect patients and healthcare professionals. Confinement is strongly advocated for patients for the first month post-operatively. Patient follow-up should preferably be by teleconsultation. # Introduction Since March 2020, the Covid-19 pandemic has caused scheduled weight-loss surgery and related therapeutic education programmes (preparation and follow-up) to be paused. The expected duration of the pandemic is uncertain (vaccine unavailable in the short term), acquired immunity is unsure (short-lived antibodies), and obesity and comorbidity rates have been increasing. De-scheduling and confining have numerous adverse effects, including psychological harms, injudicious dietary behaviour, and lack of physical exercise. These effects in turn cause weight gain or regain, worsened comorbidities, a risk of contracting a severe form of Covid-19, and increased morbidity/mortality risk in future candidates for weight-loss surgery. To mitigate these harms arising from the epidemic and the resulting confinement, and to better prepare this vulnerable section of the population for an extension of the epidemic, there is an obvious real need to resume weightloss surgery. It is therefore urgent to set guidelines for the gradual resumption of surgical care, especially as the conventional indications for this surgery based on BMI reflect neither the severity of the obesity nor the urgency or semiurgency of some indications. The SOFFCO-MM tasked an expert working group with addressing these questions in readiness for the resumption of surgery. The aim of these guidelines is to cogently rank the urgency of rescheduling surgery based on evidence-based criteria, benefit/risk ratios and clinical good sense. ## Why resume weight-loss surgery? ## Benefit of weight-loss surgery on overweight and comorbidities Obesity increases the risk of illnesses such as diabetes, high blood pressure, hepatic steatosis and steatohepatitis, coronopathy, stroke, certain cancers, infertility, psychosocial disorders, arthropathy, nephropathy and many others. Epidemiological studies confirm that severe obesity reduces life expectancy by 5-20 years [bib_ref] Years of life lost due to obesity, Fontaine [/bib_ref]. Among the complications linked to obesity, some are especially life-threatening or potentially disabling It is estimated that two thirds of persons with diabetes will die of a cardiovascular illness with a relative risk 1.8-2.6 times higher than the general population . Similarly, the presence of an obstructive sleep apnoea syndrome is especially frequent in persons with obesity, and if untreated is associated with an excess mortality of 24% at 1.5-2 years [bib_ref] Combining risk estimates from observational studies with different exposure cutpoints: a meta-analysis..., Hartemink [/bib_ref]. It is currently proven that the only effective long-term treatment of obesity is surgery. Besides improving comorbidities, weight-loss surgery reduces the relative risk of death by 35-89% [bib_ref] Effects of bariatric surgery on mortality in Swedish obese subjects, Sjöström [/bib_ref]. Weight-loss surgery has lengthened life expectancy, despite the peri-operative risks [bib_ref] Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS..., Sjöström [/bib_ref]. Perioperative mortality has tended to diminish with time and accumulated experience, with rates in France now of 0.07% [bib_ref] Reduction in early mortality outcomes after bariatric surgery in France between 2007..., Lazzati [/bib_ref]. This is true metabolic surgery: its other benefits, especially on diabetes, are detailed in the other chapters. ## Impact of obesity on disease severity in covid+ patients Persons with obesity are among those most vulnerable to the Covid-19 epidemic, obesity being an independent complications factor: a recent study found that more than 47% of infected patients admitted to IC had obesity. Obesity significantly increased the risk of being placed under invasive artificial ventilation. In the Lille study, Grade II and III obesity in patients admitted to IC for Covid-19 was an independent risk factor for a severe form of the infection [bib_ref] High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring..., Simonnet [/bib_ref]. Despite improved knowledge of Covid-19, there are still no data supporting a protective effect of bariatric surgery in patients who have undergone it, although the weight loss itself probably mitigates the consequences of infection. Nor are there any data by which to judge the impact of infection during the weight loss period. Special vigilance is thus called for. ## Who is eligible for scheduled bariatric surgery? in what setting? Resumption of surgical care must allow for a possible 'second wave' or medium-term extension of the epidemic after confinement measures are lifted. An extreme vigilance is necessary concerning the indicators that govern response to reduce the risk of peri-operative Covid-19 infection: - access to Intensive care (IC) after the crisis; - replication rate of the virus less than 1 outside epidemic peaks; - access to operating room: several factors hinder access to the operating room. Physical distancing measures in healthcare centres reduce the fluidity and availability of accommodation (which depends on policy decisions made by the centre) and there may also be shortages of medical drugs (independently of the centre and the healthcare professionals). There are two contrasting strategies by which weightloss surgery can be resumed. Each has its justifications, its advantages, and its drawbacks. [fig_ref] Table 1: Strategies for resuming bariatric surgery [/fig_ref] summarizes these two strategies. - strategy 1 ('benefit outweighs risk') is based on the severity scores for each pathology. Several studies propose prioritizing indications by considering the degree of severity of the associated comorbidities and the socioeconomic impact [bib_ref] Obesity Surgery Score (OSS) for Prioritization in the Bariatric Surgery Waiting List:..., Pérez [/bib_ref] [bib_ref] Using the Edmonton obesity staging system to predict mortality in a population-representative..., Padwal [/bib_ref] [bib_ref] Obesity surgery mortality risk score: proposal for a clinically useful score to..., De Maria [/bib_ref] [bib_ref] Edmonton Obesity Staging System: association with weight history and mortality risk, Kuk [/bib_ref]. In this strategy, and especially in the case of blood sugar imbalance, need for insulin therapy, or diabetes evolving for more than 5 years and the occurrence of macro-or microangiopathy are factors of poor outcome. However, these patients are also the most at risk in the event of surgical complications [bib_ref] Edmonton Obesity Staging System: association with weight history and mortality risk, Kuk [/bib_ref] ; - strategy 2 ('safe and preventive'), conversely, consists in operating only on patients at low operative risk to achieve a longer-term benefit. To guide decision-making during this unprecedented health crisis, the SOFFCO-MM set objectives according to means: - make as little use of IC beds as possible by selecting patients whose expected surgical complication rates will be low; - perform bariatric surgery on those categories of patient whose state of health will deteriorate in the medium term without surgical care; - resume this surgical care equally in both public and private sectors; - do not operate on Covid+ patients or patients with known Covid+ history (given the current lack of evidence for effective immunization). Strategy 3 advocated by the SOFFCO [fig_ref] Table 1: Strategies for resuming bariatric surgery [/fig_ref] is a degraded intermediate strategy based on benefit/risk ratios. The flow charts for indications are summarized in Figs. 1-3. [fig_ref] Figure 4: Resumption of overall activity according to the evolution of the Covid-19 pandemic [/fig_ref] shows the flow chart for all indications (vitally urgent, semi-urgent, priority and not urgent). In other words, priority patients (for surgery when confinement is lifted and in the subsequent 6 months) will have the following characteristics: Decision of multidisciplinary concertation meeting: - already validated; - being validated. Indication (further criterion to be added to the multidisciplinary concertation file to qualify for priority ranking): - diabetes: - time since diagnosis < 3 years, or, - needing insulin treatment, or, - with equilibration difficulties, or; - comorbidities (other than diabetes): - ≥ 2 comorbidities, or, - 1 severe comorbidity, or; - waiting for other important treatment (organ transplant, joint prosthesis, medically assisted procreation), or; - with specific symptoms that can be improved by surgery because they are resistant to medical treatment (gastrooesophageal reflux, pain, dysphagia, etc.). The priority criteria proposed are established according to the severity of the comorbidities and the benefit/risk ratios for surgery. These criteria are tools to guide resumption of bariatric surgery. They are to be weighted according to the local status of the epidemic, the types of patients in each centre, and the procedures envisaged. There will be disparities between patients from one centre to another. Some centres will have small numbers of group A patients [fig_ref] Figure 1: Benefits of weight-loss surgery by category during the Covid-19 crisis [/fig_ref]. A group B patient scheduled for bariatric surgery in a centre barely affected by the epidemic may thus be operated on despite a lower priority, with a favourable benefit/risk ratio. In all cases, patents must be warned of the risks, and their informed written consent obtained systematically. Each bariatric surgery centre will have a list of patients whose indications have been validated by multidisciplinary concertation after a preparation lasting more than 6 months. The ways in which care will be resumed will vary from one centre to another according to the human, physical, and medication resources of each entity. No guidelines are therefore given concerning care resumption thresholds. The priority is to avoid having to deny care. Patients on waiting lists are to be re-contacted by the multidisciplinary teams to keep in touch, continue follow-up and prepare them for surgery. The objectives are weight control with weight stability, stabilization of any comorbidities, particularly in patients with diabetes, and achievement of optimal blood sugar levels. Teleconsultation is to be preferred and can be replaced by telephone contact for persons without Internet access. ## What surgical techniques and indications are to be preferred for scheduled bariatric surgery? The surgical techniques that can be used during a pandemic are those validated by the public health regulatory authorities . There is no reason to prefer, in first line surgery, one surgical technique over another as regards the two most frequent weight-loss operations performed in France, namely sleeve gastrectomy and the Roux-en-Y gastric bypass, as the rate of complications [bib_ref] Is laparoscopic sleeve gastrectomy a lower risk bariatric procedure compared with laparoscopic..., Zellmer [/bib_ref] [bib_ref] Reduction in early mortality outcomes after bariatric surgery in France between 2007..., Lazzati [/bib_ref] and shortterm weight loss are similar [bib_ref] Laparoscopic sleeve gastrectomy versus Roux-Y-Gastric bypass for morbid obesity-3-year outcomes of the..., Peterli [/bib_ref]. In a pandemic setting, it may be preferable to avoid malabsorptive surgery when the de-nutrition risk is higher, and the follow-up of patients may be more difficult. The surgical indications to be preferred in the case of scheduled surgery are those designated as primary surgery. Morbidity rates are lower than for secondary surgery irrespective of the type of surgery [bib_ref] 30-day outcomes of revisional bariatric stapling procedures: first Report Based on MBSAQIP..., Chaar [/bib_ref] [bib_ref] Revisional bariatric surgery for weight regain and refractory complications in a single..., Qiu [/bib_ref] , hospital stay duration being generally shorter [bib_ref] Revisional bariatric surgery in Israel: findings from the Israeli bariatric surgery registry, Keren [/bib_ref] , and efficacy for weight loss probably greater [bib_ref] Revisional Roux-en-Y gastric bypass and sleeve gastrectomy: a systematic review of comparative..., Mahawar [/bib_ref]. Concerning secondary surgery, a distinction must be made between surgery for weight regain or insufficient weight loss, and surgery for complications and/or sequelae of earlier surgery. Concerning secondary surgery for weight loss, the best strategy would be to wait for the pandemic/epidemic to abate locally or regionally. As explained above, such surgery has an increased rate of complications and very wideranging weight loss results according to the technique and the indication. Continued nutritional and/or psychological follow-up by telemedicine offers a good alternative that can help optimise and/or maintain preparation for later surgery. Concerning secondary surgery for complications or for secondary effects of earlier weight-loss surgery, there are several distinct cases. First, the indications when there is a short-term threat to life, e.g., the presence of a chronic post-operative digestive fistula resistant to endoscopic treatment. In this type of indication, the alternative with continued endoscopic treatment may be hazardous after a certain time lag, with the appearance of other even worse complications [bib_ref] Persistent gastric fistula after sleeve gastrectomy: an analysis of the time between..., Rebibo [/bib_ref] [bib_ref] Gastrobronchial fistula in sleeve gastrectomy and Roux-en-Y gastric bypass-a systematic review, Silva [/bib_ref]. In this type of case, surgery must be performed in a care centre where post-operative IC and/or continuous care with a Covid -circuit is possible. If not, transfer to a care centre that can offer these services is preferable. This type of strategy also holds for post-operative digestive stenosis if several endoscopic treatments have been necessary and have failed to relieve the patient's symptoms lastingly. For indications where there is no short-term threat to life, it is preferable to have recourse to surgery at a time when the epidemic is at a lull, and if medical treatment has failed. For example: - in the case of disabling reflux after sleeve gastrectomy, medical treatment by continued hygiene and diet measures, continued treatment by a proton pump inhibitor associated or not with antacids; - in the case of severe de-nutrition when revision or reversal surgery is envisaged, it is preferable to defer the operation and continue with nutritional support of the enteral or parenteral nutrition type that can be given at home. Concerning robot-assisted bariatric surgery, no literature data contraindicate this type of surgical approach. The choice of this support over a conventional laparoscopic approach will depend on the surgeon's experience in robotassisted surgery. ## Clinical pathway to bariatric surgery for a covid-negative patient ## Pre-operative stage Patients must be called on the day before consultations to make sure they have no symptoms that point to a Covid-19 infection [23]. The consultations must be spaced with no waiting time. The patients must wear a mask. The patients must be warned that there is a risk of nosocomial Covid-19 infection. Patient education programmes must be delivered with a limited number of patients in one small group (at most 5 persons) or remotely. During patient education programmes for weight-loss surgery, if videoconferencing is impossible, the number of persons present must be kept to a strict minimum. Physical presence is thus not compulsory, and a go-ahead certificate in the patient's file will suffice. Any bariatric surgeon who displays symptoms suggesting Covid-19 infection should be tested. If the test is positive, then the surgery must be performed by another bariatric surgeon (in the same or a different centre) if that surgery is urgent or semiurgent. ## Peri-operative stage/covid -circuit An RT-PCR screening test (nasopharyngeal swab) must be carried out at surgery D-2. The patient goes to a reception service at the centre and undergoes the test as an outpatient. Ideally, patients, even if asymptomatic, should take a pre-operative PCR test or serological test. However, the SOFFCO-MM is aligned with the guidelines of other learned societies concerning infection status. The patient is told the results of the test by the surgeon before admission on the day before the surgery. If the test is positive, then the surgery is cancelled, because the risks of respiratory complications or death are increased [bib_ref] Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period..., Lei [/bib_ref]. However, the obesity follow-up must be ensured by protocols specific to Covid+ patients. Care for persons with obesity and suspected Covid-19 infection is still the same as for the general population. A minimum time of one month before rescheduling seems reasonable, with in all cases a clinical and biological reassessment and a Covid-19 expert opinion. If the test is negative, a chest CT scan is recommended to look for any abnormality suggestive of a Covid-19 infection (frosted glass appearance, pleuropneumopathy, etc). This scan must be carried out at surgery D-1 to limit the risk of performing anaesthesia on an asymptomatic Covid-19 patient. These screening procedures (RT-PCR on naso-pharyngeal swab, chest CT scan), drawn up from knowledge available at the time they were issued, may evolve as new findings emerge. The patient's consent must be checked and signed. This consent must state the risk of nosocomial Covid-19 infection and commit the patient to post-operative home confinement [fig_ref] Figure 5: Preoperative measures before scheduled surgery [/fig_ref]. On admission and on the day of surgery, a complete examination, including temperature measurement, must be performed [bib_ref] COVID-19 & the general surgical department -measures to reduce spread of SARS-COV-2..., Yeo [/bib_ref]. All healthcare professionals must wear a surgical mask whenever they come close to patients. Treatment by night ventilation for patients with a sleep apnoea syndrome must also be continued. ## Post-operative stage and confinement If the patient's condition permits, we recommend that the hospital stay be as short as possible. The patients should be included in bariatric protocols of the fast-track type (early mobilisation and feeding) to shorten hospital stay. During the pandemic, bariatric surgery can be performed on outpatients provided the surgery team were recognised experts in this field before the pandemic [bib_ref] Laparoscopic sleeve gastrectomy as day-case surgery (without overnight hospitalization), Rebibo [/bib_ref]. A hospital stay duration of two days is acceptable for simple cases. It is strongly advised that the patient remain confined at home for the first month post-operatively. The initial weight loss may be rapid in the first month, which can increase the risk of contracting a severe form of Covid-19. Post-operative follow-up consultations must be by telemedicine. Follow-up remains multidisciplinary and adapted to the patient (individualised): primary care physician, nutritionist, surgeon, dietitian, nurse, and psychologist. The frequency of follow-up must be the same as that set by the centre in which the bariatric surgery was performed and comply with the HAS 2009 guidelines. A first teleconsultation or consultation by telephone should be carried out in the week following the patient's discharge from hospital (highest rate of complications) and then at one month. A dematerialised follow-up programme via smartphone is also suitable during this period. The SOFFCO-MM emphasises the utility of post-operative nutritional and psychological follow-up because the risk of de novo depression occurring increases after this surgery [bib_ref] Association of bariatric surgery vs. medical obesity treatment with long-term medical complications..., Jakobsen [/bib_ref]. It is preferable to favour delivery of medication, including vitamin supplements, directly by the pharmacy or via nursing care at home, if medication prescribed at discharge could not be purchased beforehand. In view of the unusual nature and uncertainty of the current period, bariatric surgery can be envisaged only with complete records for all the patients operated on, and medium-term follow-up at 6 months post-operatively. The aim of this follow-up and data collection is to check for the absence of excess mortality arising from the resumption of bariatric surgery, which will be regularly monitored. If there is no added mortality risk, the operating indications can be re-assessed to allow wider provision of surgery. In parallel to the existing register in place at the SOFFCO-MM, indicators specific to the current epidemic setting will be added. Procedures for collecting data specific to Covid-19 are the same as those for the current SOFFCO-MM register. ## Urgent medical and surgical care for patients with obesity, and care for bariatric surgery complications This section applies equally to patients operated on during and before the pandemic. Some 1% of French nationals have a weight-loss surgery history. Confinement causes psychological stress, fosters self-medication (e.g. NSAIDs), and favours the resumption of addictive behaviour such as tobacco use and other addiction disorders. Special attention must be paid to patients aged over 60 [bib_ref] Obesity in patients younger than 60 years is a risk factor for..., Lighter [/bib_ref] and who have a history of weight-loss surgery. This is especially relevant if the patient has an associated comorbidity such as diabetes, HT or respiratory insufficiency [bib_ref] Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis, Wang [/bib_ref]. All unnecessary or dispensable steps or procedures liable to impede care provision must be eliminated. ## Initial stance to be taken when there is a medical or surgical problem in a patient with obesity in a covid-negative stream The organisation of elective surgery programmes and their follow-up permits an orderly, controlled patient flow. The advent of a complication and the emergency it may create can upset this regulation. It is essential to dissuade patients from coming to the hospital for no good reason, but also to ensure that any complication underestimated by a patient does not evolve threateningly. Teleconsultation and public health insurance cover currently allow a first selection of patients. It is therefore essential to set in place rapid access to teleconsultation to avoid excessive recourse to emergency services, especially at busy times. After this teleconsultation, it will be possible to direct the patient towards simple monitoring or, if a physical examination is necessary, towards a rapid physical consultation or emergency admission. This system seems reasonable in working hours. The patient must be encouraged to elicit the emergency services only when a teleconsultation is impossible outside working hours. To summarize: every medical or surgical problem in a patient with obesity must be dealt with in a consultation (ideally a teleconsultation) with the referring physician or with a specialist physician or surgeon. These last will decide whether the patient must come in person for care at the hospital. ## Opinion of a bariatric surgeon in urgent cases Even in a setting where Covid-19 infection must be suspected, any patient with or without a recent history of weight-loss surgery who presents signs such as a cough, high temperature, abdominal pains, tachycardia or other digestive signs (nausea, diarrhoea) requires a prompt opinion from a surgeon specialised in weight-loss surgery to prevent unwarranted delay in surgical care. This is particularly important as some clinical signs that point to Covid-19 infection can be post-operative effects (simple or complicated) of bariatric surgery. ## Avoid general anaesthesia as much as possible Whenever possible, general anaesthesia must be avoided because of the heightened risk of respiratory complications needing IC monitoring, or of finding and worsening an occult Covid-19 pneumopathy [bib_ref] High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring..., Simonnet [/bib_ref]. Local anaesthesia (e.g. drainage of cutaneous abscesses on scars), or locoregional anaesthesia must be favoured as much as possible. ## The least invasive, shortest, and most effective treatment Even though this rule already holds outside pandemics, it is preferable to use all the therapeutic means available, starting with the least invasive. For example, in the case of a post-sleeve fistula without serious signs, a conservative treatment (radiological drainage and endoscopic treatment) must be tried. In the case of resumed bariatric surgery, laparoscopy should if possible be the preferred approach rather than laparotomy owing to its shorter hospital stay time and lower risk of post-operative respiratory complications. This resumed surgery must be effective and fast at the outset. Possible Covid-19 infection that would require the opinion of the local Covid-19 crisis unit must be constantly watched for. ## Think of medical complications after weight-loss surgery Certain signs pointing to Covid-19 infection (ageusia, dizziness, etc.) can also be neurological signs of postoperative complications after weight-loss surgery. Among these complications, we note de-nutrition, which must be treated urgently, because it is on the list of risk factors for severe forms of Covid-19. Vitamin deficiencies may also be responsible for unsteady balance or confusion (vitamin B1 deficiency). These symptoms are rare in Covid-19. Such deficiency must be corrected urgently with thiamine by the parenteral route, avoiding glucose-rich serum, which causes lysis of nerve cells. Sensitivity disorders, tingling and diplopia point to possible vitamin B12 deficiency and are not recognised signs of Covid-19 [bib_ref] Nervous system involvement after infection with COVID-19 and other coronaviruses, Wu [/bib_ref]. # Conclusions These SOFFCO-MM guidelines are designed to allow resumption of bariatric surgery through appropriately adapted pre-, peri-and post-operative procedures to ensure the safe care of persons with obesity after confinement is lifted. ## Highlights - Obesity is a risk factor for severe forms of Covid-19. - Weight-loss surgery is the only effective treatment for obesity, offering prompt, lasting benefit. - Weight-loss surgery is a metabolic surgery that improves metabolic syndrome (diabetes, HT, etc.). - Resumption must be gradual and adapted to the current health risk. It will vary regionally. - Weight-loss surgery must be deferred in the case of Covid-19 infection or recent history of Covid-19 (immunisation uncertain). - No single surgical technique is to be preferred among those validated by the public health regulating authorities. - A Covid-negative circuit must be put in place. - Any medical or surgical problem in a patient with obesity must be dealt with in a consultation (ideally a teleconsultation) with the referring physician or the specialist physician or surgeon. The latter will decide whether the patient must come for care to the hospital. - The possibility of Covid-19 infection must be entertained at all stages of care. - Resumption of surgery can be envisaged only with complete records of patients operated that include data specific to Covid-19. # Disclosure of interest The authors declare that they have no competing interest. [fig] Figure 1: Benefits of weight-loss surgery by category during the Covid-19 crisis. [/fig] [fig] Figure 2: Risks of morbidity in weight-loss surgery by category during the Covid-19 crisis. [/fig] [fig] Figure 3: Categories of patients undergoing primary weight-loss surgery in the current Covid-19 setting. BRR: benefit/risk ratio. [/fig] [fig] Figure 4: Resumption of overall activity according to the evolution of the Covid-19 pandemic. [/fig] [fig] Figure 5: Preoperative measures before scheduled surgery. [/fig] [table] Table 1: Strategies for resuming bariatric surgery. [/table]	None	None	None
cb66ff6df8cb0ddbefd634bb781e4febb0893a43	pubmed	The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society	The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society # Abstract With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first three months of 2020, the COVID-19 pandemic has emerged as an unprecedented healthcare crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, healthcare delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and healthcare workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. While mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography (CXR) and computed tomography (CT) are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pre-test probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing COVID-19 patients across a spectrum of healthcare environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based upon the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of CXR and CT in the management of COVID-19. ## Editor's note: this article is being simultaneously published in chest. On March 11, 2020 the World Health Organization (WHO) officially characterized the rapid global spread of coronavirus disease 2019 (COVID-19) as a pandemic and called for urgent international action in four key areas: to prepare and be ready; detect, protect, and treat; reduce transmission; and innovate and learn. At the time of writing (April 1, 2020), there are over 900,000 confirmed COVID-19 cases and nearly 50,000 deaths in 205 countries around the world, with the majority of cases concentrated in 4 countries: United States, Italy, Spain, and China. With sustained community transmission now established in multiple countries on multiple continents, the WHO public health goal has changed from containment to mitigation of the pandemic's impact. Consequently, strategies are now focused on efforts to reduce the incidence, morbidity, and mortality of COVID-19 by breaking the chain of human transmission through social distancing and imposed quarantine. ## Diagnostic testing Early detection and containment of infection caused by the novel coronavirus SARS-CoV2 has been hindered by the need to develop, mass produce, and widely disseminate the required molecular diagnostic test, a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Early reports of test performance in the Wuhan outbreak showed variable sensitivities ranging from 37% to 71% [bib_ref] Stability Issues of RT-PCR Testing of SARS-CoV-2 for Hospitalized Patients Clinically Diagnosed..., Li [/bib_ref]. While laboratory-based performance evaluations of RT-PCR test show high analytical sensitivity and near-perfect specificity with no misidentification of other coronaviruses or common respiratory pathogens, test sensitivity in clinical practice may be adversely affected by a number of variables including: adequacy of specimen, specimen type, specimen handling, and stage of infection when the specimen is acquired (CDC guidelines for in-vitro diagnostics) [bib_ref] SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients, Zou [/bib_ref]. False negative RT-PCR tests have been reported in patients with CT findings of COVID-19 who were eventually tested positive with serial sampling [bib_ref] Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR, Fang [/bib_ref]. Limited testing capacity due to insufficient specimen collection kits, lab test supplies, and testing equipment precluded early widespread testing and is believed to have contributed to rapid and unchecked transmission of infection within communities by undetected individuals with milder, limited, or no symptoms [bib_ref] Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany, Rothe [/bib_ref]. For example, CT screening of 82 asymptomatic individuals with confirmed COVID-19 from the cruise ship "Diamond Princess" showed findings of pneumonia in 54% [bib_ref] Chest CT Findings in Cases from the Cruise Ship "Diamond Princess, Inui [/bib_ref]. ## Imaging logistics during pandemic Provision of diagnostic imaging services to large numbers of patients suspected or confirmed to have COVID-19 during an outbreak can be challenging, as each study is lengthened and complicated by the need for strict adherence to infection control protocols designed to minimize risk of transmission and protect healthcare personnel [bib_ref] Radiology Department Preparedness for COVID-19: Radiology Scientific Expert Panel, Mossa-Basha [/bib_ref]. Droplet transmission followed by contaminated surfaces are believed to be the main modes of spread for SARS-CoV2 in radiology suites; all patients undergoing imaging should be masked and imaged using dedicated equipment that is cleaned and disinfected after each patient encounter [bib_ref] COVID-19) Outbreak: What the Department of Radiology Should Know, Kooraki [/bib_ref]. Although personal protection equipment (PPE) recommendations vary between countries, the current Centers of Disease Control (CDC) guidelines recommend radiology staff wear a mask, goggles or face shield, gloves, and an isolation gown. In countries with more stringent PPE protocols, a surgical cap and shoe covers may be added, while a surgical mask and goggles or face shield are suggested in some countries with less stringent PPE protocols. Additional precautions are required for specific situations that are more likely to generate aerosols, including patients receiving non-invasive ventilation, during intubation or extubation, throughout bronchoscopy, or when receiving nebulized therapies. Portable imaging, including imaging patients through glass walls, has been used in some hospitals to further reduce the chance of spreading infection. Written from multidisciplinary and multinational perspectives, this Fleischner statement is intended to provide context for the use of imaging to direct patient management during the COVID-19 pandemic in different practice settings, different phases of epidemic outbreak, and environments of varying critical resource availability. This document is structured around three clinical scenarios and three additional situations in which chest imaging is often considered in the evaluation of patients with potential COVID-19 infection. The committee elected to present this document as a consensus statement rather than a guideline given the limited evidence base and the urgent need for direction on this topic for the medical community. imaging is also often considered [fig_ref] Figure 4: Panel members [/fig_ref]. The entire panel was convened during a single session using a live audio and video interface (Zoom Video Communications, San Jose, CA). The three scenarios and three additional situations were presented, discussed, and refined. The panel independently and anonymously rated the appropriateness of imaging with chest radiography (CXR) or CT at each of these decision points on a five-point scale. At least 70% agreement on the direction of a recommendation was considered consensus. The scenarios are intended to support the management of adults only. Children, who are typically spared from severe infections [bib_ref] Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China, Dong [/bib_ref] , merit separate consideration, particularly with regard to use of radiationassociated procedures, and are beyond the scope of the current document. # Methods ## This consensus The final document was supported by a comprehensive literature search for relevant articles. Using the search terms "((coronavirus OR COVID OR SARS-CoV OR nCoV) AND (CT OR Computed Tomography OR Radio* OR Imag*))", a total of 137 English articles published between Dec 1, 2019 and March 23, 2020 were identified. Each article was assessed for relevance to the primary objective and a summary of key findings from relevant articles was created. ## The use of imaging in covid-19 The value of an imaging test relates to the generation of results that are clinically actionable either for establishing a diagnosis or for guiding management, triage, or therapy. That value is diminished by costs that include the risk of radiation exposure to the patient, risk of COVID-19 transmission to uninfected healthcare workers and other patients, consumption of PPE, and need for cleaning and downtime of radiology rooms in resource-constrained environments. The appropriate use of imaging in each of the scenarios was considered on this basis. This statement focuses exclusively on the use of chest radiography (CXR) and computed tomography of the thorax (CT). While ultrasound has been suggested as a potential triage and diagnostic tool for COVID-19 given the predilection for the disease in subpleural regions, there is limited experience at this time [bib_ref] Is there a role for lung ultrasound during the COVID-19 pandemic?, Soldati [/bib_ref] , as well as infection control issues. CXR is insensitive in mild or early COVID-19 infection [bib_ref] Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients, Wong [/bib_ref]. However, with respect to the relative value of CXR or CT for detecting the presence of viral pneumonia, the experience is vastly different dependent upon community norms and public health directives. When patients are encouraged to present early in the course of their disease, as was the case in Wuhan, China, CXR has little value. The greater sensitivity of CT for early pneumonic changes is more relevant in the setting of a public health approach that required isolation of all infected patients within an environment where the reliability of COVID-19 testing was limited and turnaround times were long (4). Alternatively, in New York City where patients were instructed to stay at home until they experienced advanced symptoms, CXR was often abnormal at the time of presentation. Equipment portability with imaging performed within an infected patient's isolation room is another factor that may favor CXR in selected populations, effectively eliminating the risk of COVID-19 transmission along the transport route to a CT scanner and within the room housing a CT scanner, particularly in environments lacking PPE. In hospitalized patients CXR can be useful for assessing disease progression and alternative diagnoses such as lobar pneumonia, suggestive of bacterial superinfection, pneumothorax and pleural effusion. CT is more sensitive for early parenchymal lung disease, disease progression, and alternative diagnoses including acute heart failure from COVID-19 myocardial injury [bib_ref] Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the..., Driggin [/bib_ref] and when acquired with intravenous contrast material, pulmonary thromboembolism. Leveraging these superior capabilities depends upon the availability of CT capacity, particularly considering the potential reduction in CT scanner availability due to the additional time required to clean and disinfect equipment following imaging of patients with suspected COVID-19. Some centers rely on the improved depiction of COVID-19 findings with CT relative to CXRand their association with clinical worsening to determine patient disposition to home, hospital admission, or intensive care. In recognition of variance amongst local practice patterns and resource availability, it is important to state at the outset that the scenarios specify the use of imaging but do not articulate the relative merit of CXR versus CT. Ultimately, the choice of imaging modality is left to the judgement of clinical teams at the point-of-care accounting for the differing attributes of CXR and CT, local resources, and expertise. ## Overview of clinical scenarios The scenarios apply only to patients presenting with features consistent with COVID-19 infection. The severity of respiratory disease and pre-test probability of COVID-19 infection are specified for each scenario, with additional key considerations including the presence of risk factors for disease progression, evidence of disease progression, and the presence of significant critical resource constraints [fig_ref] Table 1: Definitions and Criteria for Key Components of Common Clinical ScenariosDefinitions and criteria... [/fig_ref]. The scenarios distinguish mild respiratory disease from moderate-to-severe respiratory disease based on the absence vs. presence of significant pulmonary dysfunction or damage. Pre-test probability is defined by the background prevalence of infection and can be estimated by observed transmission patterns: low by sporadic transmission; moderate by clustered transmission; and high by community transmission. Individual pre-test probability is further modified if there is known exposure through contact with a confirmed case of COVID-19. For health care providers, the CDC categorizes medical-related exposures into low, medium, and high-risk groups. Within a diagnostic radiology department, brief (a few minutes or less) unprotected interaction with a patient with COVID-19 as well as prolonged close contact with a masked, infected patient by a medical provider wearing PPE are categorized as low-risk exposures. Risk factors for poor outcomes in patients with COVID-19 infection are considered separately from pre-test probability, with common risk factors including age > 65 years, cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and immune-compromised [bib_ref] Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak..., Wu [/bib_ref]. Identifying a patient as being at high risk for COVID-19 progression is not necessarily a feature of any single risk factor, but is rather a clinical judgement based on the combination of underlying comorbidities and general health status that suggests a higher level of clinical concern. Where appropriate, management variations based upon risk factors for disease progression are called out explicitly, as in Scenario 1. All clinical scenarios begin by characterizing COVID-19 status based upon the availability of laboratory test results. ## Scenario 1: mild features of covid-19 The first scenario [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref] addresses a patient presenting for evaluation at an outpatient clinic or via telehealth with mild respiratory features consistent with COVID-19 infection, any pre-test probability of COVID-19 infection, and no significant critical resource constraints. When COVID-19 test results are unavailable, patients with moderate-to-high pre-test probability should be initially managed as if COVID-19 testing is positive, while patients with low pre-test probability should be initially managed as if COVID-19 testing is negative. Imaging is advised for patients with risk factors for COVID-19 progression and either positive COVID-19 testing or moderate-tohigh pre-test probability in the absence of COVID-19 testing [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref]. Imaging provides a baseline for future comparison, may establish manifestations of important comorbidities in patients with risk factors for disease progression [fig_ref] Table 1: Definitions and Criteria for Key Components of Common Clinical ScenariosDefinitions and criteria... [/fig_ref] , and may influence the intensity of monitoring for clinical worsening. Imaging is not advised for patients with mild features who are COVID-19 positive without accompanying risk factors for disease progression, or for patients with mild features who are COVID-19 negative [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref]. The panel felt that the yield of imaging in these settings would be very low and that it was safe for most patients to self-monitor for clinical worsening. Regardless of COVID-19 test results and risk factors, imaging is advised for patients with mild clinical features who subsequently develop clinical worsening [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref]. In the absence of clinical worsening, management involves support and isolation of patients with positive COVID-19 testing or patients with moderate to high pre-test probability without COVID-19 test results available. Although not specifically addressed by this scenario, in the presence of significant resources constraints, there is no role for imaging of patients with mild features of COVID-19. ## Scenario 2: moderate to severe features of covid-19 The second scenario [fig_ref] Figure 2: The second of three clinical scenarios presented to the panel with final... [/fig_ref] addresses a patient presenting with moderate-to-severe features consistent with COVID-19 infection, any pre-test probability of COVID-19 infection, and no significant critical resource constraints. Separate ratings were obtained for COVID-19 positive patients and either COVID-19 negative patients or patients for whom COVID-19 testing is unavailable [fig_ref] Figure 2: The second of three clinical scenarios presented to the panel with final... [/fig_ref]. Imaging is advised regardless of the results or availability of COVID-19 testing given the impact of imaging in both circumstances. For COVID-19 positive patients, imaging establishes baseline pulmonary status and identifies underlying cardiopulmonary abnormalities that may facilitate risk stratification for clinical worsening. In the presence of clinical worsening, imaging is again advised to assess for COVID-19 progression or secondary cardiopulmonary abnormalities such as pulmonary embolism, superimposed bacterial pneumonia, or heart failure that can potentially be secondary to COVID-19 myocardial injury [fig_ref] Figure 2: The second of three clinical scenarios presented to the panel with final... [/fig_ref]. infection and COVID-19 test availability. Falsely negative COVID-19 testing is more prevalent in high pre-test probability circumstances and repeat COVID-19 testing is therefore advised if available. Depending upon the imaging findings, other clinical investigations may be pursued. ## Scenario 3: moderate-to-severe features of covid-19 in a resource constrained ## Environment The third scenario The third scenario first considers the potential availability of PoC COVID-19 testing. Imaging is advised when PoC COVID-19 testing is available and positive for the same reasons as described for Scenario 2. Based upon imaging findings and clinical features, patients are subsequently supported and monitored with a level of intensity consistent with clinical features. Imaging is again indicated if patients subsequently clinically worsen [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref]. Imaging is advised to support more rapid triage of patients in a resource-constrained setting when PoC COVID-19 testing is not available or negative [fig_ref] Figure 1: The first of three clinical scenarios presented to the panel with final... [/fig_ref]. Imaging may reveal features of COVID-19, which within this scenario may be taken as a presumptive diagnosis of COVID-19 for medical triage and associated decisions regarding disposition, infection control, and clinical management. In this high pre-test probability environment, and as described for Scenario 2, the possibility of falsely negative COVID-19 testing creates a circumstance where a COVID-19 diagnosis may be presumed when imaging findings are strongly suggestive of COVID-19 despite negative COVID-19 testing. This guidance represents a variance from other published recommendations which advise against the use of imaging for the initial diagnosis of COVID-19and was supported by direct experience amongst panelists providing care within the conditions described for this scenario. The relationship between disease severity and triage may need to be fluid depending upon resources and case load. When imaging reveals an alternative diagnosis to COVID-19, management is based upon established guidelines or standard clinical practice. ## Additional key questions: ## Daily chest radiographs are not indicated in stable intubated patients with covid-19 (q12) Multiple studies have shown no difference in important outcomes (mortality, length of stay, and ventilator days) for intensive care unit patients imaged on-demand as compared to a daily routine protocol [bib_ref] Abandoning daily routine chest radiography in the intensive care unit: metaanalysis, Oba [/bib_ref] [bib_ref] Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated..., Hejblum [/bib_ref] [bib_ref] AzuRea network for the RadioDay study g. Chest radiographs in 104 French..., Lakhal [/bib_ref] [bib_ref] ACR Appropriateness Criteria(R) Intensive Care Unit Patients, Suh [/bib_ref]. Avoidance of non-value-added imaging is particularly important in the COVID-19 patient population to minimize exposure risk of radiology technologists and to conserve PPE. ## Ct scan is indicated in a patient who has functional impairment and/or hypoxemia after recovery from covid-19 (q13) With the recent emergence of SARS-CoV2 as a human pathogen, there are no long-term followup studies of survivors. Postmortem evaluation of a single patient who succumbed to severe COVID-19 showed pathologic findings consistent with diffuse alveolar damage, similar to findings previously described with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Patients with functional impairment following recovery from COVID-19 should undergo imaging to differentiate between expected morphologic abnormalities as sequelae of infection, mechanical ventilation, or both versus a different and potentially treatable process. ## Covid-19 testing is indicated in a patient who is found incidentally to have typical findings of ## Covid-19 on a ct scan. (q14) While CT findings of COVID-19 infection are nonspecific, their presence in an asymptomatic patient with no or mild respiratory symptoms is concerning in a setting of known community transmission, particularly if there is no better alternative diagnosis. Asymptomatic carriers of COVID-19 have been estimated to comprise 17.9% -33.3% of all infected cases [bib_ref] Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board..., Mizumoto [/bib_ref] [bib_ref] Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19), Nishiura [/bib_ref]. Asymptomatic infection with suggestive CT findings in the lung has been documented in screened cruise ship passengers [bib_ref] Chest CT Findings in Cases from the Cruise Ship "Diamond Princess, Inui [/bib_ref]. It is believed that the presence of undetected infected and mildly symptomatic or asymptomatic individuals may be contributing to the rapid geographic spread of SARS-CoV2 [bib_ref] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2), Li [/bib_ref]. RT-PCR testing in this scenario is important to potentially identify an occult infection and limit further transmission both within the community and in the environment where the patient is receiving medical care. In highly prevalent areas, an additional uncertainty is whether CT should be used as a screening tool either as a stand-alone or as an adjunct to RT-PCR to exclude occult infection prior to surgery or intensive immunosuppressive therapies. The panel's ratings are provided in [fig_ref] Figure 4: Panel members [/fig_ref] , and a summary of all recommendations is provided in [fig_ref] Table 2: Summary of Recommendations for ImagingSummary of Recommendations for ImagingMain Recommendations Imaging is... [/fig_ref]. ## Additional resources For purposes of image interpretation and reporting, readers are referred to a recently published systematic review of imaging findings of COVID-19 (36) and a multi-society consensus paper on reporting chest CT findings related to COVID-19 [bib_ref] Radiological Society of North America Expert Consensus Statement on Reporting Chest CT..., Simpson [/bib_ref]. As an aid to improving radiologist and pulmonologist familiarity with the imaging findings of COVID-19, we provide the following link (https://www.fleischner-covid19.org) to the Fleischner Society website where an educational repository of proven COVID-19 cases can be found. # Conclusion This statement is intended to offer guidance to physicians on the use of thoracic imaging across a breadth of healthcare environments. It represents the collective opinions and perspectives of thoracic radiology, pulmonology, intensive care, emergency medicine, laboratory medicine, and infection control experts practicing in 10 countries, representative of the highest burden of COVID-19 worldwide. It also represents opinion at a moment in time within a highly-dynamic environment where the status of regional epidemics and the availability of critical resources to combat those epidemics vary daily. The evidence base supporting the use of imaging across the scenarios presented is scant and the advice presented herein may undergo refinement through rigorous scientific investigation, exposing nuances of image interpretation that may lead to prognostic information and guide management decisions. At the time of this writing, no therapy has been confirmed to alter the course of COVID-19, there is no known cure, and there is no vaccine for prevention. As effective treatments are developed, thoracic imaging may find new roles by establishing treatment response or characterizing patients as likely responders to novel therapies. ## Additional recommendations  Daily chest radiographs are NOT indicated in stable intubated patients with COVID-19  CT is indicated in patients with functional impairment and/or hypoxemia after recovery from COVID-19  COVID-19 testing is indicated in patients incidentally found to have findings suggestive of COVID-19 on a CT scan [fig] For: COVID-19 negative patients or any patient for whom testing is not performed, imaging may reveal an alternative diagnosis to explain the patient's clinical features, which should direct patient care as per existing clinical guidelines or standard clinical practice. If an alternative diagnosis is not revealed or images demonstrate features of COVID-19 infection, then subsequent clinical evaluation would depend upon the pre-test probability of COVID-19 [/fig] [fig] Figure 1: The first of three clinical scenarios presented to the panel with final recommendations. Mild features refer to absence of significant pulmonary dysfunction or damage. Pre-test probability is based upon background prevalence of disease and may be further modified by individual's exposure risk. The absence of resource constraints corresponds to sufficient availability of personnel, personal protective equipment, COVID-19 testing, hospital beds, and/or ventilators with the need to rapidly triage patients. Numbers in blue circles indicate key questions referenced in the text and presented in Figure 4. Contextual detail and considerations for imaging with CXR (chest radiography) versus CT (computed tomography) are presented in the text. (Pos=positive, Neg=negative, Mod=moderate). [Although not covered by this scenario and not shown in the figure, in the presence of significant resources constraints, there is no role for imaging of patients with mild features of COVID-19.] [/fig] [fig] Figure 2: The second of three clinical scenarios presented to the panel with final recommendations. Moderate-to-severe features refer to evidence of significant pulmonary dysfunction or damage. Pre-test probability is based upon background prevalence of disease and may be further modified by individual's exposure risk. The absence of resource constraints corresponds to sufficient availability of personnel, personal protective equipment, COVID-19 testing, hospital beds, and/or ventilators with the need to rapidly triage patients. Numbers in blue circles indicate key questions referenced in the text and presented in Figure 4. Contextual detail and considerations for imaging with CXR (chest radiography) versus CT (computed tomography) are presented in the text. (Pos=positive, Neg=negative, Alt Dx=alternate diagnosis). [/fig] [fig] Figure 4: Panel members (total n=27) developed 14 key questions (numerals in left column correspond to question numbers in text and Figures 1-3) that were used to support creation of common scenarios and recommendations related to the use of chest imaging in patients with features of COVID-19. The proportion of panel member votes for each question is presented on a 5-point scale, as well as a summary column that shows the total percentage who voted for or against imaging for each key question, excluding those members who were neutral or who abstained (1 panel member abstained for questions 1 and 2). [/fig] [table] Table 1: Definitions and Criteria for Key Components of Common Clinical ScenariosDefinitions and criteria for key components of common clinical scenarios Severity of respiratory disease  Mild: No evidence of significant pulmonary dysfunction or damage (e.g., absence of hypoxemia, no or mild dyspnea)  Moderate-to-severe: Evidence of significant pulmonary dysfunction or damage (e.g., hypoxemia, moderate-to-severe dyspnea)Pre-test probability Based upon background prevalence of disease as estimated by observed transmission patterns. May be further modified by individual's exposure risk. Sub-categorized as: o Low: Sporadic transmission o Medium: Clustered transmission o High: Community transmission Risk factors for disease progression  Present: Clinical judgement regarding combination of age > 65 years and presence of comorbidities (e.g., cardiovascular disease, diabetes, chronic respiratory disease, hypertension, immune-compromised)  Absent: Defined by the absence of risk factors for disease progressionDisease progression Progression of mild disease to moderate-to-severe disease as defined above.  Progression of moderate-to-severe disease with worsening objective measures of hypoxemia. constraints  Limited access to personnel, personal protective equipment, COVID-19 testing ability (including swabs, reagent, or personnel), hospital beds, and/or ventilators with the need to rapidly triage patients. [/table] [table] Table 2: Summary of Recommendations for ImagingSummary of Recommendations for ImagingMain Recommendations Imaging is not routinely indicated as a screening test for COVID-19 in asymptomatic individuals  Imaging is not indicated for patients with mild features of COVID-19 unless they are at risk for disease progression (Scenario 1)  Imaging is indicated for patients with moderate to severe features of COVID-19 regardless of COVID-19 test results (Scenarios 2 and 3)  Imaging is indicated for patients with COVID-19 and evidence of worsening respiratory status (Scenarios 1, 2, and 3)  In a resource constrained environment where access to CT is limited, CXR may be preferred for patients with COVID-19 unless features of respiratory worsening warrant the use of CT (Scenarios 2 and 3) [/table]	None	https://europepmc.org/articles/pmc7233395?pdf=render	With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first three months of 2020, the COVID-19 pandemic has emerged as an unprecedented healthcare crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, healthcare delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and healthcare workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. While mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography (CXR) and computed tomography (CT) are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pre-test probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing COVID-19 patients across a spectrum of healthcare environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based upon the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of CXR and CT in the management of COVID-19.
97708807bdc2847d55632d3d3a008d8e6fa3b613	pubmed	SARS‐CoV‐2 (COVID‐19) vaccination in dermatology patients on immunomodulatory and biologic agents: Recommendations from the Australasian Medical Dermatology Group	SARS‐CoV‐2 (COVID‐19) vaccination in dermatology patients on immunomodulatory and biologic agents: Recommendations from the Australasian Medical Dermatology Group As the phase III COVID-19 vaccine trials excluded patients on immunosuppressive treatments, or patients with significant autoimmunity, the Australasian Medical Dermatology Group make the following preliminary recommendations around COVID-19 vaccination in dermatology patients on immunomodulatory and/or biologic agents. # Introduction The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has accelerated vaccine development, with several vaccine candidates already attaining emergency or formal regulatory approval. Although COVID-19 vaccines such as BNT162b2 (Pfizer/ BioNTech), mRNA-1273 (Moderna) and AZD1222 (Oxford/ Astra Zeneca) have demonstrated high vaccine efficacy and a safety profile comparable to other vaccines, pivotal trials have excluded the immunocompromised or those on immunomodulatory treatments. 1,2,3 As countries roll out mass vaccination programmes for the general population, guidance is needed for dermatology patients on immunomodulatory and/or biologic agents. We formulated these recommendations based on expert opinion, [bib_ref] COVID-19 and the use of immunomodulatory and biologic agents for severe cutaneous..., Wang [/bib_ref] clinical experience and review of clinical data from key phase III COVID-19 vaccination trials. with COVAX facility (https://www.who.int/initiatives/actaccelerator/covax). In phase III trials, mRNA vaccines (BNT162b2 and mRNA-1273) have demonstrated high efficacy in preventing new, symptomatic COVID-19 infection (up to 95%) and may also impart protection against severe COVID disease. [bib_ref] Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine, Polack [/bib_ref] [bib_ref] Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, Baden [/bib_ref] Although results are promising, there are logistical challenges for mass vaccination with mRNA vaccines, including a higher manufacture cost and the need for ultra-low temperature cold chain. Furthermore, it is unclear whether these regulatory approved vaccines will be as efficacious against newer strains of SARS-CoV-2 (e.g. B.1.1.7, B.1.351 and P.1 variants). There are also insufficient data to determine whether asymptomatic transmission of SARS-CoV-2 can still occur in immunised individuals. Phase III results for the adenovirus vector vaccine AZD1222 showed an overall vaccine efficacy of 70%; however, trial limitations included variable timing of booster dosing and a low proportion of elderly subjects. [bib_ref] Safety and efficacy of the ChAdOx1 nCOV-19 vaccine (AZD1222) against SARS-CoV-2: an..., Voysey [/bib_ref] Preliminary results for the recombinant protein subunit vaccine, NVX-CoV2373, from its phase III trial are favourable with vaccine efficacy of nearly 90%; however, trial results are not yet published. Notably, all aforementioned phase III vaccine trials had limited numbers of patients on immunomodulatory treatments or patients with significant immunosuppression or autoimmunity. Currently, the vaccines in late-phase trials are non-live or utilise a replication-deficient viral vector, and would be compatible for use in patients on immunomodulatory treatments or biologic agents, but it is possible that live-vaccine candidates will progress to clinical trials. The efficacy and safety of vaccines in completed phase III trials are summarised in [fig_ref] Table 1: Phase III data for COVID-19 vaccines under regulatory approval or consideration in... [/fig_ref] , and other vaccines in phase III trials are listed in [fig_ref] Table 2: Vaccine candidate in phase III trials [/fig_ref]. The most frequent adverse reactions in the COVID-19 vaccine trials were pain at the injection site, fatigue, headache, myalgia, chills, arthralgia and fever; these were each reported in more than 1 in 10 people, which is higher than usual for vaccines. 1,2 Within 24 h of the commencement of the UK mass vaccination programme, two reports of anaphylactoid reactions to BNT162b2 were reported in patients with significant history of anaphylaxis. [bib_ref] Maintaining safety with SARS-CoV-2 vaccines, Castellis [/bib_ref] Widespread use of the vaccine so far suggests that severe allergic reactions are very rare, with initial reported rates of around 1-2 in 100 000 doses.It remains unknown whether atopy or autoimmunity increases this risk. Cutaneous reactions to COVID-19 vaccines are common, particularly injection site erythema and swelling, occurring in around 5-10% from the mRNA vaccine trials. 1,2 These have largely been mild and self-limiting, with no reported grade 4 local reactions in trials. Other cutaneous reactions have been rare in phase III trials and not significantly more frequent than in the control groups. [bib_ref] Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, Baden [/bib_ref] [fig_ref] Table 3 Dermatology: different anatomical location due to the high frequency of local and systemic... [/fig_ref] summarises commonly reported cutaneous reactions from the UK Yellow Card vaccinemonitoring programme.Notably, there are several reports of urticaria, and rare cases of erythema multiforme/Steven-Johnson syndrome/toxic epidermal necrolysis reported in the BNT162b2 vaccination programme; however, causality for any of the reported reactions has not been established. ## Preliminary recommendations Despite the limited clinical trial data, we make the following preliminary recommendations based on many years of safety data for other vaccines including seasonal influenza, human papillomavirus and the recombinant herpes zoster vaccines, in these patient groups. ## Indications and contraindications for covid-19 vaccination - We consider all dermatology patients on immunomodulatory or biologic therapies as vulnerable, and vaccination should strongly be encouraged. a Reports from the beginning of the pandemic suggested that the severity of COVID-19 illness was not significantly worse in patients on immune-mediated therapies. 7,8 Subsequent analysis of data from psoriasis registries such as Biobadaderm reported a slightly higher rate of COVID-19, hospitalisation, ICU admission and death in patients with psoriasis on systemic therapy compared to the general population, although this was not statistically significant. 9 b Nevertheless, many dermatology patients will be at higher risk of severe COVID-19 illness, such as those being treated for atopic dermatitis, immunobullous disorders, vasculitis and cutaneous drug eruptions. - Non-live COVID-19 vaccines should strongly be recommended for most patients on immunomodulatory or biologic agents, unless there are contraindications, such as: a History of anaphylaxis or severe allergic reactions to vaccines or excipients such as polyethylene glycol (most recent estimated rate of anaphylaxis being 2.5-5.0 cases per million). - There are limited data on the safety/efficacy for any of the COVID-19 vaccines during pregnancy, although no red flags have been raised in >10 000 pregnant women who have been vaccinated to date. - Patients should be counselled to the limited safety and efficacy profile of COVID-19 vaccines in immunocompromised patients, including those suffering from autoimmune disorders, although immunosuppression and autoimmunity are not a safety contraindication at this stage. ## Vaccine efficacy in the immunocompromised - Although there are no direct supporting data, based on studies with other vaccines, there is a concern that some immunomodulators, particularly if more than one is being used, may diminish COVID-19 vaccine efficacy. a Anti-TNF agents have been associated with impaired vaccine efficacy for hepatitis B, hepatitis A, pneumococcal and influenza in inflammatory bowel disease, [bib_ref] SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of..., Alexander [/bib_ref] [bib_ref] Efficacy of the vaccination in inflammatory bowel disease, Carrera [/bib_ref] although vaccination responses are relatively preserved when anti-TNF agents are used in rheumatoid arthritis. 12,13 b There is a consistent body of evidence that methotrexate impairs humoral response when used as monotherapy or in combination with a biologic.c An early case-control study indicated that ciclosporin impairs response to influenza vaccination in renal transplant recipients. 14 d Prednisolone at 10 mg/day or more was found to diminish humoral responses to influenza vaccines in patients with systemic lupus erythematosus. 15 e Patients starting tofacitinib had diminished responsiveness to pneumococcal polysaccharide vaccine - Limited studies on newer generation biologic agents used in chronic plaque psoriasis and atopic dermatitis suggest little to no interference to seasonal influenza, pneumococcal or tetanus vaccine. a Ustekinumab was associated with preserved immune responses to pneumococcal and tetanus vaccines based on antibody levels in the PHOENIX 2 long-term extension trial. [bib_ref] Immune response to pneumococcus and tetanus toxoid in patients with moderate-to-severe psoriasis..., Brodmerkel [/bib_ref] b In two small studies on secukinumab in psoriasis and psoriatic arthritis, secukinumab did not interfere with influenza or meningococcal vaccination efficacy in terms of antibody titre increase. [bib_ref] Treatment with interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of..., Chioato [/bib_ref] - Due to a lack of data in the immunocompromised, no particular COVID-19 vaccine or vaccine type (mRNA, recombinant, inactivated virus) is considered superior or preferred at this stage. - Current effective immunomodulatory therapy should not be stopped prior to vaccination, as uncontrolled disease activity may lead to disease-related complications and there is currently no evidence to suggest that short-term washout would enhance COVID-19 vaccine immune response. - Currently, there is no known role for additional vaccine dosing or neutralising antibody titre testing for vaccine efficacy in patients on immunomodulatory treatments. - Social distancing and personal hygiene measures to reduce transmission risk should be reinforced in light of a possibly reduced vaccine response in patients on immunomodulatory treatments. - There is a theoretical risk that asymptomatic transmission of SARS-CoV-2 may be greater in patients on immunomodulatory drugs, even when successfully immunised. - Vaccination of the patient's direct contacts should be strongly encouraged to maximise local herd immunity. ## Timing of covid-19 vaccination - If initiation of an immunomodulator or biologic is foreseeable or planned, COVID-19 vaccination, as well as other standard vaccinations (e.g. influenza, pneumococcal, herpes zoster, hepatitis B), should be expedited and given prior to initiation in order to maximise vaccine response. - In patients who are on a biologic or immunomodulatory agent and have not been vaccinated, it is suggested that, for the currently regulatory approved COVID-19 vaccines, vaccination should be administered at least 7 days either side of biologic/immunomodulator dosing and at a ## Other factors to consider With limited supply of vaccines, it will be necessary to prioritise some patients over others. This should be based on clinical risk (i.e. those at increased risk of acquiring disease or increased risk of developing more severe disease) and will need to take into account socioeconomic factors, age, ethnicity, co-morbidities, etc. We strongly encourage all dermatologists and their staff be vaccinated against SARS-CoV-2 to minimise risk to their patients. However, it remains essential to continue good clinical practice, mask wearing and adherence to local alert levels COVID-19 guidance, as transmission of SARS-CoV-2 can still occur despite immunisation. There are considerable gaps in the data to make evidencebased decision; it is doubtful that this will become available through randomised clinical trials, so there is a crucial role for disease and therapy registries, both national and multinational, to track outcome and performance in these patient groups. Given the common use of immunomodulatory and biologic agents across specialities, sharing of opinion and experience with COVID-19 vaccine regimens is important. Combined experience increases understanding of safe and appropriate use of vaccines and may identify specific vaccine and/or disease efficacy issues or reactions. There are no data on whether the COVID-19 vaccines will influence COVID-19-associated multisystem inflammatory disorder in children or young adults; none of the approved COVID-19 vaccines are currently licensed for use in children under 17 years of age. Data on vaccine-associated enhanced disease (VAED), particularly if vaccine supply issues result in patients receiving two different COVID-19 vaccines (as opposed to two doses of the same vaccine), are also missing: vaccineassociated enhanced diseases are modified and severe presentations of clinical infections affecting individuals exposed to a wild-type pathogen after having received a prior vaccine against the same pathogen. # Conclusion Large data gaps remain around all the COVID-19 vaccines. Due to the limited number of patients on immunomodulatory treatments in COVID-19 vaccine trials, recommendations can only be made based on empirical evidence. Therefore, anticipate the likelihood that vaccine advice will change as data become available. Currently, COVID-19 vaccination should be strongly recommended to patients on immunomodulatory and/or biologic therapies (and their direct contacts), as no specific contraindication or identifiable safety issues have been identified in this patient group to date. Nevertheless, discussion outlining the limited efficacy and safety profile prior to vaccination is essential for all patients. Adherence to social distancing and hygiene measures remains imperative, as patients should not solely rely on vaccine-mediated protection given the theoretical possibility of a diminished vaccine response, particularly in patients taking conventional immunomodulators including systemic corticosteroids. [table] Table 1: Phase III data for COVID-19 vaccines under regulatory approval or consideration in Australia/New Zealand [/table] [table] Table 2: Vaccine candidate in phase III trials [/table] [table] Table 3 Dermatology: different anatomical location due to the high frequency of local and systemic reactions.• At this stage, there are no data on the timing of co-ad- [/table]	None	None	As the phase III COVID‐19 vaccine trials excluded patients on immunosuppressive treatments, or patients with significant autoimmunity, the Australasian Medical Dermatology Group make the following preliminary recommendations around COVID‐19 vaccination in dermatology patients on immunomodulatory and/or biologic agents.
9a3bf8bd706b8ce0c60552ea7c45ae407c9eabc4	pubmed	Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology*	Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology* background: Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis. objectives: The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis. Methods: Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel. results/conclusion: The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis. # Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease, with lesions showing typical morphology and distribution, and whose hallmark is intense pruritus. AD presents in patients with a personal or family history of atopic diseases such as asthma, rhinitis, or AD itself. It is one of the most frequent diseases of childhood, and its prevalence reaches up to 20% in infants and 2.1 to 4.9% in adults in Europe, North America, and Japan. [bib_ref] Atopic dermatitis: epidemiology and pathogenesis update, Eichenfield [/bib_ref] [bib_ref] Atopic dermatitis, Watson [/bib_ref] [bib_ref] Epidemiology of atopic dermatitis in adults: Results from an international survey, Barbarot [/bib_ref] Annual incidence of new cases of AD in patients below the age of 17 in the US is 11%; 85% of AD patients first manifest the disease before the age of 5, but 20-40% of children with AD persist with the skin disease in adulthood. [bib_ref] Atopic dermatitis and the atopic march, Spergel [/bib_ref] [bib_ref] Adult-onset atopic dermatitis, Ozkaya [/bib_ref] In the Brazilian population, prevalence of AD symptoms according to in children and 5.0% in adolescents. [bib_ref] Prevalence of atopic eczema and related symptoms in Brazilian schoolchildren: results from..., Solé [/bib_ref] Due to the complex pathogenesis of AD, which involves skin barrier defects, immune dysfunction, and microbiome alterations mediated by genetic, environmental, and psychological triggers, a single therapeutic approach is hardly capable of achieving disease control. [bib_ref] Profile of skin barrier proteins and cytokines in adults with atopic dermatitis, Orfali [/bib_ref] Increased transepidermal water loss (TEWL), decreased stratum corneum water content, and reduced expression of skin barrier proteins such as filaggrin and claudin 1 are the main alterations of the skin barrier in individuals with AD. [bib_ref] Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17..., Batista [/bib_ref] [bib_ref] Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms, Elias [/bib_ref] [bib_ref] Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and..., Gittler [/bib_ref] Of note is the cytokine dysregulation, leading to Th2, Th1, Th17, and Th22 polarization, which varies according to age, ethnicity, and AD phase. [bib_ref] Severe atopic dermatitis is characterized by selective expansion of circulating TH2/ TC2..., Czarnowicki [/bib_ref] [bib_ref] New insights into atopic dermatitis: role of skin barrier and immune dysregulation, Leung [/bib_ref] [bib_ref] The skin microbiome is different in pediatric versus adult atopic dermatitis, Shi [/bib_ref] Skin microbiome plays a crucial role in AD; about 90% of the skin of atopic individuals is colonized by Staphylococcus aureus (S. aureus). [bib_ref] Bacterial and Viral Infections in Atopic Dermatitis: a Comprehensive Review, Ong [/bib_ref] The diversity of skin microbiome of AD patients shows temporal shifts, with a predominance of S. aureus during flares and Streptococcus, Propionibacterium, and Corynebacterium after treatment. [bib_ref] Temporal shifts in the skin microbiome associated with disease flares and treatment..., Kong [/bib_ref] AD remains a challenging disease. Ideal treatment is targeted to long-term disease control with reduction of flares and maintenance of good quality of life. Moreover, treatment approaches depend on geographic, economic, and genotypic/phenotypic variations. This paper aims to communicate the experience, opinions, and recommendations of Brazilian dermatology experts on atopic dermatitis treatment. # Methods Eighteen faculty members from 10 university hospitals with expertise in AD were appointed by the Brazilian Society of Dermatology. The first step was the application of an online questionnaire with 14 questions regarding the management of AD patients by the experts at university hospitals. [fig_ref] Table 1: shows the data obtained from the applied questionnaire [/fig_ref] shows the compiled answers. The second step was the analysis of recent international guidelines (American Academy of Dermatology, published in 2014, and the European Academy of Dermatology and Venereology, published in 2018). [bib_ref] Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis..., Eichenfield [/bib_ref] [bib_ref] Guidelines of care for the management of atopic dermatitis: section 2. Management..., Eichenfield [/bib_ref] [bib_ref] Guidelines of care for the management of atopic dermatitis: section 3. Management..., Sidbury [/bib_ref] [bib_ref] Guidelines of care for the management of atopic dermatitis: Section 4. Prevention..., Sidbury [/bib_ref] [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] All sections and recommendations regarding AD treatment were discussed with the 18 experts, and consensus was defined as approval by at least 70% of the panel. This paper expresses their opinions regarding international guidelines for AD treatment and provides practical guidance for dermatologists in Brazil. Daily bathing is possible for regular skin hydration, and emollients should be applied on slightly wet skin, immediately after drying; application twice daily is usually sufficient. [bib_ref] The Association Between Bathing Habits and Severity of Atopic Dermatitis in Children, Koutroulis [/bib_ref] Some emollients have additional ingredients such as urea and propylene glycol, which may lead to skin irritation, and there is still inconclusive evidence about superiority of emollients enhanced with components of the skin barrier such as ceramides. [bib_ref] The Association Between Bathing Habits and Severity of Atopic Dermatitis in Children, Koutroulis [/bib_ref] [bib_ref] Recommendations from a European Roundtable Meeting on Best Practice Healthy Infant Skin..., Blume-Peytavi [/bib_ref] Recent concepts regarding the microbiome and the skin highlight that the cutaneous microbiome in AD is not as heterogeneous as in healthy individuals, with the predominance of Staphylococcus aureus (S. aureus). [bib_ref] Temporal shifts in the skin microbiome associated with disease flares and treatment..., Kong [/bib_ref] [bib_ref] Topographical and temporal diversity of the human skin microbiome, Grice [/bib_ref] Recovery of the skin barrier by adjusting the inflammatory response reestablishes the skin microbiome in AD patients. [bib_ref] Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis..., Simpson [/bib_ref] [bib_ref] Comparison of Dermatology and Allergy Guidelines for Atopic Dermatitis Management, Mohan [/bib_ref] Bacterial lysates or topical application of commensal bacteria are promising, but skin hydration itself is able to recover the skin microbiome. [bib_ref] Temporal shifts in the skin microbiome associated with disease flares and treatment..., Kong [/bib_ref] [bib_ref] First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis, Myles [/bib_ref] There is evidence for early use of emollients in atopic dermatitis-prone children (three months of age and older) in the prevention of AD. [bib_ref] Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis..., Simpson [/bib_ref] [bib_ref] Comparison of Dermatology and Allergy Guidelines for Atopic Dermatitis Management, Mohan [/bib_ref] Recommendations by the dermatology experts for baseline therapy: # Results/discussion Daily cleansing for up to 5 minutes with mild agents with adequate pH Emollient application twice daily on slightly wet skin is the main component of baseline therapy ## Aeroallergens Aeroallergens are relevant triggering factors of AD flares. [bib_ref] Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge..., Werfel [/bib_ref] [bib_ref] House dust mite reduction in the management of atopic dermatitis. A critically..., Garritsen [/bib_ref] [bib_ref] Atopy patch test with Aleuroglyphus ovatus antigen in patients with atopic dermatitis, Lorenzini [/bib_ref] Exacerbation of an eczematous lesion after skin contact or inhalation has been reported, but studies are still inconclusive. [bib_ref] House dust mite reduction in the management of atopic dermatitis. A critically..., Garritsen [/bib_ref] The skin prick test and specific IgE are routinely utilized but have a low positive predictive value. [bib_ref] House dust mite reduction in the management of atopic dermatitis. A critically..., Garritsen [/bib_ref] In the present panel of dermatology experts, 89% do not perform the skin prick test or RAST as part of routine practice. ## Food allergy One-third of the children with moderate/severe AD have associated food allergy; however, food allergy is not the cause of AD. [bib_ref] Bath-Hextall F, Delamere FM, Williams HC. Dietary exclusions for improving established atopic..., Eigenmann [/bib_ref] Restrictive diets should only be prescribed for children with proven food allergy. [bib_ref] Bath-Hextall F, Delamere FM, Williams HC. Dietary exclusions for improving established atopic..., Eigenmann [/bib_ref] The published guidelines recommend restrictive diets only for those patients with a positive oral challenge test, the gold standard assay for food allergy. [bib_ref] Guidelines of care for the management of atopic dermatitis: Section 4. Prevention..., Sidbury [/bib_ref] [bib_ref] Bath-Hextall F, Delamere FM, Williams HC. Dietary exclusions for improving established atopic..., Eigenmann [/bib_ref] [bib_ref] Patterns of care and referral in children with atopic dermatitis and concern..., Thompson [/bib_ref] The detection of specific IgE to food through prick or serological tests does not prove food allergy, and their positive predictive value is low. [bib_ref] Specific IgE and skin prick tests to diagnose allergy to fresh and..., Cuomo [/bib_ref] The present panel of dermatology experts does not recommend restrictive diets, but considers that food allergy may be investigated in children with severe, treatment-resistant AD and in those with a history of flares following ingestion of specific foods. ## Contact dermatitis Contact dermatitis is present in 40-65% of AD patients, usually exacerbating the existing eczema. [bib_ref] Frequency of contact allergens in pediatric patients with atopic dermatitis, Herro [/bib_ref] The patch test is recommended for refractory AD with atypical skin lesions. [bib_ref] Management of difficult-to-treat atopic dermatitis, Arkwright [/bib_ref] Patients should be tested for fragrances, preservatives, topical corticosteroids, and other topical components. [bib_ref] Frequency of contact allergens in pediatric patients with atopic dermatitis, Herro [/bib_ref] Patients are more prone to develop occupational dermatoses, since AD exacerbates the irritant effect of allergens in certain professions such as hairdressers, mechanics, metalworkers, janitorial workers, and nurses, in whom hand eczema is commonly reported. [bib_ref] Contact Dermatitis in Atopic Dermatitis Children-Past, Present, and Future, Borok [/bib_ref] Preventive measures should be taken in order to reduce the incidence of AD in such patients. Fifty percent of the expert group recommend patch tests. The main problem is the difficulty in performing the test, since ideal sites are usually limited in AD patients. ## Topical anti-inflammatory therapy Topical anti-inflammatory therapy is the mainstay of AD treatment. Anti-inflammatory agents must have sufficient potency and should be applied on the skin lesions according to the recommendations and not exceeding the allowed amount per day. 41 ## Topical corticosteroids (tc) TC are the first line treatment for AD, with strong evidence of their superiority over placebo. [bib_ref] The management of moderate to severe atopic dermatitis in adults with topical..., Van Der Meer [/bib_ref] They are classified according to their potency based on vasoconstrictive effects, and every clinician should be aware of their potential local and systemic adverse effects, such as cutaneous atrophy and adrenal suppression. [bib_ref] Balancing efficacy and safety in the management of atopic dermatitis: the role..., Luger [/bib_ref] [bib_ref] Hypothalamus-pituitary-adrenal axis suppression by superpotent topical steroids, Walsh [/bib_ref] Strategies defining the use of TC vary according to their potency, but the suggested applied amounts of topical corticosteroids follow the fingertip unit rule. [bib_ref] Guidelines of care for the management of atopic dermatitis: Section 4. Prevention..., Sidbury [/bib_ref] [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] In the European guidelines, the approximate total amount of TC per month is 15g in infants, 30g in children, and 60-90g in adolescents and adults. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] The choice of corticosteroid and its vehicle depend on the affected site, the patients' age and the severity and clinical phase of AD. Wet-wrap dressings may improve AD flares, and ultrahigh potent topical corticosteroids should be applied for up to two weeks. [bib_ref] Comparison of Dermatology and Allergy Guidelines for Atopic Dermatitis Management, Mohan [/bib_ref] [bib_ref] Pathways to managing atopic dermatitis: consensus from the experts, Lebwohl [/bib_ref] TC use depends on the vehicle; as a cream, they should be applied 15 minutes before the moisturizer, and as an ointment, applied 15 minutes prior to the moisturizer. [bib_ref] Guidelines for treatment of atopic eczema (atopic dermatitis) part I, Ring [/bib_ref] Corticosteroid phobia is a relevant matter that should be addressed, especially due to its influence on adherence to treatment; it varies according to the country and culture. [bib_ref] Topical corticosteroid phobia in atopic dermatitis: International feasibility study of the TOPICOP..., Stalder [/bib_ref] Topical corticosteroids are the first-line topical treatment for AD, according to the experts. ## Calcineurin inhibitors (topical immunomodulators or tim) Tacrolimus and pimecrolimus are second-line non-corticosteroid, anti-inflammatory therapies for AD with proven efficacy. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] The role of topical calcineurin inhibitors in atopic dermatitis, Alomar [/bib_ref] The most widely reported adverse effect is burning sensation during the initial days of use (especially with tacrolimus); they do not induce skin atrophy, which makes them useful for application on eyelids, perioral lesions, axillae, and genitals. [bib_ref] Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized..., Reitamo [/bib_ref] Despite a black box warning in the package insert, studies have not reported an increased risk of lymphoma with the topical use of TIM at therapeutic doses. [bib_ref] Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in..., Arellano [/bib_ref] Intermittent use of TIM is recommended above two years of age. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] Eighty percent of the Brazilian experts use TIM as a second-line therapy for AD. ## Proactive treatment Proactive treatment has been proposed in published guidelines. It consists of long-term use of topical anti-inflammatory agents, either TC or TIM (tacrolimus), twice a week in previously affected areas, combined with moisturizers. [bib_ref] Comparison of Dermatology and Allergy Guidelines for Atopic Dermatitis Management, Mohan [/bib_ref] [bib_ref] Pathways to managing atopic dermatitis: consensus from the experts, Lebwohl [/bib_ref] [bib_ref] Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis:..., Thaçi [/bib_ref] [bib_ref] Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment, Wollenberg [/bib_ref] The rationale for proactive treatment is based on its efficacy and long-term safety (up to one year), reducing the number of flares and improving the quality of life of atopic patients. [bib_ref] Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis:..., Thaçi [/bib_ref] [bib_ref] Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment, Wollenberg [/bib_ref] The Brazilian experts recommend proactive treatment with TC or TIM in AD patients. ## Topical antimicrobial therapy Colonization by S. aureus is frequent on the skin of AD patients and is much higher than in non-atopic individuals (100% vs. Proactive therapy with either TC or TIM is safe, reduces flares and AD severity, and is indicated as long-term maintenance therapy. The use of topical antibiotics and antiseptics is still variable. Topical antibiotics can be used for short periods, and bleachers (0.005% sodium hypochlorite may be useful for pediatric AD). Wet-wrap bandages or occlusive treatment during hospitalization are helpful measures for improving flares. In patients that fail to respond to topical treatment, the following should be considered: -differential diagnoses of AD The aim of systemic antihistamines in AD is to allow better quality of sleep, since their role as anti-inflammatory agents in AD is controversial. There is no evidence of improvement of severity scores in randomized studies, and first-generation drugs are prescribed due to their sedative effect and to the relief of other conditions related to AD, such as asthma, rhinoconjunctivitis, dermographism, and urticaria. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine..., Diepgen [/bib_ref] However, our group stresses that the quality of sleep induced by anti-H1R drugs is not ideal, since they do not alter the REM phase. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine..., Diepgen [/bib_ref] Our group recommends the use of first-generation antihistamines (hydroxyzine and chlorpheniramine) based only on their sedative effect. flares. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] Pregnancy is not a contraindication to CyA use. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] Although CyA leads to prompt improvement in severity scores after 2 weeks from the initial dose, reactivation of AD after the drug's suspension is equally rapid, occurring in 2 weeks. 63 ## Anti-inflammatory agents ## Methotrexate (mtx) MTX can be indicated as initial treatment for moderate/severe AD, recalcitrant to topical treatment with corticosteroids. The drug has a good safety profile and is indicated for long-term maintenance; clinical efficacy is reached after 8-12 weeks of administration. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] The therapeutic dose varies from 15 to 25mg/week for adults and 10-15mg/m 2 /week for children (oral, intravenous, or subcutaneous), and folate should be added to the treatment, usually 1-2 days after MTX. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] Average length of treatment ranges from 6 to 12 months, and clinical improvement is seen at 8-12 weeks from the initial dose. Side effects include hematological disorders, liver enzyme alterations, and gastrointestinal discomfort. Its use is recommended for up to 2 years, with constant monitoring of bone marrow and liver function. [bib_ref] Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults..., Wollenberg [/bib_ref] [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] [bib_ref] Atopic dermatitis: a practice parameter update 2012, Schneider [/bib_ref] Contraception is mandatory, since the drug is considered category X. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] Azathioprine (AZA) AZA can be indicated as systemic treatment for refractory AD. Peak efficacy of AZA is reached after 8-12 weeks of use. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] The initial dose is usually 50 mg/day for 1-2 weeks, increased thereafter to 2-3 mg/kg/day. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] [bib_ref] Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind,..., Meggitt [/bib_ref] It can increase the risk of non-melanoma skin cancer and lymphoma. [bib_ref] Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a..., Khan [/bib_ref] [bib_ref] Waxweiler WT, Agans R, Morrell DS. Systemic treatment of pediatric atopic dermatitis..., Peyrin-Biroulet [/bib_ref] Thiopurine methyltransferase enzyme (TPMT) levels should be measured whenever possible, since TPMT deficiency while in use of AZA can lead to bone marrow aplasia. [bib_ref] Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind,..., Meggitt [/bib_ref] It can be prescribed for children (off label for AD) and is subject to restricted indication during pregnancy. [bib_ref] ETFAD/ EADV Eczema task force 2015 position paper on diagnosis and treatment..., Wollenberg [/bib_ref] suicidal ideation may be present. [bib_ref] Guidelines for treatment of atopic eczema (atopic dermatitis) Part II, Ring [/bib_ref] [bib_ref] Counseling of parents with children with atopic dermatitis, Gieler [/bib_ref] Low treatment adherence is common in AD, and educational programs are needed to reinforce the patient's understanding of the disease complexity and therapeutic approaches. [bib_ref] Evaluation of a parental training program for the management of childhood atopic..., Staab [/bib_ref] Various models focusing on AD education and with multidisciplinary approaches have shown subjective and objective improvement of AD worldwide. [bib_ref] Evaluation of a parental training program for the management of childhood atopic..., Staab [/bib_ref] [bib_ref] Improving the patientclinician and parent-clinician partnership in atopic dermatitis management, Mancini [/bib_ref] [bib_ref] Structured education program improves the coping with atopic dermatitis in children and..., Kupfer [/bib_ref] [bib_ref] Education of Patients with Atopic Dermatitis and Their Caregivers, Takaoka [/bib_ref] [bib_ref] Assessment of the quality of life of pediatric patients at a center..., Weber [/bib_ref] Future perspectives Immunobiologicals and small molecules are targeted therapies that have been developed for many inflammatory, autoimmune, and oncologic diseases. Crisaborole ointment is a topical phosphodiesterase 4 (PDE4) inhibitor that was approved in the USA in 2017 for patients above the age of 2 years with mild/moderate AD. [bib_ref] Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4)..., Paller [/bib_ref] Dupilumab is a human monoclonal antibody for AD that blocks the alfa-chain receptor for IL-4 and IL-13 (dupilumab) and is approved for adults with moderate/severe AD. [bib_ref] Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): A phase..., Simpson [/bib_ref] Its efficacy after 16 weeks as monotherapy (initial dose: 600 mg, followed by 300 mg every 2 weeks, SC), measured by the reduction of eczema severity scores (EASI) was 82.5% (EASI 50), 60.3% (EASI 75), and 36.5% (EASI 90). 81-83 Improvement of skin lesions and reduction of pruritus improved 2 weeks after initiating treatment. [bib_ref] Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): A phase..., Simpson [/bib_ref] [bib_ref] Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately..., Thaçi [/bib_ref] [bib_ref] Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis, Simpson [/bib_ref] The studies show sustained long-term efficacy (one year) with dupilumab combined with TC in AD patients. [bib_ref] The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted..., Brunner [/bib_ref] [bib_ref] Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids..., Blauvelt [/bib_ref] The main adverse event reported with dupilumab was conjunctivitis, detected in 25-50% of AD patients. [bib_ref] Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids..., Blauvelt [/bib_ref] [bib_ref] Conjunctivitis occurring in atopic dermatitis patients treated with dupilumabclinical characteristics and treatment, Wollenberg [/bib_ref] There are ongoing studies (phases 2-3) with novel immunobiologicals and small molecules for AD treatment. See Chart 1. [bib_ref] Immunologic Targets in Atopic Dermatitis and Emerging Therapies: An Update, Wang [/bib_ref] [bib_ref] New and emerging targeted systemic therapies: a new era for atopic dermatitis, Lee [/bib_ref] Chart 1: New systemic drugs for AD treatment. [bib_ref] Immunologic Targets in Atopic Dermatitis and Emerging Therapies: An Update, Wang [/bib_ref] [bib_ref] New and emerging targeted systemic therapies: a new era for atopic dermatitis, Lee [/bib_ref] # Conclusions Despite the cultural and economic differences between Brazil, USA, and Europe, including in access to immunobiological therapies, the ideal management of AD is based on a better understanding of disease pathogenesis and knowledge of treatment strategies. Basic treatment for AD includes skin hydration, topical anti-inflammatory therapy, avoidance of aggravating factors, and educational programs with a multidisciplinary approach. Systemic therapy should be only indicated for refractory or severe disease after attempts with topical therapy. Secondary infections must be diagnosed early and treated promptly, and hospitalization may be necessary to control flares [fig_ref] FIgure 1: Consensus-based recommendations of topical and systemic treatments for patients with atopic dermatitis [/fig_ref]. Novel target-oriented drugs are invaluable tools for AD treatment. q ## Basic therapy ## Systemic therapy [fig] , 68 Mycophenolate: mofetil (MMF)Clinical efficacy of MMF is reached after 8-12 weeks of use (off label in AD), and the drug has a good safety profile.21,63 The recommended doses in adults are 1-2g/day (starting dose) and 2-3g/ day (maintenance); the pediatric doses are 20-50mg/kg/day (starting dose) and 30-50mg/kg/day (maintenance).21,68 Gastrointestinal and hematological side effects have been reported.21,63 Systemic corticosteroids (SC) There are few randomized controlled studies regarding the use of systemic corticosteroids in AD. In the 2018 European consensus, SC are used in exceptional cases of AD, but only for one week.21 There is a rapid clear up of skin lesions , but severe rebound tends to occur in 2 weeks.21 One controlled trial indicates lower efficacy of systemic prednisolone in comparison to CyA in severe AD.21,69 Position/recommendations for the use of systemic anti-inflammatory drugs in AD:CyA and MTX are the most widely used systemic drugs for severe refractory AD.CyA leads to fast improvement of AD severity scores after 2 weeks of initial treatment, but reactivation of AD after drug suspension is equally fast, occurring in 2 weeks.MTX can be used as the initial systemic medication for refractory moderate/severe AD and is indicated for long-term maintenance. Clinical efficacy is reached after 8-12 weeks of administration.Oral corticosteroids are used in exceptional cases for short periods (up to 1 week). [/fig] [fig] FIgure 1: Consensus-based recommendations of topical and systemic treatments for patients with atopic dermatitis (AD) [/fig] [table] Table 1: shows the data obtained from the applied questionnaire. The majority of experts (17/18) who answered the questionnaire work in public and private institutions. About 50% of the specialists see more than 50 AD patients/month, mostly at public hospitals. Twelve out of 18 of the dermatologists follow published consensuses, with emphasis on the American and European guidelines. The most widely used topical treatments are corticosteroids, followed by calcineurin inhibitors. The first choice for systemic therapy was cyclosporin, followed by methotrexate and azathioprine. [/table]	None	http://www.scielo.br/pdf/abd/v94n2s1/0365-0596-abd-94-02-s1-0067.pdf	BACKGROUND Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis. OBJECTIVES The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis. METHODS Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel. RESULTS/CONCLUSION The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis.
51e61cd90f16147cf4972c18091d9c278d7a6cce	pubmed	Neuromodulation of chronic headaches: position statement from the European Headache Federation	Neuromodulation of chronic headaches: position statement from the European Headache Federation The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile. # Background Although headache is a common disease, its more severe manifestations such as intractable migraine and trigeminal autonomic cephalalgias have a debilitating effect on patients resulting in chronic pain and severe functional impairment. The recent Global Burden of Disease Study 2010 (GBD2010), conducted by the World Health Organization, Lifting the Burden and their partners, estimates a worldwide prevalence of migraine of 14.7%, ranking it third place among the most common diseases and at the seventh place among specific causes of disability and top of all neurological disorders as cause of total years lived with disability [bib_ref] Years lived with disability (YLD) for 1160 sequelae of 289 diseases and..., Vos [/bib_ref] [bib_ref] Migraine: the seventh disabler, Steiner [/bib_ref]. Although excellent international guidelines for organisation of headache service and management have been introduced [bib_ref] Task Force EFNS (2006) EFNS guidelines on the treatment of cluster headache..., May [/bib_ref] [bib_ref] European Federation of Neurological Societies (2009) EFNS guideline on the drug treatment..., Evers [/bib_ref] [bib_ref] European Headache Federation, Global Campaign against Headache (2011) Recommendations for headache service..., Steiner [/bib_ref] there is no single standard of care for patients presenting with primary chronic headache symptoms. For example, treatment choices for acute migraine are based on headache severity, attack frequency, associated symptoms, and co-morbidities. Despite significant improvement in management of migraine, achieving a satisfactory treatment outcome is still a challenge because of inadequate response of medications and difficulty in predicting individual response to a specific agent or dose. The medical treatment of patients with chronic primary headache syndromes (such as chronic migraine, chronic cluster headache, chronic tension-type headache or hemicrania continua) is particularly challenging as valid studies are few and in many cases even higher doses of preventative medication is ineffective and adverse side effects frequently complicate the course of medical treatment. Chronic headaches that do not or no longer respond to prophylaxis are commonly encountered at tertiary level headache centres [bib_ref] Emerging treatment for chronic migraine and refractory chronic migraine, Lionetto [/bib_ref]. The vast majority of these patients suffer from medication overuse headache which can and should be alleviated by detoxification, but a subset remains as refractory chronic migraine (RCM) [bib_ref] Emerging treatment for chronic migraine and refractory chronic migraine, Lionetto [/bib_ref]. Although much work has been accomplished, the definition of RCM is still a continuous work in progress [bib_ref] Chronic migraine plus medication overuse headache: two entities or not?, Negro [/bib_ref] [bib_ref] Defining Refractory Migraine: results of the RHSIS Survey of American Headache Society..., Schulman [/bib_ref]. Cluster headache as such can also be hard to treat but it may become impossible in chronic cluster headache (CCH) sufferers. Some patients may be intractable to the therapies recommended by national guidelines, and following the need of clinicians the word "intractable" has been defined by Goadsby et al. entitled "Towards a Definition of Intractable Headache for Use in Clinical Practice and Trials" [bib_ref] Towards a definition of intractable headache for use in clinical practice and..., Goadsby [/bib_ref]. In these patients, i.e. when the intolerance or lack of responsiveness to conservative treatments is ascertained, surgical options are considered. The options has previously ranged from application of glycerol or local anaesthetics into the cisterna trigeminalis of the Gasserian ganglion; radiofrequency rhizotomy of the Gasserian ganglion or of the trigeminal nerve; microvascular decompression; resection or blockade of the N. petrosus superficialis or of the ganglion sphenopalatinum and to a whole range of other ablative or destructive methods. Case reports of the complete inefficacy of surgical treatment, at least in cluster headache and related syndromes exists [bib_ref] Persistence of attacks of cluster headache after trigeminal nerve root section, Matharu [/bib_ref] [bib_ref] Two cases of medically and surgically intractable SUNCT: a reason for caution..., Black [/bib_ref] [bib_ref] Outcome of trigeminal nerve section in the treatment of chronic cluster headache, Jarrar [/bib_ref] [bib_ref] Gamma knife treatment for refractory cluster headache: a prospective open trial, Donnet [/bib_ref]. It follows that surgical procedures should be considered with great caution because no reliable long term observational data are available and because they can induce a secondary chronic pain condition as trigeminal neuralgia and/or anaesthesia dolorosa. Technical progress has recently introduced the opportunity to use neurostimulation rather than ablative or destructive methods and it may be applied to virtually any neural structure, including spinal cord, deep brain structures, motor cortex and peripheral nerves. It is not known how electrical stimulation of central or peripheral target structures exerts its effects, although a neuronal functional block seems the most likely option. Almost all the mentioned therapies for RCM and CCH require weeks to months of stimulation for a prophy-lactic effect to occur, suggesting neuronal plasticity as a possible mechanism, and only stimulation of the sphenopalatine ganglion in CCH has demonstrated an acute, abortive effect [bib_ref] Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1:..., Schoenen [/bib_ref]. Predictors of effectiveness for all modes of neurostimulation still need to be identified and in the future, the least invasive and most effective strategy must be preferred as first-line therapy for intractable chronic headaches [bib_ref] Neurostimulation in cluster headache: A review of current progress, Pedersen [/bib_ref]. Likewise neurostimulation should only be considered in patients that have tried all first-line therapies recommended in European guidelines [bib_ref] Task Force EFNS (2006) EFNS guidelines on the treatment of cluster headache..., May [/bib_ref] , and that clinicians need to follow international consensus on that matter [bib_ref] Towards a definition of intractable headache for use in clinical practice and..., Goadsby [/bib_ref] [bib_ref] Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection, Leone [/bib_ref]. The neuroanatomical targets for these techniques vary. The theoretical mechanisms, therefore, may vary depending on the location of stimulation. Invasive neuromodulatory procedures comprise stimulation of the central nervous system (hypothalamic deep brain stimulation (hDBS)) and spinal cord stimulation (SCS) and of the peripheral nerves (occipital nerve stimulation (ONS), sphenopalatine ganglion stimulation (SPG). Non-invasive variants comprise vagus nerve stimulation (VNS), transcutaneous electrical nerve stimulation (TENS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We aim to provide expert recommendations on the basis of a detailed review the present literature, a summary of clinical expertise and present a position for standard of care in the use of neuromodulation in chronic primary headaches in Europe. # Methods This review represents the view of the European Headache Federation (EHF) on this topic. The members of the Expert Group on Neuromodulation of chronic headache were appointed on the basis of their specific expertise on the topic with the necessary multidisciplinary approach. All currently existing methods of neuromodulation have been reviewed and analysed if at least two case series have been published and the indications and limits of each of these methods are presented. Details of the ethical considerations and various study approvals are provided in the background literature, please see the reference list. Because the field is fast evolving and because neurostimulation has the intrinsic and principal challenge of unavailable placebo or sham conditions, this recommendation cannot strictly follow evidence based methods approaches. However, a modified Delphi conference mainly using Internet facilities has been used and all participants agreed to the recommendations presented here. This paper is therefore not a conventional guideline but international expert recommendations strictly based on published evidence. # Results and discussion ## Hypothalamic stimulation theoretical background Hypothalamic stimulation for drug-refractory CCH became a therapeutical target after PET studies showed increased blood flow in the posterior hypothalamus during cluster headache attacks [bib_ref] Hypothalamic activation in cluster headache attacks, May [/bib_ref] , which was interpreted as neuronal activation of that brain area. A year later structural changes in the same brain area was demonstrated [bib_ref] Correlation between structural and functional changes in brain in an idiopathic headache..., May [/bib_ref]. ## Clinical data In 2000, soon after these seminal studies, the first hypothalamic implantation and stimulation for drugrefractory CCH (dCCH) was performed [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] with favourable results. So far, data on more than 60 hypothalamic implanted patients are archived in the literature and include cluster headache patients and other types of trigeminal autonomic cephalalgia [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Deep brain stimulation to relieve drug-resistant SUNCT, Leone [/bib_ref] [bib_ref] Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to..., Lyons [/bib_ref] [bib_ref] Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral..., Bartsch [/bib_ref] [bib_ref] Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case..., Walcott [/bib_ref] [bib_ref] Acute hypothalamic stimulation and ongoing cluster headache attacks, Leone [/bib_ref]. The overall success rate (patients pain-free or with ≥50% improvement) is around 50-60% and accumulated follow-up has made it possible to better understand advantages and limitations of the procedure. The largest series to date comprises 19 severe dCCH patients [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] : after a mean follow-up of 8.7 years, longlasting improvement was present in 71% (12/17) with 6 persistently almost pain free and another 6 no longer experiencing daily attacks but episodic attacks interspersed with long-lasting remission [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref]. The pain free state was maintained after the stimulators had been off for a median of 3 years (range 3-4) in 5 patients, but this only happened after several years of continuous stimulation [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref]. Most patients have headache recurrence a short time after the stimulator is switched off, or the battery runs out [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Deep brain stimulation to relieve drug-resistant SUNCT, Leone [/bib_ref] [bib_ref] Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to..., Lyons [/bib_ref] [bib_ref] Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral..., Bartsch [/bib_ref] [bib_ref] Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case..., Walcott [/bib_ref] [bib_ref] Acute hypothalamic stimulation and ongoing cluster headache attacks, Leone [/bib_ref]. Five patients did not have benefit; 4 of these had bilateral cluster headache. Three of the nonresponders experienced relief for the first 1-2 years but then developed tolerance [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref]. Adverse events were electrode displacement (N=2), infection (electrode N=3; generator N=1), electrode mal-positioning (N=1), transient non-symptomatic 3rd ventricle haemorrhage (N=1), persistent slight muscle weakness on one side (N=1), and a seizure (N=1) [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref]. Smaller studies have reported similar efficacy [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Deep brain stimulation to relieve drug-resistant SUNCT, Leone [/bib_ref] [bib_ref] Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to..., Lyons [/bib_ref] [bib_ref] Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral..., Bartsch [/bib_ref] [bib_ref] Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case..., Walcott [/bib_ref] [bib_ref] Acute hypothalamic stimulation and ongoing cluster headache attacks, Leone [/bib_ref]. Eleven drug-resistant CCH patients were randomized to effective vs. sham posterior hypothalamic stimulation. No difference was detected between the two arms after one month, probably in relation to the short duration of treatment [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref]. In the subsequent open-label phase, all patients received openly verum stimulation and three patients became pain free, and three others had a ≥50% reduction in attack frequency after 10 months. Posterior hypothalamic activation has also been shown to be effective in three patients with short-lasting neuralgiform headache attacks with conjunctival injec-tion and tearing (SUNCT), a rare form of trigeminal autonomic cephalgia. [bib_ref] Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache, Fontaine [/bib_ref] [bib_ref] Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache, Maniyar [/bib_ref] The first patient became pain-free but additional prophylaxis with lamotrigine was necessary. Another patient had a clinically significant reduction in attack frequency (from 120 to 25/ day after a year) [bib_ref] Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache, Fontaine [/bib_ref]. In the third patient [bib_ref] Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache, Maniyar [/bib_ref] attack frequency dropped from 30/day to sporadic attacks after 15 months of continuous stimulation. A patient with chronic paroxysmal hemicrania also obtained relief after posterior hypothalamic stimulation [bib_ref] Effect of deep brain stimulation of the posterior hypothalamic area on the..., Cortelli [/bib_ref]. Posterior hypothalamic stimulation has also been tested to abort acute cluster headache attacks. Treatment consisted of switching the stimulator on or increasing stimulation intensity. One hundred eight attacks were assessable and a ≥50% reduction in pain intensity was reported only in 23%; it was concluded that DBS is not useful for acute treatment of cluster headache [bib_ref] Acute hypothalamic stimulation and ongoing cluster headache attacks, Leone [/bib_ref]. ## Safety and adverse effects Overall, posterior hypothalamic stimulation is well tolerated years after implantation, but is not without risk: one patient died of intracerebral haemorrhage [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] and another had a subclinical 3rd ventricle haemorrhage [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref]. In movement disorders, deep brain stimulation carries about a 3% risk of brain haemorrhage. To reduce this risk Seijo et al. slightly shifted the hypothalamic target laterally so that the electrode tip was further from the lateral ventricle wall, without changing efficacy [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref]. In line with this observation, a neuroimaging study showed that the anatomical location of the stimulating electrodes did not differ significantly between responders and non-responders [bib_ref] Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache, Fontaine [/bib_ref]. Panic attacks [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] , oculomotor disturbances, intraoperative transient ischaemic attack, subcutaneous infection, transient loss of consciousness with hemiparesis and micturition syncope, erectile dysfunction, and paroxysmal sneezing [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache, Maniyar [/bib_ref] have also been reported. Heart rate, blood pressure, and respiratory rate are not affected by hypothalamic stimulation when amplitude is increased slowly; however, sudden increase in amplitude can provoke autonomic and oculomotor disturbances [bib_ref] Effect of deep brain stimulation of the posterior hypothalamic area on the..., Cortelli [/bib_ref]. Quality of sleep is improved during hypothalamic stimulation, possibly because of the suppression of nocturnal cluster headache attacks [bib_ref] Effect on sleep of posterior hypothalamus stimulation in cluster headache, Vetrugno [/bib_ref]. ## Technical considerations The first attempt to treat CCH by neuromodulation procedures was based on neuroimaging and particularly on the observation that a discrete volume of the posterior hypothalamus was activated during the pain bouts in CCH patients. The target of the procedure was the alleged hyperactive posterior hypothalamus (pHyp) and its inhibition was obtained delivering "in situ" high frequency current (180 Hz, 1-3 V, 60-90 μs pulse width) trough deep implanted electrodes. ## Limitations and recommendation for future studies DBS is an invasive, expensive and probably non-specific technique that must be employed with caution and only carefully considered for the most severely affected patients with medically refractive CCH when other less invasive strategies have been employed. The hypothesis leading to the introduction of hypothalamic stimulation as a treatment for CCH was that high frequency electrode stimulation could reduce hypothalamic activation during a headache attack [bib_ref] Two cases of medically and surgically intractable SUNCT: a reason for caution..., Black [/bib_ref]. After long-term experience with the technique, it is now evident that this hypothesis is not correct: in fact acute hypothalamic stimulation does not abort acute cluster headache attacks [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] , and it takes timelatencyfor a prophylactic effect to develop, comparable to the delay in dystonia [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref]. Taken together these observations indicate that stimulation works by a more complex mechanism, possibly brain plasticity [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Hypothalamic deepbrain stimulation modulates thermal sensitivity and pain thresholds in cluster headache, Jürgens [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation in positron emission tomography, May [/bib_ref] [bib_ref] Cortical excitation and chronic pain, Zhuo [/bib_ref]. ## Occipital nerve stimulation (ons) theoretical background The rationale for the use of occipital nerve stimulation (ONS) in headaches came from animal studies showing the convergence of cervical, somatic and dural afferents on second order nociceptors in the trigeminocervical complex [bib_ref] Stimulation of the greater occipital nerve induces increased central excitability of dural..., Bartsch [/bib_ref] [bib_ref] Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of..., Bartsch [/bib_ref]. That suboccipital steroid injections turned out to be effective in the prevention of several primary headaches [bib_ref] Headache and the greater occipital nerve, Anthony [/bib_ref] [bib_ref] Suboccipital injection with a mixture of rapid-and long-acting steroids in cluster headache:..., Ambrosini [/bib_ref] [bib_ref] Greater occipital nerve injection in primary headache syndromes-prolonged effects from a single..., Afridi [/bib_ref] was in favour of the existence of these anatomical connexions in humans. More than a decade ago, Weiner and Reed had already treated patients suffering from "occipital neuralgia" with ONS [bib_ref] Peripheral neurostimulation for control of intractable occipital neuralgia, Weiner [/bib_ref]. Their work paved the way for the use of this less invasive method of neurostimulation in various chronic headache types, essentially CCH and CM. ## Clinical data Up to now 3 randomized sham-controlled (RCTs) ONS trials have been performed in CM [bib_ref] PRISM study: occipital nerve stimulation for treatment-refractory migraine, Lipton [/bib_ref] [bib_ref] Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM..., Saper [/bib_ref] [bib_ref] Safety and efficacy of peripheral nerve stimulation of the occipital nerves for..., Silberstein [/bib_ref] and their outcome is overall disappointing. The evaluation period was set at 12 weeks of ONS treatment in all of them. In the PRISM trial [bib_ref] PRISM study: occipital nerve stimulation for treatment-refractory migraine, Lipton [/bib_ref] , available in abstract form only, 125 drug-refractory CM patients were treated with ONS or sham without any significant improvement. In the ONSTIM trial [bib_ref] Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM..., Saper [/bib_ref] , 39% of patients (N=66) treated with active ONS during 3 months had at least 50% reduction in headache frequency and/or a 3-point intensity scale decrease, while there was no improvement in the nonstimulated or ineffectively stimulated groups. Finally, in a recent trial on 157 patients [bib_ref] Safety and efficacy of peripheral nerve stimulation of the occipital nerves for..., Silberstein [/bib_ref] , the percentage of responders did not differ between active (17.1%) and control (13.5%) groups (primary endpoint). However, the number of headache days was significantly reduced in the ONS group compared to the sham population (−27.2% vs. -14.9%). The migraine-related disability also decreased with ONS. The main issue of this study is that patients were definitely not blinded to ONS (see below). Other existing studies of ONS in CM are small open trials or case reports (see [bib_ref] Advances and challenges in neurostimulation for headaches, Magis [/bib_ref] for review). Interestingly, the combination of occipital and supraorbital neurostimulation in an uncontrolled series of 7 CM patients [bib_ref] Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches:..., Reed [/bib_ref] produced a ≥90% headache frequency improvement in all patients, while there was no significant response to either stimulation alone. ONS has also been used in dCCH, but only open studies have been performed and in smaller groups of patients compared to the CM series. In the 3 main trials (13-15 patients), the success rate was slightly superior to 60% [bib_ref] Advances and challenges in neurostimulation for headaches, Magis [/bib_ref]. Burns et al. reported that after an average of 17.5 months under ONS therapy, 10/14 CCH patients were clinically improved: 3 had an improvement ≥90%, 3 a moderate amelioration (40-60%) and 4 a mild improvement (20-30%) [bib_ref] Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14..., Burns [/bib_ref]. In another study, 15 drCCH patients were prospectively followed up to 5 years after ONS implantation (mean 36.8 months) [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref] [bib_ref] Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study, Magis [/bib_ref]. One patient was not evaluable due to an immediate device infection. Among the 14 remaining patients nearly 80% had a ≥90% reduction in attack frequency and 60% remained pain-free during long time periods (months to years). In another recent prospective trial (N=13, [bib_ref] Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation, Fontaine [/bib_ref] attack frequency decreased on average by 68% and intensity improved by 49%. Eight out of 13 patients were able to reduce or stop their preventive medications. Other smaller studies also report beneficial outcome of CCH patients under ONS (see [bib_ref] Advances and challenges in neurostimulation for headaches, Magis [/bib_ref] for review). As far as other chronic forms of primary headaches are concerned, Burns et al. performed ONS in 6 patients with hemicrania continua (6-21 months [bib_ref] Treatment of hemicrania continua by occipital nerve stimulation with a bion device:..., Burns [/bib_ref] , and reported that 4 of them had a pain reduction exceeding 80%. Nine patients with drug-resistant SUNCT and 3 with SUNA (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing -SUNCT-or with autonomic symptoms -SUNA) had a benefit of at least 50% under ONS and 4 patients were nearly pain free after +/− 14 months follow-up [bib_ref] Response of SUNCT (Short-Lasting Unilateral Neuralgiform Headaches with Conjunctival Injection and Tearing),..., Marin [/bib_ref] [bib_ref] Treatment of medically intractable short-lasting unilateral neuralgiform headache attacks with conjunctival injection..., Shanahan [/bib_ref]. ## Safety and adverse effects ONS is relatively safe compared to other invasive techniques, chiefly hypothalamic deep brain stimulation. The most frequent adverse events are lead migration, local immediate or delayed infections and battery depletion due to high stimulation intensities needed to obtain an optimal nerve stimulation in some patients (64% in [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref]. Patients also complain of unpleasant traction on the connecting cables and sometimes do not tolerate the paraesthesias induced by the stimulation of the occipital nerves. Patients received generally bilateral ONS implantation even in side-locked headache forms, and in the only unilateral ONS series (in CCH) a headache side-shift was reported in 36% of them [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref] [bib_ref] Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study, Magis [/bib_ref]. Bilateral ONS is therefore recommended. ONS induces paraesthesias, like every other peripheral nerve stimulation. In our experience, the feeling of paraesthesias (covering the great occipital nerve or GON territory) appears mandatory to obtain a clinical improvement in CCH patients treated with ONS [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref] , but this is not always the case. Patients who do not feel the paraesthesias anymore (because of lead migration or battery depletion) often describe a recurrence of their headache attacks within the following days. There are no data demonstrating that ONS efficacy is conditioned by the stimulation of the GON or of the lesser occipital nerve or both, or correlated to the size of the area covered by paraesthesias. This phenomenon points out the main issue of ONS RCTs in headaches, i.e. the blinding. In CCH all available ONS studies are open trials and a placebo effect cannot be ruled out, even if in most patients attacks quickly relapsed after the stimulator was switched off. In CM more valid data are available and the outcome of the above mentioned RCTs is rather disappointing. More studies predicting a possible effect of ONS and patient selection are clearly warranted. Few studies have been performed to understand ONS mechanisms in chronic headaches, and they suggested that ONS had a nonspecific neuromodulatory effect on central pain control systems. Hence, 36% of CCH patients successfully treated with ONS had still autonomic attacks despite the disappearance of the pain itself [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref]. An 18FDG positron emission tomography (PET) study in 10 ONS-treated CCH patients showed an ipsilateral hypothalamic hyperactivity that remained unchanged during ONS therapy, contrary to the activity in pain transmitting cortical networks which normalized under ONS [bib_ref] Treatment of medically intractable short-lasting unilateral neuralgiform headache attacks with conjunctival injection..., Shanahan [/bib_ref] [bib_ref] Central modulation in cluster headache patients treated with occipital nerve stimulation: an..., Magis [/bib_ref]. Similar modifications were also reported with activation PET in CM patients treated with ONS [bib_ref] Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study, Matharu [/bib_ref]. One could speculate that the ONS stimulation has an effect on the peripheral pain transmission but not on the central modulating areas. ## Technical considerations There are many different stimulation electrodes but no comparative studies. The electrodes have to cross the GON in its subcutaneous course. Despite a great interindividual anatomical variability, the GON becomes superficial approximately 1 cm below the occiput and 2-4 cm from the midline [bib_ref] The course of the greater occipital nerve in the suboccipital region: a..., Natsis [/bib_ref]. Consequently electrodes should ideally cover this spot. The electrodes have to be implanted subcutaneously above the fascia and always above the GON, which exhibit great anatomical variability [bib_ref] The course of the greater occipital nerve in the suboccipital region: a..., Natsis [/bib_ref]. As electrode migration is the most frequent complication, the leads have to be anchored firmly to the epifascial plane. Performing loops with the leads is recommended to allow extension of the leads during movements. Bilateral stimulation is recommended to avoid headache side-shift [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref] [bib_ref] Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study, Magis [/bib_ref]. Implantation of the generator in the buttock is not recommended because the risk of migration could be higher. The release of flexible cables, epifascial anchoring and rechargeable batteries should decrease the cervical discomfort, lead migrations and battery depletion problems [bib_ref] Advances and challenges in neurostimulation for headaches, Magis [/bib_ref]. ## Limitations and recommendation for future studies ONS is an invasive, expensive and probably non-specific technique that must be employed with caution and only carefully considered for the most severely affected patients with medically refractive CCH. ONS demonstrated only preventive but no acute effect, with the exception of some chronic migraine patients [bib_ref] Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study, Matharu [/bib_ref]. Upcoming studies should be prospective, introduce a proper control and take the technical ONS challenges such as lead migration, frequent infections and proper blinding procedures into account. The mode of action is still speculative and the scientific evidence for a long lasting efficacy is lacking [bib_ref] Phenotype of patients responsive to occipital nerve stimulation for refractory head pain, Paemeleire [/bib_ref]. ## Stimulation of the sphenopalatine ganglion (spg) theoretical background Strictly half-sided trigeminal pain along with parasympathetic activation is a central diagnostic feature of all trigeminal autonomic cephalgias (TAC's). Consequently, several studies have targeted the facial parasympathetic output by blocking [bib_ref] Cluster headache and sphenopalatine block, Devoghel [/bib_ref] [bib_ref] Sphenopalatine endoscopic ganglion block: a revision of a traditional technique for cluster..., Felisati [/bib_ref] or lesioning [bib_ref] Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache, Narouze [/bib_ref] the sphenopalatine ganglion (SPG). The SPG is a large extracranial parasympathetic ganglion located in the pterygopalatine fossa (PPF). Post-ganglionic parasympathetic fibers from the SPG innervate facial structures such as the salivary and lacrimal glands, the nasopharyngeal mucosa and the cerebral and meningeal blood vessels [bib_ref] Orbital passage of pterygopalatine ganglion efferents to paranasal sinuses and nasal mucosa..., Ruskell [/bib_ref]. Because cluster headache is such a vicious pain which is not always medically treatable, various invasive interventions in the PPF have been tried including alcohol injection, thermocoagulation [bib_ref] Effects of radiofrequency thermocoagulation of the sphenopalatine ganglion on headache and facial..., Oomen [/bib_ref] , transnasal injection of lidocaine [bib_ref] Sphenopalatine endoscopic ganglion block: a revision of a traditional technique for cluster..., Felisati [/bib_ref] , neuroablation [bib_ref] Role of sphenopalatine ganglion neuroablation in the management of cluster headache, Narouze [/bib_ref] , radiofrequency lesions [bib_ref] Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache:..., Sanders [/bib_ref] and pulsed radiofrequency ablations [bib_ref] Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache, Narouze [/bib_ref]. The success rates seem promising (varying from 46 to 85%), but the benefits have been transient [bib_ref] Expert Consensus Recommendations for the Performance of Peripheral Nerve Blocks for Headaches..., Blumenfeld [/bib_ref]. Because of this transient nature and because of the irreparable side effects of the lesioning interventions, a non-destructive approach using acute percutaneous SPGS with a removable electrode was examined in five patients with cluster headache. This small pilot study showed a success rate of 61% [bib_ref] Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches, Ansarinia [/bib_ref] , which led to another pilot study in patients with acute migraine attacks which also showed some efficacy [bib_ref] Acute treatment of intractable migraine with sphenopalatine ganglion electrical stimulation, Tepper [/bib_ref]. ## Clinical data Based on these findings, a new kind of implantable microstimulator in the facial region was developed and a multicenter randomised double-blind and sham-controlled trial has been conducted to examine the efficacy of acute stimulation in refractory CCH. This device is powered and controlled transcutaneously by electromagnetic waves [bib_ref] Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1:..., Schoenen [/bib_ref]. In this study, 68% of the 32 enrolled CCH patients benefited from electrical stimulation of the SPG [bib_ref] Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1:..., Schoenen [/bib_ref]. Surprisingly, patients showed two positive effects: full stimulation of the SPG versus sham stimulation resulted in a significant pain relief (which was the main outcome parameter) and a significant reduction in attack frequency. The pain relief and pain freedom rates at 15 minutes were 67% and 34% respectively and significantly greater than with subthreshold or placebo stimulation. It needs to be pointed out that this study cannot answer the question how long these effects will continue but the impression at the moment is that these effects last and long term follow up studies are underway. The surprising observation that there was a significant reduction of headache attack frequency in addition to the acute response has to be seen with caution, as this study was designed and powered to test the acute effects on spontaneous cluster headache attacks. Overall, 43% of patients experienced an attack frequency reduction of ≥ 50% from baseline, which is remarkable as all patients had been suffering from the CCH for many years and had tried a number of preventive drugs without benefit. Given the slight tingling sensation that is accompanying stimulation of the SPG, a placebo effect cannot be excluded but the apparent preventive effects of SPG stimulation certainly warrant further investigation. ## Safety and adverse effects Of note, oral maxillofacial surgeries are inherently associated with standard peri-operative adverse events, including pain, swelling, hematoma, infections and sensory disturbances. While the rate of device-related complications was however quite low, sensory disturbance (81% of patients) and pain (38%) were the most frequent sideeffects immediately after the implantation, mainly affecting maxillary nerve branches. However, after 3 months, only 16% of patients suffered from ongoing and mild sensory disturbance and 19% from local pain, respectively [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref]. No other significant neurological side effects were observed. In summary, local sensory impairment seems to be a mild complication compared to the severe cluster attacks but the implantation procedure needs further attention. Overall, SPG stimulation appears to rank among the minimally invasive and safe neuromodulatory strategies. ## Technical considerations Implantation of the ATI-SPG-Stimulator is done under general anesthesia via a vestibular incision of the posterior maxillary mucosa of the affected side (trans-oral, gingival buccal technique). The stimulating electrodes on the integral lead are positioned within the PPF proximate to the SPG, with the body of the SPG Neurostimulator positioned on the lateral-posterior maxilla medial to the zygoma and anchored to the zygomatic process of the maxilla using the integral fixation plate. After implantation, positioning control is confirmed by doing a three-dimensional imaging (parasinus CT) of the PPF. Patients then undergo a therapy titration period during which stimulation parameters are to be adjusted bi-weekly. Individual electrical stimulation parameters are adjusted according to provoked paresthesias in the root of the nose and/or treatment effect during an attack. The maximum amplitude is usually programmed to be slightly higher than the amplitude that provoked discomfort in each patient. If neurostimulator lead positioning is determined to be incorrect, a lead revision procedure should be considered. ## Limitations and recommendation for future studies Judging from the published data, the input of the parasympathetic system in the origination of cluster headache attacks is significant. This is underlined by a recent report that low-frequency SPG stimulation can provoke attacks in patients with cluster headache which in turn can be treated with high-frequency stimulation [bib_ref] Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans, Schytz [/bib_ref]. It has to be kept in mind that all of the above data have been reported in medically intractable patients with CCH. It may be worthwhile using the method of SPG stimulation in episodic cluster headache patients, however, given the above mentioned side effects, only in patients with particularly long active bouts and failure of preventative medication. Given that only one placebocontrolled study exists to date, this method should be still seen as experimental until further studies are presented. ## Vagal nerve stimulation (vns) theoretical background The first investigations on the modulation of nociception by vagal afferents were performed approximately 20 years ago [bib_ref] Vagal afferent inhibition of primate thoracic spinothalamic neurons, Ammons [/bib_ref] [bib_ref] Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal..., Thies [/bib_ref] [bib_ref] Role of the right vagal nerve trunk in antinociception, Maixner [/bib_ref]. In animals it has been demonstrated that electrical, chemical, and physiologic activation of vagal afferents produces analgesic effect [bib_ref] Vagal afferent modulation of spinal nociceptive transmission in the rat, Ren [/bib_ref] [bib_ref] Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception..., Randich [/bib_ref] [bib_ref] Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys, Chandler [/bib_ref] [bib_ref] Antinociception produced by electrical stimulation of vagal afferents: independence of cervical and..., Aicher [/bib_ref] [bib_ref] Quantitative characterization and spinal substrates of antinociception produced by electrical stimulation of..., Thurston [/bib_ref] [bib_ref] Effects of vagal afferent stimulation on ON and OFF cells in the..., Thurston [/bib_ref]. The activation of vagal afferents decreases the activity of second order nociceptive neurons in the spinothalamic and spinoreticular tract of the spinal cord [bib_ref] Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal..., Thies [/bib_ref] [bib_ref] Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys, Chandler [/bib_ref] [bib_ref] Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve..., Rutecki [/bib_ref] resulting in inhibition of spinal nociceptive reflexes and spinal nociceptive transmission [bib_ref] Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception..., Randich [/bib_ref] [bib_ref] Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve..., Rutecki [/bib_ref] and in the trigeminal nuclear complex [bib_ref] Effects of cardiac vagal afferent electrostimulation on the response of trigeminal and..., Bossut [/bib_ref] [bib_ref] Effects of vagal afferent nerve stimulation on noxious heat-evoked Fos-like immunoreactivity in..., Evans [/bib_ref] [bib_ref] Activation of ascending antinociceptive system by vagal afferent input as revealed in..., Nishikawa [/bib_ref]. ## Clinical data Only smaller open case series exist. In a retrospective survey, three of four patients with implanted VNS reported a substantial improvement of migraine frequency and pain scores [bib_ref] The effect of vagus nerve stimulation on migraines, Hord [/bib_ref]. One of the 4 patients became migraine-free 1 month after the onset of VNS. A second patient had a reduction of >50% in both frequency and severity. A third patient reported >50% reduction in frequency. The final patient had a slight reduction in both frequency and severity. Improvement was reported to start 1 to 3 months after initiation of therapy. In another retrospective study, eight of ten patients with migraine had a 50% or more reduction in headache frequency, with five of them completely headache free in the 6 months after treatment initiation, with improvement occurring in the first 3 months following stimulator placement [bib_ref] Can vagus nerve stimulation help migraine?, Lenaerts [/bib_ref]. A case series reported a good response to VNS in two of four patients with chronic migraine (one with a subdiagnose of basilar-type migraine (BTM) and hemiplegic migraine (HM) and the other with BTM) and in two patients with CCH [bib_ref] Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches, Mauskop [/bib_ref]. Recently, a novel method has been described to non-invasively stimulate brain structures in a similar way to VNS [bib_ref] Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept, Ventureyra [/bib_ref] [bib_ref] Far field potentials from the brain stem after transcutaneous vagus nerve stimulation, Fallgatter [/bib_ref] [bib_ref] Age effect on far field potentials from the brain stem after transcutaneous..., Fallgatter [/bib_ref]. The method is based on the technique of transcutaneous electrical nerve stimulation (TENS), which is used in acute and chronic pain syndromes. t-VNS is delivered by a medical device to the left auricular branch of the vagus nerve (t-VNS) located medial of the tragus at the entry of the acoustic meatus without any surgery. Another novel method is also thought to stimulate the vagus nerve transcutaneously (tVNS). Preliminary data suggested that tVNS could be effective in selected patients [bib_ref] Non-invasive vagus nerve stimulation for the treatment of cluster headache: a case..., Nesbitt [/bib_ref]. In a pilot trial evaluating 13 primary headache sufferers, however, ten stopped tVNS because lack of efficacy and/or side effects [bib_ref] Transcutaneous Vagus Nerve Stimulation (tVNS) for headache prophylaxis: initial experience, Magis [/bib_ref]. ## Safety and adverse effects The very limited experience with both implantable and transcutaneous VNS prohibits a clear presentation of safety and limitations in use. Based on the experience of VNS in medically intractable epilepsy the method seems fairly safe and mainly hampered by infections and battery problems. The reported adverse effects are mainly transient muscle cramps and local pain, which can be reduced by the applied stimulation paradigm. So far, no significant safety issues have been raised but clinical experience is very scarce. ## Technical considerations VNS sends electrical signals along the part of the vagus nerve that runs through the neck. Data suggests that VNS reduces the amount of glutamate, substance associated with headache symptoms, in the brain. The VNS therapy is administered with a hand held device, placed on the neck, which produces a mild electrical signal transmitted to the vagus nerve through the skin. It is possible to turn up the stimulation strength until the patient feels a mild sensation underneath the skin. The duration of each treatment is approximately 2 minutes. ## Limitations and recommendation for future studies Considering the small series of patients studied, no firm conclusion can be drawn. Until proper evidence is provided devices claiming to stimulate the vagus nerve transcutaneously should be preferred to more invasive techniques. Due to the lack of evidence, VNS should only be employed in chronic headache sufferers using a randomized, placebo controlled trial design. Currently some RCTs are ongoing to validate this therapeutic approach to chronic headaches (NCT01667250, NCT01701245). ## Transcranial direct current stimulation (tdcs) theoretical background Recent progress in transcranial neurostimulation techniques has been used to approach the treatment of chronic therapy resistant headache. In particular transcranial direct current stimulation (tDCS) applied through the skull has been shown to directly modulate the excitability of cortical areas, best investigated for human motor (for a review see: [bib_ref] Transcranial direct current stimulation update, Nitsche [/bib_ref] and visual (for a review see: [bib_ref] Electrical stimulation and visual network plasticity, Antal [/bib_ref] cortices. tDCS induces both acute and persistent neuronal excitability changes in the cortex, probably by shifting neuronal resting membrane potential and hereby modulating the spontaneous discharge rates of cortical neurons [bib_ref] The Action of Brief Polarizing Currents on the Cerebral Cortex of the..., Bindman [/bib_ref] [bib_ref] Effects of repetitive transcranial magnetic stimulation on visual evoked potentials in migraine, Bohotin [/bib_ref] [bib_ref] A systematic review on reporting and assessment of adverse effects associated with..., Brunoni [/bib_ref] [bib_ref] Influence of transcortical d-c currents on cortical neuronal activity, Creutzfeldt [/bib_ref]. The after-effects of tDCS are most easily studied at the primary motor cortex (M1) by measuring the amplitude changes of the motor evoked potentials (MEP) using transcranial magnetic stimulation (TMS) [bib_ref] Excitability changes induced in the human motor cortex by weak transcranial direct..., Nitsche [/bib_ref]. A minimal duration of 3 minutes and at least 0.4 mA stimulation intensity is necessary to induce cortical excitability changes outlasting the stimulation duration [bib_ref] Excitability changes induced in the human motor cortex by weak transcranial direct..., Nitsche [/bib_ref] [bib_ref] Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans, Nitsche [/bib_ref]. At rest, cathodal stimulation induces a decrease and anodal stimulation an increase of cortical excitability. The effect of tDCS origins intracortically; pharmacological studies have shown that the effects during stimulation are mediated by ionchannels, in accordance with a primary hyper-or depolarizing effect of the stimulation, while after-effects involve the modulation of N-methyl-D-aspartate-(NMDA) receptor efficacy [bib_ref] Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor..., Liebetanz [/bib_ref]. ## Clinical data Using tDCS as a treatment for chronic headaches only data on treatment of orofacial pain [bib_ref] A case of refractory orofacial pain treated by transcranial direct current stimulation..., Antal [/bib_ref] and migraine are available. Based on a concept of cortical hyperexcitability in migraine cathodal tDCS in migraineurs is expected to normalize the cortical excitability either (i) by prophylactic treatment in the interictal phase or (ii) by an acute treatment at the beginning of the migraine attack. So far three studies evaluated the effect of repeated application of tDCS as a prophylactic treatment. Antal et al. [bib_ref] Cathodal transcranial direct current stimulation of the visual cortex in the prophylactic..., Antal [/bib_ref] has investigated cathodal stimulation of the primary visual cortex (V1). 30 patients were randomly assigned to cathodal or to sham stimulation. 26 patients participated in the final analyses (cathodal: 13, sham: 13). Compared to the sham group, only the intensity of the pain was significantly reduced after verum stimulation. Auvichayapat [bib_ref] Migraine prophylaxis by anodal transcranial direct current stimulation, a randomized, placebo-controlled trial, Auvichayapat [/bib_ref] and coworkers have investigated 42 episodic migraine patients, that were randomized to receive either active or sham stimulation on a daily basis for 20 consecutive days. The results showed statistically significant reduction in attack frequency and abortive medications at week 4 and 8 after treatment. The pain intensity was statistically significant reduced at week 4, 8, and 12. In the third study [bib_ref] ) tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic..., Dasilva [/bib_ref] thirteen patients with CM were randomized to receive 10 sessions of anodal (n=8) or sham (n=5) tDCS for 20 minutes over 4 weeks. There was a significant interaction term for the pain intensity and for the length of migraine episodes. Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only (delayed response). Phase III studies are still missing as well as data in the acute migraine phase or at the beginning of the aura. Similarly, there are no data available concerning other type of headaches, such as cluster and tension-type headache. ## Safety and adverse effects Amongst transcranial stimulation device-based interventions, tDCS is generally considered to be easier to blind than TMS [bib_ref] Repetitive transcranial magnetic stimulation or transcranial direct current stimulation?, Priori [/bib_ref]. The type of stimulation cannot be judged by an outside observer and it is easily applicable. By far the most widely reported phenomenon associated with the application of both active and sham tDCS stimulation is the itching or tingling sensation under the electrode [bib_ref] A systematic review on reporting and assessment of adverse effects associated with..., Brunoni [/bib_ref] [bib_ref] Cathodal transcranial direct current stimulation of the visual cortex in the prophylactic..., Antal [/bib_ref] [bib_ref] Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients, Poreisz [/bib_ref]. Other, less frequently reported phenomena associated with the stimulation are burning sensations, headache, redness of skin, nausea and light flashes at the beginning and the end of the stimulation [bib_ref] The fade-in-short stimulation-fade out approach to sham tDCS-reliable at 1 mA for..., Ambrus [/bib_ref]. It was recently reported that cutaneous perception does not completely disappear in the first phase of the stimulation as previously reported but never quantitatively assessed [bib_ref] The fade-in-short stimulation-fade out approach to sham tDCS-reliable at 1 mA for..., Ambrus [/bib_ref]. Nevertheless, in naive and even in experienced participants, no significant differences in the levels of perceived stimulation strength could be observed between sham and verum stimulation, thus the ramping upshort stimulation (30 sec)ramping down method might be a reliable approach to blinding in tDCS research, at least when using stimulation intensity below 1 mA [bib_ref] The fade-in-short stimulation-fade out approach to sham tDCS-reliable at 1 mA for..., Ambrus [/bib_ref]. ## Technical considerations Aftereffects of tDCS are NMDA receptor dependent [bib_ref] Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor..., Liebetanz [/bib_ref]. Patients on NMDA receptor antagonists, e.g. on dextromethorphan, an anticoughing drug, might not benefit from both anodal and cathodal tDCS. Sodium channel blocking agents such as carbamazepine and calcium channel blocking agents selectively prevent anodal tDCS aftereffects [bib_ref] Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation..., Nitsche [/bib_ref]. Flunarizine as a calcium antagonist is used in some countries for migraine prophylaxis. Also propranolol shortens both cathodal and anodal aftereffects [bib_ref] Catecholaminergic consolidation of motor cortical neuroplasticity in humans, Nitsche [/bib_ref]. Rarely safety issues play a role [bib_ref] The fade-in-short stimulation-fade out approach to sham tDCS-reliable at 1 mA for..., Ambrus [/bib_ref] [bib_ref] Safety criteria for transcranial direct current stimulation (tDCS) in humans, Nitsche [/bib_ref] ; e.g. no metal should be implanted in the head. Precautious exclusion of patients with previous history of brain surgery is warranted due to higher current density if the electrode is closer than 2 cm to a skull deficit. Neurological disorders such as stroke or epilepsy, drug/alcohol dependence, major psychiatric co-morbidities and implanted pacemaker may be seen as an exclusion criterion. There is probably no risk for women in child-bearing age without contraception, women during pregnancy and lactation to be expected, if both electrodes are fixed at the skull, however no data exist on that. It would be prudent to exclude this group from stimulation. ## Limitations and recommendation for future studies Cathodal V1 stimulation pursues the concept of inhibition of a hyperexcitable visual cortex [bib_ref] Cathodal transcranial direct current stimulation of the visual cortex in the prophylactic..., Antal [/bib_ref] whereas anodal M1 stimulation pursues the concept of M1 excitation for reduction of pain perception [bib_ref] Migraine prophylaxis by anodal transcranial direct current stimulation, a randomized, placebo-controlled trial, Auvichayapat [/bib_ref] [bib_ref] ) tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic..., Dasilva [/bib_ref]. Stimulation protocols will be further optimized in future. Repeated applications of the stimulation are probably necessary, testing different intensities and stimulation paradigms. For practical use and for longer lasting studies stimulators that can be used at home should be available. It appears to be mandatory for controlled studies that the subjects or patients are asked after the stimulation if they believe to be in the verum or placebo group. Similarly, it is important to document the expectation of the patients with regard to the stimulation outcome in order to be able to better estimate placebo effects. RCT's on other chronic primary headaches are also warranted. ## Repetitive transcranial magnetic stimulation (rtms) theoretical background Introduced by Barker et al. [bib_ref] Non-invasive magnetic stimulation of human motor cortex, Barker [/bib_ref] , transcranial magnetic stimulation (TMS) is a neurostimulation tool able to perform painless cerebral stimulation through application of magnetic fields on the scalp. The magnetic current passes through the scalp and generates a perpendicular electrical current that flows tangentially to cortex generating action potentials in cortical neurons. If given in repeated pulses, rTMS can determine long lasting plastic effects that remain also after the end of the train and depend on the stimulation frequency used: frequencies ≤1 Hz (low-frequency rTMS: LF-rTMS) reducing, while frequencies >1 Hz (high-frequency rTMS: HF-rTMS) increasing cortical excitability [bib_ref] Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models, Thickbroom [/bib_ref] [bib_ref] Magnetic flimmers: 'light in the electromagnetic darkness, Martens [/bib_ref]. TMS has been employed in two different ways in migraine, either to treat the single attack or prevent its occurrence. Different approaches were done, in consideration of mechanisms subtending the occurrence of migraine and the development into chronic form [bib_ref] Is the cerebral cortex hyperexcitable or hyperresponsive in migraine, Coppola [/bib_ref] [bib_ref] Abnormal changes of synaptic excitability in migraine with aura, Siniatchkin [/bib_ref] [bib_ref] Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine, Brighina [/bib_ref] [bib_ref] Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology, Bernstein [/bib_ref] [bib_ref] Interictal dysfunction of a brainstem descending modulatory center in migraine patients, Moulton [/bib_ref]. ## Clinical data Single pulse trans-cranial magnetic stimulation of the occipital cortex, was employed by a portable apparatus, to be tested in migraine with aura attacks in a double blind sham controlled study, involving a total of 164 patients and showed a significant effect of verum over sham treatment [bib_ref] Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a..., Lipton [/bib_ref]. Brighina et al. first [bib_ref] rTMS of the prefrontal cortex in the treatment of chronic migraine: a..., Brighina [/bib_ref] evaluated the efficacy and tolerability of HF-rTMS over the left Dorsolateral Prefrontal Cortex (DLPFC), (an area known for its top-down control on nociceptive transmission [bib_ref] Keeping pain out of mind: the role of the dorsolateral prefrontal cortex..., Lorenz [/bib_ref] for preventive treatment in patients affected by chronic refractory migraine. Patients were randomly assigned to active, real (6 patients) or placebo sham (5 patients) rTMS treatment consisting of 12 stimulation session delivered on alternate days. As compared to baseline and sham rTMS, active treatment reduced migraine attacks (about 57% less), drug consumption, headache index, and migraine disability scores) in the month during and following stimulation. Misra et al. [bib_ref] Is β endorphin related to migraine headache and its relief?, Misra [/bib_ref] used HF-rTMS of motor cortex (another area able to exert control on pain mechanisms [bib_ref] Assessment and treatment of pain with non-invasive cortical stimulation, Zaghi [/bib_ref] for prophylactic treatment in patients with episodic and chronic migraine; authors explored also the relationship between migraine pain and β endorphin plasma levels. The results demonstrated the ability of M1 rTMS to significantly reducing headache frequency (about 85% less at 1 st week after stimulation), headache severity, functional disability and analgesic intake. ## Safety and side effects TMS and rTMS are generally well tolerated and safe as only minor side effects like transient mild headache or local pain and paresthesias are reported [bib_ref] Transcranial magnetic stimulation for migraine: a safety review, Dodick [/bib_ref]. However, the procedure is to be avoided in patient with skull defect or with pacemaker, cardiac lines, metal in the head (electrodes, stimulation devices) or other apparatus that could be influenced (dislocation, induction of electric currents) by magnetic field. Caution should be paid in patient with epilepsy, because a risk (even if really low!) for seizure is reported. No side effect has been reported in pregnant women treated with HF-rTMS for refractory depression, though [bib_ref] The management of mood disorders in pregnancy: alternatives to antidepressants, Richards [/bib_ref] ; however, giving the lack of enough evidence, rTMS is not recommended in such condition [bib_ref] The management of mood disorders in pregnancy: alternatives to antidepressants, Richards [/bib_ref]. ## Technical considerations Paradoxical effects to rTMS (facilitation to inhibitory LF-rTMS or decremental response to facilitatory HF-rTMS) has been reported in patient with migraine [bib_ref] High-frequency transcranial magnetic stimulation on motor cortex of patients affected by migraine..., Brighina [/bib_ref] [bib_ref] Abnormal facilitatory mechanisms in motor cortex of migraine with aura, Brighina [/bib_ref] [bib_ref] Lack of effects of low frequency repetitive transcranial magnetic stimulation on alpha..., De Tommaso [/bib_ref] [bib_ref] Induction of long-lasting changes of visual cortex excitability by five daily sessions..., Fumal [/bib_ref]. Moreover, effects of rTMS can be consistently modulated (influenced) by several drugs (expecially antiepileptics like topiramate and valproate) employed in migraine prophylaxis. These factors should be taken into account when planning and/or interpreting results of stimulation trials. ## Limitations and recommendation for future studies Considering the few trials performed and the small series of patients studied, no firm conclusion can be drawn by these studies and it is uncertain whether the effect is acute, preventive or both. rTMS appears to be a safe [bib_ref] Transcranial magnetic stimulation for migraine: a safety review, Dodick [/bib_ref] and potentially effective tool for treatment of chronic migraine patients who showed resistance to pharmacological treatments [bib_ref] Advances and challenges in neurostimulation for headaches, Magis [/bib_ref]. Further studies are needed to assess factors underlying therapeutic effects (change in cortical excitability, better antinociceptive control, both?). It's also to seek for optimal stimulation parameters (intensity, frequency, number and duration of stimulation sessions). Another important point may be the best cortical areas to be modulated for pain control in migraine, and the most efficacy side of stimulation, though the left side has been more frequently employed in studies on pain control [bib_ref] Effects of high-frequency repetitive transcranial magnetic stimulation of primary motor cortex on..., De Tommaso [/bib_ref]. Particularly useful would be the generation of stimulation devices that patients can use at home. ## Transcutaneous stimulation of cranial nerves and tens theoretical background Transcutaneous electrical stimulation techniques have a long tradition in chronic pain management. These techniques are rather inexpensive and non-invasive, but the evidence for their effectiveness is overall of low quality [bib_ref] Transcutaneous electrical nerve stimulation (TENS) for chronic pain, Nnoaham [/bib_ref]. There are limited data on the use of electric current to stimulate cutaneous nerves (transcutaneous electrical nerve stimulation or TENS) or specific cranial nerves (supraorbital and supratrochlear) nerve stimulation (tSNS) in the treatment of headache disorders. The restrictive definition of TENS is the administration by surface electrodes of electric current produced by a device to stimulate cutaneous sensory nerves to reduce pain, both acute and chronic. Indeed, TENS treatment targets painful regions (or acupoints in electroacupuncture) instead of specific nerves. Based on the stimulation frequency, TENS can be subdivided in low frequency (frequency <10 Hz) or high frequency (frequency >10 Hz). As the biological basis of analgesia by TENS remains speculative, the 'gate control theory' of pain is the most tenable explanation but release of endogenous opiates could be involved [bib_ref] Effect of low-and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in..., Han [/bib_ref]. ## Clinical data tens and tsns tens Several meta-analyses on the efficacy of TENS in painful disorders have yielded ambiguous or negative results mainly due to inadequate methodology and/or reporting [bib_ref] Transcutaneous electrical nerve stimulation (TENS) for chronic pain, Nnoaham [/bib_ref] [bib_ref] Transcutaneous electrical nerve stimulation for acute pain, Walsh [/bib_ref] [bib_ref] Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults, Hurlow [/bib_ref] [bib_ref] Transcutaneous electrical nerve stimulation (TENS) versus placebo for chronic low-back pain, Khadilkar [/bib_ref] [bib_ref] Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain..., Dubinsky [/bib_ref]. TENS treatment for headache disorders appeared in the literature as early as 1975 [bib_ref] Transcutaneous nerve stimulation for the treatment of migraine and other head pain..., Appenzeller [/bib_ref]. Acute effects of TENS have been suggested in a study from Solomon and Guglielmo published in 1985. Sixty-two patients with migraine or "muscle contraction headache", who experienced a headache at the time of their visit, were divided into 3 different groups receiving either full high frequency-low intensity TENS, subliminal stimulation or placebo stimulation for 15 min once resulting in a significant but usually slight to moderate improvement in pain severity immediately after the intervention [bib_ref] Treatment of headache by transcutaneous electrical stimulation, Solomon [/bib_ref]. A Cochrane review from 2004 concluded that the use of TENS for chronic/recurrent headache (including migraine, tension-type headache, cervicogenic headache and post-traumatic headache) prophylaxis is not supported by conclusive evidence [bib_ref] Non-invasive physical treatments for chronic/recurrent headache, Bronfort [/bib_ref] , and ever since very little original trial data have been generated. In a recent trial, the efficacy of intermittent low frequency-high intensity TENS administered to the temporal and occipital region for a total of 10 weeks was compared to the preventative effect of 50 mg imipramine per day for 3 months in a sample of 138 patients with chronic tension-type headache [bib_ref] Comparison between efficacy of imipramine and transcutaneous electrical nerve stimulation in the..., Mousavi [/bib_ref]. After 3 months compared to the baseline, the headache intensity on the VAS score showed a significant decrease in both approaches with a numerically higher reduction in the imipramine group. Although the sample size was relatively large, a placebo arm was not included and use of the VAS score as a primary outcome is questionable. ## Tsns A recent Belgian multi-centric randomized controlled trial on the efficacy of transcutaneous supraorbital (and supratrochlear) nerve stimulation (tSNS) in episodic migraine, the PREMICE study, included 67 patients in the final analysis [bib_ref] Prevention of migraine by supraorbital transcutaneous neurostimulation using the Cefaly device (PREMICE):..., Schoenen [/bib_ref]. A significant decrease of 2.06 headache days per month was observed in the group receiving full stimulation (p=0.023) compared with only 0.32 days in the sham group (p=0.608) [bib_ref] Prevention of migraine by supraorbital transcutaneous neurostimulation using the Cefaly device (PREMICE):..., Schoenen [/bib_ref]. The comparison between both groups missed significance by a narrow margin (p=0.054). The 50% responder rate was significantly higher in the verum (38.1%) than in the sham (12.1%) group (p=0.023). However, the observed effects were only moderate and despite a number of precautions by the investigators unblinding may have occurred as effective stimulation induces marked paresthesias [bib_ref] Prevention of migraine by supraorbital transcutaneous neurostimulation using the Cefaly device (PREMICE):..., Schoenen [/bib_ref]. Therefore, assessment of unblinding should be mandatory for future neurostimulation studies. ## Safety and side effects High frequency TENS delivered at low intensities is associated with paraesthesia over the area of stimulation, and low frequency TENS delivered at high intensities is associated with a sharp flicking sensation or even muscle contractions. These sensations hamper proper blinding in controlled trials. ## Technical considerations Effective blinding with feasible sham paradigms is still an unresolved issue in transcutaneous stimulation of cranial nerves and TENS making large-scale studies difficult. In addition, stimulation parameters differ widely in TENS studies and consensus settings for clinical studies are missing. ## Limitations and recommendation for future studies The methodology in headache studies differs profoundly and a convincing sham paradigm has not been established. At present there is insufficient evidence for the use of TENS in headache prophylaxis and to abort an acute headache. Lack of evidence of effect is however different from evidence of lack of effect [bib_ref] Transcutaneous electrical nerve stimulation (TENS) for chronic pain, Nnoaham [/bib_ref]. So far, a single study provided Class III evidence that migraine attacks can be prevented with tSNS, but the effect size was small, unblinding may have occurred. The effects of tSNS on very frequent or chronic migraine are unknown, and refractory patients were excluded. Widespread use outside of controlled studies of this potentially valuable treatment modality cannot be endorsed at present [bib_ref] Prevention of migraine by supraorbital transcutaneous neurostimulation using the Cefaly device (PREMICE):..., Schoenen [/bib_ref]. ## Spinal cord stimulation theoretical background The Occipital Nerve Stimulation (ONS) technique takes advantage of the "functional overlap" of the higher cervical roots and the trigeminal nucleus to neuromodulate, in a retrograde fashion, the trigemino-cervical complex [bib_ref] Peripheral neuromodulation for migraine headache, Ellens [/bib_ref] [bib_ref] Neurobiology of migraine, Goadsby [/bib_ref]. However, it is a reasonable assumption that the application of electrical pulses directly onto the dorsal columns at the C2-C3 vertebral level will provide a neuromodulatory effect on the TCC similar toif not greater thanperipheral occipital nerves stimulation. Cervico-medullary spinal cord stimulation has been used for the last 30 years to alleviate intractable head and facial pain [bib_ref] Cervicomedullary Junction Spinal Cord Stimulation for Head and Facial Pain, Tomycz [/bib_ref] , but it requires a very costly, time consuming and complex neurosurgical procedure and the mode of action is unknown. ## Clinical data Performed in few specialised centres and in highly selected patients, and never in a controlled design, it is not a viable option for primary headaches. Recently, lowfrequency stimulation of the cervical spinal cord (C2-C3 level) has shown positive results in a case series of CCH patients implanted with a percutaneous cervical epidural lead [bib_ref] High cervical spinal cord stimulation for chronic cluster headache, Wolter [/bib_ref]. Authors reported a marked reduction in headache's frequency (−4.6 attacks per day), intensity (−2.9 on a VAS score) and duration (−27 minutes per attack) in 7 patients implanted. The procedure also facilitates a 4-19 days testing phase prior to permanent implant. However, this study was criticized [bib_ref] Concerning high cervical spinal cord stimulation for chronic cluster headache, Gaul [/bib_ref]. ## Safety and adverse effects Adverse effects such as lead migration, battery depletion and local infections are inherent in neuromodulatory approaches and have been reported in hypothalamic brain stimulation [bib_ref] Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable..., Leone [/bib_ref] [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref] [bib_ref] Hypothalamic stimulation for intractable cluster headache: long-term experience, Leone [/bib_ref] [bib_ref] Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster..., D'andrea [/bib_ref] [bib_ref] Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus,..., Benabid [/bib_ref] [bib_ref] Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and..., Starr [/bib_ref] [bib_ref] Connectivity of an effective hypothalamic surgical target for cluster headache, Owen [/bib_ref] [bib_ref] Two cases of chronic cluster headache treated successfully with hypothalamic deep brain..., Black [/bib_ref] [bib_ref] Deep brain stimulation in chronic refractory headaches: first national cases, Mateos [/bib_ref] [bib_ref] Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase..., Bartsch [/bib_ref] [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref] [bib_ref] Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster..., Leone [/bib_ref] [bib_ref] Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache, Maniyar [/bib_ref] , occipital nerve stimulation [bib_ref] Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache, Magis [/bib_ref] [bib_ref] Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study, Magis [/bib_ref] [bib_ref] Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study, Matharu [/bib_ref] , and stimulation of the sphenoid ganglion [bib_ref] Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and..., Schoenen [/bib_ref]. However, the rate reported in SCS of the cervical region seems exceedingly high [bib_ref] High cervical spinal cord stimulation for chronic cluster headache, Wolter [/bib_ref] [bib_ref] Concerning high cervical spinal cord stimulation for chronic cluster headache, Gaul [/bib_ref] and resulted in repetitive invasive procedures, mostly lead revision. Given that a dislocation of the lead is an inherent problem in spinal cord stimulation especially in parts of the spinal cord with high mobility such as the upper cervical spine, less invasive methods such as the occipital stimulation or SPG-stimulation should be preferred at least until ongoing studies (see below) are published. ## Technical considerations Different stimulation frequencies are now available (burst stimulation, 10 kHz high frequency stimulation) in SCS. Those provide a new alternative to peripheral (low-frequency) stimulation due to their ability to achieve pain relief without causing any perceived sensation but its efficacy and potential side effects are unknown. A double-blind, placebo design can now be considered when planning future randomized control trials of SCS in chronic, refractory headaches. ## Limitations and recommendation for future studies A "proof of concept" pilot study investigating the initial tolerability and efficacy of cervical high-frequency SCS in the treatment of refractory CM is under way (NCT01653340) and preliminary results are expected by the end of 2013. Until proper evidence is provided the present expert group recommends that spinal cord stimulation is strictly avoided in patients with primary headache syndromes. ## Conclusion and general recommendation The purpose of this position paper, as a result of the collaboration of an multidisciplinary Expert Group on Neurostimulation of the European Headache Federation, is to give an assessment and recommendation for the use of the currently available neuromodulation devices in headache treatment. This overview is based on the scientific level obtained through controlled studies, on existing clinical practice, directly related side effects and overall safety. Because the available data regarding the various stimulation approaches are so scarce and variable, this recommendation is also based on the definition of a clinically significant improvement. In 2008, recommendations put forth by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) panel and the IHS established a 30% reduction in pain as clinically meaningful [bib_ref] Mere surgery will not cure cluster headache: implications for neurostimulation, Hidding [/bib_ref] [bib_ref] Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster..., Seijo [/bib_ref]. The authors of this recommendation feel that this minimal requirement is only sufficient in otherwise medically intractable chronic patients, otherwise a 50% reduction in pain should be acquired. Prevention of headache days is certainly the single most clinically relevant item in medical intractable patients and the most important reason why these patients seek therapy. However, clinical trial assessments should not be limited to the degree of pain relief or headache days because this alone may not be necessary for a clinically meaningful improvement, but should include tolerability, reductions in headache-related disability, improvement in pain-specific quality of life, total costs and improvement in functional capacity. Unfortunately, regarding these outcome parameters even less data exists for neurostimulation devices in headache treatment. For all of the above mentioned methods and devices, the following recommendations are uniquely effective and have to be seen as the basic qualification and requirement which may be additional to the specific recommendations for each method as outlines in the respective chapter. 1) From a medical standpoint, the application of a neurostimulator, either in a trial or on the basis of a CE mark treatment, should be considered only once all alternative drug and behavioural therapies as recommended by international guidelines have failed and medication overuse headache is excluded. 2) This involves that the patient is considered chronic, following the current IHS definition [bib_ref] Acute hypothalamic stimulation and ongoing cluster headache attacks, Leone [/bib_ref] and have been evaluated at a tertiary care headache center. 3) This involves that the patient is considered medically intractable as defined by international consensus [bib_ref] Towards a definition of intractable headache for use in clinical practice and..., Goadsby [/bib_ref]. 4) Non-invasive medical technologies should be considered prior to implantation of a neurostimulator and the least invasive and most effective treatment should always be first line therapy. Given the heterogeneous data in terms of patient numbers, inclusion requirements, headache diagnosis, statistical methods and completeness of data in published studies, the authors cannot unequivocally give a ranking of neurostimulation methods. The global evaluation leads to the following ad interim conclusion: 1) In CCH it is advisable to use SPG [bib_ref] Expert Consensus Recommendations for the Performance of Peripheral Nerve Blocks for Headaches..., Blumenfeld [/bib_ref] [bib_ref] Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches, Ansarinia [/bib_ref] or ONS [bib_ref] PRISM study: occipital nerve stimulation for treatment-refractory migraine, Lipton [/bib_ref] [bib_ref] Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches:..., Reed [/bib_ref] , before considering DBS. Although the treatment effects seem clinically equal, the side effects of the more invasive DBS treatment are to be considered [bib_ref] Effect of deep brain stimulation of the posterior hypothalamic area on the..., Cortelli [/bib_ref] In CM the use of ONS seems acceptable although based on limited evidence. Application of the noninvasive tVNS, tDCS, rTMS, TENS and tSNS in chronic headaches are not yet evidence based, given the poor amount of controlled data. However, it needs to be mentioned that these devices are relatively harmless when compared to more invasive and costly neurostimulation devices and may be tried before using more invasive neurostimulation devices. The authors note that therapeutic neurostimulation in headache and pain is a fast evolving field and that no recommendations can be given using the methodological arsenal of evidence based medicine. One of the reasons is the limited use of a proper placebo condition or sham control and randomized sham and subthreshold stimulation was included only in the SPG study on acute Cluster headache. While sham is in principle available in central neuromodulation (DBS) [bib_ref] Safety and efficacy of deep brain stimulation in refractory cluster headache: a..., Fontaine [/bib_ref] it is nearly impossible in peripheral neuromodulation devices, given that peripheral nerve stimulation is always perceived. However, we recommend that proper done controlled and randomized studies are required before a given neurostimulation device is implemented and clinically used. A CE-mark is not equivalent to a randomized study following IHS requirements, as no clinical data supporting the benefit of a medical device are needed to acquire the CE mark, but only data showing that the respective device is probably harmless. The authors suggest the following recommendations for clinical trial involving neurostimulation devices in headache treatment: ## 1) trials investigating invasive neurostimulator devices should only involve patients who are considered chronic, following the current IHS definition. If a given method proved efficacy in the chronic state, follow-up studies may broaden the indication to severely disabling episodic states, if medically not sufficiently treatable. 2) Trials investigating neurostimulator devices should only involve patients who are not suffering from medication overuse headache and are considered medically intractable as defined by international consensus [bib_ref] Towards a definition of intractable headache for use in clinical practice and..., Goadsby [/bib_ref]. 3) Clinical trial assessments should have the primary endpoint of the degree of pain relief or reduction in headache days. Next to adverse events, secondary endpoints should include reductions in headacherelated disability, improvement in pain-specific quality of life and improvement in functional capacity. In summary, neurostimulation should only be considered in patients that have tried all first-line therapies recommended in European guidelines [bib_ref] Task Force EFNS (2006) EFNS guidelines on the treatment of cluster headache..., May [/bib_ref] , and that both pain and headache clinicians need to follow international consensus on that matter [bib_ref] Towards a definition of intractable headache for use in clinical practice and..., Goadsby [/bib_ref] [bib_ref] Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection, Leone [/bib_ref]. The greatest limitation for clinical use is the lack of proper controlled studies [bib_ref] A six year retrospective review of occipital nerve stimulation practice -controversies and..., Palmisani [/bib_ref]. Consequently, any devices that have not been investigated in such controlled studies and have shown to be effective with an acceptable side effect profile should not be used at all. The authors note that it is inherent to neurostimulation devices, perhaps with the only exception of DBS so far, to lack a proper placebo condition. Most available trials actually used infrathreshold stimulation intensities as controls, but blinding in patients perceiving no or few sensations may be difficult to maintain. It is crucial to recruit neurostimulation naïve patients for future trials, but as a recent editorial suggested this will be an increasing challenge due to the negative role of the social media (Internet blogs, Facebook etc.) [bib_ref] Analysis of occipital nerve stimulation in studies of chronic migraine and broader..., Goadsby [/bib_ref]. International guidelines, preferably agreed between the IHS and EHF how to conduct such studies are clearly warranted. ## Competing interests The following Authors declared competing interests related to the contents of this manuscript: RA received travel grants and consulting fees from Medtronic, Boston Scientific, Nevro Corporation and St Jude Medical.DF received travel grants or consulting fees from Boston Scientific and St Jude Medical. RHJ have lectured for Pfizer, Berlin-Chemie, Allergan, Merck, has received consulting fees from Autonomic Technologies Inc, Medotech, and Linde Gas, is member of advisory boards of Autonomic Technologies Inc, Medotech, Neurocore, and Linde Gas. TPJ received honoraria as speaker and consulting fees from Autonomic Technologies, Inc. PM received travel grants, consulting fees or unrestricted grants from Nevro Corporation, St Jude Medical, Allergan, Pfizer, ACRAF, Springer, is member of Advisory Board in Allergan. AM is or has been consultant or speaker for Pfizer, Bayer Vital, GSK, Allergan, ATI, MSD, and Desitin. He has received unrestricted grant support from LindeGas and Almirall. KP has received a travel grant from Medtronic and a research grant provided by Autonomic Technologies Inc. SP received travel grants from Medtronic and Nevro Corp. WP received consulting fees from EBS Technologies. Other Authors declared no competing interests.	None	https://thejournalofheadacheandpain.biomedcentral.com/counter/pdf/10.1186/1129-2377-14-86	None
d1343c17ba44a005b9f89e47c91d8b0e5d798504	pubmed	Diabetic Foot Australia guideline on footwear for people with diabetes	Diabetic Foot Australia guideline on footwear for people with diabetes Background: The aim of this paper was to create an updated Australian guideline on footwear for people with diabetes. Methods: We reviewed new footwear publications, (inter)national guidelines, and consensus expert opinion alongside the 2013 Australian footwear guideline to formulate updated recommendations. Result: We recommend health professionals managing people with diabetes should: (1) Advise people with diabetes to wear footwear that fits, protects and accommodates the shape of their feet. (2) Advise people with diabetes to always wear socks within their footwear, in order to reduce shear and friction. (3) Educate people with diabetes, their relatives and caregivers on the importance of wearing appropriate footwear to prevent foot ulceration. (4) Instruct people with diabetes at intermediate-or high-risk of foot ulceration to obtain footwear from an appropriately trained professional to ensure it fits, protects and accommodates the shape of their feet.(5)Motivate people with diabetes at intermediate-or high-risk of foot ulceration to wear their footwear at all times, both indoors and outdoors. (6) Motivate people with diabetes at intermediate-or high-risk of foot ulceration (or their relatives and caregivers) to check their footwear, each time before wearing, to ensure that there are no foreign objects in, or penetrating, the footwear; and check their feet, each time their footwear is removed, to ensure there are no signs of abnormal pressure, trauma or ulceration. (7) For people with a foot deformity or pre-ulcerative lesion, consider prescribing medical grade footwear, which may include custom-made in-shoe orthoses or insoles. (8) For people with a healed plantar foot ulcer, prescribe medical grade footwear with custom-made in-shoe orthoses or insoles with a demonstrated plantar pressure relieving effect at high-risk areas. (9) Review prescribed footwear every three months to ensure it still fits adequately, protects, and supports the foot. (10) For people with a plantar diabetic foot ulcer, footwear is not specifically recommended for treatment; prescribe appropriate offloading devices to heal these ulcers. Conclusions: This guideline contains 10 key recommendations to guide health professionals in selecting the most appropriate footwear to meet the specific foot risk needs of an individual with diabetes. # Background Diabetic foot ulcers are a costly complication of diabetes, reducing people's quality of life, and increasing morbidity, mortality and healthcare expenditure [bib_ref] Cost of diabetic foot disease to the National Health Service in England, Kerr [/bib_ref] [bib_ref] Health-related quality of life of diabetic foot ulcer patients and their caregivers, Nabuurs-Franssen [/bib_ref] [bib_ref] The global burden of diabetic foot disease, Boulton [/bib_ref] [bib_ref] The impact of foot ulceration and amputation on mortality in diabetic patients...., Jupiter [/bib_ref]. The annual incidence of foot ulcers in people with diabetes is approximately 2%, both globally [bib_ref] The global burden of diabetic foot disease, Boulton [/bib_ref] and in Australia [bib_ref] Foot complications in type 2 diabetes: an Australian population-based study, Tapp [/bib_ref] , and the lifetime risk is between 19% and 34% [bib_ref] Diabetic foot ulcers and their recurrence, Armstrong [/bib_ref]. Additionally, diabetic foot ulcers are the leading cause of lower extremity amputations and cause approximately 2% of all hospitalisations . Therefore, the prevention of diabetic foot ulcers is of paramount importance. Diabetic foot ulcers are typically caused by repetitive stresses (shear and pressure) on the foot in the presence of the diabetes-related complications of peripheral neuropathy or peripheral artery disease, and their healing is often complicated by the development of infection [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] Systematic review and individual patient data meta-analysis of prognostic factors for foot..., Crawford [/bib_ref] [bib_ref] Predictive factors for diabetic foot ulceration: a systematic review, Monteiro-Soares [/bib_ref] [bib_ref] Diabetic foot working group, Queensland statewide diabetes clinical network (Australia). Incidence and..., Jia [/bib_ref]. Use of inappropriate footwear or walking barefoot typically increases the magnitude of the local mechanical repetitive stresses on the foot that are leading causes of the development of diabetic foot ulceration [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] Systematic review and individual patient data meta-analysis of prognostic factors for foot..., Crawford [/bib_ref] [bib_ref] Predictive factors for diabetic foot ulceration: a systematic review, Monteiro-Soares [/bib_ref]. Thus, it is recommended that people with diabetes wear appropriate footwear designed to reduce repetitive stresses at all times, to help prevent diabetic foot ulceration [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref]. In 2013, the Australian Diabetes Foot Network published one of the first nationwide practical guidelines on the provision of footwear for people with diabetes [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref]. Since this publication, pivotal new studies [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] International working group on the diabetic foot. Footwear and offloading interventions to..., Bus [/bib_ref] [bib_ref] The effectiveness of footwear as an intervention to prevent or to reduce..., Healy [/bib_ref] [bib_ref] Pressure-relieving interventions for treating diabetic foot ulcers, Lewis [/bib_ref] [bib_ref] Comparison of the clinical effectiveness of different off-loading devices for the treatment..., Morona [/bib_ref] [bib_ref] Effectiveness of insoles used for the prevention of ulceration in the neuropathic..., Paton [/bib_ref] [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL..., Ulbrecht [/bib_ref] [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] Offloading effect of therapeutic footwear in patients with diabetic neuropathy at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a..., Waaijman [/bib_ref] [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref] and international guidelines [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] have been published on footwear for people with diabetes. This new literature provides a stronger evidence-base for the effectiveness of footwear in ulcer prevention for people with diabetes, new data-driven directions for the prescription of footwear, and new evidence on the importance of adherence to wearing footwear [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] International working group on the diabetic foot. Footwear and offloading interventions to..., Bus [/bib_ref] [bib_ref] The effectiveness of footwear as an intervention to prevent or to reduce..., Healy [/bib_ref] [bib_ref] Pressure-relieving interventions for treating diabetic foot ulcers, Lewis [/bib_ref] [bib_ref] Comparison of the clinical effectiveness of different off-loading devices for the treatment..., Morona [/bib_ref] [bib_ref] Effectiveness of insoles used for the prevention of ulceration in the neuropathic..., Paton [/bib_ref] [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL..., Ulbrecht [/bib_ref] [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] Offloading effect of therapeutic footwear in patients with diabetic neuropathy at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a..., Waaijman [/bib_ref] [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref]. The aim of this article is to update the 2013 Australian practical guideline [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] , and thereby creating a new Diabetic Foot Australia guideline on footwear for people with diabetes. # Methods ## Procedure for developing the guideline The Diabetic Foot Australia guideline on footwear for people with diabetes aims to provide guidance to the multidisciplinary healthcare professionals involved in the provision of footwear for people with diabetes. The Australian Diabetes Foot Network 2013 practical guideline on the provision of footwear [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] was used as a baseline for the creation of this updated guideline. Information from the 2013 footwear guideline was updated first by the primary author after reviewing and incorporating any new footwear-related recommendations from the most recent Australian National Health and Medical Research Council (NHMRC) diabetic foot guidelineand the International Working Group on the Diabetic Foot (IWGDF) guidance documents [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref]. The primary author then reviewed and incorporated common findings from all recent systematic reviews on footwear interventions for people with diabetes [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] International working group on the diabetic foot. Footwear and offloading interventions to..., Bus [/bib_ref] [bib_ref] The effectiveness of footwear as an intervention to prevent or to reduce..., Healy [/bib_ref] [bib_ref] Pressure-relieving interventions for treating diabetic foot ulcers, Lewis [/bib_ref] [bib_ref] Comparison of the clinical effectiveness of different off-loading devices for the treatment..., Morona [/bib_ref] [bib_ref] Effectiveness of insoles used for the prevention of ulceration in the neuropathic..., Paton [/bib_ref] , recent randomized controlled trials included in these reviews [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL..., Ulbrecht [/bib_ref] , and finally any further studies obtained from hand searching reference lists of these articles and an additional non-systematic search of the literature [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] Offloading effect of therapeutic footwear in patients with diabetic neuropathy at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a..., Waaijman [/bib_ref] [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref]. After collating all findings, three tables and one figure were created describing footwear requirements and offloading effects of footwear modifications to prevent diabetic foot ulceration, based on published literature [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref] [bib_ref] The biomechanics and clinical efficacy of footwear adapted with rocker profiles-evidence in..., Hutchins [/bib_ref] and expert opinion. Furthermore, to ensure a common and clear vocabulary between all the different multidisciplinary healthcare professionals involved in the provision of footwear for people with diabetes [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] , a table of definitions for common terms related to footwear for people with diabetes was developed based on literature [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref] and expert opinion [fig_ref] Table 1: List of definitions related to footwear for people with diabetes Term DefinitionAbnormal... [/fig_ref]. The first draft of this guideline was written by the first author (JvN), and then sent to two co-authors (PAL and PW) for critical review and expert opinion. A second draft incorporating consensus feedback from the three authors was sent to all authors for critical review and expert opinion feedback. The authors of this guideline, all (inter)national experts in the field of diabetic foot ulcer and footwear management, came from the following backgrounds: podiatric medicine (n = 5), podiatric surgery (n = 1), human movement science (n = 2), wound medicine (n = 2), pedorthics (n = 1), rehabilitation medicine (n = 1), endocrinology (n = 1), and vascular surgery (n = 1). A third draft incorporating feedback from all coauthors was written by the first author (JvN) and again sent to all co-authors for review. This process was repeated one more time, until consensus was reached from all authors, leading to the final version of the guideline, approved by all authors. ## Definitions for foot risk status The purchase and wearing of appropriate footwear is an important process of care for all individuals with diabetes. This importance increases as the individual's risk for developing a foot ulcer increases. Different classifications for foot risk status are used worldwide. For the purpose of this Australian footwear guideline we followed the classification provided in the Australian NHMRC guideline: (i) Low-risk of foot ulceration: people with no identifiable risk factors on foot screening (no peripheral neuropathy, peripheral artery disease, foot deformity, previous foot ulcer, or history of lower-extremity amputation). Custom-made footwear Synonym for "Custom-made medical grade footwear". Custom-made insole An insole that is custom-made to the individual's foot using a 2D or 3D impression of the foot, and that is often built-up in a multi-layer construction. This may also incorporate other features, such as a metatarsal pad or metatarsal bar. The insole is designed to conform to the shape of the foot, providing cushioning and redistribution of plantar pressure. Custom-made medical grade footwear Footwear uniquely manufactured for one person, when this person cannot be safely accommodated in pre-fabricated medical grade footwear. It is made to accommodate deformity and relieve pressure over at-risk sites on the plantar and dorsal surfaces of the foot. In-depth assessment, multiple measurements, impressions or a mould, and a positive model of a person's foot and ankle are generally required for manufacture. Customised insole Term to denote a pre-fabricated insole to which minor modifications specific to a person's foot may have been made. This term is not synonymous with "Custom-made insole". Depth-inlay footwear Synonym for Extra-depth footwear. Depth footwear Synonym for Extra-depth footwear. Extra-depth footwear Footwear constructed with additional depth and volume in order to accommodate deformity such as claw/hammer toes and/or to allow for space for a thick insole. Usually a minimum of 5 mm (~3/16″) depth is added compared to pre-fabricated footwear. Even greater depth is sometimes provided in footwear that is referred to as double depth or super extra-depth. Footwear modification Modification to existing footwear with an intended therapeutic effect, e.g. pressure relief. In-shoe orthosis/orthotic Term used for device put inside the shoe to achieve pressure reduction or alteration in the function of the foot. Can be pre-fabricated or custom-made. Liner Synonym for insole. Medical grade footwear Footwear that meets the specific needs of a person. Can be either pre-fabricated (see "Pre-fabricated medical grade footwear") or custom-made (see "Custom-made medical grade footwear"). Metatarsal pad Small pad placed proximal to the metatarsal head to relieve focal pressure and transfer load more proximally. ## Metatarsal bar Bar extending across part of or the entire forefoot placed proximal to the metatarsal heads to relieve focal pressures and transfer load more proximally. Off-the-shelf footwear Readily available footwear that has not been modified and has no intended therapeutic functions. Orthopaedic footwear Synonym for "Custom-made medical grade footwear". Pedorthic footwear Synonym for "Medical grade footwear". Can be either pre-fabricated (in that case synonym for "Pre-fabricated medical grade footwear") or custom-made (in that case synonym for "Custom-made medical grade footwear"). Pedorthic footwear modification Synonym for "Footwear modification". Pre-fabricated medical grade footwear Pre-fabricated footwear that meets the specific needs of a person, on the basis of footwear that provides extra depth, multiple width fittings and features designed to accommodate a broader range of foot types. Other features may include modified soles, fastenings and smooth internal linings. This type of footwear is usually available at specialty shoe shops. ## Pre-fabricated insole An "off-the-shelf" flat or contoured insole made without reference to the shape of the patient's foot. ## Shoe insert Synonym for insole or in-shoe orthosis. Shoe last Last used to make footwear. The upper of the footwear is moulded or pulled over the last. The last shape defines the footwear shape including the outsole shape, heel pitch and toe spring. For off-the-shelf or pre-fabricated footwear generically generated lasts in different sizes are used. Therapeutic footwear Generic term for footwear that is designed to allow some form of treatment. May refer to both custom-made or pre-fabricated medical grade footwear. Toe orthosis Synonym for "In-shoe orthosis", but specifically for the toe. Several healthcare disciplines may be involved in the provision of footwear for people with diabetes. Having a common vocabulary is essential for clear communication. We propose to use the following definitions, obtained from [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref] and authors' expert opinion (ii) Intermediate-risk of foot ulceration: people with only one risk factor on foot screening (either peripheral neuropathy, peripheral artery disease or foot deformity) and no previous foot ulcer or amputation. (iii) High-risk of foot ulceration: people with two or three risk factors on foot screening (peripheral neuropathy, peripheral artery disease or foot deformity) or with a previous foot ulcer or amputation. According to the NHMRC guideline, Aboriginal and Torres Strait Islander people with diabetes are considered to be at high-risk for foot ulceration, until the person's level of risk is adequately assessed and confirmed otherwise. To determine foot risk status, all people with diabetes should undergo at least a yearly foot screening by an appropriately trained registered healthcare professional with demonstrated competency [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref]. People with an intermediate-or high-risk foot status should be screened at least once every 3 to 6 months [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref]. In accordance with the NHMRC guideline, this should consist of screening for peripheral neuropathy (10 g monofilament sensitivity; vibration perception; neuropathy disability score), peripheral artery disease (palpation of peripheral pulses; ankle-brachial pressure index; toe-brachial pressure index), foot deformity (six point scale scoring small muscle wasting, Charcot foot deformity, bony prominence, prominent metatarsal head, hammer or claw toes and limited joint mobility), and assessment of a history of foot ulcer(s) or lower-extremity amputation. The Australian Diabetes Society has published a videoexample of such a foot examination. ## Structure of the guideline This guideline consists of three parts and a discussion. Firstly, footwear recommendations and their rationale are provided for people at-risk of foot ulceration; These recommendations apply to people at low-, intermediate-or high-risk. Secondly, additional specific footwear recommendations and their rationale are provided for people at intermediate-or high-risk of foot ulceration. Thirdly, footwear and offloading recommendations for people with a diabetic foot ulcer are summarised. Finally, considerations on footwear provision, on education and adherence, on cultural and geographical differences, and on methodology and terminology are discussed. # Results This guideline contains 10 key recommendations to guide health professionals managing people with diabetes choosing the most appropriate footwear for the person's specific foot risk needs [fig_ref] Table 2: Recommendations on footwear for people with diabetes [/fig_ref]. The recommendations and their rationale are described separately in this section. Footwear for people with diabetes at-risk of foot ulceration Recommendation 1: Advise people with diabetes to wear footwear that fits, protects and accommodates the shape of their feet. ## Rationale People with diabetes should wear footwear that fits, protects and accommodates the shape of their feet [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] (see and [fig_ref] Figure 1: Footwear features [/fig_ref]. This includes having adequate length, width, and depth (and consequently adequate girth, i.e. adequate volume) [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. A particular emphasis may need to be placed on the toe box of the shoe that should be consistent with the shape of the forefoot and toes of the person. An enclosed heel with a stabilising heel counter is recommended. Openheel footwear can result in direct trauma injury to the heel and may require a person to claw their toes in order to keep the footwear fixed to their feet, further increasing the repetitive stress under their forefoot, and in turn the risk of ulceration. Adequate closure of the footwear is needed, to prevent the foot from sliding forwards and Requirements for footwear for people with diabetes Feature Requirements ## Length Inner length of the footwear should be 1-2 cm longer than the foot length as measured from heel to the longest toe when a person is standing. Adequate length needs to be confirmed when people are weight-bearing while wearing the footwear. ## Depth Depth should accommodate the toes to move freely without causing pressure at either the medial, lateral or the dorsal side. ## Width Width should equal the width of all parts of the foot. Width is good when the upper can be slightly bunched. The relation between forefoot and hindfoot is important, as accommodating a wide forefoot may result in the heel being too wide. ## Height Footwear height can be low, ankle-high, or high. High footwear provides more firmness, stability and reduces joint motion. The shaft of high footwear also contributes to forefoot pressure reduction. See further for specific height requirements for people with a foot deformity. ## Insole The removable moulded insole can be pre-fabricated, adjusted or custom-made. The primary function of the insole is pressure redistribution. This is achieved via the principle of increasing the contact area between the foot and the insole, and the addition of corrective elements in the insole. Shock-absorbing, soft but sufficiently resilient and non-slippery materials should be used. See further [fig_ref] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/fig_ref] for the offloading effects of specific insole modifications. Outsole Rubber, plastic, and leather can all be used in construction of footwear outsoles, but rubber outsoles are thought to be superior. Outsoles can be supple, toughened or stiff. The shoe should not be more supple than the foot, or friction between foot and shoe will develop during push-off. See further for specific outsole requirements for people with a foot deformity and [fig_ref] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/fig_ref] for the offloading effects of specific modifications. Rocker profile Rocker profiles have proven effectiveness in reducing plantar pressures, especially the forefoot. The rocker profile chosen depends on the affected joints and is determined by the apex position (pivot point) and the angle from the pivot point to the tip of the toe. For plantar pressure reduction of the metatarsophalangeal joints, the pivot point needs to be proximal to these joints. The rocker profile also impacts balance; the more proximally placed, the greater the balance disturbance. A person's balance should therefore always be taken into account when deciding on the rocker profile. Heel enclosure An adequately fitting and enclosed heel is recommended, as open backed footwear or a heel enclosure that is too wide can result in injury and usually requires a person to claw their toes in order to keep them on. The heel counter needs to be free of edges protruding into the footwear. ## Heel lift The heel lift (or heel-forefoot difference, or pitch) should be generally 1.5-2 cm, and should not exceed 3 cm. ## Closure Adequate closure (or fixation) is needed to keep the foot from sliding forward. Closure should allow secure longer-term fastening and individual adjustment. Laces have long been considered the optimal choice; however, alternatives that are easier to use while still meeting these criteria are available as well, and innovative closures continue to be developed. ## Uppers The uppers consist of the 'quarter'(hindand midfoot) and 'vamp' (forefoot and toes). Uppers should be made from leather or a combination of materials (similar to sports shoes), with smooth inner lining made from a material that does not harden over time, with limited seams and preferably no seams in the vamp area as they reduce the ability of the leather to give. Uppers should be breathable and durable and have the ability to mould to deformities of the foot without resulting in pressure areas. Uppers can be supple, toughened or stiff. The vamp area should generally remain supple to accommodate the toes. See further for specific requirements for the uppers (quarter) for people with a foot deformity. ## Toe box The part of the shoe that covers and protects the toes. This should be supple (unless specific requirements (e.g. for building professionals) require otherwise), and should accommodate the shape of the toes, to avoid any rubbing on the toes. [fig_ref] Figure 1: Footwear features [/fig_ref] thus causing shear injury to the toes or plantar foot [bib_ref] Lace up for healthy feet: the impact of shoe closure on plantar..., Rahemi [/bib_ref]. All features in should be considered in combination, as their intended function is closely related and changes to one feature may affect other features and overall function [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. People at low-risk of foot ulceration can usually be safely accommodated in a wide range of off-the-shelf footwear without specific requirements, provided the footwear is correctly fitted and appropriate for the activity to be undertaken [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. For people at intermediate-or high-risk of foot ulceration, see recommendations 4-9. When new footwear is provided to a person with diabetes at low-risk of foot ulceration, advise them that a "wear-in" period may be needed where they slowly increase the number of hours per day the footwear is used, and that they should be extra vigilant of their foot health in this period. ## Recommendation 2: Advise people with diabetes to always wear socks within their footwear, in order to reduce shear and friction. ## Rationale People with diabetes should be advised to always wear socks within their footwear, to reduce shear and friction. Further, advise people with diabetes to wear socks made of mostly natural materials (to prevent undue moisture accumulation), that are seamless (to prevent undue repetitive stresses) and do not have elasticated cuffs (to prevent undue oedema). ## Recommendation 3: Educate people with diabetes, their relatives and caregivers on the importance of wearing appropriate footwear to prevent foot ulceration. ## Rationale People with diabetes, their relatives and caregivers should also be educated on the importance of appropriate footwear to prevent foot ulceration, and the importance of adherence to wearing it [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref]. Also, the importance of annual foot screens to assess their risk of foot ulceration, and to return for further footwear advice if their foot risk status increases should be emphasised [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref]. Instruct people with diabetes at intermediate-or highrisk of foot ulceration to obtain footwear from an appropriately trained professional to ensure it fits, protects and accommodates the shape of their feet. ## Rationale People with only one risk factor identified after foot screening (either peripheral neuropathy, peripheral artery disease, or foot deformity) are at intermediaterisk of foot ulceration, whereas people with two or three risk factors (peripheral neuropathy, peripheral artery disease or foot deformity) or with a previous foot ulcer or amputation are at high-risk of foot ulceration. People who develop diabetic peripheral neuropathy lose protective sensation and their ability to feel pressure and pain. Thus, they may have a tendency to purchase poorly fitting footwear in an attempt to stimulate some sensory feedback [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] [bib_ref] Therapeutic footwear for people with diabetes, Cavanagh [/bib_ref]. They also do not feel abnormally high repetitive stress (pressure or shear) caused by inappropriate footwear or walking barefoot and are more likely to develop pre-ulcerative lesions (e.g. callus or blisters) that subsequently lead to ulceration [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] Predictive factors for diabetic foot ulceration: a systematic review, Monteiro-Soares [/bib_ref]. People with peripheral artery disease are less likely to heal pre- ulcerative lesions or minor trauma due to inadequate perfusion, and as such need to avoid inappropriate footwear that may cause these situations. A foot deformity changes foot biomechanics and may lead to abnormally high repetitive stresses; high plantar pressure in particular increases the risk of foot ulceration and therefore needs to be accommodated. People with a previous foot ulcer are at high-risk of developing a new ulcer, with reported re-ulceration rates of 40-50% within the first 12 months after healing [bib_ref] Diabetic foot ulcers and their recurrence, Armstrong [/bib_ref] [bib_ref] Recurrent and other new foot ulcers after healed plantar forefoot diabetic ulcer, Orneholm [/bib_ref]. Due to the high re-ulceration rates it is recommended that the term 'diabetic foot remission' is used with patients whose ulcer has healed, to highlight the need for ongoing vigilance to prevent ulcer recurrence [bib_ref] Diabetic foot ulcers and their recurrence, Armstrong [/bib_ref] [bib_ref] Coming events cast their shadows before: detecting inflammation in the acute diabetic..., Bharara [/bib_ref] [bib_ref] Toward a change in syntax in diabetic foot care: prevention equals remission, Armstrong [/bib_ref] [bib_ref] Shift in priority in diabetic foot care and research: 75% of foot..., Bus [/bib_ref]. All people at intermediate-or high-risk of foot ulceration should be instructed to wear footwear that fits, protects and accommodates the shape of their foot and [fig_ref] Figure 1: Footwear features [/fig_ref]. Due to the complexities in accommodating the foot and the importance of preventing foot ulceration, people with diabetes should be instructed to obtain their footwear from an appropriately trained professional with demonstrated competencies in footwear fitting for this population, to ensure the footwear meets all requirements. ## Recommendation 5: Motivate people with diabetes at intermediate-or highrisk of foot ulceration to wear their footwear at all times, both indoors and outdoors. ## Rationale Because of their increased risk, people with diabetes at intermediate-or high-risk of foot ulceration should be motivated to wear their footwear at all times, both indoors and outdoors. When doing so, be aware that adherence to wearing footwear is significantly lower indoors compared to outdoors [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref] , while the majority of steps in these patient groups have been shown to be taken indoors [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref] [bib_ref] Monitoring location-specific physical activity via integration of Accelerometry and Geotechnology within patients..., Crews [/bib_ref]. Depending on cultural preference, prescribing suitable footwear for outdoors and a second pair for indoors may be advisable. The indoor footwear should meet the same requirements with regard to adequacy of fit and offloading, but compromises might be made in the materials used in manufacture, as it is likely to experience less "wear-and-tear" compared to footwear used outdoor. See further the considerations on education and adherence. ## Recommendation 6: Motivate people with diabetes at intermediate-or highrisk of foot ulceration (or their relatives and caregivers) to check their: a. footwear, each time before wearing, to ensure that there are no foreign objects in the footwear or penetrating the soles. b. feet, each time their footwear is removed, to ensure that there are no signs of abnormal pressure, trauma or ulceration. ## Rationale People with peripheral neuropathy have lost the ability to feel pressure, pain or foreign objects. They, or their relatives and caregivers, need to be motivated to check their footwear each time before they are put on, to ensure that there are no foreign objects in the footwear or penetrating the soles. Furthermore, they should also check their feet each time their footwear is removed, to ensure that there are no signs of abnormal pressure, shear, trauma or ulceration. People should be advised to immediately seek help from an appropriately trained professional when their footwear is damaged or when signs of abnormal pressure, shear, trauma or ulceration on their feet are found. ## Recommendation 7: For people with a foot deformity or pre-ulcerative lesion, consider prescribing medical grade footwear, which may include custom-made in-shoe orthoses or insoles. ## Rationale When a foot deformity, pre-ulcerative lesion is present, off-the-shelf footwear is not likely to be appropriate. Prescribing medical grade footwear (pre-fabricated or custom-made; [fig_ref] Table 1: List of definitions related to footwear for people with diabetes Term DefinitionAbnormal... [/fig_ref] needs to be considered, to accommodate the altered biomechanics. This medicalgrade footwear may also include custom-made in-shoe orthoses or insoles. Depending on the foot deformity present or the location of the pre-ulcerative lesion, the footwear requirements algorithms for prescription [fig_ref] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/fig_ref] and footwear modifications [fig_ref] Table 5: Plantar pressure reducing offloading effects of insole and footwear modifications Med [/fig_ref] should be followed [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. The outsole, uppers and tongue can be "supple", "toughened", and "stiff" [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. Toughened or stiff features facilitate the even distribution of forces exerted on the foot; unfortunately, no measurable definition of these is available [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. ## Recommendation 8: For people with a healed plantar foot ulcer, prescribe medical grade footwear with custom-made in-shoe orthoses or insoles with a demonstrated plantar pressure relieving effect at the high-risk areas. ## Rationale For people with a healed plantar foot ulcer, off-the-shelf footwear is most unlikely to be sufficient. Medical grade footwear (pre-fabricated or custom-made; [fig_ref] Table 1: List of definitions related to footwear for people with diabetes Term DefinitionAbnormal... [/fig_ref] with a demonstrated plantar pressure reducing effect at highrisk areas, including the previous ulcer location, needs to be prescribed. This medical-grade footwear should also include prescribed custom-made in-shoe orthoses or insoles to increase the plantar pressure reducing effect. Based on two recent randomised controlled trials, a 'demonstrated plantar pressure reducing effect' (combined effect of the new medical grade footwear with orthosis or insole) is defined as a > 30% reduction at the area of the highest plantar pressure in comparison to the same area in the patient's current footwear, or a level below 200 kPa if measured with a validated and calibrated system with a sensor area of 1 cm 2 [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL..., Ulbrecht [/bib_ref]. When such footwear is being worn by patients, the risk of re-ulceration is smaller [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref]. Again depending on the location of the previous ulcer and presence (or absence) of a foot deformity and high-risk areas, follow the footwear requirements algorithms for prescription [fig_ref] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/fig_ref] and footwear modifications [fig_ref] Table 5: Plantar pressure reducing offloading effects of insole and footwear modifications Med [/fig_ref] , with additional options provided by orthoses [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref]. The recommendation of prescribing footwear with a demonstrated plantar pressure reducing effect is in line with strong recommendations from the IWGDF guidelines [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] , but has yet to be implemented widely in clinical practice in Australia. Different systems with different validity and reliability are available to quantify in-shoe plantar pressure [bib_ref] Validity and repeatability of three in-shoe pressure measurement systems, Price [/bib_ref]. We encourage services to invest in regular plantar The uppers consist of quarter and vamp, the requirements here concern the quarters, as the vamp typically needs to remain supple to accommodate the toes (see further [fig_ref] Table 2: Recommendations on footwear for people with diabetes [/fig_ref] pressure measurement protocols in daily clinical practice for people with diabetes and a healed plantar foot ulcer, and implementing the algorithms outlined in [fig_ref] Table 5: Plantar pressure reducing offloading effects of insole and footwear modifications Med [/fig_ref]. ## Recommendation 9: Review prescribed footwear every three months to ensure it still fits, protects, and supports the foot. ## Rationale Both the foot and the footwear change shape over time. Prescribed footwear, and custom-made orthoses or insoles, should be reviewed every three months to ensure it still fits, protects and supports the foot. This threemonth interval is recommended based on the randomised controlled trial by Bus and colleagues, who used a three-month interval to ensure prescribed footwear remained appropriate, on expert opinion from seeing wear and tear in footwear in daily clinical practice, and aligns with the regular foot-screening interval for people at intermediate-or high-risk of foot ulceration as recommended in the NHMRC guideline [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref]. For people with a healed plantar foot ulcer who have been prescribed medical grade footwear with a demonstrated plantar pressure relieving effect, this effect still needs to be present for the footwear to be considered appropriate. Based on the findings from the trial by Bus and colleagues [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] , ongoing research into its implementation in daily clinical practice and expert opinion, we suggest a three-to six-month interval for reviewing and demonstrating the plantar pressure relieving effect with validated equipment. Footwear for people with diabetic foot ulceration Recommendation 10: For people with a plantar diabetic foot ulcer, footwear is not specifically recommended for treatment; prescribe appropriate offloading devices to heal these ulcers. ## Rationale Footwear is not specifically recommended to treat a plantar diabetic foot ulcer in the IWGDF guidelines; in contrast offloading devices are recommended and necessary to heal these ulcers [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref]. We strongly recommend that any health professional treating a patient with a plantar diabetic foot ulcer ensures their patient has an appropriate offloading device. The most strongly recommended devices in the NHMRC guideline and IWGDF guidance documents are non-removable knee-high devices, such as a total contact cast or removable cast walker made irremovable [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref]. Only when knee-high devices are contraindicated or not tolerated by people with a diabetic foot ulcer should other offloading devices (such as forefoot offloading shoes and cast shoes), and lastly custom-made temporary footwear be considered [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref]. Footwear for the unaffected foot of a person with a diabetic foot ulcer should follow the recommendations and criteria applied to people at high-risk of foot ulceration. Additionally, any height-difference caused by an offloading device may need to be corrected by adjusting the footwear of the unaffected leg. This can be achieved with internal footwear modifications or with external devices that are applied to the bottom of the shoe of the unaffected leg. Prescribed footwear is needed once the ulcer is healed, again following the recommendations for people at highrisk of ulceration. When prescribed footwear cannot be made available immediately when the ulcer has healed, continuation in the offloading device meeting the offloading requirements is needed until the prescribed footwear becomes available (see further details under 'considerations on footwear provision'). # Discussion This new 2017 Diabetic Foot Australia footwear guideline has updated the 2013 Australian footwear guideline to reflect the best available evidence from contemporary studies investigating footwear interventions, international guidelines and expert opinion. We have formulated 10 key recommendations to guide health professionals in selecting the most appropriate footwear to meet the specific foot risk needs of an individual with diabetes [fig_ref] Table 2: Recommendations on footwear for people with diabetes [/fig_ref] , and provided the rationale behind these recommendations. In this discussion, we will add considerations on footwear provision, education and adherence, cultural and geographical differences, and methodology and terminology related to this guideline. These consideration provide further background with the recommendations, and discuss aspects relevant for implementation of the recommendations in daily clinical practice. ## Considerations on footwear provision When providing footwear to a person with diabetes, ensure they know their foot risk status and confirm this via an evidence-based screening by an appropriately trained healthcare professional. In addition to the foot screening, other factors that should be considered include the person's gait pattern, activity levels, occupation, level of mobility, living situation, cultural beliefs, personal goals, and preferences. These factors may influence the possible options for appropriate footwear. When providing footwear, measure the length, width, depth and girth of the foot the footwear needs to accommodate and ensure that the footwear follows the criteria in [fig_ref] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/fig_ref]. For length and width, we suggest at a minimum using a Brannock measuring device [bib_ref] Evaluation of the accuracy of shoe fitting in older people using three-dimensional..., Menz [/bib_ref]. Although new scanning devices are becoming available to measure foot shape, we still suggest depth requires clinical assessment until accuracy of these devices can be independently quantified, taking into account that people with peripheral neuropathy cannot feel whether depth is accurate. Evaluate the shoe fit with the person in standing position, preferably at the end of the day to ensure that any developing oedema is taken into account. Further considerations in relation to oedema are footwear height (high footwear may have a compression function), outdoor temperature, and changes in oedema treatment. The timing of footwear provision is important for any footwear that is not pre-fabricated. This becomes even more important when a person with diabetes at intermediate-or high-risk does not have appropriate footwear at a given moment. The longer a person needs to wait to receive appropriate footwear, the more steps they will take in inappropriate footwear, potentially increasing the repetitive stresses on the foot and in turn the risk for foot ulceration. Timing is most important for people with a recently healed plantar foot ulcer. Delivery of their prescribed footwear should be coordinated to a point as close to healing as possible. Ideally, the transition from an offloading device required to heal the ulcer to the preventative footwear is immediate. Any delay in this transition increases the risk of ulcer recurrence. When appropriate preventative footwear is not available for a person with a nearly healed foot ulcer, footwear prescription should be initiated before the ulcer is healed. Prescription can be initiated when foot shape (especially volume), structure and function are not expected to change during the healing process, and should take the manufacturing time-schedule into account. When prescribed footwear cannot be made available immediately when the ulcer has healed, continuation in the offloading device meeting the offloading requirements is needed until the prescribed footwear becomes available. Further, when new footwear is provided to a person with diabetes after healing a foot ulcer, advise them that a "wear-in" period may be needed where they alternate the new footwear with the offloading device that was required to heal the ulcer, and that they should be extra vigilant with checking of their foot health in this period. In Australia, various state-based schemes are available that may provide financial assistance to people with diabetes who require medical-grade footwear. However, these schemes change over time and discussion of the specific schemes is outside the scope of this guideline. ## Considerations on education and adherence to wearing footwear Early education on the importance of adequate footwear for foot health is important for all people with diabetes. This education needs to continue life-long, and needs to be expanded if a person's level of risk of foot ulceration increases. The importance of footwear for people with diabetes should be discussed in the context of the individual's foot risk status and health literacy [bib_ref] Meeting the educational needs of people at risk of diabetes-related amputation: a..., Johnson [/bib_ref]. Education should aim to increase people's understanding of the requirements of their footwear to adequately fit, protect and accommodate their feet. This may also include, but is not limited to, education on proper donning of the footwear, the importance of wearing socks in footwear to reduce shear and friction, and explaining the risks to foot health of inappropriate footwear such as slippers and sandals, of narrow heels, of heels higher than 3 cm, and of pointy, flat or hard toe boxes. Education should further focus on motivating people with diabetes at intermediate-or high-risk of foot ulceration to wear their footwear at all times. Footwear can only be effective when it is worn, and adherence to wearing footwear is an important factor in foot ulcer prevention [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref]. Achieving better adherence is a challenge, and unfortunately we found no intervention studies on the effect of interventions that aim to increase footwear adherence in people with diabetes [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] Shift in priority in diabetic foot care and research: 75% of foot..., Bus [/bib_ref]. However, we found a number of observational studies investigating reasons for (non-)adherence to footwear [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Meeting the educational needs of people at risk of diabetes-related amputation: a..., Johnson [/bib_ref] [bib_ref] Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes:..., Johnson [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref] [bib_ref] Use and usability of custom-made orthopedic shoes, Van Netten [/bib_ref] [bib_ref] Patients' expectations and actual use of custom-made orthopaedic shoes, Van Netten [/bib_ref]. An improvement in walking has been described as the most important footwear-related characteristic affecting adherence, while the importance of cosmetic appearance and ease of use varies greatly between people [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Use and usability of custom-made orthopedic shoes, Van Netten [/bib_ref]. Rather than focussing on footwear characteristics, it is suggested in various studies that personal perceptions, values and experiences are more important factors to improve adherence [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Meeting the educational needs of people at risk of diabetes-related amputation: a..., Johnson [/bib_ref] [bib_ref] Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes:..., Johnson [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref] [bib_ref] Use and usability of custom-made orthopedic shoes, Van Netten [/bib_ref] [bib_ref] Patients' expectations and actual use of custom-made orthopaedic shoes, Van Netten [/bib_ref]. A perceived benefit of footwear is associated with increased adherence to wearing the footwear [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] , and conversely, a lack of understanding of the need for footwear hinders adherence [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref]. Acceptance of the need for footwear is another important factor affecting adherence [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes:..., Johnson [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref]. This does not only concern accepting the need for footwear, but also acceptance of the person's underlying diabetic foot disease [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes:..., Johnson [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref]. Footwear has been described as a "visible representation of the disease", and people with diabetes at-risk of foot ulceration may choose to moderate their adherence to align with functional requirements and societal norms [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Patient and professional perspectives on prescribed therapeutic footwear for people with diabetes:..., Johnson [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref]. These personal values and experiences cannot be assessed using a standardised measurement device. Adequate communication between healthcare professionals and patients is needed to assess these perceptions [bib_ref] Meeting the educational needs of people at risk of diabetes-related amputation: a..., Johnson [/bib_ref]. For this communication to be effective, it should be person-centred, not footwear-centred [bib_ref] Meeting the educational needs of people at risk of diabetes-related amputation: a..., Johnson [/bib_ref]. Footwear is very personal, and this should be taken into account during education and communication to ensure maximum acceptance of and adherence with the footwear provided [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Patients' experience of therapeutic footwear whilst living at risk of neuropathic diabetic..., Paton [/bib_ref]. For people at intermediate-or high-risk of foot ulceration, the importance of adherence to wearing appropriate footwear both indoors and outdoors needs extra attention. People at risk of foot ulceration have been found to perform the majority of their total daily steps indoors [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref] [bib_ref] Monitoring location-specific physical activity via integration of Accelerometry and Geotechnology within patients..., Crews [/bib_ref] , while their adherence to wearing their footwear is significantly lower indoors compared to outdoors [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref]. To improve adherence, people may need to be made aware of the greater repetitive stresses on their feet when at home resulting from the greater number of steps. It has also been suggested to provide separate footwear for indoor and outdoor use [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref]. For people from cultures that may prefer not to wear 'normal' footwear indoors, it is suggested that health professionals consider providing indoor footwear that is manufactured to not look like 'normal' footwear, which may then be more acceptable to be worn indoors. ## Considerations on cultural and geographical differences In this guideline, we describe features and criteria for footwear for people with diabetes, and specific recommendations based on a person's foot ulcer risk following the NHMRC risk classification. Footwear is very personal and multiple other factors may need to be taken into account when providing footwear to a person with diabetes and ensuring this footwear is being used. We acknowledge the cultural differences in regard to footwear behaviour, specifically for Aboriginal and Torres Strait Islander people and from other diverse ethnic backgrounds. Furthermore, individuals in geographically rural and remote areas of Australia may have a limited range of footwear options available to them, and limited access to appropriately trained professionals. However, we decided not to provide specific recommendations for different cultures or for people living in rural and remote areas. The criteria and recommendations in this guideline are to be seen as the standards to be achieved, and these recommendations can be used by clinicians in their communications to discuss the footwear requirements for each person's situation. Specific circumstances may require that a compromise is made to the recommendations, which then may be considered to be better than no footwear at all. However, in our opinion, offering deviations from the standards in this guideline, without supporting evidence and solely based on specific cultural or geographical backgrounds of people, does not align with offering equality of best practice care for all people and may increase the risk of foot ulceration and will weaken this guideline. Rather, we encourage healthcare professionals to use this guideline to discuss footwear requirements with people with diabetes, to try and achieve, if needed, a compromise that is optimal for the person's situation that most closely aligns with the requirements and recommendations described in this guideline. ## Considerations on methodology and terminology We have based this update of the 2013 guideline on contemporary evidence-based guidelines [bib_ref] International Working Group on the Diabetic Foot. Prevention and management of foot..., Schaper [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on the prevention..., Bus [/bib_ref] [bib_ref] International working group on the diabetic foot. IWGDF guidance on footwear and..., Bus [/bib_ref] , scientific evidence from systematic reviews [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] International working group on the diabetic foot. Footwear and offloading interventions to..., Bus [/bib_ref] [bib_ref] The effectiveness of footwear as an intervention to prevent or to reduce..., Healy [/bib_ref] [bib_ref] Pressure-relieving interventions for treating diabetic foot ulcers, Lewis [/bib_ref] [bib_ref] Comparison of the clinical effectiveness of different off-loading devices for the treatment..., Morona [/bib_ref] [bib_ref] Effectiveness of insoles used for the prevention of ulceration in the neuropathic..., Paton [/bib_ref] , randomised controlled trials [bib_ref] Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter..., Bus [/bib_ref] [bib_ref] Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL..., Ulbrecht [/bib_ref] , observational studies [bib_ref] Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients, Waaijman [/bib_ref] [bib_ref] Data-driven directions for effective footwear provision for the high-risk diabetic foot, Arts [/bib_ref] [bib_ref] Perceived usability and use of custom-made footwear in diabetic patients at high..., Arts [/bib_ref] [bib_ref] Offloading effect of therapeutic footwear in patients with diabetic neuropathy at high..., Arts [/bib_ref] [bib_ref] What influences a patient's decision to use custom-made orthopaedic shoes?, Van Netten [/bib_ref] [bib_ref] Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a..., Waaijman [/bib_ref] [bib_ref] Adherence to wearing prescription custom-made footwear in patients with diabetes at high..., Waaijman [/bib_ref] [bib_ref] Development and evaluation of a tool for the assessment of footwear characteristics, Barton [/bib_ref] [bib_ref] Therapeutic footwear for the neuropathic foot: an algorithm, Dahmen [/bib_ref] [bib_ref] The biomechanics and clinical efficacy of footwear adapted with rocker profiles-evidence in..., Hutchins [/bib_ref] , and expert opinion, involving experts from eight different disciplines involved in the treatment of people with diabetic foot disease. However, this should not be looked upon as an evidence-based guideline, as we did not follow a specific guideline development methodology. Developing evidence-based guidelines is an extensive and costly process. With recent studies providing a much stronger evidence-base for footwear requirements for people with diabetes we felt that a new footwear guideline to update information in the NHMRC guidelineand the 2013 Australian practical guideline on footwear provision [bib_ref] Australian diabetes foot network: practical guideline on the provision of footwear for..., Bergin [/bib_ref] was more important than waiting for completion of a full evidence-based guideline. Compared to the recommendations from the 2013 guidelines, some have not changed, and a number of new ones have been added. These include the need for health professionals to prescribe medical grade footwear that has demonstrated plantar pressure reducing effects at high-risk plantar areas for those people with a healed plantar foot ulcer, to review the adequacy of any prescribed footwear every three months, and to treat a plantar foot ulcer primarily with appropriate offloading devices. With this current document, healthcare professionals can immediately start to implement the new footwear evidence to begin to further reduce the large national burden of diabetic foot disease. The specific footwear requirements are closely related to an individual's foot risk status. This means that to provide people with diabetes with appropriate footwear, their foot risk status must be assessed first. We followed the classification as provided in the NHMRC guideline. Other countries may use different risk classifications, and we advise healthcare professionals to ensure they use the guideline that is applicable in their own country with regard to foot risk status assessment. In this guideline, we did not separate between intermediate-and high-risk. The first reason for doing so was that some recommendations do not depend on foot risk status per se, but on the presence (or absence) of the specific risk factors of foot deformity or previously healed ulcer. To cover these differences, specific recommendations were needed that applied both to people at intermediateand high-risk. Further, combining both groups while including specifically targeted recommendations also gives healthcare professionals from other countries the opportunity to match the recommendations in this guideline with their own country's foot risk status classification system. Finally, the recommendations that did not target a specific risk factor were similar for people at intermediate-or high-risk, which means they could be combined. As recommended in this guideline, people at intermediate-or high-risk of foot ulceration should be instructed to obtain their footwear from an appropriately trained professional with demonstrated competencies in footwear fitting for people with diabetes. We have not defined 'appropriately trained' or 'demonstrated competencies' , as that was beyond the scope of the current document. However, as a minimum, we suggest an appropriately trained professional should be able to show documented evidence of their training and competency, and should meet the standards of their profession when such standards are available. This way, other healthcare professionals may confidently inform people with diabetes where to obtain their footwear. The methodology followed to write this guideline does have some limitations. The first, not following a guideline development methodology, has been discussed above. A second is that no patient advocates were involved in its creation. This is a consequence of not following a specific guideline methodology, and we hope that this will be done in the next update of the NHMRC guideline. A third is the limited evidence base with regard to the recommendations for people at low-risk of ulceration [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] [bib_ref] Shift in priority in diabetic foot care and research: 75% of foot..., Bus [/bib_ref]. These recommendations might be seen as "good practice statements", a terminology used in official guideline development for recommendations that are predominantly based on expert opinion and standard of practice, when limited evidence is available [bib_ref] Guideline panels should not GRADE good practice statements, Guyatt [/bib_ref]. As argued in other publications, it is hoped that researchers and healthcare providers combine efforts to build a stronger research evidence base for these recommendations [bib_ref] Shift in priority in diabetic foot care and research: 75% of foot..., Bus [/bib_ref]. Finally, we are unaware of cost-effectiveness information for any of the proposed footwear interventions [bib_ref] International working group on the diabetic foot. Prevention of foot ulcers in..., Van Netten [/bib_ref] , and thus no such specific information can be added to this guideline. However, a recent Australian cost-effectiveness analysis reported appropriately prescribed footwear as part of a suite of optimal diabetic foot care practice was always cheaper than standard care, and with the high costs associated with foot ulceration [bib_ref] Cost of diabetic foot disease to the National Health Service in England, Kerr [/bib_ref] [bib_ref] A cost-effectiveness analysis of optimal care for diabetic foot ulcers in Australia, Cheng [/bib_ref] [bib_ref] Diabetes foot disease: the Cinderella of Australian diabetes management?, Lazzarini [/bib_ref] , it is likely that preventative footwear efforts in this regard will be cost-saving [bib_ref] Shift in priority in diabetic foot care and research: 75% of foot..., Bus [/bib_ref]. # Conclusion Appropriate footwear is important for all people with diabetes, to prevent foot ulceration and reduce the burden of diabetic foot disease. This guideline contains 10 key recommendations to guide health professionals managing people with diabetes choosing the most appropriate footwear for the person's specific foot risk needs. We hope that this guideline will be used to ensure that all Australians with diabetes have access to, and are provided with, appropriate footwear to meet their needs. This should improve footwear practice in Australia, and reduce the burden of diabetic foot disease for people and the nation. [fig] Figure 1: Footwear features. SeeTable 2for a description of the requirements of these features van Netten et al. Journal of Foot and Ankle Research (2018) 11:2 [/fig] [table] Table 1: List of definitions related to footwear for people with diabetes Term DefinitionAbnormal foot shape A foot shape that cannot be accommodated in pre-fabricated footwear. This includes, but is not limited to, feet with: hallux valgus, clawed/hammer toes, severe pes-planus or cavus foot type, abnormally wide feet, flat foot, minor amputation or Charcot foot. [/table] [table] Table 2: Recommendations on footwear for people with diabetes [/table] [table] Table 5: Plantar pressure reducing offloading effects of insole and footwear modifications Med. medial, Lat. lateral. This table is based on[25] For the blank cells in the matrix, there is either not enough information available, or pressure reduction was not statistically significant, or pressure increased; these modifications are therefore not recommended for these regions of interest [/table] [table] Table 4: Specific footwear requirements for people with diabetes and a foot deformity [/table]	None	https://jfootankleres.biomedcentral.com/track/pdf/10.1186/s13047-017-0244-z	None
4f0201c5e827a161c03280095762a89f079111f6	pubmed	Cutaneous Lyme borreliosis: Guideline of the German Dermatology Society	Cutaneous Lyme borreliosis: Guideline of the German Dermatology Society This guideline of the German Dermatology Society primarily focuses on the diagnosis and treatment of cutaneous manifestations of Lyme bor-Heidelore Hofmann 1 Volker Fingerle 2 reliosis. It has received consensus from 22 German medical societies Klaus-Peter Hunfeld 3 and 2 German patient organisations. It is the first part of an AWMF Hans-Iko Huppertz 4 (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.) interdisciplinary guideline: "Lyme Borreliosis -Diagnosis and Treatment, development stage S3". The guideline is directed at physicians in private practices and clinics who treat Lyme borreliosis. Objectives of this guideline are recommen-Bernhard Ruf 7 dations for confirming a clinical diagnosis, recommendations for a stage-Consensus grouprelated laboratory diagnosis (serological detection of IgM and IgG Borrelia antibodies using the 2-tiered ELISA/immunoblot process, sensible ## Klinik für dermatologie und Allergologie der TU München, München, Germany use of molecular diagnostic and culture procedures) and recommendations for the treatment of the localised, early-stage infection (erythema migrans, erythema chronicum migrans, and borrelial lymphocytoma), the disseminated early-stage infection (multiple erythemata migrantia, [bib_ref] Epidemiological aspects and molecular characterization of Borrelia burgdorferi s.l. from southern Germany..., Fingerle [/bib_ref] Bayerisches Landesamt für Gesundheit und flu-like symptoms) and treatment of the late-stage infection (acro-Lebensmittelsicherheit (LGL) Oberschleißheim, Germany dermatitis chronica atrophicans with and without neurological manifestations). In addition, an information sheet for patients containing recommendations for the prevention of Lyme borreliosis is attached to the guideline. Ziel der Leitlinie ist es, Empfehlungen zur Absicherung der klinischen Diagnosen, Empfehlungen zur stadiengerechten Labordiagnostik (serologischer Nachweis von IgM-und IgG-Borrelienantikörpern mit dem 2-Stufenverfahren ELISA/Immunoblot sowie der sinnvolle Einsatz molekulardiagnostischer und kultureller Verfahren) und Empfehlungen zur Therapie der lokalisierten Frühmanifestationen (Erythema migrans, Erythema chronicum migrans und Borrelienlymphozytom), zur Therapie der disseminierten Frühmanifestationen (Multiple Erythemata migrantia und/oder grippeartige Symptomatik nach Zeckenstich) und zur Therapie der Spätmanifestationen (Acrodermatitis chronica atrophicans mit und ohne neurologische Manifestationen) zu geben. Außerdem werden Empfehlungen für Patienten zur Prävention der Lyme-Borreliose und zur Nachbeobachtung eines Zeckenstiches formuliert. # Introduction The infectious disease most frequently transmitted by ticks in Europe is Lyme borreliosis. The Borrelia are transferred to the skin during the blood sucking process of the hard-bodied tick Ixodes ricinus. There the Borrelia are either killed off by the (unspecific, innate) immune system, or a localised infection occurs which leads to illness in only a small percentage of those infected. Most often there is an inflammation of the skin, typically in the form of an erythema migrans or, seldom, as borrelial lymphocytoma. In the course of the infection the Borrelia can disseminate and attack various organs. They primarily affect the skin, joints and nervous system. Acrodermatitis chronica atrophicans can develop as a chronic or late-form of skin manifestation. ## Target group This guideline is directed at physicians in private practices and clinics who treat Lyme borreliosis. ## Objectives of this guideline # Methods This guideline is based on an update of AWMF Guideline No. 013-044 "Cutaneous Manifestations of Lyme Borreliosis", development stage S1, which was created by a committee of experts in 2009. The guideline was created in accordance with the methodological requirements of the Association of the Scientific Medical Societies in Germany (AWMF) for developing and further developing diagnosis and treatment guidelines. It is an S2k guideline in accordance with the AWMF's three-stage concept. The composition of the guideline group was interdisciplinary (IDA) and the appointed mandate holders of the expert medical societies were informed of the scheduled update on 11/2/2014. Uniform formulations are used in order to standardise the recommendations of the guideline. The following gradations shall apply here: - Strong recommendation: "shall" - Recommendation: "should" - Open recommendation: "may be considered" - Recommendation against an intervention: "should not" - Strong recommendation against an intervention: "shall not" : Seroprevalence of B. burgdorferi antibodies in Germany. KIGGS and DEGS studies [bib_ref] Antibodies against Borrelia burgdorferi sensu lato among Adults, Wilking [/bib_ref] 3 Epidemiology Lyme borreliosis mainly exists between the 40 th and 60 th parallels of the northern hemisphere in line with the presence of its vectors. Few relevant epidemiological investigations have been conducted in Europe. A population-based study in southern Sweden reveals an incidence of 69 per 100,000 inhabitants [bib_ref] An epidemiologic study of Lyme disease in southern Sweden, Berglund [/bib_ref]. In a prospective, population-based study of the region around Würzburg over a 12 month period, 313 cases of Lyme borreliosis were reported, which corresponds to an incidence of 111 per 100,000 inhabitants. In terms of early manifestations, a localised erythema migrans was diagnosed in 89% of the cases and a disseminated erythema migrans in a further 3% of cases. Borrelial lymphocytoma was established in 2% of cases, early-stage neuroborreliosis in 3%, and carditis in <1%. In terms of late-stage forms of the disease, Lyme arthritis appeared in 5% of patients and acrodermatitis chronica atrophicans in 1%. No chronic neuroborreliosis was detected. Currently nine states in Germany have an obligation to report acute manifestations of Lyme borreliosis (see Annex 4 in Attachment 1). Epidemiological data obtained through this partial obligation to report are only based on the clearly diagnosable manifestations, such as erythema migrans, acute neuroborreliosis and acute Lyme arthritis. Thus, it can be assumed that the rate of incidence is considerably underreported [bib_ref] Epidemiological situation of Lyme borreliosis in germany: surveillance data from six Eastern..., Fülöp [/bib_ref] ,. Secondary data analyses of health insurance data based on the ICD 10 coding A 69.2 (G) result in much higher rates of incidence [bib_ref] Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany:..., Müller [/bib_ref]. Therefore, it can be concluded that the epidemiological data currently available is not sufficient for a definitive clarification. Data published up until now in Germany indicates the incidence of Lyme borreliosis to be somewhere between 60,000 to >200,000 cases per year. In a major nation-wide seroprevalence study of children (KIGGS) and adults (DEGGS) it was shown that the percentage of Borrelia-specific antibodies in serum increases with increasing age of the population and already has an incidence rate of 7% in the group of 14 to 17 year olds. In adults, this percentage of Borrelia antibodies is even higher. In the group of 70 to 79 year olds, 24.5% of men and 16.4% of women are seropositive [bib_ref] Antibodies against Borrelia burgdorferi sensu lato among Adults, Wilking [/bib_ref]. A prospective investigation of the incidence of Lyme borreliosis in Finland and southern Sweden (2008-2009) revealed that 78 (5%) of the 1,546 people bitten by a tick had a Borrelia burgdorferi infection. In 45 of the cases (3%) only a seroconversion occurred; 33 (2%) resulted in illness. Erythema migrans was diagnosed in 28 people, one person had borrelial lymphocytoma, two people had an acute case of neuroborreliosis and 2 had unspecified symptoms which were diagnosed as Lyme borreliosis [bib_ref] A prospective study on the incidence of Borrelia burgdorferi sensu lato infection..., Wilhelmsson [/bib_ref]. ## Transmission routes B. burgdorferi is transmitted to birds, mammals and humans from hard-bodied ticks of the I. ricinus/I. persulcatus spp. complex during the blood meal. In Europe this transmission is primarily from I. ricinus, in Asia from I. persulcatus and in the USA predominantly from I. scapularis. Ticks suck blood in the course of their cycle of development from larva to nymph to adult tick, and before they lay eggs. It is at this time that they can acquire and/or transmit Borrelia. Small rodents -particularly mice -and birds are the main reservoirs. Birds contribute to the geographical propagation of the infected ticks. In Germany, ticks are ubiquitously infected with Borrelia, however percentages can vary heavily from region to region, even between areas very close in proximity (e.g. 4-21% [bib_ref] Prevalence of Borrelia burgdorferi sensu lato in Ixodes ricinus in Southern Germany, Fingerle [/bib_ref]. The successful transmission from tick to mammal is the result of a specific, highly complex vector-pathogen interaction. First the Borrelia are activated in the tick's intestines. Then they travel to the salivary glands where they bind immunosuppressive salivary proteins to their surface [bib_ref] Differential expression of Ixodes ricinus salivary gland proteins in the presence of..., Cotté [/bib_ref]. Finally, they are secreted with the saliva in the bite wound where they are at least partially protected from the host's immune system by immunomodulating substances from the tick's saliva which probably allows them to reach a sufficiently high infection doses. A similar transmission through blood-sucking insects is therefore close to impossible due to the short blood sucking time (lack of vector competence in insects for B. burgdorferi). Xenobiotic tests reveal that it can take hours for the Borrelia to be transferred -depending on the species of Borrelia [bib_ref] Life cycle of Borrelia burgdorferi sensu lato and transmission to humans, Gern [/bib_ref]. When there is an occupationally higher risk of tick bites, cases of Lyme borreliosis (occupational disease No. 3102, diseases transmitted from animals to humans) should be reported to the accident insurer by the attending physician or employer as a work-related illness as per Art. 202 of the Social Security Code VII (see Annex 4 in Attachment 1). ## Pathogenesis The pathogenesis of the borrelial infection is primarily determined by two factors: 1. The evasion strategies of the pathogen [bib_ref] Complement evasion by Borrelia burgdorferi: it takes three to tango, De Taeye [/bib_ref] ,, [bib_ref] Variable VlsE is critical for host reinfection by the Lyme disease spirochete, Rogovskyy [/bib_ref]. 2. The quality of the host's immune response [bib_ref] Early production of IL-22 but not IL-17 by peripheral blood mononuclear cells..., Bachmann [/bib_ref] , [bib_ref] Phagocytosis of Borrelia burgdorferi, the Lyme disease spirochete, potentiates innate immune activation..., Cruz [/bib_ref] , [bib_ref] van der Poll T. The urokinase receptor (uPAR) facilitates clearance of Borrelia..., Hovius [/bib_ref] , [bib_ref] Recognition of Borrelia burgdorferi, the Lyme disease spirochete, by TLR7 and TLR9..., Petzke [/bib_ref] , [bib_ref] Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent..., Salazar [/bib_ref] , [bib_ref] Adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed..., Skogman [/bib_ref] ,, [bib_ref] Cutting edge: role of Toll-like receptor 1 in mediating immune response to..., Takeuchi [/bib_ref]. Moreover, salivary proteins that are released in the course of the tick's blood meal also show immunosuppressive effects [bib_ref] Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission..., Dai [/bib_ref] , [bib_ref] Antibodies against a tick protein, Salp15, protect mice from the Lyme disease..., Dai [/bib_ref] , [bib_ref] Tick saliva affects both proliferation and distribution of Borrelia burgdorferi spirochetes in..., Horká [/bib_ref] , [bib_ref] Preferential protection of Borrelia burgdorferi sensu stricto by a Salp15 homologue in..., Hovius [/bib_ref] ,, [bib_ref] Deconstructing tick saliva: non-protein molecules with potent immunomodulatory properties, Oliveira [/bib_ref] , [bib_ref] Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease..., Radolf [/bib_ref] , [bib_ref] The Lyme disease agent exploits a tick protein to infect the mammalian..., Ramamoorthi [/bib_ref] , [bib_ref] Antihemostatic, antiinflammatory, and immunosuppressive properties of the saliva of a tick, Ixodes..., Ribeiro [/bib_ref]. Host-specific inflammatory reactions in the skin also influence the course of the infection [bib_ref] Dermatological manifestations of Lyme borreliosis, Mullegger [/bib_ref] , [bib_ref] Elevated levels of IL-23 in a subset of patients with post-lyme disease..., Strle [/bib_ref]. Some of the many strategies the Borrelia use to evade the host's immune system include the ability to mask their cell surface with proteins/inhibitors from the tick or the host, and to modify their phenotype expression of cell surface proteins (outer surface protein: osp) according to their environment [bib_ref] The role of VlsE antigenic variation in the Lyme disease spirochete: persistence..., Bankhead [/bib_ref] , , [bib_ref] Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of..., Tilly [/bib_ref] , [bib_ref] Identification of an ospC operator critical for immune evasion of Borrelia burgdorferi, Xu [/bib_ref]. Several Borrelia species form a resistance to complementmediated lysis by binding the regulators of the complement cascade (factor H) to their surface [bib_ref] Functional characterization of BbCRASP-2, a distinct outer membrane protein of Borrelia burgdorferi..., Hartmann [/bib_ref] , [bib_ref] Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and..., Hunfeld [/bib_ref] , [bib_ref] Binding of human complement regulators FHL-1 and factor H to CRASP-1 orthologs..., Kraiczy [/bib_ref] , [bib_ref] Complement escape of human pathogenic bacteria by acquisition of complement regulators, Kraiczy [/bib_ref] , [bib_ref] Borrelia burgdorferi complement regulator-acquiring surface protein 1 of the Lyme disease spirochetes..., Rossmann [/bib_ref]. By binding to plasminogens, Borrelia are capable of breaking down collagen, fibronectin and laminin [bib_ref] Complement escape of human pathogenic bacteria by acquisition of complement regulators, Kraiczy [/bib_ref] , [bib_ref] Plasmin-coated borrelia Burgdorferi degrades soluble and insoluble components of the mammalian extracellular..., Coleman [/bib_ref] , [bib_ref] Borrelia burgdorferi induces secretion of pro-urokinase-type plasminogen activator by human monocytes, Fuchs [/bib_ref] , [bib_ref] Borrelia burgdorferi possesses a collagenolytic activity, Grab [/bib_ref] , [bib_ref] OspC is potent plasminogen receptor on surface of Borrelia burgdorferi, Önder [/bib_ref] and disseminating in the skin. The innate immune system recognises the Borrelia mainly by their surface proteins (osp lipoproteins) [bib_ref] Borrelia burgdorferi resistance to a major skin antimicrobial peptide is independent of..., Sarkar [/bib_ref] , [bib_ref] Common and unique contributions of decorin-binding proteins A and B to the..., Shi [/bib_ref] , [bib_ref] Reciprocal expression of ospA and ospC in single cells of Borrelia burgdorferi, Srivastava [/bib_ref] , [bib_ref] Lipoprotein succession in Borrelia burgdorferi: similar but distinct roles for OspC and..., Tilly [/bib_ref] , [bib_ref] Essential protective role attributed to the surface lipoproteins of Borrelia burgdorferi against..., Xu [/bib_ref]. This interaction leads to the activation of soluble factors, such as the complement system, as well as to the activation of target cells, like macrophages and dendritic cells, and to the induction of inflammatory cytokines [bib_ref] Interleukin-10 alters effector functions of multiple genes induced by Borrelia burgdorferi in..., Gautam [/bib_ref] ,, [bib_ref] Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in..., Shin [/bib_ref] , [bib_ref] Borrelia burgdorferi lipoprotein BmpA activates proinflammatory responses in human synovial cells through..., Yang [/bib_ref]. As the infection progresses, specific immune responses are generated, particularly the activation of T helper cells and B lymphocytes, and the production of Borrelia-specific antibodies [bib_ref] Variable VlsE is critical for host reinfection by the Lyme disease spirochete, Rogovskyy [/bib_ref] ,, [bib_ref] An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT..., Lee [/bib_ref] , [bib_ref] Treg cell numbers and function in patients with antibiotic-refractory or antibiotic-responsive Lyme..., Shen [/bib_ref]. In reservoir hosts, like wild mice, the antibodies that form during an infection are able to prevent disease, however they are not able to eliminate the pathogen. In contrast, the antibodies that form in patients are often unable to prevent the disease. However, antibodies against certain Borrelia antigens have also been shown to protect against subsequent infection in humans (see vaccines). There is no permanent immunity in humans after wildtype infection. Thus reinfection can occur. Lyme borreliosis is an inflammatory multi-organ disease. It manifests itself initially as a localised infection of the skin called erythema migrans. Because of its light symptoms, this early-stage inflammation of the skin can be overlooked or not even be visible. The Borrelia can spread haematogenically which is recognised clinically by flu-like symptoms or disseminated erythemas of the skin. As the disease progresses, manifestations can appear in other organs, with the nervous system and the joints primarily affected. The disease progresses very differently depending on the individual. Therefore, it doesn't make sense to classify the disease into stages. A distinction between early and late manifestations is preferable since the clinical picture determines both the diagnosis and the treatment [fig_ref] Table 1: Clinical manifestations of Lyme borreliosis [/fig_ref]. European studies show that Lyme borreliosis manifests itself as a skin disease in 80-90% of patients and in other organs in around 10-20% of patients [bib_ref] An epidemiologic study of Lyme disease in southern Sweden, Berglund [/bib_ref] ,, [bib_ref] Epidemiological situation of Lyme borreliosis in germany: surveillance data from six Eastern..., Fülöp [/bib_ref] , [bib_ref] A prospective study on the incidence of Borrelia burgdorferi sensu lato infection..., Wilhelmsson [/bib_ref] , [bib_ref] Clinical spectrum of skin manifestations of Lyme borreliosis in 204 children in..., Glatz [/bib_ref] ,. 6.1 Localised cutaneous early-stage infection [bib_ref] Lyme borreliosis, Stanek [/bib_ref] ## .1.1 erythema migrans The skin around the infectious tick bite can become infected anywhere from 3 to 30 days after the tick bite occurs [bib_ref] Clinical characteristics associated with Borrelia burgdorferi sensu lato skin culture results in..., Strle [/bib_ref]. The extent and duration of the rash varies considerably between individuals. If the diameter of the erythema is more than 5 cm, a diagnosis of erythema migrans can be made [fig_ref] Figure 2: Clinical variations of erythema migrans Fig [/fig_ref] and b) [bib_ref] Lyme borreliosis: clinical case definitions for diagnosis and management in Europe, Stanek [/bib_ref]. The clinical picture of a typical erythema migrans is a marginated erythema that centrifugally spreads out around the tick bite [fig_ref] Figure 2: Clinical variations of erythema migrans Fig [/fig_ref] and d). ## Features of a typical solitary erythema migrans - Free time interval between the tick bite and start of the erythema that is typically 3 days to several weeks. Very often the initial skin infection cannot be definitively diagnosed clinically. Borrelia have been identified in homogenously red and non-migrating erythemas, spotty and infiltrated erythemas [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref] , erysipelas-like flaming red erythemas [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref] and in centrally vesicular erythemas [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref] [bib_ref] The many faces of solitary and multiple erythema migrans, Eriksson [/bib_ref] ,. The inflammation can completely disappear in the middle and fade to such as extent that the erythema is only visible around the edges -in the area of the migrating Borrelia -when heat is applied [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref]. The erythema can also be haemorrhagic, particularly on the lower extremities [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref] and f). The centre can turn a dark purple colour [fig_ref] Figure 3: Variability of the erythema migrans Fig [/fig_ref]. The edge can be raised or urticarial. The former puncture site can be identified in the centre as a red papule [fig_ref] Figure 2: Clinical variations of erythema migrans Fig [/fig_ref] and b), . Without antibiotic treatment the Borrelia can persist for months or years in the skin and the erythema can slowly spread throughout the body. Often the red edge is the only evidence of the inflammatory reaction to the migrating Borrelia. If the erythema migrans persists for multiple weeks and months, it is referred to as erythema chronicum migrans ([66]: >4 weeks). In most cases (approx. 80%) serological detection of the IgG antibodies (sometimes even the IgM antibodies) is possible [bib_ref] van Dam AP; Dutch Working Group on Diagnosis of Lyme Borreliosis. A..., Ang [/bib_ref]. Erythema can disapear even without antibiotic treatment. Spontaneous healing is possible, however the Borrelia can persist even without a visible inflammatory reaction and, after a period of latency, this can lead to further organ manifestations. ## Borrelial lymphocytoma Pseudolymphoma (cutaneous lymphoid hyperplasia) can occur in the early stages at the puncture site or in the migrating erythema migrans [fig_ref] Figure 4: Borrelial lymphocytomaFig [/fig_ref]. Mostly it is solitary, in rare cases it is also disseminated. Borrelial lymphocytoma occurs more frequently in children than in adults (7% in children and only 2% in adults with Lyme borreliosis, [bib_ref] An epidemiologic study of Lyme disease in southern Sweden, Berglund [/bib_ref]. The favoured sites in children are the earlobes [fig_ref] Figure 4: Borrelial lymphocytomaFig [/fig_ref] and 4c), nipples and genital-anal area [fig_ref] Figure 4: Borrelial lymphocytomaFig [/fig_ref] [bib_ref] Solitary borrelial lymphocytoma in adult patients, Maraspin [/bib_ref]. The disease was first described as lymphadenosis cutis benigna by Bäferstedt in 1944. B. burgdorferi s.l. can be detected in the pseudolymphomas [bib_ref] The spirochetal etiology of lymphadenosis benigna cutis solitaria, Hovmark [/bib_ref]. Mostly it is a case of B. afzelii [bib_ref] Species of Borrelia burgdorferi complex that cause borrelial lymphocytoma in France, Lenormand [/bib_ref]. From a histological perspective, there are mixed B and T lymphocytic infiltrates. However purely B cell infiltrates can also occur which are difficult to differentiate from low-grade B cell lymphoma [fig_ref] Figure 4: Borrelial lymphocytomaFig [/fig_ref] and e). Borrelial lymphocytoma can also occur in the late stages as part of an acrodermatitis chronic atrophicans [bib_ref] Solitary borrelial lymphocytoma in adult patients, Maraspin [/bib_ref]. In the case of borrelial lymphocytoma, a substantial increase in the number of IgG antibodies can be detected in the serum regardless of the length of infection [bib_ref] Clinical spectrum of skin manifestations of Lyme borreliosis in 204 children in..., Glatz [/bib_ref] , [bib_ref] Borrelial Lymphocytoma in Children, Arnež [/bib_ref]. In rare cases, multiple borrelial lymphocytomas can occur in the early disseminated stages or even in the late stages of the disease. In these cases, precise histological, immune-histochemical and molecular-genetic clarification ## Disseminated cutaneous early manifestation Some of the patients experience haematogenous dissemination in the early stages of the disease which can be identified by flu-like symptoms such as a slight fever, arthralgia, myalgia, headaches, lymphadenopathy and multiple erythemata migrantia. This stage is very difficult to diagnose if no erythemas are visible, or cannot be identified due to an atypical morphology. ## Multiple erythemata migrantia (mem) The haematogenous dissemination of the Borrelia in the skin is noticeable by the many sharply marginated, symptomless, oval erythemas of various sizes: multiple erythemata migrantia [fig_ref] Figure 5: Multiple erythemata migrantia [/fig_ref] and 5c) [bib_ref] The many faces of solitary and multiple erythema migrans, Eriksson [/bib_ref] , [bib_ref] Solitary and multiple erythema migrans in children: comparison of demographic, clinical and..., Arnez [/bib_ref] , [bib_ref] Borrelia burgdorferi sensu lato bacteremia in Slovenian children with solitary and multiple..., Arnež [/bib_ref]. Children often experience symmetrical erythemas on their face, similar to fifth disease (parvovirus B 19 infection) [fig_ref] Figure 5: Multiple erythemata migrantia [/fig_ref] [bib_ref] Lyme borreliosis: clinical case definitions for diagnosis and management in Europe, Stanek [/bib_ref] ,. MEM can be associated with systemic symptoms and acute neurological symptoms [bib_ref] Solitary erythema migrans in children: comparison of treatment with azithromycin and phenoxymethylpenicillin, Arnez [/bib_ref]. The histological picture is initially atypical. The typical perivascular plasma-cellular infiltrates are not found until the advanced stage of the disease. There is usually a strong increase in IgM antibodies in the serum or the antibodies increase rapidly once treatment begins. There is usually an increase in IgG antibodies. Borrelia taken from skin lesions and, in rare cases, blood can be cultivated or their DNA can be detected using PCR [bib_ref] Borrelia burgdorferi sensu lato bacteremia in Slovenian children with solitary and multiple..., Arnež [/bib_ref] , [bib_ref] Quantitation of cell-associated borrelial DNA in the blood of Lyme disease patients..., Liveris [/bib_ref]. ## Cutaneous late manifestations Acrodermatitis chronica atrophicans (ACA) The disease can manifest itself in various organs after varying periods of time, from months to years depending on the individual. A chronic skin infection mostly occurs in older people and more frequently in women [bib_ref] Acrodermatitis chronica atrophicans, Asbrink [/bib_ref]. Isol-ated cases have also been reported in children [bib_ref] Acrodermatitis chronica atrophicans in two children, Andres [/bib_ref] , [bib_ref] Acrodermatitis chronica atrophicans affecting all four limbs in an 11-year-old girl, Brzonova [/bib_ref] , [bib_ref] Acrodermatitis chronica atrophicans in a 15-year-old girl misdiagnosed as venous insufficiency for..., Zalaudek [/bib_ref]. ## Oedematous infiltrative stage of aca Acrodermatitis initially manifests itself as pink reticular, then increasingly purple, oedematous infiltrated cushionlike erythemas, mostly on the extremities. The skin is inflamed, however there is initially no pain except for a feeling of heaviness of the extremity. This is the oedematous infiltrative stage of acrodermatitis chronica [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref] and 6b). These purple infiltrates can also appear on the face and be confused with lupus erythematosus or a cutaneous malignant lymphoma. ## Atrophic stage of aca In the course of the infection there is an increasing atrophy of all skin layers and skin appendages. Occasionally juxta-articular rough fibroid nodules and band-shape stripes appear [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref] , e.g. rare but typical inflammatory ulnar stripes and swelling in the heel and Achilles tendon, or in other joints around the ACA [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref]. This results in circumscribed fibrosis or pseudo-scleroderma in the area of the ACA which can be confused with circumscribed scleroderma. Arthritides, arthralgia and myalgia infiltrates dorsally on the right knee [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref] : ACA with ulnar stripes and purple blotches on the right underarm, and pronounced purple fibrous nodules below the elbow [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref] : ACA with dark red to purple colouring and atrophy of the right hand dorsally (so-called "baked apple skin") with swelling of the finger joints in the affected extremities are frequently associated with ACA [bib_ref] Acrodermatitis chronica atrophicans, Asbrink [/bib_ref]. A peripheral neuropathy occurs in 40-60% of patients in association with ACA. It is characterized by a feeling of numbness, a tingling sensation, burning and an increased sensitivity to pain (allodynia) [bib_ref] Peripheral neuropathy in acrodermatitis chronica atrophicans (Herxheimer), Hopf [/bib_ref] , [bib_ref] Peripheral neuropathy in acrodermatitis chronica atrophicansa late Borrelia manifestation, Kindstrand [/bib_ref] , [bib_ref] Neuropathy associated with acrodermatitis chronica atrophicans. Clinical and morphological features, Kristoferitsch [/bib_ref]. Without antibiotic treatment living Borrelia can be detected for years in the skin and in the fibroid nodules [bib_ref] Successful cultivation of spirochetes from skin lesions of patients with erythema chronicum..., Asbrink [/bib_ref]. In the course of the infection, all of the affected skin becomes atrophic and there is a loss of body hair, connective tissue and fatty tissue [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref]. When the changes to the ACA-affected skin are symmetrical, they are difficult to differentiate clinically from age-related skin atrophy, acrocyanosis and chronic venous insufficiency. From a histological standpoint, acrodermatitis chronica atrophicans is characterised by a pronounced perivascular plasma-cell rich inflammatory infiltrate in all layers of the skin [fig_ref] Figure 6: Late cutaneous manifestations Fig [/fig_ref] and, in the late stage, by an increasing atrophy of the epidermis, connective tissues and fatty tissues [bib_ref] Acrodermatitis chronica atrophicans: histopathologic findings and clinical correlations in 111 cases, Brehmer-Andersson [/bib_ref]. An ACA diagnosis is based on a typical clinical presentation, a typical histology and, as a rule, a high elevation of Borrelia IgG antibodies in the serum [bib_ref] Acrodermatitis chronica atrophicans, Asbrink [/bib_ref]. In unclear cases, particularly in the case of marginal elevation of antibody concentrations, the diagnosis has to be made by skin biopsy for histology and Borrelia DNA detection by NAT (PCR), or if possible through the cultivation of Borrelia from the skin. Significant clinical features of acrodermatitis chronica atrophicans (ACA) - Initial oedematous infiltrative stage (plasma-cellular dermatitis) reddish colouring of the skin, mostly on one extremity - Transition to the atrophic stage in the course of the disease, purple to brown colouring of the skin, skin atrophy, loss of body hair, connective and fatty tissues, emergence of veins, juxta-articular fibrous nodules and joint involvement - Association with a peripheral neuropathy in around 50% of the cases - Older women more strongly affected (Strong consensus: 19/19) ## Manifestations in the nervous system and joints associated with cutaneous borreliosis An acute neuroborreliosis can simultaneously appear as part of early-stage borreliosis with erythema migrans. Arnez et al. found pleocytosis in the cerebrospinal fluid of 26% of the 214 children diagnosed with multilocular erythemata migrantia. Of these, 11% had clinically symptomatic lymphocytic meningitis [bib_ref] Children with multiple erythema migrans: are there any pretreatment symptoms and/or signs..., Arnez [/bib_ref]. Radiculoneuritis with characteristic nightly pain can also occur -in rare cases with paresis of the cranial nerves or peripheral nerves. A peripheral neuropathy of the affected extremity occurs in 50% of patients with ACA [bib_ref] Neuropathy associated with acrodermatitis chronica atrophicans. Clinical and morphological features, Kristoferitsch [/bib_ref]. Rheumatic symptoms, above all myalgia and arthralgia, can occur in relatively early stages of the disease alongside erythema migrans. Cardiac symptoms with dysrhythmia (AV block) should be watched for, which can occur during or after erythema migrans. Lyme arthritis can either be the initial symptom or it can occur after a non-treated case of erythema migrans. Frequently the joint adjacent to the erythema migrans is affected. This manifests itself as acute intermittent arthritis with voluminous, at times, painful joint swelling, usually as mono or oligoarthritis. The knee joints are affected in 85% of the cases. The often massive swelling of the knee leads, unusually frequently and early on, to the development of popliteal cysts (Baker's cysts). Ankle and elbow joints are less often affected, and almost never finger joints, especially in the form of a polyarthritis, have been observed. Lyme arthritis usually proceeds episodically, in other words, with repetitive inflammatory flare-ups that are interrupted by intervals of light to no symptoms. ## Differential diagnoses for cutaneous lyme borreliosis The most frequent differential diagnoses for cutaneous Lyme borreliosis are listed in [fig_ref] Table 2: Clinical differential diagnoses of cutaneous Lyme borreliosis 13/31 GMS German Medical Science... [/fig_ref]. The variety of differential diagnoses shows that, except for typical erythema migrans, most of the cutaneous manifestations of Lyme borreliosis require careful dermatological diagnostic procedures. In particular, the lack of response to antibiotic treatment should not be uncritically interpreted as persistent borreliosis and treated for months with antibiotics. It is, therefore, recommended to refer a patient with indistinct skin afflictions that persist after treatment to dermatologists or to dermatologically experienced paediatricians. Recommendation: - Skin inflammations that were diagnosed as Lyme borreliosis and which have not healed after lege artis antibiotic treatment shall be referred to a dermatologist. (Strong consensus 11/12) 12/31 Due to the complex characteristics of the pathogen, indirect pathogen detection using serological methods continues to play a pivotal role in the diagnosis of Lyme borreliosis in practical laboratory-based medical care. In accordance with the methods and standards required in Germany, the antibodies are detected in a serum using a two tiered diagnostic approach with a standardised screening test (immunoassay: ELISA, CLIA etc.) and a confirmation assay (immunoblot). This is to ensure that the diagnostic procedure has a uniformly high level of sensitivity and specificity [fig_ref] Table 3: Two tiered serological diagnostic approach [/fig_ref]. In Europe, diagnostics tests for borrelial serology do not undergo any form of mandatory, extensive or independent clinical evaluation as part of the approval process. Thus a range of different test formats are on the market. In addition to various types of immunoassays, there are also a variety of test antigen preparations that use native and recombinant antigen combinations with, at times, different performance data. This partly explains the high degree of variability in the lab results which depend on the manufacturer and the test [bib_ref] Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany:..., Müller [/bib_ref] ,. Even though the principle testing procedures and the interpretation of serological test results are laid down as part of binding standardsin Germany, the interpretation of testing results, and in particular the evaluation criteria for immunoblot testing, are subject to manufacturer-dependent differences and have to be done in accordance with the respective manufacturer requirements as a result of the variability and insufficient standardisation of commercial test systems. This ongoing issue of insufficient testing standardisation is confirmed through meta-analytical investigations as part of external quality controls [bib_ref] Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany:..., Müller [/bib_ref] , [bib_ref] Quality of Lyme disease serology. Lessons from the German Proficiency Testing Program..., Hunfeld [/bib_ref]. In this respect, attending physicians should be aware of the qualifications of their diagnostic laboratory and the diagnostic assays and test specifications which it uses. ## The course of the immune response and interpretation of the findings In the course of a natural infection, specific IgM antibodies are usually detectable 3-6 weeks after the onset of the illness; IgG antibodies reach their peak more slowly (weeks to months). It should be further noted that, after early, successful treatment of early manifestations, seroconversion can fail to appear under certain circumstances or, in the case of a positive detection of IgM antibodies, there doesn't have to be a regular continuation of the immune response in the sense of a conversion from IgM to IgG. In contrast to textbook examples of the courses of immune response for many viral diseases, the antibody response to Lyme borreliosis often regresses very slowly both after an infec-tion that is latent or cured, and after successful treatment. Thus, under certain circumstances, IgM reactivities or specific IgG values after such infections can remain detectable for months or even years. Often low positive borrelial-specific antibody values are a sign of a previous infection in the sense of persisting antibodies from a past infection (serological scar). However, a reinfection cannot be excluded in the case of such a lab result. Such findings have been detected in 20% of the people examined in serial investigations who belong to population groups that are frequently exposed, e.g. forestry workers, without there being or having been any symptoms of illness [bib_ref] Paradigm Burgenland: risk of Borrelia burgdorferi sensu lato infection indicated by variable..., Cetin [/bib_ref] , [bib_ref] Antibodies against Borrelia burgdorferi in Bavarian forest workers, Münchhoff [/bib_ref]. Possible coincidences of these types of titres, with persisting antibodies from previous infections and unspecified findings, are also possible amongst the normal population [bib_ref] Antibodies against Borrelia burgdorferi sensu lato among Adults, Wilking [/bib_ref] , [bib_ref] Seropositivity of Lyme borreliosis and associated risk factors: a population-based study in..., Dehnert [/bib_ref] and can be responsible for erroneous interpretations and diagnoses. Detection of elevated IgM antibodies only (without IgG) effectively excludes a late manifestation of Lyme borreliosis in the case of immune-competent patients. Diagnostic use of very sensitive early-phase antigens, such as VlsE, which enable the detection of a specific IgG response very early on in the course of the infection, means specific IgM antibody findings as part of Lyme borreliosis diagnostics are playing an increasingly limited role, especially since the IgM detection exhibits a poorer overall specificity than the IgG detection [bib_ref] Performance of United States serologic assays in the diagnosis of Lyme borreliosis..., Branda [/bib_ref] , [bib_ref] VlsE C6 peptide and IgG ELISA antibody analysis for clinical diagnosis of..., Nyman [/bib_ref]. However positive IgG findings can persist, in part, in high concentrations over longer periods of time so that no conclusions can be drawn regarding the activity of Lyme borreliosis or even the necessity for treatment in the absence of a classic activity marker, without additional clinical information and only on the basis of positive serological findings. At the same time, a statement can only be made about the significance of changes in findings if the comparison tests are carried out on serum samples that were taken at different times, ideally using a parallel approach as with the preserum, but, in any case, using the same test, [bib_ref] When is the best time to order a Western blot and how..., Hunfeld [/bib_ref]. An analysis using immunoblot within the framework of the stepwise diagnostic approach generally serves to not only specifically confirm the findings of the screening test, it also enables the immune response to be divided into an early and late stage so that a better correlation can be made between the lab findings and the clinical symptoms based on the characteristic band spectrum, particularly in the IgG immunoblot. Thus a narrow spectrum of bands with antibodies against early-phase antigens (e.g. VlsE, OspC, p41) is typically compatible with an early manifestation (e.g. erythema migrans, facial paresis) or a brief latent infection. However, it does not point to persistent clinical symptoms, [bib_ref] When is the best time to order a Western blot and how..., Hunfeld [/bib_ref] , [bib_ref] Improvement of Lyme borreliosis serodiagnosis by a newly developed recombinant immunoglobulin G..., Goettner [/bib_ref] , [bib_ref] Validity of interpretation criteria for standardized Western blots (immunoblots) for serodiagnosis of..., Hauser [/bib_ref]. In contrast, a wide band spectrum, including reactions to late-phase antigens (e.g. p100, p17/p18), fits in well with a late manifestation (e.g. arthritis, acrodermatitis) [bib_ref] Improvement of Lyme borreliosis serodiagnosis by a newly developed recombinant immunoglobulin G..., Goettner [/bib_ref] , [bib_ref] Validity of interpretation criteria for standardized Western blots (immunoblots) for serodiagnosis of..., Hauser [/bib_ref] , also with an asymptomatic persistence of antibodies (serological scar), however it primarily does not point to an early manifestation or a short course of infection. Reinfections are difficult to detect based only on serological test results without additional clinical information and can only be detected based on a clearly verifiable IgG increase in a parallel approach, or significant changes in the immunoblot band pattern in serum samples that are tested in parallel. One major premise of serological testing for Lyme borreliosis is the fact that the referring physician needs to be aware that these types of tests should only be requested when there is reasonable clinical suspicion. Only when there is sufficiently high pre-test probability (prevalence of Lyme borreliosis in the patient cohort being investigated >20%) can a sufficiently utilisable positive predictive value of a positive test result even be assumed [bib_ref] Laboratory testing for suspected Lyme disease, Bunikis [/bib_ref]. If the test is only ordered to exclude Lyme borreliosis in the case of unspecified or non-typical disease symptoms, the positive predictive value of the lab test drops to almost zero with respect to the possible confirmation of Lyme borreliosis. On the other hand, due to the relatively low overall prevalence and incidence of Lyme borreliosis in the general public, a negative test result, which excludes the disease in immune-competent patients with persisting symptoms, has an excellent negative predictive value. ## Recommendation ## Direct pathogen detection The respective microbiological diagnostic quality standards (MiQ Lyme borreliosis, MiQ PCR) apply in the direct pathogen detection of Lyme borreliosis using culture and PCR. ## Culture Direct detection by culture with the modified Barbour-Stoenner-Kelly medium is considered to be the gold standard and to be clear proof of an infection with B. burgdorferi [bib_ref] Immunochemical analysis of Lyme disease spirochetes, Barbour [/bib_ref] , [bib_ref] European Borrelia burgdorferi isolated from humans and ticks culture conditions and antibiotic..., Preac-Mursic [/bib_ref]. Direct detection of skin manifestations by culture are frequently successful. To a limited degree, detection by culture is also possible in liquor and, in very rare cases, in synovial fluid, synovial biopsies and blood. In individual cases, the detection of B. burgdorferi has also been achieved in other tissue samples, e.g. heart muscle and iris [bib_ref] First isolation of Borrelia burgdorferi from an iris biopsy, Preac-Mursic [/bib_ref] , [bib_ref] Borrelia burgdorferi as an etiologic agent in chronic heart failure?, Stanek [/bib_ref]. Cultivating from patient samples using suitable media is timeconsuming and materially intensive, and usually takes more than two weeks. The sensitivity of the methods in European studies is between 40% and 90% for erythema migrans and between 20% and 60% for ACA [bib_ref] Comparison of PCR methods and culture for the detection of Borrelia spp...., Cerar [/bib_ref] , [bib_ref] Solitary erythema migrans: a clinical, laboratory and epidemiological study of 77 Dutch..., Kuiper [/bib_ref] , [bib_ref] Identification of three species of Borrelia burgdorferi sensu lato (B. burgdorferi sensu..., Picken [/bib_ref] , . Overview in: [bib_ref] Diagnosis of lyme borreliosis, Aguero-Rosenfeld [/bib_ref]. Because of the invasiveness of the sample taking, direct detection by culture should therefore be based on a clear indication and explicitly remain limited to specially identified reference laboratories, such as the National Reference Centre for Borrelia at the Bavarian State Office for Health and Food Safety in Oberschleissheim. In addition, further molecularbiological confirmation assays are required in positive cases. ## 15/31 Recommendations for direct detection by culture: - Direct detection by culture should only be used in differential-diagnostically ambiguous cases. ## Direct detection using molecular-biological detection methods The detection methods currently being used in Lyme borreliosis diagnosis should be regarded as having a low level of standardisation . This applies to DNA isolation from suitable clinical materials, as well as to the reaction conditions and the selection of the reaction starter molecules (primers). In principle, the detection of Borrelia from a skin biopsy using nucleic acid amplification techniques (NAT, usually PCR) is very reliable and, in the case of early manifestations, is more sensitive than serological antibody detection. The diagnostic sensitivity of NAT is around 70% for detection from biopsies from erythema migrans and acrodermatitis chronica atrophicans [bib_ref] Comparison of PCR methods and culture for the detection of Borrelia spp...., Cerar [/bib_ref] , [bib_ref] Diagnostic value of PCR for detection of Borrelia burgdorferi in skin biopsy..., Brettschneider [/bib_ref] , [bib_ref] Detection of Borrelia burgdorferi sensu lato in lesional skin of patients with..., Moter [/bib_ref] ,, [bib_ref] Polymerase chain reaction for detection of Borrelia burgdorferi DNA in skin lesions..., Von Stedingk [/bib_ref]. However, positive results have to be confirmed through molecular-biological confirmation assays with regard to specificity (probe hybridisation, sequencing of the amplificate) and the results must be indicated in the findings. After treatment, Borrelia DNA can still be detected for weeks -or even months -in the affected area of skin before conclusions can be drawn as to whether the therapy has failed [bib_ref] Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy, Bockenstedt [/bib_ref] , [bib_ref] Detection of Borrelia burgdorferi nucleic acids after antibiotic treatment does not confirm..., Iyer [/bib_ref] , [bib_ref] DNA persistence after treatment of Lyme borreliosis, Pícha [/bib_ref]. Molecular-biological detection of pathogens without the simultaneous presence of typical disease manifestions is not clinically relevant. Direct molecular-biological detection from urine samples is not currently recommended due to ambiguous diagnostic sensitivity and specificity [bib_ref] Diagnostic value of PCR for detection of Borrelia burgdorferi in skin biopsy..., Brettschneider [/bib_ref] , [bib_ref] Course of Borrelia burgdorferi DNA shedding in urine after treatment, Aberer [/bib_ref] , [bib_ref] Critical evaluation of urine-based PCR assay for diagnosis of Lyme borreliosis, Rauter [/bib_ref]. Because of the invasiveness of the sample taking, direct detection by culture should therefore be based on a clear indication (e.g. unexplained skin manifestation that has been differentially diagnosed) and explicitly remain limited to specially identified reference laboratories, such as the National Reference Centre for Borrelia at the Bavarian State Office for Health and Food Safety in Oberschleissheim. In addition, further molecular-biological confirmation assays are required in positive cases. Recommendations for direct molecular-biological detection: - ## Erythema migrans (atypical) If an atypical erythema migrans is suspected, antibody and pathogen detection by PCR and culture is available. A serological test should be carried out in every case. If the findings remain ambiguous, the aim should be pathogen detection using PCR, if necessary also by culture [fig_ref] Figure 7: Algorithm for diagnosing a solitary or multilocular erythema migrans • If the... [/fig_ref]. A skin biopsy should be taken near the inflamed edge. After informing the patient and obtaining written consent, the selected area of the skin is numbed using local anaesthesia. After thorough disinfection of the skin, a 4 mm punch is used to remove the skin, which is put in a sterile vessel with 0.9% saline solution. Direct inoculation in the cultivation medium only makes sense when the sample can be processed in the lab within a few hours. Otherwise, fast growing skin bacteria can hamper the cultivation of the Borrelia. A histological analysis rarely has a guiding nature in the case of erythema migrans. It can, however, make sense for differential-diagnostic clarification. Recommendation: - In the case of an atypical clinical appearance of erythema migrans, suspicion shall be clarified through a serological test. (Consensus: 18/20) ## Multiple erythemata migrantia (mem) If multiple erythemata migrantia, also known as multilocular erythema migrans (MEM) is suspected, serological antibody detection and pathogen detection using PCR and culture from a skin biopsy are available. A serological test should be carried out in every case. If the findings remain ambiguous, the aim should be to detect the pathogen using PCR, if necessary also by culture [fig_ref] Figure 7: Algorithm for diagnosing a solitary or multilocular erythema migrans • If the... [/fig_ref] (see . Clinical signs of extra-cutaneous symptoms should be watched for in the case of MEM (see [fig_ref] Table 1: Clinical manifestations of Lyme borreliosis [/fig_ref] in the section on clinical manifestations). ## Recommendations ## Borrelial lymphocytoma Confirming the diagnosis through serological antibody detection is obligatory and, in most cases, antibodies against B. burgdorferi can be detected [bib_ref] Dermatological manifestations of Lyme borreliosis, Mullegger [/bib_ref] ,, [bib_ref] Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases, Colli [/bib_ref]. ## Ambiguous dermatological pathologies with a suspicion of lyme borreliosis See [fig_ref] Table 4: Interpretation of serological result constellations [/fig_ref]. Recommendation: - If a cutaneous manifestation of Lyme borreliosis is suspected and there is no unambiguous clinical presentation, a skin biopsy with a histological examination shall be conducted along with direct pathogen detection using culture and molecular-biological methods. (Strong consensus: 20/20) ## Non-recommended diagnostic approaches In addition to the traditional diagnostic methods listed above, which are used when Lyme borreliosis is suspected, the literature describes a whole series of diagnostic techniques that, in part, have been inconclusively evaluated. This includes the immuno-histochemical detection of B. burgdorferi in biopsies and of antigens from blood and urine, as well as functional tests that test for cellular immunity (lymphocyte transformation tests (LTT), cytokine detection). Currently there is a lack of scientific investigations that prove there is a diagnostic benefit. Because the available LTT methods lack specificity, they should not be used. Methods that are not recommended for use in the diagnosis of cutaneous manifestations of Lyme borreliosis: - ## Quality control and quality assurance According to the guidelines of the German Medical Association (Bundesärztekammer), diagnostic laboratories must currently participate in infection-related serological round robin tests twice a year. This applies to serological antibody detection and to direct molecular-biological detection of Borrelia when Lyme borreliosis is suspected. The results of the external quality assessment tests (EQA tests), which INSTAND e.V. has been carrying out for years, reveal extensive heterogeneity in the testing systems currently on the market. The pass rates for the conventional serological and molecular-biological test systems, which have been collected from meta-analytical data, show that, despite good analytical pass rates for immunoassays and molecular-biological tests, clinical diagnostic interpretation of the result constellations often proves difficult and can hamper medical treatment in daily clinical practice [bib_ref] Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany:..., Müller [/bib_ref] ,. Thus, when Lyme borreliosis is suspected, infection diagnostics are to be conducted in laboratories that meet the laboratory diagnostic standards in accordance with the diagnostic guidelines of the expert medical societies and the guidelines of the German Medical Association. These laboratories must regularly and successfully participate in external quality assurance tests (round robin tests). Physicians treating patients with Lyme borreliosis should query about and ensure that these prerequisites are met in the laboratories charged with carrying out their diagnostic testing. If questionable result constellations or implausible test results are produced, expert laboratories specialising in Lyme borreliosis diagnostics and the National Reference Centre for Borreliosis at the Bavarian State Office for Health and Food Safety in Oberschleissheim should be consulted. ## Recommendation: - Attending physicians shall be aware of whether their diagnostic laboratory complies with the respective diagnostic standards and qualifications and the extent to which the diagnostic assays used there conform to guidelines. (Strong consensus: 18/19) ## Treatment of cutaneous lyme borreliosis Recommendations for treating Lyme borreliosis have been published in numerous European and American guidelines since 2004 (see Annex 2 "Comparison of Guidelines and Therapies" in Attachment 1). [fig_ref] Table 5: Treatment recommendations for cutaneous Lyme borreliosis [/fig_ref] summarises the best-evaluated antibiotic therapies taken from American and European guidelines. Doxycycline and amoxicillin are the antibiotics of choice in all guidelines. Both antibiotics are very effective in the dosages listed in [fig_ref] Table 5: Treatment recommendations for cutaneous Lyme borreliosis [/fig_ref] and are usually tolerated well. Gastrointestinal complaints can occur during treatment with doxycycline. It is particularly important that they are not taken together with dairy products. Furthermore, patients should be informed of the risk of phototoxic skin reactions and use light stabilisers when taking the antibiotics. During treatment with amoxicillin, non-allergenic skin exanthemas frequently appear on the 8 th day on the torso. If they are light exanthemas, the treatment can continue. If itching occurs, symptoms can be treated with antihistamines and skin care products. Corticosteroids are not necessary. Of the oral cephalosporins, only cefuroxime axetile has demonstrated an efficacy that is comparable to treatment with doxycycline and amoxicillin [bib_ref] Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis, Dattwyler [/bib_ref]. The absolute bioavailability of cefuroxime axetil is comparatively low (40-45%). The best resorption is achieved when it is taken directly after a meal. Other 1 st and 2 nd generation cephalosporins are not effective enough [bib_ref] In vitro activity of eight oral cephalosporins against Borrelia burgdorferi, Hunfeld [/bib_ref]. In the case of disseminated early-stage infection, intravenous treatment with ceftriaxone does not achieve any better results than oral doxycycline treatment [bib_ref] Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease, Dattwyler [/bib_ref]. Of the macrolides, azithromycin has proven to be adequately effective [bib_ref] Solitary erythema migrans in children: comparison of treatment with azithromycin and phenoxymethylpenicillin, Arnez [/bib_ref] , [bib_ref] Comparison of azithromycin and doxycycline in the treatment of erythema migrans, Barsic [/bib_ref] , [bib_ref] Azithromycin compared with amoxicillin in the treatment of erythema migrans. A doubleblind,..., Luft [/bib_ref] ,. The long tissue half-life period is advantageous because of the long generation time of Borrelia. The efficacy of clarithromycin is regarded as controversial. Clarithromycin was compared with amoxicillin in one of the newer, open, randomised comparative studies of children with erythema migrans and was classified as equally effective [bib_ref] Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin, Nizic [/bib_ref]. Roxithromycin is not effective enough. Because of its uncertain resorption and indications of resistance, erythromycin is no longer a treatment of choice [bib_ref] Cutting edge: role of Toll-like receptor 1 in mediating immune response to..., Takeuchi [/bib_ref] , [bib_ref] Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in..., Hansen [/bib_ref]. Treatment with oral penicillin V is controversial. Austrian, Swedish and Slovenian studies show that it is sufficiently effective [bib_ref] Children with multiple erythema migrans: are there any pretreatment symptoms and/or signs..., Arnez [/bib_ref] , [bib_ref] Comparison of a two-or three-week regimen and a review of treatment of..., Aberer [/bib_ref] , [bib_ref] Antibiotic treatment of children with erythema migrans, Arnez [/bib_ref] , [bib_ref] Clinical outcome of erythema migrans after treatment with phenoxymethyl penicillin, Bennet [/bib_ref]. It is particularly important that dosage and length of treatment are observed. Cutaneous early manifestations should be treated for 10-21 days [fig_ref] Table 5: Treatment recommendations for cutaneous Lyme borreliosis [/fig_ref]. The length of treatment depends on the duration and severity of the clinical symptoms; in the case of solitary erythema migrans without general symptoms, a 10 to 14 day treatment is sufficient. In a comparative study by Stupica et al. [bib_ref] Treatment of erythema migrans with doxycycline for 10 days versus 15 days, Stupica [/bib_ref] the results of treating localised erythema migrans with doxycycline for 19/31 10 versus 14 days were evaluated. There were no differences in the way the erythema healed. In both treatment groups symptoms persisted no longer or more frequently than in healthy subjects. Treatment should last 21 days if there is evidence that the Borrelia has disseminated (indicated by a flu-like feeling), or in the case of multiple erythemata migrantia and borrelial lymphocytoma. Taking doxycycline or amoxicillin orally for 30 days to treat cutaneous late manifestations (acrodermatitis chronica in the oedematous-infiltrative or atrophic stage) without neurological involvement is usually sufficient [bib_ref] Acrodermatitis chronica atrophicans, Asbrink [/bib_ref] ,. However, if there are also neurological symptoms, intravenous treatment with penicillin G or 3 rd generation cephalosporins ceftriaxone or cefotaxime may be necessary. The cure rates -defined as the reinstatement of the body's original condition with regression of the diseasespecific symptoms after successful treatment -is between 95%-100% when the localised and disseminated early manifestations are treated in time [bib_ref] Subjective symptoms after treatment of early Lyme disease, Cerar [/bib_ref] , [bib_ref] Antibiotic treatment duration and long-term outcomes of patients with early lyme disease..., Kowalski [/bib_ref]. Treatment failure with evidence of the pathogens after therapy rarely occurs if the treatment is conducted lege artis [bib_ref] Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and..., Hunfeld [/bib_ref] , [bib_ref] Treatment failure in erythema migrans--a review, Weber [/bib_ref] ; individual cases have been published [bib_ref] European Borrelia burgdorferi isolated from humans and ticks culture conditions and antibiotic..., Preac-Mursic [/bib_ref] , [bib_ref] First isolation of Borrelia burgdorferi from an iris biopsy, Preac-Mursic [/bib_ref] , [bib_ref] Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin..., Breier [/bib_ref] , [bib_ref] Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic..., Häupl [/bib_ref] , [bib_ref] Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but..., Priem [/bib_ref] , [bib_ref] Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of..., Schmidli [/bib_ref]. Two larger studies were able to show that new infections with other Borrelia strains were the reason why Lyme borreliosis returned in every case, [bib_ref] Differentiation of reinfection from relapse in recurrent Lyme disease, Nadelman [/bib_ref]. [bib_ref] Variable VlsE is critical for host reinfection by the Lyme disease spirochete, Rogovskyy [/bib_ref] Currently there are no indications of a development of secondary antibiotic resistance of B. burgdorferi to the antibiotics recommended in the guidelines [bib_ref] Antimicrobial susceptibility of Borrelia burgdorferi sensu lato: what we know, what we..., Hunfeld [/bib_ref] , [bib_ref] In vitro susceptibility testing of Borrelia burgdorferi sensu lato isolates cultured from..., Hunfeld [/bib_ref] , [bib_ref] In vitro susceptibility of Borrelia spielmanii to antimicrobial agents commonly used for..., Morgenstern [/bib_ref] , [bib_ref] Susceptibility of Borrelia afzelii strains to antimicrobial agents, Ruzic-Sabljic [/bib_ref]. If the late manifestations remain untreated for a long period of time, there is a higher risk of the patient having persistent physical symptoms and of their skin, joints and nervous system not properly healing. It is disputed whether repeated antibiotic treatment makes sense for these patients with persisting complaints. According to published randomised controlled trials (RCT), long-term antibiotic treatment is less than promising [bib_ref] A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy, Fallon [/bib_ref] , [bib_ref] A critical appraisal of "chronic Lyme disease, Feder [/bib_ref] ,, [bib_ref] Treatment trials for post-Lyme disease symptoms revisited, Klempner [/bib_ref] , [bib_ref] Two controlled trials of antibiotic treatment in patients with persistent symptoms and..., Klempner [/bib_ref] , [bib_ref] Study and treatment of post Lyme disease (STOP-LD): a randomized double masked..., Krupp [/bib_ref]. A European RCT published in 2016 (PLEASE Study) looked at 280 patients whose complaints persisted for more than 2 years after their Lyme borreliosis had been treated with antibiotics (78 patients after erythema migrans, 15 patients after meningoradiculitis) and 153 seropositive patients with borreliosis-related complaints after a tick bite. The study compared the health-related effects of a 2-week compared to a 14-week round of antibiotics. First, all of the patients that had previously been treated with antibiotics were given 2 g of ceftriaxone i.v. for 2 weeks. Then the patients were randomly placed in 3 groups. Group 1 received doxycycline 200 mg/d p.o. for 12 weeks, Group 2 clarithromycin 2x 500 mg plus hydroxychloroquin 2x 200 mg/d for 12 weeks, and Group 3 a placebo for 12 weeks. Treatment success was assessed as healthbased quality of life after 14 weeks and then up to 52 weeks using the RAND 36 Health Status Inventory. The aggregate score improved equally after treatment in all three groups without a significant difference. The assessment of the quality of life remained lower than in the general population in all three groups. No difference in treatment success between the short-term treatment and the two long-term treatments could be made. Patients receiving the long-term treatment had considerably more antibiotic-related side-effects (primarily photosensitivity (18.6%) and nausea (10.5%) in connection with doxycycline, and primarily nausea (10.4%), diarrhoea (9.4%) and allergic exanthemas (8.3%) in connection with clarithromycin/hydroxychloroquine.) Vision problems were the most frequent complaint of the placebo group (10% of the patients) [bib_ref] Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)--design of a randomized controlled trial..., Berende [/bib_ref] , [bib_ref] Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease, Berende [/bib_ref]. ## Treatment during pregnancy and nursing Oral treatment with amoxicillin p.o. is recommended during pregnancy and nursing. Alternatively, penicillin G and ceftriaxone can be administered i.v. [bib_ref] Maternal Lyme borreliosis and pregnancy outcome, Lakos [/bib_ref] , [bib_ref] Pregnant women with erythema migrans and isolation of borreliae from blood: course..., Maraspin [/bib_ref]. If the patient has an identified allergy to penicillin, azithromycin or cefuroxime axetil can be prescribed after strong indication. Ceftriaxone can be taken intravenously under clinical surveillance since the risk of a cross allergy between penicillin and 3 rd generation cephalosporins is around 1% [159]. ## Treatment of children Children can be treated with 4 mg/kg KG/day (up to a maximum dosage of 200 mg/day) of doxycycline once their tooth enamel has completely formed at age 9 and over (>8 years). For children under 8, the treatment of choice is 50 mg/kg KG/day of amoxicillin [fig_ref] Table 5: Treatment recommendations for cutaneous Lyme borreliosis [/fig_ref]. Taking it the required 3 times a day can be difficult for kindergarten-and school-aged children. Alternatively, cefuroxime axetil 30 mg/kg KG/day, azithromycin 5-10 mg/kg KG/day or clarithromycin 15 mg/kg KG/day can be prescribed, which is taken twice daily [bib_ref] Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin, Nizic [/bib_ref]. ## Therapy adherence In order to improve treatment adherence/therapy compliance, the patient should be informed before beginning the treatment of the aspects of taking prescribed antibiotics and the potential risks of undesired effects. A frequent cause of treatment failure is the incorrect administration of doxycycline. It should be noted that resorption can be compromised when it is taken together with bivalent or trivalent cations, such as aluminium, calcium (milk, dairy products and fruit juice containing calcium), and magnesium, in antacids or through iron supplements, as well as through activated charcoal and colestyramine. Therefore, there should be a 2 to 3 hour time span between when the antibiotic is taken and the medicine or food is ingested. Another reason for treatment failure is irregular administration e.g. forgetting to take the midday dose in the case of amoxicillin, or when the length of antibiotic treatment is insufficient e.g. due to a deterioration in symptoms as a result of a Herxheimer reaction, because of gastrointestinal complaints, or as a result of phototoxic skin reactions through increased sensitivity to light from doxycycline. In the case of a disseminated infection, the patient should be informed about a possible Herxheimer reaction with a flare up of the erythemas, which occurs in approx. 10% of cases, a feeling of being very unwell, and a rise in temperature in approx. 2% of cases within 24 hours of taking the antibiotics [bib_ref] Borrelia burgdorferi sensu lato bacteremia in Slovenian children with solitary and multiple..., Arnež [/bib_ref] , [bib_ref] Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin, Nizic [/bib_ref]. Occasionally this reaction is delayed. It is a temporary immunological reaction as a result of the upregulation of proinflammatory cytokines and can be treated, for example, with non-steroidal anti-inflammatory drugs (NSAID). Cortisone treatment is not necessary. The antibiotic should continue to be taken. ## Recommendations for treating cutaneous ## Dissenting opinion (onlyme aktion) - When other causal factors can be excluded and cutaneous, illness-specific symptoms recur or do not regress, another suitable antibiotic can be considered, taking into account the patient's individual situation. Dissenting opinion (German Borreliosis Society) - There are no evidence-based studies on the efficacy of treating late-stage Lyme borreliosis, particularly ACA, with antibiotics. The paper by Aberer et al.[135], cited in the text, states that the efficacy of ceftriaxone needs to be reviewed in further studies. In terms of oral antibiotics, it has been established that the length of treatment is a more critical factor than the type of antibiotic (penicillin/doxycycline). ## Persisting symptoms after treatment/post-treatment lyme disease syndrome (ptls) After antibiotic treatment has been carried out in accordance with the guidelines, inflammatory reactions can persist and symptoms such as tiredness, joint and muscle pain, headaches, a general feeling of being unwell, irritability or paraesthesia can last for months. If the unspecific constitutional symptoms last for more than 6 months, it is considered by some authors to be post-Lyme syndrome (PLS) or post-treatment Lyme disease syndrome (PTLDS) [bib_ref] A critical appraisal of "chronic Lyme disease, Feder [/bib_ref] , [bib_ref] The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis,..., Wormser [/bib_ref]. So-called PTLDS is a syndrome that has yet to be generally defined scientifically and therefore is not yet universally accepted. It can be diagnostically differentiated from diagnosed late manifestations of Lyme disease and symptoms resulting from persisting reproducible pathogens and from improper healing. The benefit of repeated and long-term treatment with antibiotics has not been verified. In a controlled study of patients with erythema migrans, in which a control group containing individuals of similar age and gender was simultaneously studied, no increased incidence of post-therapeutic symptoms compared to the control group were identified [bib_ref] Subjective symptoms after treatment of early Lyme disease, Cerar [/bib_ref]. Several studies indicate special immunological characteristics. Patients who have persisting symptoms for months to years after receiving antibiotic treatment were identified as frequently having anti-neural antibodies [bib_ref] Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and..., Chandra [/bib_ref] , as well as a weaker Th1-immune response with elevated interleukin 23 concentrations in serum [bib_ref] Elevated levels of IL-23 in a subset of patients with post-lyme disease..., Strle [/bib_ref]. Bockenstedt et al. were able to identify Borrelia DNA in mice when treatment was focussed near cartilage, however they did not find any living Borrelia [bib_ref] Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy, Bockenstedt [/bib_ref]. Persisting DNA and RNA, as well as living Borrelia, were detected in rhesus monkeys through xenodiagnoses (transfer of tissue to laboratory animals) [bib_ref] Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated..., Embers [/bib_ref]. Since these were animal studies, no statement on what this means for human infections can currently be made. ## Course of action for persisting skin changes and symptoms after antibiotic treatment A primary incorrect diagnosis is a common reason for persisting skin changes and symptoms after treatment with antibiotics [bib_ref] What should be done in case of persistent symptoms after adequate antibiotic..., Puéchal [/bib_ref]. In the case of clinically diagnosed erythema migrans and multiple erythemata migrantia that do not heal within 6 weeks, a differential diagnosis of circumscribed scleroderma (morphea), granuloma annulare, sarcoidosis, erythema annulare et diutinum, tinea (with low epidermal involvement) or uticarial vasculitis should be considered. Patients should be referred to a dermatologist for further diagnostics. Borrelial lymphocytoma often heals very slowly over many months. According to studies by Maraspin et al. on 85 patients, healing time was, on average, 28 days (7-270 days). The longer the borrelial lymphocytoma was present, the longer it took to heal [bib_ref] Solitary borrelial lymphocytoma in adult patients, Maraspin [/bib_ref]. If the knots persist for more than one year, or new knots appear, a skin biopsy should be carried out by a dermatologist for a histological diagnosis and Borrelia PCR. Cutaneous pseudolymphoma, Jessner's lymphocytic infiltration or a malignant lymphoma should be considered in the differential diagnosis. It takes years following antibiotic treatment for skin changes to slowly regress in the case of an acrodermatitis chronica atrophicans that has persisted for years. The atrophy of the skin, tissue and fat can be irreversibleespecially in older people. This also applies to ACA-associated peripheral neuropathy. (See also the AWMF-S3 Guideline on Neuroborreliosis which is in progress.) Age-related skin atrophy, chronic thermal damage to the skin, e.g. chilblains and heat melanosis, as well as chronic venous insufficiency with stasis dermatitis can be considered in the differential diagnosis. Chronic neuropathic pain after adequate antibiotic treatment of acrodermatitis chronica atrophicans with peripheral neuropathy is treated in accordance with the DGN's guideline "Neuropathic Pain" (AWMF -guidelines register no. 030/114). All patients whose symptoms persist after antibiotic treatment of cutaneous Lyme borreliosis should undergo careful differential diagnostic clarification by respective specialists, above all, for internal medicine (infectiology, rheumatology, cardiology, endocrinology), psychosomatics, psychotherapy, psychiatry or palliative care, since chronic infections with another etiology, other internal medical disorders, autoimmune diseases, chronic pain syndrome, and depressive and somatoform disorders should also be considered in the differential diagnosis and need to be treated accordingly. Recommendations for persisting symptoms after treatment in accordance with the guidelines: - If an erythema or multiple erythemas persist after treatment of erythema migrans (longer than 6 weeks), the patient shall be referred to a dermatologist for a differential diagnosis of circumscribed scleroderma (morphea), granuloma annulare, sarcoidosis, erythema annulare et diutinum, tinea or urticarial vasculitis. (Strong consensus: 17/17) - If a lymphocytoma persists or progresses after treatment the patient shall be referred to a dermatologist for a differential diagnosis (cutaneous pseudolymphoma, Jessner's lymphocytic infiltration or malignant lymphoma). (Strong consensus: 17/17) - If the acrodermatitis chronica atrophicans persists after treatment the patient shall be referred to a dermatologist for further consultation and for a differential diagnosis (age-related skin atrophy, chronic thermal damage to the skin e.g. chilblains and heat melanosis, chronic venous insufficiency with stasis dermatitis). (Strong consensus: 16/16) 9 Prophylaxis ## Preventing tick bites The best prophylaxis is to prevent tick bites by wearing clothing that covers the body, and carefully checking the skin, including the scalp, after being outdoors. This is particularly important for children, who have an increased risk when playing outdoors between spring and autumn. Insect repellents that are effective against ticks, e.g. diethyltoluamide (DEET), icaridin (1-(1-methylpropyl carbonyl)-2-(2-hydroxyethyl)piperidine), ethyl butylacetylaminopropionate (EBAAP, IR 3535) can also be used, however their effectiveness is limited to up to 4 hours [bib_ref] Pilot study assessing the effectiveness of factory-treated, longlasting permethrin-impregnated clothing for the..., Faulde [/bib_ref] , [bib_ref] The efficacy of repellents against Aedes, Anopheles, Culex and Ixodes spp. -a..., Lupi [/bib_ref]. ## Preventing lyme borreliosis Removing the ticks before they become engorged with blood is very important. The risk of a Borrelia transfer increases with the length of time that the tick sucks [bib_ref] Life cycle of Borrelia burgdorferi sensu lato and transmission to humans, Gern [/bib_ref]. Transmission within the first 12 hours has rarely been observed in laboratory animals. After being in a garden, park, field forest or meadow where there may have been contact with a tick, the body should be checked the same evening for ticks. The ticks should be removed immediately with a tick tweezer or a tick card in order to prevent the transfer of the Borrelia. If parts of the suction organ remain in the skin, they can later be removed with a needle or a curettage [bib_ref] The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis,..., Wormser [/bib_ref]. If the head or the suction organ remains in the skin, this is not critical in terms of a Borrelia transfer. When nymphs and adult ticks are engorged with blood, their bodies should not be squeezed in order to prevent a possible transfer of the Borrelia. Checking the tick that has been removed from the skin for borrelia does not make sense since the detection of the borrelia in the tick is not sufficiently predictive for whether the Borrelia has been transferred to the host and for the emergence of the disease. After removing the tick, the patient should be informed of the necessity of observing the bite site over the subsequent 6 weeks (Annex 1: "Patient information after a tick bite" in Attachment 1). ## Prophylactic treatment after a tick bite According to an American study, the risk of infection after a tick bite can be reduced through a one-time prophylactic administration of 200 mg of doxycycline (87% effectiveness) [bib_ref] Single-dose doxycycline for the prevention of Lyme disease, Leenders [/bib_ref] , [bib_ref] Prophylaxis with singledose doxycycline for the prevention of Lyme disease after an..., Nadelman [/bib_ref]. The results, however, should be interpreted with caution since only one follow-up check took place after 6 weeks. Thus no statement can currently be made as to whether this is sufficiently effective with regard to a late infection. In light of the low risk of infection, doxycycline would have to be administered unnecessarily many times in order to prevent a potential infection. According to projections of infection risk in endemic areas, 40-125 prophylaxes would have to be taken in order to prevent 1 infection [bib_ref] Epidemiology and diagnosis of Lyme borreliosis, Wilske [/bib_ref]. Impact on the intestinal flora and a possible development of resistance through frequent prophylaxis is conceivable. Therefore, oral doxycycline prophylaxis in Europe is not recommended. The prophylactic application of an antibiotic cream is also controversial. Animal studies with azithromycin cream reveal a good prophylactic efficacy [bib_ref] Evaluation of the preventive capacities of a topically applied azithromycin formulation against..., Knauer [/bib_ref] , [bib_ref] Efficacy of an experimental azithromycin cream for prophylaxis of ticktransmitted lyme disease..., Piesman [/bib_ref]. Placebocontrolled studies on the effectiveness in humans have yet to be published. This treatment is not currently recommended due to the lack of clinical data. ## Recommendations on infection prophylaxis: - Clothing that covers the body should be worn to prevent tick bites. - Using tick repellents can be recommended with some reservations. - Skin should be inspected in the evening for ticks after being outside in an area where there is a possibility of the individual coming into contact with ticks. - Ticks should be removed early in order to prevent Lyme disease. - The site of the bite should be observed for up to six weeks. ## Vaccines No approved vaccine that can be used on humans is currently available. A vaccination with recombinant lipidated Osp A has been evaluated in the USA as part of a major study and has shown to be effective [bib_ref] Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with..., Steere [/bib_ref] ,. The vaccine has been approved in the USA since 1999; however, it was taken from the market by its manufacturer. The reason for this is not medical. Reports on undesired vaccine reactions in individuals who are genetically predispositioned were refuted by multiple qualified studies [bib_ref] Lyme disease: uphill struggle, Abbott [/bib_ref] , [bib_ref] Human T lymphocyte response to Borrelia burgdorferi infection: no correlation between human..., Kalish [/bib_ref] , [bib_ref] The Lyme vaccine: a cautionary tale, Nigrovic [/bib_ref]. This monovalent vaccine is not suitable for Europe as it only protects against an infection with B. burgdorferi sensu stricto, and not against the genospecies B. afzelii and B. garinii that are frequently found in Europe. A polyvalent Osp A vaccine is currently being developed for Europe [bib_ref] A novel multivalent OspA vaccine against Lyme borreliosis shows promise in Phase..., Barrett [/bib_ref] , however approval is not expected in the foreseeable future. ## Notes Procedure for forming a consensus The guideline was created using a modified Delphi process and was voted on in an extended consensus conference of the Interdisciplinary S3 Guideline Group, moderated by Prof. Ina Kopp, Head of the AWMF Institute for Medical Knowledge Management. It was passed by the 22 expert medical societies and patient organisations involved. The guideline is a part of the registered Interdisciplinary S3 Overall Guideline on the "Diagnosis and Treatment of Lyme Borreliosis". ## Support This guideline was created without the influence or financial support of sponsors. The funds required to create and to translate this guideline were provided by the German Society for Dermatology and the Society for Promotion of Quality Assurance in Medical Laboratories (INSTAND e. V.). Travel expenses were provided by the respective expert medical societies. ## Declaration of competing interests by the authors [fig] •: Recommendations for confirming a clinical diagnosis Recommendations for a stage-related laboratory diagnosis: serological detection of IgM and IgG Borrelia antibodies using the 2-tiered ELISA/immunoblot process; sensible use of molecular-diagnostic and culture procedures Treatment of the localised, early-stage infection (erythema migrans, erythema chronicum migrans and borrelial lymphocytoma) Treatment of the disseminated early-stage infection (multiple erythemata migrantia, flu-like symptoms) Treatment of the late-stage infection (acrodermatitis chronica without neurological manifestations) Treatment of the late-stage infection (acrodermatitis chronica with neurological manifestations) Prevention of Lyme borreliosis Recommendations for observing the area around the tick bite Information sheet for patients (Annex 1 in Attachment 1) [/fig] [fig] Figure 2: Clinical variations of erythema migrans Fig. 2a: Initial seronegative erythema migrans 1 week after tick bite DD reaction to insect bite; diameter 4.9 cm, progression under observation Fig. 2b: Seronegative erythema migrans, elevation of IgM antibodies occured 5 days after start of treatment Fig. 2c: Typical marginated migrating erythema migrans Fig. 2d: Typical marginated erythema migrans with fresh areas of inflammation within the ring 6.1.2 Variability of the erythema migrans (atypical erythema migrans) [/fig] [fig] Figure 3: Variability of the erythema migrans Fig. 3a: Flaming red erythema chronicum migrans with radiculitis on the left leg, DD erysipelas Fig. 3b: Blotchy purple erythema chronicum migrans on the upper thigh for 3 months Fig. 3c: Large light-red arch-shaped erythema chronicum migrans on the abdomen Fig. 3d: Centrally vesicular erythema migrans Fig. 3e: Haemorrhagic bullous erythema migrans on the foot Fig. 3f: Purple, haemorrhagic, non-migrating erythema chronicum migrans on the outer ankle with joint swelling [/fig] [fig] Figure 4: Borrelial lymphocytomaFig. 4a: Borrelial lymphocytoma preauricular and on the left earlobe Fig. 4b: Borrelial lymphocytoma on the right auricle near a non-marginated erythema migrans Fig. 4c: Pronounced nodular borrelial lymphocytoma on the earlobe Fig. 4d/e: Borrelial lymphocytoma on the sole of the foot with erythema migrans on the lower leg, histologically initially misdiagnosed as a low-grade malignant B cell lymphoma Fig. 4f: Small perineal borrelial lymphocytoma is required in order to diagnostically differentiate them from malignant cutaneous lymphomas. Significant features of borrelial lymphocytoma • Pseudolymphoma, mostly solitary, more frequent in children • Localised, above all on the earlobes, nipples or in the genital area • Purple subcutaneous nodules or plaque • Histologically mostly mixed B and T lymphocytic infiltrates (Strong consensus: 19/20) [/fig] [fig] Figure 5: Multiple erythemata migrantia (MEM) Fig. 5a and 5b: Pronounced erythemata migrantia on the right arm, approx. 40 more on the torso and lower extremities Fig. 5c: Oval erythema on the left cheek, many similar erythemas on the torso and upper leg a sign of early disseminated borreliosis Fig. 5d: Symmetrical redness on the cheeks of a 5-year-old girl with multiple erythemata migrantia on her trunk and extremities, accompanied by flu-like symptoms [/fig] [fig] Figure 6: Late cutaneous manifestations Fig. 6a-d: Oedematous infiltrative stage of acrodermatitis chronica Fig. 6a: Acrodermatitis chronica. Homogenous reddening of the left leg without atrophy, persisting for one year Fig. 6b: Acrodermatitis chronica in the oedematous infiltrative stage. Hard swelling and purple colouring of the right leg with swelling of the Achilles tendon and swelling of the ankle joint Fig. 6c: Acrodermatitis in the oedematous infiltrative stage. Blotchy purple confluent erythemas on the left arm of a 15-year-old girl Fig. 6d: Typical perivascular plasma-cellular infiltrate in the case of acrodermatitis chronica Fig. 6 e-g: Atrophic stage of ACA Fig. 6e: ACA -Purple colouring and atrophy on the back of the right hand and little finger, and purple blotches, stripes and [/fig] [fig] Figure 7: Algorithm for diagnosing a solitary or multilocular erythema migrans • If the serological test is negative and the clinical suspicion remains, direct cultural or molecular-biological detection from biopsy material shall be used for clarification. (Strong consensus: 20/20) [/fig] [table] Table 1: Clinical manifestations of Lyme borreliosis [/table] [table] Table 2: Clinical differential diagnoses of cutaneous Lyme borreliosis 13/31 GMS German Medical Science 2017, Vol. 15, ISSN 1612-3174 [/table] [table] Table 3: Two tiered serological diagnostic approach (as per MIQ 12 and DIN 58969-44 2005-07) [/table] [table] Table 4: Interpretation of serological result constellations [/table] [table] Table 5: Treatment recommendations for cutaneous Lyme borreliosis [/table] [table] Table in the: Guideline Report, Section 5 (in German): http://www.awmf.org/uploads/tx_szleitlinien/013-044m_ S2k_Kutane_Lyme_Borreliose_2016-05_01.pdf. [/table]	None	None	This guideline of the German Dermatology Society primarily focuses on the diagnosis and treatment of cutaneous manifestations of Lyme borreliosis. It has received consensus from 22 German medical societies and 2 German patient organisations. It is the first part of an AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.) interdisciplinary guideline: “Lyme Borreliosis – Diagnosis and Treatment, development stage S3”. The guideline is directed at physicians in private practices and clinics who treat Lyme borreliosis. Objectives of this guideline are recommendations for confirming a clinical diagnosis, recommendations for a stage-related laboratory diagnosis (serological detection of IgM and IgG Borrelia antibodies using the 2-tiered ELISA/immunoblot process, sensible use of molecular diagnostic and culture procedures) and recommendations for the treatment of the localised, early-stage infection (erythema migrans, erythema chronicum migrans, and borrelial lymphocytoma), the disseminated early-stage infection (multiple erythemata migrantia, flu-like symptoms) and treatment of the late-stage infection (acrodermatitis chronica atrophicans with and without neurological manifestations). In addition, an information sheet for patients containing recommendations for the prevention of Lyme borreliosis is attached to the guideline.
deda404f9e6038cb64764ef88c9c67832ff60829	pubmed	Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted nutrition in patients with advanced cancer	Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted nutrition in patients with advanced cancer Purpose The provision of clinically assisted nutrition (CAN) in patients with advanced cancer is controversial, and there is a paucity of specific guidance, and so a diversity in clinical practice. Consequently, the Palliative Care Study Group of the Multinational Association of Supportive Care in Cancer (MASCC) formed a Subgroup to develop evidence-based guidance on the use CAN in patients with advanced cancer. Methods This guidance was developed in accordance with the MASCC Guidelines Policy. A search strategy for Medline was developed, and the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were explored for relevant reviews/trials respectively. The outcomes of the review were categorised by the level of evidence, and a "category of guideline" based on the level of evidence (i.e. "recommendation", "suggestion", or "no guideline possible"). Results The Subgroup produced 11 suggestions, and 1 recommendation (due to the paucity of evidence). These outcomes relate to assessment of patients, indications for CAN, contraindications for CAN, procedures for initiating CAN, and reassessment of patients. Conclusions This guidance provides a framework for the use of CAN in advanced cancer, although every patient needs individualised management. # Introduction The decision to initiate (or withdraw) clinically assisted nutrition (CAN) in patients with advanced cancer is a common clinical scenario. In some cases, the decision appears relatively straightforward, whilst in many cases, the decision depends on a subjective assessment of the potential benefits versus the potential risks. Research suggests that, especially at the end of life, the use of CAN varies enormously (3-53%) On the basis of the above, the Palliative Care Study Group of the Multinational Association of Supportive Care in Cancer (MASCC) formed a Subgroup to develop evidence-based guidance on the use of CAN in patients with advanced cancer. This paper gives an overview of CAN in patients with advanced cancer, the methodology involved in developing the outcomes, and the evidence to support the outcomes (and the grading of the evidence). At the time the Subgroup started the project, there were no up-to-date guidelines on the use of CAN in patients with advanced cancer, although there are older guidelines relating to this cohort of patients , and there are newer guidelines relating to cancer patients in general (which address this cohort of patients to a minor extent) . Our guidance complements the latter guidelines, and is aimed at the core multidisciplinary team involved in the care of patients with advanced cancer. # Background ## Definitions For the purposes of this guidance, CAN refers to all forms of tube-feeding (e.g. via nasogastric tube, percutaneous endoscopic gastrostomy (PEG), or parenteral nutrition (PN). It does not cover oral feeding, by cup, spoon, or any other method of delivering food or nutritional supplements into a patient's mouth . Synonymous terms within the medical literature include "medically-assisted nutrition" [10], "artificial nutrition" [5], "artificial feeding" , and "hyperalimentation" (specifically for parenteral nutrition) . The term "medical nutrition therapy" includes the use of oral nutritional supplements as well as "tube feeding" . Other definitions used in this guidance include "advanced cancer" (i.e. "cancer that is unlikely to be cured or controlled with treatment. The cancer may have spread from where it first started, to nearby tissue, lymph nodes, or distant parts of the body. Treatment may be given to help shrink the tumour, slow the growth of cancer cells, or relieve symptoms"), "end-of-life" (i.e. the last year of life), and "terminal phase" (i.e. the last days to weeks of life) [bib_ref] Management of the actively dying patient, Lacey [/bib_ref]. It should be noted that patients with advanced cancer may not be at the end-of-life (as defined), and that prognostication remains exceptionally challenging (especially when the prognosis is of the order of months to years rather than days to weeks) [bib_ref] Prognostication in advanced cancer: update and directions for future research, Hui [/bib_ref]. Thus, the trajectory of the illness may change (i.e. accelerate or decelerate), and/or acute events may intervene (i.e. cancer-related or separate condition). ## Nutritional requirements The National Institute for Health and Care Excellence/ NICE (United Kingdom) recommend a "total intake" for all adults that includes(a) 25-35 kcal/kg/day total energy; (b) 0.8-1.5 g protein (0.13-0.24 g nitrogen)/kg/day; (c) [bib_ref] Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment, Jager-Wittenaar [/bib_ref] ## Malnutrition Malnutrition (also known as undernutrition) has been defined as "a state resulting from lack of intake or uptake of nutrition that leads to altered body composition (decreased fat free mass) and body cell mass leading to diminished physical and mental function and impaired clinical outcome from disease" . Malnutrition can result from starvation, disease (gastrointestinal disease, acute injury, acute systemic disease with inflammation, chronic systemic disease with/ without inflammation), normal ageing, or a combination of these factors [bib_ref] GLIM criteria for the diagnosis of malnutrition -a consensus report from the..., Cederholm [/bib_ref]. Consensus diagnostic criteria for malnutrition include the presence of one so-called phenotypic criterion (i.e. weight loss, reduced body mass index, reduced muscle mass), and one so-called etiologic criterion (i.e. reduced food intake or assimilation, disease burden/ inflammation) [bib_ref] GLIM criteria for the diagnosis of malnutrition -a consensus report from the..., Cederholm [/bib_ref]. Malnutrition remains a major cause of mortality worldwide, and it has been estimated that malnutrition is the direct cause of death in 10-20% cancer patients [bib_ref] ESPEN expert group recommendations for action against cancer-related malnutrition, Arends [/bib_ref]. Data on the Irish Republican Army (IRA) hunger strikers suggests that on average, an otherwise healthy young adult male can survive for 61 days without food [bib_ref] Hunger strikers may have died of fat, not protein, loss, Korcok [/bib_ref] : the minimum recorded survival was 46 days, whilst the maximum recorded survival was 73 days [bib_ref] The Hunger Strike of 1981 -List of dead and other hunger strikers, Melaugh [/bib_ref]. However, survival would be expected to be "considerably reduced" in patients with an underlying malignancy [bib_ref] Undernutrition. In: Nightingale J (ed) Intestinal failure, Allison [/bib_ref]. Importantly, malnutrition also results in significant morbidity. Every system within the body is affected, resulting in physical (e.g. muscle weakness), cognitive (e.g. impaired memory), and psychological problems (e.g. depression), with associated impact on quality of life, and the ability to undertake activities of daily living [bib_ref] Undernutrition. In: Nightingale J (ed) Intestinal failure, Allison [/bib_ref] [bib_ref] Role of nutritional status in predicting quality of life outcomes in cancer..., Lis [/bib_ref]. ## Nutritional problems in cancer patients Anorexia Anorexia (loss of appetite) is a common symptom in patients with advanced cancer (30-92%) [bib_ref] Frequency and severity of gastrointestinal symptoms in advanced cancer, Potter [/bib_ref] [bib_ref] C-reactive protein, symptoms and activity of daily living in patients with advanced..., Amano [/bib_ref] , and is especially prevalent in patients at the end-of-life and in the terminal phase. Anorexia often leads to weight loss, although this is not an inevitable consequence. Anorexia may be related to a number of potentially reversible factors (e.g. "nutrition impact symptoms" -see below), and may be amenable to specific interventions (e.g. corticosteroids, progestogens) [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref] , as well as use of supportive measures (i.e. dietary advice, use of oral nutritional supplements). CAN should never be initiated solely on the basis of the development of anorexia (causing reduced oral intake). ## Weight loss Weight loss is also a common problem in patients with advanced cancer (33-93%) [bib_ref] Frequency and severity of gastrointestinal symptoms in advanced cancer, Potter [/bib_ref] [bib_ref] C-reactive protein, symptoms and activity of daily living in patients with advanced..., Amano [/bib_ref] , and is especially prevalent in patients at the end-of-life and in the terminal phase. As discussed, anorexia often leads to weight loss, but paradoxically malnutrition often leads to anorexia [bib_ref] Undernutrition. In: Nightingale J (ed) Intestinal failure, Allison [/bib_ref]. Weight loss may also be related to a number of potentially reversible factors (e.g. "nutrition impact symptoms" -see below), and again may be amenable to specific interventions (e.g. corticosteroids, progestogens) [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref] , as well as use of supportive measures (i.e. dietary advice, use of oral nutritional supplements). CAN should never be initiated solely on the basis of the development of weight loss. ## Nutrition impact symptoms Nutrition impact symptoms (NIS) are a range of symptoms/ problems that interfere with the patient's appetite, their ability to ingest food, or their ability to digest food [bib_ref] Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a..., Omlin [/bib_ref]. Examples of NIS include dry mouth, taste disturbance, oral discomfort, dental/denture problems, difficulty swallowing, nausea, vomiting, early satiety, constipation, and certain systemic symptoms/problems (e.g. fatigue, low mood). NIS form part of certain assessment tools (e.g. Patient-Generated Subjective Global Assessment / PG-SGA) [bib_ref] Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment, Jager-Wittenaar [/bib_ref] , and specific a checklist has been developed for patients with advanced cancer [bib_ref] Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a..., Omlin [/bib_ref]. However, none of these tools include a complete list of NIS, and most cancer-related/cancer treatment-related symptoms have the potential to interfere with patient nutrition (either directly, or indirectly). ## Malnutrition Malnutrition is common in patients with cancer (20-70%), with the prevalence dependent on the cancer type, the cancer stage, and the age of the patient [bib_ref] ESPEN expert group recommendations for action against cancer-related malnutrition, Arends [/bib_ref]. Thus, malnutrition is more common in patients with head and neck, lung, and gastrointestinal cancers: malnutrition is also more common in patients with advanced disease (cf. early cancer), and more common in older patients (cf. younger patients) [bib_ref] ESPEN expert group recommendations for action against cancer-related malnutrition, Arends [/bib_ref]. ## Cancer cachexia Cancer cachexia is a distinct type of disease-associated malnutrition [13], which is common in patients with advanced cancer (~ 50%) [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref]. It is the result of a variable combination of reduced food intake and abnormal metabolism [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref]. The metabolic alterations are highly complex (and not completely understood), but prominent features include systemic inflammation, and increased catabolism (or decreased anabolism) [bib_ref] Understanding the mechanisms and treatment options in cancer cachexia, Fearon [/bib_ref]. Importantly, for the reasons outlined, medical nutritional therapies (including CAN) per se are ineffective in managing cancer cachexia [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref]. International consensus diagnostic criteria for cancer cachexia are (a) weight loss > 5% over 6 months (in absence of simple starvation); or (b) Body Mass Index (BMI) < 20 and any degree of weight loss > 2%; or (c) appendicular skeletal muscle index consistent with sarcopenia (males < 7.26 kg/m 2 ; females < 5.45 kg/m 2 ) and any degree of weight loss > 2% [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref]. Of note, the wasting process in cancer cachexia is somewhat different from the wasting process in simple starvation: in the former, the predominant factor is skeletal muscle loss (with or without loss of adipose tissue), whilst in the latter, the predominant factor is loss of adipose tissue (with preservation of skeletal muscle). ## Nutritional therapies Nutritional therapies include oral nutritional supplements, enteral tube feeding (also known as enteral nutrition), and parenteral nutrition [13]. Enteral tube feeding involves the delivery of nutrients via a tube (e.g. nasogastric/NG; nasojejunal/NJ), or via a stoma (e.g. percutaneous endoscopic gastrostomy/PEG; percutaneous jejunostomy/PEJ). Enteral tube feeding may be total (TEN), or supplemental to oral intake of food. Parenteral nutrition (PN) involves delivery of nutrients through a peripheral venous line or a central venous line. Parenteral nutrition may also be total (TPN), or supplemental to oral intake of food (SPN). CAN is considered a medical treatment, and recent European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines highlight the ethical principles regarding the provision/omission of CAN [formula] [8]. [/formula] This guideline is based on universal ethical principles (i.e. autonomy, beneficence, non-maleficence, justice), but readers are encouraged to check their own national guidance on the provision/omission of CAN/medical treatments. # Methods The aim of the Subgroup was to develop comprehensive, clinically relevant, evidence-based guidance on the provision of CAN in patients with advanced cancer. Thus, it was agreed that the guidance could include ones supported by "high" levels of evidence (e.g. systematic reviews), as well as ones supported by "low" levels of evidence (e.g. expert opinion), if the topic were deemed to be clinically relevant. The guidance was developed in accordance with the MASCC Guidelines Policy. The Subgroup adopted the National Cancer Institute (NCI) definition of advanced cancer (see above), and data was included from studies involving cancer patients still receiving anti-cancer treatment, and also cancer patients only receiving palliative care (or both modalities). The physician / multidisciplinary team has the ultimate responsibility for making the decision on clinically assisted nutrition Clinically assisted nutrition should be considered if the potential benefits outweigh the potential burdens (and vice versa) Clinically assisted nutrition should be considered if it is unclear whether the potential benefits outweigh the potential burdens (i.e. give a trial of clinically assisted nutrition) The patient does not have the right to demand clinically assisted nutrition The patient does have the right to refuse clinically assisted nutrition (if the patient has capacity / competence) A valid advance directive to refuse treatment must be followed (if the patient does not have capacity / competence) The family do not have the right to demand clinically assisted nutrition A search strategy for Medline was developed (Appendix 1), and the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CEN-TRAL) were explored for relevant reviews/trials respectively . The review of the published literature was restricted to papers written in English, and to papers relating to adult (≥ 19 years) humans. All abstracts identified by the search of Medline (1946 to 10th July 2020) were downloaded into a reference management software package. These abstracts were independently assessed for relevance by the two main authors (BA, AD), and if one author deemed the abstract relevant, then the full text of the article was obtained. These articles were independently assessed for inclusion by the two main authors. All of the authors were involved in assessing the randomised controlled trials in the CENTRAL, and the two main authors were involved in assessing the systematic reviews in the Cochrane Database of Systematic Reviews. Whenever possible, the guidance was based on data from patients with advanced cancer. However, when no data was available, or only poor-quality data was available, then data from other populations was extrapolated (if deemed appropriate). The outcomes of the review were characterised by a level of evidence (i.e. I, II, III, IV, or V), and a "category of guideline" based on the level of evidence (i.e. "recommendation", "suggestion", or "no guideline possible") (Appendix 2). The outcomes were independently characterised by the two main authors (BA, AD), and a consensus reached in the case of any disagreement. All of the authors agreed with the outcomes/characterisations of outcomes. # Results The searches were last undertaken on 13th July 2020. The Medline search identified 1513 references, and 110 full text articles were retrieved (and reviewed). The search of the Cochrane Central Register of Controlled Trials (29th July 2020) identified 1368 references, and 11 more full-text articles were formally examined. Similarly, the search of the Cochrane Database of Systematic Reviews (29th July 2020) identified 39 references, and 4 reviews were formally examined. Reference lists of the retrieved articles/reviews were also checked for additional sources of information (not identified in the original searches). The Subgroup were only able to formulate 11 suggestions, and 1 recommendation (due to the paucity of evidence). ## Outcomes of review The suggestions/recommendation of the Subgroup are summarised in (with the levels of evidence, and the categories of guideline). 1. All patients with advanced cancer should have regular nutritional assessments [Level of evidence-V; category of guideline-suggestion]. All patients with advanced cancer should be regularly assessed. Initial assessment (screening) involves evaluation of current food intake, and recent weight change (loss), together with measurement of BMI [7]: subsequent assessment depends on the individual clinical situation (measurement of body composition, e.g. muscle mass; measurement of inflammatory biomarkers, e.g. C-reactive protein). A number of validated nutritional screening tools are available to facilitate screening (e.g. Nutrition Risk Screening 2002/NRS-2002, Malnutrition Universal Screening Tool/MUST) . All patients with advanced cancer should also be regularly assessed for nutrition impact symptoms (see above). Although clearly related, patients require separate assessments for the need for CAN, and the need for clinically assisted hydration. Furthermore, any decision to withhold/withdraw CAN should trigger an urgent review of the need for clinically assisted hydration. The MASCC Palliative Care Study Group are developing analogous guidance on the use of clinically assisted hydration in patients with advanced cancer. ## Patients with nutritional problems should be reviewed by a specialist dietitian (with/without other members of the nutrition support team) [level of evidence-v; category of guideline-suggestion]. Nutritional problems in cancer patients are somewhat different from those in other groups of patients, and so these patients should ideally be reviewed by a specialist dietitian (preferably who has oncology experience), with/without other members of the nutrition support team . Equally, patients with nutritional impact symptoms should be reviewed by an appropriate specialist (e.g. supportive care team, palliative care team) . It should be noted that ESPEN define a nutrition support team as "a multi-disciplinary team of physicians, dietitians, nurses and pharmacists" (and other healthcare professionals), whose primary objective is "to support hospital staff in the provision of nutrition therapy, especially enteral or parenteral nutrition, to ensure that the nutritional needs of patients are satisfied, especially for those patients with complicated nutritional problems" [13]. 3. Any decision to initiate clinically assisted nutrition should be made by an appropriately constituted multidisciplinary healthcare team together with the patient and their family [Level of evidence-V; category of guideline-suggestion]. The decision to initiate (or not) CAN/other nutritional therapies depends on a number of factors , and so requires input from the oncology team, the specialist dietitian/nutrition support team, the supportive care/palliative care team, and the patient and their family. Patients with rapidly progressive disease, patients with evidence of significant systemic inflammation (i.e. increased C-reactive protein with decreased albumin), and patients with a poor performance status (i.e. Eastern Cooperative Oncology Group performance status ≥ 3) are less likely to derive benefit from CAN [7]. However, the decision remains somewhat subjective due to the limited evidence in this cohort of patients [bib_ref] Effects of current parenteral nutrition treatment on health-related quality of life, physical..., Tobberup [/bib_ref] , and the difficulty/complexity of prognostication in this cohort of patients [bib_ref] Prognostication in advanced cancer: update and directions for future research, Hui [/bib_ref]. The "stable" Cochrane systematic review of medically assisted nutrition for adult palliative care patients (i.e. "patients receiving palliative care") [10] identified four prospective uncontrolled studies involving cancer patients [bib_ref] Home artificial nutrition in advanced cancer, Pironi [/bib_ref] [bib_ref] Quality of life and length of survival in advanced cancer patients on..., Bozzetti [/bib_ref] [bib_ref] Home parenteral nutrition: a qualitative interview study of the experiences of advanced..., Orrevall [/bib_ref] [bib_ref] Home parenteral nutrition (HTPN) for incurable patients with cancer with gastrointestinal obstruction:..., Chermesh [/bib_ref] , but no randomised controlled trials. The authors of this systematic review concluded that "There are insufficient good-quality studies to make any recommendations for practice with regards to the use of medically assisted nutrition in palliative care patients" . It should be noted that this systematic review included studies involving patients with cancer and patients with other life limiting conditions. A recent systematic review of parenteral nutrition in patients with advanced cancer (i.e. "not curable but might respond to cancer treatment or disease-directed therapy to prolong life and reduce symptoms") [bib_ref] Effects of current parenteral nutrition treatment on health-related quality of life, physical..., Tobberup [/bib_ref] identified two randomised controlled trials [bib_ref] A randomized phase II study to assess the effectiveness of fluid therapy..., Oh [/bib_ref] [bib_ref] Home parenteral nutrition increases fat free mass in patients with incurable gastrointestinal..., Obling [/bib_ref] , five prospective uncontrolled studies [bib_ref] Parenteral nutrition support for patients with pancreatic cancer. Results of a phase..., Pelzer [/bib_ref] [bib_ref] The prognosis of incurable cachectic cancer patients on home parenteral nutrition: a..., Bozzetti [/bib_ref] [bib_ref] A longitudinal study investigating quality of life and nutritional outcomes in advanced..., Vashi [/bib_ref] [bib_ref] Role of parenteral nutrition in oncologic patients with intestinal occlusion and peritoneal..., Guerra [/bib_ref] [bib_ref] Longitudinal study of quality of life in advanced cancer patients on home..., Cotogni [/bib_ref] , and one retrospective uncontrolled study [bib_ref] Predictive factors of survival in patients with peritoneal carcinomatosis on home parenteral..., Santarpia [/bib_ref]. The authors of this systematic review concluded that "Current PN treatment in patients with advanced cancer is understudied and the level of evidence is weak" [bib_ref] Effects of current parenteral nutrition treatment on health-related quality of life, physical..., Tobberup [/bib_ref] : the authors further concluded that "Regardless of antineoplastic treatment and GI function, nutritional status seems to be improved by current PN treatment in malnourished patients. No benefit on survival of PN in terminal patients or patients able to feed enterally were reported. The frequency of adverse effects was low; however, a lack of systematic reporting was observed". It appears that there is no analogous systematic review of enteral tube feeding in patients with advanced cancer. Since this systematic review was published, further studies on parenteral nutrition in advanced cancer have been reported [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] [bib_ref] Effects of enteral nutrition and parenteral nutrition on survival in patients with..., Amano [/bib_ref]. Thus, [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] reported a randomised controlled trial of parenteral nutrition versus oral feeding in patients with advanced cancer and malnutrition (and a functioning gastrointestinal tract) [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] : in this cohort of patients, parenteral nutrition was not associated with improved health related quality of life, or survival, but was associated with more adverse effects. Similarly, Amona et al. (2020) reported a secondary analysis of a prospective observational study of end-of-life care in palliative care units in Japan [bib_ref] Effects of enteral nutrition and parenteral nutrition on survival in patients with..., Amano [/bib_ref] : in this cohort of patients, enteral and parenteral nutrition was associated with increased survival as compared to oral feeding. 4. Clinically assisted nutrition should be considered in patients with an inability (reversible/irreversible) to ingest sufficient nutrients [Level of evidence-V; category of guideline-suggestion]. In some patients with advanced cancer, the cause of the nutritional disturbance is the inability to ingest sufficient food due to problems relating to the cancer and/or the cancer treatment, e.g. dysphagia from an oesophageal carcinoma. The underlying cause may or may not be reversible, and so CAN may be required in the short term or indefinitely (and may be required to either supplement or replace usual oral intake). For instance, a common application of enteral feeding is to support patients with oral mucositis during/following head and neck (chemo-) radiotherapy . Importantly, irrespective of the clinical situation, the generic principles around decision-making about CAN still apply. 5. Clinically assisted nutrition should be considered in patients with an inability (reversible/irreversible) to absorb sufficient nutrients [Level of evidence-V; category of guideline-suggestion]. In other patients with advanced cancer, the cause of the nutritional disturbance is the inability to digest sufficient food due to problems relating to the cancer and/or the cancer treatment, e.g. surgical resection of small bowel. The underlying cause may or may not be reversible, and so CAN may be required in the short term or indefinitely (and may be required to either supplement or replace usual oral intake). A common application of parenteral feeding is to support patients with malignant bowel obstruction secondary to gastrointestinal or gynaecological malignancies [bib_ref] Use of parenteral nutrition in patients with advanced cancer, Soo [/bib_ref]. Many patients with malignant bowel obstruction have issues with both the ingestion of food, and the digestion of food. Importantly, irrespective of the clinical situation, the generic principles around decision-making about CAN still apply . 6. Clinically assisted nutrition should be considered in patients at risk of dying from malnutrition before dying from their cancer [Level of evidence-V; category of guideline-suggestion]. One of the main indications for CAN in this cohort of patients is the prevention of premature death from malnutrition (as opposed to inevitable death from the cancer) [8: Druml et al., 2016]. As discussed, the data indicates that young healthy adult males with no intake will starve to death in ~ 2 months [bib_ref] Hunger strikers may have died of fat, not protein, loss, Korcok [/bib_ref] , and this time period is expected to be "considerably reduced" in patients with cancer [bib_ref] Undernutrition. In: Nightingale J (ed) Intestinal failure, Allison [/bib_ref]. Thus, our suggestion is that relevant cancer patients with an estimated prognosis of > 1 month should be considered for CAN, but that cancer patients with a prognosis of days to short weeks should generally not be considered for CAN (unless there is another indication -see below). Moreover, our suggestion is that in cases of uncertainty (of prognosis), a trial of CAN should be considered (with precise criteria for continuation/discontinuation) . It should be noted that guidelines on the use of parenteral nutrition differ somewhat in terms of Cancer cachexia is defined as "a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment" [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref]. Indeed, CAN is not indicated/recommended for the treatment of cancer cachexia [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref] , although oral nutritional supplements may be useful as part of a multimodal intervention [bib_ref] Combination therapy in cachexia, Fabbro [/bib_ref]. Expert opinion is that the enteral route should be used in preference to the parenteral route, with the parenteral route being used in cases where enteral tube feeding is either inadequate, or inappropriate (or impossible) . The rationale involves lower adverse effects, ease of usage, and lower direct costs (and similar effectiveness) . In terms of adverse effects, a recent meta-analysis determined that enteral tube feeding is associated with fewer infectious complications (e.g. wound infection, pneumonia), but similar levels of non-infectious complications (e.g. nausea and vomiting, diarrhoea), as compared to parenteral nutrition [bib_ref] Enteral and parenteral nutrition in cancer patients, a comparison of complication rates:..., Chow [/bib_ref]. 11. Clinically assisted nutrition should be available in all settings, including the home setting [Level of evidence-IV; category of guideline-suggestion]. The provision of CAN for patients with advanced cancer is feasible (and safe) in the home/similar settings , and so a planned discharge from hospital should not be a major factor in the decision to withhold/withdraw relevant treatments. Recently, ESPEN produced detailed guidance on the provision of enteral nutrition at home [bib_ref] ESPEN guideline on home enteral nutrition, Bischoff [/bib_ref] , and also on the provision of parenteral nutrition at home [bib_ref] ESPEN guideline on home parenteral nutrition, Pironi [/bib_ref]. 12. All patients receiving clinically assisted nutrition should be regularly reassessed [Level of evidence-V; category of guideline-suggestion]. All patients receiving CAN should be regularly reassessed with regard to the continuation, amendment, or discontinuation of the relevant treatment . The objectives of reassessment are to (a) ensure the CAN is meeting the patient's nutritional requirements; (b) ensure the CAN is well tolerated; (c) ensure the CAN remains acceptable (to the patient); and (d) ensure the CAN remains appropriate/ consistent with the "goals of care". Patients receiving TPN require regular biochemical monitoring, whilst patients receiving enteral tube feeding require minimal biochemical monitoring [bib_ref] ESPEN guideline on home enteral nutrition, Bischoff [/bib_ref] [bib_ref] ESPEN guideline on home parenteral nutrition, Pironi [/bib_ref]. A decision to withdraw CAN is not a decision to stop feeding, and relevant patients require a new nutritional care plan (which often involves so-called comfort feeding) . Importantly, many patients in the terminal phase do not experience hunger, and those patients in the terminal phase that do experience hunger appear to respond to "small amounts" of food [bib_ref] Comfort care for terminally iii patients: the appropriate use of nutrition and..., Mccann [/bib_ref]. # Conclusion CAN is a well-established medical intervention, which is primarily indicated for the prevention of death from malnutrition in selected individuals from specific groups of patients with advanced cancer, i.e. patients with an inability to ingest sufficient nutrients, and/or an inability to digest sufficient nutrients. CAN is not indicated for the management of anorexia, weight loss, cancer cachexia, or reduced oral intake due to nutrition impact symptoms (generally). ## Supplementary information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s00520-021-06613-y. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Clinically-assisted nutrition and hydration (CANH) and adults who lack the capacity to consent: guidance for decision-making in England and Wales. British Medical Association website. https:// www. bma. org. uk/ media/ 1161/ bma-clini cally-assis ted-nutri tionhydra tion-canh-full-guida nce. pdf. Accessed October 2020. ## References [fig] [ 1 ]: and that patients and their families often have very positive views about CAN, whilst healthcare professionals often have disparate views about CAN [2-4]. [/fig] [fig] Figure 1: Decision [/fig] [fig] . 2: Recommendations/suggestions on clinically assisted nutrition in patients with advanced cancer 1 -All patients with advanced cancer should have regular nutritional assessments [Level of evidence -V; category of guideline -suggestion] -Patients with nutritional problems should be reviewed by a specialist dietitian (with / without other members of the nutrition support team) [Level of evidence -V; category of guideline -suggestion]. 3 -Any decision to initiate clinically assisted nutrition should be made by an appropriately constituted multidisciplinary healthcare team together with the patient and their family [Level of evidence -V; category of guideline -suggestion]. 4 -Clinically assisted nutrition should be considered in patients with an inability (reversible / irreversible) to ingest sufficient nutrients [Level of evidence -V; category of guideline -suggestion]. 5 -Clinically assisted nutrition should be considered in patients with an inability (reversible / irreversible) to absorb sufficient nutrients [Level of evidence -V; category of guideline -suggestion]. 6 -Clinically assisted nutrition should be considered in patients at risk of dying from malnutrition before dying from their cancer [Level of evidence -V; category of guideline -suggestion]. 7 -Clinically assisted nutrition is not indicated for the treatment of cancer cachexia [Level of evidence -V; category of guideline -suggestion]. 8 -Protocols / processes should be in place to deal with conflicts over the initiation (or withdrawal) of clinically assisted nutrition [Level of evidence -V; category of guideline -suggestion]. 9 -Patients receiving clinically assisted nutrition should have a nutritional care plan which defines the agreed objectives of treatment, and the agreed conditions for withdrawal of treatment [Level of evidence -V; category of guideline -suggestion]. 10 -Enteral tube feeding is generally preferable to parenteral nutrition (if possible) [Level of evidence -I; category of guideline -recommendation]. 11 -Clinically assisted nutrition should be available in all settings, including the home setting [Level of evidence -IV; category of guidelinesuggestion]. 12-All patients receiving clinically assisted nutrition should be regularly reassessed [Level of evidence -V; category of guideline -suggestion]. [/fig] [fig] 8: Protocols/processes should be in place to deal with conflicts over the initiation (or withdrawal) of clinically assisted nutrition [Level of evidence-V; category of guideline-suggestion].The provision of CAN is often an emotive subject for patients and their families (particularly at the end-of-life) [2, 53]. As discussed, CAN is a medical treatment, and patients (and/or their families) do not have the right to demand the treatment. In cases of conflict, it is recommended obtaining a second opinion from a suitably qualified healthcare professional:other options such as involvement of a clinical ethics committee, or involvement of the legal system are not generally required in this cohort of patients [8]. 9. Patients receiving clinically assisted nutrition should have a nutritional care plan which defines the agreed objectives of treatment, and the agreed conditions for withdrawal of treatment [Level of evidence-V; category of guideline-suggestion]. Patients receiving CAN should have a nutritional care plan which includes the rationale for treatment, the specifics of treatment (e.g. method of CAN), details about ongoing follow-up, details about ongoing reassessment, the indications for continuation of treatment, the indications for discontinuation of treatment, and contact details for the specialist dietitian/nutritional support team (and other relevant healthcare professionals) [7, 8]. 10. Enteral tube feeding is generally preferable to parenteral nutrition (if possible) [Level of evidence-I; category of guideline-recommendation]. [/fig] [fig] 1: Raijmakers NJ, van Zuylen L, Costantini M, Caraceni A, Clark J, Lundquist G et al (2011) Artificial nutrition and hydration in the last week of life in cancer patients. A systematic literature review of practices and effects. Ann Oncol 22:1478-1486 2. del Rio MI, Shand B, Bonati P, Palma A, Maldonado A, Taboada P et al (2012) Hydration and nutrition at the end of life: a systematic review of emotional impact, perceptions, and decision-making among patients, family, and health care staff. Psychooncology 21:913-921 3. Amano K, Morita T, Miyamoto J, Uno T, Katayama H, Tatara R (2018) Perception of need for nutritional support in advanced cancer patients with cachexia: a survey in palliative care settings. Support Care Cancer 26:2793-2799 4. Amano K, Maeda I, Morita T, Masukawa K, Kizawa Y, Tsuneto S et al (2020) Beliefs and perceptions about parenteral nutrition and hydration by family members of patients with advanced cancer admitted to palliative care units: a nationwide survey of bereaved family members in Japan. J Pain Symptom Manage 60:355-361 5. Bozzetti F, Amadori D, Bruera E, Cozzaglio L, Corli O, Filiberti A et al (1996) Guidelines on artificial nutrition versus hydration in terminal cancer patients. Nutrition 12:163-167 6. Bachmann P, Marti-Massoud C, Blanc-Vincent MP, Desport JC, Colomb V, Dieu L et al (2003) Summary version of the standards, options and recommendations for palliative or terminal nutrition in adults with progressive cancer (2001). Br J Cancer 89(Suppl1):S107-S110 7. Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F et al (2017) ESPEN guidelines on nutrition in cancer patients. Clin Nutr 36:11-48 8. Druml C, Ballmer PE, Druml W, Oehmichen F, Shenkin A, Singer P et al (2016) ESPEN guideline on ethical aspects of artificial nutrition and hydration. Clin Nutr 35:545-556 9. British Medical Association, Royal College of Physicians (2018) [/fig] [table] Table 3: Factors influencing the decision to initiate clinically assisted nutrition in patients with advanced cancer * Prognosis is dependent on many of the other factors [/table]	None	https://link.springer.com/content/pdf/10.1007/s00520-021-06613-y.pdf	None
19b2ffe2fa12aaaa7a996aa60bd6f23f3575bf51	pubmed	Stereotactic Radiosurgery for Intracranial Noncavernous Sinus Benign Meningioma: International Stereotactic Radiosurgery Society Systematic Review, Meta-Analysis and Practice Guideline	Stereotactic Radiosurgery for Intracranial Noncavernous Sinus Benign Meningioma: International Stereotactic Radiosurgery Society Systematic Review, Meta-Analysis and Practice Guideline [bib_ref] Treatment and survival of patients with nonmalignant intracranial meningioma: results from the..., Cahill [/bib_ref] [bib_ref] Effects of using combined transpetrosal surgical approaches to treat petroclival meningiomas, Mathiesen [/bib_ref] [bib_ref] Effects of using combined transpetrosal surgical approaches to treat petroclival meningiomas, Mathiesen [/bib_ref] [bib_ref] Della Rocca R. Sphenoorbital meningiomas: surgical limitations and lessons learned in their..., Shrivastava [/bib_ref] [bib_ref] The contemporary role of stereotactic radiosurgery in the treatment of meningiomas, Cohen-Inbar [/bib_ref] [bib_ref] Fractionated radiotherapy and radiosurgery of intracranial meningiomas, Biau [/bib_ref] [bib_ref] Radiosurgery for intracranial meningiomas: a systematic review and meta-analysis, Pinzi [/bib_ref] [bib_ref] Stereotactic radiosurgery for benign (World Health Organization grade I) cavernous sinus meningiomas-International..., Lee [/bib_ref] # Methods ## Article selection The ISRS clinical practice guideline taskforce conducted a systematic review of the literature specific to the management of intracranial meningioma with SRS, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (2009) and the Cochrane guidelines for systematic reviews of interventions.Articles were included when inclusion criteria were met. ## Inclusion criteria Retrospective and prospective studies reporting outcomes on adult patients with a radiological and/or pathological diagnosis of intracranial WHO grade I meningioma were included. In those series that included other grades of meningioma (WHO grade II and III), only those studies that segregated outcomes for the WHO grade I population were included. Similarly, those studies including CS meningioma were excluded, unless outcomes were segregated for non-CS meningioma. For series reporting outcomes without segregating the study population to non-CS patients and CS patients, an exception was made, provided that the proportion of CS patients included did not exceed 30% to 40% of the overall population. A minimum follow-up period of 3 yr was deemed mandatory for the analysis of LC and progression-free-survival (PFS); series with a mean/median follow-up period lower than 36 mo have been considered if specified the number of patients for which a longer than 3 yr follow-up is available. Studies which included re-irradiated patients, or whose population amounted to less than 10 patients, were also excluded. SRS and HSRT, delivered over 2 to 5 fractions, were permitted. Lastly, patients who had been treated with primary or adjuvant/salvage SRS were included. ## Objectives The primary objective of the study was to define the efficacy of SRS in the treatment of intracranial WHO grade I meningioma (excluding CS lesions). The primary outcomes analyzed were rates of LC, PFS, and overall survival. Secondary objectives included analyses of symptoms-control, radiation-induced toxicity, and prognostic factors. ## Search strategy The Medline, Embase, and Cochrane database were searched for English abstracts and keywords of relevant studies published until June 6, 2018. The details of the search strategy are listed in Supplemental Digital Content 1. Exclusion criteria have been recorded and listed in [fig_ref] FIGURE 1: Flowchart of search process [/fig_ref]. ## Data extraction The extracted data include information on study design, follow-up interval, patient's demographic features, tumor characteristics, treatment parameters (including primary adjuvant and salvage setting), outcomes, and prognostic factors. ## Risk-of-bias assessment There is no single recommended instrument to assess the risk of bias for systematic reviews that includes both prospective and retrospective observational studies. We chose to evaluate the risk of bias by using a previously published system based on a 10-item assessment (see Supplemental Digital Content 2). [bib_ref] Radiosurgery for intracranial meningiomas: a systematic review and meta-analysis, Pinzi [/bib_ref] The system was developed to evaluate the kind of bias and the completeness of information. Particularly, items 1 and 2 assess the selection bias, items 3 to 5 the reporting bias, item 6 the attrition bias, and items 7 to 10 assess the extensiveness of information on treatments and outcomes. Specifically, an affirmative answer, "yes," indicates a low risk of bias, while a negative answer, "no," a high risk. Unclear or unknown risks are indicated by the definition "unclear." ## Ranking the evidence quality The evidence quality was ranked by applying an evidence hierarchy developed by the ISRS Guidelines Committee for a number of studies: diagnostic, prognostic, therapeutic, and decision modeling. The method used to assess the quality of the evidence is exemplified in this link: https://www.cns.org/guidelines/guideline-development-methodology. ## Strength of recommendation rating scheme Recommendation level I: high degree of clinical certainty (class I evidence or overwhelming class II evidence). Recommendation level II: clinical certainty (class II evidence or a strong consensus of class III evidence). Recommendation level III: clinical uncertainty (inconclusive or conflicting evidence or opinion). # Statistical methods The 3-yr, 5-yr, and 10-yr rates and the respective CI and/or standard errors (SE) for efficacy end points were extracted and reported from each study, where available or deducible. The percentage of patients with symptom control and the percentage of patients suffering at least from one toxicity (together with the 95% CI) were also extracted or calculated. The Freemen-Tukey double arcsine transformation was performed to obtain the overall estimates, and the DerSimonian-Laird random effect model has been applied to calculate the weighted pooled estimate. The overall estimate was backtransformed. The STATA software, version 14.3 (StataCorp), has been used to analyze the data. # Results ## Selection of the studies The PubMed, Embase, and Cochran searches identified 2844 studies. After the removal of duplicates, 2233 papers remained, out of which 1927 were excluded upon title and abstract evaluation. Following a full text scrutiny of the remaining 305 studies, 27 studies 10-36 were deemed to have met the inclusion criteria and selected for this review and summarized in [fig_ref] FIGURE 1: Flowchart of search process [/fig_ref]. One study was prospective, [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] in 4 studies the study design was unclear, [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in..., Massager [/bib_ref] and the remaining studies were retrospective. Two studies were multicenter, [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] while the remaining were single-center institutional series. ## Risk-of-bias assessment Based on the established risk-of-bias assessment method, none of the analyzed studies fulfill the criteria for low risk of bias, according to the defined 4 sections (selection bias, reporting bias, attrition bias, extensiveness of information on intervention analyzed). Four studies could be considered at low risk for selection bias, as they enrolled patients in a consecutive manner and reported the reasons to exclude some patients from the study. [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] Five studies were considered at low risk for reporting bias. [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] A total of 14 studies should be considered at low risk of attrition bias. [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] All but one 35 of the series included was at risk of bias with respect to the reporting of the results. Details about the Risk-of-Bias evaluation are reported in Supplemental Digital Content 3. ## Patient and tumor characteristics From the reviewed literature summarized in [fig_ref] TABLE 1: Studies, Tumors, and Treatments Features [/fig_ref] , a total of 3654 patients (3750 tumors) were included. The median followup was 60 mo. The mean patient age at the time of treatment ranged from 40 to 71 (median, 57 yr). The percentage of male patients across studies ranged from 11% to 41% (median, 26%). The analysis includes WHO grade I meningiomas treated with SRS and HSRT; the grade was based on pathological confirmation or based on radiological assessment. A single study included grade II and II meningiomas; however, WHO grade I tumors were reported separately and, as a result, they have been than included in this analysis. [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] The tumor site distribution is represented in [fig_ref] TABLE 2: The Meningiomas Sites Are Here Described [/fig_ref]. The overall tumor volume ranged from 0.5 to 26 cc (median, 6.4 cc), and ranged from 0.5 to 15.2 cc (median, 5.6 cc) in the SRS series and from 7.6 to 26 cc (median, 16.2 cc) in the HSRT series. ## Tumor control and pfs rates A total of 16 studies provide data specific to LC, 5 of which, evaluating 662 patients, reported a 10-yr LC rate ranging from 71% to 100% (median, 94.2%). [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] Eight studies, including more than 783 patients, reported a 5-yr posttreatment LC rate ranging from 85% the 100% (median, 93.8%). [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] Ten studies, evaluating more than 750 patients, reported LC rates ranging from 52% to 100% based on the last follow-up. [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in..., Massager [/bib_ref] [bib_ref] Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign..., Ryttlefors [/bib_ref] PFS was reported in 15 studies. The longest reported observation period was 15 yr in one study with a PFS of 89%. [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] Eight-to ten-year PFS rates were reported in 10 studies [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] that evaluated more than 1146 patients, with a PFS rate ranging from 55% to 97% (median, 85.0%). Four-to five-year PFS rates ranged from 74% to 99% (median, 89.4%) in 14 studies, based on more than 1057 patients. [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] Amongst those reporting predictive factors, the most common factors associated with tumor control were smaller tumor volume 12,18,26,33 and patient age (lower than 65). [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] The impact of tumor location on the tumor control was investigated by 4 studies. [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] Two out of these studies [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] suggest that parafalcine, parasagittal, and convexity locations are significant negative prognostic factors in terms of tumor control, while other 2 studies 18,20 did not observe statistical significance. Tumor-control rates and the PFS are summarized in [fig_ref] TABLE 3: Local Control and Progression-Free-Survival Rates [/fig_ref]. ## Treatment features and dose A total of 22 papers reported specifically on single-fraction SRS (3458 tumors have been included), [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in..., Massager [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] one of which included staged SRS (8/200 total treatments). [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] Three studies (based on 181 tumors) reported outcomes specific to HSRT. [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] [bib_ref] Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign..., Ryttlefors [/bib_ref] Two studies included both SRS and HSRT treatments; in these studies, 51 tumors had SRS and 60 tumors had HSRT. [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] The Gamma Knife (Elekta AB) was the reference device in 20 studies (3316 tumors), [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in..., Massager [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] the LINAC in 4 (231 tumors), [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] the CyberKnife (Accuray) in 2 (184 tumors), [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] and proton SRS in 1 study . [bib_ref] Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign..., Ryttlefors [/bib_ref] The SRS prescription dose ranged from 11 to 17 Gy (median, 14 Gy), and the prescription isodose line ranged from 20% to 90% (median, 50%). The maximum point dose ranged from 15 to 32 Gy (median, 27 Gy). Doses varied widely across all analyzed papers; older series generally included treatments whose total dose was higher than in more recent series (15 to 12 Gy, marginal). The most common schedule for HSRT was 25 Gy in 5 fractions. [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] The observed HSRT schedules ranged from 14 to 30 Gy delivered in 2 to 5 fractions. The prescription isodose line ranged from 44% to the 95% isodose line. ## Primary, adjuvant, or salvage therapy Approximately half of the study population in this analysis underwent SRS as primary treatment. Two studies found that previous surgery was associated with worse tumor LC. [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] Similarly, El-Khatib et al [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] reported better PFS at 5, 10, and 15 yr when SRS was performed as a primary treatment as opposed to an adjuvant or salvage indication. From the Mayo clinic, Pollock et al 33 also reported prior surgery (hazard ratio: 6.9, P = .002) to be a negative risk factor in terms of local tumor control, as did Sheehan et al, [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] who concluded that more than one prior surgery significantly increased the likelihood of tumor progression after SRS. However, a recent series by Kim et al 25 failed to detect any relationship with prior surgery and LC following SRS. ## Single-session or fractionated treatments Single-session SRS was considered the reference treatment (level II recommendation) as an established practice, with consistent reports of LC with mature followup. [bib_ref] Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5..., Abdelaziz [/bib_ref] [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Treatment modalities and outcomes for asymptomatic meningiomas, Jo [/bib_ref] [bib_ref] Longterm follow-up confirms the efficacy of LINAC radiosurgery for acoustic neuroma and..., Kalogeridi [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Long-term outcomes following Gamma Knife radiosurgery for small, newly diagnosed meningiomas, Lee [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Long-term tumor control of benign intracranial tumors after Gamma Knife radiosurgery in..., Massager [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] Five series evaluated HSRT and, although the data are limited, similar results were observed. [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] [bib_ref] Long-term evaluation of the effect of hypofractionated high-energy proton treatment of benign..., Ryttlefors [/bib_ref] Despite the limited number of the analyzed patients, 2 studies comparing SRS with HSRT would suggest a potential role of HSRT for large lesions. [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] Four studies, all analyzing SRS, found that a higher tumor volume is a negative prognostic factor in terms of tumor control. [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Radiosurgery as definitive management of intracranial meningiomas, Kondziolka [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] One of the few studies on HSRT (120 patients with follow-up longer than 3 yr) did not show any correlation between tumor volume and PFS. 31 ## Imaging and contouring techniques The oldest series included treatments based on computed tomography (CT) images. In more modern series, the target and the critical structures are additionally defined using magnetic resonance imaging (MRI) scans. Specific to the MRI protocol, the T1 axial contrast-enhanced MRI was the most used sequence to define the target volume (TV). The TV was contoured according to the contrast enhancement without any further margin in most of the series. A T2 fast spin echo with a slice thickness of 1 to 1.5 mm could be recommended for inner-ear and/or cranial nerve definition. Two studies specifically debated the inclusion of the dural tail and concluded that it should be included in the TV, although without any specific analysis to support such practice. [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] ## Neurological outcomes and adverse events Eight studies suggest a post-SRS neurological deterioration rate ranging from 0% to 13.3% (median, 7.4%). [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Multisession radiosurgery for sellar and parasellar benign meningiomas: long-term tumor growth control..., Marchetti [/bib_ref] The meta-analysis, possible for 6 out of these studies, [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Gamma Knife radiosurgery in sphenopetroclival meningiomas: preliminary experience at the Iran Gamma..., Azar [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Gamma knife radiosurgery for petroclival meningioma: long-term outcome and failure pattern, Kim [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] suggests an overall symptoms control rate of 95.1% (95% CI: 92.1%-97.5%); an estimate for the relative frequency of patients with symptom control was obtained, with high heterogeneity among studies (I2 = 53.8%) (see [fig_ref] FIGURE 2: Proportion of patients with symptom control [/fig_ref]. In general, toxicity rates ranged from 2.5% to 34.6% (median, 8.0%) in 13 papers. [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Hypofractionated stereotactic radiotherapy (HFSRT) for who grade I anterior clinoid meningiomas (ACM), Demiral [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] A single study reported 2 cases of grade 4 toxicity (system of reporting not mentioned). [bib_ref] Cyber Knife stereotactic radiosurgery and hypofractionated stereotactic radiotherapy as first-line treatments for..., Manabe [/bib_ref] The meta-analysis was possible for 11 out of these studies [bib_ref] Gamma Knife radiosurgery of skull base meningiomas, Aichholzer [/bib_ref] [bib_ref] Outcomes and complications of Gamma Knife radiosurgery for skull base meningiomas, Bir [/bib_ref] [bib_ref] Development of dose-volume relation model for Gamma Knife surgery of non-skull base..., Chung [/bib_ref] [bib_ref] Postoperative Gamma Knife surgery for benign meningiomas of the cranial base, Davidson [/bib_ref] [bib_ref] Factors predicting local tumor control after Gamma Knife stereotactic radiosurgery for benign..., Dibiase [/bib_ref] [bib_ref] Volumetric follow-up of meningiomas: a quantitative method to evaluate treatment outcome of..., Feigl [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Predictors of response to Gamma Knife radiosurgery for intracranial meningiomas, Mansouri [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Long-term outcomes and patterns of tumor progression after Gamma Knife radiosurgery for..., Zada [/bib_ref] ; the data showed an overall relative frequency of patients with toxicity of 11.0% (95% CI: 6.4%-16.5%) with a high heterogeneity (I2 = 88.1%) among studies [fig_ref] FIGURE 3: Proportion of patients with at least one toxicity event [/fig_ref]. Possible prognostic factors for a negative clinical outcome were higher marginal dose [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] and larger volumes. [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] Two studies [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] suggest that the postradiosurgery edema rate may be related to the parafalcine, parasagittal, and convexity locations, while 2 studies 28,30 failed to observe a correlation between tumor location and clinical or radiological toxicity. The clinical and toxicity data are summarized in [fig_ref] TABLE 4: Treatment Response in Terms of Symptom Control [/fig_ref]. # Discussion The results of this systematic review support the effectiveness of SRS with respect to LC for WHO grade I meningioma. The 5-yr PFS ranged from 85% to 100% (median, 89%) and the 10-yr PFS ranged from 53% to 100% (median, 85%). These data are consistent with what we observe in the surgical literature [bib_ref] EANO guidelines for the diagnosis and treatment of meningiomas, Goldbrunner [/bib_ref] and may further explain the reason why SRS is being increasingly used as the primary therapeutic modality for meningioma. Regarding the dose, the most recent data show that a marginal dose ranging from 15 to 12 Gy is generally sufficient with respect to durable LC. [bib_ref] Long term experience of Gamma Knife radiosurgery for benign skull base meningiomas, Kreil [/bib_ref] [bib_ref] Stereotactic radiosurgery of intracranial meningiomas, Pollock [/bib_ref] With regards to HSRT, the literature lacks the mature longterm outcomes to draw any firm conclusions; however, the preliminary data summarized in this review suggest a potential role of such a technique in selected cases, and the most common fractionation schedule is 25 Gy in 5 fractions. Whether SRS as a primary treatment is preferable to adjuvant SRS remains to be confirmed. However, the evidence suggests that previous surgery may adversely affect tumor control. [bib_ref] Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and..., El-Khatib [/bib_ref] [bib_ref] Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas: clinical article, Hasegawa [/bib_ref] [bib_ref] Single-fractionated stereotactic radiosurgery for intracranial meningioma in elderly patients: 25-year experience at..., Hasegawa [/bib_ref] [bib_ref] Single-fraction radiosurgery of benign intracranial meningiomas, Pollock [/bib_ref] [bib_ref] Gamma knife radiosurgery for sellar and parasellar meningiomas: a multicenter study, Sheehan [/bib_ref] This could be related to a more complex definition of the target volume due to the complexity of the postoperative radiological images and/or to a potentially more aggressive inherent biology, given that patients required surgery as upfront treatment without a GTR possible. There is no evidence that adjuvant SRS may yield better results than salvage SRS, or vice versa. The choice has been largely been based on the clinician's or institution's preference and by taking into account a variety of factors such as tumor volume and location, previous surgery, clinical condition, age, etc. The specifics with respect to decision making were not stipulated in the relevant series and are beyond the scope of this review. The issue regarding optimal imaging has not been defined yet; it is very important to establish a common strategy to delineate the TV and critical structures. Most studies define the TV as the contrast-enhanced tumor without margins. The role of biological imaging (CT/MRI positron emission tomography) requires a more in-depth investigation as well. Finally, regarding clinical outcome and toxicity, it is well known that specific treatment-related risks are often closely linked to the tumor location. For example, skull base meningioma often involves cranial nerves, and sparing them becomes challenging both in terms of surgery and SRS. Parasagittal meningiomas are also associated with an increased risk of post-SRS edema, and there is a lack of outcome data co-relating the risk of edema with dose fractionation and volume. The results on neurological toxicity from this review suggest a low risk of neurological deterioration (median 7.4%) and a low rate of serious adverse events (median 8.0%). The role of the tumor location in term of both tumor control and clinical outcome is also of importance and requires further investigation. Cognitive status and quality-of-life were not analyzed in the literature reviewed and are an active area of investigation. A summary of recommendations based on this review of the evidence as endorsed by the ISRS are provided in [fig_ref] TABLE 6: Summary of the ISRS Recommendations for SRS and Meningioma [/fig_ref]. Key Areas for Future Investigation -Although SRS in the treatment of intracranial benign meningioma is being increasingly used, the literature lacks class I and II evidence. Higher-level evidence is needed, particularly in regards to comparative analysis of SRS, HSRT, intensity modulated radiation therapy, charged particle radiation, and the various surgical techniques, in order to help clinicians make optimal therapeutic decisions. -The timing of SRS (primary, adjuvant, or as salvage treatment) requires further investigation. ## Recommendations level Recommendation level II. SRS may be proposed as a primary treatment modality for an asymptomatic or mildly symptomatic meningioma, and should be considered when a complete surgical excision cannot be achieved or is not amenable Recommendation level II. After surgery, when a residual tumor is not evident or is minimal, a wait-and-scan approach appears to be reasonable with a regular radiological follow-up. At the time of recurrence or progression, SRS should be taken into consideration as a treatment modality. Some studies suggest that the recurrence/progression rate is lower when SRS is delivered as the primary treatment as compared to an adjuvant treatment and this remains to be confirmed. Recommendation level III. Single-fraction SRS with a dose of 12 to 15 Gy appears to be sufficient to manage benign intracranial meningioma. A prescription dose of at least 14 Gy would be advisable. Recommendation level III. HSRT may be considered for the treatment of large or/and critically located meningioma. Optimal practice has yet to be defined; however, 25 Gy in 5 fractions is a common approach. Recommendation level III. SRS generally entails a low risk of neurological deterioration. Patients may experience a clinical improvement without tumor shrinkage. -Before HSRT can be recommended as a standard of care, mature follow-up of existing series is needed and ideally comparative clinical trials, especially for large or meningioma located in critical locations where SRS is limited by dose tolerances. -Further research as to the ideal MR sequence to define the TV, including the dural tail, and the incorporation of multimodal imaging, including biological imaging, is needed. -While there is consensus on the prescription dose for SRS, the best treatment schedule, dose-per-fraction, and total dose for HSRT require further investigations. # Study limitations The main limitations with respect to the conclusions from this systematic review lie in the lack of strong evidence and, in general, the lack of a common terminology with respect to endpoints, as pointed out by the risk-of-bias assessment. The limited number of studies reporting the CI and/or the number of patients at risk at any given time limited the possibility of a meta-analysis about the efficacy. Randomized controlled trials would be recommended; on the other hand, such studies are unlikely to be performed given current practice patterns, funding constraints, and clinical equipoise. # Conclusion SRS has traditionally been considered to be an adjuvant treatment modality in case of remnants or recurrent tumors, or as primary treatment for patients who are not surgically amenable. Regardless of the indication, SRS represents an important treatment option for most benign intracranial meningiomas. Given the strong consensus of class III evidence studies with favorable outcomes, today SRS can be considered a primary treatment in many cases (recommendation level II). Tumor control rates are generally high, with rare events of post-SRS deterioration. However, due to the lack of class level I and II evidence, further investigation with longer periods of observation and larger, multiinstitutional series are needed. Finally, the development of common terminology criteria and reporting methodology is desirable to ensure consistency in the interpretation of the evidence. # Disclosures This evidence-based clinical practice guideline was supported by the International Stereotactic Radiosurgery Society. Dr Sahgal is an advisor/consultant with Elekta (Gamma Knife Icon); belongs to the Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases, and Linac Based SRS Consortia; had past educational seminars with Elekta AB, Accuray Inc, Varian (CNS Teaching Faculty), and BrainLAB; and had a Medtronic Kyphon Research grant with Elekta AB Travel accommodations/expenses by Elekta, Varian, and BrainLAB. Dr Marchetti and Dr Fariselli have grants from Accuray Europe for unrelated research. Mr Paddick is a consultant for and has received a research grant from Elekta AB. Dr Regis is a consultant for and has received research grants from Medtronic and Elekta AB. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Sahgal is an advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), BrainLAB, and VieCure (Medical Advisory Board). Dr Suh is consultant for Abbvie. ## Disclaimer These consensus reviews should not be considered inclusive of all methods of care or exclusive of other methods or care reasonably directed to obtain similar results. The physician must make the ultimate judgment depending on characteristics and circumstances of individual patients. Adherence to this guideline will not ensure successful treatment in every situation. The authors of this guideline and the International Stereotactic Radiosurgery Society assume no liability for the information, conclusions, and recommendations contained in this report. [fig] FIGURE 1: Flowchart of search process. [/fig] [fig] 4: yr rate; b = 8 yr rate. [/fig] [fig] FIGURE 2: Proportion of patients with symptom control. ES = estimate; Iˆ2 = heterogeneity Higgins index; p = P-value. [/fig] [fig] FIGURE 3: Proportion of patients with at least one toxicity event. ES = estimate; Iˆ2 = heterogeneity Higgins index; p = P-value. [/fig] [table] TABLE 1: Studies, Tumors, and Treatments Features [/table] [table] TABLE 2: The Meningiomas Sites Are Here Described [/table] [table] TABLE 3: Local Control and Progression-Free-Survival Rates [/table] [table] TABLE 6: Summary of the ISRS Recommendations for SRS and Meningioma [/table]	None	https://academic.oup.com/neurosurgery/article-pdf/87/5/879/33880708/nyaa169.pdf	Abstract BACKGROUND Stereotactic radiosurgery (SRS) for benign intracranial meningiomas is an established treatment. OBJECTIVE To summarize the literature and provide evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS Articles in English specific to SRS for benign intracranial meningioma, published from January 1964 to April 2018, were systematically reviewed. Three electronic databases, PubMed, EMBASE, and the Cochrane Central Register, were searched. RESULTS Out of the 2844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but one were retrospective studies. The 10-yr local control (LC) rate ranged from 71% to 100%. The 10-yr progression-free-survival rate ranged from 55% to 97%. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. CONCLUSION The current literature supporting SRS for benign intracranial meningioma lacks level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based treatment option (recommendation level II) for grade 1 meningioma.
7a82ce8ecfde0278bac81d71d692bf03c97ed39d	pubmed	Ramping Up Delivery of Cardiac Surgery During the COVID-19 Pandemic: A Guidance Statement From The Society of Thoracic Surgeons COVID-19 Task Force	Ramping Up Delivery of Cardiac Surgery During the COVID-19 Pandemic: A Guidance Statement From The Society of Thoracic Surgeons COVID-19 Task Force ## Ramping up delivery of cardiac surgery during the covid-19 pandemic: a guidance statement from the society of thoracic surgeons covid-19 task force The coronavirus disease 2019 (COVID-19) pandemic has had a profound global impact. Its rapid transmissibility has transformed healthcare delivery and forced countries to adopt strict measures to contain its spread. The vast majority of the United States cardiac surgical programs have deferred all but truly emergent/urgent operative procedures in an effort to reduce the burden on the healthcare system and to mobilize resources to combat the pandemic surge. While the number of COVID-19 cases continue to increase worldwide, the incidence of new cases has begun to decline in many North American cities. This "flattening of the curve" has prompted interest in reopening the economy, relaxing public health restrictions, and resuming nonurgent healthcare delivery. The following document provides a template whereby adult cardiac surgical programs may begin to ramp-up the care delivery in a deliberate and graded fashion as the COVID-19 pandemic burden begins to ease. "Resuscitating" the timely delivery of care is guided by three principles: (1) Collaborate to permit increased case volumes, balancing the clinical needs of patients awaiting surgical procedures with the local resources available within each healthcare system. (2) Prioritize patients awaiting elective procedures while proactively engaging all stakeholders, focusing on those with high-risk anatomy, changing/symptomatic clinical status, and, once these variables have been addressed, prioritizing by waiting times. (3) Reevaluate local conditions continuously to assess for any increase in admissions due to a recrudescence of cases, to assure adequate resources to care for patients, and to monitor in-hospital infectious transmissions to both patients and healthcare workers. to safely modify public health restrictions and resume nonurgent and emergent healthcare delivery, specifically, elective cardiac surgical procedures. During the early phases of the pandemic, significant efforts were made to prioritize and defer nonurgent cases to preserve mechanical ventilators and other critical care resources, personal protective equipment (PPE), blood products, hospital beds, and maintain sufficient healthcare personnel in preparation for the pandemic surge. In addition, the Centers for Disease Control and Prevention recommended 3 delaying elective inpatient and outpatient operations and procedures. This recommendation was intended to protect healthcare workers and uninfected, vulnerable patients (ie, older with cardiovascular disease) by limiting their exposure to those with known COVID-19 and asymptomatic, undiagnosed carriers of the virus. However, there is growing concern about the increased risk of further delaying cardiac surgical procedures with established survival benefits. Programs need to start planning for the resumption of care for patients awaiting postponed elective operations. However, any decision to "ramp up" surgical case volume will require thoughtful and appropriate caution, with frequent reevaluation as we navigate through the uncertainties of this global pandemic. There will be a need to make collaborative decisions with precise local and regional situational awareness of disease burden, carefully balancing the risks and benefits of increasing the number of non-urgent surgical cases. Furthermore, we must maintain flexibility to readjust our escalation strategy in response to evolving conditions and rapidly changing diagnostic and therapeutic COVID-19 processes. There is the possibility of secondary surges as populations reemerge from lockdown and the potential for increased COVID-19 infections in combination with other seasonal respiratory pathogens such as influenza virus. These guidance statements, which are based on the expert opinions of cardiac surgical and critical care leaders, provide a template whereby cardiac surgical programs may consider safely increasing case volume in a deliberate and graded fashion as the COVID-19 local disease burden begins to ease. 1. Working with public health officials, local COVID-prevalence in the community must be under control. Communities should have a low COVID-19 burden that can be physically isolated within the hospital or a consistent decrease in COVID-19 incidence creating the resource capacity to perform elective procedures.If COVID-19 incidence resurges locally, plans should be in place for reentering the surge triage and mitigation phase. 1,2 2. Many patients are reluctant to enter hospitals for fear of exposure to COVID-19.Patients should feel comfortable they can safely undergo cardiac surgical procedures without significant risk of exposure to COVID-19 within the hospital environment. This includes enhanced attention to equipment, meals, medication administration, PPE, and interactions with other patients, visitors, and hospital personnel. Hospitals should adjust policies, protocols, and procedures to limit patient movement and exposure to potential COVID-19 fomites and personnel. [bib_ref] Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals, Liu [/bib_ref] All attempts should be made to avoid excessive imaging, blood work, procedures, and in-hospital transport to limit these exposures. [bib_ref] Commentary: rethinking surgical protocols in the COVID-19 era [e-pub ahead of print, Engelman [/bib_ref] Recommendations surrounding the need for repeat laboratory testing, imaging, and physical examinations should be reassessed. Video conferencing should be used for preoperative family meetings and postoperative visits, where available. In addition, the hospitals' newly formed COVID-19 infection control processes and procedures should be discussed with patients at the time of surgical consent. This necessitates shared decision-making surrounding the risk of an operation during a pandemic versus the risk of further deferring treatment of the patient's cardiovascular pathology. The surgical team should describe the special precautions being undertaken and disclose the uncertain risk of nosocomial COVID-19 infection. Patients should be advised of limited hospital visitor policies and the potential for unexpected case cancellations. Cardiac surgical patients should be limited to designated "COVID-19-secure" units (free from known COVID-19 patients), whenever possible. New signage and messaging should be used to educate healthcare workers and patients. Offices, clinics, hospital public areas, and waiting rooms should practice physical distancing (eg, 6-feet spacing of chairs). Hospital visitation rules need to be carefully considered to limit potential exposures. Finally, deliberate attempts should be made to preoperatively assess each patient's potential need for a postacute care upon discharge, given the high incidence of known COVID-19 outbreaks in those facilities.Expectations for discharge should be reviewed preoperatively because longer hospital stays after a cardiac surgical procedure potentially place patients at additional risk. As such, patients should plan to be safely discharged to their homes as soon as possible after an uncomplicated recovery.3. Healthcare providers should be aware that their safety also remains a priority. Cardiac surgical programs should follow precautions and guidelines that have been put in place by their respective institutions, adhering to the recommendations of local, regional, and national public health authorities to manage and contain COVID-19 transmission.The risk of nosocomial infection may be significantly reduced by vigilant attention to frequent hand hygiene, environmental cleaning, appropriate use of PPE, the creation of "COVID-19-secure" units, social distancing in the hospital, [bib_ref] Implementing physical distancing in the hospital: a key strategy to prevent nosocomial..., Arora [/bib_ref] and self-isolation of COVID-19-positive healthcare workers. It is imperative that healthcare workers continue to follow institutional policies about reporting symptoms, undergoing testing, and implementing self-quarantine when appropriate. They must abstain from work if they become sick, no matter how mild their symptoms. Contingency planning for staffing must be in place for healthcare workers who require selfisolation. This is particularly relevant for the small and highly specialized cardiac teams. In addition, support and treatment services should be available for providers who experience mental health concerns, physical and/or emotional exhaustion as a result of professional or personal experiences during the pandemic. [bib_ref] The mental health consequences of COVID-19 and physical distancing: the need for..., Galea [/bib_ref] [bib_ref] Factors associated with mental health outcomes among health care workers exposed to..., Lai [/bib_ref] Finally, there will likely be evolution and institutional variation in COVID-19 nasopharyngeal and serologic screening for asymptomatic healthcare workers. Healthcare leaders must be aware of this dynamic process. 4. Hospitals should develop and implement comprehensive screening procedures to identify patients at increased risk for COVID-19 as cardiac surgical programs begin to ramp up. These include the following: a. Standardized clinical screening telephone questionnaires within 48 hours before hospital admission, focusing on the clinical history of patients and their cohabitants (including viral-like symptoms, anosmia, [bib_ref] Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms, Yan [/bib_ref] and ageusia, all of which are frequently associated with COVID-19). b. Unless recent outpatient testing suggests the patient is infection free, if possible, the initial admission should be to a single room within the hospital where additional rapid same-day preoperative screening or testing, or both, may be performed as needed. c. Once admitted to the ward, each patient must be clinically screened for the signs and symptoms of viral illness, with COVID-19 testing administered as needed. ## Nucleic acid amplification testing (naat) for covid-19 (eg, by polymerase chain reaction [pcr]) should be strongly considered for patients in areas of high disease burden, those who have recently been exposed to infected individuals, and those who exhibit even mild symptoms. If there has been a recent exposure, a 2-week quarantine is recommended. Finally, when possible, all preoperative patients should be tested before admission. Unfortunately, there is no test currently available that can reliably rule out COVID-19. Despite this, tests using nasopharyngeal swabs for COVID-19 NAAT, including rapid PCR tests, are being increasingly performed across the country, often with the ability to return results within minutes or hours. In light of this, we propose the following guidance regarding COVID-19 test interpretation in the ramp-up phase based on the best available evidence at this time. a. Nasopharyngeal swab NAAT (or its equivalent) for COVID-19 should be considered before all elective cardiac surgical procedures. The timing of sampling should be as close to the surgical procedure as possible (preferably within 24-48 hours), allowing sufficient time for the results to be processed. b. When NAAT testing is positive, these results can be very helpful because delaying the operation should strongly be considered. c. When NAAT testing is negative, results must be interpreted with caution because false-negative rates in asymptomatic patients can be as high as 30% to 50%. [bib_ref] COVID-19 testing: the threat of false-negative results, West [/bib_ref] Clinical sensitivity can be reduced due to poor quality specimen collection [bib_ref] Diagnostic testing for severe acute respiratory syndrome-related coronavirus-2: a narrative review, Cheng [/bib_ref] or specimen collection early in the disease process (higher false-negative rates have been noted in the asymptomatic or preclinical period).For patients in areas of high COVID-19 disease activity who require urgent or emergent procedures, if the NAAT testing and initial symptom screen are negative, consider repeat NAAT testing by nasopharyngeal swabs separated by more than 24 hours apart and consulting with local infection control practitioners. d. Elective surgical patients with negative NAAT testing in whom the clinical suspicion of COVID-19 infection remains high should self-quarantine for a 2-week period of observation. Before the surgical procedure, patients should be rescreened for symptoms and exposures and retested in conjunction with local infectious disease consultation. e. If a suspicious clinical syndrome concerning for COVID-19 develops in a patient postoperatively, additional investigative tools may include repeat nasopharyngeal specimen collection, endotracheal aspirates for NAAT testing, computed tomographic imaging, or a combination of these. 18 f. Clearly, as improved testing methods become available, they should be used, all the while recognizing that these are elective surgical procedures, and a 2-week quarantine with retesting may be the safest approach for any patient, regardless of pretest probabilities. 6. Nonurgent patients waiting for prolonged periods before an operation are at risk for clinical deterioration or adverse events. Cardiac surgery programs should proactively reassess each patient on their waiting list while pursuing a graded increase in elective case volume. Aspects of this management may include, but are not limited to, the following: a. All waiting list patients should be contacted by telephone or video conference for reassessment at least every 2 to 4 weeks to assess their clinical status and should be instructed to call if their symptoms worsen. b. Hospitals should have a clear plan in place to formally escalate the care of patients with deteriorating symptoms or unstable clinical characteristics, particularly in the face of high-risk anatomy. c. Peer review among the interdisciplinary heart team is highly encouraged for complex patients. d. Continued reevaluation of local pandemic conditions should occur regularly as part of the cardiac surgical ramp-up strategy. Programs should be prepared to immediately stop ramping up or to even deescalate cardiac surgical volumes should there be a resurgence in the number of local COVID-19 cases, admissions, and deaths. 7. A phased approach is recommended to resuming elective procedures based on each hospital's reexpansion capacity. We have defined an increase in hospital capacity as the percentage of resources previously allocated to the COVID-19 pandemic that have now been reallocated to the management of non COVID-19 patients. Phase 1 reflects up to a 25% increase in capacity, phase 2 a 25% to 50% increase, and phase 3 a 50% to 100% increase or a return to normal institutional activity. Depending on which phase of reexpansion your institution is currently in, your cardiac surgical program should have a defined approach about which elective cases will be given priority during the rampup. The number of elective cases by which each program may ramp-up depends on the urgent case demands at the institution and the overall institutional capacity in the context of COVID-19 prevalence and the impact on the healthcare workforce. 8. Hospitals should create and put into operation sustainable plans to ensure that they continue to care for patients with COVID-19 infections while concurrently addressing all the other healthcare needs of their noninfected local populations. Increased surgical volume will consume PPE and other resources, which should be modeled to ensure capacity. Policies regarding the use of PPE during operations for patients deemed to be non-COVID-19 should be established. Those institutions with a high incidence of persistent COVID-19 disease burden will likely need to designate separate "COVID-19-care" and "COVID-19-secure" units for the foreseeable future. We must continue to assume we will have hospitalized symptomatic COVID-19 patients until we have a vaccine or sufficient herd immunity. 9. Efforts to escalate cardiac surgical volumes require regular communication between members of the cardiac surgical team, intensive care units, hospital administration, and public health officials. Ideally, a regional dashboard that provides real-time trending of resource use (eg, hospital admissions, intensive care unit admissions, ventilator use, and PPE availability) should be created to facilitate communication and well-informed forecasting to allow for thoughtful decision making. 10. Real-time quality assurance teams should be focused on monitoring COVID-19 transmission within cardiac surgical units, postoperative complications related or unrelated to COVID-19, deficiencies in hospital workflow, or other related quality issues. Potential sources of concern may include noncardiac-specific personnel staffing our operating rooms and the cardiac intensive care unit, expedited workups, inadequate preoperative testing, and "pandemic"level of care. ## Summary The COVID-19 pandemic has introduced unique challenges for cardiac surgical programs. Elective cases have been cancelled and urgent cases delayed to reallocate resources for patients with COVID-19. Waiting lists have grown, and patients being asked to postpone their operation have been forced to experience necessary but prolonged delays. Patients who were once deemed surgical candidates have increasingly been referred for medical management or alternative percutaneous therapies, with potential adverse long-term impacts. The effect of the COVID-19 pandemic on individual hospitals varies widely. It is important for institutions to continuously reassess their capabilities and potential ◄ limitations, while simultaneously surveying for potential subsequent waves of COVID-19. As new data emerge, these statements may change over time given the fluidity and scope of the current pandemic. Geographic differences in epidemiology and practice patterns across the country must be acknowledged and do not substitute for individualized expertise when putting into operation a deliberate and graded increase in cardiac surgical volume as the incidence of COVID-19 begins to ease. Clearly, economic factors remain highly relevant in United States healthcare. Some surgeons are compensated on a model that correlates with production of relative value units. Nonmilitary hospitals are also heavily reimbursed based on procedural volume. The financial impacts to medical centers has also been well described and are substantial, with hospitals under major financial crises. [bib_ref] COVID-19 and the financial health of US hospitals, Khullar [/bib_ref] Nevertheless, it is imperative that cardiac surgeons advocate in the best interest of their patients and function as good citizens for their institutions by supporting the principles stated in The Society of Thoracic Surgeons Adult Cardiac Triage Guidance Document 1 : (1) protect our patients, (2) protect the healthcare team, and (3) protect society. [fig] Figure 1: (see previous page) Phased implementation approach to cardiac surgery ramp-up based on the increase in hospital capacity. (AS, aortic stenosis; ASD, atrial septal defect; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; ECMO, extracorporeal membrane oxygenation; ELSO, Extracorporeal Life Support Organization; EF, ejection fraction; ICU, intensive care unit; LM, left main artery; LAD, left anterior descending artery; LOS, length of stay; MR, mitral regurgitation; PFO, patent foramen ovale; TAVR, transcatheter aortic valve replacement; VAD, ventricular assist device.) (Reprinted with permission from Hassan A, Arora RC, Adams C, et al. Cardiac surgery in Canada during the COVID-19 pandemic: a guidance statement from the Canadian Society of Cardiac Surgeons. Can J Cardiol. 2020;36:952-955.) [/fig]	None	https://europepmc.org/articles/pmc7215160?pdf=render	None
148779b77f3b4424b6776c486f3e49c09b40b271	pubmed	Palliative Care in the Global Setting: ASCO Resource-Stratified Practice Guideline	Palliative Care in the Global Setting: ASCO Resource-Stratified Practice Guideline Purpose The purpose of this new resource-stratified guideline is to provide expert guidance to clinicians and policymakers on implementing palliative care of patients with cancer and their caregivers in resource-constrained settings and is intended to complement the Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update of 2016.Methods ASCO convened a multidisciplinary, multinational panel of experts in medical oncology, family medicine, radiation oncology, hematology/oncology, palliative and/or hospice care, pain and/or symptom management, patient advocacy, public health, and health economics. Guideline development involved a systematic literature review, a modified ADAPTE process, and a formal consensus-based process with the Expert Panel and additional experts (consensus ratings group).Results The systematic review included 48 full-text publications regarding palliative care in resource-constrained settings, along with cost-effectiveness analyses; the evidence for many clinical questions was limited. These provided indirect evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% (by consensus ratings group including Expert Panel).Recommendations The recommendations help define the models of care, staffing requirements, and roles and training needs of team members in a variety of resource settings for palliative care. Recommendations also outline the standards for provision of psychosocial support, spiritual care, and opioid analgesics, which can be particularly challenging and often overlooked in resource-constrained settings. Additional information is available at www.asco.org/ resource-stratified-guidelines.Recommendations 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. The guideline is intended to complement but not replace local guidelines. executive summary special article # Introduction American Society of Clinical Oncology (ASCO) is committed to the integration of palliative care in oncology [bib_ref] Integration of palliative care into standard oncology care: American Society of Clinical..., Ferrell [/bib_ref] [bib_ref] Defining high-quality palliative care in oncology practice: An American Society of Clinical..., Bickel [/bib_ref] [bib_ref] Toward individualized care for patients with advanced cancer, Peppercorn [/bib_ref] [bib_ref] Palliative cancer care a decade later: Accomplishments, the need, next steps: From..., Ferris [/bib_ref] [bib_ref] Management of chronic pain in survivors of adult cancers, Paice [/bib_ref] and recognizes differences in access to services, especially specialist palliative care, across settings. The purpose of this new resource-stratified guideline is to provide expert guidance to clinicians and policymakers on implementing palliative care in resource-constrained settings and is intended to complement the Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update of 2016. Most of the research on which the nonresource-constrained guidelines were based was conducted in maximal resource institutions, for example, in the United States, Canada, and Britain. Research on palliative care began relatively recently in all settings, but much work is still needed to ensure that palliative care in lowand middle-income countries (LMICs) and other resource-constrained settings is based on a rigorous and relevant research base. [bib_ref] Disparities in the contribution of low-and middleincome countries to palliative care research, Pastrana [/bib_ref] The 2016 Guideline Update reviewed the lack of palliative care information and research in underserved communities in the United States and that patients identified as white have been over-represented in palliative care research. Most evidence and guidelines [fig_ref] Table 1: Selected Examples of Existing Palliative Guidelines and Relevant Sections [/fig_ref] come from high-income countries (HICs) [bib_ref] Integration of palliative care into standard oncology care: American Society of Clinical..., Ferrell [/bib_ref] ; research findings related to specialist-based interventions in tertiary care centers in HICs can often not a well-developed palliative care team, with its different specialties (Type of recommendation: formal consensus; not rated). ## Timing Recommendation 2.0 General: Palliative care needs should be addressed for all patients with cancer at presentation using appropriate screening, especially when disease-modifying interventions are not available (Type of recommendation: formal consensus; not rated). ## Workforce, knowledge, and skills recommendation 3.1 basic (primary health care provider): All health professionals should be trained in basic palliative care skills. This basic training should include identifying the palliative care needs of patients and their families, communication skills, assessment and management of pain and other symptoms, supportive care, and prescribing and/or dispensing of medications at a level appropriate to responsibilities. These needs may be addressed by primary health care providers, nurses, community health workers, volunteers, and/or clinical officers. If trained professionals are not available at the local level, health professionals should seek distance consultation and referral where appropriate (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 3.2 limited (district-level facility): Interdisciplinary teams are the core of palliative care. At this level, teams should include at least a nurse and a medical officer who have palliative care training. An appropriately trained counselor should be added, if available. Team members should be trained to assess, diagnose, and deliver care. All specialists in fields relevant to palliative care should have the knowledge and skills described in the basic level plus additional training in symptom assessment and management, communication issues, and psychosocial and spiritual needs. Oncologists practicing at this level should have basic training ## The bottom line (continued) (continued on following page) in palliative care. This level may or may not have professionals with formal advanced training in palliative care (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 3.3 enhanced (regional facility): A team including a physician, a nurse, and a counselor should provide palliative care. The team should include a health care provider trained to prescribe and with access to someone licensed to dispense medications. In the absence of a palliative care specialist, oncologists at this level should be trained in basic palliative care. All health professionals in relevant fields should have the knowledge and skills described in Recommendations 1.1 and 1.2, plus enhanced skills on how to treat refractory symptoms and how to manage emotional crisis and existential distress. This level should include professionals with formal advanced training and education in palliative care, such as (but not limited to) physicians, nurses, counselors, and pharmacists (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Nurse role in pain management ## Recommendation 4.0 (across all settings): The nurse should participate in ensuring care coordination and meeting patient and family needs. Where permitted, appropriately trained nurses may prescribe medicines, including controlled medicines. Nurses should be trained to assess patients' palliative care needs, including pain control assessment and evaluation (as well as other knowledge and skills described in recommendations under Palliative Care Models recommendations), make recommendations, and communicate needs to adequately trained health care providers who are permitted to prescribe (Type of recommendation: evidence based; Evidence quality: intermediate; Strength of recommendation: strong). ## Spiritual care Recommendation 5.0 (Across All Settings): Spiritual care provided by appropriately trained providers should be available in all settings, whether locally or by referral. In addition to providing direct patient care, spiritual care providers may advise and support the care team to support the patients and their families. Nurses or counselors may be trained to assess the spiritual needs of patients and their families. Providers should be observant of and sensitive to the religious norms of patients and families (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). ## Social work/counseling Qualifying statement: The psychosocial needs of patients and their families should be addressed in all settings and across the cancer care continuum. This role can be addressed by social workers, mental health professionals, or community health workers with training in the needs of palliative care patients and the special approaches required in this population. The role of the social worker/counselor becomes more critical in patients with advanced illness or when curative therapies are not an option, as is often the case in limited-resource settings. Collaboration with counselors/social workers can assist with communication between patients and clinicians, when available. Recommendation 6.1 Basic: When staffing is limited and specialized counselors are not available, physicians and/or nurses may play this role. They should receive the training to provide psychosocial care and be given enough time with the patient to allow them to provide it (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). Recommendation 6.2 Limited: Physicians and nurses may address the psychosocial needs of patients and families and should receive the training to do so. If possible, a social worker/counselor/volunteer/spiritual care provider should be available to attend to patients and families with a high burden of psychosocial issues (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). ## The bottom line (continued) (continued on following page) be readily extrapolated to resource-constrained or resource-poor settings, and "there is a great need for evidence-based regional and local research that takes into account the location and nature of care, access to medical and nonmedical resources, community attitudes and support, distinct cultural milieus, and multiple other local factors." As this Expert Panel's literature search confirms and others have observed, most research from LMICs is observational and descriptive. Reasons for this include the lack of resources, training, and interest to conduct research and the higher priority of providing palliative care itself. There are some moves to develop instruments that could be used in research, for example, the African Palliative Care Association developed the African Palliative Outcome Scale with collaborators from Kings College.Therefore, this ASCO guidance makes expert consensus recommendations regarding implementing aspects on, for example, the personnel, training, workforce, model, and timing of palliative care in resource-constrained settings [fig_ref] Table 2: ASCO Framework of Resource Stratification [/fig_ref] describes the levels of settings used in this guideline). In addition, it complements the non-resource-constrained ASCO guideline by examining the role of specific personnel, including nurses, spiritual care providers, and counselors. ## The bottom line (continued) "Multidisciplinary team approach" refers to a patient care model that includes experts from different disciplines, whereas an "interdisciplinary team approach" requires a more integrated and coordinated approach to patient care, where experts from different disciplines establish shared patient care goals for a more holistic approach to patient care. As in the Integration of Palliative Care Into Standard Oncology Care Guideline Update: "In this guideline, a family caregiver is defined as either a friend or a relative whom the patient describes as the primary caregiver; it may be someone who is not biologically related" and this guideline recognizes there are cultural variations in the definition of families/primary caregivers. 1(pp96,97) ## Guideline questions This clinical practice guideline addresses seven overarching questions: (1) Who should provide palliative care in the absence of specialized palliative care physicians, and what is the minimum training necessary to meet the palliative care needs of the community (whether by an oncologist or other clinicians/providers)? [bib_ref] Defining high-quality palliative care in oncology practice: An American Society of Clinical..., Bickel [/bib_ref] What is the most effective model of palliative care delivery? (3) When is the best time to involve a palliative care team in cancer care? (4) What is the role of the nurse in palliative care assessment, pain and symptom control, and drug prescriptions (opioid prescriptions)? [bib_ref] Management of chronic pain in survivors of adult cancers, Paice [/bib_ref] At what level of health care (health centers, dispensary, hospitals) should oral opioids be available? [bib_ref] Disparities in the contribution of low-and middleincome countries to palliative care research, Pastrana [/bib_ref] What is the place of spiritual care in palliative care? [bib_ref] Provision of palliative care in low-and middle-income countries: Overcoming obstacles for effective..., Hannon [/bib_ref] What are the roles of social workers/counselors in palliative care? # Methods ## Guideline development process This systematic review-based guideline product was developed by a multidisciplinary Expert Panel, which included two patient representatives and ASCO guidelines staff with health research methodology expertise (Appendix [fig_ref] Table 1: Selected Examples of Existing Palliative Guidelines and Relevant Sections [/fig_ref]. The Expert Panel met via teleconference and in person and corresponded through e-mail. Based upon the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review and submitted to a peer-reviewed journal for editorial review and consideration for publication. This guideline was partially informed by ASCO's modified Delphi Formal Expert Consensus methodology, during which the Expert Panel was supplemented by additional experts recruited to rate their agreement with the drafted recommendations. The entire membership of experts is referred to as the Consensus Panel (the Data Supplement provides a list of members). All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Clinical Practice Guideline Committee prior to publication. This guideline adaptation was also informed by the ADAPTE methodology and consensus processes used together as an alternative to de novo guideline development. Adaptation of guidelines is considered by ASCO in selected circumstances, when one or more quality guidelines from other organizations already exist on the same topic. The objective of the ADAPTE process is to take advantage of existing guidelines to enhance the efficient production, reduce duplication, and promote the local uptake of quality guideline recommendations. All funding for the administration of the project was provided by ASCO. (3) published between 1966 and 2017. Searches for cost-effectiveness analyses were also conducted. Articles were excluded from the systematic review if they were (1) meeting abstracts, phase I trials, retrospective studies, and (2) books, editorials, commentaries, letters, news articles, case reports, or narrative reviews. The guideline recommendations were crafted, in part, using the Guidelines Into Decision Support (GLIDES) methodology and accompanying BRIDGE-Wiz software. [bib_ref] Building better guidelines with BRIDGE-Wiz: Development and evaluation of a software assistant..., Shiffman [/bib_ref] In some selected cases where evidence was lacking, but there was a high level of agreement among the Expert Panel, informal consensus was used (as noted with the Recommendations). Detailed information about the methods used to develop this guideline is available in the Methodology Supplement and Data Supplement at www.asco.org/ resource-stratified-guidelines. The ASCO Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. On the basis of formal review of the emerging literature, ASCO will determine the need to update. This is the most recent information as of the publication date. For updates, the most recent information, and to submit new evidence, please visit www.asco.org/resource-stratified-guidelines. ## Guideline disclaimer The Clinical Practice Guidelines and other guidance published herein are provided by ASCO to 7 jgo.org JGO -Journal of Global Oncology District-level facility Enhanced Third-tier resources or services that are optional but important; enhanced-level resources should produce further improvements in outcome and increase the number and quality of therapeutic options and patient choice. ## Regional facility Maximal May use high-resource settings' guidelines. ## National-level facility High-level/state-of-the art resources or services that may be used/available in some highresource countries and/or may be recommended by high-resource setting guidelines that do not adapt to resource constraints but that nonetheless should be considered a lower priority than those resources or services listed in the other categories on the basis of extreme cost and/ or impracticality for broad use in a resource-limited environment; to be useful, maximal-level resources typically depend on the existence and functionality of all lower-level resources. Health budgets still require hard choices, and private insurers or public systems may carefully ration access to the most costly therapies. assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions. ## Guideline and conflicts of interest The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Policy Implementation for Clinical Practice Guidelines ("Policy," found at http://www.asco.org/ rwc). All members of the Expert Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy. # Results A total of 48 full-text articles regarding resourceconstrained settings were reviewed per the methodology described above. After reviewing these articles and observing the paucity of evidence from resource-constrained settings, as noted by other authors as well, [bib_ref] Disparities in the contribution of low-and middleincome countries to palliative care research, Pastrana [/bib_ref] ## Recommendations ## Clinical question 1 (palliative care models) What is the most effective model of palliative care delivery? Recommendation 1.0 General: There should be a coordinated system where the palliative care needs of patients and families are identified and met at all levels, in collaboration with the team providing oncology care. The health care system should have trained personnel who are licensed to prescribe, deliver, and dispense opioids at all levels. Distance communication should be instituted at the national or regional level through oncology centers (or other tertiary care centers) to support those providing oncology care to patients in lower resource areas (Type of recommendation: formal consensus; not rated). ## Recommendation 1.1 basic (primary health care): Palliative care needs should be addressed in the community or at the primary health care center. These needs may be addressed by primary health care providers, nurses, community health workers, volunteers, and/or clinical officers (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: moderate). ## Recommendation 1.2 limited (district): In addition to provision of palliative care in the community and at primary health care centers, outpatient palliative care services should be established. When a counselor is not available, psychosocial and spiritual needs may be addressed by team members trained in basic palliative care (Type of recommendation: formal consensus; Evidence quality: intermediate; Strength of recommendation: moderate). ## Recommendation 1.3 enhanced (regional): In addition to the community-based and outpatient palliative care services available at the limited level, inpatient consultation services should be available to hospitalized patients with palliative care needs. Consultation services should be provided by an interdisciplinary team, including (but not limited to) a physician, nurse, counselor, and pharmacist. Mental health and spiritual services may be added to the team when possible (Type of recommendation: formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 1.4 maximal (national): In addition to the palliative care services available at the enhanced level, dedicated inpatient palliative care beds should be established, staffed with trained professionals. No oncology center, hospice, or palliative care facility should exist without a well-developed palliative care team, with its different specialties (Type of recommendation: formal consensus; not rated). Literature Review and Analysis/Discussion: Downing et al 17 evaluated seven palliative care programs in Kenya 3 and Malawi, 4 using mixed methods, including case studies, literature review, an audit tool, and observations. The article outlined models for Specialist, District, and community-level palliative care. Downing et al concluded the benefit of involvement of "community volunteers or homebased care assistants" at a level similar to the recommendations the ASCO Expert Panel made for basic-setting palliative care, in addition to nurses leading palliative care in a limited setting with potential volunteer involvement. In that model, the Health Center/Community Level included: (1) pain and symptom assessment and management, (2) holistic care provision, (3) counseling and support for patients and families, (4) bereavement support, (5) social and nutritional support, (6) use of local resources, and (7) medications, if available, at no cost to patients. The emphasis is on home-based care, including outpatient care, led by nurses, and including volunteers. (This agrees with the ASCO basic recommendation-primary health care workers, community health outreach workers, and/or clinical officer-outpatient or home.) There are other existing models for home-based, community-supported palliative care, notably in the state of Kerala, India. Palliative care in Kerala linked a system of outreach clinics, all with access to morphine with care involving family caregivers and volunteers. There have been several publications on the Kerala system, a WHO demonstration project, although not formal evaluations, [bib_ref] India: Status of cancer pain relief and palliative care, Rajagopal [/bib_ref] [fig_ref] Table 1: Selected Examples of Existing Palliative Guidelines and Relevant Sections [/fig_ref] in the Data Supplement for a list. One example of a study the Panel discussed is a descriptive study by Devi et al 23 of using homebased care in Sarawak, Malaysia, to extend a strong primary health care network; similar systems would likely need preexisting primary health care networks. The palliative care providers included at least a physician and a nurse trained in basic palliative care (and counselor and pharmacists, if available). The program included training, nurse empowerment, simplified referrals, access to medications, and pain reduction interventions. Facilitators included political support and public awareness. While the program trained > 1,200 clinicians, most were nonphysicians (and physicians had high turnover). The results were descriptive and included numbers of those trained and those receiving care. There was a low refusal rate by care recipients. Discussion: Different models of palliative care delivery include home care, outpatient, inpatient consult, and inpatient unit models. Although most of the studies found in the literature are descriptive, they report positive outcomes. ASCO recommends community-based and home care in Basic; outpatient-(the development of), home-, and hospital-based consult in Limited; home-based, consultation, and inpatient beds in Enhanced; and all four in Maximal. The Panel believes that health care institutions should have care/case manager(s) in place when and where it is feasible. Some models can use components of other models, such as referrals, making the patient journey cyclical/multidirectional and remaining flexible and dynamic, while making the model more patient-centered at the community level (v provider centered) and developing more role definition and training for community-level health care providers. [bib_ref] Understanding models of palliative care delivery in sub-Saharan Africa: Learning from programs..., Downing [/bib_ref] It is important to consider the policy environment, public support and awareness, resources, access to essential medicines, and training of health professionals. ## Clinical question 2 (timing) When is the best time to involve a palliative care team in cancer care? Recommendation 2.0 General: Palliative care needs should be addressed for all patients with cancer at presentation using appropriate screening, especially when disease-modifying interventions are not available (Type of recommendation: formal consensus; not rated). ## Recommendation 2.1 basic and limited: The palliative care needs of patients with cancer should be addressed early in the course of illness by existing health professionals trained in the basics of palliative care. [bib_ref] End-of-life care policy: An integrated care plan for the dying: A joint..., Myatra [/bib_ref] We did not identify any additional studies related to timing of referral in resource-constrained settings and therefore depend on the literature used in the ASCO nonresource-stratified palliative care guideline. [bib_ref] Integration of palliative care into standard oncology care: American Society of Clinical..., Ferrell [/bib_ref] The non-resource-stratified guideline included the recommendation that "For newly diagnosed patients with advanced cancer, the Expert Panel suggests palliative care service involvement, starting early in the diagnosis process and ideally within 8 weeks of diagnosis (Type: informal consensus; Evidence quality: intermediate; Strength of recommendation: moderate)." The Resource-Stratified Guideline palliative care Expert Panel emphasizes the addition of the subject word "palliative care team" to highlight the role of the team. Examples of screening tools are listed in the Maximal Resource Settings and given in Data Supplement (National Comprehensive Cancer Network Distress Thermometer, Edmonton Symptom Assessment Scale, Condensed Memorial Symptom Assessment Scale, Brief Pain Inventory). Evidence is emerging, for some diseases, that specialist palliative care teams may also benefit those diagnosed with early-stage disease, in addition to those with advanced disease. The panel stresses the additional comment that 8 weeks is the maximum time within which clinicians should make referrals to palliative care services, but earlier referral is preferable. ## Clinical question 3 (workforce, knowledge, and skills): Who should provide palliative care in the absence of specialized palliative care physicians? What is the minimum training necessary to meet the palliative care needs of the community (whether by an oncologist or other clinicians/providers)? Introduction: This clinical question recognizes that outside of maximal settings, palliative care specialists are often not available. Some resource-constrained settings do not have oncologists, although this is changing in some settings. In Basic and Limited settings, palliative care is especially important, as patients often present at late stages and have greater palliative care needs ## Recommendation 3.1 basic (primary health care provider): All health professionals should be trained in basic palliative care skills. This basic training should include identifying the palliative care needs of patients and their families, communication skills, assessment and management of pain and other symptoms, supportive care, and prescribing and/or dispensing of medications at a level appropriate to responsibilities. These needs may be addressed by primary health care providers, nurses, community health workers, volunteers, and/or clinical officers. If trained professionals are not available at the local level, health professionals should seek distance consultation and referral where appropriate (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 3.2 limited (district-level facility): Interdisciplinary teams are the core of palliative care. At this level, teams should include at least a nurse and a medical officer who have palliative care training. An appropriately trained counselor should be added if available. Team members should be trained to assess, diagnose, and deliver care. All specialists in fields relevant to palliative care should have the knowledge and skills described in the basic level plus additional training in symptom assessment and management, communication issues, and psychosocial and spiritual needs. Oncologists practicing at this level should have basic training in palliative care. This level may or may not have professionals with formal advanced training in palliative care (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 3.3 enhanced (regional facility): A team including a physician, a nurse, and a counselor should provide palliative care. The team should include a health care provider trained to prescribe and access to someone licensed to dispense medications. In the absence of a palliative care specialist, oncologists at this level should be trained in basic palliative care. All health professionals in relevant fields should have the knowledge and skills described in Recommendations 1.1 and 1.2, plus enhanced skills on how to treat refractory symptoms and how to manage emotional crisis and existential distress. This level should include professionals with formal advanced training and education in palliative care, such as (but not limited to) physicians, nurses, counselors, and pharmacists (Type of recommendation: evidence based and formal consensus; Evidence quality: intermediate; Strength of recommendation: strong). ## Recommendation 3.4 maximal (national cancer center/institute)-see the ferrell et al 1 guideline. Literature Review and Analysis/Discussion: There is evidence from several studies conducted in resource-constrained settings that health care personnel other than specialized palliative care physicians can provide basic palliative care when the latter are not available. In settings with a limited number of adequately trained physicians, palliative care can be successfully provided by nurses or even laypeople (ie, nonmedically trained persons) given the right support and training. In many palliative care studies, interventions by nonmedically trained caregivers and nurse-led interventions have been found to have a positive impact. These include several cited in the ASCO nonresource-stratified guideline. 1 This is confirmed in the literature found for the current guideline, which included primarily observational studies. (The role of nurses will be discussed in more detail in Clinical Question 4.) Literature on family caregivers supports the concept that lay (also known as nonmedically trained) people (such as volunteers or community health workers) can be trained to provide care and have a positive impact on the patients. Some studies evaluating the impact of family caregivers participating in the provision of palliative care were included in the non-resource-stratified ASCO guideline. Family caregivers often provide handson primary care to patients in the community setting. One of the only randomized controlled trials (RCTs) found in the literature search for this resource-stratified guideline was a small RCT conducted in a non-US HIC, Singapore. [bib_ref] A pilot randomized, controlled trial of the effectiveness of a psychoeducational intervention..., Leow [/bib_ref] Family caregivers are impacted by the illness experience, and palliative care aims to address the psychosocial needs not only of patients, but also of family members. This small, randomized, controlled trial included four home hospice organizations and an outpatient clinic in Singapore. Eighty caregivers were randomly assigned to experimental and standard care groups, and received a psychoeducational intervention to enhance their quality of life (QoL); the outcomes showed statistically significant improvements in QoL measures. The authors attributed the effective results to increases in understanding of four phases of anticipatory grief and the importance of caregiver-patient communication (according to this study, not well studied). Limitations of this study included the convenience sample, language barriers (English only), selection bias, and a small sample size. In another example, Kristanti et al 26 had nurse educator(s) train family caregivers in basic patient care, such as oral care, in an Indonesian pilot study. In this prospective quantitative study, there was an increase in the primary measure, patient QoL. ## 12 jgo.org JGO -Journal of Global Oncology Integrating palliative care volunteers and community health workers and empowering the health care workforce, especially nurses (Clinical Question 4), is essential to achieve universal access to palliative care services in settings where access to physicians may be limited. ## Clinical question 4 (nurse role in pain management) What is the role of the nurse in palliative care assessment, pain and symptom control, and medicine prescriptions, including controlled medicines (opioid prescriptions)? ## Recommendation 4.0 (across all settings): The nurse should participate in ensuring care coordination and meeting patient and family needs. Where permitted, appropriately trained nurses may prescribe medicines, including controlled medicines. Nurses should be trained to assess patients' palliative care needs, including pain control assessment and evaluation (as well as other knowledge and skills described in recommendations under Clinical Question 1), make recommendations, and communicate needs to adequately trained health care providers who are permitted to prescribe (Type of recommendation: evidence based; Evidence quality: intermediate; Strength of recommendation: strong). ## Literature review and analysis/discussion: Machira et al 31 published a quasi-experimental program evaluation of registered nurse education on pain management in Kenya that included 31 nurses caring for adults with life-limiting illness in one hospital. "The study highlighted the fact that palliative care, specifically pain management, in Kenya has no critical mass that would provide mentorship and improve clinical practice. This suggests the need for formal palliative care and specifically pain management training for nurses at preregistration and as part of continuous professional development within clinical practice." Nurses were either the focus of an intervention or on a team in many of the other studies reviewed, as well. ## Nurse-led programs: The role of nurses is paramount. Nurses should be able to carry out a basic palliative care assessment of the patient, follow-up, and communication. For complicated communication scenarios and symptom management, the nurse can assist the trained physician/psychologist/counselor/spiritual care providers. If nurses receive special training, they can be licensed to prescribe opioids. For example, a link-nurse program at Mulago Hospital (described in the next paragraph) increased nurses' confidence in their ability to write morphine prescriptions in Uganda (although their role was limited to making recommendations to physicians, the latter of whom had prescribing ability). [bib_ref] A palliative care link nurse programme in Mulago Hospital, Uganda: An evaluation..., Downing [/bib_ref] Downing et al 32 conducted a mixed method study at Mulago Hospital Uganda, a tertiary hospital with hospital-based palliative care. They provided "generalist" palliative care training to 27 nurses, and outcomes included nurses' confidence in providing palliative care. The study found changes in attitudes, developing new skills and knowledge, developing relationships, and an increase in access to and strengthening of palliative care. Challenges were found regarding writing morphine prescriptions, lack of interest by colleagues, and difficultly in convincing physicians of the value of palliative care. A pilot qualitative study on a nurse-practitionerled, general-practitioner-supported palliative care program was carried out in rural Australia. The study evaluated a single multidisciplinary case conference that found the nurse practitioners assumed prescribing of new medications or made dosing changes; there was a decrease in hospital utilization and an increase in the development of new advanced care plans as a result of this program. 33 Discussion: Along with the role of the oncologist trained in palliative care, an advanced practice nurse (APN) could play an important role in building and maintaining an interdisciplinary network of care, necessary for the management of complex palliative situations. The APN is a vital member of the interdisciplinary team and a key player who collaboratively integrates palliative practices throughout the patient's disease course by promoting QOL and reducing fragmented delivery of care. In the absence of trained palliative care physicians and oncologists, APNs could spearhead the development, implementation, and evaluation of palliative care services. In resource-constrained settings, nurses are professionally the most important health workers who could excel in palliative care delivery system(s). Although the designation and licensing of APNs may not be an option in many countries, studies have shown that nurses can provide quality palliative care if they have the training to do so and the system is structured to allow them to play that role. Their role should not be limited to only the hospital, but also to the community and home care level and could be the linkage among patients, caregivers, physicians, and other interdisciplinary teams. ## Clinical question 5 (spiritual care) What is the place of spiritual care in palliative care? Recommendation 5.0 (Across All Settings): Spiritual care provided by appropriately trained providers should be available in all settings, whether locally or by referral. In addition to providing direct patient care, spiritual care providers may advise and support the care team to support the patients and their families. Nurses or counselors may be trained to assess the spiritual needs of patients and their families. Providers should be observant of and sensitive to the religious norms of patients and families (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). Discussion: This section is based on expert opinion and formal consensus. Literature was not found by the systematic review from resource-constrained settings. Medical care providers should make appropriate referrals to certified chaplains or other spiritual support professionals. Professionals and volunteers interacting with patients/caregivers should use culturally appropriate language. This is critical for global work, as spiritual care professional/ training needs to be developed from indigenous culture. Models such as from a US National Consensus Conference may need to be adapted or developed de novo in different cultures. As with other components of the medical history, a spiritual history is important for clinicians to take, especially during the initial consultation. If the patient describes difficulty with coping and/ or that spiritual or religious resources are not working well for him or her, referral to a trained provider is advised. In the Basic Model, spiritual care should be available, at the minimum, during end-of-life care and at bereavement. In the Limited Model, spiritual care should be available whenever patients and/or caregivers are in need for this aspect of necessary psychosocial support. In the Enhanced Model, whenever possible, spiritual care provided by appropriately trained providers may be involved as a part of the interdisciplinary team in cancer care as soon as diagnosis, including in helping to break bad news. This may be especially helpful when clinicians are initially communicating a diagnosis to patients and caregivers. Early involvement may help patients and families to cope with grief and receive help to reach optimal decisions. Clinicians should document a patient's spiritual/existential distress. All patients may be offered basic spiritual support, for example, giving a framework so they may consider goals and receive hope along with medical outcomes. Ongoing assessment and evaluation are suggested. Psychosocial, spiritual, and bereavement support are key elements of palliative care. Most programs in Maximal settings use an interdisciplinary team that may include social workers, chaplains, psychiatrists, psychologists, and/or bereavement counselors. For many patients, spirituality plays an important role in coping with serious or terminal illnesses; spiritual distress is highly correlated with a desire for a hastened death. [bib_ref] Cancer and the experience of meaning: A group psychotherapy program for people..., Greenstein [/bib_ref] A growing body of literature (primarily from Maximal resource settings) supports the notion that spiritual care is a patient need. The data also suggest that patients' spiritual, religious, and cultural beliefs affect health care decision making and health care outcomes, including coping, QOL, and pain management. Studies have reported that spirituality and/or religion may be important to patients with cancer and may influence medical decision making. [bib_ref] Meeting spiritual needs: What is an oncologist to do?, Ferrell [/bib_ref] Research shows spirituality or religion impact QOL, coping, depression, and anxiety, and play a role in improved social functioning and maintaining social relationships. [bib_ref] Existential well-being is an important determinant of quality of life. Evidence from..., Cohen [/bib_ref] Other guidelines from Maximal settings have commented on the role of spiritual care [fig_ref] Table 3: Examples of Existing Training Materials From [/fig_ref] in Data Supplement 6). ## Clinical question 6 (social work/ counseling) What are the roles of social workers/counselors in palliative care? Qualifying Statement: The psychosocial needs of patients and their families should be addressed in all settings and across the cancer care continuum. This role can be addressed by social workers, mental health professionals, or community health workers with training in the needs of palliative care patients and the special approaches required in this population. The role of the social worker/counselor becomes more critical in patients with advanced illness or when curative therapies are not an option, as is often the case in limited-resource settings. Collaboration with counselors/social workers can assist communication between patients and clinicians, when available. ## Recommendation 6.1 basic: When staffing is limited and specialized counselors are not available, physicians and/or nurses may play this role. They should receive the training to provide psychosocial care and be given enough time with the patient to allow them to provide it (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). ## Recommendation 6.2 limited: Physicians and nurses may address the psychosocial needs of patients and families and should receive the training to do so. If possible, a social worker/ counselor/volunteer/spiritual care provider should be available to attend to patients and families with a high burden of psychosocial issues (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). ## Recommendation 6.3 enhanced: Counselors with special training in palliative care should be core members of the palliative care interdisciplinary team to provide psychosocial services to patients and families (Type of recommendation: formal consensus; Evidence quality: insufficient; Strength of recommendation: weak). Discussion: This section is based on clinical experience and formal consensus. No studies were found by the literature search from resource-constrained settings specifically on the intervention of the inclusion of social workers/ dedicated counselors. However, counseling is a recognized domain of palliative care. Elements such as counseling, emotional support and assessment, care coordination, and patient education are woven throughout (part of the AAHPM-ASCO domains: communication and shared decision making, advance care planning, carer support, coordination and continuity of care, psychosocial assessment and management, spiritual and cultural assessment and management). [bib_ref] Defining high-quality palliative care in oncology practice: An American Society of Clinical..., Bickel [/bib_ref] Much of the discussion under Clinical Question 6 is relevant to the role of mental health professionals. Several studies reviewed to inform the Expert Panel discussion included counselors/mental health services. Please see [fig_ref] Table 2: ASCO Framework of Resource Stratification [/fig_ref] in Data Supplement 5 for relevant points from these studies. ## Clinical question 7 (opioid availability) At what level of health care (health centers, dispensary, hospitals) should opioids (primarily oral) be available? # Introduction: The regular administration of oral morphine to patients with advanced cancer improves QOL and relief of suffering. Morphine was included in the first WHO Essential Medicines List and Cancer Pain Relief, together with the WHO three-step ladder. 46 Many barriers to patient access have been identified, 47 and have been addressed by the WHO in guidelines on the principles of balance. 48,49 While the consumption of medical opioids increased in higher income countries, there continue to be great disparities in medical opioid consumption when compared with low-and middle-income countries. This disparity has been highlighted since the 1990s in multiple publications, but recognized most recently by the World Health Assembly in its palliative care resolution of 2014 50 and the United Nations General Assembly 2016, 51 the International Narcotics Control Board, 52,53 Disease Control Priorities 3 (http://dcp-3.org), [bib_ref] The International Bank for Reconstruction and Development/The World Bank, Cleary [/bib_ref] and a Lancet Commission report of 2017. [bib_ref] Alleviating the access abyss in palliative care and pain relief-an imperative of..., Knaul [/bib_ref] These references were identified outside of the systematic literature review. ## Recommendation 7.0 general (across all settings): Health care systems should safely provide opioids and ensure that the supply is readily and continually available for dispensing by trained professionals and accessible to patients to meet their needs, following the principles of balance through regulations, policy, and existing recommendations. Health care systems should strive to offer all pain control interventions on the WHO Essential Medicines List (Type of recommendation: formal consensus; Evidence quality: intermediate; Strength of recommendation: moderate). One of the few articles potentially relevant to resource-constrained settings for this clinical question found in the literature search included patients with cancer hospitalized with pain in a palliative care and hospice ward of a Hong Kong public hospital. In this randomized, prospective study, patients participated in a pain management program provided by nurses. While pain scores showed no difference between groups, the use of as-needed-only analgesics was higher in the intervention group, as was the use of nonpharmacologic methods. [bib_ref] The effect of a pain management program on patients with cancer pain, Tse [/bib_ref] The scope of this guideline does not include reviewing the literature on opioids for cancer pain relief. However, we will cite one systematic review from Cochrane, [bib_ref] Oral morphine for cancer pain, Wiffen [/bib_ref] which was an update of previous Cochrane reviews conducted by Wiffen et al. [bib_ref] Oral morphine for cancer pain, Wiffen [/bib_ref] [bib_ref] Oral morphine for cancer pain, Wiffen [/bib_ref] [bib_ref] Oral morphine for cancer pain, Wiffen [/bib_ref] It included seven new studies, but they did not meet criteria for updating their past systematic review, which had a total of 62 RCTs included, primarily investigating efficacy, specifically pain and pain relief and adverse events reported by patients with cancer. The authors assessed the evidence as being of poor quality and having a high risk of bias (in most studies); however, studies found that > 90% of participants experienced decreases in pain to "no worse than mild pain" and providers can "titrate with oral morphine of any formulation," although they did not reveal which formulation was best. [bib_ref] Oral morphine for cancer pain, Wiffen [/bib_ref] There is a large disparity between opioid availability in HICs and LMICs.The WHO Essential Medicines List now includes fentanyl skin patches and methadone, which provides support of the recommendation in this guideline for Enhanced settings. The WHO Palliative Care Strategy states that policymakers should address "medicine availability, education, and government policy"; WHO also provides a model on access to opioids. According to LeBaron et al, [bib_ref] Recommendations to support nurses and improve the delivery of oncology and palliative..., Lebaron [/bib_ref] hospitals should have a first priority of making oral IR morphine available. "Institutions that have been successful in procuring morphine…could serve as role models and mentors to other institutions who wish to improve access to pain relief for their patients. Resources exist through international organizations, such as the Pain and Policy Studies Group, as well as regional institutions, such as the Indian Association of Palliative Care and Pallium India, to support improving access to opioids." Other existing policies/recommendations advise finding balance between controlling opioids to prevent abuse and/or diversion and ensuring patients with cancer in pain have access. The WHO recommends that national policies establish a system "that prevents diversion and ensures adequate availability for medical use"and that the former should not impede the latter. The WHO Guidance is based on the principle of "balance," which asserts that governments' obligation to control narcotic drugs is not only to prevent drug abuse, but also to ensure the availability of opioid analgesics for medical purposes. Controls aimed at preventing drug abuse and diversion must not interfere with the adequate availability of opioid analgesics for patients' pain relief. The International Drug Control Board states the importance of countries' cooperation with WHO, United Nations Office on Drugs and Crime, and International Drug Control Board to insure this balance in international drug control conventions. 53(p4) ## Cost implications There are very few articles on the economics of palliative care in LMICs, and clearly the form of such care is different than in HICs. HICs have until recently provided such care primarily in institutions (hospitals, long-term care homes/ nursing homes, and in growing popularity, hospices). Typically, care in the last year/last 3 months/last month can be quite costly to the health sector. There has been a move more recently in HICs to shift dying from hospitals to hospices or home (where most patients prefer to die). This can reduce costs to health care institutions/systems. We can, however, extrapolate from the experience of HICs. Drug costs tend to be only a small fraction of care at the end of life (7% in Poland and 4.7% in France), [bib_ref] How much does care in palliative care wards cost in Poland, Ciałkowska-Rysz [/bib_ref] with salaries tending to be the large majority of costs. Since salaries go up with national income, this gives an indication of the costs of care also in low-income countries. Expressing costs of care at a ratio to gross national income (GNI) per capita, cost in the last year of life is 170% of GNI per capita in Ireland, [bib_ref] Costs of formal and informal care in the last year of life..., Brick [/bib_ref] in the last year of life is 25% of GNI per capita in Netherlands (unless the individual also has dementia, in which case, it goes up to 100% of GNI per capita), 67 and in the last 15 days of life in Poland, hospital care is 12% of GNI per capita [bib_ref] How much does care in palliative care wards cost in Poland, Ciałkowska-Rysz [/bib_ref]. In Thailand, the only LMIC for which data could be located, the societal cost was 71% of GNI per capita for the last 1 to 3 months of life for those with end-stage renal disease who were not on dialysis. [bib_ref] Economic evaluation of palliative management versus peritoneal dialysis and hemodialysis for end-stage..., Teerawattananon [/bib_ref] There are many estimates for the United States, but these are likely not a good guide for other countries. One difference between the HICs and Thailand (an upper-middle-income country) is that in the former, up to 75% of the total cost is paid by the public sector (eg, Brick et al 66 provide estimates for Ireland), whereas in Thailand, only 25% of the cost falls on the government. [bib_ref] Economic evaluation of palliative management versus peritoneal dialysis and hemodialysis for end-stage..., Teerawattananon [/bib_ref] Informal caregiving and out-of-pocket expenditures can be considerable and form a large share of the costs in LMICs. Studies suggest that good planning and specialist expertise can both improve pain control for patients and allow them a greater possibility of dying at home (typically the preferred choice). This can be assisted by advance directives (provided that these are determined early enough and not as the patient arrives for the last time at the hospital) and where nurses coordinate palliative care. [bib_ref] The health economics of palliative care, Payne [/bib_ref] Summarizing the findings of these studies above suggests that for the most resource-constrained countries, the limiting factor for palliative care is not cost of drugs, but rather, the availability of trained nurses to coordinate care and support for family members who are likely to provide the majority of care. Having appropriately trained human resources available can cost a substantial fraction of national per capita income, per patient needing such care. ## Limitations of the research and future directions There were limitations on the evidence to inform some of the recommendations, due to many recognizable factors, such as prioritization of patient care and limited funding and infrastructure for research. Limitations include: - Results from resource-limited countries/ regions [fig] Recommendation 2. 1: Basic and Limited: The palliative care needs of patients with cancer should be addressed early in the course of illness by existing health professionals trained in the basics of palliative care. Recommendation 2.1 Basic and Limited: The palliative care team should address the needs of all patients with cancer, at a minimum: • Patients with overwhelming symptoms, whether physical, psychological, or spiritual • Patients who develop metastasis, regardless of the type of cancer • Patients who cannot receive active treatment with curative or life-prolonging intent • Patients with malignancies with limited life expectancy, eg, hepatocellular carcinoma Recommendation 2.1 Basic and Limited: (Type of recommendation: formal consensus; Evidence quality: intermediate; Strength of recommendation: weak). Recommendation 2.2 Enhanced and Maximal: Please note, this recommendation is from the Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update, Journal of Clinical Oncology, 2016; the only change is in bold. 1 Enhanced and Maximal: For newly diagnosed patients with advanced cancer, the Expert Panel suggests a modification of the non-resource-stratified guideline recommendation to early palliative care team involvement, starting early in the diagnosis process and ideally within 8 weeks of diagnosis. Enhanced and Maximal: Note: In maximal resource settings, the intent is to provide concurrent antitumor therapy and referral to interdisciplinary palliative care teams (Type of recommendation: informal consensus; Evidence quality: intermediate; Strength of recommendation: moderate). [/fig] [table] Table 1: Selected Examples of Existing Palliative Guidelines and Relevant Sections [/table] [table] Table 2: ASCO Framework of Resource Stratification: Palliative Care [/table] [table] Table 3: Examples of Existing Training Materials From [/table]	None	None	Purpose The purpose of this new resource-stratified guideline is to provide expert guidance to clinicians and policymakers on implementing palliative care of patients with cancer and their caregivers in resource-constrained settings and is intended to complement the Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update of 2016. Methods ASCO convened a multidisciplinary, multinational panel of experts in medical oncology, family medicine, radiation oncology, hematology/oncology, palliative and/or hospice care, pain and/or symptom management, patient advocacy, public health, and health economics. Guideline development involved a systematic literature review, a modified ADAPTE process, and a formal consensus-based process with the Expert Panel and additional experts (consensus ratings group). Results The systematic review included 48 full-text publications regarding palliative care in resource-constrained settings, along with cost-effectiveness analyses; the evidence for many clinical questions was limited. These provided indirect evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% (by consensus ratings group including Expert Panel). Recommendations The recommendations help define the models of care, staffing requirements, and roles and training needs of team members in a variety of resource settings for palliative care. Recommendations also outline the standards for provision of psychosocial support, spiritual care, and opioid analgesics, which can be particularly challenging and often overlooked in resource-constrained settings. Additional information is available at www.asco.org/resource-stratified-guidelines. 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. The guideline is intended to complement but not replace local guidelines.
c07dee9770526ba463c97f86a78c38a10ac9aac8	pubmed	BSACI guidelines for the management of allergic and non‐allergic rhinitis	BSACI guidelines for the management of allergic and non‐allergic rhinitis This guidance for the management of patients with allergic and non-allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co-morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research. # Introduction Rhinitis significantly reduces quality of life (QOL) [bib_ref] Quality of life during pollen season in patients with seasonal allergic rhinitis..., Laforest [/bib_ref] , interferes with both attendance and performance at school and work [bib_ref] Allergic rhinitis and impairment issues in schoolchildren: a consensus report, Blaiss [/bib_ref] [bib_ref] Loss of work productivity due to illness and medical treatment, Cockburn [/bib_ref] and results in substantial NHS costs [bib_ref] Cognitive, social, and economic costs of allergic rhinitis, Blaiss [/bib_ref]. The nose is the gateway to the respiratory tract and rhinitis is associated with symptoms arising from the sinuses [bib_ref] Complications of allergic rhinitis: implications for sinusitis and asthma, Slavin [/bib_ref] , middle ear [bib_ref] The link between allergic rhinitis and otitis media, Doyle [/bib_ref] , the nasopharynx and lower airways [bib_ref] An update on the asthma-rhinitis link, Passalacqua [/bib_ref]. Occupational rhinitis often precedes the development of occupational asthma. Both allergic rhinitis (AR) and non-AR are risk factors for the development of asthma [bib_ref] An update on the asthma-rhinitis link, Passalacqua [/bib_ref]. Rhinosinusitis can also be the presenting complaint of potentially severe systemic disorders such as Wegener's granulomatosis, sarcoidosis and Churg-Strauss syndrome [bib_ref] Rhino-sinus manifestations of systemic diseases, Barry [/bib_ref]. Therefore, all patients presenting with nasal symptoms require appropriate treatment based on an accurate diagnosis. Separate British Society for Allergy and Clinical Immunology (BSACI) guidelines on rhinosinusitis and nasal polyposis will also be published. These guidelines for the management of patients with rhinitis are intended for use by physicians treating allergic conditions. Evidence for the recommendations was obtained by using electronic literature searches using the primary key words -rhinitis and non-AR. Further searches were carried out by combining these search terms with allergy, asthma, immunotherapy, sublingual immunotherapy (SLIT), corticosteroid, antihistamine, anti-leukotriene, ipratropium bromide, decongestant, cromoglicate, cat, house dust mite (HDM), anti-IgE, child, pregnancy, lactation, surgery and aspirin. Each article was reviewed for suitability for inclusion in the guideline. The recommendations were evidence graded at the time of preparation of these guidelines. The grades of recommendation and the levels of evidence are defined as in our previous guideline on urticaria [bib_ref] BSACI guidelines for the management of chronic urticaria and angio-oedema, Powell [/bib_ref]. During the development of these guidelines, a web-based system was used to allow consultation with all BSACI members. The draft guidelines were amended by the Standards of Care Committee (SOCC) after careful consideration of all comments and suggestions. Where evidence was lacking, a consensus was reached among the experts on the committee. Conflicts of interests were recorded by the SOCC; none jeopardized unbiased guideline development. ## Executive summary and recommendations ## Allergic rhinitis Is common and affects over 20% of the UK population. Affects QOL, school and work attendance and performance. Is diagnosed by history and examination backed up by specific allergy tests. Is a risk factor for the development of asthma. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. (Grade of recommendation = A) Standardized allergy education improves disease-specific QOL. (Grade of recommendation = C) Treatment failure may be related to poor technique in the use of nasal sprays and drops and therefore appropriate training is imperative. (Grade of recommendation = C) Treatment of rhinitis is associated with benefits for asthma. (Grade of recommendation = A) Immunotherapy is highly effective in selected cases. (Grade of recommendation = A) Occupational rhinitis often precedes the development of occupational asthma. ## Non-allergic rhinitis Has a multifactorial aetiology. Is a risk factor for the development of asthma. If eosinophilic, usually responds to treatment with corticosteroids. May be a presenting complaint for systemic disorders such as Wegener's granulomatosis, Churg-Strauss and sarcoidoisis. ## Infective rhinitis Can be caused by viruses, and less commonly by bacteria, fungi and protozoa. Is often more severe in allergic patients especially if infection occurs at the time of allergen exposure. ## Definitions Rhinitis describes inflammation of the nasal mucosa but is clinically defined by symptoms of nasal discharge, itching, sneezing and nasal blockage or congestion. As the sinus linings are also usually involved, the term rhinosinusitis is more accurate, but is conventionally reserved for more severe disease. Rhinitis can be classified into allergic, non-allergic and infective. However, acute viral upper respiratory infections are not considered in detail in this document. ## Classification and aetiology of rhinitis ## Allergic rhinitis The prevalence of AR has increased over the last three decades [bib_ref] Increase of asthma, allergic rhinitis and eczema in Swedish schoolchildren between 1979..., Aberg [/bib_ref] [bib_ref] Are asthma and allergies in children and adolescents increasing? Results from ISAAC..., Maziak [/bib_ref]. At most risk are those with atopy, with a family history of rhinitis, first-born children and immigrants [bib_ref] Risk factors in allergy/asthma, Kaiser [/bib_ref] [bib_ref] The role of outdoor air pollution and climatic changes on the rising..., D'amato [/bib_ref] [bib_ref] Effect of pollutants in rhinitis, Peden [/bib_ref]. AR is the predominant form in children, but accounts for about a third of rhinitis cases in adults. In AR, the immediate reaction resulting from IgEmediated mast cell degranulation and mediator release is rapid and leads to sneezing, rhinorrhoea, itch and nasal blockage. The late-phase reaction involves inflammation, with an eosinophilic infiltrate [bib_ref] Mechanisms of allergic rhinitis, Park [/bib_ref] [bib_ref] Local IgE synthesis in allergic rhinitis and asthma, Smurthwaite [/bib_ref] [bib_ref] Mediators of inflammation in the early and the late phase of allergic..., Hansen [/bib_ref]. Symptoms are chronic obstruction, hyposmia, post-nasal mucous discharge and nasal hyper-reactivity. illustrates the mechanisms leading to AR. [fig_ref] Table 1: Allergic triggers for rhinitisPre-existing rhinitis can be aggravated by work-place irritantsFig [/fig_ref] specifies the common causes of occupational rhinitis. The WHO ARIA workshop 'Allergic Rhinitis and its impact on Asthma' [bib_ref] Allergic rhinitis and its impact on asthma, Bousquet [/bib_ref] suggested a new classification of AR based on frequency and severity of symptoms as these are the major factors involved in determining treatment; see [fig_ref] Figure 2: Classification of allergic rhinitis [/fig_ref]. These recommendations have been validated subsequently [bib_ref] Validation of the classification of ARIA (allergic rhinitis and its impact on..., Demoly [/bib_ref]. A clinical classification of seasonal and perennial rhinitis is useful in UK practice, especially for diagnosis and immunotherapy, and can be used alongside the ARIA classification. The ARIA recommendations emphasized the concept of treating 'one airway, one disease' with a similar unified therapeutic approach to the management of co-morbidities such as asthma, sinusitis, otitis media and conjunctivitis [bib_ref] Allergic rhinitis, rhinosinusitis, and asthma: one airway disease, Bachert [/bib_ref]. ## Infective rhinitis Any cause of congestion of the nasal mucosa can lead to occlusion of the sinus ostia, predisposing to facial pain, sinusitis and/or eustachian tube dysfunction. The causes and disease patterns of infective rhinitis are summarized in [fig_ref] Table 3: Infective causes of rhinitis [/fig_ref]. ## Non-allergic rhinitis The numerous diagnoses in this category need to be borne in mind for patients with negative skin prick tests (SPTs). [fig_ref] Table 4: Types and possible triggers of non-allergic rhinitis ACE, angiotensin-converting enzyme [/fig_ref] summarizes the causes and disease patterns of non-AR. ## Diagnosis of rhinitis History A detailed history is vital for an accurate diagnosis. The patient is asked to list their main symptoms in order of priority and this usually produces a short list of differential diagnoses. ## Symptoms Sneezing, itchy nose, itchy palate. AR is likely and further refinement of the diagnosis is aided by asking whether the symptoms are intermittent or persistent although this is not a substitute for specific allergen testing. Seasonal at the same time each year? -pollens or mould spores. At home? -pets or HDM. At work? -occupational allergens. On holiday? -remission suggests an environmental cause. Rhinorrhoea. Rhinorrhoea is either anterior or leads to post-nasal drip: Clear -infection unlikely. Unilateral -is uncommon and cerebrospinal fluid (CSF) leak should be excluded [bib_ref] CSF rhinorrhoea: the place of endoscopic sinus surgery, Marshall [/bib_ref]. Coloured yellow -allergy or infection green -usually infection blood tinged unilateral -tumour, foreign body, nose picking or misapplication of nasal spray bilateral -misapplication of nasal spray, granulomatous disorder, bleeding diathesis or nose picking. ## Nasal obstruction Unilateral -usually septal deviation but also consider foreign body, antrochoanal polyp and tumours. Bilateral -may be septal (sigmoid) deviation but more likely rhinitis or nasal polyps. Alternating -generalized rhinitis exposing the nasal cycle [bib_ref] Spontaneous changes of unilateral nasal airflow in man. A re-examination of the..., Flanagan [/bib_ref]. ## Nasal crusting Severe nasal crusting especially high inside the nose is an unusual symptom and requires further investigation. Consider nose picking, Wegener's granulomatosis, sarcoidosis, other vasculitides, ozaena (wasting away of the bony ridges and mucous membranes inside the nose), non-invasive ventilation and chronic rhinosinusitis [bib_ref] Wegener's granulomatosis -a review of diagnosis and treatment in 53 subjects, Jennings [/bib_ref]. Rarely, topical steroids may cause crusting. Eye symptoms. Eye symptoms associated with AR and particularly with seasonal rhinitis include intense itching, hyperaemia, watering, chemosis and periorbital oedema. Symptoms typically resolve within 24 h if removed from the allergen source. Other symptoms. Other symptoms such as snoring, sleep problems, repeated sniffing or a nasal intonation of the voice can be caused or exacerbated by nasal obstruction and rhinorrhoea from any cause. In some patients with seasonal allergic rhinitis (SAR), oral allergy syndrome is triggered by ingestion of cross-reacting antigens in some fruits, vegetables and nuts [bib_ref] The oral allergy syndrome, Ortolani [/bib_ref]. ## Lower respiratory tract symptoms Cough, wheeze, being short of breath. Disorders of the upper and lower respiratory tract often coexist: Most asthmatics have rhinitis -see 'Co-morbid association' on rhinitis and asthma. In asthma with aspirin sensitivity -36-96% have nasal polyps with rhinosinusitis [bib_ref] Nasal polyps in asthma and rhinitis. A review of 6,037 patients, Settipane [/bib_ref]. Family history. A family history of atopy, seasonal rhinitis or asthma makes the diagnosis of AR more likely [bib_ref] Frequency and hereditability of asthma and allergic rhinitis in college students, Van Arsdel [/bib_ref]. Social history. In order to assess possible allergen and irritant exposure, a full history of housing conditions, pets, occupation or schooling and, in young children, feeding details should be obtained. [bib_ref] Allergen exposure, atopy and smoking as determinants of allergy to rats in..., Cullinan [/bib_ref] [bib_ref] Incidence and host determinants of probable occupational asthma in apprentices exposed to..., Gautrin [/bib_ref] [bib_ref] Natural history of sensitization, symptoms and occupational diseases in apprentices exposed to..., Gautrin [/bib_ref] , crab processing industry [bib_ref] Occupational asthma in snow crab-processing workers, Cartier [/bib_ref] Vegetable proteins Wheat and other cereal flours and grains, latex [bib_ref] Respiratory occupational allergies: the experience of the hospital operative unit of occupational..., Cortona [/bib_ref] Baking [bib_ref] Wheat sensitization and workrelated symptoms in the baking industry are preventable. An..., Houba [/bib_ref] , milling, food processing, hospital workers Enzymes Protease, amylase, cellulase, lipase Food processing, detergent manufacture, pharmaceuticals Pharmaceuticals Antibiotics, morphine, cimetidine Pharmaceutical manufacture and dispensing Chemicals Diisocyanates, colophony fumes, (trimellitic) acid anhydrides (TMA) [bib_ref] Prevalence and onset of rhinitis and conjunctivitis in subjects with occupational asthma..., Grammer [/bib_ref] , cyanoacrylates, epoxy resins, alkyd/polyunsaturated polyester resins [bib_ref] Phthalic anhydride-induced occupational asthma, Wernfors [/bib_ref] Spray painting, electronic soldering, plastics and paint manufacture, vinyl flooring, resin production Drugs. A detailed drug history is vital as drugs such as topical sympathomimetics, a-blockers and other antihypertensives as well as aspirin and non-steroidal antiinflammatory drugs may cause rhinitis symptoms (see [fig_ref] Table 4: Types and possible triggers of non-allergic rhinitis ACE, angiotensin-converting enzyme [/fig_ref]. It is important to enquire about the efficacy of previous treatments for rhinitis and details of how they were used and for how long. Occupation. Exposure to occupationally related triggers is common and may have to be addressed in order to improve rhinitis symptoms. ## Examination ## Visual assessment Horizontal nasal crease across the dorsum of the nosesupports a diagnosis of AR. Depressed nasal bridge -post-surgery, Wegener's granulomatosis or cocaine misuse. Widened bridge; polyps (see also BSACI guideline on rhinosinusitis and nasal polyposis). Purple tip in lupus pernio due to sarcoidosis. An assessment of nasal airflow -(e.g. metal spatula misting in young children). ## Anterior rhinoscopy Appearance of the turbinates. The presence/absence of purulent secretions. The presence/absence of nasal polyps, but it may not be possible to see a small ones. Larger polyps can be seen at the nares and are distinguishable from the inferior turbinate by their lack of sensitivity, yellowish grey colour and the ability to get between them and the side wall of the nose. Yellow sub-mucosal nodules with a cobblestone appearance suggest sarcoidosis [bib_ref] The nasal manifestations of sarcoidosis: a review and report of eight cases, Fergie [/bib_ref]. Crusting and granulations raise the possibility of vasculitis. Septal perforation may occur after septal surgery, due to chronic vasoconstriction (cocaine, a-agonists), Wegener's granulomatosis, nose picking and very rarely steroid nasal sprays. ## Investigations Objective measures of nasal airway. Objective measurements of the nasal airway are not made in routine clinical practice but can be useful when allergen or aspirin challenges are undertaken and may be helpful when septal surgery or turbinate reduction are being contemplated. Peak nasal inspiratory flow. Measurement of peak nasal inspiratory flow provides a simple and inexpensive method for determining nasal airway patency using a nasal inspiratory flow meter. The results are reproducible and correlate with rhinoscopic evidence of rhinitis but not with symptom scores [bib_ref] Repeatability of peak nasal inspiratory flow measurements and utility for assessing the..., Starling-Schwanz [/bib_ref]. The technique is most useful for comparing changes in airway patency within the same subject, although some normative data are now available [bib_ref] Peak nasal inspiratory flow; normal range in adult population, Ottaviano [/bib_ref]. Acoustic rhinometry. Acoustic rhinometry can be used to measure changes in mucosal congestion using reflected sound. The technique is based on the physical principle that sound in the nasal cavity is reflected by changes in acoustic impedance caused by changes in cavity dimensions. The change in acoustic impedance between the incident wave and reflected sound waves is proportional to the cross-sectional area. The method requires standardization and considerable experience to interpret and obtain reproducible results. Guidelines for its use are published [bib_ref] Acoustic rhinometry: recommendations for technical specifications and standard operating procedures, Hilberg [/bib_ref]. Rhinomanometry. Rhinomanometry allows an estimation of nasal resistance from pressure-flow relationships and is difficult to perform reproducibly but is still regarded by some as the most accurate measure of nasal airway patency. With anterior rhinomanometry, the pressure sensor is placed at the tip of each nostril and resistance is measured in each nostril separately. With posterior rhinomanometry, the pressure sensor is placed in the back of the nasal cavity and total nasal airway resistance is determined. The technique requires expensive equipment and considerable experience in interpretation [bib_ref] Committee report on standardization of rhinomanometry, Clement [/bib_ref]. Nasal endoscopy. Used in specialist centres, this is more specific than rhinoscopy and alters the diagnosis in up to a fifth of patients with nasal disease [bib_ref] The role of nasal endoscopy in outpatient management, Hughes [/bib_ref]. Allergen-specific immunoglobulin E. Allergen-specific IgE can be detected with SPTs or by a serum immunoassay. Skin prick tests. SPTs should be carried out routinely in all cases in order to determine whether the rhinitis is allergic or non-allergic. Injectable adrenaline should be available, but is unlikely to be needed. Must be interpreted in the light of the clinical history. At least 15% of people with a positive SPT do not develop symptoms on exposure to the relevant allergen [bib_ref] Association of skin test reactivity, specific IgE, total IgE, and eosinophils with..., Droste [/bib_ref]. Have a high negative predictive value. Suppressed by antihistamines, tricyclic antidepressants and topical but not oral steroids [bib_ref] Effect of cetirizine and prednisolone on cellular infiltration and cytokine mRNA expression..., Taborda-Barata [/bib_ref]. Are inadvisable outside specialist allergy clinics if the patient has a history of anaphylaxis. Serum total and specific immunoglobulin E. Serum-specific IgE may be requested when skin tests are not possible or when the SPT, together with the clinical history, give equivocal results. Total IgE alone can be misleading but may aid interpretation of specific IgE. Allergen-specific IgE correlates with the results of SPTs and nasal challenges although there are exceptions. Currently available SPTs and immunoassays show similar sensitivity for HDM, but SPTs are more sensitive to other inhalant allergens such as cat epithelium, mould and grass pollen [bib_ref] A clinical evaluation in children of the Pharmacia ImmunoCAP system for inhalant..., Gleeson [/bib_ref]. Routine laboratory investigations. Other investigations to help with the initial management of patients with rhinitis are guided by the findings from the history, examination and results of SPTs. Examples of routine laboratory investigations include: Full blood count and differential white cell count. C-reactive protein. Nasal smear/brushing for eosinophils. Microbiological examination of sputum and sinus swabs. Nasal secretions -CSF asialotransferrin for CSF rhinorrhoea. Urine toxicology when cocaine abuse is suspected. Olfactory tests. The University of Pennsylvania Smell Identification Test is well validated, can identify malingerers [bib_ref] University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test..., Doty [/bib_ref] and is accepted for legal cases. Cytology. The techniques for obtaining cells for cytology in secretions, lavage, scraping, cotton pledgelets or brushings have not been standardized, nor have the criteria for evaluating cell counts [bib_ref] Eosinophilia in nasal secretions compared to skin prick test and nasal challenge..., Romero [/bib_ref]. Nevertheless, the presence of eosinophils implies inflammation and may be helpful in predicting response to corticosteroids. Exhaled nitric oxide. Exhaled nitric oxide (FeNO, fractional exhaled nitric oxide) measurement can be useful clinically in the diagnosis and monitoring of asthma. Normal levels are o20 p.p.b., but become elevated in eosinophilic lower respiratory tract inflammation [bib_ref] Effect of inhaled budesonide on seasonal changes in sensitivity and maximal response..., Prieto [/bib_ref]. ## Nasal challenge Is not routinely available outside specialist centres. There is no standardized methodology. Asthmatic reactions can occur. May be useful to confirm aspirin sensitivity. May be useful in patients with an unclear history and negative or equivocal tests for allergen-specific IgE or when the trigger is not IgE mediated. Has a role in occupational AR, where there is a discrepancy between history and when there are potentially important occupational implications. Tests for asthma. Measurements of lung function should be considered in all patients with persistent rhinitis e.g. peak expiratory flow rate and spirometry as detailed in the British Thoracic Society guidelines on the management of asthma. Treatment of rhinitis [fig_ref] Figure 3: Algorithm for the treatment of rhinitis [/fig_ref] shows an algorithm for the treatment of rhinitis. Grades of recommendation are given in [fig_ref] Table 4: Types and possible triggers of non-allergic rhinitis ACE, angiotensin-converting enzyme [/fig_ref]. ## Education Standardized allergy education of health personnel improves disease-specific QOL [bib_ref] Standardized training for healthcare professionals and its impact on patients with perennial..., Sheikh [/bib_ref]. (Grade of recommendation = C) The patient or parents of children should be informed about the nature of the disease, causes and mechanisms of rhinitis, the symptoms and available treatments. Education on means of allergen avoidance and drug therapy, including safety and potential side effects, should be provided. Treatment failure may be related to poor technique in the use of nasal sprays and drops and therefore appropriate training is imperative [bib_ref] The role of patient training in the management of seasonal rhinitis and..., Gani [/bib_ref] [bib_ref] An evaluation of the best head position for instillation of steroid nose..., Kayarkar [/bib_ref]. It is important to provide patients with education on the complications of rhinitis including sinusitis and otitis media, and comorbid conditions such as asthma and nasal polyps. They should be aware of how such complications are recognized and treated. Patients should be made aware of the potential negative impact of rhinitis on their QOL and benefits of complying with therapeutic recommendations. Patients should be provided with realistic expectations for the results of therapy and should understand that complete cures do not usually occur in the treatment of chronic diseases, including rhinitis, and that longterm treatment may be needed. ## Allergen avoidance Allergen avoidance decisions are complicated and the clinician's task of providing advice to patients is not facilitated by the paucity of available evidence. Avoidance is clearly beneficial in allergy to domestic pets, horses and certain occupational allergens (laboratory animals, latex), where clinical trials are unnecessary. However, a number of measures designed to reduce mite exposure have not shown the expected results. The appendix to this document includes several tables providing advice on allergen avoidance (see [fig_ref] Table 1: Allergic triggers for rhinitisPre-existing rhinitis can be aggravated by work-place irritantsFig [/fig_ref]. House dust mite. HDM is the most common indoor allergen causing rhinitis. It is logical to assume that reduction of allergens such as HDM would reduce symptoms in sensitized patients. However, the evidence to refute or confirm this hypothesis is lacking. Use of mite-proof bed covers as a single intervention in mite-allergic adults or children is not of proven value according to a number of placebo-controlled trials [bib_ref] A review of the effects of impermeable bedding encasements on dust-mite allergen..., Recer [/bib_ref] [bib_ref] Evaluation of impermeable covers for bedding in patients with allergic rhinitis, Terreehorst [/bib_ref]. A Cochrane meta-analysis in 2001 [bib_ref] House dust mite avoidance measures for perennial allergic rhinitis, Sheikh [/bib_ref] addressed the potential benefit of HDM avoidance measures for perennial allergic rhinitis. It was found that the benefit of using a single measure to improve symptoms of perennial rhinitis was questionable. Efforts to obtain maximal mite elimination may lead to clinical benefits in selected highly motivated patients, and clinical benefits are most likely with multiple interventions [bib_ref] Home environmental intervention in inner-city asthma: a randomized controlled clinical trial, Eggleston [/bib_ref]. Pollen avoidance in seasonal allergic rhinitis. Nasal filters have been shown to reduce symptoms of AR and allergic conjunctivitis significantly during the ragweed and grass pollen seasons [bib_ref] The reduction of rhinitis symptoms by nasal filters during natural exposure to..., O'meara [/bib_ref]. A number of other measures are often recommended to patients with pollen allergy to minimize symptoms but these are based on expert consensus rather than clinical trial data [fig_ref] Table 2: Common causes of occupational rhinitis [/fig_ref]. Cat allergen. There are no trials examining whether measures to minimize cat allergen levels lead to clinical improvement in rhinitis as it takes several months for cat allergens to disappear from a home once the cat has been removed. Therefore, trials of brief cat removal are ineffective [bib_ref] The control of allergens of dust mites and domestic pets: a position..., Colloff [/bib_ref]. However, it is likely that cat removal will produce an improvement in symptoms, and a number of measures to minimize cat allergen levels at home are recommended [fig_ref] Table 3: Infective causes of rhinitis [/fig_ref]. Occupational allergens. Rhinitis may be induced by workplace exposure to a respiratory sensitizing agent ('occupational rhinitis'), [fig_ref] Table 2: Common causes of occupational rhinitis [/fig_ref]. Where pre-existing disease is provoked by an (irritant) occupational agent, it is described as 'work-exacerbated' rhinitis. The agents that can give rise to occupational rhinitis, numbering over 300, are the same as those that induce occupational asthma. Particle size is probably important in determining the site of disease. Occupational rhinitis is as much as three times more frequent than occupational asthma but the two conditions frequently occur together [bib_ref] Risk of asthma among Finnish patients with occupational rhinitis, Karjalainen [/bib_ref] [bib_ref] Epidemiology of occupational rhinitis: prevalence, aetiology and determinants, Siracusa [/bib_ref]. An understanding of those occupations that incur relevant exposures and a detailed history of such exposures and their relationship with the onset and pattern of symptoms are essential for identification of occupational rhinitis. If a diagnosis of occupational rhinitis is established, then avoidance of further exposure to the causative agent may lead to cure. Symptoms caused by continuing exposure may be very difficult to treat. Occupational rhinitis generally precedes, and may be a risk factor for, occupational asthma. The risk of occupational asthma is the highest in the year after the development of occupational rhinitis [bib_ref] Risk of asthma among Finnish patients with occupational rhinitis, Karjalainen [/bib_ref] [bib_ref] Respiratory occupational allergies: the experience of the hospital operative unit of occupational..., Cortona [/bib_ref]. The early identification of a causative occupational agent and the avoidance of exposure are important measures for the management of occupational rhinitis and prevention of progression to occupational asthma [bib_ref] The reduction of rhinitis symptoms by nasal filters during natural exposure to..., O'meara [/bib_ref] [bib_ref] The control of allergens of dust mites and domestic pets: a position..., Colloff [/bib_ref] [bib_ref] Risk factors associated with asthma and rhinoconjunctivitis among Swedish farmers, Kronqvist [/bib_ref] [bib_ref] Latex allergy: a follow up study of 1040 healthcare workers, Filon [/bib_ref]. (Level of evidence = 211; grade of recommendation = B) Prevention of latex allergy by removing powdered gloves or substituting non-latex ones is essential. All healthcare environments should have a latex policy [bib_ref] Latex allergy: a follow up study of 1040 healthcare workers, Filon [/bib_ref] [bib_ref] A clinical and serological follow-up study of health care workers allergic to..., Hemery [/bib_ref]. (Level of evidence = 21 and 4; Grade of recommendation = D, C for adults and children with perennial rhinitis or adults and children with latex allergy.) Irritant avoidance. Many patients with active rhinitis exhibit nasal hyper-reactivity to substances such as smoke, pollutants, perfume and dust and to temperature change. In many cases, it is likely that improved management of rhinitis will lead to an improvement in symptoms of nasal hyper-reactivity. (Grade of recommendation = D) ## Nasal douching and drops In mainland Europe, nasal douching is a more commonly used therapy than in the United Kingdom. Saline douching reduced symptoms in children and adults with seasonal rhinitis [bib_ref] Hypersaline nasal irrigation in children with symptomatic seasonal allergic rhinitis: a randomized..., Garavello [/bib_ref] [bib_ref] Clinical study and literature review of nasal irrigation, Tomooka [/bib_ref] (Grade of recommendation = A). It is a safe, inexpensive treatment. ## Adverse events Sodium load should be considered in hypertensive patients. ## Place in therapy Additional to therapy in rhinitis. Effective in children with seasonal and other forms of AR in combination with conventional treatment [bib_ref] Hypersaline nasal irrigation in children with symptomatic seasonal allergic rhinitis: a randomized..., Garavello [/bib_ref] [bib_ref] Nasal rinsing with hypertonic solution: an adjunctive treatment for pediatric seasonal allergic..., Garavello [/bib_ref]. Sterile saline eyedrops are a simple, non-toxic and effective addition for seasonal allergic conjunctivitis [bib_ref] Seasonal allergic conjunctivitis: overview and treatment update, Joss [/bib_ref]. ## Pharmacotherapy Despite allergen and trigger avoidance, many rhinitis sufferers continue to have persistent symptoms, the nature of which should determine the selection of medication. Available treatments and their effects on individual symptoms are detailed in [fig_ref] Table 5: Effect of therapies on rhinitis symptoms [/fig_ref]. ## (all have a grade of recommendation = a) Oral H1-antihistamines [fig_ref] Table 6: Oral antihistamines licensed in the UK according to age [/fig_ref] Reduce total nasal symptom scores by a mean of 7% (5-9%) more than placebo [bib_ref] Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis, Wilson [/bib_ref]. Effective predominantly on neurally mediated symptoms of itch, sneeze and rhinorrhoea. Desloratadine, fexofenadine, cetirizine and levocetirizine have modest effects on nasal blockage [bib_ref] Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis, Nayak [/bib_ref] [bib_ref] Fexofenadine reduces nasal congestion in perennial allergic rhinitis, Ciprandi [/bib_ref] [bib_ref] Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal..., Ciprandi [/bib_ref] [bib_ref] Comparison of five new antihistamines (H1-receptor antagonists) in patients with allergic rhinitis..., Van [/bib_ref] [bib_ref] Pathophysiology of nasal obstruction and meta-analysis of early and late effects of..., Patou [/bib_ref] [bib_ref] Efficacy of desloratadine in the treatment of allergic rhinitis: a metaanalysis of..., Canonica [/bib_ref]. Improve allergic symptoms at sites other than the nose such as the conjunctiva, palate, skin and lower airways [bib_ref] Ketotifen alone or as additional medication for long-term control of asthma and..., Schwarzer [/bib_ref] [bib_ref] Review of cetirizine hydrochloride for the treatment of allergic disorders, Portnoy [/bib_ref] [bib_ref] Prospects for antihistamines in the treatment of asthma, Nelson [/bib_ref]. Regular therapy is more effective than 'as-needed' use in persistent rhinitis [bib_ref] H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects, Leurs [/bib_ref]. Can significantly improve QOL [bib_ref] Levocetirizine improves quality of life and reduces costs in long-term management of..., Bachert [/bib_ref]. ## Adverse events First-generation antihistamines, e.g. chlorphenamine, diphenhydramine, cause sedation and reduce academic and/or work performance and should be avoided [bib_ref] Seasonal allergic rhinitis and antihistamine effects on children's learning, Vuurman [/bib_ref] [bib_ref] Structured allergy training for health professionals improves quality of life in patients..., Sheikh [/bib_ref]. Second-generation antihistamines, e.g. acrivastine, cetirizine, desloratadine, fexofenadine levocetirizine, loratadine and mizolastine are less sedating in most patients, with fexofenadine the least sedating [bib_ref] An evaluation of the effects of high-dose fexofenadine on the central nervous..., Hindmarch [/bib_ref] [bib_ref] Doubleblind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120..., Howarth [/bib_ref]. In addition, they do not cause significant QT prolongation at normal therapeutic doses have few major drug interactions, except for increased risk of ventricular arrhythmias, when mizolastine is co-administered with some antiarrhythmics, antibiotics and b-blockers. ## H 1 -antihistamines -topical nasal Azelastine À therapeutic effects superior to oral antihistamines for rhinitis symptoms [bib_ref] Intranasal azelastine. A review of its efficacy in the management of allergic..., Mcneely [/bib_ref] [bib_ref] Evidence-based strategies for treatment of allergic rhinitis, Portnoy [/bib_ref]. Do not improve symptoms due to histamine at other sites, such as the eye, pharynx, lower airways and skin. Fast onset of action within 15 min [bib_ref] Intranasal azelastine. A review of its efficacy in the management of allergic..., Mcneely [/bib_ref] -useful as rescue therapy. ## Adverse events Local irritation. Taste disturbance with azelastine. ## Place in therapy -oral and topical antihistamines First-line therapy for mild to moderate intermittent and mild persistent rhinitis. Additional to intranasal steroids for moderate/severe persistent rhinitis uncontrolled on topical intranasal corticosteroids alone [bib_ref] Comparison of beclomethasone dipropionate aqueous nasal spray, astemizole, and the combination in..., Juniper [/bib_ref] [bib_ref] Budesonide and terfenadine, separately and in combination, in the treatment of hay..., Simpson [/bib_ref] [bib_ref] A comparison of the efficacy of fluticasone propionate aqueous nasal spray and..., Ratner [/bib_ref]. ## Topical intranasal corticosteroids Meta-analysis shows that intranasal corticosteroids (INS) are superior to antihistamines [bib_ref] Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic..., Yanez [/bib_ref] [bib_ref] Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review..., Weiner [/bib_ref]. Act by suppression of inflammation at multiple points in the inflammatory cascade [bib_ref] Local corticosteroid treatment: the effect on cells and cytokines in nasal allergic..., Fokkens [/bib_ref]. Reduce all symptoms of rhinitis by about 17% greater than placebo, with a variable effect on associated allergic conjunctivitis [bib_ref] Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis, Wilson [/bib_ref]. Onset of action is 6-8 h after the first dose, clinical improvement may not be apparent for a few days and maximal effect may not be apparent until after 2 weeks [bib_ref] Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review..., Weiner [/bib_ref]. Starting treatment 2 weeks before a known allergen season improves efficacy [bib_ref] A placebo-and activecontrolled randomized trial of prophylactic treatment of seasonal allergic rhinitis..., Graft [/bib_ref]. Similar clinical efficacy for all INS but bioavailability varies considerably. Systemic absorption negligible with mometasone and fluticasone, modest for the remainder and high for betamethasone and dexamethasone -these should be used short term only [bib_ref] Cushing's syndrome induced by betamethasone nose drops. In rhinological disease betamethasone should..., Homer [/bib_ref] [bib_ref] Cushing's syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids, Perry [/bib_ref] [bib_ref] A randomized doubleblind study to compare the effects of nasal fluticasone and..., Fowler [/bib_ref]. Long-term growth studies in children using fluticasone, mometasone and budesonide have reassuring safety data, unlike beclomethasone [bib_ref] Systemic effects of intranasal steroids: an endocrinologist's perspective, Allen [/bib_ref] [bib_ref] Safety and tolerability profiles of intranasal antihistamines and intranasal corticosteroids in the..., Salib [/bib_ref] [bib_ref] Safety of nasal budesonide in the long-term treatment of children with perennial..., Moller [/bib_ref] [bib_ref] Absence of growth retardation in children with perennial allergic rhinitis after one..., Schenkel [/bib_ref] [bib_ref] Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate, Skoner [/bib_ref]. Concomitant treatment with CYP3A inhibitors such as itraconazole or ritonivir may increase systemic bioavailability of intranasal corticosteroids [bib_ref] Cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and..., Johnson [/bib_ref] [bib_ref] Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and..., Skov [/bib_ref]. ## Adverse events Local nasal irritation, sore throat and epistaxis affect around 10% of users. Benzalkonium chloride is used as a preservative in all topical corticosteroids, except Rhinocort s (Astrazeneca International, London, UK) nasal spray and Flixonase s nasules, and may irritate the nose, but does not adversely affect mucociliary clearance [bib_ref] Immediate and short-term effects of benzalkonium chloride on the human nasal mucosa..., Mcmahon [/bib_ref]. Reduction of local adverse effects can probably be achieved by correct use; see Hypothalmic-pituitary axis suppression may occur when multiple sites are treated with topical corticosteroids in the same person (e.g. skin, nose and chest). It is advisable to monitor growth in children [bib_ref] No growth suppression in children treated with the maximum recommended dose of..., Allen [/bib_ref] (see also [fig_ref] Table 7: Nasal corticosteroids licensed for use in the United Kingdom according to age [/fig_ref]. Raised intra-ocular pressure has been described with INS [bib_ref] Discontinuing nasal steroids might lower intraocular pressure in glaucoma, Bui [/bib_ref] , and patients with a history of glaucoma should be monitored more closely. ## Place in therapy First-line therapy for moderate to severe persistent symptoms and treatment failures with antihistamines alone [bib_ref] Allergic rhinitis and its impact on asthma, Bousquet [/bib_ref] [bib_ref] Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review..., Weiner [/bib_ref]. Topical steroid drops should be used initially in nasal polyposis and severe obstruction. ## Systemic glucocorticosteroids Rarely indicated in the management of rhinitis, except for: severe nasal obstruction short-term rescue medication for uncontrolled symptoms on conventional pharmacotherapy important social or work-related events, e.g. examinations, weddings Oral corticosteroids should be used briefly and always in combination with a topical nasal corticosteroid. A suggested regime for adults is 0.5 mg/kg given orally in the morning with food for 5-10 days. ## Injectable corticosteroids Injected preparations are not recommended unless under exceptional circumstances [bib_ref] Lesson of the week: depot corticosteroid treatment for hay fever causing avascular..., Nasser [/bib_ref] [bib_ref] Any place for depot triamcinolone in hay fever, Anonymous [/bib_ref]. Compared with other available treatments, the riskbenefit profile for intramuscular corticosteroids is poor [bib_ref] Lesson of the week: depot corticosteroid treatment for hay fever causing avascular..., Nasser [/bib_ref]. ## Anti-leukotrienes Anti-leukotrienes are of two kinds: (i) receptor antagonists (LTRAs, e.g. montelukast and zafirlukast) [bib_ref] Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance..., Bisgaard [/bib_ref] and (ii) synthesis inhibitors, e.g. zileuton (unavailable in the United Kingdom). There is a spectrum of individual responsiveness to LTRAs that is currently not predictable [bib_ref] 5-Lipoxygenase polymorphism and in-vivo response to leukotriene receptor antagonists, Fowler [/bib_ref] [bib_ref] Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts..., Sampson [/bib_ref] [bib_ref] Clinical and genetic features underlying the response of patients with bronchial asthma..., Mastalerz [/bib_ref]. Therapeutic profile similar to antihistamines, with efficacy comparable to loratadine in SAR [bib_ref] Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed..., Philip [/bib_ref]. How-ever, the response is less consistent than that observed with antihistamines. A study found that LTRAs reduced the mean daily rhinitis symptom scores by 5% more than placebo [bib_ref] Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis, Wilson [/bib_ref]. Anti-leukotrienes are less effective than topical nasal corticosteroids [bib_ref] Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed..., Philip [/bib_ref] [bib_ref] Randomized placebo-controlled study comparing a leukotriene receptor antagonist and a nasal glucocorticoid..., Pullerits [/bib_ref] [bib_ref] Fluticasone propionate aqueous nasal spray provided significantly greater improvement in daytime and..., Ratner [/bib_ref] [bib_ref] A comparison of topical budesonide and oral montelukast in seasonal allergic rhinitis..., Wilson [/bib_ref]. Anti-leukotriene plus antihistamine combinations do not improve efficacy to a clinically relevant extent compared with either drug used alone [bib_ref] Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized,..., Meltzer [/bib_ref] [bib_ref] Efficacy and tolerability of montelukast alone or in combination with loratadine in..., Nayak [/bib_ref] [bib_ref] Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotriene..., Wilson [/bib_ref] [bib_ref] A comparison of once daily fexofenadine versus the combination of montelukast plus..., Wilson [/bib_ref] , and their use in rhinitis is thus disputed [bib_ref] Exploring the role of leukotriene receptor antagonists in the management of allergic..., Pawankar [/bib_ref]. The combination of antihistamine and anti-leukotriene is no more effective than topical corticosteroid alone [bib_ref] Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and..., Pullerits [/bib_ref] [bib_ref] Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus..., Lorenzo [/bib_ref]. May have a place in patients with SAR and asthma [bib_ref] The effect of montelukast on rhinitis symptoms in patients with asthma and..., Philip [/bib_ref]. ## Adverse events Usually well tolerated; occasional headache, gastrointestinal symptoms or rashes. Occasional reports of Churg-Strauss syndrome that may relate more to steroid withdrawal rather than a direct effect of the drug, although further long-term evaluation is needed. ## Place in therapy Montelukast is licensed in the United Kingdom for those with SAR who also have concomitant asthma (UK license for age 46 months; Zafirlukast UK license 412 years). May be useful in patients with asthma and persistent rhinitis. Some patients with aspirin sensitivity appear to show marked improvement [bib_ref] Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant..., Dahlen [/bib_ref] , although at present, it is not possible to predict responders other than by use of a trial of therapy. Topical anti-cholinergic: ipratropium bromide (Rinatec s , Boehringer Ingelheim Ltd., Berkshire, UK) Decreases rhinorrhoea but has no effect on other nasal symptoms [bib_ref] Use of ipratropium bromide nasal spray in chronic treatment of nonallergic perennial..., Grossman [/bib_ref] [bib_ref] The anticholinergic agent, ipratropium bromide, is useful in the treatment of rhinorrhea..., Kaiser [/bib_ref] [bib_ref] Optimum treatment of rhinitis in the elderly, Tan [/bib_ref]. Needs to be used three times daily, mainly in the morning, e.g. before breakfast, after breakfast and after morning tea break (symptoms of rhinorrhoea occur mainly in the morning). Regular use may be effective, particularly: In 'old man's drip' As an 'add on' for AR when watery rhinorrhoea persists despite topical steroids and antihistamines For autonomic rhinitis when the dominant symptom is profuse watery rhinorrhoea in response to irritant triggers or changes in temperature [bib_ref] Common cold and high-dose ipratropium bromide: use of anticholinergic medication as an..., Ostberg [/bib_ref] [bib_ref] Cold-induced rhinitis in skiers -clinical aspects and treatment with ipratropium bromide nasal..., Bonadonna [/bib_ref] Also useful in the common cold. ## Adverse events Dry nose and epistaxis [bib_ref] Product characteristics and pharmacokinetics of intranasal ipratropium bromide, Wood [/bib_ref]. Systemic anti-cholinergic effects are unusual [bib_ref] A clinical trial of ipratropium bromide nasal spray in patients with perennial..., Bronsky [/bib_ref] Urinary retention [bib_ref] Urinary retention associated with ipratropium bromide, Pras [/bib_ref] Glaucoma [bib_ref] Acute angle-closure glaucoma as a complication of combined beta-agonist and ipratropium bromide..., Hall [/bib_ref] Caution advised in the elderly. ## Place in therapy Autonomic rhinitis. Persistent rhinorrhoea from other causes. Intranasal decongestants. The a1-agonist ephedrine (as nasal drops) and a2-agonist xylometazoline (available as nasal drops or spray for adults and children over 3 months of age) are sympathomimetics that increase nasal vasoconstriction and are effective for nasal obstruction in both allergic and non-AR [bib_ref] Pharmacologic approaches to daytime and nighttime symptoms of allergic rhinitis, Storms [/bib_ref]. Oxymetazoline has an action that starts within 10 min and lasts up to 12 h. ## Adverse events Regular use can lead to rhinitis medicamentosa with tachyphylaxis to the drug and marked chronic nasal obstruction [bib_ref] Rhinitis medicamentosa, Scadding [/bib_ref]. Nasal irritation. May increase rhinorrhoea. ## Place in therapy Brief use of o10 days is advised in order to avoid rebound effect for eustachian tube dysfunction when flying in children with acute otitis media to relieve middle ear pain/pressure post-URTI to reduce nasal/sinus congestion to increase nasal patency before intranasal administration of nasal steroids ## Oral decongestants (pseudoephedrine) Weakly effective in reducing nasal obstruction [bib_ref] Pharmacological background to decongesting and anti-inflammatory treatment of rhinitis and sinusitis, Malm [/bib_ref]. Do not cause a rebound effect on withdrawal but are less effective than topical preparations for nasal obstruction [bib_ref] Optimizing treatment options, Naclerio [/bib_ref]. Effect lasts 30 min -6 h or longer with slow-release preparations. ## Side-effects Hypertension Interact with antidepressants Insomnia Agitation Tachycardia ## Place in therapy Not generally recommended. Chromones [sodium cromoglicate ( = cromolyn) and nedocromil sodium]. Sodium cromoglicate and nedocromil sodium inhibit the degranulation of sensitized mast cells, inhibiting the release of inflammatory and allergic mediators [bib_ref] Use of intranasal cromolyn sodium for allergic rhinitis, Ratner [/bib_ref]. Sodium cromoglicate is weakly effective in rhinitis, with some effect on nasal obstruction [bib_ref] Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate..., James [/bib_ref] [bib_ref] Efficacy and patient satisfaction with cromolyn sodium nasal solution in the treatment..., Meltzer [/bib_ref]. The spray needs to be used several times (three to four) per day. ## Adverse events ## Local irritation rarely transient bronchospasm occasional taste perversion headache Place in therapy Generally very well tolerated (pregnancy) Children and adults with mild symptoms only and sporadic problems in season or on limited exposure [bib_ref] Cost-effective pharmacotherapy for inhalant allergic rhinitis, Hadley [/bib_ref]. Cromoglicate and nedocromil eyedrops are useful in conjunctivitis as topical therapy [bib_ref] Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate..., James [/bib_ref] [bib_ref] Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy..., Owen [/bib_ref]. ## Allergen immunotherapy Allergen immunotherapy involves the repeated administration of an allergen extract in order to reduce symptoms and the need for rescue medication on subsequent exposure to that allergen [bib_ref] Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper, Bousquet [/bib_ref]. Immunotherapy can be highly effective and is the only treatment that is able to modify the natural history of AR and offer the potential for long-term disease remission [bib_ref] Long-term clinical efficacy of grass-pollen immunotherapy, Durham [/bib_ref] [bib_ref] Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis..., Moller [/bib_ref] (level of evidence = 11). Recent reviews include the 'ARIA Update' [bib_ref] Allergic rhinitis and its impact on asthma update: allergen immunotherapy, Passalacqua [/bib_ref] and 'Standards for Practical Immunotherapy' (European guideline) [bib_ref] Standards for practical allergen-specific immunotherapy, Alvarez-Cuesta [/bib_ref]. Whereas non-sedating anti-histamines and topical nasal corticosteroids remain first-line treatments for AR, immunotherapy is recommended in those subjects with IgE-mediated disease in whom allergen avoidance is either undesirable or not feasible and who fail to respond to optimal treatment [bib_ref] Allergic rhinitis and its impact on asthma, Bousquet [/bib_ref]. The benefit to risk ratio should be considered in every case. The quality of allergen vaccines is important and only standardized extracts should be used. An optimal maintenance dose of 5-20 mg of major allergen per maintenance injection has been shown to correspond with clinical efficacy [bib_ref] Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper, Bousquet [/bib_ref]. ## Adverse events Pain and swelling at the site of injection is seen in the majority of patients. Systemic reactions (particularly in patients with asthma [bib_ref] Survey of fatalities from skin testing and immunotherapy 1985-1989, Reid [/bib_ref] : including urticaria, angio-oedema, asthma and anaphylaxis. Chronic asthma is a contraindication in the United Kingdom. For these reasons, immunotherapy should only be performed: under the supervision of a physician fully trained in the management of allergic disease with immediate access to adrenaline and other resuscitative measures patients should be observed for a minimum of 60 min (30 min in mainland Europe) following injections [bib_ref] The incidence and nature of adverse reactions to injection immunotherapy in bee..., Youlten [/bib_ref] Place in therapy At present, within the United Kingdom, allergen injection immunotherapy is recommended in patients with: IgE-mediated seasonal pollen-induced rhinitis and/or conjunctivitis in patients whose symptoms respond inadequately to usual therapy [bib_ref] Injection immunotherapy. British Society for Allergy and Clinical Immunology Working Party, Frew [/bib_ref] [bib_ref] Immunotherapy in Europe, Malling [/bib_ref]. (Level evidence = 11; Grade of recommendation = A) persistent symptoms despite a trial of medical therapy in carefully selected patients with an allergy to animals (e.g. cat) or HDM and where the allergen is not easily avoided e.g. occupational allergy in vets or public sector workers. systemic allergic reactions to stinging insect venom (wasp or bee). ## Sublingual immunotherapy SLIT has been proposed as an alternative to the subcutaneous route [bib_ref] Noninjection routes for immunotherapy, Canonica [/bib_ref]. SLIT has been shown to be effective in both rhinitis and asthmatic patients and to have a good safety profile (no anaphylactic reactions reported) [bib_ref] Noninjection routes for immunotherapy, Canonica [/bib_ref] [bib_ref] The safety of sublingual-swallow immunotherapy: an analysis of published studies, Gidaro [/bib_ref]. A recent Cochrane meta-analysis [bib_ref] Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis, Wilson [/bib_ref] concluded that 'SLIT is a safe treatment which significantly reduces symptoms and medication requirements in AR. The size of the benefit compared with that of other available therapies, particularly injection immunotherapy, is not clear, having been assessed directly in very few studies. Further research is required concentrating on optimizing allergen dosage and patient selection'. Recent studies performed in large samples of patients have shown a clear dose effect of tablet-based SLIT in patients with grass pollen-induced rhinoconjunctivitis [bib_ref] Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in..., Durham [/bib_ref] [bib_ref] Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis, Dahl [/bib_ref] [bib_ref] Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized,..., Khinchi [/bib_ref]. In one study in which subcutaneous and SLIT for seasonal rhinitis were compared, both were effective compared with placebo, although the study was underpowered to detect differences between treatments [bib_ref] Efficacy and safety of sublingual immunotherapy (slit) tablets in patients with grass..., Didier [/bib_ref]. A further recent trial of grass allergen tablets for sublingual use demonstrated a 30-40% improvement in symptom and medication scores and an approximate 50% increase in the responder rate, compared with placebo [bib_ref] Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal..., Dahl [/bib_ref]. A further follow-up for 5 years is planned in order to assess possible long-term benefits of SLIT as has already been confirmed for the subcutaneous route. ## Anti-immunoglobulin e At present, this is only licensed for severe allergic asthma in patients over 12 years of age. It is likely that associated AR would also improve in patients who respond with an improvement in their asthma control. Future use may include combined treatment with immunotherapy in high-risk patients. ## Surgery Surgery is required only for a small minority of cases. Indications for surgical intervention are: Drug-resistant inferior turbinate hypertrophy [bib_ref] Treatment of inferior turbinate hypertrophy: a randomized clinical trial, Passali [/bib_ref]. Anatomical variations of the septum with functional relevance. Anatomical variations of the bony pyramid with functional relevance. ## Rhinitis and pregnancy Rhinitis affects at least 20% of pregnancies [bib_ref] Treatment of allergic rhinitis during pregnancy, Keles [/bib_ref] and can start during any gestational week [bib_ref] The etiology and management of pregnancy rhinitis, Ellegard [/bib_ref]. Although the pathogenesis is multifactorial, nasal vascular engorgement and placental growth hormone are likely to be involved [bib_ref] The etiology and management of pregnancy rhinitis, Ellegard [/bib_ref] [bib_ref] Diagnosis and treatment of allergic rhinitis and sinusitis during pregnancy and lactation, Incaudo [/bib_ref]. Informing the patient that pregnancy-induced rhinitis is a self-limiting condition is often reassuring. Most medications cross the placenta, and should only be prescribed when the apparent benefit is greater than the risk to the foetus [bib_ref] Rhinitis in pregnancy, Gani [/bib_ref]. Regular nasal douching may be helpful. It is a good practice to start treatment with 'tried and tested' drugs [bib_ref] Rhinitis in pregnancy, Gani [/bib_ref]. Beclomethasone, fluticasone and budesonide appear to have good safety records as they are widely used in pregnant asthmatic women [bib_ref] Treatment of allergic rhinitis during pregnancy, Demoly [/bib_ref] [bib_ref] Fluticasone propionate aqueous nasal spray in pregnancy rhinitis, Ellegard [/bib_ref] [bib_ref] Treating allergic rhinitis in pregnancy. Safety considerations, Mazzotta [/bib_ref]. Chlorphenamine, loratadine and cetirizine may be added but decongestants should be avoided [bib_ref] Pregnancy outcome after gestational exposure to loratadine or antihistamines: a prospective controlled..., Diav-Citrin [/bib_ref] [bib_ref] Fetal safety of loratadine use in the first trimester of pregnancy: a..., Moretti [/bib_ref]. Chromones have not shown teratogenic effects in animals and are the safest drug recommended in the first 3 months of pregnancy although they require multiple daily administrations. Patients already on immunotherapy may continue if they have already reached the maintenance phase but each case must be considered individually. However, initiation of immunotherapy and updosing is contraindicated [bib_ref] Treatment of allergic rhinitis during pregnancy, Keles [/bib_ref]. ## Co-morbid association Rhinitis and asthma -the link Rhinitis and asthma are common diseases associated with substantial cost to patients, employers and health care systems. Asthma and rhinitis usually co-exist [bib_ref] Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history, Sibbald [/bib_ref] [bib_ref] Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and impact on..., Yawn [/bib_ref] [bib_ref] Epidemiology of physician-diagnosed allergic rhinitis in childhood, Wright [/bib_ref] [bib_ref] Prevalence of asthma and asthma-like symptoms in three French cities, Neukirch [/bib_ref] [bib_ref] Incidence and prevalence of asthma among adult Finnish men and women of..., Huovinen [/bib_ref] [bib_ref] Co-existence of asthma and allergic rhinitis: a 23-year follow-up study of college..., Greisner [/bib_ref] , with symptoms of rhinitis found in 75-80% of patients with asthma [bib_ref] Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history, Sibbald [/bib_ref] [bib_ref] Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results..., Leynaert [/bib_ref]. Although the costs of rhinitis and asthma are independently high, medical care costs are higher in those with asthma and rhinitis compared with those with asthma alone [bib_ref] Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and impact on..., Yawn [/bib_ref]. Rhinitis is a risk factor for the development of asthma [bib_ref] Epidemiology of physician-diagnosed allergic rhinitis in childhood, Wright [/bib_ref]. A number of allergens affect both the nose and the lungs [bib_ref] Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history, Sibbald [/bib_ref] and allergy to HDM or cat dander is a risk factor for both asthma and rhinitis [bib_ref] The relative risks of sensitivity to grass pollen, house dust mite and..., Sears [/bib_ref] [bib_ref] The role of IgE in asthma, Yssel [/bib_ref]. Many patients with AR have increased non-specific bronchial reactivity [bib_ref] Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis..., Townley [/bib_ref] [bib_ref] Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and..., Ramsdale [/bib_ref] during seasonal [bib_ref] Seasonal variation of airway function in allergic rhinitis, Gerblich [/bib_ref] and perennial [bib_ref] Different prevalence and degree of nonspecific bronchial hyperreactivity between seasonal and perennial..., Verdiani [/bib_ref] allergen exposure. Asthma [bib_ref] Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results..., Leynaert [/bib_ref] and bronchial hyperresponsiveness are more common and severe in perennial compared with seasonal rhinitis [bib_ref] Different prevalence and degree of nonspecific bronchial hyperreactivity between seasonal and perennial..., Verdiani [/bib_ref] [bib_ref] Sensitivity and maximal response to methacholine in perennial and seasonal allergic rhinitis, Prieto [/bib_ref]. Patients with SAR develop seasonal increases in nonspecific bronchial responsiveness (BR) but not necessarily asthma symptoms, and these patients often have normal BR during the winter months [bib_ref] Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial, Walker [/bib_ref]. BR is also increased in viral rhinitis [bib_ref] Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions, Lemanske [/bib_ref] [bib_ref] Virus-induced airway hyperresponsiveness in man, Sterk [/bib_ref] and following nasal allergen challenge [bib_ref] Changes in bronchial responsiveness following nasal provocation with allergen, Corren [/bib_ref] [bib_ref] Protective effect of theophylline on bronchial hyperresponsiveness in patients with allergic rhinitis, Aubier [/bib_ref]. These observations suggest that bronchial inflammation is associated with nasal inflammation, and is supported by the fact that bronchial hyperreactivity is reversed by intranasal treatment with sodium cromoglycate [bib_ref] Modification of bronchial hyperreactivity after treatment with sodium cromoglycate during pollen season, Lowhagen [/bib_ref] and corticosteroids [bib_ref] Effect of inhaled budesonide on seasonal changes in sensitivity and maximal response..., Prieto [/bib_ref] [bib_ref] Seasonal increase of carbachol airway responsiveness in patients allergic to grass pollen...., Sotomayor [/bib_ref]. Nasal allergen challenge results in eosinophil ingress not only to the nose but also to the bronchi, and vice versa [bib_ref] Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper..., Braunstahl [/bib_ref]. Segmental bronchoprovocation with allergen in AR patients leads to significant changes in mast cell and basophil numbers in both the nasal and bronchial mucosa [bib_ref] Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers..., Braunstahl [/bib_ref]. A systemic link has been postulated with inhaled allergen, causing a release of immature eosinophils from the bone marrow into the circulation, from where they migrate to the whole respiratory tract, not just to the site of allergen contact [bib_ref] Hemopoietic progenitor cells and hemopoietic factors: potential targets for treatment of allergic..., Sehmi [/bib_ref]. Allergen-specific immunotherapy for rhinitis has been shown to reduce the development of asthma in children [bib_ref] Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis..., Moller [/bib_ref] and to reduce non-specific bronchial hyper-reactivity and seasonal asthma in adults with seasonal rhinoconjunctivitis [bib_ref] Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial, Walker [/bib_ref]. Patients with co-morbid asthma and rhinitis who are receiving treatment for AR have a significantly lower risk of hospitalizations or attending accident and emergency departments for asthma [bib_ref] Treating allergic rhinitis in patients with comorbid asthma: the risk of asthma-related..., Crystal-Peters [/bib_ref] [bib_ref] Inadequate use of asthma medication in the United States: results of the..., Adams [/bib_ref] [bib_ref] Rhinitis therapy and the prevention of hospital care for asthma: a case-control..., Corren [/bib_ref] [bib_ref] Intranasal steroids and the risk of emergency department visits for asthma, Adams [/bib_ref] [bib_ref] The connection between allergic rhinitis and bronchial asthma, Corren [/bib_ref]. ## Allergic rhinitis in children Selection of treatment should be considered in the context of the child's needs and response to a given agent. Adherence issues are important because treatment is given chronically. It is essential to explain treatment options to parents [bib_ref] Management of rhinosinusitis in children, Clement [/bib_ref]. ## First-line treatments Antihistamines. Compliance with once-daily administration of a long-acting antihistamine is likely to be better than medication that requires multiple daily doses. Antihistamines are useful if the main symptoms are rhinorrhoea and sneezing, or if there are symptoms outside the nose such as conjunctivitis or rash. Desloratadine, cetirizine, levocetirizine and fexofenadine may also be beneficial for symptoms of nasal congestion [bib_ref] Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis, Nayak [/bib_ref] [bib_ref] Fexofenadine reduces nasal congestion in perennial allergic rhinitis, Ciprandi [/bib_ref] [bib_ref] Pathophysiology of nasal obstruction and meta-analysis of early and late effects of..., Patou [/bib_ref] [bib_ref] Efficacy of desloratadine in the treatment of allergic rhinitis: a metaanalysis of..., Canonica [/bib_ref] [bib_ref] Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal..., De Blic [/bib_ref]. For optimal results, they should be given continuously or prophylactically as opposed to 'as required' [bib_ref] Seasonal rhinitis and azelastine: long-or short-term treatment?, Ciprandi [/bib_ref]. Nasal steroids. Nasal steroid with low systemic bioavailability should be used at the lowest possible dose to control symptoms and are useful for nasal congestion and obstruction. Intermittent use may be beneficial due to the rapid vasoconstrictor effect of corticosteroids [bib_ref] Fluticasone propionate aqueous nasal spray improves nasal symptoms of seasonal allergic rhinitis..., Dykewicz [/bib_ref] [bib_ref] Asneeded use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic..., Jen [/bib_ref]. Compliance and efficacy is improved if the child is taught how to use the nasal spray, [bib_ref] The role of patient training in the management of seasonal rhinitis and..., Gani [/bib_ref]. ## Second-line treatments For relief of nasal congestion, short-term use (o14 days) of corticosteroid nose drops (e.g. betamethasone or fluticasone) and a topical decongestant may be helpful [bib_ref] Loratadine-pseudoephedrine in children with allergic rhinitis, a controlled double-blind trial, Serra [/bib_ref]. The best position for administration of nose drops is with the child lying, head back; see inferior turbinate bones may be indicated only if extensive medical treatment fails [bib_ref] Treatment of inferior turbinate hypertrophy: a randomized clinical trial, Passali [/bib_ref]. For refractory rhinorrhoea, ipratropium bromide 0.03% may be helpful [bib_ref] Cold-induced rhinitis in skiers -clinical aspects and treatment with ipratropium bromide nasal..., Bonadonna [/bib_ref] [bib_ref] Ipratropium nasal spray in children with perennial rhinitis, Meltzer [/bib_ref]. For SAR, saline nasal irrigation during the pollen season may improve symptoms and reduce antihistamine requirement [bib_ref] Hypersaline nasal irrigation in children with symptomatic seasonal allergic rhinitis: a randomized..., Garavello [/bib_ref]. Leukotriene receptor antagonists may have a role if there is concomitant asthma [bib_ref] Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed..., Philip [/bib_ref]. To treat underlying allergic disease, allergen immunotherapy is widely used in Europe but has yet to gain general acceptance in the United Kingdom [bib_ref] Long-term clinical efficacy of grass-pollen immunotherapy, Durham [/bib_ref] [bib_ref] Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis..., Moller [/bib_ref]. Efficacy has been demonstrated with both subcutaneous [bib_ref] Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis..., Moller [/bib_ref] [bib_ref] Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children..., Kuehr [/bib_ref] and SLIT [bib_ref] Oral immunotherapy of children with rhinoconjunctivitis due to birch pollen allergy. A..., Moller [/bib_ref] [bib_ref] Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in..., Vourdas [/bib_ref] [bib_ref] Double-blind placebo-controlled evaluation of sublingualswallow immunotherapy with standardized Parietaria judaica extract in..., Larosa [/bib_ref] [bib_ref] Sublingual immunotherapy and influence on urinary leukotrienes in seasonal pediatric allergy, Yuksel [/bib_ref] but is contraindicated in children with asthma. # Future research SLIT, its safety, long-term effectiveness and ability to reduce disease progression. Utility of anti-IgE therapy in conjuction with specific immunotherapy. Value of extensive, multi-allergen avoidance measures -particularly HDM. Aetiological factors that can be altered to reduce the incidence of rhinitis. Prospective study examining whether early identification and effective therapy for rhinitis in children reduces progression to asthma. Prospective study examining whether effective therapy for rhinitis reduces asthma exacerbations and cost. These guidelines inform the management of allergic and non-AR. Adherence to these guidelines does not constitute an automatic defence for negligence and conversely non-adherence is not indicative of negligence. It is anticipated that these guidelines will be reviewed 5 yearly. [fig] Figure 2: Classification of allergic rhinitis. Each box may be further subclassified into seasonal or perennial. [/fig] [fig] Figure 3: Algorithm for the treatment of rhinitis. Ã Spray or drops. OC, oral corticosteroids; a-H1, antihistamines; LTRA, leukotriene receptor antagonist; Sx, symptoms; Rx, treatment; SPT, skin prick test. c 2008 The Authors Journal compilation c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 38 : 19-42 [/fig] [fig] Figure 4: (a) Correct procedure for the application of nasal sprays. (b) Correct procedure for the installation of nasal drops. [/fig] [table] Table 1: Allergic triggers for rhinitisPre-existing rhinitis can be aggravated by work-place irritantsFig. 1. Mechanism of allergic rhinitis. Sensitized patients with allergic rhinitis have IgE antibodies for specific allergen(s) bound to receptors on the surface of mast cells.On re-exposure to the specific allergen(s), cross-linking of adjacent IgE molecules occurs, and mast cell degranulation (rupture) takes place, releasing a variety of chemical mediators that may be preformed (e.g. histamine) or newly synthesized (e.g. leukotrienes, prostaglandins). These chemicals give rise to the typical immediate symptoms experienced by the patient. In many patients, there is also a late-phase reaction in which T helper type 2 cytokines induce an eosinophilic inflammatory infiltrate, similar to that seen in asthma. This results in chronic, less obvious symptoms. GM, granulocyte macrophage; CSF, cerebrospinal fluid; PAF, platelet-activating factor. [/table] [table] Table 2: Common causes of occupational rhinitis [/table] [table] Table 3: Infective causes of rhinitis [/table] [table] Table 4: Types and possible triggers of non-allergic rhinitis ACE, angiotensin-converting enzyme; HRT, hormone replacement therapy; NSAID, non-steroidal anti-inflammatory drugs; SLE, systemic lupus erythematous. [/table] [table] Table 5: Effect of therapies on rhinitis symptoms (adapted from [235]) 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 38 : 19-42 [/table] [table] Table 6: Oral antihistamines licensed in the UK according to age [/table] [table] Table 7: Nasal corticosteroids licensed for use in the United Kingdom according to age [/table] [table] Table A4: Grades of recommendation for various interventions CS, corticosteroid; SIT, specific immunotherapy. [/table] [table] Table A3: Recommendations on cat allergen avoidance measures Measure In favour Ã Against Remove cat, followed by thorough cleaning of house, steam cleaning walls, shampooing carpets D None Keeping cat out of bedroom and other commonly used rooms D None Washing cat weekly D None Removing carpets and replacing with hardwood floors and cleaning regularly D None Air filtration units in rooms where the patient spends the majority of their time D None Increase ventilation with fans, air-conditioning or by opening windows D None Ã Letters denote grade of recommendation. c 2008 The Authors Journal compilation c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 38 : 19-42 [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1365-2222.2007.02888.x	This guidance for the management of patients with allergic and non‐allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web‐based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co‐morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research.
9b9701eeabebe684ad8cb1e5ef3d82d54400c275	pubmed	Optimizing observer performance of clinic blood pressure measurement: a position statement from the Lancet Commission on Hypertension Group	Optimizing observer performance of clinic blood pressure measurement: a position statement from the Lancet Commission on Hypertension Group High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-to-middle-income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/ automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice. # Introduction H igh blood pressure (BP) is the leading modifiable risk factor for death and disability in the world, affecting an estimated 1.4 billion adults globally, and leading to over 10 million deaths per year [bib_ref] Global disparities of hypertension prevalence and control: a systematic analysis of population-based..., Mills [/bib_ref]. It is a leading cause of heart disease, stroke, and chronic kidney disease and a major contributor to escalating healthcare costs. With an overall global adult prevalence of 31%, high BP is highly prevalent in all major regions of the world [bib_ref] Global disparities of hypertension prevalence and control: a systematic analysis of population-based..., Mills [/bib_ref]. However, in absolute numbers, it is low-to-middle income countries (LMICs) that bear the highest burden of illness, having over one billion individuals affected, and possessing awareness, treatment and control proportions that lag high-income countries to a considerable degree [bib_ref] Global disparities of hypertension prevalence and control: a systematic analysis of population-based..., Mills [/bib_ref]. Accordingly, ongoing efforts to improve the diagnosis, prevention, treatment, and control of hypertension globally must include tailored interventions that prioritize reductions in regional disparities [bib_ref] A call to action and a lifecourse strategy to address the global..., Olsen [/bib_ref]. Accurate and reliable BP measurement is essential for the proper diagnosis and management of hypertension [bib_ref] Recommendations for blood pressure measurement in humans and experimental animals: Part 1:..., Pickering [/bib_ref]. On a population-wide level, a 5-mmHg difference in SBP corresponds to an estimated 6% absolute and 30% relative change in hypertension prevalence [bib_ref] Estimate of the benefits of a population-based reduction in dietary sodium additives..., Joffres [/bib_ref]. Accordingly, the effect of a 5-mmHg error in BP measurement, assuming a global prevalence of 1.4 billion [bib_ref] Global disparities of hypertension prevalence and control: a systematic analysis of population-based..., Mills [/bib_ref] , could lead to the incorrect classification of hypertension status in 84 million individuals worldwide. Therefore, the ramifications of inaccurate measurement on a global level are profound. Blood pressure is a physiological parameter that changes constantly in response to endogenous factors and exogenous stimuli [bib_ref] Blood pressure regulation XI: overview and future research directions, Raven [/bib_ref]. This variability makes assessment of 'usual' BP, which is defined as an individual's true or genuine BP, challenging. BP measurement is perhaps the most commonly performed procedure in clinical medicine and, although, at first glance, it seems simple, in reality, many steps must be performed sequentially and optimally in order to produce a reproducible result reflective of usual BP. Accordingly, the individual responsible for measuring BP, herein referred to as the 'observer', must be meticulous in terms of following recommended techniques [bib_ref] Franz Volhard lecture: should doctors still measure blood pressure? The missing patients..., Pickering [/bib_ref]. The challenges posed by the variable nature of BP were recognized over a century ago by Riva-Rocci et al. [bib_ref] A new sphygmomanometer. Sphygmomanometric technique, Riva-Rocci [/bib_ref] , who noted that taking multiple measurements and standardizing the measurement conditions could optimize use of the technique in clinical practice. He concludes, in his seminal paper written in 1896, that '. . . if the procedures are neglected, and the doctor is satisfied with a crude reading, the method will become useless and will be quickly abandoned as a scientists' indulgence' [bib_ref] A new sphygmomanometer. Sphygmomanometric technique, Riva-Rocci [/bib_ref]. Unfortunately, in contemporary clinical practice, BP measurement is often suboptimally performed, and this type of unstandardized BP measurement leads to errors that can inappropriately alter management decisions in 20-45% of cases [bib_ref] Is usual measurement of blood pressure meaningful?, Campbell [/bib_ref] [bib_ref] Assessment of blood pressure measuring techniques, Mckay [/bib_ref] [bib_ref] Blood pressure monitoring technique impacts hypertension treatment, Ray [/bib_ref] [bib_ref] The pursuit of accurate blood pressure measurement: a 35-year travail, O'brien [/bib_ref]. The problem of unstandardized BP measurement has persisted for decades despite extensive education and substantial efforts to raise awareness on the adverse consequences of inaccurate clinic BP measurement [bib_ref] Recommendations for blood pressure measurement in humans and experimental animals: Part 1:..., Pickering [/bib_ref] [bib_ref] Achieving reliable blood pressure measurements in clinical practice: It's time to meet..., O'brien [/bib_ref]. Time constraints and suboptimal technique leading to poorly performed auscultation are responsible for much of this error [bib_ref] Is usual measurement of blood pressure meaningful?, Campbell [/bib_ref] [bib_ref] Misclassification of blood pressure by usual measurement in ambulatory physician practices, Campbell [/bib_ref]. Potential solutions to minimize error, discussed below, include simplifying the measurement process by using automated devices and encouraging observers to undergo certified training and re-training to promote ongoing use of standardized measurement techniques. The aim of the Lancet Commission on Hypertension was to identify key actions to improve the global management of BP both at the population and the individual levels, and to generate a campaign to adopt the suggested actions at national levels to reduce the impact of elevated BP globally [bib_ref] A call to action and a lifecourse strategy to address the global..., Olsen [/bib_ref]. The purpose of this position statement is to provide guidance towards optimizing observer-related clinic BP measurement performance for hypertension diagnosis and treatment, with special attention given to measurement in LMIC settings. We begin with a brief review of different measurement modalities, including a discussion of optimal measurement technique and the errors that result from deviating from standardized measurement practices. We then outline the impact of observer training on performance of BP measurement. Subsequently, we discuss BP measurement in LMIC settings, specifically the practical considerations that limit achievement of best practice. We close with recommendations for optimizing observer accuracy in clinic BP measurement and provide suggestions on future directions. ## Types of blood pressure measurement used in clinical practice and optimal measurement technique Direct (or intra-arterial) and indirect (cuff-based) BP measurement are the two major methods employed in the clinical care setting and are summarized in [fig_ref] TABLE 1: Blood pressure measurement methods commonly used in clinical practice [/fig_ref]. Indirect measurement is typically performed via auscultation or by using a semi-automated or fully automated device, which most often uses the oscillometric technique [fig_ref] TABLE 1: Blood pressure measurement methods commonly used in clinical practice [/fig_ref]. Although there are definitions in the literature for semi-automated and automated BP measurements, herein we refer to semi-automated as those devices that require a manual inflation (e.g. A good technique, if performed optimally, because SBP and DBP correspond to distinctly detectable physiological phenomena -the appearance and disappearance of the Korotkoff sounds, respectively. However, rarely performed properly in clinical practice, which is a major limitation. Can be performed using a mercury, aneroid, or electronic sphygmomanometer. Mercury has been banned in many jurisdictions and aneroid sphygmomanometers contain moving parts that require frequent calibration, which is often not performed, limiting accuracy over time. Simultaneous, two-observer, blinded, auscultatory measurement performed according to standardized methods using a mercury sphygmomanometer and a proper bladder size is the reference standard for BP validation studies but is too impractical for clinical practice. Semi-automated or fully automated Both approaches typically use the oscillometric technique, although, rarely, a fully automated device may employ electronic auscultation or both. Semiautomated devices are not commonly used but may be advantageous in LMIC settings as inflation is performed manually (obviating the need for a power source). Semiautomated deflation is device-controlled. Fully automated devices control both inflation and deflation. An important issue with automated devices is that many available on the market have not been properly validated for measurement accuracy. Major advantages of automated BP measurement that make it the preferred technique to use in the clinic include simplification of the measurement process and elimination of observer-related errors in auscultation. Automated office BP (AOBP) measurement offers the ability to take multiple, sequential, unobserved measurements (reducing white-coat effect), but these devices are relatively costly and may require more space and time in the clinical visit -further research to define their role is needed. Outside of the clinic setting, automated home and ambulatory BP measurement modalities provide superior diagnostic and prognostic capabilities relative to clinic measurements, including detection of white-coat and masked hypertension effect. If resources allow, use of AOBP, home and ambulatory BP measurement is recommended. A disadvantage is that the oscillometric technique indirectly estimates BP (i.e. no discrete 'oscillometric' physiological phenomena that herald the occurrence of systole and diastole exist) and is less accurate in some patients. In addition, the proprietary nature of the algorithm makes it difficult to consider oscillometry as a singular measurement method and makes device (and algorithm) validation a critically important consideration in automated device selection for clinical use. BP, blood pressure; LMIC, low-to-middle-income countries. with using bulb compressions). Once inflation has been completed, these devices typically use an automated deflation process to determine BP. In contrast, fully automated devices have automated inflation and deflation -the user initiates a measurement, usually by pressing a button, and the remainder of the inflation-deflation process is automated. Automated office BP (AOBP) measurement is a subtype of automated measurement that involves taking sequential automated measurements rather than a single measurement at a time. In the oscillometric technique, arterial pulses are first sensed, filtered, processed and, then, a proprietary algorithm is applied to estimate BP [bib_ref] Oscillometric blood pressure: a review for clinicians, Alpert [/bib_ref]. BP measurement should be performed carefully by a trained observer using standardized methodology [fig_ref] TABLE 2: Essential elements of performing a standardized clinic blood pressure measurementElement CommentDevice Use... [/fig_ref] and [fig_ref] FIGURE 1: Standardized blood pressure measurement procedure [/fig_ref] ; Supplementary Figures S1-S5, http://links.lww.com/HJH/B93) [bib_ref] Recommendations for blood pressure measurement in humans and experimental animals: Part 1:..., Pickering [/bib_ref]. The mean of multiple research quality auscultatory and, more recently, automated oscillometric measurements, sometimes taken over two or more clinical visits, was the method used to estimate the usual BP in many foundational prognostic and therapeutic studies in the field of hypertension [bib_ref] Blood pressure lowering for prevention of cardiovascular disease and death: a systematic..., Ettehad [/bib_ref] [bib_ref] Methods of blood pressure assessment used in milestone hypertension trials, Chen [/bib_ref] [bib_ref] A review of blood pressure measurement protocols among hypertension trials: implications for..., Giorgini [/bib_ref]. Multiple readings over time are required to estimate the usual BP, allow for regression to the mean, and reduce the white-coat effect [bib_ref] How many measurements are necessary in diagnosing mild to moderate hypertension, Brueren [/bib_ref]. ## Causes of inaccurate blood pressure measurement in clinical practice Unfortunately, standardized auscultatory measurement is not performed commonly in clinical practice [bib_ref] Blood pressure monitoring technique impacts hypertension treatment, Ray [/bib_ref] [bib_ref] Blood pressure measurements are unreliable to diagnose hypertension in primary care, Sebo [/bib_ref]. It is also rarely performed by medical trainees [bib_ref] Assessment of blood pressure measuring techniques, Mckay [/bib_ref] [bib_ref] Medical students and measuring blood pressure: results from the American Medical Association..., Rakotz [/bib_ref]. Instead, 'casual' measurement, in which standardized methodology is not followed, is common. Casual measurement typically leads to higher variability, overestimation of SBP by 5-10 mmHg, and poorer correlation with hypertension related end-organ damage [bib_ref] Is usual measurement of blood pressure meaningful?, Campbell [/bib_ref] [bib_ref] Assessment of blood pressure measuring techniques, Mckay [/bib_ref] [bib_ref] Misclassification of blood pressure by usual measurement in ambulatory physician practices, Campbell [/bib_ref] [bib_ref] Evaluation of blood pressure measurement and agreement in an academic health sciences..., Minor [/bib_ref]. Multiple causes of inaccuracy exist and can be categorized into patient-related, procedure-related, equipment-related, or observer-related [fig_ref] TABLE 3: Major sources of error during blood pressure measurement [/fig_ref] [bib_ref] Sources of inaccuracy in the measurement of adult patients' resting blood pressure..., Kallioinen [/bib_ref]. Poorly performed auscultation is responsible for much of the error [bib_ref] Is usual measurement of blood pressure meaningful?, Campbell [/bib_ref] [bib_ref] Misclassification of blood pressure by usual measurement in ambulatory physician practices, Campbell [/bib_ref]. Major barriers to standardized BP measurement include insufficient attention paid to optimal technique, lack of observer education, competing demands and observer time constraints, and use of inaccurate equipment [bib_ref] Franz Volhard lecture: should doctors still measure blood pressure? The missing patients..., Pickering [/bib_ref] [bib_ref] Achieving reliable blood pressure measurements in clinical practice: It's time to meet..., O'brien [/bib_ref] [bib_ref] European Society of Hypertension Working Group on Blood Pressure Monitoring. Practice guidelines..., O'brien [/bib_ref]. Common observerrelated errors in the clinical setting include failure to include a 5-min rest period, talking during the measurement procedure, using an incorrect cuff size, and failure to take multiple or bilateral measurements [bib_ref] Blood pressure monitoring technique impacts hypertension treatment, Ray [/bib_ref] [bib_ref] Evaluation of blood pressure measurement and agreement in an academic health sciences..., Minor [/bib_ref]. Time constraints are a particularly common reason for casual measurements, as a casual reading takes about 2 min to perform versus 8 min for a standardized measurement [bib_ref] Blood pressure monitoring technique impacts hypertension treatment, Ray [/bib_ref] [bib_ref] Office blood pressure measurement types: different methodology-different clinical conclusions, Stergiou [/bib_ref]. Physician readings are higher than nurse readings, which has been attributed to incremental white-coat effect [bib_ref] Doctors record higher blood pressures than nurses: systematic review and meta-analysis, Clark [/bib_ref]. Ultimately, the observer is responsible for performing a proper measurement and ensuring to the greatest extent possible that all of the potential causes of inaccuracy are avoided. ## Advantages of automated blood pressure measurement Use of automated BP measurement is also supported by many foundational prognostic and therapeutic studies in the field of hypertension [bib_ref] Blood pressure lowering for prevention of cardiovascular disease and death: a systematic..., Ettehad [/bib_ref] [bib_ref] Methods of blood pressure assessment used in milestone hypertension trials, Chen [/bib_ref] [bib_ref] A review of blood pressure measurement protocols among hypertension trials: implications for..., Giorgini [/bib_ref]. Its major advantage is that it reduces observer error by automating the BP measurement Mercury columns should be at zero when at rest and the mercury column should be fully intact and readable. Aneroid devices require regular calibration. Electronic devices should be validated against two-observer mercury-based auscultation in an independently performed clinical study using an internationally accepted protocol. Validated device listings are available at https://bihsoc.org/bp-monitors and https://hypertension.ca/hypertension-andyou/managing-hypertension/measuring-blood-pressure/devices/. Preparation and positioning Aneroid devices or mercury columns should be clearly visible at eye level. The patient should be resting comfortably in a quiet environment for 5 min in a chair in the seated position, back-supported, legs uncrossed, feet flat on the floor, and the arm supported with the BP cuff at heart level. There should be no talking by the patient or observer during the entire measurement procedure. The patient should have an empty bladder and not have eaten, ingested caffeine, smoked, or engaged in physical activity at least 30 min prior to the measurement. Cuff Inflatable bladder width should be about 40% of arm circumference and bladder length should be about 80-100% of arm circumference. For electronic devices, select cuff size as recommended by the manufacturer. Using too large a cuff leads to falsely low readings and using too small a cuff, falsely high readings. Markings on the cuff clearly indicate the ideal arm circumferences appropriate for the cuff size. For auscultation, the lower edge of the cuff should be 2-3 cm above the elbow crease and the bladder should be centered over the brachial artery. For electronic devices, place the cuff as recommended by the manufacturer. Procedure For auscultation, increase the pressure rapidly to 30 mmHg above the level at which the brachial or radial pulse is extinguished, place the stethoscope head over the brachial artery, deflate the cuff by approximately 2 mmHg per heartbeat, and determine systolic (appearance of Korotkoff sounds) and diastolic (disappearance of Korotkoff sounds). If the Korotkoff sounds persist towards zero, use the point of muffling of the sounds to indicate DBP. For automated devices, initiate the measurement as per the device instructions. Record the BP to the closest 2 mmHg for auscultation or exactly as displayed on the screen of an automated device. Avoid terminal digit preference (rounding up or down to a zero or five for the last digit). On the initial visit, readings should be taken in both arms and the arm with the higher BP should be used for subsequent measurements. Two or more readings should be taken at each visit and the mean calculated and used for making clinical decisions. Data from [bib_ref] Recommendations for blood pressure measurement in humans and experimental animals: Part 1:..., Pickering [/bib_ref]. Observer performance in blood pressure measurement Journal of Hypertension www.jhypertension.com process. Accordingly, less observer expertise is needed, auscultatory training is not required, and the observer can focus on mastering a smaller number of essential aspects of BP measurement [bib_ref] Policy statement of the world hypertension league on noninvasive blood pressure measurement..., Campbell [/bib_ref]. Automated BP could improve BP measurement technique even further if devices programmed to take BP in a guideline-concordant fashion were available. Examples include electronically displayed step-by-step instructions to remind observers of proper technique and auto-controlled initiation sequences that require a timed rest period before the first reading is performed. An additional, and critically important advantage of automated BP, although beyond the immediate focus of this position paper, is that it enables many measurements to be taken in the out-of-clinic setting in the usual environment of each individual. Out-of-clinic measurement includes 24-h ambulatory monitoring and home BP monitoring and leads to much better assessment of usual BP because, in addition to eliminating observer error, it eliminates white-coat (high clinic but normal out-of-office BP) and detects masked hypertension (normal clinic but high out-of-office BP) phenomena. Indeed because of the existence of white-coat, and masked hypertension effect, which affect 9-24 and 9-17% of untreated and treated individuals, respectively, even meticulously performed standardized office BP may not be representative of usual BP [bib_ref] Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true..., Fagard [/bib_ref]. Contemporary guidelines recommend confirming the diagnosis of hypertension with out-of-office BP measurements and treating masked, but not white-coat, hypertension [bib_ref] ESC/ESH guidelines for the management of arterial hypertension: The Task Force for..., Williams [/bib_ref]. Twenty-four-hour ambulatory and home BP monitoring are far superior to clinic measurements in terms of their ability to predict cardiovascular events [bib_ref] European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society..., O'brien [/bib_ref] [bib_ref] Home blood pressure monitoring in the diagnosis and treatment of hypertension: a..., Stergiou [/bib_ref]. 24-h BP monitoring is the gold standard for diagnosing hypertension and home BP monitoring is ideal for performing long-term follow-up monitoring of treated hypertensive patients, especially when coupled with nurse or pharmacist case management [bib_ref] A new algorithm for the diagnosis of hypertension in Canada, Cloutier [/bib_ref] [bib_ref] Effectiveness of home blood pressure telemonitoring: a systematic review and metaanalysis of..., Duan [/bib_ref] [bib_ref] European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring, Parati [/bib_ref]. If resources allow, use of both of these measurement methods is highly recommended [bib_ref] ESC/ESH guidelines for the management of arterial hypertension: The Task Force for..., Williams [/bib_ref] [bib_ref] Hypertension Canada's 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of..., Nerenberg [/bib_ref]. Both out-of-clinic measurement modalities require proper technique, and healthcare professionals must understand that home BP monitoring requires patient training in order to be effective in improving clinical decisions [bib_ref] A new algorithm for the diagnosis of hypertension in Canada, Cloutier [/bib_ref] [bib_ref] European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring, Parati [/bib_ref] [bib_ref] Unreliability of home blood pressure measurement and the effect of a patient-oriented..., Milot [/bib_ref]. As mentioned above, AOBP offers the ability to perform three to five unattended, sequential BP measurements and auto-calculate the mean [bib_ref] Eliminating the human factor in office blood pressure measurement, Myers [/bib_ref]. AOBP is a subtype of fully automated BP measurement; the critical distinction is that sequential readings are automated. Practically, this means the observer is required to initiate only the first reading of the sequence; she or he can then leave and return when the entire sequence is finished (as opposed to remaining in the room to initiate each sequential measurement). Use of AOBP, particularly when performed when the patient is alone in the room, facilitates a more standardized measurement process (e.g. no talking, multiple automated measurements taken sequentially). Consequently, the AOBP technique is associated with reduced white-coat effect [bib_ref] Eliminating the human factor in office blood pressure measurement, Myers [/bib_ref] [bib_ref] Comparing automated office blood pressure readings with other methods of blood pressure..., Roerecke [/bib_ref] [bib_ref] Are automated blood pressure monitors comparable to ambulatory blood pressure monitors? A..., Jegatheswaran [/bib_ref] [bib_ref] Comparability of automated office blood pressure to daytime 24-Hour ambulatory blood pressure, Ringrose [/bib_ref] [bib_ref] Effect of intensive versus standard clinic-based hypertension management on ambulatory blood pressure:..., Drawz [/bib_ref]. AOBP requires additional space and time and the cost of AOBP devices is also 5-fold to 10-fold higher than regular automated (home) devices, which also limits use in the LMIC setting. However, if these barriers are not present, use of AOBP should be considered to enable greater standardization of in-clinic BP measurements. Some automated devices have been specifically designed for use in the LMIC setting [bib_ref] Development of an accurate oscillometric blood pressure device for low resource settings, De Greeff [/bib_ref] [bib_ref] Introduction of automated blood pressure devices intended for a low resource setting..., Baker [/bib_ref] [bib_ref] A new solar-powered blood pressure measuring device for low-resource settings, Parati [/bib_ref]. ## Automated device accuracy An important issue with automated devices is that many have not been clinically validated for measurement accuracy [bib_ref] The quest for accuracy of blood pressure measuring devices, O'brien [/bib_ref]. Clinical validation involves demonstrating that the device meets the accuracy requirements of international BP measurement standards. This process involves performing a protocol-based comparison using multiple measurements against a blinded, two-observer auscultatory reference standard. To maximize accuracy, only validated devices should be used in clinical practice [bib_ref] Reliability of home blood pressure monitoring: in the context of validation and..., Jung [/bib_ref]. In some individuals, even validated devices may produce BP measurements that differ substantially from auscultation; this may result from variations in algorithm performance and/or arterial wall properties [bib_ref] Unreliable oscillometric blood pressure measurement: prevalence, repeatability and characteristics of the phenomenon, Stergiou [/bib_ref] [bib_ref] Accuracy of oscillometric blood pressure algorithms in healthy adults and in adults..., Padwal [/bib_ref]. For this reason, it is desirable to ensure that a specific device is performing well in a specific patient. Unfortunately, there is no consensus on how to do this in an efficient and feasible manner that is applicable in clinical practice. This issue is discussed in further detail elsewhere [bib_ref] History and justification of a national blood pressure measurement validated device listing, Cohen [/bib_ref] [bib_ref] A novel and simple protocol for the validation of home blood pressure..., Eguchi [/bib_ref]. ## Observer training to improve clinic blood pressure measurement Observer training has been proposed as a solution to poor measurement technique. Training programs leading to shortterm success in improving measurement technique have been described, all emphasizing the fundamentals of proper BP measurement [fig_ref] TABLE 2: Essential elements of performing a standardized clinic blood pressure measurementElement CommentDevice Use... [/fig_ref] , and varying in their delivery format, from web-based to in-person, and in length, from 30 min to full-day sessions [bib_ref] A curriculum for the training and certification of blood pressure measurement for..., Grim [/bib_ref] [bib_ref] Promoting sustainability in quality improvement: an evaluation of a web-based continuing education..., Block [/bib_ref] [bib_ref] Blood pressure measurement education and evaluation program improves measurement accuracy in communitybased..., Dickson [/bib_ref]. Clearly, shorter, web-based programs are preferred because of their practical advantages, lower cost and scalability. Beyond observer training alone, bundled quality improvement programs that combine use of automated office BP measurement with provider education on proper measurement and advice on clinical workflow improvement have been examined and shown to increase use of automated measurement and reduce terminal digit preference [bib_ref] A bundled quality improvement program to standardize clinical blood pressure measurement in..., Boonyasai [/bib_ref]. Additional approaches that have been proposed include training patients to recognize when their care providers are performing improper measurement and having regulatory agencies enforce use of standardized measurement, but the practical implementability of these propositions is uncertain [bib_ref] Improving the measurement of blood pressure: is it time for regulated standards, Appel [/bib_ref] [bib_ref] Is it time for a blood pressure measurement 'bundle'?, Umscheid [/bib_ref]. A trained nurse with auscultatory expertise can approximate daytime ambulatory BP, a commonly used reference standard, better than automated devices [bib_ref] The trained observer better predicts daytime ABPM diastolic blood pressure in hypertensive..., Graves [/bib_ref]. However, the generalizability of this finding to an observer with less expertise undergoing a single training seminar, in the LMIC setting or otherwise, is likely to be low. Auscultation appears to be particularly difficult to perform in a uniform manner over time. The inter-observer variability of auscultatory BP measurements between expert observers was minimized by repeated training sessions, validating the importance of retraining [bib_ref] Observer bias in blood pressure studies, Bruce [/bib_ref]. However, following each training session, between-observer variability increased after just 1-2 months, indicating that very frequent retraining is required to maintain auscultatory skills. These data indicate that training requirements are greater over the short-term and long-term if the auscultatory technique is used, which is not feasible for widespread implementation, particularly in the LMIC setting. Accordingly, use of automated devices is recommended to minimize additional training requirements. Overall, training improves BP measurement practices over the short term and retraining is required to maintain skills over the long term. The optimal frequency of retraining is unclear. As a practical compromise, to avoid a burdensome retraining schedule yet ensure relatively frequent refreshment of skills, retraining is recommended at least annually. ## Additional challenges to optimizing clinic blood pressure measurement in the low-to-middle-income setting Additional challenges exist in LMIC settings and many are not easily solved. These are summarized in , together with proposed solutions. ## Recommendations for optimizing observer performance in blood pressure measurement and for stakeholder implementation Recommendations for optimizing observer performance in BP measurement and stakeholder implementation are listed in and focus on performing simplified, standardized measurements using validated semi-automated or automated devices in a properly configured setting, and ensuring proper observer training and periodic retraining. Tasksharing by training nonphysician healthcare or lay providers, such as nurses and community health workers to perform measurement, is strongly advised because it frees physicians, who are in short supply relative to other healthcare providers, to perform other work and also reduces . Challenges to and potential solutions for optimizing clinic blood pressure measurement in the low-to-middle-income setting ## Challenges Proposed solution Lack of prioritization of and funding for hypertension care and proper BP measurement, including provider reimbursement, programmatic funding, and equipment. Increased advocacy and recognition of the importance and scope of the problem. Limited observer education and training in standardized BP measurement. Training that is easily accessible and affordable. Eliminate the need for expertise in auscultation, and errors resulting from poorly performed auscultation, by using semi-automated or fully automated devices. High provider workload and limited time to perform proper measurement, including between-patient cuff changes. Lack of dedicated clinic space to perform BP measurements. Simplify measurement practices by modifying workplace ergonomics to facilitate best measurement practices (e.g. have a dedicated BP measurement station including a chair with arm-rest, even if not in a segregated clinical space, and arrange furniture to optimize patient and observer position). Lack of availability of inexpensive, easily operable, clinically validated automated BP devices necessitating use of auscultation. Increased advocacy and awareness of the need for clinical validation and lowcost devices. Encourage manufacturers to market low-cost clinic, home, and ambulatory devices. Lack of availability of BP device accessories, including batteries and additional cuffs. Lack of proper environmentally responsible battery disposal mechanisms. Limited and/or lack of access to electrical power. Choose validated semi-automated or solar-charged device overcome requirements for batteries or electrical power. A reasonable compromise if only one cuff size is available is to choose the cuff size that is considered optimal for most of the patients seen in that clinical setting. Extremely high environmental temperatures in some regions that may theoretically affect the performance of BP devices. Requires further study. BP, blood pressure. white-coat effect [bib_ref] Doctors record higher blood pressures than nurses: systematic review and meta-analysis, Clark [/bib_ref]. Task shifting alone may not improve BP control if clinics are overburdened, equipment is unreliable, or antihypertensive therapy is unavailable [bib_ref] Can lay health workers support the management of hypertension? Findings of a..., Goudge [/bib_ref]. The core curricula of healthcare professional schools and postgraduate training programs should include standardized training and performance testing in blood pressure measurement. ## Future directions Given the importance of proper observer training, programs are needed to assist observers in acquiring the necessary skills to perform proper BP measurement. To this end, training courses that provide certification in standardized measurement, endorsed by prominent national and international organizations working in the field, would encourage and substantiate best measurement practices. The World Hypertension League has developed resources to assist providers to perform BP screening [bib_ref] Resources for blood pressure screening programs in low resource settings: a guide..., Mangat [/bib_ref]. Proper BP measurement Certification programs should not be onerous and need to be simple, brief, multilingual, low-cost (ideally, free), easily repeatable and widely accessible. Research is needed to identify the best methods of delivering training, and further work is required to identify how and where training and certification could be best performed and if certification should be required. # Conclusion Given the enormous, and increasing, global burden of hypertension, the need to improve all aspects of prevention, detection, treatment and control is clear [bib_ref] A call to action and a lifecourse strategy to address the global..., Olsen [/bib_ref]. The importance of proper BP measurement to optimal hypertension diagnosis and management cannot be overemphasized. Much of the error in BP measurement is within the control of the observer. Therefore, simplifying, standardizing, and automating measurement practices and ensuring proper observer education, training and certification is needed. Even these relatively straightforward recommendations can be challenging to implement, but they have the potential to markedly improve detection and management of hypertension across the world. Given the importance of accurate BP assessment, and the lack of impact of previous efforts to train healthcare workers, consideration should be given to regular certification in BP assessment. ## Conflicts of interest ## Recommendaɵons Configure seƫngs for BP measurement to ensure use of standardized measurement pracƟces. Use task sharing (training non-physician health care or lay providers) to perform BP measurement. Ensure proper observer training, preferably with cerƟficaƟon, and refresh training annually. Perform BP measurement using recommended, standardized technique. Use cuffs properly sized to arm circumference. If mulƟple cuff sizes are unavailable, use the cuff size opƟmal for most of the populaƟon. Use validated upper-arm cuff semi-automated or automated devices instead of auscultaƟon to reduce the need for training and opƟmize BP measurement. Use validated semi-automated or solar-charged devices if resources constrain use of baƩery-operated or electrically operated automated devices. ## Governments and regulatory agencies [fig] FIGURE 1: Standardized blood pressure measurement procedure. [/fig] [table] TABLE 1: Blood pressure measurement methods commonly used in clinical practice [/table] [table] TABLE 2: Essential elements of performing a standardized clinic blood pressure measurementElement CommentDevice Use a calibrated (for aneroid devices) or clinically validated (for automated devices) instrument. [/table] [table] TABLE 3: Major sources of error during blood pressure measurement [/table]	None	None	High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-to-middle-income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice.
d1260e1e1a04523b9c12c8aaf6d64b38e704193b	pubmed	Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002)	Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002) Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20 -50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney.In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months.The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive. Carcinomas of unknown primary site are metastatic malignant epithelial tumours whose primary site cannot be identified during pretreatment assessment. They are characterised by their slow local development and their high metastatic potential. The primary site remains unknown in 20 -50% of the patients, but the results from autopsies show that the primary tumours are most often located in the pancreas, lung, gut or kidney. In France, the incidence of carcinomas of unknown primary site is eight out of 100 000 per year, corresponding to between 5 and 7% of the solid tumours in adults. The average age at detection is 60 years old, with slightly more men being affected. The median survival time is only a few months. The heterogeneity of carcinoma of unknown primary site is due to the different histopathological types and anatomical localisations, making this a difficult topic to cover. In this document, we present the diagnostic strategy based on these two parameters, with the first entry point being the histopathological type. The therapeutic strategies to be used depend on the prognostic factors: specific anatomoclinical entities (neuroendocrine tumours, cervical lymph node metastases from squamous cell carcinoma, axillary lymph node metastases from an adenocarcinoma in women, undifferentiated carcinoma of the mediastinum in young men) and other nonspecific situations. Although primary papillary serous carcinoma is no longer included in the classification of peritoneum carcinomas of unknown primary site, we covered the management in women here in an attempt to be exhaustive. ## Objectives The objective was to define guidelines for the management of adult patients with carcinomas of unknown primary site. These guidelines are aimed at health professionals treating these patients with the goal of helping to homogenising clinical practice. The principal questions addressed in this document are: What pathological diagnostic strategies should be used for each localisation? To what extent should the primary site be searched for, and what are the limits for this strategy? What are the prognostic factors? What treatment strategies should be used for each anatomoclinical type? # Methods The details of the full methodology have been previously published [bib_ref] SOR: project methodology, Fervers [/bib_ref]. In summary, 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) to review the literature on the management of patients with carcinomas of unknown primary site. Medline s was searched between 1980 and 2001 using keywords pertinent for each topic covered and this was completed with references provided by the members of the working group. The majority of the articles were in English and French. After selection and critical appraisal of this literature, the working group defined the 'Standards', for the management of patients with carcinomas of unknown primary site, based on a synthesis of the best available evidence and expert agreement. These guidelines were then reviewed by a group of independent experts (see the Appendix) and finalised after taking into consideration their comments. SORs are considered as being validated when the members of the working group give their agreement for publication. 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 professional experience and consensus of the expert group ('expert agreement'), and this is then validated by the peerreview process. This is a translation of the French version of the summary rapport [bib_ref] ) Standards, Options and Recommendations for the management of patient with carcinoma..., Bugat [/bib_ref] , which was based on the full-text version in French, available on internet at the following address: http://www.fnclcc.fr. The document will be updated as new evidence becomes available or there is a change in expert agreement. The list of abbreviations used in this article and their meaning is given in [fig_ref] Table 3: Abbreviations and their meanings [/fig_ref]. ## Pathological examination ## Treatment of samples prior to pathological examination Samples should be fixed using buffered formalin or AFA (acetic acid, formaldehyde, alcohol) (standard, level of evidence: B2). The standard staining technique is haematoxylin and eosin (standard, level of evidence: B2). Immunohistochemical investigations should be performed using a panel of antibodies (standard, level of evidence: B2). Samples can be frozen directly in liquid nitrogen and then stored in a freezer at À801C or lower, or stored in liquid nitrogen (option, expert agreement). ## Strategies for specific histopathological types (figures 1 -3) Undifferentiated malignant tumour An immunohistochemical investigation should be performed to eliminate the diagnosis of lymphoma, melanoma or germ cell tumour. This should involve the use of a panel of reference antibodies against epithelial antigens (pan-cytokeratins), lymphoid antigens (CD45, CD20, CD3), melanotic antigens (PS100 et HMB45) and germ cell tumour antigens (aFP, bHCG, PLAP) depending on the clinical presentation (standard, level of evidence: B2). Undifferentiated carcinoma or adenocarcinoma Neuroendocrine tumour markers should be used in the immunohistochemical investigation (e.g. chromogranin, synaptophysin), as well as carcinoma markers (cytokeratins: CK5/6, CK7, CK19, CK20, ACE) and other antibodies depending on the anatomoclinical presentation (e.g. thyroglobulin, prostate specific antigen (PSA), hormonal receptors) (standard, level of evidence: B2). Level A There exists a high-standard meta-analysis or several high-quality randomised clinical trials that give consistent results ## Level b There exist good quality evidence from randomised trials (B1) or prospective or retrospective studies (B2). The results are consistent when considered together Level C The methodology of the available studies is weak or their results are not consistent when considered together Level D Either the scientific data do not exist or there is only a series of cases ## Expert agreement The data do not exist for the method concerned, but the experts are unanimous in their judgement ## Diagnostic strategy systematic diagnostic assessment Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment (standard, level of evidence: B2). For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary (standard, level of evidence: B2). The systematic diagnostic assessment is summarised in step 1 in . Specific work-up to eliminate diagnosis of extragonadal germ cell tumour The main differential diagnoses for patients with carcinomas of unknown primary site are extragonadal germ cell tumour and lymphoma, because they are potentially curable. The specific work-up for eliminating the diagnosis of extragonadal germ cell tumour, includes a systematic diagnostic work-up and a specific work-up for adenocarcinomas and undifferentiated carcinomas (standard). Diagnostic work-up depending on histopathological and anatomic localisation [fig_ref] Figure 4: Second diagnostic step for adenocarcinoma and undifferentiated carcinoma [/fig_ref] The diagnostic steps (steps 2 and 3), performed depending on the histopathological and anatomic localisation, are shown in . [formula] + + + - CK - CD45 - PS100 + − − - CK - CD45 - PS100 − + − - CK - CD45 - PS100 − − + - CK - CD45 - PS100 − − − [/formula] ## Prognostic factors for carcinoma of unknown primary site No prospective studies or meta-analyses for prognostic factors have been published, but there are several retrospective studies with coherent results, which suggest that the following are the best prognostic factors: general good health status; women; lymph node metastases; neuroendocrine or squamous cell carcinoma; and few metastatic sites (level of evidence: B2). It is recommended to include patients with carcinomas of unknown primary site in good-quality studies assessing prognostic factors (recommendation). ## Treatment strategy ## Treatment of specific anatomoclinical entities Treatment of neuroendocrine carcinoma The treatment of metastases from a neuroendocrine carcinoma is not modified by the identification of the primary site (expert agreement). The management of patients with neuroendocrine carcinoma of unknown primary site should take into consideration the cellular differentiation (standard, expert agreement). Poorly differentiated forms are considered to be chemosensitive (level of evidence: C). The usual treatment is based on a combination of a platinum salt and etoposide (level of evidence: C). Although the results from clinical trials do not provide evidence for efficacy in terms of increased survival, clinicians should prescribe this treatment (standard, expert agreement). There is no standard for the forms that are well differentiated. The treatment decision should be based on a multidisciplinary decision taking into consideration the patient's symptoms and the progression of the carcinoma, particularly for those with welldifferentiated forms (recommendation). Treatment of cervical lymph node metastases in patients with squamous cell carcinoma Patients with cervical lymph node metastases from squamous cell carcinoma should be offered lymph node dissection and complementary radiotherapy (standard, level of evidence: C). If surgery is not possible, radiotherapy should be performed (standard). Chemotherapy can be proposed to patients with tumours that are not suitable for resection or surgery (option). Diagnostic work-up for carcinoma of unknown primary site as a function of their histopathological and anatomic localisation Step 1 Step 2 Step 3 ## Diagnostic step 3 standards ## Diagnostic step 3 standards (women) ## Diagnostic step 3 standards ## Diagnostic step 3 options ## Diagnostic step 3 option ## Diagnostic step 3 Options ( Locoregional treatment (axilla): Axillary dissection should be offered (standard, expert agreement). Axillary and/or supraclavicular irradiation can be undertaken (option, expert agreement). Systemic treatment: The management of these patients should be identical to that for patients with breast cancer with lymph node metastases (recommendation). Treatment of primary papillary serous carcinoma in women By analogy with ovarian cancer, the standard treatment is tumour reduction by surgery (level of evidence: D) followed by poly-chemotherapy containing a platinum salt (standard, expert agreement). About six cycles of treatment should be undertaken (recommendation). Treatment for carcinomas of unknown primary site not belonging to a specific anatomoclinical entity [fig_ref] Figure 1: First diagnostic step for carcinoma of unknown primary site [/fig_ref] treatment only, or a treatment based on bisphosphonates in patients with bone metastases. If chemotherapy is prescribed, it is recommended to administer a combination therapy with two drugs, containing cisplatin (recommendation, expert agreement) for patients with a good general health status (WHO performance status of 1 or less). The treatment response should be evaluated early (after two cycles) to avoid treatment in patients with known progressive disease (recommendation). [fig_ref] Figure 9, Figures: Figure 9 [/fig_ref] Treatment of axillary lymph node metastases in patients with adenocarcinoma. General treatment for carcinoma of unknown primary site not belonging to a specific anatomoclinical entity [fig_ref] Figure 1: First diagnostic step for carcinoma of unknown primary site [/fig_ref] General treatment of carcinoma of unknown primary site not belonging to a specific anatomoclinical entity. [fig] Figure 1: First diagnostic step for carcinoma of unknown primary site. [/fig] [fig] Figure 2: Histopathological diagnosis for carcinoma of unknown primary site. [/fig] [fig] Figure 3: Histopathological diagnosis of undifferentiated carcinoma and adenocarcinoma. [/fig] [fig] Figure 4: Second diagnostic step for adenocarcinoma and undifferentiated carcinoma. [/fig] [fig] Figure 9, Figures: Figure 9 [/fig] [fig] Figure 5: Third diagnostic step for adenocarcinoma and undifferentiated carcinoma. of Cancer (2003) 89(Suppl 1), S59 -S66 & 2003 FNCLCC Treatment of axillary lymph node metastases in women with adenocarcinoma (Figure 9) Locoregional treatment (breast): If the results from the breast MRI are negative, surgery and breast radiotherapy should not be offered (standard, expert agreement). [/fig] [fig] Figure 6, Figure 7, Figure 8: Complementary examinations for squamous cell carcinoma. Treatment of neuroendocrine carcinoma. Treatment of cervical lymph node metastases in patients with squamous cell carcinoma. [/fig] [table] Table 2: Definition of level of evidence [/table] [table] Table 3: Abbreviations and their meanings [/table] [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 or harmful by a majority, based on the best available evidenceRecommendations Additional information to enable the available options to be ranked using explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies (standard). This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later (option). The clinician and pathologist should compare their opinions before and after the pathological diagnosis (recommendation, expert agreement). [/table]	None	https://www.nature.com/articles/6601085.pdf	None
5b85d2773a4e52c03407969554c158bfc43bf91b	pubmed	Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014	Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014 ## Background of this guideline Rapidly progressive glomerulonephritis (RPGN) is defined in Japan as ''a syndrome that progresses rapidly within a few weeks or months to renal failure and is accompanied by urinary findings of nephritis.'' The clinical concept of RPGN includes various renal diseases that cause renal function to deteriorate over a subacute course. Necrotizing crescentic glomerulonephritis is often observed in histopathological findings. In 2002, a joint committee formed by JSN and a research group on progressive renal disorders from the specific disease program of the Ministry of Health, Labour, and Welfare released Japan's first ''Clinical Guidelines for Rapidly Progressive Glomerulonephritis.'' These landmark guidelines were based on the results of research conducted overseas and a national survey on RPGN and took the particular characteristics of Japan into consideration. The RPGN guidelines were divided into diagnostic guidelines for early discovery and guidelines for making definitive diagnoses. RPGN was categorized into either a myeloperoxidase (MPO-ANCA) or proteinase-3 antineutrophil cytoplasmic (PR3-ANCA) type based on ANCA-related vasculitis. Furthermore, a practical therapeutic algorithm was created for MPO-ANCA types that took into consideration factors such as clinical severity, age, and presence of dialysis. Treatment guidelines for anti-GBM antibody RPGN were also presented. These guidelines were widely used in Japan and contributed greatly to improving RPGN prognosis. These guidelines were revised 9 years later, in 2011, and published as ''Clinical Guidelines for Rapidly Progressive Glomerulonephritis-2nd edition.'' This edition took into account medical advances that had occurred since 2002, and eGFR, not serum creatinine level, was adopted for diagnosing RPGN. Moreover, MPO-ANCA RPGN and PR3-ANCA RPGN were combined under ANCA-positive RPGN. The new edition also included concise statements for treatments and dealing with complications. Since then, marked progress has been made in RPGN research both in Japan and overseas. Globally, kidney disease improving global outcomes (KDIGO) released & Yoshihiro Arimura arimuray@ks.kyorin-u.ac.jp clinical guidelines for glomerulonephritis (''pauci-immune focal and segmental necrotizing glomerulonephritis,'' ''anti-GBM antibody glomerulonephritis,'' and ''lupus nephritis'' were addressed as diseases that present with RPGN, and treatment guidelines with recommendation levels were given). In 2012, the American College of Rheumatology and European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) published guidelines for lupus nephritis. There was also the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, which changed the names of vasculitis diseases and performed other tasks. In Japan, the biological drug rituximab for ANCA-related vasculitis (microscopic polyangiitis, granulomatosis with polyangiitis) became eligible for health insurance coverage in 2013. Against this background, JNS and a research group on progressive renal disorders from the Ministry of Health, Labour, and Welfare decided to create the ''2014 RPGN Clinical Guidelines Based on Evidence.'' A working group was formed to draft the guidelines. ## The intended purpose, anticipated users, and predicted social significance of the guidelines The objective of these guidelines is to present evidencebased clinical guidelines that reflect the conditions in Japan. The text was created in the format of answers to CQ that nephrologists have when treating RPGN in everyday practice. Each answer comes in the form of a statement, and statements related to treatment are given recommendation grades based on the level of evidence. The first part is in a text format and describes areas that include the definition, concept, classification, epidemiology, diagnosis, and pathology of RPGN. Data from Japan are presented in figures and tables. These guidelines are not intended to serve as a comprehensive textbook but rather to answer nephrologists' questions and provide information on standard medical care to aid clinical judgments. For this reason, the RPGN clinical guidelines working group independently evaluated the related evidence and presented applicability criteria for therapeutic interventions, with the goals of suppressing the advance of renal dysfunction and improving survival prognosis. Evidence from the literature can provide information but is no substitute for the specialized skills and experiences of individual physicians. Whether a particular statement applies and how it applies to a particular patient depends on the specialist abilities of each physician. The times demand that medical care shift from a one-size-fits-all approach to a tailor-made approach. Clinical guidelines are not supposed to impose a uniform style of care on physicians. Each physician needs to determine what kind of care each patient needs, based on an understanding of the content of clinical guidelines. As such, these guidelines are not intended to limit physicians to certain forms of medical behavior but were created to assist them in exercising their discretion to decide the type of care to be provided. In addition, it should be stated clearly that these guidelines are not criteria for deciding physician-patient conflicts or medical malpractice lawsuits. ## Patients within the scope of the guidelines In clinical practice, RPGN encompasses a wide range of renal diseases such as ANCA-positive RPGN, anti-GBM antibody RPGN, proliferative lupus nephritis, IgA nephropathy, and forms of immune complex RPGN such as purpura nephritis, as well as infection-associated RPGN, acute interstitial nephritis, and thrombotic microangiopathy. As each of these has different prognoses and treatment strategies, it is not possible to encompass all the diseases. These guidelines focus on ANCA-positive RPGN, which appears frequently and for which there is relatively strong evidence, and on addressing the severe primary diseases, namely lupus nephritis and anti-GBM antibody RPGN. Treatment strategies with recommendation grades are presented for each of these diseases. There is little evidence for other forms of RPGN, so these are merely mentioned in the text. These guidelines apply to RPGN patients of all ages. Finally, pregnancy-related items were, as a rule, not included. ## Preparation procedure Creating evidence-based guidelines first requires the enormous task of gathering and evaluating evidence. We would like to sincerely thank the members of the RPGN Clinical Guidelines Working Group for their dedication and effort (show list of contributors). The first meeting of the clinical guidelines working group was held on September 23, 2011. The group was led by Dr. Kenjiro Kimura of the St. Marianna University School of Medicine, who explained the significance of creating the guidelines and the procedures for the task. The working group then met three more times, submitting on August 24, 2012, a table of contents and a draft of the CQ. The RPGN clinical guidelines committee met on August 25, 2012 for the first time as the working group for drafting the guidelines. This was essentially considered the startup meeting. From then on, the working group began drafting the guidelines based on a shared understanding. The MINDS handbook for creating clinical guidelines was followed, and the Delphi method was used in composing CQ, which is the core of the guidelines. Recommendation grades were determined by an informal consensus. As a rule, PubMed records up to July 2012 were used to search the literature. If necessary, important studies from after this date were included, with reasons given. Several meetings of the RPGN clinical guidelines committee were held (including review discussions among committee members through e-mail). Through this process, the initial CQ and text items were appropriately revised, and a few deletions and additions were made. The algorithm was also repeatedly revised to make the guidelines easier to use. From September 13 to October 13, 2013, each part was reviewed by two designated referees and two designated academic societies. Simultaneously, public comments were solicited from members of the Japanese Society of Nephrology (JSN). The manuscript was then revised based on the referees' opinions and public comments. The RPGN clinical guidelines committee met on January 26, 2014, to examine the revised manuscript. Afterward, additional revisions were made as needed until a final draft was obtained. The guidelines, as well as responses to the referees' opinions and public comments, were posted on the JSN Web site. ## Contents of the guideline The guidelines comprise the following chapters: I. Disease concepts and definitions, II. Diagnosis, III. Epidemiology and prognosis, IV. Algorithms, and V. Diagnostic and treatment CQ. Chapters I to III and the section on the side effects of immunosuppressant therapy and the methods of treating these effects are in text format. Chapter IV-2 contains 20 CQ on particularly problematic areas of everyday care. The answers to these come in the form of statements and are accompanied by recommendation grades. The evidence and background for the recommended treatments are explained in the commentary, which should be referenced as needed. The algorithms of chapter IV-1 are presented in flowcharts for diagnosis and treatment, which were created so the location of the CQ can be easily determined. Note that these guidelines were created in tandem with the ''2013 CKD clinical guideline based on evidence,'' and so were written by the same authors. ## Evidence levels and recommendation grades Evidence levels were evaluated in a manner similar to that described in the ''2013 CKD clinical guideline based on evidence.'' [Evidence Levels] Level 1: Systematic review/meta-analysis. Level 2: At least 1 randomized controlled trial (RCT). Level 3: A non-RCT. Level 4: An analytical epidemiologic study (cohort study or case-control study) or a single-arm intervention study (no controls). Level 5: A descriptive study (case report or case series). Level 6: Opinion of an expert committee or an individual expert, which is not based on patient data. Evidence levels for meta-analyses and systematic reviews were determined from the designs of the studies on which they were based. If the underlying studies had mixed designs, consensus was reached to adhere to the lowest level (e.g., a meta-analysis of cohort studies would be level 4, as would a meta-analysis that included both RCT and cohort studies). Consensus was also reached to assign evidence level 4 to all RCT subanalyses and post hoc analyses. Therefore, an RCT with a clear primary outcome would be considered level 2, while a subanalysis or post hoc analysis of this RCT would be considered level 4. The following recommendation grades were assigned to statements about treatments, which were based on the level of evidence for each statement. [Recommendation Grades] Grade A: Strongly recommended because the scientific basis is strong. Grade B: Recommended because there is some scientific basis. Grade C1: Recommended despite having only a weak scientific basis. Grade C2: Not recommended because there is only a weak scientific basis. Grade D: Not recommended because scientific evidence shows treatment to be ineffective or harmful. As a rule, standard treatments in Japan were recommended, but eligibility for health insurance coverage was not necessarily required. Drugs ineligible for insurance coverage were denoted as such. Recommendation grades were assigned to statements about treatment-related CQ. In addition, questions such as ''To which subgroup would this be recommended?'' and ''To which subgroup would this not be recommended?'' were addressed whenever possible. Recommendation grades were decided through consultations among the working group members by considering the tradeoffs between and balance of benefits, damage, side effects, and risk. If differing views existed among the referees or in the public comments, the group reexamined the area through an exchange of opinions. The reasons for choosing a recommendation grade and the decision-making process involved were described in the commentary, as a rule. ## Issues on the preparation of this guideline Although evidence regarding renal diseases that present with RPGN is gradually increasing in Japan, it is still insufficient, which means that these guidelines were heavily influenced by evidence from Europe and the United States. Whether the results of clinical research from the West can be applied as is to Japan is a question that deserves careful consideration. Even in the West, only a few large clinical studies on RPGN have been conducted, so the quality of evidence is limited. In creating the guidelines, we strove to ensure they would not deviate greatly from clinical practice in Japan. The guidelines were made to be used by nephrologists. Furthermore, although there have been calls recently for clinical guidelines to address the viewpoint of patients and provide information on medical economics, these areas were not taken into consideration. ## Financial sources and conflict of interest The funds used in creating the guidelines were provided by a research group on progressive kidney disorders funded by the Ministry of Health, Labour, and Welfare's research project for overcoming intractable diseases. These funds were used to pay for transportation to and from meetings, to rent space for meetings, and for box lunches and snacks. The committee members received no compensation. Everyone involved in creating the guidelines (including referees) submitted conflict-of-interest statements based on academic society rules, which are managed by JSN. Opinions were sought from multiple referees and related academic societies to prevent the guidelines from being influenced by any conflicts of interest. Drafts were shown to the society members, and revisions were made based on their opinions (public comments). ## Publication and future revisions The guidelines are to be published in Japanese-language journal of JNS and concurrently released in book form by Tokyo Igakusha. This guideline was also uploaded to the homepage of the JSN. They will also be posted on the MINDS Web site of the Japan Council for Quality Health Care. It will also be necessary to verify the extent to which these guidelines are being implemented and complied with, particularly for treatments of recommendation grade B. We hope to form a new working group on RPGN to follow up on compliance under a Ministry of Health, Labour, and Welfare research group. In addition, we want to extract and organize the various research questions that came up while creating these guidelines so that new clinical research (particularly prospective interventional studies) and basic research can be conducted. We intend to participate in structuring further evidence that is accumulated on RPGN for rituximab and other new therapies. At the same time, by continuing to collect evidence regarding RPGN overall, we hope to work toward a revision of these guidelines several years from now. We will also study how to address in the next guidelines the viewpoint of patients and medical economics, which were not mentioned this time. In the future, guidelines for patients also need to be considered. ## I. disease entity á definition (pathogenesis á pathophysiology) The World Health Organization defines rapidly progressive glomerulonephritis (RPGN)/rapidly progressive nephritic syndrome as an abrupt or insidious onset of macroscopic hematuria, proteinuria, anemia, and rapidly progressing renal failure. The Research Committee of Progressive Glomerular Disease of the Ministry of Health, Labor and Welfare of Japan and the Japanese Society of Nephrology defined RPGN as rapidly progressing renal failure within several weeks to several months that is associated with urinary findings such as proteinuria, hematuria, red blood cell casts, and granular casts indicating glomerulonephritis. Without treatment, most patients will develop end-stage renal disease. RPGN is one of the clinical syndromes resulting from glomerulonephritis. In most cases of RPGN, the histopathological diagnosis is necrotizing crescentic glomerulonephritis (NCGN). NCGN is classified into three types-linear, granular, and paucity-immune patternbased on immunofluorescence microscopic findings. A linear pattern indicates anti-glomerular basement disease, including in situ immune complex formation disease based on the Chapel Hill consensus criteria (2012). Granular staining is seen in circulating immune complex diseases such as systemic lupus erythematosus and IgA vasculitis. Most cases with the paucity-immune pattern are glomerulonephritis induced by antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Myeloperoxidase (MPO)-specific ANCA-associated vasculitis is more widely known than proteinase 3 ANCA-associated vasculitis in Japan. ## Ii. diagnosis (symptoms and signs) General fatigue, slight fever, appetite loss, flu-like symptoms, and abnormal body weight loss are also frequently observed. Microscopic, or occasionally macroscopic, hematuria is observed accompanied by dysmorphism of red blood cells and cellular cast formation. Proteinuria is In blood chemistry tests, elevation of serum creatinine, decrease of estimated glomerular filtration rate, and elevation of C-reactive protein and erythrocyte sedimentation rate, often refractory to treatment by antibiotics, are observed. Rapidly progressive anemia, gradual elevation of neutrophil-dominant white blood cells, and thrombocytes are frequently observed. Complement levels tend to be elevated in RPGN because of systemic vasculitis; in contrast, systemic lupus erythematosus (SLE) decreases complement levels. As autoantibodies for detecting the causative disease of RPGN, anti-glomerular basement membrane (GBM) antibody, ANCA, and anti-dsDNA antibody are highly specific. Concerning signs in renal imaging, renal atrophy on echography is relatively rare. Renal pathology frequently reveals crescentic glomerulonephritis. The ''Clinical criteria of RPGN for early discovery of the disease,'' which promotes early presentation of patients to specialists, and the ''Guideline for the definite diagnosis of RPGN'' are proposed as diagnostic criteria for RPGN. Diagnostic differential criteria for diseases that manifest RPGN Important differential diagnoses include primary vasculitis syndrome, Goodpasture syndrome, SLE, IgA vasculitis, malignancies, cryoglobulinemia, infectious diseases such as post-streptococcal acute glomerulonephritis, infectious endocarditis, and type C hepatitis infection. It is important to first exclude infectious diseases and malignancies. III. Epidemiology and prognosis (incidence, prevalence, and outcome) . Epidemiology RPGN is a rare renal disease; however, the number of Japanese patients with RPGN has increased in recent years. Although the precise incidence of RPGN in Japan or worldwide is not known, a recent questionnaire survey estimated the number of new cases of RPGN in Japan at 1600-1800 per year. Based on a questionnaire survey of 1772 Japanese cases collected from 1989 to 2007, the most common clinical form of RPGN in this country is pauci-immune-type necrotizing glomerulonephritis without systemic vasculitis, and the second most common form is microscopic polyangiitis. In recent years, the age at onset has increased. ## Prognosis The survival and renal prognosis of Japanese patients with RPGN or ANCA-associated RPGN has improved in recent years. In contrast, patients with anti-GBM antibody-associated RPGN show an extremely poor prognosis. Infection has been, and continues to be, the leading cause of death in patients with RPGN. IV. Treatment Indirect immunofluorescence (IIF) and enzyme immunoassay (EIA) have been used for ANCA testing. The labeling characteristics (cytoplasmic or perinuclear) are obtained by IIF, and identification of the specific target antigen with quantitative measurements is achieved by EIAs: enzyme-linked immunosorbent assay (ELISA), fluorescence enzyme immunoassay (FEIA), and chemiluminescent enzyme immunoassay (CLEIA). The different procedures for the measurement of ANCA affect the diagnostic assessments and disease activity evaluation. The absolute values obtained through different assays cannot be directly compared, and multicenter clinical/epidemiological studies need to consider the differences in assay methods when comparing data. It should also be noted that assessment of disease activity should not rely on the Pulse Methylprednisolone, followed by oral corticosteroid (Pulse methylprednisolone 500-1000 mg i.v. daily 9 3 days, followed by oral prednisolone 0.6-0.8 mg/kg/day) C Pulse Methylprednisolone, followed by oral corticosteroid ? oral CY (Pulse methylprednisolone 500-1000 mg i.v. daily 9 3 days, followed by oral prednisolone 0.6-0.8 mg/kg/day ? oral CY 25-100 mg/day) Remission is defined as the absence of disease activity after a course of induction treatment for ANCA-associated vasculitis. The remission maintenance phase is defined as the period of sustained absence of disease activity. Relapse is a new or recurrent disease activity that occurs after remission has been initially induced. There are no definitions for ''remission'' and ''relapse'' in RPGN. The ANCA binding level usually decreases in response to the treatment; thus, it is a useful marker that reflects disease activity. Persistent ANCA may occur in some cases. Treatment should not be tapered solely based on the ANCA level, and a comprehensive evaluation with careful observation of clinical symptoms and other physical/laboratory manifestations is required. Persistence of ANCA positivity after induction therapy or an increase in ANCA during the remission phase increases the risk of relapse in ANCA-associated vasculitis. It is recommended to check the ANCA level once every 1-3 months during the remission maintenance phase. There is a lack of evidence to support changing of treatment to prevent disease relapse based on the reappearance of ANCA or an increase in ANCA binding level during the remission maintenance phase. An increase in ANCA indicates an increase in relapse risk, and clinical manifestations should be monitored carefully. Treatment should not be escalated solely because of an increase in ANCA. [Summary] Anti-GBM disease, also known as Goodpasture disease, is an autoimmune disorder characterized by rapidly progressive glomerulonephritis (RPGN) and a high risk for alveolar hemorrhage. Anti-GBM antibodies have been proven to be pathogenic in disease initiation. The target GBM antigen for circulating antibodies was subsequently identified as the non-collagenous-1 (NC1) domain of the a3 chain of collagen IV, whereas further studies revealed that collagen IV is a family of six achains (a1 through a6). Two major immunodominant regions, EA and EB, have been mapped to residues 17-31 and 127-141 of a3(IV)NC1. Antibodies against linear epitopes on the Goodpasture autoantigen could be detected in human anti-GBM disease and were associated with kidney injury. Another study defines them as conformational epitopes that are sequestrated in the quaternary structure of GBM dependent on a critical sulfilimine bond. No high-level evidence exists from published clinical trials on the association between anti-GBM antibody levels and disease activity, although many experiment-based studies are well established. According to a retrospective study, high antibody titers at diagnosis seemed to be associated with poor renal and patient survival. Therefore, treatment with plasmapheresis in combination with immunosuppression is recommended to remove the antibodies. In patients with a recurrence of anti-GBM disease, the anti-GBM level is useful in the diagnosis and in deciding the therapy. ## Recommendation grade: c1 Renal biopsy is useful in determining the treatment strategy for RPGN. It is important to evaluate and examine the histological parameters that determine the response to therapy and affect the renal prognosis. ## [summary] Evidence for the necessity to perform treatment, along with the presence of adverse effects, can be obtained through renal biopsy when the findings show reversible lesions. Excess immunosuppression can be prevented if the findings show irreversible changes. Thus, renal biopsy is useful in determining the treatment strategy for RPGN. On the other hand, treatment should be prioritized in patients who are positive for ANCA or anti-GBM antibody and are at high risk of complications with renal biopsy. In most papers, the renal prognosticator of ANCA-associated nephritis has been reported to be the percentage of normal glomeruli. A scoring system for glomerular, tubulointerstitial, and vascular lesions of ANCA-associated vasculitis was proposed in Japan in 2008. European Vasculitis Society (EUVAS) proposed the new classification stratified only based on glomerular lesions. In anti-GBM glomerulonephritis, most papers report the percentage of crescents to be the renal prognosticator. ## Cq 5. is it recommended that the immunosuppressive treatment of anti-neutrophil cytoplasmic antibody (anca)-negative pauci-immune rapidly progressive glomerulonephritis (rpgn) be the same as that of anca-positive disease? Recommendation grade: C1 For ANCA-negative pauci-immune RPGN, we recommend that the treatment be similar to that of ANCA-positive disease. ## [summary] Reports from Japan and other countries showed that some patients with pauci-immune RPGN lacked ANCA. Some showed that there were no differences between patients with ANCA and those without ANCA; however, other studies reported the opposite. Because treatment of ANCA-negative pauci-immune RPGN has not been discussed in detail, we recommend that the treatment be similar to that of ANCA-positive disease. ## Cq 6. is it recommended that the treatment of pr3-anca-positive rpgn be the same as that of mpo-anca-positive disease? Recommendation grade: B For ANCA-associated RPGN, we recommend that the treatment be based on the severity and extent of disease, not on the ANCA subtype. [Summary] PR3-ANCA-positive RPGN is more common in Europe and the United States, whereas MPO-ANCApositive RPGN is more common in Japan. Therefore, the treatment in Europe and the United States, which focuses on PR3-ANCA-positive RPGN, should not be directly adopted in Japan. However, the recent treatments introduced in Europe and the United States as well as in Japan are based on the severity and extent of disease, and not on the ANCA subtype. In fact, in Europe and the United States as well as in Japan, no differences in renal outcome and survival were observed between ANCA subtypes. However, special care should be taken to prevent relapse of PR3-ANCApositive RPGN. ## Cq 7. should special care be given in the treatment of older patients with anca-associated rpgn compared with younger patients? Recommendation grade: B Because older patients with ANCA-associated RPGN have a higher risk of infection compared with younger patients, we recommend decreasing the dose of immunosuppressants (especially cyclophosphamide) in older patients. ## [summary] Patients with RPGN in Japan are older compared with those in Europe and the United States. Recently, Japanese patients with RPGN have shown better survival. Therefore, we recommend preventing infection due to over-immunosuppression in patients older than 70 years old, although they may have a higher risk of relapse. Infection is the most common and severe complication of ANCA-associated vasculitis in Europe and the United States, as well as in Japan. It is recommended that older patients, especially those with poor renal function, should be given reduced cyclophosphamide dose according to their age. Furthermore, steroids could cause serious adverse events such as diabetes mellitus, bone fractures, and cerebrovascular accidents, as well as infection. Careful attention should be given to the dose given to older patients to prevent the high incidence of serious adverse events with the use of several drugs. ## Cq 8. is initial therapy with corticosteroids alone recommended for improving renal function and survival in patients with rpgn? ## Recommendation grade: c1 In patients with ANCA-positive RPGN, high or moderate doses of corticosteroids have been shown to improve renal function and survival. However, combination with immunosuppressive agents is more effective; therefore, initial therapy with corticosteroids alone is recommended only in cases in which the use of immunosuppressive agents is not desirable. ## Recommendation grade: c1 In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), high or moderate doses of corticosteroids have been shown to improve renal function and survival. However, combination with immunosuppressive agents is more effective, and therefore initial therapy with corticosteroids alone is recommended only in cases in which the use of immunosuppressive agents is not desirable. ## Recommendation grade: c1 In patients with anti-GBM antibody glomerulonephritis presenting with RPGN, high doses of corticosteroids may improve renal function and survival. However, the combined use of immunosuppressive agents is more effective; therefore, initial therapy with corticosteroids alone is recommended, in combination with plasmapheresis, in cases in which the use of immunosuppressive agents is not desirable. ## [summary] In patients with ANCA-positive RPGN, the combined use of corticosteroids and immunosuppressive agents is currently recommended as the standard therapy, and there are no randomized controlled trials (RCTs) that compared treatment with and without corticosteroids. Therefore, initial therapy with corticosteroids alone is indicated only in cases in which aggressive treatment is required but the use of immunosuppressive agents is not desirable, such as in patients in whom systemic infection is present or cannot be ruled out, thus conferring increased risk by addition of immunosuppressive agents, dialysis-dependent patients, elderly patients (particularly those older than 70 years), and those in whom immunosuppressive agents are contraindicated because of leukopenia and liver dysfunction. In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), the combined use of corticosteroids and immunosuppressive agents is the current standard therapy. Therefore, initial therapy with corticosteroids alone is indicated only in cases in which aggressive treatment is required to prevent the progression of renal disease or to improve severe systemic complications in other vital organs, including the lung and the central nervous system, but in which the use of immunosuppressive agents is not desirable. The prognosis of anti-GBM antibody disease is poor without treatment, with the worst patient survival in the presence of pulmonary hemorrhage. In patients with anti-GBM antibody glomerulonephritis presenting with RPGN, the combined use of corticosteroids and immunosuppressive agents, in addition to plasmapheresis, is suggested as the standard treatment. Therefore, initial therapy with corticosteroids alone is recommended, usually combined with plasmapheresis, in cases in which the use of immunosuppressive agents is not desirable because of adverse effects. ## Cq 9. which of oral corticosteroid or intravenous pulse corticosteroid is recommended as an initial corticosteroid therapy for improving renal function and survival in patients with rpgn? ## Recommendation grade: c1 In patients with ANCA-positive RPGN, adding intravenous pulse corticosteroid therapy to oral corticosteroids may be considered when the decline of renal function is very rapid, or when severe systemic complications such as pulmonary hemorrhage are present. ## Recommendation grade: c1 In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), adding intravenous pulse corticosteroid therapy to oral corticosteroids is recommended when the decline of renal function is very rapid, or when severe systemic complications such as pulmonary hemorrhage or central nervous system (CNS) lupus are present. ## Recommendation grade: c1 In patients with anti-GBM antibody disease presenting with RPGN, adding intravenous pulse corticosteroid therapy to oral corticosteroids is recommended to improve survival when pulmonary hemorrhage is present (i.e., Goodpasture syndrome). In patients with anti-GBM antibody glomerulonephritis without pulmonary hemorrhage, adding intravenous pulse corticosteroid therapy to oral corticosteroids is recommended to improve renal function, except for those whose renal function is not likely to recover even with aggressive immunosuppressive therapy. ## [summary] In ANCA-positive glomerulonephritis, lupus nephritis (class IV and some class III cases), or anti-GBM antibody glomerulonephritis presenting as RPGN, there are no RCTs that have compared the effect on renal survival or patient Clin Exp Nephrol (2016) survival between oral corticosteroids and intravenous pulse corticosteroid therapy. However, this is considered to confer rapid, strong anti-inflammatory and immunosuppressive effects in patients with high disease activities such as - ANCA-positive glomerulonephritis, in which the decline of renal function is very rapid or is associated with severe systemic complications, including pulmonary hemorrhage - Lupus nephritis presenting with RPGN (class IV and some class III cases), in which the decline of renal function is very rapid or is associated with severe systemic complications, including pulmonary hemorrhage and CNS lupus - Anti-GBM antibody glomerulonephritis presenting with RPGN but without pulmonary hemorrhage, except for those whose renal function is not likely to recover despite aggressive therapy, or almost all cases of Goodpasture syndrome that is complicated by pulmonary hemorrhage The standard protocol in pulse corticosteroid therapy is intravenous administration of 500 mg to 1 g of methylprednisolone for three consecutive days, followed by 0.6-0.8 mg/kg body weight of oral prednisolone. ## Cq 10. is initial therapy with immunosuppressive agents recommended for improving renal function and survival in patients with rpgn? ## Recommendation grade: b In patients with ANCA-positive RPGN, the addition of immunosuppressive agents to corticosteroids in the initial therapy has been shown to improve renal function and survival. We recommend immunosuppressive agents with corticosteroids as the initial therapy for these patients. ## Recommendation grade: a In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), the addition of immunosuppressive agents to corticosteroids in the initial therapy has been shown to improve renal function and survival. We recommend immunosuppressive agents with corticosteroids as the initial therapy for these patients. ## Recommendation grade: c1 In patients with anti-GBM antibody-positive RPGN, the addition of immunosuppressive agents to corticosteroids in the initial therapy may improve renal function and survival. We recommend immunosuppressive agents with corticosteroids as the initial therapy for these patients. ## [summary] (1) ANCA-positive RPGN Treatment with corticosteroids and cyclophosphamide has improved the outcome of patients with ANCA-positive RPGN. We recommend daily oral cyclophosphamide (25-100 mg/day) or intravenous pulses of cyclophosphamide (250-750 mg/m 2 /month) with corticosteroids as the initial therapy, considering the clinical grade, patient age, and dialysis requirement. (2) Lupus nephritis presenting with RPGN We recommend immunosuppressive agents (cyclophosphamide or mycophenolate mofetil) with corticosteroids as the initial therapy for patients with diffuse proliferative lupus nephritis. (3) Anti-GBM antibody-positive RPGN Patient survival and kidney survival in anti-GBM antibodypositive RPGN are poor. The clinical guideline in Japan recommends immunosuppressive therapy (corticosteroids and cyclophosphamide) plus plasmapheresis. We recommend cyclophosphamide (1-2 mg/kg/day) for patients with refractory GN. However, it is necessary to reduce the dose of cyclophosphamide in patients with advanced renal dysfunction. CQ 11. Which is recommended for improving renal and patient survival in RPGN, oral cyclophosphamide or intravenous pulses of cyclophosphamide? ## Recommendation grade: b There are no differences in renal and patient survival between oral cyclophosphamide and intravenous pulses of cyclophosphamide. Both therapies have been shown to improve renal function and survival in patients with RPGN. ## [summary] The clinical guideline in Japan recommends immunosuppressive agents with corticosteroids as the initial therapy, considering the clinical grade, patient age, and dialysis requirement. The guideline recommends daily oral cyclophosphamide (25-100 mg/day) or intravenous pulses of cyclophosphamide (250-750 mg/m 2 /day/month) in patients with clinical grade I and II in whom the effects of corticosteroids are not enough, and in patients with clinical grade III and IV who are younger than 70 years. There are no differences in renal and patient survival between oral cyclophosphamide and intravenous pulses of cyclophosphamide, although treatment with intravenous pulses of cyclophosphamide has reduced the rate of relapse and adverse events. ## Cq 12. is immunosuppressive therapy recommended for improving renal function and survival in patients with rpgn who are receiving dialysis at the time of diagnosis? ## Recommendation grade: c1 In patients with ANCA-positive RPGN who are receiving dialysis at the time of diagnosis, immunosuppressive therapy is shown to improve renal function and survival. ## Recommendation grade: c1 In patients with lupus nephritis presenting with RPGN (class IV and some class III cases) who are receiving dialysis at the time of diagnosis, immunosuppressive therapy is shown to improve renal function and survival. ## Recommendation grade: not graded In patients with anti-GBM antibody glomerulonephritis presenting with RPGN who are receiving dialysis at the time of diagnosis, immunosuppressive therapy may not improve renal survival. However, in patients with pulmonary hemorrhage, immunosuppressive agents are recommended to improve survival. ## [summary] In patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have severe active renal disease, the addition of plasma exchange to cyclophosphamide and glucocorticoid therapy is currently recommended by the European league against rheumatism (EULAR) guideline. Even in patients with dialysis-dependent ANCA-associated vasculitis, the chance of renal recovery is high when they have a high percentage of normal glomeruli. However, as therapyrelated deaths usually occur in older patients and in those with poor general condition, carefully decisions for safer treatment regimens are warranted. In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), the combined use of corticosteroids and immunosuppressive agents such as intravenous cyclophosphamide or mycophenolate mofetil is the current standard therapy by American College of Rheumatology (ACR) guideline. Liang reported that 59.3 % patients with lupus nephritis with recent-onset renal failure recovered their renal function after 6 months of follow-up, whereas 11.1 % had died. As the chronic component of renal function loss is often irreversible with immunosuppressive therapy, renal echogram and renal biopsy should be performed to determine whether the renal failure is reversible. In patients with anti-GBM antibody glomerulonephritis presenting with RPGN who are receiving dialysis at the time of diagnosis, immunosuppressive therapy may not improve renal survival. However, in patients with pulmonary hemorrhage, immunosuppressive agents are recommended to improve survival. CQ 13. Is rituximab recommended for improving renal function and survival in patients with RPGN? Recommendation grade: B As the initial therapy for ANCA-positive RPGN, addition of rituximab to corticosteroids may improve renal and patient survival. Therefore, rituximab is recommended in cases in which standard therapy cannot be given because of adverse effects, or in those who are refractory to or relapsed after standard therapy (insurance is applicable only for patients with MPA and GPA in Japan). ## Recommendation grade: c1 In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), there is no evidence to support that treatment with rituximab improves renal function and survival; however, it could be considered if there is no other treatment available (not covered by insurance in Japan). ## Recommendation grade: not graded In patients with anti-GBM antibody disease presenting with RPGN, there is no evidence to support that treatment with rituximab improves renal function and survival. [Summary] B-cell-targeted therapy has recently been introduced for patients with ANCA-associated vasculitis, considering that production of ANCA may be involved in the pathogenesis of this disease. Based on the promising results of two recent RCTs, rituximab has just become available in Japan, as well as in the United States and Europe, but only for cases in which standard therapy cannot be given because of adverse effects or in patients who are refractory to or relapsed after standard therapy. However, the patient profiles of renal-limited ANCA-positive or MPO-ANCA-associated RPGN, which is more common in Japan, were not described in those trials. Moreover, there is a substantial risk of infection, as well as concerns about long-term safety concerning the incident risk of malignancy and leukoencephalopathy. Thus, it is necessary to perform screening tests to detect infection and to take preventive measures before starting rituximab. Furthermore, careful follow-up to detect the occurrence of infection and other adverse events is mandatory after the administration of rituximab. B-cell-targeted therapy has been used for patients with SLE to suppress antibody production and immune complex formation. However, in lupus nephritis presenting with RPGN (class IV and some class III cases), there have been no RCTs that demonstrate the superiority of B-cell-targeted therapy over standard immunosuppressive therapy. Therefore, the use of rituximab may be considered only if standard therapy cannot be given because of adverse effects, or in patients who are refractory to or relapsed after standard therapy. In patients with anti-GBM antibody disease with or without pulmonary hemorrhage, a treatment regimen including rituximab has been attempted for suppressing the production of anti-GBM antibody, and evidence is accumulating that suggests its effectiveness. However, rituximab is usually given concomitant with other drugs such as corticosteroids, cyclophosphamide, and plasmapheresis; thus, at present, there is no sufficient evidence that rituximab itself is actually effective. ## Cq 14. is initial therapy with plasmapheresis recommended for improving renal function and survival in patients with rpgn? ## Recommendation grade: c1 In patients with ANCA-positive RPGN complicated with advanced renal dysfunction or pulmonary hemorrhage, the addition of plasmapheresis to immunosuppressive therapy as the initial therapy may improve renal function and survival. We recommend the addition of plasmapheresis in such patients. ## Recommendation grade: c1 In patients with lupus nephritis presenting with RPGN (class IV and some class III cases) in whom the standard therapy is insufficient, the addition of plasmapheresis to immunosuppressive therapy as the initial therapy may improve renal function and survival. We recommend the addition of plasmapheresis in such patients. ## Recommendation grade: b In patients with anti-GBM antibody-positive RPGN, the addition of plasmapheresis to immunosuppressive therapy as the initial therapy has improved renal function and survival. We recommend plasmapheresis for these patients. ## [summary] (1) ANCA-positive RPGN ANCA is thought to be involved in the clinical conditions of ANCA-associated vasculitis and RPGN. The removal of ANCA may therefore result in controlling disease activity and preventing organ damage. The addition of plasmapheresis to the initial therapy with corticosteroids and cyclophosphamide is indicated for patients presenting with advanced kidney failure (serum creatinine, [5.8 mg/dL) or those with diffuse alveolar hemorrhage. (2) Lupus nephritis presenting with RPGN The addition of plasmapheresis to the initial therapy is indicated for patients in whom the standard therapy (corticosteroids and immunosuppressive agents) is insufficient. (3) Anti-GBM antibody-positive RPGN We recommend the addition of plasmapheresis for improving renal function and survival in patients with anti-GBM antibody-positive RPGN. On the other hand, in patients with advanced kidney failure or a requirement for dialysis, there is rare evidence that the addition of plasmapheresis improves renal function and survival. (4) Medical care insurance Patients with SLE presenting with RPGN have insurance coverage for plasmapheresis. However, plasmapheresis for patients with ANCA-positive RPGN and anti-GBM antibody-positive RPGN is not covered by the medical care insurance in Japan. ## Cq 15. does anticoagulant or antiplatelet therapy improve mortality and morbidity in patients with rpgn? Statement: Anticoagulants or antiplatelet therapies may improve mortality and morbidity in patients with RPGN in the condition that they have no hemorrhagic lesions. Recommendation grade: C1 Anticoagulants or antiplatelet therapies are recommended if the patient has no hemorrhagic lesions. Recommendation grade: D Anticoagulants or antiplatelet therapies are not recommended if the patient has any hemorrhagic lesions. ## [summary] The efficacy of anticoagulant or antiplatelet therapy in improving mortality and morbidity in the treatment of rapidly progressive glomerulonephritis has not been established by solid evidences. However, anticoagulants such as heparin and warfarin or antiplatelet therapies with aspirin and eicosapentaenoic acid were reported to be helpful in the treatment of ANCA-associated vasculitis in some cases. In fact, these agents are sometimes used to prevent thrombosis-associated cardiovascular events, especially in patients treated with steroids. On the other hand, as pulmonary hemorrhage and/or gastrointestinal bleeding can occur as complications in ANCA-associated vasculitis, careful attention should be given to treatment with anticoagulants and antiplatelet drugs. ## Cq 16. do intravenous immunoglobulins (ivig) improve renal and patient survival in rpgn? ## Recommendation grade: c1 Although there is limited evidence showing that IVIg improves renal and patient survival in RPGN, IVIg can be used as an alternative option for patients with refractory ANCA-associated vasculitis or those with concurrent complications such as severe infections when it is advisable to avoid the standard therapy with high-dose steroids and immunosuppressant (offlabel use). [Summary] IVIg can be used as an alternative option for patients with refractory ANCA-associated vasculitis or those with concurrent complications such as severe infections when the optimal standard therapy with high-dose steroids and immunosuppressant is not recommended (off-label use). Sulfonated immunoglobulin has been used according to label directions for refractory peripheral neuropathy caused by eosinophilic granulomatosis with polyangiitis/Churg-Strauss syndrome since 2010 in Japan, and it has been reported to improve polyneuropathy and cardiac function, as well as to have a steroid sparing effect. In addition, a clinical trial to evaluate the efficacy for MPA with peripheral neuropathy has been initiated. Thus, IVIg might improve renal and patient survival in RPGN, although evidence is lacking thus far and there is a need for further evaluation in clinical trials. ## Cq 17. is maintenance therapy with corticosteroids alone recommended for improving renal function and survival in patients with rpgn? ## Recommendation grade: a In patients with ANCA-positive RPGN, low-dose corticosteroids have been shown to improve renal function and survival. We recommend corticosteroids as maintenance therapy for these patients. ## Recommendation grade: a In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), low-dose corticosteroids have been shown to improve renal function and survival. We recommend corticosteroids as maintenance therapy for these patients. ## Recommendation grade: b In patients with anti-GBM antibody glomerulonephritis presenting with RPGN, low-dose corticosteroids have been shown to improve renal function and survival. We recommend corticosteroids as maintenance therapy for these patients. ## [summary] Maintenance immunosuppressive therapy for RPGN may prevent relapse, although it may also increase the risk of opportunistic infection. Therefore, it is necessary to consider the total duration of treatment and the dose of corticosteroids in maintenance therapy to prevent relapse and opportunistic infection. (1) ANCA-positive RPGN We recommend a corticosteroid dose of \10 mg/day orally as maintenance therapy, and suggest continuing administration for 12-18 months in patients who remain in complete remission. A study reported that a reduction rate [0.8 mg/month was associated with a higher relapse rate. Shortening the treatment period should be considered in aged or dialysis-dependent patients. (2) Lupus nephritis presenting with RPGN We recommend continuing low-dose corticosteroids (5-7.5 mg/day) orally as maintenance therapy in patients with lupus nephritis presenting with RPGN. (3) Anti-GBM antibody-positive RPGN There is rare evidence suggesting the efficacy of low-dose corticosteroids in patients with anti-GBM antibody-positive RPGN. We suggest continuing corticosteroids for 6-12 months as maintenance therapy. CQ 18. What should be the reduction rate of oral corticosteroids? ## Recommendation grade: b We recommend a reduction of oral prednisolone dose to 20 mg within 8 weeks at the initial therapy and a reduction rate of :0.8 mg/month during maintenance therapy. ## [summary] We recommend a reduction of the oral prednisolone dose to 20 mg within 8 weeks at the initial therapy to prevent opportunistic infection. However, a too early decrease in the amount of steroid was reported to be a risk factor for relapse, and the recommended reduction rate of the oral prednisolone dose during maintenance therapy is \0.8 mg/month. ## Cq 19. is maintenance therapy with immunosuppressive agents recommended for improving renal function and survival in patients with rpgn? ## Recommendation grade: b In patients with ANCA-positive RPGN, the addition of immunosuppressive agents to corticosteroids in the maintenance therapy has been shown to improve renal function and survival. We recommend immunosuppressive agents with corticosteroids as maintenance therapy for these patients. ## Recommendation grade: a In patients with lupus nephritis presenting with RPGN (class IV and some class III cases), the addition of immunosuppressive agents to corticosteroids in the maintenance therapy has been shown to improve renal function and survival. We recommend immunosuppressive agents with corticosteroids as maintenance therapy for these patients. ## Recommendation grade: c1 In patients with anti-GBM antibody-positive RPGN, the addition of immunosuppressive agents to corticosteroids in the maintenance therapy may improve renal function and survival. We recommend the use of immunosuppressive agents with corticosteroids as maintenance therapy for these patients. ## [summary] Maintenance immunosuppressive therapy for patients with RPGN may prevent relapse; however, it may also increase the risk of opportunistic infection. Therefore, it is necessary to consider immunosuppressive agents as maintenance therapy to prevent relapse and opportunistic infection. We recommend treatment with azathioprine or mizoribine in patients with ANCA-positive RPGN, and mycophenolate mofetil or azathioprine in patients with lupus nephritis presenting with RPGN as maintenance therapy to prevent relapse. (1) ANCA-positive RPGN The effectiveness of cyclophosphamide along with azathioprine, mizoribine, mycophenolate mofetil, and methotrexate as immunosuppressive agents in patients with ANCA-associated vasculitis has been reported. We recommend either azathioprine or mizoribine in combination with corticosteroids as maintenance therapy in patients with ANCA-positive RPGN, to prevent relapse. (2) Lupus nephritis presenting with RPGN The effectiveness of azathioprine and mycophenolate mofetil as immunosuppressive agents in patients with lupus nephritis has been reported. We recommend either azathioprine or mycophenolate mofetil in combination with corticosteroids as maintenance therapy in patients with lupus nephritis presenting with RPGN, to prevent relapse. (3) Anti-GBM antibody-positive RPGN There is rare evidence in patients with anti-GBM antibodypositive RPGN. We suggest continuing corticosteroids and immunosuppressive agents (azathioprine, etc.) for 6-12 months as maintenance therapy. ## Cq 20. does trimethoprim/sulfamethoxazole improve renal prognosis and life prognosis? Recommendation grade: A The use of trimethoprim/sulfamethoxazole (TMP/ SMX) improves life prognosis in RPGN. Therefore, prophylactic use of TMP/SMX is recommended in patients with RPGN treated with immunosuppressive therapy. ## Recommendation grade: not graded The effects of TMP/SMX on renal prognosis have not been clarified. ## [summary] The rate of pneumocystis pneumonia (PCP) without the prophylactic use of TMP/SMX has been reported to be 4.0 or 17.6 % in Japan. In other countries, the rate of PCP has been reported to be 1, 6, or 20 %. The doses of corticosteroids and cyclophosphamide used may be related with the incidence. The mortality rate after the onset of PCP has been reported to be 9-60 %. When TMP/SMX was administered, a 91 % reduction of PCP incidence rate was observed and PCP-related mortality was significantly reduced according to a systematic review and meta-analysis of randomized controlled trials of PCP prophylaxis for immunocompromised non-HIV-infected patients. [fig] CQ 3: Is monitoring of anti-GBM antibody levels a useful tool to assess the disease activity and relapse in patients with anti-GBM nephritis and Goodpasture syndrome accompanied by RPGN?Recommendation grade: not graded Anti-GBM antibodies are a useful clinical tool for the treatment of anti-GBM nephritis and Goodpasture syndrome because there is a significant correlation between anti-GBM antibody titer and the activity of those diseases. The levels of anti-GBM antibodies seem to be a useful tool in monitoring the recurrence of anti-GBM nephritis and Goodpasture syndrome. [/fig] [fig] CQ 4: Is renal biopsy useful in determining the treatment strategy for RPGN? [/fig] [table] Table 3: Treatment regimen [/table] [table] Table 4: Pulsed CYC reductions for renal function and age [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs10157-015-1218-8.pdf	None
af66a43fe019a0a41b1ed52ce38980a6297e051d	pubmed	Development of Quality Management Systems for Clinical Practice Guidelines in Korea	Development of Quality Management Systems for Clinical Practice Guidelines in Korea This study introduces the Clinical practice guidelines (CPGs) appraisal system by the Korean Academy of Medical Sciences (KAMS). Quality management policies for CPGs vary among different countries, which have their own cultures and health care systems. However, supporting developers in guideline development and appraisals using standardized tools are common practices. KAMS, an organization representing the various medical societies of Korea, has been striving to establish a quality management system for CPGs, and has established a CPGs quality management system that reflects the characteristics of the Korean healthcare environment and the needs of its users. KAMS created a foundation for the development of CPGs, set up an independent appraisal organization, enacted regulations related to the appraisals, and trained appraisers. These efforts could enhance the ability of each individual medical society to develop CPGs, to increase the quality of the CPGs, and to ultimately improve the quality of the information available to decisionmakers. # Introduction Clinical practice guidelines (CPGs) are used to improve the quality of care by providing scientific information that can inform decision-makers [bib_ref] The impact of clinical practice guidelines and clinical trials on treatment decisions, Darling [/bib_ref]. In terms of several notable characteristics, quality management policies vary among different countries [bib_ref] Clinical guidelines in the European Union: mapping the regulatory basis, development, quality..., Legido-Quigley [/bib_ref] , which have their own cultures and health care systems; CPGs management methods also vary accordingly. In Korea, over 100 CPGs have been developed in the past decade, with more than 70 CPGs currently in development [bib_ref] Current status of development of clinical practice guidelies in Korea and application..., Jo [/bib_ref]. Futhermore, Korean-specific appraisal tools have also been introduced [bib_ref] Developing a scoring guide for the Appraisal of Guidelines for Research and..., Lee [/bib_ref]. However, the development of these CPGs is disparate, and development competency remains insufficient [bib_ref] Development and implementation of clinical practice guidelines: current status in Korea, Ahn [/bib_ref]. Unfortunately, there have been no discussions on the governance of CPGs at the early stages; as a result, CPG quality management policies are minimal and differ according to the organizations developing the CPGs. In the case of the Korean government, the majority of their focus has been on financial support, but this has not been based on a long-term, detailed plan. Furthermore, different departments within the government support different developers. Guidelines have been developed by only a few research groups or academics working individually, such that an interdisciplinary approach is lacking. Moreover, support is not provided after development, and appraisals or implementation strategies are not taken into consideration. As a result, low-quality CPGs and significant variations in their quality represent a serious problem [bib_ref] Development and implementation of clinical practice guidelines: current status in Korea, Ahn [/bib_ref]. To address this situation, the Korean Academy of Medical Sciences (KAMS), an organization representing medical science in Korea, has been striving to establish quality control systems and is working in collaboration with the government to create policies that ensure the quality of CPGs. CPG development is now a priority; the situation has reached a point in Korea whereby systematic CPG quality management policies can To identify future directions in CPG quality management policies in Korea, this study describes the CPG quality management systems used in Western countries, and introduces the appraisal system of the KAMS, an organization that provides the main policies that provide CPG quality control in Korea. ## Special article ## Cpgs quality contrtol systems in korea and other countries Countries that have actively introduced CPGs have established unique systems that enable the organization and step-by-step management of the development, distribution, evaluation of CPGs as well as the implementation phases for quality control. Furthermore, they manage the whole process in accordance with the cooperation of both public and private organizations; cooperation with the public and private sectors is achieved at a higher administrative level. For such collaborative development of CPGs to address national diseases, building consensuses for various forms of cooperation between countries have been achieved concerning the legal status of CPGs [fig_ref] Table 1: Main body and activities of CPGs quality control in Korea and other... [/fig_ref]. Among quality control agencies, the relevant public organizations include the National Institute for Health and Care Excellence (NICE) in the UK, the National Health and Medical Research Council (NHMRC) in Australia, and the Agency for Healthcare Research and Quality (AHRQ) in the US. These bodies are responsible for policies on healthcare quality management, which include CPGs (9,10). The private sector for CPG quality control is represented by the following organizations: the Canadian Medical Association (CMA), the Association of the Scientific Medical Societies in Germany (AW MF), and the German Agency for Quality in Medicine (AZQ). In Canada, the CMA has led CPG quality management activities, including development strategies and the application and implementation of guidelines [bib_ref] What is the quality of drug therapy clinical practice guidelines in Canada?, Graham [/bib_ref]. The AWMF is responsible for the development of CPGs and for the provision of professional training, whereas the AZQ focuses on quality assurance activities such as effective implementation and CPG quality management programs [bib_ref] Reflections on 20 years of clinical practice guideline programmes in Germany: what..., Nothacker [/bib_ref]. However, public and private cooperation is prevalent in the development of CPGs for high-burden chronic diseases and in quality control in Germany [bib_ref] The German program for disease management guidelines. Background, methods, and development process, Ollenschläger [/bib_ref]. In Korea, KA MS has carried out activities concerned with CPG quality control in Korea. To achieve this, KAMS has established a CPG committee that supports the development and dissemination of CPGs. In particular, KAMS has studied the scientific methodology underlying the development of CPGs, including Korean-specific appraisal tools, scoring guides, etc. Moreover, it has enhanced the capabilities of developers by educating them on the development of CPGs. With respect to the government, the level of cooperation has increased to include CPG topic selection rather than just merely initial financial support. In the majority of countries, appraisals have commonly been done using standardized tools to improve the quality of the development process. However, CPG accreditation processes vary among countries. Both the US and Canada require checklists to develop CPGs, in addition to periodic updates after guideline registration . Germany also considers each criterion separately during the development and registration of CPGs, and assigns a rating based on the degree of development. In contrast, the UK has a management process involving strict regulatory and certification procedures. To accredit CPGs, Accreditation Advisory Committee meetings are held, with CPGs certi- fied in accordance with regular evaluation procedures. NICE introduces all CPGs that are registered on the National Health Service, but the Accreditation Advisory Committee introduces only those guidelines that have obtained final accreditation. Australia also has a CPG accreditation process, which involves eight recommendations with respect to the legal implications of guidelines pertaining to early breast cancer (18). In accordance with the CPG development process suggested by the NHMRC, these recommendations were then included at an institutional level [bib_ref] Clinical practice guidelines before the law: sword or shield?, Pelly [/bib_ref]. When it comes to the dissemination of CPGs, almost all countries operate on-line databases for the distribution of CPGs. Clearing houses in the US and Canada verify the requirements for CPGs upon guideline registration, and play a key role in evaluating their quality. In Korea, the Korean Medical Guideline Information center (KOMGI) -a CPG portal -also plays an important role in dissemination and quality assessment. However, strategies and activities concerning the implementation of CPGs are insufficient with respect to the active development and dissemination of CPGs. Countries have attempted to improve their level of CPG use, but establishing effective strategies is difficult because influential factors and health environments vary among countries [bib_ref] A comprehensive model of factors affecting adoption of clinical practice guidelines in..., Kim [/bib_ref]. The proportion of CPGs implemented in Korea reportedly remains at 30%-50% [bib_ref] Experiences and barriers to implementation of clinical practice guideline for depression in..., Yang [/bib_ref]. ## Korean cpg quality control: the kams system ## Establishment of a quality management organization In Korea, KAMS, the main quality management body, has been engaged in efforts to contribute to the development of evidence based medicine (EBM). Since 2006, KAMS has implemented new offices dedicated to CPGs, and has also operated both CPG and Executive committees. The CPG committee, composed of individuals drawn from 26 specialized academy societies, promotes dissemination activities (through networks that exist between societies) and development projects (by cooperating with societies). The Executive Committee facilitates these practices by developing CPG-related systems and methodologies and by promoting direct training pertaining to guideline quality management. These activities have led to the development of management quality policies and a quality appraisal system, which have in turn enabled higher-quality CPGs . Establishment of the quality appraisal system CPG quality appraisal involves the assessment of development processes rather than guideline contents, so that the most-reliable information and recommendations are provided to guideline users [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref]. In Korea, the demands are higher for the appraisal and quality control of CPGs led by expert groups. Through several studies done on policies aimed at developing quality evaluation tools and on building a quality management system, KAMS developed a quality appraisal model reflecting the characteristics of the Korean health care system, and then collected opinions from other societies through two public hearings. As a result, in April 2013, regulations for CPG appraisal were established in accordance with the principles of independence, transparency, objectiveness and timeliness. Furthermore, procedures and methods related to quality appraisal were organized such that the Executive Committee and a research agency independently evaluate the CPGs [fig_ref] Table 2: Establishment activities for quality amanagement system of CPGs by KAMS [/fig_ref]. ## Manpower training for quality appraisal To appraise CPGs, an Evaluative committee was established consisting of the Executive Committee members, clinical specialists recommended by the various societies, and external experts. Appraisers were able to provide professional-quality evaluations and CPG appraisal following completion of the KAMS education program. To date, 58 appraisers have been trained and participated in these quality appraisal activities. ## Quality appraisal process The quality appraisal of CPGs starts with requests from guideline developers to KAMS. Following registration of a formal request of a developer, the Executive Committee appoints four KAMS appraisers with professional interests relevant to the guideline in question. These appraisers are forwarded the appraisal request and information on the guideline, and evaluate the CPG using the Korean AGREE II Scoring Guide document, which improves the reliability of the AGREE II tool [bib_ref] Improving the reliability of clinical practice guideline appraisals: effects of the Korean..., Oh [/bib_ref]. Appraisers evaluate the CPG for 2 weeks, and submit the results of their appraisal, including their opinions on whether the guideline should be used, to the Executive Committee. The Executive Committee then determines whether KAMS recommends use of the CPG, based on the results of the appraisals, and informs the developers of their final decision. If there is no objection from the guideline developers, the decision of the Committee is finalized, and remains in effect for 5 yr. If there is an objection from the developer, the Executive Committee appoints four new appraisers, who re-appraise the CPG, in terms of whether it should be used, before making a final decision. The whole process from the request of a developer to the appraisal by the appointed appraisers and final notification of the appraisal results is conducted using the on-line portal KoMGI [fig_ref] Figure 2: CPGs appraisal processs by KAMS [/fig_ref]. # Conclusion The goals of CPG quality management are to improve the quality of the development process, to provide fair and reliable eval-uation recommendations, and to ensure evidence-based decision-making during patient care and management. US and Europe share common features in their quality management policies on CPGs with which to appraise the development process by using standardized tools and disseminating qualified CPGs through clearinghouses. Besides, to ensure professionalism and objectivity, and to manage quality on a continuous basis, appraisal by an independent organization of experts is guaranteed [bib_ref] The Clinical Practice Guideline Initiative: A joint collaboration designed to improve the..., Bussières [/bib_ref]. Following the introduction of EBM, the requirement for specialized agencies to support the development of CPGs, and to evaluate developed guidelines, has increased in Korea. KAMS, as a professional body representing the medical community, carries influence regarding the development and management of CPGs; it has established foundations for the assessment of CPGs, including the development of Korean-specific quality appraisal tools. KAMS has also set up an independent appraisal organization (the Executive Committee), established regulations related to appraisals, and improved the evaluation system for CPG quality (which is appropriate to the Korean health care environment). The Executive Committee appraises CPGs and gives accreditation only to those with high quality, which motivates the various societies to manage quality continuously. KAMS has trained staff to conduct appraisals in accordance with the participation of medical academies, to which it assigns appraisals, thereby enhancing the ability of each society to develop CPGs and increasing the quality of CPGs. KAMS has established a CPG quality management system that reflects the characteristics of the Korean healthcare environment and the needs of its users. In particular, CPG quality appraisals assess their independence and the scientific methodologies used during the development process, and provide users with the most reliable guidelines and recommendations. This could improve the quality of information available to decision-makers and thus ultimately enhance EBM in practice. # Disclosure The authors have no conflicts of interest regarding the material presented here. # Author contribution [fig] Figure 2: CPGs appraisal processs by KAMS. [/fig] [table] Table 1: Main body and activities of CPGs quality control in Korea and other countries KAMS, Korean Academy of Medical Sciences; NICE, National Institute for Health and Care Excellence; AHRQ, Agency for Healthcare Research and Quality; NHMRC, National Health and Medical Research Council; CMA, Canadian Medical Association; AZQ, German Agency for Quality in Medicine; AWMF, Association of the Scientific Medical Societies in Germany; KoMGI, Korean Medical Guideline Information center; NGC, National Guideline Clearinghouse. [/table] [table] Table 2: Establishment activities for quality amanagement system of CPGs by KAMS [/table]	None	None	This study introduces the Clinical practice guidelines (CPGs) appraisal system by the Korean Academy of Medical Sciences (KAMS). Quality management policies for CPGs vary among different countries, which have their own cultures and health care systems. However, supporting developers in guideline development and appraisals using standardized tools are common practices. KAMS, an organization representing the various medical societies of Korea, has been striving to establish a quality management system for CPGs, and has established a CPGs quality management system that reflects the characteristics of the Korean healthcare environment and the needs of its users. KAMS created a foundation for the development of CPGs, set up an independent appraisal organization, enacted regulations related to the appraisals, and trained appraisers. These efforts could enhance the ability of each individual medical society to develop CPGs, to increase the quality of the CPGs, and to ultimately improve the quality of the information available to decision-makers.
82c33ce92991db13577b9cd5640bacad069fb1d6	pubmed	Korean Clinical Practice Guidelines: Otitis Media in Children	Korean Clinical Practice Guidelines: Otitis Media in Children Acute otitis media (AOM) and otitis media with effusion (OME) are common infections in children, and their diagnosis and treatment have significant impacts on the health of children and the costs of providing national medical care. In 2009, the Korean Otologic Society organized a committee composed of experts in the field of otolaryngology, pediatrics, and family medicine to develop Korean clinical practice guidelines (CPG) for otitis media in children with the goal of meeting regional medical and social needs in Korea. For this purpose, the committee adapted existing guidelines. A comprehensive literature review was carried out primarily from 2004 to 2009 using medical search engines including data from Korea. A draft was written after a national questionnaire survey and several public audits, and it was editorially supervised by senior advisors before publication of the final report. These evidence-based guidelines for the management of otitis media in children provide recommendations to primary practitioners for the diagnosis and treatment of children younger than 15 yr old with uncomplicated AOM and OME. The guidelines include recommendations regarding diagnosis, treatment options, prevention and parent education, medical records, referral, and complementary/alternative medicine for treating pediatric otitis media. # Introduction Acute otitis media (AOM) and otitis media with effusion (OME) are highly prevalent in the pediatric population and represent major disease burdens worldwide. Following the Korea National Health Survey performed in 2009, otitis media (OM) was ranked as the seventh most frequent disease responsible for hospital visits among patients younger than 18 yr old. AOM is a very common disease in children younger than 3 yr old. Two of three children experience AOM once, and about one in three children could have more than three episodes of AOM. The prevalence of AOM in Korea has not been reported, although previous studies have revealed AOM incidence rates of 62% and 83% in children under 1 and 3 yr old, respectively [bib_ref] Otitis media with effusion in infants and children. Primary care concerns addressed..., Terris [/bib_ref]. The incidence rate differs according to age; the incidence is low in the neonatal period but rises markedly after 6 months old, peaking at around 2 yr old, with another slightly lower peak from 4 to 7 yr old. Despite its considerable economic impact, there have been no prospective studies regarding the incidence of AOM in Korea. According to the 2008 statistics of the Health Insurance Review and Assessment Service, the yearly cost of AOM was 140 billion Won, which is 9.3% that of acute respiratory tract infections. Following a nationwide survey of Korean children under 15 yr old, the prevalence rates of AOM and OME were reported to be 0.08% and 1.22%, respectively [bib_ref] Prevalence of otitis media and allied diseases in Korea-results of a nation-wide..., Kim [/bib_ref]. The prevalence of OME in Korean kindergarten children has been reported as 10.8-16.4% [bib_ref] Prevalence of silent otitis media with effusion in preschool children in Kunsan..., Yeom [/bib_ref] [bib_ref] The prevalence of otitis media with effusion among kindergarten and elementary school..., Pyo [/bib_ref] [bib_ref] The point prevalence of otitis media with effusion among kindergarten and elementary..., Chae [/bib_ref] [bib_ref] A prevalence study of otitis media with effusion in kindergarten children in..., Chang [/bib_ref]. Two of these studies reported that 90% of affected children did not display subjective symptoms [bib_ref] The point prevalence of otitis media with effusion among kindergarten and elementary..., Chae [/bib_ref]. OME also has major medical, social, and economic consequences. The dishttp://dx.doi.org/10.3346/jkms.2012. ease course typically takes months and may occur repeatedly during childhood, when functional maturation of the Eustachian tube is incomplete. Furthermore, it can cause hearing loss, which may delay language/speech acquisition and cognitive development in the affected child. It can also cause permanent changes in the tympanic membrane, such as cholesteatoma, which can be prevented through a relatively simple surgical intervention. OME also has a marked adverse effect on the quality of life of the affected children and their families [bib_ref] Effect of ventilation tube insertion on the quality of life, Kim [/bib_ref]. Considering the high prevalence and societal significance of AOM and OME in children, evidence-based guidelines for OM in the pediatric population have been developed in many countries and continue to be updated to reflect new evidence and changing social circumstances [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref] [bib_ref] Acute otitis media: from diagnosis to prevention. summary of the Italian guideline, Marchisio [/bib_ref]. As medical decisions should be based on the balance between risk and benefit based on existing evidence, national guidelines should reflect evidence from the particular region, and careful modification may be necessary considering the availability of medical facilities and social costs applied in each particular country. The development of Korean clinical practice guidelines for pediatric OM is necessary and important for several reasons. First, the microbiology and antibiotic resistance of AOM in Korea differ from cases reported in other countries [bib_ref] Emergence of macrolide resistance and clinical use of macrolide antimicrobials in children, Choi [/bib_ref]. Second, the need for nationally based guidelines became apparent with the publication of the 2004 clinical practice guidelines in the USA [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref]. Third, a 2010 Korean survey of otolaryngologists concerning the treatment of childhood OM revealed 90% agreement among respondents on the need for Korea-based clinical practice guidelines for pediatric OM. Thus, the Korean Society of Otology launched a committee in 2009 tasked with the development of Korean clinical practice guidelines for pediatric AOM and OME. The committee developed a set of guidelines for the diagnosis and treatment of OM in children, grounded in evidence-based studies, with the intent of implementation in actual clinical practice. This paper reports the core recommendations of the Korean clinical practice guidelines for pediatric AOM and OME with brief commentary. Algorithms for the diagnosis and treatment of pediatric AOM and OME are shown in [fig_ref] Figure 2: Algorithm for management of pediatric otitis media with effusion [/fig_ref]. The full version of the guidelines, in Korean, and full references, are available at the website of the Korean Medical Guideline Information Center (KMGIC) (http://www.guideline.or.kr/guideline/ guide/contents.php?number = 45&F_sid = 974). ## Development of the guidelines The Korean Society of Otology launched a committee to develop clinical practice guidelines for pediatric OM in May 2009. The multidisciplinary committee consisted of seven members from the Korean Society of Otology and two members each recommended by the Korean Society of Pediatrics and the Korean Society of Family Medicine. The development team adapted the 2004 AOM guidelines of the American Academy of Pediatrics (AAP), 2004 OME guidelines of the American Academy of Otolaryngology-Head and Neck Surgery (AAO), and the 2008 OME surgical guidelines of the National Institute for Health and Clinical Excellence (NICE) as optimal models. The guideline development subcommittee conducted a nationwide survey among otolaryngologists in August 2009 to collect public opinion and investigate the current trends in clinical practice for pediatric OM in Korea as part of the guideline development project. During the development period, the process and preliminary recommendations were presented several times at scientific meetings and public hearings. For 2 months starting in August 2009, three researchers individually searched resources from 2004 to 2009 using the keywords "acute otitis media, " "pathogen, " "otitis media with effusion, " "ventilation tube, " and "antibiotics" using PubMed, Cochrane database, EBSCO, and KoreaMed search engines. Additionally, systematic reviews and references of meta-analyses were also collected. The above-mentioned existing guidelines and 2009 Japanese guidelines for pediatric AOM were reviewed and analyzed. The literature search included systematic reviews, existing guidelines, randomized controlled trials, and other types of original papers on clinical issues, with additional material identified manually by subcommittee members. The search covered materials published in English and Korean. The collected evidence was reviewed and assessed using a grading system from Level I (well-designed randomized, controlled trials or meta-analyses) to Level IV (expert opinion, animal studies, in vitro research). The evidence level was downgraded when the study seemed to be biased or the evidence quality was not sufficiently strong to enable generalization of the findings. The recommendations in the guidelines are based on the best available published data identified by the committee members. Where qualified evidence was lacking, an expert consensus based on clinical experience was used. Each recommendation statement was graded using a modified system based on that used in the 2004 American Academy of Pediatrics guidelines for AOM, which consisted of four levels considering the quality of supporting evidence and clinical significance [fig_ref] Table 1: Definitions and implications of the recommendation grades [/fig_ref]. According to this system, variability in clinical practice is expected to be less with a strong recommendation than that with a recommendation. Options provide the best chances for practice variability. The final draft guidelines underwent an external review by five otology experts based in both university and private clinics and two methodologists from the KMGIC. ## Objectives ## Guidelines for aom in children The practice guidelines are for children under 15 yr old, including those under 6 months of age without other underlying diseases or any complications caused by AOM. Those in whom AOM complications were expected (i.e., Down's syndrome, craniofacial anomalies, including cleft palate, and those with immunodeficiencies, cochlear implant patients, patients with AOM that recurred within 30 days, AOM occurrence in a diseased state, or recurrent OM) were excluded; individual management is mandated for such patients. ## Guidelines for ome in children The clinical practice guidelines are intended to provide evidencebased recommendations to support clinical decisions regarding diagnosis, treatment, and prevention of OME in otherwise healthy Korean children under 15 yr old. Application of these guidelines may be inappropriate for children simultaneously suffering from other co-existing disease(s) or at risk of complication associated with OM. An individualized approach to managing every problem in a comprehensive manner would be preferred in such cases. ## Scope of the guidelines Intended users of these guidelines include all physicians in Korea who care for children with AOM and OME, including otolaryngology, pediatrics, and family medicine specialists. The guidelines are not intended as the sole source for managing children with AOM and OME, but have been designed to assist physicians by providing current evidence regarding OM in children. Clinical findings and environmental factors of each child should be taken into consideration first, and clinical decisions made based on the individual experience of the physician may be more appropriate in certain situations. These guidelines do not provide any considerations for administrative matters or legal issues. ## Implementation of the guidelines for aom in children ## Diagnosis of aom Diagnosis of AOM is made based upon subjective symptoms and objective signs. Subjective symptoms refer to 1) acute onset and 2) middle ear or systemic symptoms due to acute inflammation. Objective signs include 1) tympanic membrane findings, including bulging, bullae, hyperemia, perforation with otorrhea, middle ear effusion (MEE), etc., and 2) tympanometry showing type B or C or identification of MEE via tympanocentesis. "Definite diagnosis" requires both of the subjective symptoms and one or more objective signs; "suspicious diagnosis" is defined as fulfilling all of the subjective symptoms but none of the objective signs (Recommendation grade: A). The definition of "acute" in the diagnosis of AOM involves abrupt onset of inflammatory symptoms, which are clinically evident within 48 hr and no longer than 3 weeks from onset. In Japan, Harabuchi et al. [bib_ref] Outcome of acute otitis media and its relation to clinical features and..., Harabuchi [/bib_ref] defined AOM as acute onset infection of the middle ear with otalgia, fever, and otorrhea, where "acute" is defined as symptoms identified by the child or a parent/caregiver, with medical examination within 48 hr. The diagnosis of AOM is based on an abrupt onset of otalgia and fever with fluid in the middle ear (tympanic membrane bulging, decreased or absent tympanic membrane mobility, fluid level behind the tympanic membrane, or acute otorrhea) and an erythematous membrane. Local middle ear symptoms due to acute inflammation include otalgia and otorrhea, and systemic symptoms include crying, irritability, fever, and other physical symptoms due to the affected ear [fig_ref] Table 2: Diagnostic criteria for acute otitis media in children in Korea TM findings [/fig_ref]. Younger age and tympanic membrane findings are highly correlated with severity, and there may be no improvement in the tympanic membrane even though systemic symptoms may have disappeared [bib_ref] Factors associated with clinical outcomes in acute otitis media, Hotomi [/bib_ref] [bib_ref] Treatment and outcome of severe and non-severe acute otitis media, Hotomi [/bib_ref]. In these guidelines, "severe" AOM is defined as severe otalgia or irritability lasting longer than 24 hr or when fever exceeds 38.5°C . In a previous study performed in Korea, the tympanic membrane temperature of children suffering from unilateral acute suppurative otitis media was reported as 37.1°C-38.5°C (mean 37.92°C), and in most cases, ear temperature did not exceed 38°C [bib_ref] Clinical usefulness of temperature of tympanic membrane in diagnosisg unilateral acute suppurative..., Jang [/bib_ref]. Based on these results, "severe" AOM is defined in Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present. ## B: recommendation The benefits of the recommended intervention exceed the harm, but the quality of evidence is not as strong. Clinicians would be prudent to follow a recommendation, but should remain alert to new information and sensitive to patient preferences. C: Option The quality of evidence that exists is suspicious, or well-done studies show little clear advantage. Clinicians should consider the option in their decision-making, and patient preference may play a substantial role. ## D: no recommendation As pertinent published evidence is lacking, the anticipated balance of benefits and harm is unclear. Clinicians should be alert to new published evidence that clarifies the balance of benefit vs harm. the guidelines as fever over 38.5°C, but the development team agreed that additional research is needed to clarify this issue. The age of the patient should also be considered as an important factor to determine treatment options. In children younger than 2 yr of age, Eustachian tube dysfunction and middle ear abnormalities, measured by tympanometry, during upper respiratory tract infections have been reported to be more severe compared with those in older children [bib_ref] Tympanometric findings in young children during upper respiratory tract infections with and..., Revai [/bib_ref]. Among Korean children with type B tympanogram at diagnosis, those older than 4 yr old showed significantly better prognosis than those under 4 yr old (23) . . Indications for administering antibiotics initially without conservative therapy in pediatric acute otitis media 1) "Severe" AOM* 2) Age younger than 6 months 3) 6-24 months old with definite diagnosis of AOM 4) Recent use of antibiotics 5) Presence of co-morbidities, such as tonsillitis, which require administration of antibiotics 6) Patients incapable of clinical follow-up after 2-3 days 7) Patients who had already undergone clinical monitoring for 2-3 days Severe otalgia or irritability lasting longer than 24 hr or fever higher than 38.5°C. AOM, acute otitis media. ## Observation policy The "observation policy" as initial management of AOM refers to watchful waiting for natural improvement for 48 to 72 hr without use of antibacterial agents (Recommendation grade: A). This policy does not imply neglecting the patient without any treatment. Rather, acute symptoms such as otalgia and fever should be managed. The observation policy should include a follow-up visit after 2-3 days and a decision concerning subsequent treatment options; if symptoms continue, antibiotic therapy should be considered, and a follow-up appointment within 2-3 days should be made. Rosenfeld and Kay (24) also reported "observation" as a treatment option. However, in cases of 1) age under 6 months, 2) definite diagnosis of AOM in a patient under 24 months old, 3) severe AOM, 4) accompanying disease, such as tonsillitis, requiring administration of antibiotics, 5) inability to follow up after 48-72 hr, and 6) recent antibiotic use, the "observation policy" is inappropriate for initial treatment . This option without antibacterial treatment should be limited to cases such as 1) non-severe illness, 2) mild cases in patients older than 6 months old or suspected diagnosis for those 6-24 months old, and 3) considering other patient factors (no recent history of taking antibiotics, no other accompanying disease, capability of clinical follow-up after 2-3 days) (25). During conservative therapy without antibiotics for 2-3 days, antiinflammatory agents such as acetaminophen (10-15 mg/kg per dose every 4-6 hr, maximum of five times daily, no more than 75 mg/ kg daily) or ibuprofen (5-10 mg/kg per dose every 6-8 hr, maximum of 40 mg/kg/day) are prescribed for mild otalgia and fever. Gastrointestinal distress induced by analgesics can be reduced if they are taken simultaneously with food. In cases managed with conservative therapy, a follow-up visit or telephone contact with the clinician within 48-72 hr is necessary; if this is not possible, antibiotics can be prescribed in advance [bib_ref] Treatment of otitis media with observation and a safety-net antibiotic prescription, Siegel [/bib_ref]. Tympanocentesis can be performed to relieve severe otalgia when the patient is cooperative, and Gram staining, microbial culture, and antibacterial agent sensitivity studies in these cases can be useful in selecting antibiotics for use in the event of treatment failure [bib_ref] Bequignon A. Failure of antibiotic therapy in acute otitis media, Babin [/bib_ref]. AOM guidelines published in other countries suggest that watchful waiting with symptomatic treatment only constitutes an appropriate treatment option for children with non-severe AOM [bib_ref] Acute otitis media: from diagnosis to prevention. summary of the Italian guideline, Marchisio [/bib_ref]. This observation policy could significantly reduce the carriage of multidrug-resistant organisms and the costs of AOM care. However, parent education is essential for this observation approach to AOM treatment to be successful because many parents expect antibiotics when their child is diagnosed with AOM. Clinicians should also make a correct diagnosis and explain the policy of AOM observation to parents. Both American and Japanese guidelines emphasize the conservative management of otalgia, with consideration of antibiotic administration by age and symptom severity, and recommended observation with conservative management for older children and mild cases [bib_ref] Antibiotics for acute otitis media in children, Glasziou [/bib_ref]. In 2006, Spiro et al. [bib_ref] Waitand-see prescription for the treatment of acute otitis media: a randomized controlled..., Spiro [/bib_ref] conducted a randomized controlled trial of 283 children with AOM, in which patients were randomized into either the WASP group ("wait-and-see prescription" for antibiotics, in which parents were asked not to fill the prescription unless the child either showed no improvement or worsened in 48 hr) or the SP group (standard prescription, antibiotics administered initially). Substantially more parents in the WASP group did not fill the antibiotic prescription (62% vs 13%; P < 0.001). There were no statistically significant differences between the groups in the frequencies of subsequent fever, otalgia, or unscheduled visits for medical care. The WASP approach substantially reduced unnecessary use of antibiotics in children with AOM and may be an alternative to routine use of antimicrobials for treatment of such cases [bib_ref] Bequignon A. Failure of antibiotic therapy in acute otitis media, Babin [/bib_ref] [bib_ref] Waitand-see prescription for the treatment of acute otitis media: a randomized controlled..., Spiro [/bib_ref]. In a randomized controlled trial, there were no statistically significant differences in otalgia or fever between groups with and without antibiotic prescription [bib_ref] The concept and practice of a wait-and-see approach to acute otitis media, Spiro [/bib_ref]. [fig_ref] Table 4: Recommended antibacterial agents for pediatric acute otitis media Antibiotic prescription and change... [/fig_ref] We recommend high-dose amoxicillin (80-90 mg/kg/day) as the first-line antibiotic (Recommendation grade: A). However, if the patient is older than 24 months with no recent antibiotic administration and has not been to a childcare facility, the standard dose of amoxicillin (40-50 mg/kg/day) is recommended as the first-line antibiotic. For severe AOM, high-dose amoxicillin/ clavulanate (14:1) (80-90/6.4 mg/kg/day) is recommended as the first-line antibiotic, considering the possibility of βlactamaseproducing Haemophilus influenzae, Moraxella catarrhalis, and penicillin-resistant pneumococci as the causative organisms (11) (Recommendation grade: A). ## First-line antibiotic therapy As the first-line antibiotic therapy, oral high-dose amoxicillin (80-90 mg/kg/day) and oral amoxicillin/clavulanate (14:1) 80-90/6.4 mg/kg/day for severe cases are recommended in the 2004 AAP guidelines and other large-scale, randomized controlled studies [bib_ref] Effect of amoxicillin and co-amoxiclav on the aerobic and anaerobic nasopharyngeal flora, Brook [/bib_ref]. However, the amoxicillin/clavulanate 14:1 formula is not available in Korea, and therefore amoxicillin can be added to available amoxicillin/clavulanate to boost the amoxicillin dose to 80-90 mg/kg. For example, in cases where amoxicillin/clavulanate 7:1 formula is used, amoxicillin/clavulanate 40-50/6.4 mg/kg/day dosage plus amoxicillin 40 mg/kg/day can be administered. In cases with amoxicillin/clavulanate 4:1 formula, amoxicillin/clavulanate 23/5.75 mg/kg/day plus amoxicillin 57 mg/kg/day should be prescribed. When prescribing amoxicillin/clavulanate, the clavulanate dosage should not exceed 10 mg/kg/day because the frequency of diarrhea may increase at higher doses [bib_ref] Antibiotics therapy of respiratory infection in outpatients department, Park [/bib_ref] [bib_ref] Diagnostic inaccuracy and subject exclusions render placebo and observational studies of acute..., Pichichero [/bib_ref]. Indications for exceptional administration of antibiotics initially without an observation period were mentioned above . Alternative drugs are recommended for children with a history of type I hypersensitivity reaction to penicillins (e.g., urticaria, anaphylaxis), including macrolides. For non-type I hypersensitivity reactions, cephalosporins are recommended as the first-line antibiotics. The standard antibiotic administration period is 10 days for moderate and severe cases, but 5-7 days is possible in mild cases with close observation of the antibiotic response and disease progression recommended after 2-3 days of antibiotic use [bib_ref] Shortened course of antibacterial therapy for acute otitis media, Ovetchkine [/bib_ref]. These recommendations for the first-line antibiotics are supported by previous studies on antimicrobial susceptibility of pathogenic bacteria in Korea. In a study in pediatric patients with community-acquired respiratory infections due to Streptococcus pneumoniae in Korea, standard-dose aminopenicillin treatment did not result in different outcomes between susceptible and resistant groups. However, in a recent study using a pharmacodynamics model, high-dose oral amoxicillin was predicted to be effective against 82.6% of S. pneumoniae isolates from healthy Korean children, whereas the standard-dose regimen was effective in only 30.4% of cases [bib_ref] Antibiotics susceptability of Streptococcus pneumoniae isolated from pharynx in healthy Korean children..., Paik [/bib_ref]. In randomized controlled trials performed in the USA comparing the effects of amoxicillin/clavulanate and azithromycin on nasopharyngeal bacterial carriage in children with AOM, significant decreases in carriage of S. pneumoniae and H. influenzae were observed in both groups, but the effects were more pronounced in the amoxicillin/clavulanate treatment group [bib_ref] Effects of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae and..., Ghaffar [/bib_ref] [bib_ref] Effects of large dosages of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of..., Ghaffar [/bib_ref]. In 2008, a study investigating macrolide use in Korea showed that the clinical use of macrolides led to the emergence of bacterial resistance, and especially azithromycin, which has a longer half-life, was closely related to the emergence of resistance to other macrolide antibiotics. As S. pneumoniae isolated from Korean children also showed rapid increases in macrolide resistance, careful consideration is required when choosing antibiotics for treating AOM in children [bib_ref] Emergence of macrolide resistance and clinical use of macrolide antimicrobials in children, Choi [/bib_ref]. In a 2011 study, susceptibility to erythromycin was reported as 4.3% among S. pneu-moniae isolates from healthy Korean children [bib_ref] Antibiotics susceptability of Streptococcus pneumoniae isolated from pharynx in healthy Korean children..., Paik [/bib_ref]. The routine use of other medications, such as antihistamines and decongestants, for treating AOM in children was shown to lack clinical benefits in a recent Cochrane review [bib_ref] Decongestants and antihistamines for acute otitis media in children, Coleman [/bib_ref]. [fig_ref] Table 4: Recommended antibacterial agents for pediatric acute otitis media Antibiotic prescription and change... [/fig_ref] We recommend oral amoxicillin/clavulanate (14:1) 80-90/6.4 mg/kg/day as second-line antibiotic therapy. In cases in which second-line antibiotic therapy fails, parenteral administration of 50 mg/kg/day of ceftriaxone for 3 days is recommended as third-line antibiotic therapy (Recommendation grade: A). However, when the results of the antibacterial agent sensitivity test are available, the most appropriate type of antibiotic can be chosen at any time after obtaining the result (Recommendation grade: B). ## Second-and third-line antibiotic therapy Antibiotic treatment failure refers to a lack of improvement in symptoms, including otalgia, fever, and otorrhea, after 48-72 hr of antibiotic administration. Persistent symptoms, including rhinorrhea, cough, or OME, should not be regarded as treatment failure. Infection with organisms resistant to the first-line antibiotics, viral infection alone, or simultaneous infection can be considered as causes of treatment failure. OME occurs after AOM in 50% of patients regardless of treatment period and initial antibiotic selection. OME was reported to persist in 60%-70% of patients after 2 weeks of AOM, 40% after 1 month, and 10%-25% after 3 months. It should not be considered as a complication of AOM, and only observation of disease progression is needed. In these cases of persistent OME, continuous follow-up is required due to bacteriological persistence and the possibility of recurrence, even if symptomatic improvement occurs [bib_ref] Persistence of pathogens despite clinical improvement in antibiotic-treated acute otitis media is..., Asher [/bib_ref] [bib_ref] Seasonality of antibiotic-resistant Streptococcus pneumoniae that causes acute otitis media: a clue..., Dagan [/bib_ref]. Second-line antibiotics are used if no symptomatic improvement is seen after first-line antibiotic administration for 48-72 hr, and third-line antibiotics after failure of second-line antibiotics to elicit an improvement in the patient's condition. In the case of antibiotic treatment failure, tympanocentesis for microbial culture with an antibacterial agent sensitivity test should be performed. These procedures and changes in antibiotic can be performed at any time as necessary, but it is best for this to be done before commencement of antibiotic treatment because of the increased possibility of negative bacterial culture results after antibiotic administration. Methods to acquire samples for bacterial culture include tympanocentesis, sampling otorrhea from the external auditory canal with a perforated tympanic membrane, and collecting nasopharyngeal mucus by the transnasal approach. If tolerable, tympanocentesis can relieve otalgia in severe cases, and the procedure can help in the selection of antibiotics by a microbial culture with an antibacterial agent sensitivity test after failure of first-line antibiotic treatment [bib_ref] Bequignon A. Failure of antibiotic therapy in acute otitis media, Babin [/bib_ref]. In cases with symptom persistence after macrolide administration in patients with type I hypersensitivity reaction (e.g., urticaria, anaphylaxis) to penicillins, clindamycin can be used as the second-line antibiotic. In cases of non-type I hypersensitivity reactions, cephalosporins such as cefuroxime, cefprozil, cefpodoxime, cefdinir, and cefditoren can be used as first-line antibiotics, and 3 days of parenteral ceftriaxone can be used if symptoms persist. However, as the resistance rate of S. pneumoniae identified in Korea to new macrolides exceeds 70%, bacterial culture is recommended if the child is cooperative, preferably before the first administration of antibiotics [bib_ref] Antibiotics therapy of respiratory infection in outpatients department, Park [/bib_ref]. Recurrence of disease by the same pathogen was seen in only 28% of cases of recurrent OM after antibiotic treatment. ## Education to prevent aom When examining children diagnosed with AOM, it is recommended that the parent/caregiver be educated concerning the risk factors of AOM to prevent recurrent AOM (Recommendation grade: B). Groups at high risk for recurrent AOM include children attending child care centers, those under 2 yr old, those with a short breast-feeding history, those who use a milk bottle in the supine position or use pacifiers, those with craniofacial anomalies, and those with passive tobacco smoke exposure. In these instances, education of parents/caregivers to decrease the incidence of recurrent AOM is required. Education of parents/caregivers regarding preventable risk factors, such as preventing upper respiratory tract infections at child care centers and kindergartens, recommending breastfeeding for at least the first 6 months of life, avoiding bottle feeding in the supine position, reducing or eliminating pacifier use in the second 6 months of life, and prohibiting smoking by family members, is important. A study analyzing 257 papers indicated that the risk factors for recurrent AOM were use of pacifiers, attendance at daycare facilities, less breastfeeding history, siblings, craniofacial anoma-lies, indirect exposure to cigarette smoke, and adenoid vegetations [bib_ref] Systematic literature review of modifiable risk factors for recurrent acute otitis media..., Neto [/bib_ref]. ## Prevention: pneumococcal conjugate vaccine Injection of pneumococcal conjugate vaccine for prevention of AOM should be decided based on the benefits and risks, the clinician's judgment, and parent's/caregiver's preferences (Recommendation grade: C). However, vaccination is recommended in patients with a high risk of meningitis following AOM, (i.e., children with/expecting a cochlear implant or with congenital inner ear anomalies) (Recommendation grade: A). Vaccinations such as pneumococcal conjugate vaccine reduce the prevalence of AOM [bib_ref] Efficacy of pneumococcal vaccination in children younger than 24 months: a meta-analysis, Pavia [/bib_ref]. In a retrospective study of the changing patterns of antibiotic resistance rates and clinical features in pneumococcal infections in Korea, pneumococcal conjugate vaccination for prevention of multidrug resistance was proposed [bib_ref] Changing patterns of antibiotic-resistant rates and clinical features in pneumococcal infections, Jang [/bib_ref]. In a study performed by Kim et al. [bib_ref] Epidemiological study of pneumococcal nasal carriage and serotypes among Korean children, Kim [/bib_ref] in 2004 in a total of 213 children younger than 5 yr old, the pneumococcal nasopharyngeal carriage rate was 34.3%, and 83.8% of S. pneumoniae isolates were resistant to penicillin. Therefore, the authors advocated introduction of pneumococcal conjugate vaccine in Korea [bib_ref] Changing patterns of antibiotic-resistant rates and clinical features in pneumococcal infections, Jang [/bib_ref] [bib_ref] Epidemiological study of pneumococcal nasal carriage and serotypes among Korean children, Kim [/bib_ref]. After the introduction of the 2008 CLSI (Clinical and Laboratory Standards Institute) standards for antimicrobial susceptibility testing, the ratio of penicillin-susceptible S. pneumoniae changed from 74.7% to 93.2% in the USA. In Korea, penicillin susceptibility of S. pneumoniae has been reported to be 78.3% with the same updated 2008 standards, which suggested a higher resistance rate than in the USA [bib_ref] Antibiotics susceptability of Streptococcus pneumoniae isolated from pharynx in healthy Korean children..., Paik [/bib_ref]. The United States Centers for Disease Control and Prevention recommends pneumococcal conjugate vaccination of patients with a cochlear implant or congenital inner ear anomalies who are at high risk of cerebrospinal fluid leakage because of the elevated risk of bacterial meningitis [bib_ref] Review of randomized controlled trials on pneumococcal vaccination for prevention of otitis..., Straetemans [/bib_ref]. Therefore, our guidelines also recommend pneumococcal conjugate vaccine in patients at high risk of meningitis after AOM due to the presence of a cochlear implant and/or congenital inner ear anomalies. However, in cases without these meningitis risk factors, pneumococcal conjugate vaccine injection in AOM should be decided according to the individual benefits and risks considering the clinician's judgment and parent's/caregiver's preferences because insufficient information is available regarding the cost-effectiveness of vaccination for AOM in Korea. ## Documentation When examining pediatric patients with suspected AOM, the physician should take the patient's history and document the following categories to achieve consistency in future examinations of the individual: 1) onset of AOM symptoms such as otalgia, otorrhea, fever, and irritability; 2) associated symptoms such as rhinorrhea, nasal obstruction, and sore throat; 3) past history of AOM treatment and other diseases; and 4) presence of high- For the accurate diagnosis of AOM, thorough history taking is required, and the onset of symptoms of otalgia, otorrhea, fever, irritability, and the presence and severity of fever should be determined [bib_ref] Factors associated with clinical outcomes in acute otitis media, Hotomi [/bib_ref]. History taking about past AOM treatment history, antibiotic prescription history, associated diseases, and symptoms is necessary to decide on the use of antibiotics. Even in patients with a past history of AOM, high-risk factors of recurrent AOM (attendance at child care center, age less than 2 yr, lack of breastfeeding history, supine bottle feeding or pacifier use, craniofacial anomalies, and indirect exposure to cigarette smoke) should be identified and documented. ## Referral Referral to other medical centers, including higher institutes for further evaluation and surgical treatment, is made by the primary clinician during the course of AOM in the following situations: 1) recurrent AOM; 2) tympanic membrane perforation lasting longer than 6 weeks; 3) mastoiditis or subperiosteal abscess; 4) labyrinthitis; 5) facial palsy; 6) spontaneous nystagmus; 7) central nervous system symptoms such as severe headache, high fever, or vomiting; or 8) suspicion of other intracranial complications. The primary clinician should provide the referral center with basic patient information and can request the results of medical examinations and treatment and also retransfer of the patient (Recommendation grade: B). To diagnose complications of AOM, it is essential to determine the precise medical history over time. First, it is important to determine whether the disease is acute or chronic because the causative agent, medical treatment, and complications differ between these two conditions. History-taking should include details of the last time the patient had a medical examination of the ear, when and how the patient was treated in the event of previous AOM, whether antibiotics were taken for AOM, the time course and severity of present symptoms, and the results of tests, including tympanometry, audiometry, and radiological examinations. Concurrent severe vertigo implies labyrinthitis and the patient's alertness can change over time with intracranial complications. Changes in alertness are also important because alertness rapidly deteriorates within 1-2 days in cases of meningitis, but several weeks after disease onset with a brain tumor. Especially, intracranial complications such as headache, fever, vomiting, neck stiffness, convulsions, or changes in vision and alertness arising with disease progression should be considered in patients with severe otalgia without improvement after adequate treatment [bib_ref] Suppurative complications of acute otitis media: changes in frequency over time, Thorne [/bib_ref]. ## Complementary and alternative medicine No recommendations for complementary and alternative medicine for treatment of AOM are made based on limited supporting data (Recommendation grade: D). Evidence regarding nutritional supplements, herbal medicines, and acupuncture for treatment of AOM is limited by a lack of published studies, so recommendations regarding complementary and alternative medicine cannot yet be made [bib_ref] Complementary ENT": a systematic review of commonly used supplements, Karkos [/bib_ref]. ## Implementation of the guidelines for ome in children Diagnosis of OME OME is defined as the presence of middle ear fluid without acute signs or symptoms. Acute signs and symptoms associated with OM should be identified as absent by history taking and physical examination. The presence of fluid in the middle ear can be determined by physical examination using electric otoscopy, pneumatic otoscopy, otoendoscopy, or otomicroscopy with support of tympanometry (Recommendation grade: A). Each particular modality has advantages and drawbacks. Electric otoscopy is convenient and easy to apply but does not allow bimanual manipulation. Hence, examination of the tympanic membrane is difficult when a substantial amount of cerumen is present. The 2004 AAO guidelines recommended pneumatic otoscopy as the most sensitive tool for diagnosis of OME [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref]. This method enables examination of tympanic membrane mobility, but it has the drawback of being difficult to use. Correct occlusion is mandatory to guarantee a correct diagnosis. The greatest disadvantage of pneumatic otoscopy in Korea is that it is not widely used in primary clinical settings. Otoendoscopy provides a magnified view of the tympanic membrane, but it can induce traumatic injury of the tympanic membrane and the external auditory canal if not applied carefully. More importantly, the color and shape of the image can be distorted depending on the quality of the instruments used, including the endoscope, camera, and monitor. Otomicroscopy has been reported to be the most sensitive and specific approach, but the child's cooperation is necessary for proper examination, and it is not widely used in the primary care setting [bib_ref] How to improve the accuracy of diagnosing otitis media with effusion in..., Lee [/bib_ref] [bib_ref] The accuracy of otomicroscopy for the diagnosis of paediatric middle ear effusions, Young [/bib_ref]. The guidelines recommend applying any of the available methods but taking each of their advantages and disadvantages into consideration. Findings of the tympanic membrane that suggest middle ear fluid include air-fluid level, air bubbles, retraction, atelectasis, hyperemia, and change in color (amber, brownish, dark blue, etc.). Hyperemia of the tympanic membrane may be examined while the child is crying. Tympanometry can assist diagnosis of OME and is very useful when cooperation is lacking. OME can be suggested based on a type B or C tympanogram [fig_ref] Figure 2: Algorithm for management of pediatric otitis media with effusion [/fig_ref]. ## Hearing tests Evaluation of hearing status in affected children is strongly recommended in these guidelines (Recommendation grade: A). Audiometric tests can be performed 1) at the time of diagnosis to measure hearing threshold, 2) any time during the follow-up period when presenting symptoms necessitate confirmation of hearing status, and 3) after a 3-month observation period for treatment planning. The appropriate method according to the developmental age of the particular child should be applied. Generally, recommended tests for measuring hearing threshold for young children are behavioral observation audiometry for children under 6 months old, visual reinforcement audiometry for children 6-24 months old, and play audiometry for children 24-48 months old. Standard pure tone audiometry is usually applicable in children over 4 yr old. When cooperation is insufficient, the threshold of auditory brainstem response or distortion-product otoacoustic emission audiogram may be used to estimate hearing threshold, but cannot replace behavioral measurements. The indications for hearing test recommended in these guidelines are highlighted to a greater extent than in other published guidelines [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref] , a policy that reflects the easier accessibility and lower cost of audiometric tests in Korea than in other countries. With regard to hearing status as one of the most significant factors for medical decisions and parental concern, these guide-lines adopted a positive policy on hearing tests, and so formulated recommendations according to which audiometry can be repeated whenever necessary. ## High-risk group Similar to other published guidelines, patients with medical conditions that warrant prompt and active intervention in OME and related hearing loss were defined as the high-risk group. This was to facilitate individualized intervention to prevent considerable negative impact on the development of language and other cognitive functions [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref]. Criteria to define children at high risk in these guidelines are: 1) sensorineural hearing loss independent of OME; 2) uncorrectable visual impairment; 3) Down's syndrome or craniofacial anomalies; 4) cleft palate; 5) autism spectrum disorder or pervasive developmental disorder; 6) suspected or diagnosed speech and language delay; and 7) the developmental or other cognitive impairments (Recommendation grade: B). Children at high risk are those with factors that make them vulnerable to the negative influence of OME-driven hearing impairment with regard to education and development. In chil- dren with cleft palate, in whom the incidence and recurrence of OME have been reported to be elevated, OME-related hearing loss has been shown to be more frequent and more profound than in otherwise healthy children with OME [bib_ref] Long-term clinical, audiologic, and radiologic outcomes in palate cleft children treated with..., Valtonen [/bib_ref] [bib_ref] Evaluation of otitis media with effusion in cleft palate patients, Lee [/bib_ref] [bib_ref] The high prevalence of otitis media with effusion in children with cleft..., Flynn [/bib_ref]. In children with the aforementioned risk factors, their medical and developmental status should be carefully investigated, if necessary including consultation with related professionals such as an otolaryngologist, pediatrician, pediatric psychiatrist, speech therapist, audiologist, and physical therapist. Management of children at increased risk for developmental delay should include age-appropriate hearing testing and active intervention for associated hearing loss. Surgical intervention may be placed earlier and a hearing aid may be applied according to the hearing status either with or without surgical intervention. When a child is suspected to have language delay, prompt evaluation of language development is recommended to enable appropriate therapy designed for the specific problem of the child. ## Observation policy The guidelines recommend that clinicians manage children with OME according to the observation policy for at least 3 months from onset, unless the child has any of the following exceptional factors. Exceptional cases that warrant earlier intervention include 1) children with high-risk factors as listed above, 2) when an irreversible change of the tympanic membrane is anticipated, and 3) presenting signs and symptoms suggesting complications, such as sudden aggravation of hearing loss or dizziness. Further treatment should be planned according to the status of the tympanic membrane, hearing status, and developmental status of language after a 3-month observation period (Recommendation grade: A). Current evidence regarding the efficacy of OME treatment discourages the use of medications, including antibiotics, oral and nasal steroids, antihistamines, and decongestants [bib_ref] Antihistamines and/or decongestants for otitis media with effusion (OME) in children, Griffin [/bib_ref] [bib_ref] A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4-to 11-year-old..., Williamson [/bib_ref] [bib_ref] Cost-utility analysis of topical intranasal steroids for otitis media with effusion based..., Petrou [/bib_ref] [bib_ref] Systemic steroid for chronic otitis media with effusion in children, Mandel [/bib_ref] [bib_ref] Oral or topical nasal steroids for hearing loss associated with otitis media..., Simpson [/bib_ref]. The short-term benefits of antibiotics and antibiotic-steroid combination therapy have been reported, but the benefit becomes non-significant over long-term follow-up [bib_ref] Systemic steroid for chronic otitis media with effusion in children, Mandel [/bib_ref] [bib_ref] Oral or topical nasal steroids for hearing loss associated with otitis media..., Simpson [/bib_ref]. A randomized study performed in Korea also showed that there is no difference in the cure rate in children treated with antibiotics, antibiotics + steroid, antibiotics + antihistamine, and antibiotics + steroid + antihistamine compared to controls treated with only a mucolytic [bib_ref] Management for the children with otitis media with effusion in the tertiary..., Choung [/bib_ref]. Antihistamine or steroid use also showed no benefit for pediatric OME patients with nasal allergy [bib_ref] Management for the children with otitis media with effusion in the tertiary..., Choung [/bib_ref]. In some cases, parents may be reluctant to agree to surgical intervention even in cases where early intervention is required, or may express anxiety over the lack of medication despite sufficient consultation. In such cases, antibiotic or antibiotic-steroid combination therapy can be administered for a short time (Recommendation grade: C). However, the observation policy suggested in these guidelines is not averse to medical therapy for symptoms associated with other concomitant diseases, such as sinusitis, pharyngitis, and adenotonsillitis. Children should be treated for all current problems with appropriate medical, surgical, and educational interventions. The irreversible changes in the tympanic membrane that may accompany OME include retraction pocket, cholesteatoma, ossicular erosion, and adhesive OM. Immediate surgical intervention is generally recommended in children showing changes in the tympanic membrane during the 3-month observation period that may progress to any of the irreversible changes. This observation policy is not intended to leave patients without intervention. To evaluate the status of the middle ear and the tympanic membrane, physicians may perform audiometric tests, such as impedance audiometry, tests for Eustachian tube function, and tests to measure hearing thresholds during the follow-up period. Hearing status of the affected child should be monitored carefully at the time of diagnosis of OME and during the observation period using age-appropriate means of audiometry. For children who show symptoms and signs of hearing impairment, information should be provided to the parent or caregiver with the goal of optimizing the listening environment at home and school. Autoinflation may be used in cooperative children during the observation period, as the risks and costs related to this maneuver are very low, although the evidence supporting the benefit of autoinflation is not robust (61). As stated above, the guidelines emphasize close monitoring of hearing and parental education in agreement with the concept of "active observation" and "watchful waiting" proposed in previous guidelines published in other countries [bib_ref] Clinical practice guideline: otitis media with effusion, Rosenfeld [/bib_ref]. ## Indications for surgical treatment Surgical intervention for OME should be decided after considering the bilaterality of the disease, hearing status, duration of disease in the affected ear(s), parental preference, and effects on educational and developmental status of the child. The decision for surgical intervention is made after 3 months of observation with evaluation of hearing. Exceptional cases for which surgical intervention should be considered earlier are 1) children at high risk and 2) children for whom changes in the tympanic membrane are anticipated to progress to irreversible changes (Recommendation grade: A). For otherwise healthy children, hearing status is a key factor determining whether surgery should be performed. In bilaterally affected cases, surgical intervention is recommended if hearing level in the better ear is 40-dB HL or above. If hearing level is between 20-and 40-dB HL, the guidelines recommend making a decision considering the medical/developmental status of child and parental preference (Recommendation grade: A). In unilaterally affected children, physicians may consider surgery, taking the duration of disease, hearing status, and parental preference into consideration (Recommendation grade: C). In some cases, even though the hearing level meets the criteria for surgery, the surgical approach may not be possible for reasons such as other medical problems or lack of consent by the parent or caregiver. For these children, hearing status should be monitored at 1-3-month intervals, and clinicians may discuss the application of hearing aids and strategies to minimize the impact of hearing impairment. If an affected child shows a hearing threshold of 20-dB HL or better, physicians can offer a regular checkup for physical examination and audiometric surveillance to decide on further interventions when necessary. It is generally agreed that surgical intervention is necessary when a child shows hearing loss of a moderate degree or worse and when the tympanic membrane is anticipated to develop irreversible changes. When OME persists over the 3-month observation period but the hearing threshold in the better ear is lower than the criterion demanding surgical intervention, the duration of disease is considered as the most crucial factor to determine whether surgical intervention should be performed. The potential negative impact of hearing impairment on language delay can be a concern over a prolonged period of observation [bib_ref] Early surgery compared with watchful waiting for glue ear and effect on..., Maw [/bib_ref] [bib_ref] The effect of treatment with ventilating tubes on language development in preschool..., Rach [/bib_ref] , but recent evidence from randomized prospective studies supports delayed intervention [bib_ref] Hearing thresholds and tympanic membrane sequelae in children managed medically or surgically..., Stenstrom [/bib_ref] [bib_ref] Which children would benefit most from tympanostomy tubes (grommets)? A personal evidence-based..., Lous [/bib_ref] [bib_ref] The effect of ventilation tubes on language development in infants with otitis..., Rovers [/bib_ref]. In a series of prospective studies, children in a late-intervention group, who underwent surgery based on an examination conducted 9 months later in unilateral cases and 6 months later in bilateral cases, compared with an early intervention group, showed no difference in linguistic/social/educational status examined by repeated measurement over 11 yr [bib_ref] Effect of early or delayed insertion of tympanostomy tubes for persistent otitis..., Paradise [/bib_ref] [bib_ref] Developmental outcomes after early or delayed insertion of tympanostomy tubes, Paradise [/bib_ref] [bib_ref] Tympanostomy tubes and developmental outcomes at 9 to 11 years of age, Paradise [/bib_ref]. For a child with OME who does not meet the surgical criteria after the 3-month observation period, clinicians should discuss with the parent or caregiver whether to extend the observation period considering hearing threshold and developmental/social status of the child to minimize the risks and medical costs associated with surgery. Placement of a ventilation tube is the preferred method for surgical intervention as the initial procedure (refer the next section for details). ## Choice of surgical intervention Ventilation tube insertion is the preferred initial procedure when a child becomes a surgical candidate. Adenoidectomy and/or tonsillectomy may be performed simultaneously if the status of the adenoid and the pharyngeal tonsil indicates these additional procedures. Adenoidectomy may be performed with ventilation tube insertion in recurrent cases for repeated surgical intervention (Recommendation grade: B). Ventilation tube insertion is a safe procedure and improves hearing during placement of the tube, but it frequently produces abnormalities in the tympanic membrane such as tympanosclerosis and segmental atrophy [bib_ref] Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion..., Browning [/bib_ref] [bib_ref] Otological and audiological outcomes five years after tympanostomy in early childhood, Valtonen [/bib_ref] [bib_ref] A 14-year prospective follow-up study of children treated early in life with..., Valtonen [/bib_ref] [bib_ref] A 14-year prospective follow-up study of children treated early in life with..., Valtonen [/bib_ref] [bib_ref] Myringotomy versus ventilation tubes in secretory otitis media: eardrum pathology, hearing, and..., Cayé-Thomasen [/bib_ref] [bib_ref] Factors that affect the development of tympanosclerosis after ventilation tube insertion, Park [/bib_ref]. As the ventilation tube may not show long-term effects, surgical decisions should be made with the parents considering the risks and costs associat-ed with the procedure. Data from a recent meta-analysis and evidence from Korea support the benefit of adenoidectomy to reduce recurrence of OME, but the cost effectiveness of this procedure as the initial surgery is still debatable [bib_ref] Adenoidectomy for otitis media in children, Van Den Aardweg [/bib_ref] [bib_ref] Efficacy of adenoidectomy in preventing recurrence of otitis media with effusion, Jung [/bib_ref]. Adenoidectomy may be combined in the first surgery for OME, but the surgeon should consider the status of adenoidal pathology and cost effectiveness before making a decision. Tonsillectomy has been reported to have no effect on OME and requires additional hospitalization with increased complication rates [bib_ref] Efficacy of adenoidectomy in preventing recurrence of otitis media with effusion, Jung [/bib_ref] [bib_ref] Adenoidectomy and adenotonsillectomy for recurrent acute otitis media: parallel randomized clinical trials..., Paradise [/bib_ref] [bib_ref] Adenoidectomy for middle ear effusion: a study of 50,000 children over 24..., Kadhim [/bib_ref]. Therefore, tonsillectomy may be performed if a distinct indication for the procedure exists concomitant with surgical procedures for OME, but should not be performed to treat OME. After ventilation tube insertion, the guidelines recommend performing audiometric tests to confirm hearing recovery. In rare cases, hearing impairment may persist due to a hidden pathology that is independent of OME. Regular check-ups at 1-3month intervals are recommended to examine tube-associated infection and extrusion of the tube. After extrusion of the ventilation tube, healing of the tympanic membrane and recurrence of OME should be evaluated. ## Other recommendations for ome When a clinician provides medical care for a child with OME, the guidelines recommend providing clear information about the etiology and natural course of the disease as well as treatment options to the patient and his/her parent or caregiver (Recommendation grade: B). It is good practice for medical professionals to provide not only verbal information but also written documents for patients and their family members. As OME may be recurrent or persistent during childhood until the function of the Eustachian tube develops, constant follow-up lasting from months to many years is necessary. Sufficient knowledge and appropriate understanding about the disease by the patient and the family is essential for a good doctor-patient relationship. To facilitate continuing care, documentation of detailed history is recommended including details of the onset of OME, symptoms derived from OME, associated symptoms, past medical history, and presence of high-risk factors of the child (Recommendation grade: B). Primary clinicians may refer the patient to other medical centers, including higher referral centers for audiometric/developmental evaluation and surgical intervention. The primary clinician should provide the referred center with basic patient information and can request the results of medical examinations and treatment and also retransfer of the patient (Recommendation grade: B). Examples of documentation and referral forms are included as appendices in the full version available on the website. No recommendations for complementary and alternative medicine for treatment of OME are made based on limited support- ing data (Recommendation grade: D). After a literature search, we found four published papers in Korean regarding herbal medicine and acupuncture as treatments for OME. However, the sizes of these studies were very small, and the diagnostic criteria used were unclear. Therefore, the evidence levels were determined to be insufficient for inclusion in the development of these guidelines. Therefore, no recommendations are made regarding this subject. # Conclusion These are the first guidelines for pediatric OM in Korea, and they represent an important and meaningful base on which to incorporate future revisions as necessary. These first guidelines call for regular nationwide surveys to improve scientific evidence on pediatric OM in Korea to be included in the next update. Future research topics should include better methods for diagnosis of pediatric OM and hearing assessment, better definition of children at high risk, the causative bacteria for AOM and changes in multidrug-resistant bacteria, long-term follow-up studies to evaluate developmental status according to treatment options for OME, cost-effectiveness of various treatments, and both medical and socioeconomic effects of alternative medicine for pediatric OM. The recommendations are not intended to restrain professional judgment. Rather, they may be considered as professional advice on individual clinical circumstances. Guidelines represent the consensus of a team of experienced clinicians addressing the scientific evidence for a particular topic. Due to differences in physical characteristics and circumstances among patients, individual clinical characteristics and environmental factors should be given priority, and the clinical experience and judgment of attending physicians must be respected. In practice, all clinicians should always act and decide in a manner that they believe will best serve the individual patient's well-being regardless of the recommendations. Clinicians should actually select a treatment based on their professional knowledge and experience, along with the preference and values of the patient and parents/caregivers. [fig] Figure 2: Algorithm for management of pediatric otitis media with effusion (OME) in Korea. dB, decibel; HL, hearing level. Surgical intervention should not be delayed if irreversible changes in the tympanic membrane or complications are anticipated, regardless of the duration of watchful waiting. [/fig] [table] Table 1: Definitions and implications of the recommendation grades [/table] [table] Table 2: Diagnostic criteria for acute otitis media in children in Korea TM findings: drum bulging, bullae, hyperemia, discharge, effusion, etc. ② Tympanometry results of B or C type or tympanocentesis confirmed middle ear effusion [/table] [table] Table 4: Recommended antibacterial agents for pediatric acute otitis media Antibiotic prescription and change can be done at any time necessary considering the bacterial culture and antibacterial agent sensitivity results, but it is desirable for the test to be conducted before the start of antibiotic treatment to increase positive results of the bacterial culture.5) Summary of AOM treatment in childrenObservation/Conservative therapy → First-line antibiotics → Second-line antibiotics → Third-line antibiotics In severe cases † , Second-line antibiotics → Third-line antibiotics [/table]	None	http://synapse.koreamed.org/Synapse/Data/PDFData/0063JKMS/jkms-27-835.pdf	Acute otitis media (AOM) and otitis media with effusion (OME) are common infections in children, and their diagnosis and treatment have significant impacts on the health of children and the costs of providing national medical care. In 2009, the Korean Otologic Society organized a committee composed of experts in the field of otolaryngology, pediatrics, and family medicine to develop Korean clinical practice guidelines (CPG) for otitis media in children with the goal of meeting regional medical and social needs in Korea. For this purpose, the committee adapted existing guidelines. A comprehensive literature review was carried out primarily from 2004 to 2009 using medical search engines including data from Korea. A draft was written after a national questionnaire survey and several public audits, and it was editorially supervised by senior advisors before publication of the final report. These evidence-based guidelines for the management of otitis media in children provide recommendations to primary practitioners for the diagnosis and treatment of children younger than 15 yr old with uncomplicated AOM and OME. The guidelines include recommendations regarding diagnosis, treatment options, prevention and parent education, medical records, referral, and complementary/alternative medicine for treating pediatric otitis media.
21dbdcdf9f975d6a1e8c1aa252a47b57601e0e41	pubmed	Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas	Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of . We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations. # Introduction Pheochromocytomas (PCCs) and paragangliomas (PGLs)-hereinafter PPGL to include both entities-are rare neuroendocrine tumors (NETs) that arise from chromaffin cells of the adrenal medulla and the sympathetic/ parasympathetic neural ganglia, respectively. PPGLs often secrete catecholamines (CMNs) that can mimic a wide range of medical disorders and may be lethal if misdiagnosed or improperly handled. PPGLs are also characterized by a very heterogeneous natural history and a low to moderate but unpredictable ability to metastasize. Surgical resection may be challenging, including adequate timing and perioperative medical management, and optimal treatment of advanced disease is controversial. Over one-third of PPGLs are inherited, and adequate genetic counseling is key to implementing screening strategies and tailoring therapy. All these factors make PPGL diagnosis and treatment very complex, and clinical experience is difficult to achieve due to their low incidence. In this context, the aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective. Experts from the national societies of the different disciplines involved participated in the elaboration of these guidelines, including clinical specialists from the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), and Surgery (AEC), and geneticists from the Spanish National Cancer Research Center (CNIO). ## Epidemiology The joint annual incidence of PPGL is estimated to be 2-8 cases per million inhabitants. A recent study from Canada disclosed an annual incidence of 6.6 cases per million inhabitants, half of them corresponding to pheochromocytomas and 37% of them to head and neck paragangliomas [bib_ref] Epidemiology of pheochromocytoma and paraganglioma: population-based cohort study, Leung [/bib_ref] , most of them known to be parasympathetic. Head and neck paragangliomas have geographic variations as a function of altitude [bib_ref] High-altitude paragangliomas diagnostic and therapeutic considerations, Rodriguez-Cuevas [/bib_ref]. In another study from Holland [bib_ref] Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study..., Berends [/bib_ref] , the annual incidence of PCCs and of sympathetic PGLs were 4.6 and 1.1 cases per million inhabitants, respectively, which had increased compared to previous years likely due to improved diagnostic techniques and clinical awareness. The distribution by gender does not show significant differences, although a greater incidence in females has been observed for vagal and jugulotympanic PGLs [bib_ref] Paragangliomas of the head and neck region: a clinical study of 69..., Lack [/bib_ref] , and in high-altitude PGLs [bib_ref] High-altitude paragangliomas diagnostic and therapeutic considerations, Rodriguez-Cuevas [/bib_ref]. PPGLs are commonly diagnosed within the 4th and 6th decades, although these neoplasms can occur over a wide age range. They appear at a younger age when they occur as part of a hereditary syndrome. At pediatric ages, extra-adrenal PGLs account for more than two-third of the cases, and four of five cases are associated with a hereditary form of the disease [bib_ref] A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma..., Waguespack [/bib_ref] [bib_ref] Characteristics of pediatric vs adult pheochromocytomas and paragangliomas, Pamporaki [/bib_ref]. Bilateral or multiple forms are mostly associated with hereditary syndromes, but an advanced age at diagnosis or the absence of family history does not exclude the possibility of carrying a germline mutation. In fact, between 14 and 24% of clinically sporadic tumors may also be due to a germline mutation [bib_ref] PheoSeq: a targeted next-generation sequencing assay for pheochromocytoma and paraganglioma diagnostics, Curras-Freixes [/bib_ref] [bib_ref] Pathology and genetics of phaeochromocytoma and paraganglioma, Turchini [/bib_ref]. The rate of metastatic disease (mPPGL) ranges from less than 1% to 79%, depending upon tumor site and size, age at diagnosis and genotype [bib_ref] The North American neuroendocrine tumor society consensus guideline for the diagnosis and..., Chen [/bib_ref] [bib_ref] Clinical characteristics and outcomes of SDHB-related pheochromocytoma and paraganglioma in children and..., Jochmanova [/bib_ref]. Although some features included size greater than 5 cm, extra-adrenal primary tumor site, or high levels of plasma 3-metoxitiramine (3-MT) [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] provide useful information to assess the risk of metastasis, the presence of mutations in the succinate dehydrogenase complex iron sulfur subunit B (SDHB Mut ) is the only universally accepted criterion associated with a high risk of distant disease, both at diagnosis or during follow-up, ranging from 20 to 70% in different patient cohorts [bib_ref] Clinical characteristics and outcomes of SDHB-related pheochromocytoma and paraganglioma in children and..., Jochmanova [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas..., Amar [/bib_ref] [bib_ref] Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): a European network for..., Hescot [/bib_ref]. Recent data also suggest a higher metastatic risk in patients with mutations in other genes involved in the Krebs cycle [bib_ref] Pheochromocytomas and paragangliomas: bypassing cellular respiration, Cascón [/bib_ref]. Overall, the prognosis of PPGL is heterogeneous. Goffredo et al. analyzed 508 PPGL patients from 18 US registries (time frame 1988-2009) and reported a 5-year overall survival (OS) rate of 58% for metastatic PCCs and 80% for metastatic PGLs [bib_ref] Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over..., Goffredo [/bib_ref]. More recently, a retrospective study of 169 patients from 18 European centers (time frame 1998-2010) by Hescot et al. [bib_ref] Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): a European network for..., Hescot [/bib_ref] reported a global 5-year OS rate of 62% and a median OS of 6.7 years for mPPGL. ## Anatomy, pathology and molecular pathways Anatomy and PGL (extra-adrenal) are neoplasms that originate from chromaffin cells of the autonomic nervous system, derived from the neural crest, and can be classified as either sympathetic or parasympathetic. The sympathetic system is distributed through the paraganglia of the prevertebral and paravertebral axes, reaching the abdominal organs and innervating the urogenital system, and it includes the adrenal medulla, which is considered the greatest paraganglion. The parasympathetic system is distributed through the head and neck and mediastinum, following the territories of the glossopharyngeal (carotid and tympanic paraganglia) and vagus (jugular, upper and lower laryngeal, subclavian and aortopulmonary) nerves [bib_ref] Adrenal medulla and extra-adrenal paraganglia, Oudijk [/bib_ref]. These neoplasms are also grouped into cervicocephalic, thoracic and abdominal PPGLs [bib_ref] Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients, Erickson [/bib_ref]. ## Histopathological features The characteristic microscopic feature of PPGLs is the proliferation of polygonal chromaffin cells distributed in nests (zellballen, in German), surrounded by a fine capillary network and sustentacular cells, easily identifiable through immunohistochemical (IHC) detection of S-100. This pattern is more evident in parasympathetic PGLs. Chromogranin A (CgA) and synaptophysin, but not cytokeratins, are expressed in tumor cells. Tyrosine hydroxylase is also expressed in PCCs and sympathetic PGLs but not in parasympathetic PGLs. IHC studies with Ki67 (Mib-1) are also recommended to estimate the cellular proliferation index. ## Stratification of risk and staging All PPGLs are potentially metastatic; therefore, benign vs malignant discrimination was eliminated in the last World Health Organization (WHO) classification for endocrine tumors. Several scoring systems have been established to estimate the metastatic risk of these tumors. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) [bib_ref] Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from..., Thompson [/bib_ref] , applicable only to PCCs, is based solely on morphological criteria, some of which may be too subjective to evaluate [fig_ref] Table 1: Pheochromocytoma and paraganglioma risk stratification systems Parameter Score Pheochromocytoma of the adrenal... [/fig_ref]. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) scale [bib_ref] Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a..., Kimura [/bib_ref] is applicable to both PCCs and PGLs and combines morphological, IHC and analytical findings [fig_ref] Table 1: Pheochromocytoma and paraganglioma risk stratification systems Parameter Score Pheochromocytoma of the adrenal... [/fig_ref]. IHC studies of SDH components are indicated and are especially useful in the study of subunit B of SDH (SDHB), as the loss of expression indicates the presence of an SDH germline mutation and an increased risk of aggressive behavior [bib_ref] Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma..., Curras-Freixes [/bib_ref] [bib_ref] SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using..., Papathomas [/bib_ref]. In fact, SDHB loss of expression is included in the most recent risk stratification score, COPPS (Composite Pheochromocytoma/paraganglioma Prognostic Score) [fig_ref] Table 1: Pheochromocytoma and paraganglioma risk stratification systems Parameter Score Pheochromocytoma of the adrenal... [/fig_ref] [bib_ref] COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts..., Pierre [/bib_ref]. The eighth edition of the American Joint Committee on Cancer (AJCC) staging system [bib_ref] Adrenal-neuroendocrine tumors, Jimenez [/bib_ref] includes a new chapter to address PCC and sympathetic PGL, but not parasympathetic PGL, given its low risk of malignant behavior (~ 5%) [bib_ref] Natural history of cervical paragangliomas: outcomes of observation of 43 patients, Langerman [/bib_ref] [bib_ref] Surgical resection of carotid body paragangliomas: 10 years of experience, Amato [/bib_ref]. ## Molecular basis of ppgl A total of 30-50% of PPGLs occur in the context of a hereditary syndrome [bib_ref] High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in..., Lima [/bib_ref] [bib_ref] The genetics of paragangliomas, Burnichon [/bib_ref] [bib_ref] An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes, Gimenez-Roqueplo [/bib_ref]. The most common hereditary syndromes are those derived from germline mutations in genes encoding the different subunits of SDH (type 1: SDHD; type 2: SDHAF2; type 3: SDHC; type 4: SDHB; type 5: SDHA; including Carney-Stratakis syndrome) , Von Hippel-Lindau (VHL) syndrome due to mutations in the VHL gene (9%), multiple endocrine neoplasia-2 (MEN2) syndrome due to mutations in the RET proto-oncogene (5%) and neurofibromatosis type 1 (NF-1) syndrome due to mutations in the NF1 gene (2%). Less frequent familial forms (< 1-2%) are caused by mutations in the transmembrane protein 127 (TMEM127), MYCassociated factor X (MAX), fumarate hydratase (FH), multiple endocrine neoplasia type 1 (MEN1), egg-layingdefective nine (egl-9) family hypoxia-inducible factor 1 gene (EGLN1), egl-9 family hypoxia-inducible factor 2 (EGLN2), malate dehydrogenase 2 (MDH2), kinesin family member 1B (KIF1B) genes [bib_ref] Germline mutations in TMEM127 confer susceptibility to pheochromocytoma, Qin [/bib_ref] [bib_ref] MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma, Burnichon [/bib_ref] [bib_ref] Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas, Castro-Vega [/bib_ref] [bib_ref] Comprehensive molecular characterization of pheochromocytoma and paraganglioma, Fishbein [/bib_ref] , solute carrier family 25 Member 11 (SLC25A11) and dihydrolipoamide S-succinyltransferase (DLST) [bib_ref] Recurrent germline DLST mutations in individuals with multiple pheochromocytomas and paragangliomas, Remacha [/bib_ref] [bib_ref] Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition..., Buffet [/bib_ref]. Susceptibility genes and familial PPGL syndromes have been comprehensively reviewed recently [bib_ref] Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging, Alrezk [/bib_ref] , and their main features are summarized in [fig_ref] Table 3: PPGL susceptibility genes [/fig_ref]. ## Molecular classification of ppgl The genomic characteristics of PCCs and PGLs allow us to distinguish among three groups or main clusters. Cluster 1 groups tumors with germinal or somatic mutations in genes related to the Krebs cycle (SDHA, SDHAF2, SDHB, SDHC, SDHD, FH, MDH2, GOT2, IDH1, SLC23A11, etc.), in EPAS1 and in VHL. The presence of mutations in these genes leads directly or indirectly to HIF1a and HIF2a stabilization and, therefore, to a situation of pseudohypoxia, which causes an increase in angiogenesis and cell proliferation. PPGLs associated with mutations in genes of the Krebs cycle show a characteristic pattern of higher overall methylation, known as the CpG island methylator phenotype (CIMP). The level of CIMP is higher among SDHB-Mut tumors. This phenotype leads to expression deregulation of genes involved in neuroendocrine differentiation or in the epithelial-mesenchymal transition process, findings that could explain the increased risk of metastasis among patients with SDHB Mut tumors. In a recent study higher DNA methylation levels were found in metastatic SDHB-PPGLs as compared to SDHB-PPGLs without metastasis, and this included de novo methylation of protocadherins (PCDH). Furthermore, in vitro assays suggested PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis [bib_ref] Epigenetic deregulation of protocadherin PCDHGC3 in pheochromocytomas/ paragangliomas associated with SDHB mutations, Bernardo-Castiñeira [/bib_ref]. Cluster 2 groups tumors with mutations in NF1, RET, HRAS and TMEM127 genes, which activate the MAP kinase signaling pathway [bib_ref] Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related..., Lopez-Jimenez [/bib_ref]. The Cancer Genome Atlas (TCGA) project has identified a third group or cluster related to alterations in the Wnt pathway [bib_ref] Comprehensive molecular characterization of pheochromocytoma and paraganglioma, Fishbein [/bib_ref] , which also seems to be associated with an increased risk of developing metastatic disease [fig_ref] Table 3: PPGL susceptibility genes [/fig_ref]. ## Clinical presentation The clinical presentation of PPGLs is extremely variable and depends on the anatomical location, tumor size and extent of locoregional or distant involvement; the secretion or not of catecholamines (CMNs), including type, amount and pattern of secretion (adrenaline/epinephrine: A/E; noradrenaline/ norepinephrine: NA/NE, and dopamine: DA); the hereditary or sporadic nature; the malignancy potential; and the time elapsed from initiation of symptoms to diagnosis. PPGLs arising from sympathetic paraganglia are characterized by adrenergic and noradrenergic symptoms, such as the classic triad of palpitations, headache and diaphoresis or tremor, facial pallor and dyspnea. However, the predominant symptom remains severe, variable hypertension (65%), with target tissue damage such as hypertrophic or dilated cardiomyopathy (including Tako Tsubo idiopathic cardiomyopathy-like forms), potentially leading to fatal cardiac events, arrhythmias, myocardial infarction, congestive heart failure and chronic lung disease. Hemodynamic instability due to alterations in sympathetic vascular tone and orthostatic hypotension has also been described [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Catecholamine synthesizing enzymes in 70 cases of functioning and non-functioning phaeochromocytoma and..., Kimura [/bib_ref] [bib_ref] Extra-adrenal pheochromocytoma, Whalen [/bib_ref] [bib_ref] Update on adrenal tumours in 2017 world health organization (WHO) of endocrine..., Lam [/bib_ref] [bib_ref] Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma, Parikh [/bib_ref] [bib_ref] Pheochromocytoma as a reversible cause of cardiomyopathy: analysis and review of the..., Zhang [/bib_ref] [bib_ref] Hereditary paraganglioma-pheochromocytoma syndromes, Else [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry..., Geroula [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. Other symptoms of CMN excess include increased basal metabolism, weight loss, sweating, heat intolerance, altered glucose homeostasis resulting in type 2 diabetes mellitus, polyuria, polydipsia, constipation, ischemic colitis, altered vision, increased erythrocyte sedimentation rate and leukocytosis, psychiatric symptoms, and, rarely, hypercalcemia and polycythemia. Symptoms are variable in duration and frequency and can be spontaneous or induced by various stimuli, such as food with high tyramine content (chocolate, coffee, smoked meat, cheese, red wine), sustained physical exercise (sometimes during urination in bladder PGLs), delivery, trauma, the induction of anesthesia, invasive diagnostic or therapeutic procedures, surgery, tumor biopsy or fine-needle aspiration and some medications (DA-2 antagonists, β-adrenergic blockers, sympathomimetics, opioids, tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase (MAO) inhibitors, corticosteroids, peptides or neuromuscular blocking agents) [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. Patients with A/NA PPGLs may be asymptomatic due to early diagnosis in the setting of abdominal imaging Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys) Definition of regional lymph node (N) N category N criteria NX Regional lymph nodes cannot be assessed N0 No lymph node metastasis N1 Regional [fig_ref] Table 1: Pheochromocytoma and paraganglioma risk stratification systems Parameter Score Pheochromocytoma of the adrenal... [/fig_ref] Any N M0 III Any T Any N M1 IV performed for other reasons (5% of adrenal incidentalomas) or screening procedures in at-risk family members [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Hereditary paraganglioma-pheochromocytoma syndromes, Else [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. Early case detection reduces cardiovascular morbidity and mortality due to chronic untreated CMN secretion [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma, Parikh [/bib_ref] [bib_ref] Pheochromocytoma as a reversible cause of cardiomyopathy: analysis and review of the..., Zhang [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. PGLs distributed along the parasympathetic chains of the head and neck (glossopharyngeal and vagal nerves) tend to be silent or pseudo-silent tumors (up to 15% of PPGLs). Usually, they do not produce CMNs, have a low metastatic potential, present as a head and neck mass with symptoms related to tumor bulk and local compression, or are incidentally discovered on imaging studies done for other purposes [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Hereditary paraganglioma-pheochromocytoma syndromes, Else [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. Recently, PPGLs have been classified based on translational clinical-biochemical-gene mutation cluster features into five groups: silent, biochemically pseudo-silent, noradrenergic, adrenergic and dopaminergic phenotypes [bib_ref] Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging, Alrezk [/bib_ref] [bib_ref] Current management of pheochromocytoma/ paraganglioma: a guide for the practicing clinician in..., Nolting [/bib_ref]. PPGLs associated with hereditary predisposition syndromes are more likely to be recurrent, multifocal and bilateral; occur at a younger age [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Hereditary paraganglioma-pheochromocytoma syndromes, Else [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref] ; have a higher malignancy potential; and are associated with genetically driven comorbidities. [fig_ref] Table 4: Screening indications for PPGLs [/fig_ref] summarizes the main screening indications for PPGLs. Clinical severity and prognosis are marked by the malignancy potential of PPGLs and the risk of aggressive metastatic evolution. Malignancy, defined as the presence of metastasis in non-chromaffin tissues [bib_ref] New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification, Crona [/bib_ref] , has a prevalence of 10% in PCCs and reaches 35-40% in PGLs [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Hereditary paraganglioma-pheochromocytoma syndromes, Else [/bib_ref] [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref] , with symptoms and disease burden depending on the affected tissue. Translational risk scores are currently focusing on the identification of tumors with an aggressive outcome. ## Hereditary predisposition syndromes and genetic counseling and testing A hereditary form of PPGL should always be ruled out following the diagnoses of PPGL. Syndromic PPGL is strongly suspected in an individual with multiple, multifocal, recurrent, early onset of the disease and/or a family history of PPGL or related tumors (see predisposition syndromes associated with germinal mutations in [fig_ref] Table 3: PPGL susceptibility genes [/fig_ref]. There are currently over 22 susceptibility genes identified. Among them, genes related to syndromic presentation drive nearly half of the cases. PPGLs present the highest rate of germline susceptibility in cancer genetics, at almost 40% [bib_ref] Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas, Castro-Vega [/bib_ref] [bib_ref] Genomic landscape of pheochromocytoma and paraganglioma, Jochmanova [/bib_ref] [bib_ref] RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A..., Valdés [/bib_ref]. These include genes encoding neurofibromin 1 (NF1), RET, VHL, menin (MEN1), SDH complex (SDHx: SDHA, SDHB, SDHC, SDHD), SDH complex assembly factor 2 (SDHAF2), TMEM127, MAX, FH, hypoxia-inducible factor 2A (EPAS1/ HIF2A), EGLN1/PHD2, SLC25A11 and DLST. These genes are inherited in an autosomal-dominant manner. However, pathogenic variants in SDHD cause disease only when the pathogenic variant is inherited from the father. Similarly, SDHAF2 and possibly MAX follow an autosomal dominant inheritance, modified by maternal imprinting. Taking into account this genetic heterogeneity, next-generation sequencing (NGS) has been currently established as the new standard screening tool for genetic testing in patients with PPGL. Susceptibility genes and familial PPGL syndromes have been comprehensively reviewed recently [bib_ref] Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging, Alrezk [/bib_ref] , and their main features are summarized in [fig_ref] Table 3: PPGL susceptibility genes [/fig_ref]. The genotype-phenotype correlation is a useful tool to assess the clinical outcome of patients. These include tumor location and CMN secretion profile, as well as the presence of metachronous tumors, aggressive behavior and overall prognosis. Regarding the biochemical profile, genes involved in the pseudohypoxia pathway (Cluster 1) typically are associated with NE and its main metabolite, normetanephrine (NMN) [bib_ref] The value of plasma markers for the clinical behaviour of phaeochromocytomas, Van Der Harst [/bib_ref] [bib_ref] Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use..., Eisenhofer [/bib_ref] and tumors are commonly located outside the adrenal glands [bib_ref] The value of plasma markers for the clinical behaviour of phaeochromocytomas, Van Der Harst [/bib_ref] [bib_ref] Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use..., Eisenhofer [/bib_ref]. When located in the head and neck region (HNPGLs), PPGLs have been traditionally classified as biochemically "silent" tumors [bib_ref] Malignant carotid paraganglioma. A case report, Righini [/bib_ref] [bib_ref] Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of..., Van Duinen [/bib_ref]. However, HNPGLs can also produce high levels of DA and its main metabolite, 3-MT, with normal or near-normal levels of NE/NMN [bib_ref] Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome, Pacak [/bib_ref] [bib_ref] Dopamine excess in patients with head and neck paragangliomas, Van Der Horst-Schrivers [/bib_ref]. Elevated levels of DA/3MT/ NE have been reported in approximately 65% of patients with SDHx Mut tumors [bib_ref] Dopamine excess in patients with head and neck paragangliomas, Van Der Horst-Schrivers [/bib_ref] [bib_ref] Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary..., Eisenhofer [/bib_ref]. Hereditary forms related to Cluster 1 genes often present with variable expressivity and incomplete penetrance. For instance, patients with a driver mutation in SDHA/C usually lack a positive family history and rarely present with more than one tumor. Finally, regarding recurrence or aggressive disease, almost 90% of patients with metastatic PGLs present a SDHA/B Mut or FH Mut tumor [bib_ref] Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas, Castro-Vega [/bib_ref] [bib_ref] Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene..., Neumann [/bib_ref] [bib_ref] Genetic testing in pheochromocytoma or functional paraganglioma, Amar [/bib_ref] [bib_ref] Clinical, diagnostic, and treatment characteristics of SDHA-related metastatic pheochromocytoma and paraganglioma, Jha [/bib_ref]. On the other hand, genes involved in the kinase signaling group pathway (Cluster 2) commonly present with adrenal tumors that produce either purely elevated E or its main metabolite, metanephrine (MN) [bib_ref] Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use..., Eisenhofer [/bib_ref] , or both E/MN and NE/NMN. This hereditary form often presents with higher expressivity, and complete penetrance occurs more frequently. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis could be considered in certain syndromes, such as VHL disease. Furthermore, genetic identification provides valuable information for the establishment of a treatment plan and for appropriate guidance for follow-up surveillance. ## Diagnostic procedures The diagnosis of PPGLs includes clinical suspicion, biochemical hormonal detection of excess CMN secretion, imaging studies for tumor localization and staging, genetic screening and, if a genetic germline mutation is confirmed, additional diagnostic procedures for genetic syndromic features as appropriate. PPGLs diagnosed as incidental masses in imaging studies require the same approach. A proposed diagnostic algorithm is provided in [fig_ref] Figure 1: Diagnostic algorithm for PPGLs [/fig_ref]. ## Biochemical testing The biochemical diagnosis and follow-up of PPGLs rely on the quantification of CMN metabolites, such as plasma-free NMN, MN, and 3-MT or urinary fractionated MNs (e.g., MN, NMN). CMN measurement is less informative. Reference intervals (supine position; children) and standard preanalytical conditions (supine position for plasma determination, diet and medication interferences for urine testing) have to be carefully followed. Biochemical testing for PPGLs should be performed before imaging studies. Prior to the 24-h urine and plasma CMN metabolite determination, a 3-day diet without caffeine, black tea, nicotine, alcohol, bananas, cheese, almonds, nuts, chocolate, eggs, or vanilla is recommended. Some drugs, such as MAO inhibitors, ephedrine, cocaine, tricyclic antidepressants, serotonin reuptake inhibitors, morphine, amoxicillin, levodopa, sulfasalazine, acetaminophen, methyldopa and buspirone, can also cause false-positive results and should be avoided if possible [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Drugs and pheochromocytomadon't be fooled by every elevated metanephrine, Neary [/bib_ref] [bib_ref] Utility of plasma free metanephrines for detecting childhood pheochromocytoma, Weise [/bib_ref] [bib_ref] Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for..., Casey [/bib_ref]. [bib_ref] Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic..., Ayala-Ramirez [/bib_ref] In/ 99 mTc/ 68 Ga SSTRI, is recommended before MIBG versus radionuclide-SSTR analogs treatment Guidelines accept both plasma-free and urinary MNs for the screening of PCCs and PGLs, with both determinations being considered to have similar sensitivities (97%) and specificities (91%) [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref]. Some reports showed a better sensitivity (99% versus 80%) and a lower specificity (85% versus 98%) for plasma versus urinary MNs. Urinary creatinine is required to normalize urinary metanephrine excretion to renal function (metanephrine-to-creatinine ratio). Recent results, conversely, reported that plasma-free MNs in the supine position have higher specificity than 24-h urinary fractionated MNs (95% versus 90%), with the highest accuracy (95%) for liquid chromatography-mass spectrometry (LC-MS) methods compared with immunoassays [bib_ref] Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for..., Casey [/bib_ref] [bib_ref] Accuracy of recommended sampling and assay methods for the determination of plasma-free..., Darr [/bib_ref] [bib_ref] Biochemical diagnosis of pheochromocytoma: how to distinguish true-from false-positive test results, Eisenhofer [/bib_ref]. LC-MS or electrochemical detection [liquid chromatography electron capture dissociation (LC-ECD)] is considered the gold standard, avoiding drug interference [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Drugs and pheochromocytomadon't be fooled by every elevated metanephrine, Neary [/bib_ref] [bib_ref] Utility of plasma free metanephrines for detecting childhood pheochromocytoma, Weise [/bib_ref] [bib_ref] Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for..., Casey [/bib_ref] [bib_ref] Accuracy of recommended sampling and assay methods for the determination of plasma-free..., Darr [/bib_ref]. Plasma levels of NMNs, MNs or 3-MT more than twice the upper cutoff value of the reference interval indicate a high probability of PPGL, and further imaging studies are recommended. Combined increases in two or more metabolites also suggest a high probability of a PPGL. In the case of borderline elevated values, false-positive results due to an inappropriate preanalytical preparation, testing method, CMN-metabolism-interfering medication, intense physical stress, severe illness or laboratory error must be considered, and the test shall be repeated upon condition optimization [bib_ref] Utility of plasma free metanephrines for detecting childhood pheochromocytoma, Weise [/bib_ref]. In patients with PPGLs, MN levels are generally greater than CMNs (A/NA/D) due to continuous production and release of MNs by tumor cells. Patients with false-positive results usually have larger increments in CMNs than in plasma-free MNs because of sympathoadrenal activation [bib_ref] Biochemical diagnosis of pheochromocytoma: how to distinguish true-from false-positive test results, Eisenhofer [/bib_ref] [bib_ref] Diagnosis of endocrine disease: biochemical diagnosis of phaeochromocytoma and paraganglioma, Van Berkel [/bib_ref] [bib_ref] Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake..., Van Berkel [/bib_ref]. The clonidine suppression test is indicated in inconclusive situations with borderline elevated NMN levels. A persistently increased level and a lack of a decrease in plasmafree NMN (< 40%) 3 h after the administration of clonidine support the diagnosis of PPGL (sensitivity of 100% and specificity of 96%, respectively) [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Biochemical diagnosis of pheochromocytoma: how to distinguish true-from false-positive test results, Eisenhofer [/bib_ref]. Provocative testing (e.g., glucagon) can be dangerous, adds no value to other current testing methods and is not recommended [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma, Lenders [/bib_ref]. In case the probability of a tumor diagnosis is low and there are borderline elevated values, intrapatient longitudinal serial assessments can be useful (e.g., retesting patients 6 months later or more), as the disease growth rate is slow in most cases and involves a doubling time of over 2 years [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Longitudinal plasma metanephrines preceding pheochromocytoma diagnosis: a retrospective case-control serum repository study, Olson [/bib_ref]. The measurement of urinary fractionated MNs or concomitant measurement of plasma-free MNs and urinary MN, and CgA should be considered as follow-up tests [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic..., Algeciras-Schimnich [/bib_ref]. In the setting of prospective screening in hereditary forms of the disease, even low increased values have to be considered positive. False-negative results are less frequent but can be observed in microscopic asymptomatic tumors, DA-producing tumors and tumors with CMN synthesis and/or metabolism defects (e.g., in a silent SDHB Mut subtype, the enzyme that catalyzes the initial and rate-limiting step in CMN biosynthesis is missing). Additional measurements including CgA (after stopping proton pump inhibitors for at least 10 days) and nonspecific neuroendocrine secretory proteins, as well as imaging studies, are strongly indicated in cases of nonfunctional PPGLs, particularly in SDHB Mut carriers [bib_ref] Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake..., Van Berkel [/bib_ref] [bib_ref] Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma, Rao [/bib_ref]. The measurement of 3-MT, the main metabolite of DA, should be considered in patients in whom extra-adrenal HNPGLs are strongly suspected despite normal plasma and urinary MN levels or when metastatic disease is suspected. High-elevated levels of plasma 3-MT indicate the need for preoperative staging, if possible, by radionuclide imaging [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary..., Eisenhofer [/bib_ref] [bib_ref] Diagnosis of endocrine disease: biochemical diagnosis of phaeochromocytoma and paraganglioma, Van Berkel [/bib_ref] [bib_ref] Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma, Rao [/bib_ref]. Recently, the CMN secretion profile has also been related to the recent molecular cluster classification (see Sect. ## Imaging studies The diagnosis of PPGL relies on the imaging identification of an appropriately located mass with consistent clinical and biochemical features. Once the diagnosis is clinically and biochemically confirmed, imaging studies should be performed to localize and stage the tumor [bib_ref] Current diagnostic imaging of pheochromocytomas and implications for therapeutic strategy, Ctvrtlik [/bib_ref]. However, PCGLs, particularly PCCs, are sometimes encountered incidentally on imaging procedures performed for other causes [bib_ref] Missed clinical clues in patients with pheochromocytoma/paraganglioma discovered by imaging, Rogowski-Lehmann [/bib_ref]. CT is the most common imaging method used because it is widely available, less expensive and offers better spatial resolution than MRI. PPGLs are usually solid and hypervascular, well-circumscribed masses, ranging from 1 to 15 cm [fig_ref] Figure 2: Typical morphological and functional imaging of PPGLs [/fig_ref]. Smaller tumors are usually homogeneous, and larger tumors tend to have central necrosis. Some PPGLs can have macroscopic fat simulating adenomas or may have very high attenuation due to hemorrhage or calcifications. There is also a pure cystic form [bib_ref] New imaging approaches to phaeochromocytomas and paragangliomas, Havekes [/bib_ref] [bib_ref] Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging, Leung [/bib_ref]. MRI is not a first-choice imaging tool, but it has the advantage of being free of ionizing radiation and is suitable for children, pregnant women and patients with adverse reactions to iodinated contrast medium. Cystic PPGLs with central necrosis are characteristically "light-bulb" bright lesions on T2-weighted imaging, with low signal intensity at T1. The signal intensity of hemorrhage is predominantly 1 3 high in T1. If PPGLs contain macroscopic fat, they may also be dark on T2 MR images [bib_ref] Imaging of nonmalignant adrenal lesions in children, Sargar [/bib_ref] [fig_ref] Figure 2: Typical morphological and functional imaging of PPGLs [/fig_ref]. PPGL cells express different transporters on their surface that allow images to be obtained by different radiotracers depending on the capture mechanisms (NE transporters [ 123 I/ 131 I-Metaiodobenzylguanidine (MIBG)], type of transporters (glucose transporters (GLUT ( 18 F-FDG)), amino acid transporters ( 18 F-DOPA) or membrane surface receptors [somatostatin (SST) receptors ( 111 In/ 99 mTc/ 68 Ga SST analogs)], thus yielding different functional information [bib_ref] European association of nuclear medicine practice guideline/society of nuclear medicine and molecular..., Taieb [/bib_ref]. The most sensitive functional image for each tumor will depend on the clinical and biochemical profiles and the location of the primary tumor, which are also predictors of the underlying genotype [bib_ref] Pheochromocytoma: a genetic and diagnostic update, Mercado-Asis [/bib_ref]. Positron emission tomography (PET)/CT technology has been shown to be superior to scintigraphy with single photon emission computed tomography (SPECT/CT), with higher spatial resolution, greater sensitivity and fewer indeterminate or equivocal studies [bib_ref] Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging, Alrezk [/bib_ref] [bib_ref] European association of nuclear medicine practice guideline/society of nuclear medicine and molecular..., Taieb [/bib_ref]. I 123− MIBG-sensitivity and specificity reach 83-100% and 95-100%, respectively, for the diagnosis of sporadic PCCs. The sensitivity of I 123− MIBG decreases to 52-75% for the diagnosis of PGLs and to 18-50% for HNPGLs. [bib_ref] Diagnosis of endocrine disease: biochemical diagnosis of phaeochromocytoma and paraganglioma, Van Berkel [/bib_ref] Galium ( 68 Ga)-DOTA peptide PET showed an overall detection rate of 98.6% in patients with metastatic SDHB Mut PPGLs. In HNPGLs, this is considered the functional image of choice. In polycythemia-related PPGLs and in FH Mut or MAX Mut PPGLs, [bib_ref] Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients, Erickson [/bib_ref] F-DOPA PET is the functional imaging of choice, and if not available, I 123− MIBG-SPECT/CT is recommended [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] European association of nuclear medicine practice guideline/society of nuclear medicine and molecular..., Taieb [/bib_ref] [bib_ref] Diagnosis and management of pheochromocytoma: a practical guide to clinicians, Pappachan [/bib_ref] [bib_ref] Gasomatostatin receptor analogs and (18)F-FDG PET/CT in the localization of metastatic pheochromocytomas..., Kan [/bib_ref]. Generally, when facing metastatic disease, better results are reported with the use of 18 F-FDG PET/CT [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] European association of nuclear medicine practice guideline/society of nuclear medicine and molecular..., Taieb [/bib_ref] [bib_ref] Diagnosis and management of pheochromocytoma: a practical guide to clinicians, Pappachan [/bib_ref] [bib_ref] Gasomatostatin receptor analogs and (18)F-FDG PET/CT in the localization of metastatic pheochromocytomas..., Kan [/bib_ref]. In these cases, I 123− MIBG and studies with SST analogs would be reserved for patients with metastatic disease for whom radiometabolic treatment with 131 I-MIBG and/ or 90 Ytrium ( 90 Y)/ 177 Lutethium ( 177 Lu)-DOTA peptidespeptide receptor radionuclide therapy (PRRT)-is being considered. Recommended PPGL functional imaging studies according to genotype and anatomic location are summarized in [fig_ref] Figure 1: Diagnostic algorithm for PPGLs [/fig_ref]. ## Treatment ## Therapeutic strategy The therapeutic strategy for PPGLs should be discussed by an expert multidisciplinary team based on patient characteristics (e.g., age, performance status, comorbidities) and tumor features (i.e., primary tumor site, local and distant spread, hormone secretion profile, tumor growth rate, functional imaging and genetic profile). Surgical resection is the mainstay of therapy for the majority of localized PPGLs, with adequate perioperative CMN blockade and cardiovascular monitoring in PCCs and functional PGLs. Adequate timing for surgery and optimal surgical approach are still a matter of debate. Advanced, unresectable disease is not curable, and treatment goals are to slow tumor progression and maintain quality of life. Medical treatment of secretory PPGLs is mandatory to prevent life-threatening events [fig_ref] Figure 3: Therapeutic algorithm of metastatic paragangliomas [/fig_ref]. Treatment options include watch and wait strategies for indolent tumors, radiometabolic therapy, radiotherapy, chemotherapy, targeted therapy (i.e., antiangiogenic tyrosine kinase inhibitors) and PRRT. Indications and contraindications of these therapeutic options are discussed below, and a therapeutic algorithm is proposed in [fig_ref] Figure 3: Therapeutic algorithm of metastatic paragangliomas [/fig_ref]. ## Catecholamine blockade Anesthesia, tumor manipulation during surgery, tumor biopsy, adrenal venography and arteriography with ionic contrast can induce excess CMN secretion, hyperadrenergic symptoms and hypertensive crises in patients with PCCs and functional PGLs (FPGLs) [bib_ref] CT of pheochromocytoma and paraganglioma: risk of adverse events with i.v. administration..., Bessell-Browne [/bib_ref]. To prevent this potentially fatal phenomenon, the European Endocrine Society Guidelines recommend that patients with PCCs and FPGLs should undergo a 7-to 14-day preoperative preparation with adrenergic receptor blockers as the first choice. Some authors have questioned the universal indication of preoperative α-adrenoceptor blockade given the potential side effects of this therapy, but prospective studies are needed to identify in which patients' preoperative therapy may be safely avoided. α1 selective blockers (e.g., doxazosin: initiate with 4 mg/day and then titrate up to 16-32 mg/day) are associated with fewer adverse effects, such as reactive tachycardia and sustained postoperative hypotension, compared to nonselective α-blockers (e.g., phenoxybenzamine: initiate with 10 mg/day and then titrate up to 1 mg/kg/day). Calcium channel blockers are the most often used add-on drug class to further improve blood pressure (BP) control. Only after administration of α-adrenergic receptor blockers may a β-adrenergic receptor antagonist (e.g., propranolol or atenolol) be added 2 or 3 days before surgery if the heart rate (HR) exceeds 80/minute (bpm) [bib_ref] Preoperative levels of catecholamines and metanephrines and intraoperative hemodynamics of patients undergoing..., Weingarten [/bib_ref]. Phone or e-mail-based preoperative monitoring of BP and HR, orthostatic hypotension, and pharmacological side effects may be implemented in the clinic to avoid multiple visits [bib_ref] The use of telemedicine in the preoperative management of pheochromocytoma saves resources, Heslin [/bib_ref]. Presurgical antihypertensive treatment has been also advised for patients with PPGL and a normal blood pressure [bib_ref] Approach to the patient: perioperative management of the patient with pheochromocytoma or..., Berends [/bib_ref]. A high-sodium diet and fluid intake are also recommended to reverse CMN-induced blood volume contraction preoperatively and thereby reduce orthostatic hypotension and minimize the risk of severe hypotension after surgical tumor removal [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref]. Saline infusion (1-2 L) the evening before surgery is also helpful for this purpose. Esmolol β-adrenergic blockade can be employed during surgery. After surgery, BP and HR monitoring is needed to detect postoperative hypotension requiring vasopressor support. Alpha blockade is not specifically required before iv administration of nonionic contrast media in patients with suspected or known PPGL or related tumors [bib_ref] CT of pheochromocytoma and paraganglioma: risk of adverse events with i.v. administration..., Bessell-Browne [/bib_ref]. ## Surgery Surgical resection is the cornerstone of therapy for most localized PPGLs, as it is the only potentially curative therapeutic modality. Careful preoperative planning is required to select the most appropriate surgical technique. This includes precise anatomical characterization of the primary tumor (or tumors if multifocal) location and extension to adjacent structures and/or distant organs and adequate perioperative medical management. The goal of surgery is to achieve complete tumor resection without rupture, including en bloc resection of adjacent infiltrated organs if needed. The complete resection of HNPGLs, indicated in young patients, usually requires previous embolization and may be performed in one or more steps depending on the extent of intradural space (IDS) and/or internal carotid artery (ICA) involvement [bib_ref] Head and neck paragangliomas: experience in 126 patients with 162 tumours, Álvarez-Morujo [/bib_ref]. Elderly or frail patients and those with bilateral multicentric lesions or residual disease may be considered for watch and wait strategies or alternative nonsurgical treatment options [bib_ref] Management of multicentric paragangliomas: review of 24 patients with 60 tumors, Alvarez-Morujo [/bib_ref]. For cervical and mediastinal PGLs, a transcervical approach is generally used, while rarely being associated with a transmandibular, transmastoid or infratemporal approach. Carotid body PGLs with ICA involvement have a higher incidence of complications [bib_ref] Clinicopathologic analysis of ninety cases, Shamblin [/bib_ref]. For vagal PGLs, a cervical or posterior tear hole approach is recommended. A 2-stage surgery may be required if there is significant intradural extension. The resection of jugulotympanic PGLs [bib_ref] Strategies and long-term outcomes in the surgical management of tympanojugular paragangliomas, Prasad [/bib_ref] has different degrees of complexity. Tympanic PGLs are resected through a low-morbidity transcanal, microscopic/endoscopic approach. Tympanomastoid PGLs implicate transmastoid, transcanal, and infralabyrinthic techniques, occasionally with middle ear removal, that have low morbidity over facial and lower cranial nerves. Jugular PGLs can compromise the ICA and the lower cranial nerves and extend to the IDS. The infratemporal approach employed in these cases entails important technical challenges (protection of the ICA with a stent or its occlusion may be required for complete resection) and functional morbidity, particularly if the IDS is involved or the low facial and hypoglossal nerves are affected (> 30%). There is no consensus on the systematic rerouting of the facial nerve. Partial resection may be a valid option in tumors that reach the external auditory canal (EAC) and generate recurrent hemorrhages in elderly patients. For abdominal localized PPGLs, a complete surgical resection (PGL) or adrenalectomy (PCC) is indicated. Bilateral adrenal involvement requires bilateral adrenalectomy. Subtotal adrenalectomy with cortical preservation prevents adrenal insufficiency and the need for hormonal supplementation in up to 90% of patients. This procedure is recommended only for cases with a low risk of malignancy, such as MEN2 or VHL syndrome, and not for other genetic syndromes with a greater risk of distant spread or local relapse due to remnant microscopic disease (e.g., SDHx Mut or MAX Mut ) [bib_ref] One hundred two patients with pheochromocytoma treated at a single institution since..., Shen [/bib_ref] [bib_ref] Extent of surgery for phaeochromocytomas in the genomic era, Rossitti [/bib_ref] [bib_ref] Functional adrenal cortex preservation: a good reason for posterior retroperitoneal endoscopic approach, Vidal [/bib_ref]. In the presence of metastatic disease, total or partial palliative resection may be considered to reduce the disease burden and improve hormonal syndrome control [bib_ref] Malignant pheochromocytoma, Zarnegar [/bib_ref]. PCC resection may be open or laparoscopic. Laparoscopic adrenalectomy (LA) is recommended for most PCCs because it is associated with lower morbidity and a shorter postoperative stay than open adrenalectomy (OA). Recurrence rates do not differ between the 2 surgical approaches, with a rate of conversion to OA between 5 and 12% [bib_ref] Evaluation of open and minimally invasive adrenalectomy: a systematic review and network..., Heger [/bib_ref]. Minimal tumor manipulation is recommended to avoid excessive CMN release, and anesthetists must also be aware that adrenal vein ligation may induce sudden hypotension. Potential hemodynamic instability is not a contraindication for LA, and the time when the adrenal vein is ligated does not seem to be relevant [bib_ref] One hundred two patients with pheochromocytoma treated at a single institution since..., Shen [/bib_ref] [bib_ref] Evaluation of open and minimally invasive adrenalectomy: a systematic review and network..., Heger [/bib_ref] [bib_ref] Adrenal surgery in Spain: final results of a national survey, Moral [/bib_ref]. LA can be performed transabdominally or retroperitoneally. Both LA approaches achieve adequate resection and have minimal morbidity, with no clear hemodynamic benefits of one over the other. The retroperitoneal approach is especially favorable for simultaneous bilateral adrenalectomy [bib_ref] Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161..., Walz [/bib_ref] [bib_ref] Minimally invasive approach for adrenal lesions: systematic review of laparoscopic versus retroperitoneoscopic..., Conzo [/bib_ref]. OA is indicated in bulky (> 6-8 cm) PCCs or in PCCs with a high suspicion of 1 3 malignancy and/or involvement of neighboring organs or complex locations [bib_ref] One hundred two patients with pheochromocytoma treated at a single institution since..., Shen [/bib_ref]. PGL resection may be more challenging because such tumors are usually located in complex sites (e.g., retroperitoneum, paravertebral, para-aortic in the Zuckerkandl organ and along the inferior hypogastric plexuses adjacent to the urogenital organs) and have a higher risk of malignancy and recurrence. Therefore, an open approach is generally recommended. Non-infiltrative PGLs in favorable locations can be resected by endoscopic surgery [bib_ref] Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161..., Walz [/bib_ref]. Acute postoperative complications, such as hemodynamic and metabolic instability with hyper-or hypotension and hypoglycemia, can be avoided with appropriate CMN blockade and fluid replacement. Acute and chronic adrenal insufficiency should be assessed, and hormonal replacement therapy should be appropriately administered in bilateral total and cortical sparing adrenalectomy or unilateral cortical sparing adrenalectomy of a sole remaining adrenal gland. ## Radiotherapy and radiometabolic therapy ## Radiotherapy The greatest experience of PGL radiotherapy (RT) comes from the treatment of glomus jugular tumors, as RT constitutes a noninvasive therapeutic option that is appropriate in locations with high surgical risk or when patients are not candidates for surgery (patients with carotid or intracranial involvement) [bib_ref] Results of a systematic literature review of treatment modalities for jugulotympanic paraganglioma,..., Jansen [/bib_ref]. Conventional RT achieved modest responses (20-30%) that were surpassed by radiosurgical techniques administered in single doses [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas..., Amar [/bib_ref] [bib_ref] Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono Study): a European network for..., Hescot [/bib_ref] [bib_ref] Pheochromocytomas and paragangliomas: bypassing cellular respiration, Cascón [/bib_ref] and, thereafter, by stereotaxic ablative radiotherapy (SABR), with doses of 20-25 Gy in 3-5 fractions, leading to tumor control rates of 90-100% and symptomatic improvement in 80% of patients [bib_ref] A 10-year experience of linear accelerator-based stereotactic radiosurgery/radiotherapy (SRS/SRT) for paraganglioma: a..., Gigliotti [/bib_ref]. ## Radiometabolic therapy Systemic radiometabolic treatment is an option for disease control in patients with inoperable locally advanced or metastatic disease and documented tumor uptake of the corresponding radioisotope. It is generally considered for symptomatic patients with slow-growing tumors and significant tumor volume or disease progression [bib_ref] EANM EANM procedure guidelines for 131I-meta-iodobenzylguanidine 131I-mIBG) therapy, Giammar Ile [/bib_ref] [bib_ref] Current consensus on I-131 MIBG therapy, Kayano [/bib_ref]. Functional imaging studies should be carried out with 123 I-MIBG and/or radiolabeled SST analogs to assess the affinity of the tumor for the radiotracer and to choose the most appropriate radiopharmaceutical for each case before peptide receptor radionuclide therapy (PRRT) [bib_ref] Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma, Baudin [/bib_ref]. The largest accumulated experience with 123 I-MIBG shows that over 50% of patients with mPPGL are candidates for radiometabolic treatment. There is no consensus regarding the preferred treatment protocol, optimal dose and time interval between doses, or response criteria. With the administration of a medium-high activity (200-275 mCi) of 123 I-MIBG, repeated every 3 months depending on the achieved response, objective responses have been documented in 30-60% of cases, a hormonal response in 10-71% of patients and a symptomatic response in 23-90% of patients [bib_ref] I-131 metaiodobenzylguanidine therapy of pheochromocytoma and paraganglioma, Carrasquillo [/bib_ref]. The main side effects are related to cumulative dose-dependent bone marrow toxicity and renal toxicity. Thyroid radiotracer uptake should be blocked prior to therapy to prevent hypothyroidism, and blood counts and renal function should be monitored. More recently, a novel 123 I-MIBG derivative has been developed, Iobenguane 131 I or high-specific-activity (HSA)- [bib_ref] Prolonged survival in a patient with pulmonary metastases of a malignant pheochromocytoma, Van Den Broek [/bib_ref] I-MIBG, produced from a solid-phase ultratrace precursor that eliminates the presence of cold MIBG and is able to deliver a high radioactivity level per dose (~ 2500 mCi/mg; 92.5 MBq/μg). With conventional 123 I-MIBG cold MIBG competes with radiolabeled MIBG for the NE transporter, reducing labeled MIBG uptake by the tumor cell, thus limiting efficacy and increasing the levels of circulating NE that can lead to life-threatening acute hypertensive crisis during or shortly after drug administration. A phase 2 trial showed that 17 of 68 PPGL patients (25%) treated with HSA-123 I-MIBG had a durable reduction in baseline antihypertensive medication use, and 92% achieved a partial response or stable disease as the best objective response within 12 months. The median OS was 36.7 months, and no patients had drugrelated acute hypertensive events. Based on these data, HAS-123 I-MIBG received FDA breakthrough therapy designation and was approved in July 2018 for the treatment of patients with iobenguane scan-positive, advanced or mPPGLs who require systemic anticancer therapy [bib_ref] Efficacy and safety of high-specific-activity (131)I-MIBG therapy in patients with advanced pheochromocytoma..., Pryma [/bib_ref]. Experience in the use of PRRT for the treatment of PPGLs is limited, although early results look promising. Radiological control has been described in 80% of patients with metastatic SDHB Mut PPGL treated with 177 Lu-DOTA-TATE [bib_ref] Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma, Kong [/bib_ref] [bib_ref] A clinical efficacy of PRRT in patients with advanced, nonresectable, paraganglioma-pheochromocytoma, related..., Kolasinska-Cwikla [/bib_ref]. However, prospective studies are necessary to determine the role of PRRT in the control of patients with inoperable advanced or mPPGLs. ## Systemic therapy Metastatic disease, unless amenable to complete surgical resection, is incurable. Systemic treatment options are limited but can offer symptom palliation and disease control. However, due to the relatively indolent nature of PPGLs, these therapies are generally reserved for patients with clear disease progression or severe symptoms caused by hormone secretion or mass effects. Evidence to support treatment decisions is poor, although increasing data suggest that different molecular subtypes driven by distinctive oncogenic pathways may have unique sensitivity profiles to specific 1 3 drugs [bib_ref] New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification, Crona [/bib_ref] [bib_ref] Pheochromocytomas and paragangliomas: from genetic diversity to targeted therapies, Pang [/bib_ref]. International collaborative efforts are key to make adequately sized prospective trials feasible. Chemotherapy is considered the treatment of choice for patients with advanced PPGLs who have progressed to or are not suitable candidates for MIBG or PRRT. Cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy is the most widely used regimen and is considered the standard of care despite the lack of prospective trials [bib_ref] New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification, Crona [/bib_ref] [bib_ref] Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic..., Ayala-Ramirez [/bib_ref] [bib_ref] Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic..., Niemeijer [/bib_ref]. A systematic review of four retrospective series that included 50 patients reported an objective tumor response rate of 41% (4% complete and 37% partial responses) and a biochemical response rate of 54% (14% complete) [bib_ref] Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic..., Niemeijer [/bib_ref]. Two of these studies reported median durations of response of 20 and 40 months, respectively. In the largest singleinstitution experience with chemotherapy (54 patients), 33% of patients achieved a response, defined as improved BP control and/or reduced tumor size. OS was 6.4 years for responders vs 3.7 years for non-responders, a difference that was statistically significant in multivariate analysis [bib_ref] Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic..., Ayala-Ramirez [/bib_ref]. The most common toxicities include myelosuppression, peripheral neuropathy and gastrointestinal toxicity, which may occasionally be severe but are generally transient and manageable. A retrospective study of 15 patients treated with temozolomide (150-200 mg/m 2 /day d1-5 q28 days), 8 of whom had received prior chemotherapy, documented 5 partial responses (33%) that occurred only in patients with SDHB mutations [bib_ref] SDHB mutations are associated with response to temozolomide in patients with metastatic..., Hadoux [/bib_ref]. The median progression-free survival (PFS) was 13.3 months (19.7 vs 2.9 months in SDHB Mut vs noncarriers). SDHB-germline mutations were associated with O-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation and low MGMT protein expression in a cohort of 190 samples of the French national PPGL network [bib_ref] SDHB mutations are associated with response to temozolomide in patients with metastatic..., Hadoux [/bib_ref]. These findings suggest that MGMT epigenetic silencing in SDHB Mut carriers may render them particularly sensitive to this alkylating agent. Successful outcomes have also been reported in two patients with SDHB Mut metastic PGLs treated with temozolomide metronomic schedules (75 mg/m 2 /day × 21/28 days) following progression to prior CVD therapy [bib_ref] Successful second-line metronomic temozolomide in metastatic paraganglioma: case reports and review of..., Tena [/bib_ref]. More recently, an increased activity in the Poly(ADP-ribose)polymerase (PARP) DNA repair system has been described in SDH-B Mut PPGLs, associated with chemo-resistance [bib_ref] Targeting NAD(+)/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated..., Pang [/bib_ref]. The PARP-inhibitor olaparib was shown to markedly potentiate the therapeutic effect of TMZ with prolonged overall survival of mice with SDHB knockdown PPGL allograft [bib_ref] Targeting NAD(+)/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated..., Pang [/bib_ref]. Based on these findings, a trial investigating the synergistic effect of the addition Olaparib to TMZ is currently undergoing (NCT04394858). A number of tyrosine kinase inhibitors (TKIs) are being explored due to the key role that angiogenesis regulation plays in PPGLs, particularly in Cluster 1 (SDH-and VHLdriven PPGLs) and some Cluster 2 tumors (i.e., RET). The phase II SNIPP trial evaluated sunitinib in 25 patients with progressive PPGLs [bib_ref] A phase 2 trial of sunitinib in patients with progressive paraganglioma or..., O'kane [/bib_ref]. The overall response rate was low (13%) in the overall unselected population, although all three partial responses occurred in patients with germline mutations in SDHA, SDHB and RET (with this last patient remaining on treatment 7 years later). The disease control rate (DCR) was 83%, meeting the study primary endpoint, and the median PFS was 13.4 months. The most common severe side effects were fatigue and thrombocytopenia (16% each), and three patients discontinued treatment due to cardiovascular adverse events. Sunitinib is currently being assessed in the first randomized, placebo-controlled trial ever conducted in PPGLs, the FIRSTMAPPP trial. A phase II trial with pazopanib was terminated early due to poor patient accrual. One of the six evaluable patients achieved a partial response (17%), and the median PFS and OS periods were 6.5 and 14.8 months, respectively [bib_ref] Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma, Jasim [/bib_ref]. Similarly, preliminary data of a phase II trial with axitinib reported an objective response in three of nine treated patients (33%) and some degree of tumor shrinkage that did not qualify for partial response in five additional patients, which was associated with biochemical response [bib_ref] Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG):..., Pichun [/bib_ref]. Other TKIs (cabozantinib, lenvatinib, etc.) are currently being evaluated in clinical trials (https:// clini caltr ials. gov/). Finally, some other drugs active in the treatment of NETs, such as 'cold' SST analogs and interferon, have been poorly addressed in this setting although they are also used for the treatment of PPGLs [bib_ref] Successful second-line metronomic temozolomide in metastatic paraganglioma: case reports and review of..., Tena [/bib_ref] [bib_ref] Interferon-alpha treatment for disease control in metastatic pheochromocytoma/paraganglioma patients, Hadoux [/bib_ref]. Currently, a phase II prospective trial is assessing the role of the SST lanreotide in patients with advanced disease (NCT03946527). ## Local ablative therapy and supportive care In patients with progressive advanced or mPPGLs, the treatment goals are to manage hormone-related symptoms, control tumor growth and prolong OS. The use of local ablative therapies in this setting can improve local control and palliate symptoms [bib_ref] Efficacy and safety of ablative therapy in the treatment of patients with..., Kohlenberg [/bib_ref]. The indication must be individualized and discussed within the multidisciplinary team and carefully balanced versus other treatment options for patients with mPPGLs. There is no prospective study to assess differences in outcome for patients receiving different ablative treatments for advanced disease. However, two recent retrospective studies published by the Mayo Clinic have analyzed the outcome of patients with mPPGLs receiving local therapies. The first study showed median OS and PFS rates of 24.6 and 33.7 years, respectively, at a median follow-up of 8.2 years (range, 0.01 to 54.1 years). Among the 272 patients analyzed, 97% underwent additional surgical resection (for primary tumors or metastases). In addition, palliative RT, radiofrequency ablation, embolization procedures, stereotactic radiotherapy, cryoablation and percutaneous ethanol injection were performed in 47%, 9%, 8.8%, 5.8%, 4.7% and 2% of the patients, respectively. Almost half of the patients (45%) survived > 10 years [bib_ref] Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years, Kittah [/bib_ref]. The second study reported the efficacy and safety of radiofrequency ablation, cryoablation and percutaneous ethanol injection in these patients. Radiographic local control was achieved in 69/80 (86%) lesions. Improvement in metastasis-related pain or symptoms of CMN excess was achieved in 12/13 (92%) patients. Thirty-three (67%) procedures had no reported complications [bib_ref] Efficacy and safety of ablative therapy in the treatment of patients with..., Kohlenberg [/bib_ref]. PPGLs are among the solid tumors that most frequently spread to the skeleton and cause skeletal-related events (SRE) (i.e. pain, bone fracture, and spinal cord compression are commonly the first manifestation of metastatic disease (31%). SREs should, therefore, be properly addressed, as they compromise survival and can seriously impair patients' quality of life. A multidisciplinary approach with specialists in endocrinology, oncology, palliative care, radiotherapy, orthopedic surgery and neurosurgery is of utmost importance. ## Follow-up recommendations Short-term postoperative follow-up should include clinical and biochemical evaluation (MNs, 3MT/CgA if other markers are negative) 2-6 weeks after recovery. Imaging is recommended 3 months after recovery in patients with persistent postoperatively altered biochemical markers, silent PPGLs and absence of preoperative biochemical evaluation [bib_ref] European society of endocrinology clinical practice guideline for long-term follow-up of patients..., Plouin [/bib_ref]. Long-term follow-up is mandatory in all patients, as they are all considered at risk of tumor recurrence, and the clinical behavior of PPGLs is remarkably variable, especially in PPGLs associated with hereditary syndromes. Ten-year follow-up is recommended for all patients with resected PPGLs and lifelong personalized follow-up for patients with hereditary forms of the disease; such follow-up should be performed by a multidisciplinary team at a tertiary center whenever possible. Whereas in some patients with mPPGLs, the discovery of metastases may precede the discovery of the primary tumor, others may develop metastases many years after the initial diagnosis [bib_ref] Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years, Kittah [/bib_ref] [bib_ref] Prolonged survival in a patient with pulmonary metastases of a malignant pheochromocytoma, Van Den Broek [/bib_ref]. Candidates for intensified surveillance have to be identified. Male sex, older age at primary tumor diagnosis (≥ 76 years), larger tumor size (> 4.5-5 cm), failure to undergo complete surgical resection of the primary tumor, DA hypersecretion and synchronous metastases are associated with shorter survival [bib_ref] Pheochromocytomas and paragangliomas: bypassing cellular respiration, Cascón [/bib_ref] [bib_ref] Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over..., Goffredo [/bib_ref] [bib_ref] Adrenal medulla and extra-adrenal paraganglia, Oudijk [/bib_ref] [bib_ref] Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients, Erickson [/bib_ref] [bib_ref] Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from..., Thompson [/bib_ref] [bib_ref] Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a..., Kimura [/bib_ref] [bib_ref] Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma..., Curras-Freixes [/bib_ref]. Tumor size, extra-adrenal location and germline SDHB mutations are independent risk factors for mPPGLs [bib_ref] Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas..., Amar [/bib_ref] [bib_ref] Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene..., Neumann [/bib_ref] [bib_ref] Genetic testing in pheochromocytoma or functional paraganglioma, Amar [/bib_ref] [bib_ref] Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas..., Ayala-Ramirez [/bib_ref] [bib_ref] Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant..., King [/bib_ref] [bib_ref] The size of the primary tumor and age at initial diagnosis are..., Schovanek [/bib_ref]. Currently, no specific follow-up protocols are established. The frequency of surveillance should be based on a number of factors, such as the affected gene, genotype-phenotype correlation, symptomatic or silent pattern of the disease, potential severity of the disease, penetrance and family history. Overall, it is recommended to carry out annual clinical anamnesis, physical exam (including blood pressure control) and biochemical monitoring (MNs, ± 3-MT and optional CgA in MNs/3-MT negative PPGLs). Imaging studies are recommended yearly in suspected cases (based on clinical or biochemical evaluation) or every 2-3 years in silent PPGLs. To avoid cumulative irradiation, body or head/neck MRI should be considered the imaging procedure of choice for surveillance, especially in children and during pregnancy, reserving CT and functional NM imaging to characterize pathological findings in cases of relapse. Specific monitoring of the other diseases associated with each syndrome should also be performed [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] [bib_ref] European society of endocrinology clinical practice guideline for long-term follow-up of patients..., Plouin [/bib_ref]. Regarding the role of functional imaging during followup, experts [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] recommend the use of 123 I-MIBG scintigraphy when the risk of metastasis or disease recurrence is high, and 18 F-FDG PET/CT is only indicated in established metastatic disease. The use of more than one functional imaging modality may be considered in selected cases, such as the use of both [bib_ref] Diagnosis of endocrine disease: biochemical diagnosis of phaeochromocytoma and paraganglioma, Van Berkel [/bib_ref] Ga-DOTATATE and 18 F-FDG PET/CT in patients with small lesions when there is a high likelihood of metastatic disease and in SDHx Mut patients [bib_ref] Update of pheochromocytoma syndromes: genetics, biochemical evaluation, and imaging, Alrezk [/bib_ref] [bib_ref] Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization..., Janssen [/bib_ref]. Follow-up of asymptomatic carriers There is no sufficient clinical epidemiological evidence from clinical data to perform general recommendations for surveillance. The main aim of surveillance programs in healthy mutation carriers, especially in SDHX-mutation carriers, is to identify disease at an early stage in order to allow a successful intervention at the appropriate time, improve cure rates and limit the chance of malignant transformation and metastasis. Modality and frequency of screening that individual centers adopt will be dependent on local expertise, availability and costs. The appropriate age to start screening will vary according to the specific hereditary syndrome including the malignant and metastatic potential associated with the identified genetic mutation. In children it is generally recommended between 5 and 10 years of age or 5 years before the youngest clinical manifestation in the family. Biochemical and clinical monitoring follows diagnosis recommendations mentioned above. Debate is ongoing regarding the frequency and type of the functional image probe to be done. Most tumors are diagnosed in the first screening image performed. The Endocrine Society Guidelines [bib_ref] Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline, Lenders [/bib_ref] emphasized that consideration for any imaging modality requires prior positive clinical or biochemical evidence of disease, except in case of a personal or family history of HNPGL related or not to a hereditary form. More recent studies and meta-analysis report the need of periodical image evaluation, the recommended frequency varying generally between 2 and 3 years [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref] [bib_ref] Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma, Muth [/bib_ref] [bib_ref] A review of the tumour spectrum of germline succinate dehydrogenase gene mutations:..., Macfarlane [/bib_ref] [bib_ref] Can subunitspecific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?, Tufton [/bib_ref] [bib_ref] Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision..., Casey [/bib_ref]. Currently, translational research stratification scores have been developed to estimate the risk of new PPGL events and the frequency of metastatic disease [bib_ref] What have we learned from molecular biology of paragangliomas and pheochromocytomas?, Papathomas [/bib_ref] ; however, evidence from longitudinal studies is still needed, and guidelines for follow-up continue to evolve. National and international registries are fundamental to collect information necessary to deliver updates that permit the elaboration of clinical guidelines. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. [fig] Figure 1: Diagnostic algorithm for PPGLs. CT computed tomography, FDG fluorodeoxyglucose, HNPGL head and neck paraganglioma, MN metanephrine, Mtx metastasis, NMN normetanephrine, MIBG metaiodobenzylguanidine, 3-MT 3-methoxytyramine, MRI magnetic resonance imaging, PCC pheochromocytomas, PGL paragangliomas, PPGL pheochromocytomas and paragangliomas, SSTRI somatostatin receptor imaging, VHL von Hippel-Lindau. a Plasma 3-MT: only in high clinical suspicion of dopamine-secreting tumors/hereditary syn-dromes associated with HNPGL. b Chromogranin A: nonspecific neuroendocrine tumor marker that may be considered if high clinical suspicion of silent PPGLs. c Recommended at diagnosis only in cases of high suspicion of metastasis, particular if there is family history or silent tumor. d 123-I-MIBG versus [/fig] [fig] Figure 2: Typical morphological and functional imaging of PPGLs. a, b Axial contrast-enhanced CT portal (a) and delayed phase (b) of the upper abdomen showing the pheochromocytoma in the right adrenal gland (yellow arrowhead). Intravenous contrast administration typically enhances avidly due to the capillary-rich framework of the tumor. c, d Coronal T2-weighted MRI images revealed a homogeneous pheochromocytoma (c) in the right adrenal gland (yellow arrowhead), and other pheochromocytomas in the left adrenal gland (yellow arrowhead) with central necrosis are characteristically "lightbulb" bright lesions on T2-weighted imaging (d). Pheochromocytomas are potentially malignant (10%), and the only reliable criterion for the diagnosis of malignancy is metastatic spread. e A 61-year-old woman with metastatic cervical paraganglioma. 68 Ga-DOTATOC PET/CT study showing bilateral laterocervical lymph nodes, mediastinal involvement and multiple bone metastases. f A 56-year-old man was diagnosed with a 44 × 39-mm right adrenal incidentaloma. After right adrenalectomy, a histological study showed pheochromocytoma without evidence of malignancy. Negative genetic study. During follow-up, he presented with recurrence. Body scan with 123-I-MIBG shows lesions in the right renal cell and multiple peritoneal implants, some in contact with the liver surface without being able to rule out secondary infiltration. The patient has received treatment with 131I-MIBG with stabilization of the disease 1 3 [/fig] [fig] Figure 3: Therapeutic algorithm of metastatic paragangliomas. CVD, Cyclophosphamide, Vincristine, Dacarbazine; MIBG, 123-I-Metaiodobenzylguanidine; MGMT, O-methylguanine-DNA methyltrans-ferase; RF, radiofrequency; RT, radiotherapy; SDH, Succinate dehydrogenase; SSTRI, somatostatin receptor imaging; TKI, Tyrosine kinase inhibitors; TMZ, Temozolomide 1 3 [/fig] [table] Table 1: Pheochromocytoma and paraganglioma risk stratification systems Parameter Score Pheochromocytoma of the adrenal gland scaled score (PASS) [/table] [table] Table 3: PPGL susceptibility genes [/table] [table] Table 4: Screening indications for PPGLs [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-021-02622-9.pdf	None
322c69cc2afb5040ed79c92730eec74306ba9611	pubmed	Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a clinical practice guideline	Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a clinical practice guideline Background: Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. A clinical practice guideline was developed based on a systematic review investigating neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer.Methods:A systematic review with meta-analysis was developed and clinical recommendations were drafted. External review of the practice guideline report by practitioners in Ontario, Canada was obtained through a mailed survey, and incorporated. Final approval of the practice guideline was obtained from the Practice Guidelines Coordinating Committee.Results:The systematic review was developed and recommendations were drafted, and the report was mailed to Ontario practitioners for external review. Ninety percent of respondents agreed with both the evidence summary and the draft recommendations, while only 69% approved of the draft recommendations as a practice guideline. Based on the external review, a revised document was created. The revised practice guideline was submitted to the Practice Guidelines Coordinating Committee for review. All 11 members of the PGCC returned ballots. Eight PGCC members approved the practice guideline report as written and three members approved the guideline conditional on specific concerns being addressed. After these recommended changes were made, the final practice guideline report was approved.Conclusion:In consideration of the systematic review, external review, and subsequent Practice Guidelines Coordinating Committee revision suggestions, and final approval, the Gastrointestinal Cancer Disease Site Group recommends the following:For adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice. # Background Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a clinical practice guideline. This clinical practice guideline was developed by the Gastrointestinal Cancer Disease Site Group (DSG) of Cancer Care Ontario's Program in Evidence-based Care (PEBC), using the methods of the Practice Guidelines Development Cycle [bib_ref] The practice guidelines development cycle: a conceptual tool for practice guidelines development..., Browman [/bib_ref]. This practice guideline report is a convenient and up-to-date source of the best available evidence on neoadjuvant or adjuvant therapy for resectable esophageal cancer, developed through systematic review, evidence synthesis, and input from practitioners in Ontario. The PEBC has a formal standardized process to ensure the currency of each clinical practice guideline report. This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original clinical practice guideline information. The systematic review on neoadjuvant or adjuvant therapy for resectable esophageal cancer, which forms the basis for this clinical practice guideline, is available in a companion document [bib_ref] Zuraw L, members of the Gastrointestinal Cancer Disease Site Group of Cancer..., Malthaner [/bib_ref]. Based on the systematic review, draft recommendations were developed by consensus of the Gastrointestinal Cancer DSG to create the clinical practice guideline report. The clinical practice guideline is intended to promote evidence-based practice in Ontario, Canada. As part of the PEBC's clinical Practice Guideline Development Cycle, all draft recommendations are sent to Ontario practitioners for external review. The efficacy of this external review process has been previously described [bib_ref] Progress of clinical oncology guidelines development using the practice guidelines development cycle:..., Browman [/bib_ref]. The external review is a mailed survey consisting of items that address the quality of the draft practice guideline report and draft recommendations and whether the draft recommendations should serve as a practice guideline. Final approval of this practice guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC). # Methods ## Clinical practice guideline development systematic review A systematic review with meta-analysis on neoadjuvant or adjuvant therapy for resectable esophageal cancer was developed by the Gastrointestinal Cancer DSG of Cancer Care Ontario's Program in Evidence-based Care [bib_ref] Zuraw L, members of the Gastrointestinal Cancer Disease Site Group of Cancer..., Malthaner [/bib_ref]. The evidence examined did not support the use of neoadju-vant or adjuvant chemotherapy or radiotherapy for resectable thoracic esophageal cancer. ## Gastrointestinal cancer disease site group consensus In discussions regarding the completed systematic review, the Gastrointestinal Cancer DSG agreed that the evidence did not support a recommendation for neoadjuvant or adjuvant chemotherapy or radiotherapy for resectable thoracic esophageal cancer. A recommendation that surgery alone should be the standard of care for this patient population was drafted, and it was recommended that the draft practice guideline be sent out to Ontario practitioners for external review. The role of radiotherapy alone and chemoradiation alone without surgery is addressed in a separate Gastrointestinal Cancer DSG Clinical Practice Guideline: Combined modality radiotherapy and chemotherapy in the non-surgical management of localized carcinoma of the esophagus [bib_ref] Rumble RB, the Cancer Care Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease..., Wong [/bib_ref]. # Results ## External review Practitioner feedback was obtained through a mailed survey of 163 practitioners in Ontario (27 medical oncologists, 21 radiation oncologists, 112 surgeons, and three gastroenterologists). The survey consisted of items evaluating the methods, results, and interpretative summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer DSG reviewed the results of the survey. Eighty-six surveys (58%) were returned. Twenty-nine respondents (34%) (nine medical oncologists, seven radiation oncologists, and 13 surgeons) indicated that the report was relevant to their clinical practice and completed the survey. Key results of the practitioner feedback survey are summarized below. 6. Approval of the recommendation as a practice guideline: 69% ## Summary of main findings Three (10%) respondents provided written comments. One practitioner hypothesized that preoperative chemoradiation might have a role in adenocarcinoma of the lower third of the esophagus (as suggested by Walsh et al [bib_ref] A comparison of multimodal therapy and surgery for esophageal adenocarcinoma, Walsh [/bib_ref] with 100% adenocarcinoma and by Urba et al [bib_ref] Strawderman M: Randomized trial of preoperative chemoradiation versus surgery alone in patients..., Urba [/bib_ref] with 75% adenocarcinoma), but not in squamous cell carcinoma (as suggested by Bosset et al [bib_ref] Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of..., Bosset [/bib_ref] and by Le Prise et al [bib_ref] A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for..., Prise [/bib_ref]. Another respondent noted that the survival advantage at three years for combined treatment for preoperative chemoradiotherapy is discounted in the guideline report, and suggested that the guideline recommend the selection of the option preferred by informed patients. There was a request for an algorithm to help in deciding between surgical and non-surgical treatment. The same respondent commented on the limited discussion on quality of life. Two radiation oncologists disagreed with the recommendations and thought that the draft practice guideline report should not be approved as a practice guideline, but neither provided written comments. # Discussion ## Gastrointestinal cancer disease site group modifications and actions After completion of the practitioner feedback survey, additional trials were found. The results of two randomized trials both found surgery alone to be significantly superior to radiation alone [bib_ref] Prospective randomised study in the treatment of oesophageal carcinoma, Fok [/bib_ref] [bib_ref] The quality of swallowing for patients with operable esophageal carcinoma, Badwe [/bib_ref] , which resulted in an original draft recommendation regarding radiation alone as a primary modality for localized esophageal cancer being removed from the final practice guideline. In response to this feedback, the Gastrointestinal Cancer DSG acknowledged that the majority of studies have been performed in squamous cell carcinomas. While adenocarcinomas were included in some studies, a distinction between the two histological subtypes was not made because previous studies have not consistently found that they respond differently to chemotherapy or radiation, and nine references [bib_ref] Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer..., Forastiere [/bib_ref] [bib_ref] Long-term results of infusional 5-FU, mitomycin-C and radiation as primary management of..., Coia [/bib_ref] [bib_ref] Treatment of locoregional esophageal cancer, Forastiere [/bib_ref] [bib_ref] Patterns of treatment failure and prognostic factors associated with the treatment of..., Gill [/bib_ref] [bib_ref] Preoperative chemotherapy and radiotherapy for esophageal carcinoma, Naunheim [/bib_ref] [bib_ref] Induction chemoradiotherapy followed by esophagectomy in patients with carcinoma of the esophagus, Jones [/bib_ref] [bib_ref] Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced..., Ilson [/bib_ref] [bib_ref] Transhiatal esophagectomy: clinical experience and refinements, Orringer [/bib_ref] [bib_ref] Three-field lymphadenectomy for esophageal cancer, Altorki [/bib_ref] were added to support this. The Gastrointestinal Cancer DSG did not feel the evidence was compelling enough to recommend preoperative chemoradiotherapy over surgery alone based on the threeyear data. After consideration, the Gastrointestinal Cancer DSG decided not to create an algorithm as suggested as a similar project is currently under development. After addressing the comments obtained from practitioners during the external review, the Gastrointestinal Cancer DSG voted that the overall guideline recommendations should be approved, and submitted the practice guideline to the Practice Guidelines Coordinating Committee for review. ## Practice guidelines coordinating committee approval process The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee for review and approval. All 11 members of the PGCC returned ballots. Eight PGCC members approved the practice guideline report as written and three members approved the guideline conditional on the Gastrointestinal Cancer DSG addressing specific concerns. PGCC members requested that the following issues be addressed prior to the approval of the guideline report: One member noted that although the majority of studies had been performed in squamous cell carcinomas, some studies included adenocarcinomas, and it would be helpful if the pathological subtypes were discussed. In particular, this member wanted to know if there was any difference in response or outcome for the two histological subtypes. Another member noted that although the pooled analysis for preoperative chemoradiation versus surgery alone detected no difference at one year, the pooled estimate almost reached significance. This member was concerned that the discussion may be too dismissive of the data, and suggested there be some acknowledgment that further follow-up and additional studies are needed. In response to this feedback, the Gastrointestinal Cancer DSG expanded on the earlier revisions concerning the similarities in response to treatment between squamous cell carcinomas and adenocarcinomas. Also, after the original practice guideline was submitted to the PGCC, two meta-analyses [bib_ref] Preoperative radiotherapy and chemotherapy in patients with esophageal carcinoma: a meta-analysis, Fiorica [/bib_ref] [bib_ref] A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery..., Urschel [/bib_ref] both detecting a statistically significant difference in survival at three years favouring preoperative chemoradiation versus surgery alone were obtained. The Gastrointestinal Cancer DSG repooled the mortality data from the six trials [bib_ref] A comparison of multimodal therapy and surgery for esophageal adenocarcinoma, Walsh [/bib_ref] [bib_ref] Strawderman M: Randomized trial of preoperative chemoradiation versus surgery alone in patients..., Urba [/bib_ref] [bib_ref] Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of..., Bosset [/bib_ref] [bib_ref] A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for..., Prise [/bib_ref] [bib_ref] Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study..., Nygaard [/bib_ref] [bib_ref] A prospective study of combined therapy in esophageal cancer, Apinop [/bib_ref] at three years and obtained similar results. # Conclusions In consideration of the systematic review, external review, and subsequent Practice Guidelines Coordinating Committee revision suggestions, and final approval, the Gastrointestinal Cancer Disease Site Group developed the following Clinical Practice Guideline: ## Practice guideline This practice guideline reflects the most current information reviewed by the Gastrointestinal Cancer DSG. ## Target population These recommendations apply to adult patients with resectable and potentially curable thoracic (lower two-thirds of esophagus) esophageal cancer for whom surgery is considered appropriate. ## Recommendation - If surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice for resectable thoracic esophageal cancer. This Clinical Practice Guideline report is based on work completed in October, 2003. All approved PEBC Clinical Practice Guideline reports are updated regularly. Please see the PEBC's web site http://www.cancercare.on.ca/ access_PEBC.htm for a complete list of current and ongoing projects. [table] 1: Number surveyed: 163 practitioners in Ontario, Canada involved in the care of cancer patients [/table]	None	https://bmccancer.biomedcentral.com/counter/pdf/10.1186/1471-2407-4-67	None
ef2c8181373877ef14b369692164b5bd98510f01	pubmed	Management of chronic urticaria in children: a clinical guideline	Management of chronic urticaria in children: a clinical guideline The aim of this guidance is to provide recommendations to clinicians and other interested parties on chronic urticaria in children. The Italian Society for Pediatrics (SIP), the Italian Society for Allergy and Immunology (SIAIP), the Italian Society for Pediatric dermatology (SIDerP) convened a multidisciplinary panel that prepared clinical guidelines for diagnosis and management of chronic urticaria in childhood. Key questions on epidemiology, natural history, diagnosis, and management were developed. The literature was systematically searched and evaluated, recommendations were rated and algorithms for diagnosis and treatment were developed. The recommendations focus on identification of diseases and comorbidities, strategies to recognize triggering factors, improvement of treatment by individualized care. # Introduction Chronic urticaria (CU) is characterized by recurrent migrating skin lesions, called wheals or hives, angioedema (AE) or both lasting over 6 weeks. Wheals consist of a swelling area of different size and shape with a larger erythema, often pruritic. Lesions usually disappear in 24 h. In vasculitis and pressure urticaria lesions persist longer. AE is a submucosal or subcutaneous swelling, and involves areas such as lips, eyelids, back of the hands and feet, scrotum. AE resolves in 1-3 days and causes pain, tingling, burning sensation or tension, but not itching. Prognosis quoad vitam and quoad valetudinem of CU is generally good. However, comorbidities can occur. Overall, it is a condition of mostly unknown etiopathogenesis, and a frequent cause of specialist consultation and inappropriate diagnostic investigation, aimed at identifying a causal factor which is often not evident by history alone. Many guidelines on CU are available. None of them is dedicated to the paediatric population and some difference occurs among guidelines. Many documents do not address specifically CU, whose etiopathogenesis is believed to be different from acute urticaria (AU), while many others discuss only chronic spontaneous urticaria (CSU). Therefore, the aim of the present guideline is to provide an evidence-based approach for the management of CU in children for use in clinical practice. # Methods In 2016, the Italian Society for Pediatrics (SIP), the Italian Society for Allergy and Immunology (SIAIP), the Italian Society for Pediatric dermatology (SIDerP) convened a multidisciplinary panel that included primary care paediatricians, general pediatricians, hospital paediatricians, allergist, immunologist, dermatologist, psychologist, methodologist skilled in systematic reviews and guideline. No conflict of interest was declared by panel members. Team members defined the most relevant questions on CU in childhood, then they agreed on systematic literature research and literature evaluation strategy. Search strategy aimed at gathering studies, published from June 1, 2009 that is the last year included in the previous SIAIP/SIP/ SIDerP guideline on CU, to January 1, 2018 concerning prevalence, incidence, aetiology, diagnosis, therapy, prognosis and psychological issues of CU in children. The research was limited to studies published in English and Italian, with no preferential type of study. In order to select the studies to be included in the final analysis, a hierarchic selection of literature sources was chosen, starting from secondary sources (evidence-based guidelines and systematic reviews) and proceeding with primary studies (RCTs and non-randomized trials). Guideline documents were searched in the main general guideline websites and in the websites of the main scientific societies pertinent to CU. Systematic reviews were searched in Cochrane Database, DARE and Pubmed, using keywords as "urticaria" or "chronic urticaria" and "systematic review". Evidence on primary studies was obtained by literature searches of PubMed/EMBASE. In PubMed, the following search strings and keywords were used -("Epidemiology" Other studies, with no restriction of type were found through the electronic databases, references of the selected studies, hand searches or papers suggested by experts were also used. Two authors have independently selected the studies relevant to each clinical question from the systematic research. They critically appraised each article, using the following validated tools when appropriate: SNLG criteria [13] and Grilli criteriafor Guidelines. AMSTAR toolfor Systematic reviews. AMSTAR-2was not used, as it has been recently published and its validity has not yet been verified. Assessment of Risk of Bias tool from Cochrane Collaborationfor randomized controlled trials (RCT). Newcastle-Ottawa scale for cohort studies, case-control studies and cross-sectional studies, when comparativefor observational studies. QUADAS-2for diagnostic studies. Users' Guides to the Medical Literaturefor prognostic studies. A complete list of appraisals of selected papers is available at http://www.siaip.it. Any disagreement in evaluation has been resolved via discussion. An evidence-based critical analysis was used to formulate conclusions and recommendations. Expert consensus was used when there was a lack of data. When it was possible, it was provided a recommendation based on grading of the quality of available evidence from the literature according to the Italian National Guideline (PNLG) method . The criteria are as follows. Level of evidence. I. Evidence obtained from more than one properly designed randomized controlled trial and/or systematic revision of randomized study. II. Evidence obtained from one properly designed randomized controlled trial.III. Evidence obtained from non-randomized cohort studies with concurrent or historical controls, or their metanalysis. IV. Evidence obtained from retrospective case-control studies or their metanalysis. V. Evidence obtained from caseseries with no control group. VI. Opinions of respected authorities, group of experts as shown in guidelines, consensus conferences or based on opinion of members of the panel of the current guideline. Strength of recommendation. A. Strong recommendation for performing diagnostic test or procedure, high quality evidence even not necessarily of level I or II. B. It is uncertain that diagnostic test or procedure should be recommended but the intervention should be carefully considered. C. Evidence not allowing recommendation for or against intervention. D. Performing diagnostic test or procedure is not recommended. E. Strong advisement against performing diagnostic test or procedure. Panel members reached agreement on levels of evidence and strength of recommendations. Before approval, the guideline was reviewed by nurses, parents, in order to consider the need for health and the expectations of affected children and their families, and experts who were identified by the panel. All comments were considered in the final document when appropriate. The recommendations in these guidelines will be disseminated through publishing articles and promoting courses. The impact of the current guideline on practice will be assessed by clinical studies. The guideline will be updated after 5 years to maintain validity. Question 1. What is the definition of CU, in the paediatric age? Answer. CU in paediatric age is defined by the daily presence of wheals, that are not always associated with angioedema, for over 6 weeks or with brief periods of well-being due to therapy. Urticaria, AE or both are defined as chronic when they last for over 6 weeks. This definition allows to discriminate CU from AU, typically self-healing in a few days or weeks, usually caused by viral infections or IgE mediated mechanisms. In a child with urticaria onset it is not possible to establish in which cases it will last over 6 weeks. In the paediatric population no markers have been identified. Isolated AE is usually recurrent not persisting. Thus far, there is no reason to believe that CU with AE is a different clinical entity from CU without AE, although some studies on adults seem to suggest that the presence of AE correlates with a higher chance of positive autologous serum skin test (ASST). Conversely, isolated AE without urticaria often involves pathogenetic mechanisms and have clinical features that are different from AE associated with CU. Therefore, it must be considered that isolated chronic AE without urticaria should be distinguished from CU, especially in the process of differential diagnosis. ## Question 2. what is the classification of cu? Answer. CU in the child must be classified in "spontaneous" or "inducible", in relation to the evidence of a triggering factor. In CSU, there is no eliciting factor. In chronic inducible urticaria (CIU), one or more triggers, often physical agents, can be identified by history and/or laboratory tests. Although "spontaneous" and "idiopathic" are often used as interchangeable terms, the definition of CSU is to be preferred as there is an anti-IgE autoantibody mediated form that should not be considered idiopathic. However, separating CU associated with anti-IgE autoantibodies from CSUis not justified as many studies in adults have not found any histological differences between CSU and autoimmune CU. Moreover, although some studies in adults found that autoimmune CU can have a more severe and prolonged course, there is no such evidence in children. Finally, in adults, data suggest that some forms of CIU may have an autoimmune mechanism. Question 3. What is the prevalence and incidence of CU in the paediatric population? Answer. Few data exist on epidemiology of urticaria in children, however it is reasonable to think that prevalence and incidence of CU in developmental age are both below 1% (Level of evidence IV). Few data are available on epidemiology of CU in children. Studies on mixed adult and children populations reported a lifetime prevalence of 0.8%. A Korean survey on children aged 4-13 found a prevalence of 0,7%, with no difference among the two sexes. Concerning incidence, an Italian study on children aged 0-14, where the diagnosis of CU was made by a paediatrician, showed an annual incidence of 0.6 to 2.1 /1000 children, and a prevalence fluctuating between 0,38% and 0,84%. Overall, the prevalence of CU in children seems to be below 1%, and there is no significant difference among males and females. Question 4. What is the natural history of CU in paediatric age? Answer. Remission at 3 years from onset of CSU in children happens in 30% to 50% of cases. Anaphylaxis is reported only in CIU (Level of evidence IV). Prospective as well as retrospective studies of good methodological quality on representative paediatric populations showed that chance of remission of CSU at a year from onset ranged from 10 to 32%. At 3 years from onset, remission chance varied from 31 to 54% and at 5 years from 38 to 72%. The variability of the percentages was due to the different duration of the observation period, different criteria to define remission and sample size. A recent study reported a remission incidence of 10.3% per year. In the same study, a positive basophil activation test (BAT) or the lack of circulating basophils were associated to an almost double chance of remission after one year of follow-up. The natural course of CU in children is therefore not different from adults. However, some studies on adult and children samples have shown a higher probability of improvement of symptoms in subjects below 19 years old. Female, age above 10 years and severe disease at onset have been related to a lesser chance of remission at 3-5 years of age. The natural course of physical factors induced CU and cholinergic CU is not well known, but it is probably like CSU. Some studies, mainly performed on adults, reported a more prolonged duration of disease in patients with cold urticariaand solar urticaria. A longer persistence of CIU in atopic subjects compared to non-atopic ones has been found. Question 5. What is the etiopathogenesis of CU in children? Answer. In most cases, CU in children is spontaneous and no external cause is found. However, in half of the cases of CSU, an autoimmune mechanism is possible. In a minority of patients, CU is associated with inducing factors, often physical (Level of evidence V). Pathogenesis of CU in children has been poorly investigated and studies have a low methodological quality. A systematic reviewand subsequent studieshave showed that in most cases, an external cause of CU is not identified. In a recent survey, a potential cause has been found only in 8.8% of children with CU. Most studies in children describe the frequency of factors associated with CU that were considered as causal agents, without being compared to a control population. Moreover, in most studies the association with a causal factor was established without evaluating the effectiveness of its removal (e.g. Infections, allergens). So, the prevalence of each potential causative factor varies among studies, even considering differences in setting and diagnostic criteria. In CSU, an autoimmune pathogenesis has been reported in almost half of the cases. - What is the role and the effect of inducing factors in children? Answer. Inducing factors are the most frequent and often the only identifiable cause of CU in children (Level of evidence V). Inducing factorsare usually the most frequent cause of CU in children. The evidence of the role of inducing factors in children's CU has been confirmed by the reproduction of skin lesions when the relevant stimuliare applied. In children, inducing factors triggered CU in 6.2 to 52.9% of cases. In studies where inducing factors were investigated following international guidelines, the relative prevalence of CIU ranged from 22 to 40.1% of cases. The discrepancy of prevalence is due to heterogeneity of population samples and different diagnostic approaches. Dermographism, cholinergic urticaria and cold urticaria are the most common. Different types of CIU can coexist in the same subject. Moreover, in patients with CSU, hives may develop following exposure to physical stimuli, mainly dermographism and pressure. The pathogenesis of CIU is unclear. Serum from affected subjects (e.g. dermographism or cholinergic urticaria) injected into a monkey passively transfers the symptoms. More recently, in patients with solar urticaria or cold urticaria, an IgE-mediated response against cutaneous, trigger-released auto-allergens seems to be implied. Systemic symptoms such as bronchospasm, hypotension, loss of conscience, intestinal wall oedema, up to anaphylaxis and exitus may occur in solar urticaria, cold urticaria, pressure urticaria, cholinergic urticaria and aquagenic urticaria . About 1/3 of patients with cold urticaria has had at least one episode of anaphylaxis, most commonly after bath in the sea or in the pool. In children, cold urticaria is rarely due to cryoglobulinemia or paraproteinemia. - What is the role of infections/infestations in children's CU? Answer. The evidence on the role of viruses, bacteria or parasites in inducing CU is sparse and limited to single cases or case series. Few paediatric patients with CU and parasitical infestations that healed after the eradication of parasites have been described. This correlation has been occasionally reported in other infections (Level of evidence V). Viral and bacterial infections have been reported to aggravateor causeCU in children with a frequency ranging from 0 to 35% of patients with CU, while parasitical infestations from 0 to 37.8% . The causal role of infections in patients with CU requires a high incidence of the infection in affected patients, and remission of symptoms after treatment. However, the prevalence of chronic infections in patients with CU is not different from the general population. Moreover, children with CU, affected by chronic infections or parasitic diseases, that are still symptomatic after eradication therapy have commonly been reported. These findings suggest that the association between infection and CU is mostly accidentaland that in many cases CU recovers because of the disease's natural course rather than because of the treatment of the infection. Bacteria are the most studied, particularly Helicobacter pylori. Protein components of H. pylori of molecular weight 21 and 35 Kd, can activate mast-cells in vitro, causing the release of histamine, TNF-alfa, IL-3, IFN-gamma and LTB4. Differences among studies in design and diagnostic methods make it challenging to interpret the association between H. pylori and CU. Furthermore, studies in children are few. A systematic review concluded that the chance of remission of CU in patients with H. pylori infection after eradicating therapy is significantly higher than in those who did not undergo eradication therapy or in those with CU without H. pylori infection. A slightly more recent systematic review concluded that the evidence on benefits of eradicating therapy for H. pylori in CU was weak and conflicting. Moreover, in a Turkish non-comparative study, performed on 222 children with CU, 32,8% of patients were tested positive to C13-UBT but only in one case a complete remission of cutaneous symptoms after eradicating therapy was observed. Similar results have been reported in studies on smaller paediatric case series. Even in adults, studies that show that eradicating H. pylori infection leads to the resolution or improvement of CU symptoms, are lacking. Concerning other bacterial infections (e.g. Streptococcus, Staphylococcus, Chlamydia Pneumoniae), prevalence in CU does not differ from that in general population. Clinical trials either do not often clarify whether there was resolution of symptoms after the clearance of the infective agentor they found that treatment did not resolve the disease. For example, in a Turkish study on a large population of children, CSU resolved following antibiotic therapy in only one out of three patients with positive urine culture. In children with CU and parasitic infection, anti-parasitic agents have been sporadically reported to improve cutaneous lesions in Western countries. Blastocystis hominis, Giardia lamblia, Dientomobea fragilis, Ascaris lumbricoides and Strongyloides stercoralis have been frequently detected. The incidence of parasitic infestations in children with CU varied from 0% to 37,8%. In children, remission of CU after anti-parasitic treatment ranged from 0 to 100% of cases. In the only study with a control group, the rate of resolution after anti-helminthic treatment was similar in children with and without parasitic infection. Therefore, the relationship between CU and parasitic infestation in children remains unclear. A parasitic infestation may be considered a potential cause of urticaria in a few patients. Non-controlled studies in adults have shown a high frequency of sensitization to Anisakis in patients with CU, with improvement of symptoms in a variable proportion of patients after a seafood-free diet. No data is available on the association between Anisakis infestation and CU in children. Viral infections (Herpesviridae, HBV and HCV) have been identified as a cause of CU in anecdotal cases or non-controlled studies. A possible role of latent infections by HHV-6 in adults has been suggested. Up to date, however, there is no evidence of a role of viruses in CU in children. - What is the role of allergy in CU in children? Answer. There is no clear evidence that food allergens or medications provoke CU in children (Level of evidence V). In children with CU, COX-1 inhibitors should not be used unless necessary because they could aggravate symptoms. (Level of evidence IV. Strength of recommendation D). There is no evidence that IgE-mediated hypersensitivity reactions play a pathogenetic role in CU in children. Atopy is not predictive of severity or longer duration of CU in children. Nevertheless, a longer duration in atopic children with CIU has been reported. ## Contact allergy Contrasting data have been reported on the role of contact hypersensitivity in CSU in adults. Positive patch tests for common contact allergens have been shown in 42,9% of 543 patients, mostly adults (aged 5-85), with differences in sensitization due to age and occupation. There is no evidence that avoidance of aptens can improve CU. ## Prevalence of atopic diseases Adults with CU have a significantly higher prevalence of asthma, allergic rhinitis and atopic eczema compared to controls (10,8%, 9,8% and 19,9% vs 6,5%, 3,7% and 10,1% respectively). Similar trials are lacking in children. Prevalence of atopy, defined as positive skin test or personal history of allergic diseases, ranged from 13 to 35.9% in case series of children with CU. This confirms a similar frequency in a general paediatric population. ## Total ige levels In adults, levels of serum IgE are related to severity and duration of CU. Higher levels of total IgE have been reported in children with CU than in those with AU, with no significant differences in inhaled or food allergens sensitisation and circulating eosinophils. The meaning of this association is unclear. ## Food allergy Despite parents' views, food allergy is a rare cause of CU in childhood. In case series of children with CU, the prevalence of food allergy varied from 0 to 8.6%. It must be pointed out that in many studies the oral food challenge (OFC) was not performed or, when performed, it was not double-blind controlled but open. So, reported rates are less reliable since CU is characterized by daily symptoms. Furthermore, in children with a positive OFC, the elimination diet did not always cure urticaria. In a mixed adult and children population, the rate of IgE mediated food allergy ascertained by open OFC was 2,8%. Studies in adults but not in children show a possible correlation between IgE to lipid transfer protein and CU. ## Aeroallergens Although, it has been shown that aeroallergens may trigger CU, there is no evidence of an association between IgE mediated sensitization to inhaled allergens and CU in children. ## Medications Medications causing CSU in children have been sparsely reported. In a large population of children with CSU, no suspected drug allergy was confirmed. Regarding NSAIDs, COX-1 inhibitors, even the ones that are not related to one-another, can exacerbate CU through non-immune-mediated mechanismsindependently from a causing role. In children with CSU, single blind oral challenge with ASA was positive in 24% of cases, and lip angioedema was the more common manifestation. CU appears also to be the main risk factor for NSAIDs hypersensitivity in childhood. Therefore, it is advisable not to give NSAIDs to children with CU unless necessary. - What is the role of pseudo allergens and vasoactive amine rich foods in children's CU? Answer. There is insufficient evidence that pseudo allergens and vasoactive amine rich foods can modify CU's course (Level of evidence V) Intolerance to additives has been associated to CU in 2,6 to 21% of children in low quality studies that did not report whether a low additive diet improved symptom. In 81% (13/16) of children with idiopathic CU, symptoms recovered after a 3-week low pseudo allergen diet; only 6/13 patients underwent a double-blind OFC with suspected additives, which was positive in 5/6 cases. In 100 patients with CU aged between 14 and 67 years old, two adults did not pass single blind OFCs to 11 additives including food colourings and preservatives. These two patients passed a double-blind controlled OFC to the same additives. In an open study in adults, a low pseudo allergen diet improved CSU in around a third of the patients. Limitations of the study included lack of a control group and missing evaluation of reintroduction of excluded foods. The same methodological bias had an open study in adults that showed the effectiveness of a 3-4-week low vasoactive amine diet in 75% of patients. In conclusion, existing data do not support the causative role of pseudo allergens in CU. - What is the role of autoimmunity in children's CU? Answer. In 30-50% of children with CSU, autoimmune mechanisms are probably implied (Level of evidence IV). We can hypothesize the role of auto-allergens in some forms of inducible urticaria (Level of evidence V). In contrast to adults, the paucity of studies on autoimmune diseases allowed to associate children's CU only with anti-thyroid antibodies, autoimmune thyroiditis and coeliac disease (Level of evidence V). CSU is often associated with autoimmune thyroiditis and coeliac disease in children. Large longitudinal studies in adults show that co-morbidity of CU and autoimmune diseases is common. There is accumulative evidence that a causal relationship between type I autoimmunity and CU is "suggestive" and between type II autoimmunity and CU is "probable". ## Serum autoantibodies activating mast cells and basophils The presence of circulating IgG autoantibodies against high affinity receptor for IgE (FcεR1α) or anti-IgE antibodies (type II autoimmunity) that can release mediators from mast-cells and basophils is well established in many patients with CSU. Functional tests used to detect these autoantibodies include in vitro tests, such as basophil histamine release assay (BHRA) and basophil activation test (BAT), as well as in vivo tests, notably autologous serum skin test (ASST) and autologous plasma skin test (APST). In vitro and in vivo tests are not interchangeable and study different pathogenetic mechanisms of the disease. A positive ASST has been reported in 22 to 53.5% of children with CU . ASST can be positive even in healthy subjects or in patients affected by different diseases. Only a subgroup of patients with positive ASST has a positive in vitro histamine releasing test. It has also been noted that ASST uses non-purified IgG. A positive ASST result persists after removal of complement protein and IgG adsorption. Therefore, ASST indicates a mast cell activation induced not only by autoantibodies but also by other serum factors that can promote histamine release. There is no difference in the frequency of positive ASST between children with CU affected by parasitic infestation and those without infestation. In adults with CU, APST is more frequently positive than ASST. There is no experience in children about the use of APST. Regarding in vitro tests, histamine releasing IgG anti-FcεR1α functional antibodies have been documented in 47% of children with CU compared to 0% of controls with atopic eczema. Other studies reported significantly higher levels of BAT in children with CSU compared to healthy controls. In these studies, there was an overlapping of values between the two populations, so that it was not possible to identify a cut-off value to separate them. Autoantibodies have been detected by Western blot method or ELISA immunoenzymatic method in adults with CU, but not in children. Regarding Witebsky's criteria, that are necessary to define CU as a type II autoimmune disease, direct evidence and circumstantial evidence, drawn from clinical practice, are not complete and an animal model is lacking. Some forms of CIU (solar, cholinergic, cold) may involve the production of IgE against auto-allergens expressed in the skin as an effect of thermic stress or other physical factors, as shown by positive passive transportation test. ## Thyroid autoimmune disease Patients with CU are at risk of thyroid autoimmune disease (particularly Hashimoto thyroiditis). Case-control studies show that in children with CSU the prevalence of autoimmune thyroiditis is 10 to 30 times higher than in a general population. Levels of IgG anti-thyroid antibodies are significantly increased in patients with CU compared to controls; these levels are also higher in adults than in children. It is unclear whether anti-thyroid antibodies play a pathogenic role. Higher anti-thyroperoxidase IgE levels were found in adults with CSU, making it possible to hypothesize auto-allergy mechanisms. The presence or absence of antibodies do not confirm nor exclude the diagnosis of thyroiditisand up to date a causal role of thyroid disease on CU onset has not been proven unequivocally. In adults, thyroid diseases are often associated with CU, while in children the prevalence of hypothyroidism, often due to Hashimoto thyroiditis more than Graves' disease, is below 1% and hyperthyroidism has not been reported. There is no clear evidence that in patients with thyroid autoimmunity, CU has a different course or that treatment with thyroid supplementation therapy improves urticaria. ## Coeliac disease Case reports and case control studies have shown the association between CU and coeliac disease in children as well as adults. The prevalence of coeliac disease in patients with CSU varies among studies, and it is increased by 8-10 times when compared to a general population. A remission of cutaneous symptoms after a gluten free diet has been also reported. Conversely, studies on large populations highlighted a slightly higher prevalence of CU as well as AU in patients with coeliac disease in comparison to healthy controls. ## Other autoimmune diseases Adults with CU seems to have an increased risk of developing other autoimmune diseases compared to children, possibly because incidence of autoimmune diseases rises with age. In children with systemic lupus erythematosus, CU is rare (0-1% of cases) when compared to adults. Few cases of systemic lupus erythematosus in children with CU have been described. The presence of anti-nucleus and anti-DNA antibodies without connective tissue disorders has been rarely observed in children with CU. The prevalence of rheumatoid arthritis, Sjogren syndrome, type 1 diabetes is increased in adults with CU. In childhood data are lacking. Vitiligo, pernicious anaemia and Raynaud's phenomenon with anti-centromere antibodies have been sparsely reported in children as well as in adults. What is the role of the activation of coagulation and fibrinolysis in CU in children? Answer. Insufficient data have been reported on the role of coagulation and fibrinolysis processes in the pathogenesis of CU in children (Level of evidence V). Studies on adults have shown that the coagulation 7cascade can have a role in the pathogenesis of CU. The cascade seems to be initiated by expression of tissue factor by activated eosinophils and the release of thrombin. In animal models, thrombin increased vascular permeability with a direct action on endothelial cells as well as an indirect one on histamine and other mediators released by mast-cells. During urticaria exacerbations, adults with CU showed increased prothrombin fragments serum levels. In adults with CU, there was fibrinolysis. Serum levels of Ddimer and fibrin degradation product increased during exacerbations of CU in adults and they have been proposed as markers of severity and response to antihistamines. The activation of the processes of coagulation and fibrinolysis in CU in paediatric age is supported by few studies on mixed adult and paediatric populationsand by a Japanese study that showed the increase of serum levels of prothrombin fragments 1 and 2 in the small group of children with CU. Question 6. Is CU in children associated to other organ diseases or systemic diseases more frequently than in non-selected population? Answer. There is no evidence of an association of CU in children and other organ or systemic diseases (Level of evidence V) Although in adults it has been reported that CU is associated with rheumatic, inflammatory and psychiatric diseases, irritable bowel disease, cancerand metabolic syndrome, the evidence is insufficient. There are no similar studies on children. Constipation and irritable bowel are not more frequent in children with CU.Question 7. Can psychological factors determine CU or exacerbate it? Answer. Studies performed on adults might suggest a role of psychological factors in the development or exacerbation of CU. In small populations of children, weak data seem to support this hypothesis (Level of evidence IV). Many studies suggested that psychological factors might contribute to the development or the exacerbation of CU, supposing that they could play a role in its pathogenesis. Some authors suggested an interaction between nervous and immune systems. Animal models have pointed out that acute stress caused the activation of skin mast-cells and the expression of corticotrophin releasing hormone receptors. Adults with CU had significantly higher scores in tests to diagnose obsessivecompulsive disorders, depression, anxiety, insomnia, stressing events than controls. In adults, numerous studies have been performed, but in children data are still few. In 27 children with CU, there was a higher prevalence of psychiatric disorders (70% vs 30%), mainly anxiety and depression, but also separation anxiety, specific phobias, psychosomatic disorders than in controls. No correlation has been found with severity or duration of disease. About 2/3 of children underwent a stressing event in the 6 months before the onset of CU. More trials are needed to clarify the role of psychological factors in causing or aggravating CU, and the efficacy of a multidisciplinary approach with appropriate psychological and pharmacological support. Question 8: Can clothes or temperature changes worsen CU? Answer. There are no studies that document the role of clothes and temperature on the course of CU in children, excluding subjects with cold-urticaria, heaturticaria, cholinergic urticaria (Level of evidence VI). ## Diagnostic work-up The aim of the diagnostic work-up is to establish criteria to recognize patients with urticaria, make a differential diagnosis, identify triggering factors, assess disease activity and its control. Question 9. Which are the criteria that allow to diagnose CU in children? Recommendation. The diagnosis of childhood CU is based on appearance of itchy wheals, not always associated with AE, persisting daily or on most days for at least 6 weeks. No laboratory test is needed to diagnose CU (Level of evidence VI. Strength of the recommendation A) The diagnosis of CU is based on history and occurrence and duration of wheals, typically itchy, migrating, fading with finger pressure. The duration of a single lesion is usually less than 24 h with episodes lasting over 6 weeks. AE is characterized by non-erythematous oedema, associated to a burning or pain sensation lasting up to 72 h, often located in the face, genitalia and extremities. There is no instrumental or laboratory test to diagnose CU. Question 10. Which conditions should be considered in the differential diagnosis of CU and what are the clinical or laboratory criteria that help in the differential diagnosis? Are vasculitic urticaria, monogenic syndrome associated urticaria and bradykinin mediated AE different clinical entities from common CU? Recommendation. Differential diagnosis is necessary in any case of CU as wheals can be found in many acquired or hereditary conditions, with different pathogenic mechanisms, such as papular urticaria, mastocytosis, some vasculitis and genetic syndromes. Wheals must also be differentiated from other elementary lesions, as papulae. Recurrent isolated AE should be distinguished from bradykinin mediated angioedema, hypoproteinemic oedema and some cancers. An evaluation of morphology of lesions, duration and associated signs and symptoms leads toward a diagnostic hypothesis that must be confirmed or not by diagnostic tests listed in(Level of evidence VI. Strength of recommendation A). CU should be distinguished from many genetic or acquired diseases, based on various clinical characteristics and the result of diagnostic tests. Vasculitic urticaria and monogenic syndrome associated urticaria can be differentiated from common CU because of their different macroscopic appearance, histology, clinical evolution of lesions and response to therapy. Question 11. What is the role of history and physical examination in identifying the aetiology of CU in children? Recommendation. History and physical examination are the guide to identify a possible underlying cause of CU and decide whether other diagnostic tests are needed (Level of evidence V. Strength of recommendation A). History is the first step in the diagnostic process of CU. Clinical history is helpful to differentiate CSU from CIU and to identify a specific cause. Clinicians should investigate: Frequency and duration of skin lesions. Wheals lasting over 24 h lead to delayed pressure related CU or vasculitic urticaria. On the contrary, wheals lasting less than an hour are common in physical urticaria (except for pressure induced urticaria). Shape, dimension, distribution of wheals. Presence of isolated or associated angioedema. Family history of atopy, urticaria, systemic disorders. Age at onset of symptoms. Triggering and aggravating factors, particularly food habits, medications, physical exercise or physical factors, supposed interval between exposure a wheal appearance. Circumstances and places when symptoms occur (night/day, inside/outside, free time...). Systemic signs and symptoms that suggest organ or systemic diseases, such as coeliac disease, vasculitic urticaria or auto-inflammatory conditions such as periodic cryopyrin-associated syndromes. Subjective symptoms, as pain, burn, itch. Quality of life. Former tests executed. Effectiveness of present or past treatment. Any laboratory test should be performed when history and clinical data suggest an eliciting factor or a systemic disease to confirm its role in the pathogenesis. Question 12. In case of suspected CIU, is it necessary to perform diagnostic tests for inducible urticaria? Recommendation. Specific tests should be used to confirm the suspect of inducible CU (Level of evidence V. Strength of recommendation B).should be performed to confirm the suspicion of inducible urticaria and when possible, to determine minimal stimulation cut-off, useful to define the activity of disease and response to therapy. It must be underlined, however, that in 1/3 of cases tests result negative. Different types of inducible urticaria can co-exist in the same subject; in this case the various triggers should be tested in sequence. To make the tests more reliable, anti-histamines and corticosteroids should be interrupted 3 and 7 days before the test respectively. Stimuli should be applied to parts of the body that were not involved by urticaria in the last 24 h, to avoid a reduced response due to temporary local refractoriness. ## Specific tests Question 13. When clinical history does not indicate an underlying cause, is it recommended to perform laboratory tests to identify allergic or infective triggers, in a child? Recommendation. When clinical history does not suggest a temporal relationship between exposure to an allergen and onset of symptoms, it is not recommended to perform allergy tests to foods, additives, inhaled particles or medications (Level of evidence VI. Strength of recommendation D). When there is a history of cause-effect relationship between exposure to an allergen and occurrence of urticaria and IgE tests are positive to the relevant allergen, diagnosis can be ascertained by effectiveness of allergen avoidance and positive provocation test to the same allergen (Level of evidence V. Strength of recommendation A). Diagnostic tests for infectious disease should be performed only when there is a suspicion based on clinical history or laboratory tests (Level of evidence V. Strength of recommendation B). An IgE mediated reaction to foods or medications can be considered a potential cause of CU when the reaction develops within one or two hours following allergen exposure and it vanishes in a few hours. Regarding allergic reaction to NSAIDs, they can occur within 24 h. If the interval time between allergen exposure and urticaria occurrence is different, IgE mediated reactions are ruled out and allergy tests (skin prick test, serum specific IgE, challenge) to foodsand medicationsshould not be performed. Patch tests to foods are not recommended. Additives, preservatives and colouring free diet in foods and medications should be advised only in the rare cases in which we can suspect a relationship between their intake and the onset of symptoms. If the diet is effective, a double-blind placebo-controlled provocation test is needed to firmly establish the diagnosis. The rate of resolution of CU after the eradication of infectious agent is low. Therefore, viral, bacterial and parasitic infections must be investigated only in patients with suggestive history or laboratory tests. There is weak evidence that laboratory testing for parasites should be performed in patients with history of abdominal pain, earlier infestations, staying in regions at risk, unexplained eosinophilia. In patients with CU a parasitic infestation is not associated with AE, total IgE levels, high CRP, positive prick test, positive ASST. Functioning circulating IgG antibodies against high affinity receptor of IgE (Fc (epsilon) RI (alfa) receptor), and against IgE themselves, can be measured in vitro by BHRA or by BAT, which are both poorly standardized methods. It is also possible to use Western Blot or ELISA, non-commercialized immunoassay, which are expensive, have little specificity and sensitivity and do not differentiate between functional and non-functional autoantibodies. In vivo, ASST showed lower diagnostic accuracy when compared to BHRAsince it contains both IgG and serum factors that can promote histamine release. Therefore, the test must be considered an expression of auto-reactivity, and not of the presence of functional autoantibodies. Negative ASST excludes an autoimmune pathogenesis even in patients with positive BHRA or BAT. In children, there is a concordance of 83% between ASST and BHRA. None of the proposed tests allows to formulate a certain diagnosis of autoimmune CU and it has been proposed as diagnostic gold standard the presence of a positive biological test (BHRA, BAT with CD63 expression), of ASST and of an enzymatic immunoassay. From a clinical point of view, in children with CU, there are contrasting data on the association of positive ASST and CU severity, time courseor response to treatment. In adults, it is unclear whether ASST negativization occurs when CU resolves. Therefore, ASST should not be routinely performed. In BAT, high levels of expression of CD63 are associated with a higher urticaria activity score 7 (UAS7), although with low sensitivity and specificity. Question 15. Is it useful to perform tests to rule out coeliac disease, thyroiditis, other autoimmune or neoplastic disorders in children with negative history and physical examination? Recommendation. Children with CU should be screened for coeliac disease and thyroid diseases (Level of evidence V. Strength of recommendation B) but not for other autoimmune diseases or malignancies (Level of evidence V. Strength of recommendation D). CU in children is rarely associated with hypothyroidism, anti-thyroid antibodies, or coeliac disease. Coeliac disease can cause CU2. Laboratory tests to identify these conditions should be obtained in all patients, even when specific symptoms are lacking. It has also been advised to monitor patients with CU because they can develop hypothyroidism or anti-thyroid antibodiesover time. In childhood, it is not adviseable to investigate autoimmune diseases or cancers, since case reports have been hardly reported. ## Question 16. which diagnostic workup is appropriate for children with csu? Recommendation. In children with CSU with negative history and physical examination, it could be considered to perform blood tests for inflammatory diseases (blood cell count, CRP, ESR (Level of evidence V. Strength of recommendation B), and to test for autoimmune diseases (coeliac disease, thyroiditis) (Level of evidence V. Strength of recommendation B.) In the diagnostic workup of CSU (with or without AE), history and physical examination are the basis to establish the need to perform laboratory tests and to choose their sequence. If history and physical examination are negative, laboratory tests are rarely useful. Diagnostic testing for autoimmune diseases, associated to CU, can be performed. This task force proposes, therefore, a simple diagnostic workup. 1. If a single wheal lasts over 24 h, and delayed pressure urticaria is ruled out, a skin biopsy can be necessary to confirm a diagnosis of vasculitic urticaria. 2. If a single wheal lasts less than 24 h, different possibilities must be considered. a) If history or clinical features are suggestive for underlying causes (physical factors, medications, foods, additives, infections, autoimmune diseases) specific diagnostic tests should be performed. Dermographism, however, should be searched in all children with CU. b) In case of recurrent, isolate AE, without any clinical feature or history of associated diseases, hereditary AE should be ruled out. c) When there is a suspicion of a genetic disorder, cryopyrin gene should be analysed. d) In the remaining cases, children might undergo additional tests including blood cell count, ESR, CRP to reassure parents on the benignity of the clinical condition; FT4, TSH, anti-microsome antibodies, anti-thyroglobulin and anti-thyroperoxidase antibodies, DGP-AGA (under 2 years of age), anti-TTG, IgA to identify the association with autoimmune diseases. e) ASST and BAT should not routinely be performed to better understand the pathogenesis or for research purposes. Question 17. Is it advisable to use severity scores in children with CSU? Recommendation. Currently there are no validated severity scores for CSU in paediatric age. However, in clinical practice it is possible to use adult scores (Urticaria Activity Score 7-UAS 7) to rate the severity of disease and to assess the response to treatment (Level of evidence V. Strength of recommendation B). The severity of CU should be evaluated in daily practice as well as in clinical trials. Currently there is no severity score that is validated for CU in children. Urticaria Activity Score (UAS7)is the most used score to determine disease activity, its impact on quality of life and response to therapy. Some authors proposed its use in the child, even adapting it to body surface. UAS7 is the sum of daily symptoms' scores during a period of 7 consecutive days. It is requested to the patient to fill a sheet where he daily records the severity of itch and the number of wheals for 7 days. UAS7 allows then to categorise the severity of CSU in severe, moderate, mild (7-15), well controlled (1-6), absent (0), and to define response to treatment. UAS7 should be checked at follow-up visits. UAS7 has some weaknesses. It is based on self-evaluation only; being a prospective score, it cannot be used during the first evaluation of the patient; its evaluation is difficult if the patient forgets to mark the score on some of the days. Other scores have been validated in adults: Angioedema Activity Score to evaluate AE, Urticarial Control Test to evaluate the control of the disease. ## Treatment The first goal of treatment of urticaria is to control symptoms by avoidance of the triggering factor. When this is not possible, the approach to treatment of CU requires a symptomatic medication. Question 18. Can treatment of autoimmune thyroiditis or coeliac disease cure CU? Recommendation. There is no clear evidence that treatment of autoimmune thyroid disease or coeliac (Level of evidence V). The hormone replacement therapy, used in patients with hypothyroidism, can positively affect CU. In case of euthyroidism, even in presence of anti-thyroid antibodies, the treatment with L-Tiroxine is not advised, and thyroid monitoring should be continued. The resolution of CU during a gluten free diet has been sporadically observed in patients with coeliac disease. Question 19. Is it advisable to start an additive and/or pseudo allergen free diet in the child with CU? Recommendation. When history is negative, children should not go on an additive and/or pseudo allergen free diet (Level of evidence V. Strength of recommendation E). Studieson the efficacy of a pseudo allergen free diet, including additives and preservatives, in CU are few and performed on mixed case series of adults and children. These studies did not provide evidence that these interventions are effective when history is negative. Second (new)-generation H1-antihistamine are the first option in the treatment of CSU. A recent review of 73 studies with 9759 participants, including adolescents over 12 years of age, although none of them included specific paediatric data, concluded that anti-H1 anti-histamine drugs are beneficial in less than 50% of cases. More recently, a blind randomized controlled trial, performed on mixed adult and adolescent populations, confirmed the efficacy of cetirizine (10 mg), fexofenadine (180 mg), bilastine (20 mg), desloratadine (5 mg), ebastine (20 mg). In a non-controlled prospective study in subjects with AU or CU aged 11 to 92 years, levocetirizine 5 mg daily for 2-6 weeks greatly improved or resolved symptoms in 60-80% of patients. Overall, 50-74% of patients perceived improvements in quality of sleep/daily activities and 50-65% of patients rated the onset of action for levocetirizine as very rapid or rapid. In a comparative double-blind placebo-controlled trial, in subjects aged 2-11 years old, no significant difference has been found between desloratadine and rupatadine in wheal reduction. However, rupatadine, but not desloratadine, reduced the itch significantly compared to placebo. Quality of life was significantly better in patients treated both with rupatadine and with desloratadine. No difference was found in incidence of adverse effects between active groups and placebo group. Second generation H1 antagonists are generally well tolerated, except for astemizole and terfenadine whose metabolism by P450 liver cytochrome can be blocked by the concomitant administration of ketoconazole or erythromycin, causing cardiotoxic effects. H1-antihistamines should be given for 1-2 weeks and, if effective, the need to continue should be re-evaluated every 3-6 months. Second generation H1 antagonists, approved for paediatric use, are listed in. Levocetirizine, active enantiomer of cetirizine, has been approved by FDA to treat non-complicated CSU in children from 6 months of age. Earlier long-term studies have shown a good safety and tolerability profile of cetirizine and levocetirizine administered at a double dose in children aged between 12 and 24 months old, suffering from atopic dermatitis. Bilastine has a good tolerability and safety profile in children aged 2 to 12 years old suffering from CU. It is desirable to have more clinical trials that can make the data applicable to the whole paediatric population and that can be transposed into law by the drug regulation authorities. The use of first-generation H1-antihistamines (es. hydroxyzine) is not recommended. They are poorly selective against H1 receptor and can easily cross the blood-brain barrier. Consequently, they more frequently determine adverse event than second-generation antihistamines, including sedation, dry mouth, headache, blurred vision, glaucoma, urinary retention. Question 21. Is there any evidence of greater efficacy of a H1-antihistamine compared to the others? In case of failure of H1-antihistamine at standard dosing, should a different H1-antihistamine be used? Answer: There is no evidence that any H1antihistamine is more effective than the others in the treatment of CU, therefore no specific H1antihistamine is recommended as a first option. (Level of evidence I. Strength of recommendation D.) The efficacy of the available H1-antihistamines at standard doses has been evaluated in a recent systematic review. Desloratadine exhibited superior efficacy than placebo in inducing complete remission in medium-term (5 mg q.d./2 weeks-3 months) and shortterm (20 mg q.d./2 weeks) therapies, although no difference was observed between 5 mg q.d. and 10 mg q.d. or short-term treatments. Comparisons between loratadine (10 mg q.d.) vs placebo and vs cetirizine (10 mg q.d.) in short-and medium-term therapies did not show significant differences in terms of "good or excellent response" or complete remission of CU. No significant differences were found between loratadine (10 mg q.d.) vs desloratadine (5 mg q.d.) in medium-term therapy efficacy. Loratadine (10 mg q.d.) and hydroxyzine (25 mg q.d.) were found to be effective and comparable to each other in inducing complete remission in short-term treatments. There was no difference between loratadine (10 mg q.d.) and mizolastine (10 mg q.d.) in terms of complete remission of symptoms and improvement of the quality of life ≥50%. Levocetirizine was effective at a dose of 5 mg/day in medium-term therapies, but not in short-term ones, while a higher dose (20 mg q.d.) proved to be effective in short-term therapy. In comparative studies, levocetirizine (5-20 mg q.d.) was more effective than desloratadine (5-20 mg q.d.). Cetirizine has been shown to determine the remission of CU in more patients then fexofenadine. The authorsconcluded that none of second generation H1-antihistamines was more effective than the others in the control of CU symptoms, although the quality of evidence was heterogeneous. Adverse events of H1-antihistamine have some interindividual variability, some subjects "tolerate" an antihistamine better than another. In a placebo-controlled comparative study, there were no significant differences in drug withdrawal rates due to adverse events between the active group (cetirizine 10 mg q.d. and 20 mg q.d., desloratadine 5 mg q.d., hydroxyzine 25 mg q.d.) and placebo. Rupatadine at standard doses (10 mg q.d.) has a good tolerability and safety profile in children aged 2-11 years. In a double-blind, randomized, placebo-controlled study carried out in children aged 2-11 years with CSU, no significant differences were found in reducing wheals between desloratadine and rupatadine, although rupatadine but not desloratadine was statistically superior to placebo in reduction of pruritus (− 57%). Children's quality of life was statistically improved both in subjects treated with rupatadine and with desloratadine compared to placebo. The incidence of adverse events was equal to placebo in both active groups. In a prospective, open, randomized studyin 100 patients aged 12-65 years old, levocetirizine was found to be more effective than rupatadine in CU patients, but both drugs caused mild sedation. Some authors have described the benefit of a higher dosage (up to fourfold) of second generation H1-antihistamines, in order to control symptoms without compromising the safety profile of these drugs. This approach is recommended by European guidelinesbased on the assessment of the risk-benefit ratioThe efficacy of this approach has been shown in randomized controlled studies on adolescents aged> 12 years old and adults using up to fourfold higher dosage than standard one of cetirizine, fexofenadine, bilastine, ebastine, desloratadine in CUand desloratadine, rupatadine and bilastine in cold-induced urticaria., without significant increasing in side effects. Other studies have observed the efficacy of H1-antistamines at increased dosage. The evidence about the use of H1antihistamines at increased dosage over long term is not yet available. Few studies have evaluated the combined use of different anti-H1 antihistamines at standard or increased dosage. A systematic review concludes that there is no evidence for recommending this option, although it is sometimes used in clinical practice. In adults with CU, adding a first-generation H1-antihistamine (hydroxyzine) to a second generation H1-antihistamine (levocetirizine) is not more effective than levocetirizine alone. A systematic review, including studies in adults, pointed out that the evidence about the efficacy of H2-antagonists for the treatment of CU is weak and unreliable. Question 24. When second-generation H1antihistamine do not adequately control CU, could other treatments be recommended in children? Several treatments have been proposed for use as second and third line therapy in antihistamines-refractory patients. In children, clinical trials on these therapies are lacking or of low quality, except for omalizumab. Therefore, the strength of recommendation is weak, except for omalizumab because of little or no evidence of efficacy, high costs and frequent poor tolerability. When these treatments are started, antihistamines and other drugs that were helpful to the patient should be continued. ## Omalizumab Recommendation. In patients 12 years of age and older with CSU, omalizumab should be added to second-generation H1-antistamines as a second-line therapy when second-generation H1-antistamines alone do not give adequate relief. (Level of evidence I. Strength of recommendation A)Omalizumab, a monoclonal antibody against IgE, is approved for the treatment of children with CSU 12 years of age and older when CSU is not controlled by H1-antihistamine. Studies on omalizumab for the treatment of CSU were mainly performed on adult subjects, and in some cases, paediatric patients (> 12 years old) were also included. Omalizumab achieved statically significant reduction of clinical score and it was safe. Three randomized controlled trialsincluding paediatric patients are available. Ninety patients (5 aged < 18 years) with UAS7 > 12 where analysed in a prospective, randomized, quadruple-blind, placebo-controlled, dose-ranging study. They were randomized to receive placebo or omalizumab every 4 weeks in 3 different dose injections (75 mg, 300 mg, 600 mg). Both the 300-mg omalizumab group and the 600-mg omalizumab group showed greater improvement than the placebo group in UAS7 (13.0 e 7.7 points respectively). The multicentre phase III ASTERIA II study, randomly assigned 323 patients (10 aged < 18 years) with CSU resistant to standard H1-antihistamine therapy and UAS7 > = 16 to receive omalizumab at doses of 75 mg, 150 mg, or 300 mg or placebo, during a period of 12 weeks. The authors found a significant reduction in the average itch-severity-scores (ISS) in the group receiving doses of 150 and 300 mg (primary efficacy outcome), and also a reduction in UAS7, number of lesions, DLQI (Dermatology Life Quality Index), number of patients with UAS7 < 6 and proportion of patients with MID (minimally important difference) response in weekly itchseverity scores at 12 weeks (secondary outcome). Adverse events observed showed no significant differences in the different groups, although the rate was higher in the group treated with 300 mg. The multicentre phase III ASTERIA I trial, a randomized, double-blind, placebo-controlled study, evaluated the efficacy and safety of omalizumab in 319 patients (18 of whom < 18 years). Patients were randomized to receive omalizumab 75 mg, 150 mg, or 300 mg or placebo for 24 weeks. The treatment groups (75 mg, 150 mg and 300 mg) had significant improvement in secondary outcomes and maintenance of efficacy at 24 weeks compared to placebo, without significant adverse events. The three trialshad a low risk of bias in randomization, masking, blindness, dropouts during treatment or follow-up, coherence in reporting. Potential biases were represented by the sponsorship of the studies and by the limited number of paediatric patients. Two other randomized trials have shown the efficacy and safety of omalizumab in adult patients. The response was often observed within a week after the first dose and there are slow responders after 3-5 months. Patients usually relapse after a few months when omalizumab is stopped. A prospective open-label (real-life) study evaluated the efficacy of 150 mg of omalizumab, at intervals ranging from 15 days to 7 weeks, in 68 patients with severe refractory urticaria. 78% achieved complete remission during omalizumab therapy (UAS-7 0). Another study treated 47 CU patients aged from 16 to 74 years with Omalizumab at a dose of 150 mg/month or 300 mg/ month. 84% of patients treated with the highest dose achieved clinical remission. Of the 20 patients who started the treatment with 150 mg of omalizumab, 12 (60%) had a complete response. In 6 of the partial responders, a higher dose of 300 mg was used: 4 of them (66.7%) had a complete resolution of symptoms with 300 mg but 2 still have symptoms. Despite the lack of studies in children, the trials published up to date showed efficacy and tolerability of omalizumab. The small number of adolescents who were enrolled in the phase 3 trialsis a limitation. Whether the baseline clinical findings reportedcan be generalized for this patient population is unknown. This, in combination with the small number of real-world studies, highlights the need for larger studies focusing on efficacy of omalizumab in the subgroup of adolescents with CSU. Case reports of efficacy of omalizumab in children less than 12 years of age have been reported. A limitation of omalizumab is the cost that may be unaffordable in many circumstances. Regarding CIU, there are sparse reports of efficacy of omalizumab in children with cold urticariaand solar urticaria. ## Cyclosporin-a Recommendation. The use of ciclosporin-A can be considered when the combination of second-generation H1-antistamines and omalizumab is not enough to control CSU or patients have not access to omalizumab. Its use is limited by possible side effects (Level of evidence V. Strength of recommendation C). The efficacy of cyclosporin A has been shown in some children with CSU, that was not controlled by high-dose antihistamineor the combination of antihistamine and prednisone. In a prospective, open-label study in 30 patients aged over 18 years, a 5-month cyclosporin-A course has shown good efficacy, 87% of patients was symptom-free after one year of follow-up but there was also a significant number (7/30) of dropouts due to adverse events and failure of low-dose therapy. In adults, cyclosporine A is less effective than omalizumab. Prescription of Ciclosporin A is off-label. Oral corticosteroids should be used as a rescue therapy in severe CU exacerbations. There are no controlled studies on the use of corticosteroids in patients with CU, although they are useful in clinical practice to control symptoms. A retrospective cohort study found that the use of systemic corticosteroids in CU increased risk of corticosteroid-related adverse events and health care costs compared to patients not treated with steroids. Corticosteroids should be given for short periods (3-10 days) given the unacceptable adverse events of their long-term use. ## Systemic corticosteroids ## Montelukast Recommendation. Montelukast in children with CU may be added to a second generation H1-antistamine if they do not control symptoms at standard dose (Level of evidence VI. Strength of Recommendation C). There are no paediatric studies on montelukast in CU. In adults, some randomized trials on montelukast alone in CSU did not improve symptoms better than H1-antistamine, while there was weak evidence of efficacy when it is added to H1-antistamine. The choice of this drug can also be justified by its excellent safety profile. ## Other therapies Recommendation. There is insufficient data to evaluate indication of other treatments in paediatric CU (Level of evidence VI. Strength of Recommendation D). Methotrexate is a drug of uncertain efficacy in CSU, considering the scarcity of studies concerning its efficacy and tolerability. Moreover, there are no data in children. There is no evidence of efficacy in children for the following drugs: sulfasalazine, interferon, plasmapheresis, phototherapy, immunoglobulin ev, danazol, warfarin, ac. tranexamic, hydroxychloroquine, rituximab, heparin, anakinra, anti-TNF alpha, colchicine, miltefosine, mirtazapine, camostat mesylate, mycophenolate mofetil. A systematic review analysed the efficacy of allergenspecific immunotherapy in CU, including 2 very low-quality paediatric studies that would demonstrate significant efficacy in improving urticaria symptoms. Allergenspecific immunotherapy in CU and in atopic dermatitisis supported by preliminary evidence of effectiveness as opposed to respiratory allergies. A controlled study analysed the use of atorvastatin in combination with an antihistamine, another randomized the use of levothyroxine in euthyroid patients with positive blood antibodies. In a randomized parallel single blind trial, performed on 88 adult patients, no significant difference was found in the improvement of CSU after the injection of autologous whole blood or autologous serum or placebo after 6 weeks of treatment. A randomized study on 24 patients with CSU, aged between 14 and 58 years old, who were treated with PUVA or with NB-UVB and evaluated at 20 weeks, did not find any significant differences in the efficacy of both therapies. An open study is available on the use of vitamin D in CSU in 57 patients aged 14 to 75 years old, with vitamin D values below 30 mcg/L. They were treated with 300.000 IU/month for 3 months and a significant improvement of UAS4 and Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) was found. Therefore, vitamin D supplementation can be helpful in patients with demonstrated vitamin D deficiency. The efficacy of a Peony derivative in combination or not with cetirizine was examined in a randomized study in patients aged between 16 and 65, with significant results although not standardized. The effects of herbs were described in a randomized trial of patients of unknown age. - A multidimensional strategy which includes psychoeducational and behavioural interventions, would be appropriate for all patients with CU. Regular monitoring of the patient's emotional state through periodic (every six-months) psychological counselling can reduce maladaptive strategies, prevent or timely identify the onset of significant psychological problems, and intervene timely (Level of evidence VI. ## Strength of recommendation b). - It is recommended to investigate the presence of anxiety, depressive symptoms, isolation or stressful events in patients with CU, as well as to evaluate any signs of psychological or relational distress in patient's parents and/or siblings (Level of evidence VI. Strength of recommendation B) - It is recommended that the multidisciplinary team has a "psychological approach", oriented to empathic listening, availability, clarity, and using a shared language. (Trial Level VI Strength of Recommendation B). - It is recommended that referral of the patient to a psychological consultation happens in a valid team/ patient/family relationship. Is should not be a delegation, but a common route (Level of evidence VI. Strength of recommendation B). - Type of the psychoeducational approach (individual or group) varies according to the doctor's availability and family's needs and availability (Level of evidence VI Strength of recommendation B). ## Psychological impact and quality of life Several studies agree that CU is a disabling skin disease with a very significant impact on patient's psychological state and quality of life. In a mixed population of children and adults, higher levels of anxiety and depression were found in patients with an uncertain diagnosis. The most used tool for assessing children's quality of life is Children's Dermatology Life Quality Index (CDLQ). CU-Q2oL has been recommended. Unfortunately, all the studies on psychological aspects and impact on the quality of life were carried out on adult patients and there is very little on children. A paediatric disease is an event that may influence the parent-child relationship, becoming very important and central in family life. Parents can experience feelings of guilt and frustration, financial strain, inadequacy that can be "silently" transmitted to the child, who can perceive themselves as very ill, and create a personal identity that revolves around the disease. In this context, the characteristics of the family, its resources, the social context are very important to avoid the onset of possible experiences of diversity, limitation, fragility and non-amiability in the child. Several studies reported that, in children with CU, discomfort caused by itching, aesthetic aspect and unpredictability of manifestations can cause, in the children, concern about their health and some internalizing symptoms, anxiety, a higher risk of depression, in a circular reaction in which it is difficult to identify causes and effects. Children with CU mainly complain about itching and pain with emotional, behavioural and relational impairment and a negative impact on quality of life. Perception of pain and pruritus can be influenced by an individual emotional component, due to patient characteristics, stressful events, and family attitude towards the disease. Studies have reported that parents of patients with CU report feelings of fatigue, despair and sleep disorders, as well as a constant time commitment to therapy and check-ups. ## Monitoring and approach of emotional/psychological distress Some studies have affirmed that, since children with CU have high psychiatric morbidity, their psychological status should be screened by clinicians. A regular sixmonthly monitoring allows early detection of signs of discomfort such as tension, anxiety, depressive feelings, social isolation, somatic complaints, sleep and eating disorders, bad school performance. A psychiatric evaluation of all family members is necessary to investigate any personal and/or couple problems, feelings of inadequacy, guilt and inability to give attention to other children, sibling rivalry because of attention focused on the child with disease. In order to be effective, psychological consultation must take place within a valid and trust-based relationship between clinicians, patient and his family. The referral must be "protected and accompanied" because the emotional area is considered an integral part of the treatment process. It is desirable that the first psychological consultation takes place in the presence of the attending specialist, sharing information about the necessary therapeutic interventions, that must be well explained to the family. Therapeutic programs must be integrated and beneficial, they can be individualized or group-based (paediatrician-psychologist plus any other specialists such as dermatologist, allergist or immunologist). The group psychoeducational intervention allows child and his family to confront with other patients, reducing the feeling of isolation, loneliness and diversity. The psychoeducational approach presupposes a holistic vision, based on collaboration, skills increasing, coping and mobilization of the resources of the patient and his parents.	None	None	None
0a98b22704a47893b469e003a71c1e1c50d3d220	pubmed	Practice guidelines for teledermatology in Australia	Practice guidelines for teledermatology in Australia Despite the potential of teledermatology to increase access to dermatology services and improve patient care, it is not widely practised in Australia. In an effort to increase uptake of teledermatology by Australian dermatologists and support best practice, guidelines for teledermatology for the Australian context have been developed by The University of Queensland's Centre for Online Health in collaboration with The Australasian College of Dermatologists' E-Health Committee. The guidelines are presented in two sections: 1. Guidelines and 2. Notes to support their application in practice, when feasible and appropriate. Content was last updated March 2020 and includes modalities of teledermatology; patient selection and consent; imaging; quality and safety; privacy and security; communication; and documentation and retention of clinical images. The guidelines educate dermatologists about the benefits and limitations of telehealth while articulating how to enhance patient care and reduce risk when practicing teledermatology.GUIDELINESTeledermatologyStructure of these guidelines These guidelines are divided into two sections. # Introduction These guidelines aim to inform dermatologists practicing in Australia of best practice in teledermatology and provide guidance to standardise and support the appropriate, safe and effective use of teledermatology in the provision of patient care. The Medical Board of Australia (MBA)'s 'Good Medical Practice: A Code of Conduct for Doctors in Australia' (Good Medical Practice) describes what is expected of all doctors registered to practice medicine in Australia. The application of Good Medical Practice will vary according to individual circumstances, but the principles should not be compromised. These principles are equally valid for technology-based models of medical practice as they are for traditional in-person models.'Practice guidelines for teledermatology in Australia' complement the MBA's Good Medical Practice and 'Guidelines for Technology-based patient consultations' 2 and the Australian Medical Association's guidelines 'Clinical images and the use of personal mobile devices' 3 to provide specific guidance on teledermatology. They are designed to take account of the changing models of care for delivery of dermatological services and work practices of dermatologists, in particular the use of smartphones to capture and transmit clinical information. These guidelines have been developed by The University of Queensland's Centre for Online Health in collaboration with the Australasian College of Dermatologists' E-health Committee, and have been approved by the Australasian College of Dermatologists' Board of Directors. To support their development, a review of the literature and relevant national and international guidelines relating to teledermatology was undertaken to reflect current evidence supporting best practice, tailored for the Australian health-care setting.- Guidelines for dermatologists practicing teledermatology. - A series of Notes to support dermatologists in following the Guidelines. These include detailed information on the types of steps dermatologists, and referrers can take when feasible and practical to do so. The Notes cover the following topics: 1. Appropriate technology, environment and practices to ensure quality, confidentiality and privacy 2. Patient selection 3. Informed consent 4. Requisite quality of information -Clinical image acquisition and review 5. Medical records -Storing clinical images securely A glossary of terms and abbreviations used in the Guidelines is outlined in. ## Scope ## Audience These guidelines are for use by specialist dermatologists practicing in Australia. Teledermatology should only be practised by a dermatologist credentialed to practice traditional in-person dermatology. They should: - Be registered with the Australian Health Practitioner Regulation Agency (AHPRA). - Have specialist registration with AHPRA. - Be registered with the Medical Board of Australia. - Be a Fellow of the Australasian College of Dermatologists. In satisfying the above criteria, specialist dermatologists should have sufficient knowledge, experience and understanding of teledermatology to appropriately select patients and visits suitable for teledermatology, and sufficient knowledge and understanding of the limitations of teledermatology when making a diagnosis or recommending treatment. Accredited trainees with the Australasian College of Dermatologists may engage in teledermatology under the supervision of a dermatologist as defined above. These guidelines may also be a useful resource for primary care practitioners and other medical specialists in understanding the technical, clinical and medico-legal considerations of best practice teledermatology. ## Application The guidelines cover the use of teledermatology for a consultation with a patient whether referred by another practitioner or self-referred, providing advice to a clinician managing a patient including informal advice, and for the purposes of triaging a patient or long-term follow-up of a patient. These guidelines apply to store-and-forward (SAF), real-time videoconsultation (RTVC) and hybrid modalities of teledermatology. Teledermatology consultations may be provided outside of typical referral from other medical practitionersfor example: - When the patient self-refers (often known as direct-toconsumer teledermatology). - When the dermatologist provides long-term follow-up to their patients. These models of care should adhere to the same clinical and technical standard of care as other teledermatology models of care. ## Categories of teledermatology Subject to appropriate assessment of the patient and other relevant circumstances, these guidelines may apply to one or more categories of teledermatology. The categories used in these guidelines are listed in. ## Medico-legal risk mitigation These guidelines support dermatologists practising teledermatology. The medico-legal risk mitigation strategies include: - Confirming that their indemnity insurance covers telehealth. - Using telehealth only for patients who meet appropriate criteria and have provided informed consent. - Using open disclosure practices as outlined in the Australian Open Disclosure Framework 5 . - Keeping accurate and contemporaneous records. - Adhering to all relevant practice guidelines. Consultation for a nonreferred patient - Used to provide advice to a clinician managing a patient without the managing clinician referring the patient. - May use any telehealth modality. - Communication is typically between the managing clinician and dermatologist and the patient may not attend the consultation. - Clinician managing the patient would ordinarily be responsible for follow-up care. - May be an informal request for advice. ## Direct-to-patient - Used to provide dermatology services directly to the patient. - May use any modality of telehealth. However, store-and-forward of patient-acquired images is the most common model of care. ## Triage of a referred patient - Used to assess the need and urgency of dermatological care. - A referral for dermatological care from a referring clinician is reviewed by a dermatologist prior to seeing the patient. - The dermatologist then makes and communicates a management plan which may include the following options: schedule for in-person consultation with appropriate urgency, direct booking for procedure or surgery, management of the patient by the referrer without a need for further dermatologist advice, management of the patient by the referrer and subsequent review by the dermatologist, or discharge without need for follow-up. - When the dermatologist recommends the referrer manage the patient, a treatment plan should be included in the response. - Triage teledermatology typically uses store-and-forward. Triage of a non-referred patient - Used to provide triage advice to a clinician managing a patient without the managing clinician referring the patient. - Communication is typically between managing clinician and dermatologist. - The clinician managing the patient is responsible for follow-up care. - Often informal requests for advice. - Taking into account the limitations of telehealth, such as not being able to perform a physical examination or limitations in the technology, when making the diagnosis or recommending treatment. - Choosing good quality telehealth technology and optimising this technology. - Taking reasonable steps to ensure patient privacy. Note. Adapted from 'Medico-legal aspects of telehealth services for Victorian Public Health Services', by the Department of Health and Human Services. 2015. State Government of Victoria, Australia. p10-17. ## Emergency situations In an emergency, it may not be possible to practise according to these guidelines. If an alternative is not available, a teledermatology consultation or investigation should be as thorough as possible and lead to more suitable arrangements for the care and follow-up of the patient. ## Guidelines Dermatologists practicing teledermatology should: Provider competency 1. Ensure they have sufficient knowledge and understanding of teledermatology to allow them to appropriately select patients and visits suitable for teledermatology, and sufficient knowledge and understanding of the limitations of teledermatology when making a diagnosis or recommending treatment. 2. Ensure they have sufficient expertise in image interpretation especially if using advanced imaging techniques including dermoscopy, reflectance confocal microscopy, optical coherence tomography and total body photography. Appropriate technology, environment and practices to ensure quality, confidentiality and privacy 3. Be compliant with all relevant State and Territory and Commonwealth legislationfor example, the Privacy Act 1988including taking reasonable steps to help protect the privacy of their patients and the privacy of their patient's health records and reporting of privacy breaches if it is likely to result in serious harm. 4. Select, and optimise use of, appropriate and reliable technology, platforms, equipment, data services and physical environment to fulfil their obligations to deliver teledermatology services safely and effectively, while protecting patient privacy and confidentiality. 5. When capturing images using a mobile device, manage these in accordance with the guidelines prescribed by the Australian Medical Association entitled 'Clinical images and the use of personal mobile devices'.6. When conducting RTVC, determine if the technical and socio-technical factors of the videoconference interaction are of sufficient quality to undertake a teledermatology consultation. See Note 1 for further information. ## Patient selection 7. Use their professional judgement to determine on a case-by-case basis whether teledermatology is an appropriate modality. The need for a direct physical examination should be considered when determining if teledermatology is appropriate. If suitable for teledermatology, determine whether a blended approach to delivering care is appropriate where a proportion of visits are provided in-person and a proportion are provided by teledermatology. 8. Use teledermatology as means of delivering dermatology care for a patient who consents to the use of telehealth as an alternative or adjunct to in-person care (or for whom consent is given in accordance with the Guardianship and Administration Act 1985). 9. Where a referral is for an individual lesion and the dermatologist believes a full skin examination is required, initially manage the individual lesion and make recommendation for a full skin examination where feasible. Note. Adapted from 'Quality Standards for Teledermatology', by Primary Care Commissioning with input from the Department of Health. UK. 2013. p14.See Note 2 for further information. ## Informed consent 10. When offering directly to the patient the choice of teledermatology, obtain the patient's informed consent. When the use of teledermatology is recommended by the clinician managing/referring a patient, it is the responsibility of that clinician to obtain the patient's informed consent to the use of teledermatology, including the provision of the patient's health information to the dermatologist. Informed consent should include an explanation of teledermatology and its risks and limitations. 11. Where the consultation is directly with the patient using RTVC, adhere to the guidelines for technologybased consultations published by the Medical Board of Australia including making their identity known to the patient, confirming the identity of the patient at each consultation, ensuring all persons attending an RTVC are on screen and identified, and explaining the process.It should not be routine practice to record and store the RTVC. If the RTVC is going to be recorded, obtain patient consent. 12. Informed consent in health-care means the patient will be given understandable and clear information about their choices so they can make the right decisions about their health and health-care. 13. Consent is their agreement for a health-care professional to provide them with treatment and care, e296 LM Abbott et al. including any tests, medicines, treatments or procedures they agree to. 14. Before they give their consent, make sure: - The patient is aware of options available. - That any risks, and the likelihood of those risks, are explained. - They understand the purpose of the action they are consenting to. 15. Informed consent is different for different people. To provide informed consent you may need: - An interpreter if English is not their first language and you find it hard to communicate. - A patient's friend, family member or support person to discuss options. See Note 3 for further information. ## Requisite quality of clinical information 16 Evaluate whether the quality and completeness of the clinical information and images provided by the referring/managing clinician are sufficient for the modality of teledermatology. If insufficient, additional information should be requested from the referrer, or the patient should be referred for an in-person consultation. 17 Only use store-and-forward teledermatology for patients with pigmented lesions if a dermoscopic image taken by a person trained in the use of a dermatoscope is included with the referral. 18 Where the consultation is directly with the patient, adhere to guidelines for technology-based patient consultations published by the Medical Board of Australia 3 to communicate with the patient to collect relevant medical and medicines history to make a diagnosis, ensure sufficient clinical justification for the proposed treatment and ensure the proposed treatment is not contra-indicated. See Note 4 for further information. Documentation and secure storage of medical records including images 19 Keep contemporaneous notes of the consultation and document the clinical consultation in the patient notes in usual manner with the addition of the following telehealth details: - That the service was performed by telehealth. - The modality of the telehealth (i.e. RTVC, SAF). - The date and time of consultation. - Responsibilities among the team for each element of the patient's management. Both the dermatologist and patient-end clinicians should document the clinical consultation. 20 For RTVC: - Record the names of all attendees and sites that were linked. - Record any technical difficulties that occurred that impacted on the clinician's ability to discharge their duty of care. Communication with the referrer: follow-up and feedback 24 To support high quality referral images, consider publishing image acquisition guidelines in a format accessible to referrerssee Note 4 for further information. 25 Inform the referrer of the outcome of the teledermatology referral. For a SAF consultation, the referring clinician is responsible for informing the patient of the outcome of the teledermatology referral. 26 If a diagnosis of possible skin malignancy or other urgent diagnosis is made, ensure communication directly to the referring clinician is appropriately rapid, so that the patient can be informed and appropriate action taken. 27 Ensure all communication with the referrer regarding ongoing management within primary care includes: - An agreed process for implementing the management plan, including any responsibility for prescribing and follow-up. - Guidance as to when and in what circumstances further dermatologist advice may be needed. - Where appropriate and available, any educational materials that may support the referrer and patient. - Responsibilities among the team for each element of the patient's management. 28 When feasible, ensure the patient is informed of the agreed processes for implementing the management plan if this has not already been done during the RTVC. 29 For SAF consultations, respond to the referrer with the following information: Teledermatology guidelines e297 - A management plan and differential diagnosis. - If appropriate, arrangements for an in-person visit. - If appropriate, arrangements for the onward referral to another specialist. 30 If no diagnosis or management plan can be given after a SAF teledermatology referral, inform the referring clinician that they will need to consider alternative options to obtain dermatological advice. 31 Provide feedback to the referrer on the quality and completeness of referral information and imaging as part of continuous quality improvement. In scenarios where a diagnosis or management plan cannot be given, the dermatologist should provide feedback as to why the referral was unsuitable (e.g. poor-quality image, or patient unsuitable for teledermatology). Note. Adapted from 'Quality Standards for Teledermatology', by Primary Care Commissioning with input from the Department of Health. UK. 2013. p32-34. 7 ## Note 1 Teledermatology: Appropriate technology, environment and practices to ensure quality, confidentiality and privacy The following notes are provided for dermatologists when selecting an appropriate device, application, messaging/ mail service, display, data network and physical environment for teledermatology. When practicing teledermatology a dermatologist must comply with all relevant State and Territory and Commonwealth legislationfor example, the Privacy Act 1988. This includes taking reasonable steps to help protect the privacy of their patients and their health records and reporting of privacy breaches if it is likely to result in serious harm. Selection of technology is important to ensuring the quality of the consultation and privacy of patients and their health records. Physical environment and etiquette are important to ensuring patient privacy and confidentiality. Dermatologists should use good quality telehealth technology and optimise this technology. The technical information provided below aims to assist dermatologists and can be applied when relevant, feasible and practical to do so. ## Note 2 teledermatology: patient selection This Guidance Note provides information on the types of factors that dermatologists should consider when making case-by-case decisions on the suitability of teledermatology for the patient and for individual visits within an episode of care. The decision to provide telehealth should be informed by the following criteria: - The dermatologist's ability to make a definitive diagnosis. - The provider's comfort and expertise with teledermatology. - Whether the referrer will accompany the patient during an RTVC, and whether the referrer can adequately undertake a physical examination. - Whether there is a need to perform a full skin examination. - Clinical factors such as the presenting condition, complexity of consultation, type of consultation (e.g. new versus review) and location of skin condition (e.g. hair bearing skin, mucosa). - Whether the health-care organisation where the dermatologist is employed has a set of criteria about which patients are suitable for telehealth. - Coordination factors such as continuity of care, shared care and existing doctor-patient relationship. - Practical factors such as the availability of specialists, local clinical staff and technology. - Patient factors such as the ability of the patient to travel, willingness of the patient to travel and the patient's family, work and cultural situation. Note. Adapted from the 'Handbook for the Telehealth online education module', by the Australian College of Rural and Remote Medicine. 2013. Australian Government Department of Health and Ageing. p15-16.Note. Adapted from 'Quality Standards for Teledermatology', by Primary Care Commissioning with input from the Department of Health. UK. 2013. p14.Note. These factors are not of equal value or importance. That will depend on the circumstances of the individual's case. ## Note 3 teledermatology: informed consent This Guidance Note provides further information for both dermatologists and referrers/managing clinicians on: - The types of circumstances in which a dermatologist should obtain patient informed consent and when it is a referrer or managing clinician's responsibility to do so. - What to do in circumstances where the patient is unable to provide informed consent or is a minor. - Ways to support referrers to obtain appropriate informed consent. It may be helpful to use a pro forma/template to enhance the completeness of the referral and clinical information and to show how the patient consent was given. ## Who is responsible for obtaining informed consent? There are a number of entry points to teledermatology and these determine who is responsible for obtaining the patient's informed consent (see. ## Obtaining informed consent -what to include Informed consent may be written or verbal. The consent information provided to a teledermatology patient should include: e298 LM Abbott et al. - What the teledermatology process involves (this will vary between services) and why it may be helpful for their care. - Medical opinion can only be based on the images and information provided. - That there may be a difference in diagnostic accuracy between teledermatology and an in-person consultation. - The issues referred to above about risks and limitations of teledermatology. - Encrypt all data (e.g. images, referral and response) transmitted over a data network. Be aware this precludes using unencrypted email that is transmitted across public networks for teledermatology. - Avoid using smartphone text messages, multi-media messaging and consumer messaging services. Instead use purpose-built secure teledermatology, medical photography or electronic medical record applications. ## Smartphone devices - Ensure device is password protected and secure from unauthorised access. - Ensure images do not auto-upload to any social media networks or backup sites. - Delete the image form any personal device once it is saved to the patient record. - Automatically adapts video and audio settings to changing bandwidth availability without losing the connection. - Allows encryption of authentication, video and audio traffic using encryption protocols that are nonproprietary, standards-based in order to foster interoperability, inspectability and trust. - Supports a minimum frame rate of 25 frames per second (to avoid poor video quality). - Supports a minimum of 16 kilobits per second audio channel (to avoid poor audio intelligibility). - Supports content sharing (additional video channel for sharing screen). ## Videoconferencing display (screen) - Dermatologist's display (screen) should support a minimum resolution of 1280 9 720 pixels. - Size of the display should be appropriate for the viewing distance (rule of thumb that may be employed is that minimum display size = viewing distance/2.5). ## Data network for videoconferencing When the dermatologist has carriage over the choice of data network, they should choose a broadband network which allows sufficient connection speed to ensure image quality is maintained and disruptions are minimal. - To avoid poor performance, round-trip latency should be lower than 300ms.- To avoid poor performance, packet loss should be less than 0.1%.- To avoid connection issues, the dermatologist may install a network connection dedicated to videoconferencing. ## Physical environment - Take measures to ensure visual privacy. - Take measures to ensure that the content of the consultation is not overheard from outside of the room. This may include using headphones or acoustic insulation (including acoustic panels, acoustic tiles, carpet and curtains). ## Etiquette for online communication - Test the video and audio prior to connecting to the videoconsultation. - Use a headset if typing (e.g. consultation notes) during the consultation to eliminate keyboard noise being transmitted. If not using a headset, place the microphone/speaker close. - If there is more than one participant at either end-point, they should be seated adjacent to each other and seated approximately two metres from the camera. - Frame all participants in camera view so their head and shoulders occupy the majority of the frame (newsreader view) and their faces are clearly visible. - At the beginning of the videoconsultation, dermatologists should: - Introduce themselves and state their credentials. - Verify all participants at each end can be seen and heard. - Give instructions to patient-end on what will occur if there is a disruption in the videoconference connection (contingency plan). - Document all persons in attendance during the videoconsultation in the patient notes. - It should not be routine practice to record and store RTVC. If the teledermatology consultation is going to be recorded, then patient consent should be taken. - They may still need to have an in-person consultation. - They may bring a family member or companion or, if appropriate, a chaperone to the teledermatology session. Note. Adapted from 'Quality Standards for Teledermatology', by Primary Care Commissioning with input from the Department of Health. UK. 2013. p18-20.Circumstances where the patient is unable to provide consent or is a minor If an adult is temporarily unable to consent and treatment is required, permission (consent) to refer and/or manage the patient via teledermatology should be obtained from the person highest on the list of the order of persons from which consent can be obtained relevant to Commonwealth, State or Territory legislation. In the case of an emergency where the patient is not competent to consent, teledermatology services can lawfully be provided without consent, although treatment cannot be administered if the patient had prior to becoming incompetent expressed a wish not to receive the treatment contemplated (in some States or Territories). Even if a patient is a minor, if the minor is mature enough to understand the nature and effect of the service proposed, consent could be obtained from the minor. Generally speaking, most adolescents aged 16 and over are capable of providing informed consent. Those aged 13 and under are generally not. It depends whether they can understand the issues involved. If in doubt, obtain legal advice. Note. Adapted from 'Medico-legal aspects of telehealth services for Victorian Public Health Services', by the Department of Health and Human Services. 2015. State Government of Victoria, Australia. p28-30. ## Note 4 Teledermatology: Requisite quality of information -Clinical image acquisition and review The quality of images is critical to being able to deliver teledermatology services. This Guidance Note aims to assist both dermatologists and referrers by providing further information on: - Collection, use, and disclosure of clinical images - Camera settings - Technique - Dermoscopic image acquisition - Image review This Note should be followed when relevant, feasible and practical to do so. To support high quality referral images, dermatologists could consider making available image acquisition guidelines in a format accessible to referrers. ## Collection, use and disclosure of clinical images Images acquired on a mobile device should be acquired and managed in accordance with the guidelines prescribed by the Australian Medical Association entitled 'Clinical images and the use of personal mobile devices'.These provide important information on the decision making process for collecting, using and storing clinical images for the purposes of clinical care to ensure privacy and confidentiality obligations are met. ## Camera settings To optimise image quality, it is recommended that images acquired for teledermatology have the following camera settings: - Minimum resolution of 2000 9 1500 pixels or 3 megapixels. - White balance should be set to automatic. - Flash set to always on. - Cameras set to capture maximum quality JPEG files. - Consistent camera settings should be used from one visit to the next to aid comparability of imaging. ## Technique It is recommended that the following technique be employed when imaging for teledermatology assessment: - Patients must consent to imaging. - To avoid risk of misidentification, each individual patient session should begin and end with a photograph to identify the patient. Take one photograph of something to identify the images as belonging to an individual patient, for example unique identification number. Repeat at the end of the individual patient session. - If possible remove jewellery and clothing. - Acquire images with the camera perpendicular to skin surface. - Acquire images in cephalic orientation, that is with patient's head towards the superior of the frame. - Acquire one or more overview image/s of relevant areas of the body (e.g. back, legs, arms) to demonstrate the distribution of skin lesions or pathology. - Acquire one or more mid-close-up image/s to include some anatomical marker (e.g. joint, navel) establishing the location, laterality and providing some general context for the lesion or pathology. Lesions should be identified. Identification markers should be placed adjacent to the lesion without covering any portion of it. Lesions can be identified using adhesive labels, surgical tape or washable markers. - Store laptop or portable storage device in a locked physical location. - Alternatively, employ full disk encryption when the laptop or portable is not physically secured. ## Do not modify original images - Images should not be modified. - Take care not to (re)apply the Joint Photographic Experts Group (JPEG) compression to images as can happen when saving images to storage media. - Save any images manipulated in any software program as a copy. Do not save them over the original file. Mitigate data loss To mitigate data loss: - Archive images on a hardware device that has fault tolerancefor example, redundant array of independent disks (RAID). Alternatively, images should be backed up and the backup copy stored in a separate geographical location to the original image. - Store images in architecture that employs disaster recovery procedures. ## Control access - Control access to images so that access is limited only to those persons directly involved in the patient's care or responsible for managing the image archive. - Limit access to read-only to prevent accidental image loss. - Keep an audit trail of persons viewing images. ## Encode images - Store images in Digital Imaging and Communications in Medicine (DICOM) format as this: - Permits portability of both the image and metadata. - Ensures there is no separation of the images and the metadata. - If DICOM is not used, use a standards-based consumer image file format such Joint Photographic Experts Group (JPEG), Portable Network Graphic (PNG), Tagged Image File Format (TIFF) or RAW. ## Store in an image repository Store images in an image repository such as: - A health-care organisation's Picture Archiving and Communication System (PACS) or Vendor Neutral Archive (VNA). - A non-DICOM image repository. - An electronic medical record. - A managed network drive, storage server or a cloud storage provider (See Cloud computing storage below). When using these storage devices, images should be stored using a file structure that at root level identifies the patient and subdirectories based on date to identify the imaging study. The image file name shall include a patient identifier to help prevent misidentification. Only store images in a repository where there exists functionality to export the images and associated metadata in a standards-based format to facilitate portability and avoid vendor lock in. Do not archive images on a local hard drive of computers, removable storage devices (e.g. portable hard disk drives, thumb drives) or a non-validated cloud provider (See Cloud computing storage below). Do not archive images on an imaging modality before verifying that the modality meets the requirements for images to be archived securely and for the period of time mandated by relevant legislation. Cloud computing storage A dermatologist may outsource the storage of images to a cloud service provider. Imaging repositories (e.g. PACSs, VNAs), electronic medical records, network drives and storage servers may use cloud computing storage. If using a cloud storage provider, apply the recommendations of the Australian Cyber Security Centre 13 , namely: - Use a locally owned vendor or a foreign owned vendor that is located in Australia and stores data only within Australia. - Perform a risk assessment before using a cloud service provider for the storage of images. - Use the risk assessment 14 prescribed by the Australian Signals Directorate. - Consider the sensitivity of the images that will be stored and the choice of cloud provider should reflect these sensitivities. Highly sensitive images such as nude photographs should be stored on cloud services listed on the Australian Signals Directorate Certified Cloud Services List (CCSL). - Acquire at least two macro (close-up) images of the lesion or pathology using either macro mode or optical zoom. The camera should be approximately 20 cm from the skin surface. Acquire using electronic flash and acquire two images at two different angles to help ensure specular reflection does not obscure any of the skin surface. - If possible, use a solid, neutral colour with a non-reflective surface (e.g. a towel) as a background to the image. ## Image review The dermatologist should review teledermatology images: - On a display that is less than five years old to mitigate luminance decay. - Using review software that allows rotation, panning and zooming. - On a display not affected by reflection. This can be achieved by high brightness display or by reducing the ambient room lighting. ## Note 5 Teledermatology: Storing images securely Dermatologists should ensure images, as with other medical records, are transmitted and archived securely to protect them from theft, damage or alteration. They should also ensure they are retained for the period of time mandated by legislation. This Note provides information on the physical and technical considerations and steps dermatologists can take to store images securely.	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ajd.13301	Despite the potential of teledermatology to increase access to dermatology services and improve patient care, it is not widely practised in Australia. In an effort to increase uptake of teledermatology by Australian dermatologists and support best practice, guidelines for teledermatology for the Australian context have been developed by The University of Queensland's Centre for Online Health in collaboration with The Australasian College of Dermatologists’ E‐Health Committee. The guidelines are presented in two sections: 1. Guidelines and 2. Notes to support their application in practice, when feasible and appropriate. Content was last updated March 2020 and includes modalities of teledermatology; patient selection and consent; imaging; quality and safety; privacy and security; communication; and documentation and retention of clinical images. The guidelines educate dermatologists about the benefits and limitations of telehealth while articulating how to enhance patient care and reduce risk when practicing teledermatology.
f4f0265c3cc81eb2a9e757675cb95a4ece71a28f	pubmed	Building capacity to improve respiratory care: the education strategy of the International Primary Care Respiratory Group 2014–2020	Building capacity to improve respiratory care: the education strategy of the International Primary Care Respiratory Group 2014–2020 Significant attention has been given to the global burden of noncommunicable diseases including respiratory diseases and the potential of primary care to address this challenge. The International Primary Care Respiratory Group (IPCRG) has a potentially significant role to build capacity through research and education in a complex global network with varying degrees of capability. In this paper we outline a comprehensive strategy, which revisits the IPCRG's educational role, our aims, audiences and approach in this context. The paper was developed through a collaborative process involving experts in global health, primary care and respiratory education, leading to a consensus educational strategy statement. This is further informed by a review of recent trends in continuing medical education. Professional education and training of health-care workers is a core component of the global response to the challenge of managing respiratory conditions in primary care. This paper offers a revised strategy for building capacity and improving clinical practice in IPCRG member countries by revisiting and broadening our aims, exploring the key audiences, focus and approaches. # Introduction The global burden and prevalence of respiratory disease is well established.In 2013, the World Health Assembly endorsed an action plan for the prevention and control of noncommunicable diseases (NCDs) including a monitoring framework for a 25% relative reduction in mortality from four NCDs-including chronic respiratory disease-by 2025 and a 30% reduction in prevalence of current tobacco smoking.In addition, the World Health Organization has recognised that improved access to, and application of, the principles and approaches of primary health care can contribute to the management of this global disease burden.The high prevalence of asthma, chronic obstructive pulmonary disease (COPD), tobacco dependence and respiratory infections means that primary care needs to be equipped to deal with respiratory diseases and yet there is substantial global variation, investment and development. What, given the right support, could primary care professionals do to address this ever increasing burden of global respiratory disease?Education can build capacity to improve respiratory care by addressing inequalities and empowering health-care workers to detect, diagnose and support their patients with chronic respiratory disease within their local contexts. A recent survey conducted by the International COPD Network suggests that the global guidelines continue to have limited reach and impact in many regions, and information on the management of COPD patients in primary care is sparse, suggesting a need for 'more ongoing education and information' for primary care physicians, particularly outside Europe and North America. [bib_ref] Primary care physician perceptions on the diagnosis and management of chronic obstructive..., Aisanov [/bib_ref] A GLOBAL CHALLENGE FOR IPCRG The International Primary Care Respiratory Group (IPCRG) aims to support primary care professionals to provide better quality respiratory diagnoses, treatment and care. As a network of member countries, our educational strategy has in the past concentrated on endorsing existing cross-national educational products and national programmes relevant to members and the context in which they work.However, given the strategic development of IPCRG as an international 'community of practice', 8 reaching further into low and middle-income countries with different primary care systems of variable strengths, our strategy needs to evolve accordingly. In 2011, the IPCRG launched a flagship educational programme 'E-Quality', which seeks to build educational capability in member and associate member countries. We developed an evidencebased decision-making framework that we use to guide our investment in educational projects (see . The framework is based on a published scoping exercise and review of literature. [bib_ref] Effecting change in primary care management of respiratory conditions: a global scoping..., Mcdonnell [/bib_ref] We identified features of educational interventions that are likely to show evidence of effectiveness, although the evidence base, particularly relating to clinical outcomes, is limited. We encourage applicants to anticipate the challenges and barriers they are likely to encounter in local contexts. Applicants from member countries present and discuss their ideas with an expert panel as part of the selection process. IPCRG offers support, mentoring and small-scale ('seed') funding; working with successful bidding teams to build confidence; ensuring delivery of projects; and sharing learning (see . Our objective now is to build on and extend E-Quality and to develop a more comprehensive strategy, which revisits the IPCRG's educational role, our aims, audiences and approach in the context of our investment capability and the increasing global attention to the challenges of NCDs. These highlight the need to strengthen primary health-care capacity if we are to achieve the World Health Organization monitoring framework targets. ## Building capacity to improve respiratory care Our aims The strategy outlined in this paper supports the longstanding goals of IPCRG. We seek to improve clinical practice, with attention to the needs of patients and clinicians, the nature of primary care practice (see Box 3) and with a particular focus on respiratory medicine. Our membership includes low, middle and high-income countries with wide variations in capacity and capability. We recognise that the primary care respiratory leaders from our member countries hold significant expertise in education. [bib_ref] An international course for faculty development in family medicine: the Slovenian model, Svab [/bib_ref] [bib_ref] Faculty development for teachers of family medicine in Europe: reflections on 16..., Bulc [/bib_ref] There are established regional organisationsand international programmes that address respiratory education in low and middle-income countries; however, these are not created or led by primary care peers, and this we believe diminishes their appropriateness and value for implementation in primary care settings. As a global network, IPCRG can best add value by: (1) stimulating debate on the most effective educational methods and evaluation (2) building capacity and capability-nationally or regionally-by testing locally acceptable programmes (3) sharing best practice in primary care and practical experience of respiratory programmes Box 1. Decision-making framework for IPCRG E-quality programme 9 - Clear problem definition in relation to primary and respiratory care, including a justification for the project - Consideration of the context for change - An explicit educational or quality-improvement approach - Measurement of effectiveness of education on clinical practice outcomes - A consideration of how the intervention complements existing educational practices and culture - Clarity about how the intervention sits within the wider educational system - Consideration regarding sustainability - Identification of a project team, the key stakeholders and collaborative relationships - The role of information communication technologies (ICT) - Management arrangements including incentives - Evaluation Box 2. E-quality example projects 35 - Disseminating online spirometry training and feedback in Australia, based on the Spirometry 360 train the trainer programme and remote over reading service: University of Washington/Adelaide. This is an example of a blended learning programme for primary care spirometry use and interpretation. An established US programme was introduced in Australian general practice. The programme transferred well but success was limited by the lack of aligned payment incentives - Assessing the 'Impact of CHAMPS' (Changing Asthma Management Practices), a 1-day training programme on Asthma Diagnosis and Management, on the clinical practice of primary care physicians: The Chest Research Foundation, Pune, India. This project evaluates the impact of an educational programme and measures changes in practice, concerned with prescribing inhaled medicines by GPs who currently prescribe only oral medicines; yet to report - A Multidisciplinary Educational Programme to develop knowledge and practice for diagnosis and treatment of asthma and COPD: San Bernardo do Campo, Sao Paulo, Brazil. A 'matrix programme' that integrates primary and secondary care, using workshops, joint consultations and multiprofessional 'circle discussions' seeks to improve chronic respiratory practice in family health teams and reduce referrals to secondary care. Knowledge has increased; the next challenge is to ensure sustainability, given the high turnover among family doctors Box 3. The nature of primary care practice - Diagnosing, treating, managing (including referring) patients presenting with undifferentiated symptoms sometimes before advanced symptoms and signs described in the international and national respiratory guidelines have developed (IPCRG undertakes mapping to systematically collect and present information on national guidelines used by primary care for the chronic lung conditions commonly found in primary care. (https://www.theipcrg.org/display/ResMapping/Mapping+of+national+guidelines+used+by+primary+care) - Practising in a low-tech environment, often without the sophisticated investigations and treatment modalities of secondary care, where the goal is to take a good history and 'rule out' conditions especially those requiring acute action or referral - This is of particular importance in many low and middle-income countries where the few pulmonary specialists tend to be concentrated in academic centres, which may be difficult to access. The cost expended to seek and undergo specialist evaluation may be difficult to justify, and treatments recommended by a specialist may not be readily or at all available - Not all systems have a clear distinction between primary and secondary care. For example, in Asia Pacific specialist doctors may work in primary care practice in the evening on a pay per visit basis and in some countries primary care is still episodic and market driven - Using generalist expertise to manage people with multimorbidity as opposed to treating single diseases - Seeing patients in the context of their families, homes and communities We want to promote rigorous thinking about the way that local educational programmes are implemented and evaluated. We have a role in addressing gaps in specialised respiratory education and enabling translation to primary care. We can build capability by advocating and joining up existing programmes and leading 'teach the teacher' programmes with a primary care respiratory focus. We see potential in developing a cadre/network of global respiratory leaders, equipped with the experience, approach and competence to cope with the complex challenges such as raising quality standards, lobbying, networking and developing national programmes. Who are our audiences and collaborators? Given the varied nature of health-care policy, primary care provision and practice across our membership, we recognise a range of audiences and collaborators. We propose four target groups: 1. Clinicians and health-care workers in primary care-working with particular challenges (see Box 3). Respiratory disease is a specialised area of practice not always addressed in existing primary care educational programmes, and in some lowincome countries COPD is not a condition recognised within the medical curriculum. 2. Academic workforce-those delivering undergraduate and postgraduate teaching; this links to our proposal to build capacity and capability in member countries. There is potential here to work in partnership with locally established organisations.3. Experts-in specific clinical areas (asthma, rhinitis, COPD, tobacco dependence and respiratory infections) or in particular skills of respiratory care (for example, spirometry and inhaler technique). There is strong potential here to share good practice and to join up existing programmes. Experts are important collaborators who can contribute by taking a consultancy role, sharing their knowledge and supporting the testing and careful adaptation of their intellectual property to different settings. 4. Potential leaders-who may have a more strategic role and may not be primary care clinicians. For example, public health or health policy/government officials/politicians and managers may be respiratory leaders. We anticipate that these categories overlap and people may adopt more than one role depending on the task. This applies to low, middle and high-income countries, although we anticipate that the focus will vary between countries: some needing support in establishing basic respiratory knowledge, or 'righting' poor practice such as high levels of antibiotic prescribing for uncomplicated viral respiratory tract infections; others in developing expertise, or promoting a strategic respiratory policy. How can IPCRG support learning and build capacity? IPCRG is not primarily an education provider, although we may on occasion lead educational programmes. We might equally 'signpost' member countries to appropriate educational provision or facilitate/broker collaborations between member countries concerning educational initiatives. The balance of provision and signposting will depend on the audience. We recognise that continuing medical education has traditionally focused on 'knowledge transfer' but is evolving towards a more complex construct that addresses adult learning principles (how and when professionals learn); and the complexity of health systems in which learning and practice take place. [bib_ref] Selecting educational interventions for knowledge translation, Davis [/bib_ref] In addition, the idea that high-income 'developed' countries teach other 'less developed' countries has also been challenged: everyone has something to learn and everyone has something to teach. [bib_ref] Health professionals for a new century: transforming education to strengthen health systems..., Frenck [/bib_ref] Given our aims and the varied audiences identified so far in this paper, we will broaden our scope to support learning and build capacity through: 1. Teaching clinical practice-this might be based on a particular theme, e.g., born out of IPCRG research or discrete projects such as focusing on 'difficult-to-manage' asthma rather than severe asthma. 21 2. Developing teaching capacity in primary care-which includes understanding adult learning principles, assessing learning needs, setting learning and teaching objectives, learning design, methods and assessment such as the approach taken by WONCA in schemes in Macedonia. [bib_ref] medical-education-pilot-macedonia-two-year-fol low, Wonca [/bib_ref] 3. Stimulating discussion about effective educational methods and evaluation. Moving beyond education to consider approaches to quality and service improvement; measurement Box 4. IPCRG education strategy: next steps - We will continue to support E-Quality as a flagship programme supporting the development of 'bottom up' educational or pilot projects in member countries 35 - We will design a 'teach the teacher' programme template. This programme will be tailored to national or regional programmes and include identification of a work-based educational project (including pre and post course work) that then provides the material for the programme. Opportunities exist to test this template with IPCRG leading the programme in collaboration with local leaders in respiratory care (a 'teaching faculty') and providing the core content - We anticipate that 'teach the teacher' programmes will enable us to identify and develop a network of respiratory leaders, thus building strategic capability in member countries - We plan to explore the potential to develop a respiratory distance-learning module for primary health-care professionals-in partnership with higher education institutions - Where educational programmes exist within member countries, we will adapt our current 'endorsement policy' and offer an 'education peer review' service, based on clear criteria and with a team of education reviewers. The main difference from our current endorsement policy is that it would not be essential that IPCRG be involved in the programme development as long as it met the specified criteria - We will help endorsed programmes to apply for formal accreditation - We will share best practice, narratives and case studies using the IPCRG web platform- We will consider what IPCRG's role might be in disseminating information from the npjPrimary Care Respiratory Medicine to primary care colleagues who do not currently read it or have access to it. Potentially, this might be digests in translation and/or news and features adapted for local member use - We see advantages in exploring technology as a way to capture the key messages and teaching methods to reach wide audiences with short illustrative films that could be relabelled and used for different audiences of practice; understanding and working in health systems with 'context appropriate interventions'. . Promoting leadership-capacity building through mentoring and coaching; self-awareness, building confidence, presentation skills, facilitating and influencing skills, project management.Which educational interventions are appropriate-and what is the evidence base? In a review of the literature underpinning our E-Quality programme we stated that 'educational interventions sit within complex health-care, economic and policy contexts and evaluations that seek to test specific approaches to education show equivocal results. [bib_ref] Effecting change in primary care management of respiratory conditions: a global scoping..., Mcdonnell [/bib_ref] There is some evidence that carefully designed, multifaceted educational programmes that engage health professionals in their learning, provided ongoing support, are sensitive to local circumstances and delivered in combination with other quality-improvement strategies or incentives, are most effective'. [bib_ref] Effecting change in primary care management of respiratory conditions: a global scoping..., Mcdonnell [/bib_ref] These principles also reflect patient behaviour change literature. [bib_ref] The behaviour change wheel: a new model for characterising and designing behaviour..., Michie [/bib_ref] We thus anticipate that educational programmes supported or endorsed by IPCRG will be multifaceted (or 'blended') and will seek to demonstrate positive outcomes in both professional practice and patient outcomes. Outcomes could be increased knowledge leading to changes in clinical practice, patient outcomes or system-wide impacts (see . We have identified a number of trends in the field of health-care education that require further attention, given the varied geographical, cultural and resource differences of IPCRG member countries. For example, distance and online learning is an area of rapid development supported by advances in technology and access. A 'new cycle of technology' includes increased use of mobile devices (tablets/mobile phones) and web 2.0 technologies (wikis, podcasts and other social media) that have the potential to contribute to collaborative practice and education in health care. [bib_ref] Education in health research methodology: use of a wiki for knowledge translation, Hamm [/bib_ref] [bib_ref] blogs and podcasts a new generation of web based tools for virtual..., Boulos [/bib_ref] Examples include e-learning packages offered by the European Respiratory Society or accredited distance learning programmes in Global Health and NCDs at the University of Edinburgh. 15,The ways that consumers use technology are also changing, with a growth in watching video online and live streaming.Given that IPCRG's membership reaches a global primary care audience of 125,000, 32 this opens up possibilities for engaging large (IPCRG) audiences in new ways. It has been suggested that Massive Open Online Courses, available through portals such as NextGenU, 33 may be a 'game changer' in medical education-allowing unprecedented access to online content and academic communities. However, critics highlight issues such as lack of context or cultural relevance, quality assurance, low interactivity and difficulty in assessing learning and changes in practice. [bib_ref] Are MOOCs the future of medical education?, Harder [/bib_ref] These are important considerations if IPCRG has a role in developing online materials that fill gaps in local provision, and in contributing to research and evaluation of online and distance education. # Conclusions Professional education and the training of health-care workers is a core component of the global response to the challenge of managing respiratory conditions in primary care. IPCRG has a potentially significant role in a complex global network, which has varying degrees of capacity and capability. In recent years our primary focus has been on developing research, but increasingly we are aware of the need to revisit our role in supporting education and the dissemination of research and of educational training skills. This paper offers a revised strategy (see Box 4) for building capacity to improve clinical practice in IPCRG member countries by revisiting and broadening our aims, exploring the key audiences, focus and approaches. © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14072 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14072 npj Primary Care Respiratory Medicine (2014) 14072 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited ACKNOWLEDGEMENTSWe would like to acknowledge the contribution of Carlos Gonçalves, João Ramires, Rui Costa, from GRESP, Portugal, who contributed to a strategy meeting in Porto, January 2014. Members of the IPCRG Board and the Education Sub Committee, Dr Liz Grant, Senior Lecturer in Global Health and Development, University Edinburgh and Professor Jim Stout, University of Washington for comments on drafts of this paper. We would also like to thank the reviewers for their invaluable comments on earlier drafts of this paper.CONTRIBUTIONSSW, JCDeS and JM designed a collaborative event to discuss an education strategy for IPCRG. All the authors took part in the event in Porto January 2014. Subsequently, SW and JM wrote the first draft of the paper, to which all the authors contributed.COMPETING INTERESTSJCDeS and HP are Associate Editors of npj Primary Care Respiratory Medicine, but were not involved in the editorial review of, nor the decision to publish, this article. The remaining authors declare no conflicts of interest.FUNDINGThe IPCRG commissioned this work as part of their education strategy development.	None	https://www.nature.com/articles/npjpcrm201472.pdf	None
97fa414b41c7277b40b5188c34346b3b96807ece	pubmed	Guidelines on Management of Human Infection with the Novel Virus Influenza A (H1N1) – A Report from the Hospital das Clínicas of the University of São Paulo	Guidelines on Management of Human Infection with the Novel Virus Influenza A (H1N1) – A Report from the Hospital das Clínicas of the University of São Paulo # Introduction In April 2009, the first two cases of human infection with a novel influenza A (H1N1) virus were reported in the United States.During the same period, an outbreak of respiratory infection was reported in Mexico.The virus was found to be an H1N1 virus that was antigenically and genetically unrelated to human seasonal influenza viruses and genetically related to viruses known to circulate in swine.In the ensuing weeks, the swine-origin influenza virus (S-OIV) H1N1 spread worldwide, constituting a pandemic, as defined by the World Health Organization. [bib_ref] Emergence of a novel swine-origin influenza A (H1N1) virus in humans, Dawood [/bib_ref] The novel H1N1 virus has distinct molecular properties of human, avian, and swine influenza, resulting from antigenic drift, which is the main cause of the seasonal epidemic of swine flu. [bib_ref] Emergence of a novel swine-origin influenza A (H1N1) virus in humans, Dawood [/bib_ref] As of , the S-OIV caused over than 296.471 virologically confirmed human cases and at least 3.486 deaths in countries worldwide.Almost five months after the description of the first cases, the pandemic S-OIV infection continues to spread globally, presents a high rate of transmission among humans, and can lead to serious complications and mortality. The purpose of this guideline is to review the evidence concerning diagnosis, prevention, and treatment of S-OIV infection. In addition, we emphasize the Hospital das Clínicas' plan for the management of the pandemic novel influenza A (H1N1). This report is an initiative from the "Cabinet Crisis" -a group of healthcare professionals at the Hospital das Clínicas da Faculdade de Medicina da Unversidade de São Paulo who continuously evaluate the "bundles" for control of S-OIV infection, meaning the groups of interventions and advertisements, to obtain better outcomes in the management of this disease. ## Historical aspects An estimated 58% of the 1407 human pathogens are zoonotic, which means that they normally occur in animals but can also infect humans. [bib_ref] Host range and emerging and reemerging pathogens, Woolhouse [/bib_ref] The ability of a microorganism to cross the species barrier in association with a high transmissibility rate between humans may result in epidemics. The novel influenza A (H1N1) virus, which is responsible for the current pandemic, is derived from two unrelated swine viruses, one of which is a derivative of the 1918 human virus.The notorious 1918 pandemic of influenza A (H1N1), the Spanish flu, was derived from an avian source and caused 50 million deaths. [bib_ref] Host range and emerging and reemerging pathogens, Woolhouse [/bib_ref] Some authors proposed that the virus resided in an avian reservoir and affected humans either directly upon exposure to birds or through an intermediate host. [bib_ref] Emergence of a novel swine-origin influenza A virus (S-OIV) H1N1 virus in..., Peiris [/bib_ref] As the 1918 influenza virus can replicate and cause disease in swine, scientists believe that it has continued to circulate in swine and this fact would facilitate the genetic reassortment between different influenza virus strains. [bib_ref] The persistent legacy of the 1918 influenza virus, Morens [/bib_ref] A practical way to think about influenza A events over the past 91 years is to recognize that we are living in a pandemic era that began in 1918. The novel H1N1 virus associated with the ongoing 2009 pandemic is a fourth-generation descendant of the 1918 virus. The complex evolutionary history of this virus combines unique structural properties and genetic mixing among human viruses and avian and swine-adapted influenza viruses. [bib_ref] Clinical review: update of avian influenza A infections in humans, Sandrock [/bib_ref] Two features of the influenza virus explain its ability to cause widespread disease. One is the high error rate during genomic replication. [bib_ref] Clinical review: update of avian influenza A infections in humans, Sandrock [/bib_ref] [bib_ref] Epidemiologic implications of changes in the influenza virus genome, Kendal [/bib_ref] The other is the segmented influenza virus genome, which allows reassortment between different viral strains. [bib_ref] Clinical review: update of avian influenza A infections in humans, Sandrock [/bib_ref] [bib_ref] Epidemiologic implications of changes in the influenza virus genome, Kendal [/bib_ref] Because of this continual change phenomenon, a seemingly endless variety of new viruses with potentially new properties are continuously being engineered. In contrast, this new virus is not only infecting humans and causing some disease, but it is also being transmitted efficiently from human to human. ## Epidemiology The pandemic novel influenza A (H1N1) infection was considered as widespread in Brazil on July 16.Since then, the Ministry of Health in Brazil, as suggested by the World Health Organization, has maintained a continuous epidemiologic vigilance of cases of acute respiratory syndrome (ARS). The strategy of vigilance considers any persons with flu syndrome as potential cases of influenza A (H1N1) and designates these individuals as presenting acute respiratory syndrome patients with cough, dyspnea, and fever. Until now, 46.810 cases of ARS were reported notified in Brazil. [bib_ref] Historical perspective--Emergence of influenza A (H1N1) viruses, Zimmer [/bib_ref] Of these, 9.249 (20%) patients presented infection with S-OIV or influenza A (H1N1). Seasonal influenza A infection was confirmed in 1.152 (2.5%) patients.The observed age distribution is unusual and differs from seasonal influenza, being skewed towards younger age groups. There is a marked underrepresentation of infections in persons over 65 years of age, who make up only 2% of the reported cases. In Brazil, among the reported cases, the affected individuals tend to be young, with a median age of 26 years. Most patients are 15-49 years of age. Considering the gender distribution, 57.5% of the confirmed cases of novel virus influenza A (H1N1) occur in women. [bib_ref] Historical perspective--Emergence of influenza A (H1N1) viruses, Zimmer [/bib_ref]. Among these 9.249 confirmed cases in Brazil, 899 deaths are reported with mortality rate of 0,47/per 100.000 inhabitants.All Brazilian states have reported cases of S-OIV infection, with the exception of Sergipe. Most cases and deaths are concentrated in São Paulo, but major mortality rate was observed in Paraná (2,08/ 100.000 inhabitants). As of .069 cases of ARS were registered in São Paulo and 3.733 are due to novel influenza A (H1N1) infection.São Paulo state registers 40.3% (3.733 of 9.249) of all confirmed cases from Brazil, the majority identified in the city. The Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) is the largest tertiary health care hospital in Brazil, with 6 medical institutes and other associated hospitals, and is a reference center for H1N1 cases in São Paulo. Three months after the report of the first case of novel H1N1 infection in Brazil, the Hospital das Clínicas has accumulated experience with about 1500 cases registered and 472 confirmed with a low lethality rate (7.14%). The management of this disease requires specific knowledge and the expertise to provide an adequate diagnosis and treatment of patients. With the goal of obtaining better outcomes in diseased patients, the Hospital Council established a "Cabinet Crisis" to continuously obtain information from Health Organs, Epidemiological Surveillance Systems and from literature regarding epidemiological data and clinical presentations of S-OIV infection and to provide an adequate structure for the care of patients. ## Pathogenesis Influenza A, B, and C are RNA viruses of the Ortomyxoviridae family and cause both pandemic and seasonal disease in humans. 14 Influenza A viruses are enveloped, single-stranded RNA viruses with a segmented genome. They are categorized into subtypes on the basis of the antigenic properties of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins on the surface of the virus.The HA glycoprotein mediates attachment and entry of the virus on the cell surface and is the main target for immunity by neutralizing antibodies. The NA glycoprotein allows the spread of the virus by cleaving the glycosidic linkages to sialic acid on host cells and on the surface of the virus. [bib_ref] Evolution and ecology of influenza A viruses, Webster [/bib_ref] Influenza A viruses are characterized according to their pathogenicity, which results in severe disease and death in different species. This S-OIV results from frequent antigenic changes (i.e., antigenic drift) due to point mutations and recombination events that occur during viral replication. [bib_ref] Evolution and ecology of influenza A viruses, Webster [/bib_ref] The novel influenza A (H1N1) virus is not a new subtype, but because the large majority of humans appear to have no pre-existing antibodies to this virus, a substantial potential for widespread infection exists. [bib_ref] Evolution and ecology of influenza A viruses, Webster [/bib_ref] The novel influenza A (H1N1) virus has distinct properties that enable it to cause disease in both swine and humans and confers high rates of transmissibility among humans. The pathogenesis of human infection due to S-OIV is poorly understood, but appears to involve two phenomena: a) direct cytotoxic viral damage and b) a cytokine storm, resulting from the inflammatory response to viral infection. [bib_ref] The pathology of influenza virus infections, Taubenberger [/bib_ref] [bib_ref] Immune dysregulation in severe influenza, Heltzer [/bib_ref] The interaction between host and virus may result in different forms of disease, depending on the viral load and the inflammatory response. In patients with co-morbidities, host mechanisms of defense may be defective and such patients can present an altered innate immune response. In the most severe cases, co-infection with other viruses and bacteria (Streptococcus pneumoniae, Haemophilus influenza, and Staphylococcus aureus) can occur contributing to the high rates of mortality. [bib_ref] Predominant role of bacterial pneumonia as a cause of death in pandemic..., Morens [/bib_ref] There is no evidence to date suggesting that the virus disseminates any differently from other human influenza viruses, i.e., by droplets from coughing and sneezing and direct and indirect contact with respiratory secretions from infected persons. An individual may sometimes become infected by touching something contaminated with flu viruses and then touching his or her mouth or nose. There is no evidence to suggest unusual transmission routes for influenza, and there is no reason to suggest transmission via food. Patients may be contagious from one day before developing symptoms to up to 7 days after they get sick. Children and persons with deficient immunity might be contagious for longer periods of time. ## Clinical features ## Human infection with the novel virus influenza a (h1n1) is characterized by a variable clinical presentation. We can describe a spectrum of disease presentations: the asymptomatic form, "flu-like syndrome", and the severe form with acute respiratory distress syndrome leading to death [fig_ref] Figure 1 -: Spectrum of novel influenza A [/fig_ref].The majority of patients present the "flu-like syndrome" with fever, myalgia, sore throat, arthralgia, cough, headache, chills, and fatigue. [bib_ref] Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico, Perez-Padilla [/bib_ref] Fever is the most frequent symptom and usually lasts for three days. Respiratory symptoms generally disappear three or four days after the fever ends. Diarrhea, emesis, and weakness can be present in a significant number of cases. [bib_ref] Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico, Perez-Padilla [/bib_ref] Despite the fact that in most patients the disease has a benign evolution and a limited duration, some patients may present respiratory failure, rapidly developing acute respiratory distress syndrome. [bib_ref] Severe respiratory disease concurrent with the circulation of H1N1 influenza, Chowell [/bib_ref] [bib_ref] H1N1 2009 influenza virus infection during pregnancy in the USA, Jamieson [/bib_ref] Published data describe systemic disease and complications due to S-OIV infection such as: [bib_ref] Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico, Perez-Padilla [/bib_ref] a. Worsening of previous existing disease b. Sinusitis, otitis, asthma [bib_ref] Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico, Perez-Padilla [/bib_ref] [bib_ref] Severe respiratory disease concurrent with the circulation of H1N1 influenza, Chowell [/bib_ref] From these analyses we can describe a list of risk groups, i.e., groups that experience more severe infections than the general population [fig_ref] Figure 2 -: Risk groups for S-OIV infection Review of novel human influenza A [/fig_ref]. Pregnant women have a potential for complicated disease. For that, in Hospital das Clínicas, there is a specific protocol of care for this group, which include hospital admission in suspected or confirmed cases with clinical complications and a careful vigilance system for mild forms of disease with home treatment. ## Hospital admission To date, most human cases of new influenza A (H1N1) virus infection have exhibited an uncomplicated illness of limited duration. Hospitalization or antiviral therapy is therefore not likely to be required for most patients. Supportive care includes antipyretics, such as dypirone or acetaminophen for fever or pain, and fluid rehydration that can be provided as needed.The specific risk factors that predict an increased risk of progressive disease are incompletely understood. Clinicians and caregivers should watch for signs of possible clinical deterioration (for example, difficulty breathing, chest pain, coughing up colored sputum, dyspnea, altered level of consciousness, and confusion) and refer immediately such patients to the hospital. Clinicians should also take into account any underlying co-morbidities, the already described risk groups (such as immunocompromising conditions, preexisting chronic lung or cardiovascular disease, diabetes, pregnancy, and young age). Patients who present one or more of the following signs and symptoms must be hospitalized in an intensive care unit: a) Hemodynamic instability b) Acute respiratory failure c) Extensive lung compromise on chest X-ray d) Severe hypoxemia e) An PO2/FiO2 < 300, characteristic of acute lung injury f) Compromise of other organs: acute renal failure, myositis, encephalitis, and other g) Organ dysfunction ## 5.2 Intensive care: 5.2.1 Ventilatory support: until now, there has been no unique, definite pattern of lung disease. Patients who present serious hypoxemia may present different forms of lung damage. [bib_ref] Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico, Perez-Padilla [/bib_ref] [bib_ref] Severe respiratory disease concurrent with the circulation of H1N1 influenza, Chowell [/bib_ref] Most patients present diffuse alveolar damage, but localized disease, bronchiolitis, lobar pneumonia, and pleural effusion may be present. Ventilator support indications will then depend on the clinical condition of the patients, evaluated through signs, symptoms, and laboratory analysis (including arterial gas). -Non-invasive ventilation (NIV): despite the theoretical risk of aerosol production with this modality, we recommend NIV in patients with hypoxemia due to the reduced rates of orotracheal intubation. Indications for and limitations of this method in patients with S-OIV infection are the same as those for patients with respiratory failure due to other etiologies. [bib_ref] A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients..., Antonelli [/bib_ref] NIV should be used in patients without hemodynamic instability or consciousness alterations. [bib_ref] A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients..., Antonelli [/bib_ref] [bib_ref] Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress..., Ferguson [/bib_ref] The preferred modality is the BiPAP, with inspiratory pressure (IPAP) and expiratory pressure (EPAP) adjusted independently. After selecting and fitting the mask, the recommended initial settings are IPAP = 8-12 cmH 2 O and EPAP = 3-5 cmH 2 O. The IPAP is increased gradually as tolerated, with the therapeutics goals of dyspnea relief, good patient-ventilator synchrony, and improved gas exchange. The EPAP may be increased as needed for alveolar recruitment. -Invasive ventilation: -Treatment of ARDS associated with new influenza A (H1N1) virus infection should be based on published evidence-based guidelines for sepsis-associated ARDS. [bib_ref] Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress..., Ferguson [/bib_ref] Lung-protective mechanical ventilation strategies should be used. The rationale is not to cause damage of nonaffected areas. We recommend the following therapy: a) Ventilatory mode: most ARDS patients are ventilated using conventional volume-cycled positivepressure ventilators. Most studies using low tidal volume for ARDS employed this mode. [bib_ref] Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress..., Ferguson [/bib_ref] However, no differences in outcomes are detected if pressurecontrolled ventilation is chosen, since the low tidal volume strategy is reached. b) Oxygen: treatment of hypoxemia in ARDS induced by H1N1 virus is almost always initiated using 100% oxygen (FIO 2 = 1.0), and the concentration of O 2 is reduced with the goal of maintaining a PaO 2 greater than 60 mmHg (arterial O 2 saturation of about 90%). The FIO 2 should be lowered to less than 0.5 as soon as possible to reduce the risk of lung damage due to oxygen toxicity. c) Positive End-Expiratory Pressure (PEEP): Positive end-expiratory pressure works by counteracting the tendency toward alveoli collapse during pulmonary edema, low lung volume, and loss of surfactant. [bib_ref] A high PEEP-low tidal volume ventilatory strategy improves outcome in persistent ARDS:..., Villar [/bib_ref] In ARDS, the majority of the lung is atelectatic. [bib_ref] Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress..., Ferguson [/bib_ref] PEEP recruits partially collapsed areas, improving gas exchange. [bib_ref] A high PEEP-low tidal volume ventilatory strategy improves outcome in persistent ARDS:..., Villar [/bib_ref] However, in some cases it is associated with barotrauma, pneumothorax, lung injury, inflammation, a cardiac output decrease, and shock. [bib_ref] Evaluation of a ventilation strategy to prevent barotrauma in patients at high..., Stewart [/bib_ref] Consequently, we recommend a PEEP level between 5 and 12 cm H 2 O in most patients, and we can adjust the PEEP levels using a combination of the PV curve, the response of arterial blood gases, the hypothetical maximum and minimum PEEP values, and the hemodynamic response. d) Low-tidal-volume strategy: the most important development in the management of ARDS is that mechanical ventilation with a lower tidal volume than previously used is associated with an improved clinical outcome. [bib_ref] Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress..., Ferguson [/bib_ref] This type of ventilation has been termed as the low-tidal volume or lung-protective strategy. The best risk:benefit ratio would be gained with a tidal volume of 6 ml/Kg or less, to reach a target plateau pressure of less than 30 cm H 2 O. 30 e) Recruitment maneuvers and the prone position: recruitment maneuvers and the prone position must be reserved for refractory hypoxemia, as in other cases of ARDS. [bib_ref] Lung recruitment in patients with acute respiratory distress syndrome, Gattinoni [/bib_ref] [bib_ref] Prone positioning and low-volume pressure limited ventilation improve survival in patients with..., Stocker [/bib_ref] 5.2.2 Hemodynamic support: Patients admitted to the intensive care unit with S-OIV infection and ARDS may present shock. It is of main importance to maintain hemodynamic goals in these patients to avoid organ failure. Fluid management in this population should be performed carefully. Current evidence indicates that a net negative balance is desirable in ARDS. [bib_ref] Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective,..., Dubois [/bib_ref] However, in these patients, hypovolemia must be avoided. Therefore, we recommend dynamic evaluation of the fluid status and a more conservative strategy for fluid replacement. In some cases, albumin associated with furosemide may offer benefit in the net balance. [bib_ref] Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective,..., Dubois [/bib_ref] [bib_ref] Comparison of two fluid-management strategies in acute lung injury, Wiedemann [/bib_ref] Hemodynamic goals: -Mean arterial pressure > 65 mmHg -SVO 2 > 70% -Lactate < 2 mmol/L -Diuresis higher than 1ml/Kg/h For optimal tissue perfusion and to obtain adequate arterial pressure, it is often necessary to use vasopressors and inotropics. We suggest norepinephrine as the first-line vasopressor and dobutamine as the inotropic. Vasopressin should be reserved for refractory shock. [bib_ref] Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, Russell [/bib_ref] ## 5.2.3 Renal support: acute renal failure has been observed in patients with S-OIV infection, especially in cases presenting shock.The etiology of acute renal failure is usually acute tubular necrosis, and in such cases renal replacement therapy may be needed. ## Corticosteroids: controversy exists as to whether we should use high-dose corticosteroids in ARDS due to S-OIV infection. [bib_ref] Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill..., Marik [/bib_ref] The positive effect would be a reduction of the inflammatory lung injury, potentially resulting in a better PO2/FIO2 ratio and less intubation, as in ARDS of other etiologies. [bib_ref] Steroid treatment in ARDS: A critical appraisal of the ARDS network trial..., Meduri [/bib_ref] The adverse events in influenza virusinfected patients would be higher rates of opportunistic infection and, possibly, prolonged viral replication. We do not have pathology data for H1N1 infection to guide the choice of therapy. So, we recommend the use of methylprednisolone (2 mg/Kg per day) just in cases of ARDS that do not response to initial measures. Low doses of corticosteroids (hydrocortisone 50 mg IV four times per day) may be considered for patients in septic shock who require vasopressors and have suspected adrenal insufficiency. 5.2.5 Antibiotics: antibiotic chemoprophylaxis should not be used. When pneumonia is present, treatment with antibiotics should follow the recommendations from published guidelines. However, seasonal influenza and past influenza pandemics have been associated with an increased risk of secondary Staphylococcus aureus infections, which may be severe, progress rapidly, have necrotizing effects, and, in some areas, may be caused by methicillinresistant strains. [bib_ref] Bacteriology and histopathology of the respiratory tract and lungs in fatal Asian..., Hers [/bib_ref] The results of microbiological studies, wherever possible, should be used to guide antibiotic usage for suspected bacterial coinfection in patients infected with the new influenza A (H1N1) virus. Several patients worldwide have developed community pneumoniae due to Streptococcus pneumoniae and Haemophilus influenza and ventilator-associated pneumonia or hospital-acquired pneumonia caused by typical nosocomial pathogens. [bib_ref] Studies on influenza in the pandemic of 1957-1958. II. Pulmonary complications of..., Louria [/bib_ref] 5.2.6 Glycemic control: tight glucose control (< 140 mg/ dL) must be achieved in critically ill patients, according to the local protocol. This measure is associated with a decrease of morbidity and mortality in critical patients. [bib_ref] Glycemic control, Fahy [/bib_ref] 5.2.7 Thromboembolic prophylaxis: patients infected with S-OIV should receive mechanical thromboprophylaxis and pharmacological if possible because, as critically ill patients with co-morbidities, they present a high risk for thromboembolic events. In a series of cases from Michigan, of 10 patients with S-OIV infection, five had a pulmonary embolism, although the higher incidence of thrombosis could be explained because seven were extremely obese (body mass index > 40). ## Diagnosis Laboratory confirmation of the novel influenza A (H1N1) virus, especially at the beginning of a new community outbreak, or for unusual cases, has important implications for case management, consideration of antiviral treatment options, and avoidance of the inappropriate use of antibiotics. [bib_ref] Evaluation of multiple test methods for the detection of the novel 2009..., Ginocchio [/bib_ref] Reverse transcriptase-polymerase chain reaction (RT-PCR) will provide the most timely and sensitive evidence of infection with the novel influenza A (H1N1) virus. [bib_ref] Evaluation of multiple test methods for the detection of the novel 2009..., Ginocchio [/bib_ref] [bib_ref] Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans, Faix [/bib_ref] Real-time RT-PCR is available in reference centers around the world.Samples for laboratory tests should be obtained from the deep nasal passages (nasal swab), nasopharynx (nasopharyngeal swab), or the bronchial aspirate if available. [bib_ref] Analytical sensitivity of rapid influenza antigen detection tests for swine-origin influenza virus..., Chan [/bib_ref] Upper respiratory tract sampling using a combination of nasal or nasopharyngeal and a throat swab is advised and may facilitate virus detection. It is not yet known which clinical specimen provides the best diagnostic yield for this specific infection. [bib_ref] Low sensitivity of rapid diagnostic test for influenza, Uyeki [/bib_ref] Specimen collection should be carried out with precautions since the procedure may expose the collector to respiratory secretions from infected patients. The real-time test through polymerase chain reaction, includes the use of specific primers and probes to diagnose S-OIV infection.The set of influenza primers and probes was created to detect: ## (a) seasonal influenza a virus (b) swine-origin influenza a virus (c) novel virus influenza a (h1n1) Currently, the data show that this method has a sensitivity of 99.3% and a specificity of 92.3% for the diagnosis of infection due to novel virus influenza A (H1N1).We recommend the following types of cases to be submitted for the test: a) patients who require hospitalization b) patients with risk factors for severe forms of disease c) patients in an individualized protocol -according to the clinical judgment No validated rapid bedside diagnostic test is presently available to detect novel influenza A (H1N1) virus infection. As part of the HC "bundles" for control of novel H1N1 infection, a real-time RT-PCR is available for patients and workers who fill criteria to be tested. ## Treatment and prophylaxis The novel influenza A (H1N1) virus is currently susceptible to the antiviral medications known as neuraminidase inhibitors (NAIs), specifically oseltamivir and zanamivir. 49, [bib_ref] Who should receive Tamiflu for swine flu ?, Ellis [/bib_ref] The virus is resistant to the adamantane medications amantadine or rimantadine. Clinical efficacy data on antiviral treatment are not yet available. Based on its in vitro susceptibility patterns and the clinical experiences derived from seasonal and avian influenza infection, early administration of NAIs might reduce the severity and duration of illness caused by the novel H1N1 virus infection and might also help to prevent progression to severe disease and death. [bib_ref] Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and..., Tanaka [/bib_ref] Only sporadic cases of oseltamivir-resistant 2009 influenza A (H1N1) viruses have been detected worldwide, including nine cases in the United States. [bib_ref] Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States, Dharan [/bib_ref] Eight of nine patients had a documented exposure to oseltamivir through either treatment or prophylaxis. [bib_ref] Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States, Dharan [/bib_ref] Clinical judgment is an important factor in the treatment decision. People with suspected novel H1N1 influenza who present with an uncomplicated febrile illness typically do not require treatment unless they are at higher risk for influenza complications, and in areas with limited antiviral availability, local public health authorities might provide guidance about prioritizing treatment within groups at higher risk. [bib_ref] Compliance and side effects of prophylactic oseltamivir treatment in a school in..., Wallensten [/bib_ref] Antiviral therapy may be beneficial, especially for the following groups: [bib_ref] Susceptibility of antiviral drugs against 2009 influenza A (H1N1) virus, Rungrotmongkol [/bib_ref] 1. All hospitalized patients with confirmed, probable, or suspected novel influenza (H1N1). 2. Patients who are at a higher risk for complications (listed above). If used, antiviral treatment should ideally be initiated early, as soon as possible, but it may also be used at any stage of the active disease when ongoing viral replication is anticipated or documented. Evidence for the benefits of antiviral treatment in studies of seasonal influenza is highest when treatment is started within 48 hours of the onset of illness. [bib_ref] Swine flu outbreak. What role for antiviral drugs?, Couzin-Frankel [/bib_ref] However, studies investigating oseltamivir treatment of hospitalized patients have indicated a benefit, including reductions of mortality or duration of hospital stay, even for patients whose treatment was initiated after 48 hours. [bib_ref] Influenza virus resistance to antiviral agents: a plea for rational use, Poland [/bib_ref] There are important pharmacological differences to consider when choosing NAIs for treatment. Oseltamivir is administered orally and provides a higher systemic level.Zanamivir is delivered by oral inhalation, with low systemic absorption.Oseltamivir is the recommended treatment for lower respiratory tract complications.The recommended treatment duration is five days. In Brazil, oseltamivir is used for the treatment and prophylaxis of S-OIV infection [fig_ref] Table 1 -: Recommended antiviral treatment and prophylaxis for novel influenza A [/fig_ref]. Rare neuropsychiatric symptoms, such as confusion or abnormal behavior, have occurred after beginning treatment for seasonal influenza with oseltamivir, particularly in children, but the contribution of oseltamivir to these events remains unknown. [bib_ref] Influenza diagnosis and treatment in children: a review of studies on clinically..., Uyeki [/bib_ref] Post-exposure antiviral chemoprophylaxis with either oseltamivir or zanamivir for 10 days can be considered for the following situations: [bib_ref] Safety and Efficacy of Extended-Duration Antiviral Chemoprophylaxis Against Pandemic and Seasonal Influenza, Khazeni [/bib_ref] 1. Close contact of cases (confirmed, probable, or suspected) who are at a high risk for influenza complications 2. Health care personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with novel (H1N1) influenza virus infection during the patient's infectious period. In patients presenting renal failure, with a creatinine clearance between 10 and 30 ml/min/m2, a 50% dosage reduction of oseltamivir is recommended. [bib_ref] The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and..., Robson [/bib_ref] There are no data available on the ideal dosage during renal replacement therapy. Patients with hepatic failure do not require dosage correction. [bib_ref] The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and..., Robson [/bib_ref] Zanamivir is indicated for the treatment of influenza in adults and children (>5 years).The recommended dose for treatment of adults and children older than 5 years of age is two inhalations (2 x 5mg) twice daily for 5 days. Inhaled zanamivir has been temporally associated with bronchospasm, and patients with preexisting airway disease appear to be at an increased risk for this severe adverse reaction.Available products in Brazil: (a) Tamiflu ® Roche -75-mg capsule and 52-ml oral suspension (12 mg/ml) (b) Oseltamivir Farmanguinhos -75-mg capsule (c) Oseltamivir HC -50-ml oral suspension (15 mg/ml) ## Prevention Until now, no vaccine has been commercially available to protect against novel H1N1 virus, although there are everyday actions known to prevent the spread of infection, such as: [bib_ref] H1N1 influenza, public health preparedness, and health care reform, Lurie [/bib_ref] · Wash your hands often with soap and water. Alcoholbased hand cleaners are also effective. · Try to avoid close contact with sick people. · Cover your nose and mouth with a tissue when you cough or sneeze. · Stay home if you are sick for 7 days after your symptoms begin or until you have been symptom-free for 24 hours. · Follow public health advice regarding school closures, avoid crowds. ## Care of patients with confirmed, sus-pected, or probable infection with the novel virus influenza a (h1/n1) Health care professionals must use the following personal protective equipment 62 : a) A surgical mask when the professional is working at a distance of less than1 meter from the patients, in procedures without aerosol production. b) Special clothes to avoid contact with blood and fluids. c) A N95 mask, protective glasses, and gloves in procedures with aerosol production, such as intubation, secretion manipulation, and autopsies. ## Hc "bundles" for novel influenza a (h1n1) infection As already mentioned, as a reference center for H1N1 infection, the Hospital das Clínicas da Universidade de São Paulo created the "Cabinet Crisis" with the objectives of implementing "bundles" for control of S-OIV infection, a group of interventions to obtain better outcomes in the management of this disease. We adopted some measures to obtain continuous and everyday information on the H1N1 infection, to implement actions to control the pandemics and to evaluate the impact of these interventions such as: 1. Periodical meetings among healthcare professionals from all institutions -directors, professors, epidemiologists, infectologists, intensive care physicians -to discuss new data and information about the disease 2. Continuous local Epidemiologic Surveillance to collect and analyze the data to assess the impact of the virus and determine the groups at an increased risk of complications. 3. Information for all professionals and patients about the infection, symptoms, diagnosis, and prevention. 4. Availability of a real time RT-PCR for novel influenza A (H1N1) virus in admitted patients. 5. Reduction of daily visits of families to the hospital. 6. Implementation of hygienic measures: alcohol-based hand cleaner, gloves, masks. 7. Internet published recommendations on the management of infection (www.hcnet.usp.br) 8. Specific units for the care of patients with suspected or confirmed S-OIV infection including emergency room attending, regular ward and specialized intensive care units. 9. Guidance for the staff and coworkers to limit contact with other people when symptoms are present. 10. Risk groups specialized protocols of care: pregnant women, children, immunocompromised patients, and chronic diseases. 11. Immediate availability of antiviral therapy. In the last weeks, we could observe a significant reduction in the incidence and mortality of novel influenza A (H1N1) infection in São Paulo and in Hospital das Clínicas. We suppose that an association of factors contribute to these numbers including a global actions plan, the continuous epidemiologic monitoring and the acquired expertise to diagnosis and adequate treatment of patients. We wish to maintain all the adopted measures in Hospital das Clínicas with the ongoing objective of obtain better outcomes in the management of novel influenza A (H1N1) infection. With the accumulating experience and groups of study, we hope to contribute continuously with information regarding epidemiology, pathogenesis and clinical aspects of this pandemics. # Conclusions and perspectives The 2009 pandemic novel influenza A (H1N1) infection continues to spread globally and displays the complexity of preexisting viruses, which become highly transmissible through genetic mutations and reassortments. In less than 200 days of known disease in humans, we learned that the replication competence and virulence of the novel H1N1 virus enable it to cause severe clinical presentations and death. As a consequence of this outbreak, the world learned the value of nonpharmacologic interventions, which can save many lives. A vaccine is expected as a potential control measure for the pandemic. [bib_ref] Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine..., Greenberg [/bib_ref] In the Hospital das Clínicas da Universidade de São Paulo, a "Cabinet Crisis" was created to implement a group of interventions to obtain better outcomes in the management of H1N1 infection. In our opinion, to control this pandemic, global actions are required without a geographic barrier. More studies are needed in zoonotic virology to allow a better understanding concerning the pathogenesis and epidemiologic aspects of the new viruses to prevent emergent diseases. [fig] Figure 1 -: Spectrum of novel influenza A (H1N1) infection Review of novel human influenza A (H1N1) infection Hajjar LA et al. [/fig] [fig] Figure 2 -: Risk groups for S-OIV infection Review of novel human influenza A (H1N1) infection Hajjar LA et al. [/fig] [table] Table 1 -: Recommended antiviral treatment and prophylaxis for novel influenza A (H1N1) infection [/table] [table] Table 2 -: Recommended [/table] [table] Table 3 -: Recommended antiviral chemoprophylaxis for children younger than 1 year using oseltamivir [/table]	None	http://www.scielo.br/pdf/clin/v64n10/13.pdf	The pandemic novel influenza A (H1N1) infection was considered widespread in Brazil on July, 2009. Since then, 9.249 cases were confirmed in Brazil, most of them concentrated in São Paulo. The Hospital das Clínicas of the University of São Paulo is a reference center for H1N1 cases in São Paulo. The purpose of this review is to analyze the evidence concerning diagnosis, prevention, and treatment of novel influenza A (H1N1) infection. In addition, we propose guidelines for the management of this pandemic emphasizing Hospital das Clínicas “bundles” for the control of the pandemic novel influenza A (H1N1).
373ace7608cba7af80f2f77e0dd6406eceaf3721	pubmed	Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea	Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea # Introduction Hemolytic uremic syndrome (HUS) is a syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) [bib_ref] Hemolyticuremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic..., Gasser [/bib_ref]. HUS typically develops in children, is preceded by bloody diarrhea, and responds well to supportive care. Typical HUS is caused by bacterial infection associated with Shiga toxin-producing Escherichia coli (STEC) or other bacteria and is called STEC-HUS [bib_ref] Hemolytic uremic syndromes in childhood, Gordjani [/bib_ref]. However, atypical HUS (aHUS) can develop at any age; 5%-10% of cases do not have prodromal diarrhea and have a poor prognosis [bib_ref] Atypical hemolytic-uremic syndrome, Noris [/bib_ref]. The major pathogenesis of aHUS involves dysregulation of the complement system, such as genetic abnormalities or autoantibodies, which are responsible for 60%-70% of cases [bib_ref] Atypical hemolytic uremic syndrome, Kavanagh [/bib_ref]. Mutation in the complement factor H (CFH) gene is the most frequent cause of aHUS, followed by membrane cofactor protein (MCP), complement factor I (CFI), C3, complement factor B (CFB), thrombomodulin (THBD), and others [bib_ref] Genetic studies into inherited and sporadic hemolytic uremic syndrome, Warwicker [/bib_ref] [bib_ref] Rodríguez de Córdoba S. Gain-of-function mutations in complement factor B are associated..., Goicoechea De [/bib_ref] [bib_ref] International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and..., Noris [/bib_ref]. Autoantibodies against CFH are detected in 6%-10% of cases of aHUS [bib_ref] Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome, Dragon-Durey [/bib_ref]. Recently, complement-independent forms of aHUS, such as mutations in diacylglycerol kinase Ɛ (DGKE) and plasminogen (PLG), are reported [bib_ref] Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome, Lemaire [/bib_ref]. Eculizumab, a humanized monoclonal antibody that blocks complement C5 activation and terminal complement component formation, has recently been proven effective against aHUS [bib_ref] Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome, Legendre [/bib_ref] [bib_ref] Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation, Zuber [/bib_ref] [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. It can rescue native kidney function or allow successful kidney transplantation, and may dramatically change the prognosis of this potentially fatal syndrome [bib_ref] Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation, Zuber [/bib_ref]. aHUS is often misdiagnosed as thrombotic thrombocytopenic purpura (TTP) or STEC-HUS, all of which show common clinical features of microangiopathic hemolytic anemia and thrombocytopenia. However, the pathogenesis and response rate to plasma exchange (PEX) treatment differ between syndromes [bib_ref] Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic..., Menne [/bib_ref] [bib_ref] Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in..., Rock [/bib_ref] [bib_ref] Genetics of HUS: the impact of MCP, CFH, and IF mutations on..., Caprioli [/bib_ref]. Delayed treatment of aHUS can cause death or end-stage renal disease (ESRD) [bib_ref] Genetics of HUS: the impact of MCP, CFH, and IF mutations on..., Caprioli [/bib_ref]. Therefore, a differential diagnosis of aHUS from other forms of thrombotic microangiopathy (TMA) such as TTP and STEC-HUS is very important for its appropriate management. Since clinical trials of eculizumab with regard to aHUS began [bib_ref] Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation, Zuber [/bib_ref] [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] , guidelines for aHUS have been developed in Europe for the standardization of management of aHUS [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref]. The guidelines accelerated the detection and clinical trials of patients with aHUS [bib_ref] An audit analysis of a guideline for the investigation and initial therapy..., Johnson [/bib_ref]. However, in Korea, the diagnosis and management of aHUS have not been studied sufficiently due to the lack of physicians' awareness and the shortage of referral diagnostic laboratories. Hitherto, only 26 patients with genetically confirmed aHUS are reported in Korea [bib_ref] Atypical hemolytic uremic syndrome: Korean pediatric series, Lee [/bib_ref] [bib_ref] Analysis of genetic factors in 9 Korean adult patients with atypical hemolytic..., Kim [/bib_ref]. Furthermore, aHUS management in Korea is in the pre-eculizumab era and needs to be improved. The guidelines offer recommendations for the management of aHUS in Korea. The guidelines' scope includes the diagnosis and treatment of aHUS, with information on investigator networks in Korea. The guidelines were developed by the Korean aHUS Working Group (KHWG), which was organized to study aHUS in October 2015 and is composed of physicians representing the Korean Society of Pediatric Nephrology, the Korean Society of Nephrology, the Korean Society of Hematology, and the Korean Society on Thrombosis and Hemostasis as experts. The guidelines have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population. The GRADE system (http://www.gradeworkinggroup. org) is used to classify the strength of the recommendations and the quality of the evidence [fig_ref] Table 1: Strength of recommendations and quality of evidence Weak recommendation [/fig_ref]. ## Disease overview definition HUS was earlier divided into diarrhea-positive and diarrheanegative HUS. The former, also referred to as typical HUS, primarily results from STEC infections, and less frequently from other infections, including Shigella dysenteriae type 1 infection. All other causes of HUS are referred to as aHUS or diarrheanegative HUS, even though some patients with non-STEC-HUS also present with diarrhea. Currently, the term aHUS applies to a heterogeneous group of diseases that have TMA associated with some degree of AKI. TMA syndromes are united by common clinical and pathological features, including microangiopathic hemolytic ane-mia, thrombocytopenia, organ injury, and vascular damage manifested by microvascular thrombosis [bib_ref] Syndromes of thrombotic microangiopathy, George [/bib_ref]. [fig_ref] Table 1: Strength of recommendations and quality of evidence Weak recommendation [/fig_ref] For aHUS, multiple underlying disease mechanisms are likely involved, including increased complement activation, drugs, non-Shiga toxin infectious agents, cobalamin deficiency, malignancy, transplant, and autoimmune disease. On the basis of current diagnostic criteria, aHUS is usually defined to include all types of HUS that are unrelated to Shiga toxins. However, only HUS associated with complement dysregulation may be defined as aHUS as in these guidelines, because complement dysregulation accounts for most non-STEC cases of HUS and complement blockade using eculizumab should be considered in this group of patients [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref]. Ongoing research provides improved understanding of the underlying causes and new therapeutic target of HUS. The definition and nomenclature of aHUS need to be redefined based on the underlying pathophysiology and possible treatment options. ## Incidence The incidence of aHUS in the Korean population is not available due to a lack of data. The prevalence of aHUS in Western populations is thought to be approximately 2 per million in adults and 3.3 per million in children younger than 18 years, whereas the prevalence of aHUS in Japan was much lower than that of Western populations and was estimated as approximately 0.84 per million population according to the Nara Medical University Registry [bib_ref] Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe..., Ohanian [/bib_ref] [bib_ref] Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome, Zimmerhackl [/bib_ref] [bib_ref] Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara..., Fujimura [/bib_ref]. Since April 2012, when aHUS emerged at the global level, 681 patients have been enrolled worldwide by , and over 1,000 patients with aHUS caused by genetic abnormalities of the complement system are reported [bib_ref] Genetics of HUS: the impact of MCP, CFH, and IF mutations on..., Caprioli [/bib_ref] [bib_ref] Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic..., Sellier-Leclerc [/bib_ref] [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility..., Esparza-Gordillo [/bib_ref] [bib_ref] The high frequency of complement factor H related CFHR1 gene deletion is..., Dragon-Durey [/bib_ref] [bib_ref] Mutations in components of complement influence the outcome of Factor I-associated atypical..., Bienaimé [/bib_ref]. ## Pathogenesis of thrombotic microangiopathy Complement-mediated aHUS aHUS is caused by complement dysregulation. An alternative complement pathway is constitutively activated and tightly regulated in normal conditions by multiple regulators to prevent damage to the endothelium and platelets. However, uncontrolled and excessive activation of this pathway, mostly due to genetic mutations or autoantibodies against numerous regulator proteins in the complement system, occurs in patients with aHUS and causes various clinical manifestations [bib_ref] Syndromes of thrombotic microangiopathy, George [/bib_ref] [bib_ref] STEC-HUS, atypical HUS and TTP are all diseases of complement activation, Noris [/bib_ref]. The complement cascade can cause lysis of target cells by forming a pore in the cell membrane. Failure of normal control mechanisms to downregulate the alternative pathway may cause endothelial damage. Complement activation triggers several inflammatory responses. Endothelial cells express complement receptors; they are also susceptible to complement attack. Renal cells are especially sensitive to complement activation, which may explain the predominance of AKI in aHUS. Von Willebrand factor (VWF) may activate the complement [bib_ref] The interaction between factor H and VWF increases factor H cofactor activity..., Rayes [/bib_ref]. Hemostatic factors involved in the clotting cascade, especially those with regulatory roles, interact with complement proteins, but their specific mechanisms and roles are less well understood. ## Adamts13-mediated ttp TTP is caused by the severely deficient activity of the ADAMTS13 protease, clinically defined as an activity level < 10% [bib_ref] What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura, Sadler [/bib_ref]. AD-AMTS13 cleaves VWF multimers attached to the endothelial surface and prevents the formation of platelet microthrombi. ADAMTS13 deficiency is caused by acquired autoantibodies to ADAMTS13 or hereditary ADAMTS13 gene mutations. The histopathology of TTP and other primary TMAs is characterized by small vessel changes, including swelling of endothelial cells and the subendothelial space, along with vessel wall thickening and platelet microthrombi, typically in small arterioles and capillaries [bib_ref] Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome, Tsai [/bib_ref]. Renal and central nervous system involvement is common. ## Other types of tma Recently, complement-independent forms of aHUS, such as mutations in DGKE and PLG, have also been reported [bib_ref] Syndromes of thrombotic microangiopathy, George [/bib_ref]. The implicated factors are generally negative regulators of coagulation or fibrinolysis that also cross-talk with complement factors. Affected individuals generally present during infancy or early childhood. Recessive mutations in the gene encoding DGKE or intronic DGKE mutation (c.888+40A>G) have been reported in familial TMA. Homozygous or compound heterozygous mutations may be seen. DGKE is expressed in endothelium, platelets, and podocytes. Because DGKE is a control enzyme that inactivates the diacylglycerol (DAG) signaling pathway, which promotes thrombosis, loss of DGKE function results in endothelial injury, podocyte dysfunction, thrombosis, AKI, and aHUS [bib_ref] Characterization of a new DGKE intronic mutation in genetically unsolved cases of..., Mele [/bib_ref]. Four variants in PLG (c.112 A>G, p.Lys38Glu; c.2134 G>A, p.Gly712Arg; c.758 G>A, p.Arg253His; c.505 C>T, p.Pro169Ser) are associated with aHUS. Because plasmin is able to disintegrate formed platelet aggregates, reduced proteolytic activity of plasmin may result in a prethrombotic state of aHUS development [bib_ref] Minor role of plasminogen in complement activation on cell surfaces, Hyvärinen [/bib_ref]. TMA has been reported in individuals with mutations in the gene encoding methylmalonic aciduria and homocystinuria type C (MMACHC) [bib_ref] Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder, Sharma [/bib_ref]. Homozygosity or compound heterozygosity appears to be required for clinical disease. MMACHC is involved in cobalamin (vitamin B12) metabolism. Infants with cobalamin C disease, a type of methylmalonic acidemia, present with various neurologic and developmental findings. The patients show markedly elevated plasma homocysteine levels, but plasma cobalamin levels are normal. Hyperhomocystein-emia-induced damage to glomerular endothelium has been suggested as the putative mechanism for aHUS [bib_ref] Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase..., Labrune [/bib_ref]. Complete responses of this TMA to the accessible and inexpensive therapy with high-dose cobalamin and folinic acid have been reported. Evaluation of these abnormalities in cobalamin metabolism is available by measuring serum homocysteine and methylmalonic acid levels. Drug-induced TMA (DITMA) has been reported following exposure to several types of drugs, especially those containing quinine. Drug-induced antibodies reactive with endothelial cells and possibly margination of granulocytes in renal glomeruli may be responsible for aHUS [bib_ref] Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome: clinical and serological findings in..., Gottschall [/bib_ref]. ## Etiology Defective complement regulation by mutations or autoantibodies is responsible for 60%-70% of cases of aHUS [fig_ref] Figure 1: Etiology of atypical hemolytic uremic syndrome [/fig_ref] [bib_ref] Atypical hemolytic uremic syndrome: Korean pediatric series, Lee [/bib_ref] [bib_ref] Syndromes of thrombotic microangiopathy, George [/bib_ref] [bib_ref] STEC-HUS, atypical HUS and TTP are all diseases of complement activation, Noris [/bib_ref]. aHUS can occur due to a mutation in one of the several genes encoding complement factors. CFH, CFI, CFB, C3, THBD, and MCP have been implicated. CFH mutations are the most common abnormality according to registry data from the United States and Europe and account for approximately 23%-27% of the mutations [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Mutations in alternative pathway complement proteins in American patients with atypical hemolytic..., Maga [/bib_ref]. Along with genetic mutations causing decreased CFH activity, 6%-10% of patients develop anti-CFH antibodies [bib_ref] Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3..., Lee [/bib_ref]. CFH autoantibodies impair the regulatory function of the complement system by inhibiting the binding of CFH to C3b. Some cases have a coexisting complement gene mutation, and large deletion of the CFHR1 and CFHR3 genes are associated with the development of auto anti-CFH-associated aHUS. MCP gene mutations are responsible for 5%-7% of aHUS cases, whereas the CFI and C3 gene have also been reported to occur at frequencies of 4%-8% and 2%-7%, respectively [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Mutations in alternative pathway complement proteins in American patients with atypical hemolytic..., Maga [/bib_ref]. Up to 12% of patients with aHUS have combined mutations, usually CFH with CFI or MCP [bib_ref] Genetics of HUS: the impact of MCP, CFH, and IF mutations on..., Caprioli [/bib_ref]. Interestingly, the incidence of anti-CFH antibody is demonstrated to be higher (29.7%) in a recent multicenter cohort study of 51 Korean children with aHUS [fig_ref] Figure 1: Etiology of atypical hemolytic uremic syndrome [/fig_ref] [bib_ref] Atypical hemolytic uremic syndrome: Korean pediatric series, Lee [/bib_ref]. Heterozygous mutations may be sufficient to cause clinical manifestations. As most genes associated with aHUS showed incomplete penetrance, an additional trigger such as infection, drugs, autoimmune disease, vaccination, pregnancy, cancer, or transplantation is necessary to develop full clinical manifestations of aHUS in a patient with a mutation of these genes [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Acute intravascular haemolysis due to quinine, Webb [/bib_ref] [bib_ref] Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations, Fakhouri [/bib_ref] [bib_ref] Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases, Lechner [/bib_ref] [bib_ref] Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic..., Ho [/bib_ref] [bib_ref] Genetics and complement in atypical HUS, Kavanagh [/bib_ref]. Therefore, even in patients with combined genetic mutations, the clinical syndrome may not develop until middle age [bib_ref] Genetics and complement in atypical HUS, Kavanagh [/bib_ref]. Several other disorders such as autoimmune diseases, malignancies, drugs, eclampsia or pregnancy associated HELLP syndrome can also cause clinical and pathological features of HUS and should be considered as possible alternative causes or triggering factors of aHUS. However, some of these disorders are likely to provoke TMA directly in which effective treatment of disorders often leads to complete resolution of TMA [bib_ref] Syndromes of thrombotic microangiopathy, George [/bib_ref]. Despite substantial advances in identifying defects in the complement regulation, 35% to 40% of cases of aHUS are still classified as "idiopathic" because no demonstrable genetic mutations have been found [bib_ref] Atypical hemolytic uremic syndrome, Kavanagh [/bib_ref]. Whether these patients have no complement abnormalities or unknown genetic mutations of the complement system remains unknown at present. ## Clinical presentations and prognosis Common symptoms of aHUS include gastrointestinal phenomena such as abdominal pains or diarrhea, although it should be noted that such symptoms may be insufficient to differentiate aHUS from typical HUS. Nonimmunologic microangiopathic hemolytic anemia and thrombocytopenia are the most common clinical manifestations, which ultimately affect the kidneys and brain, leading to acute renal failure and neurologic abnormalities such as confusion or convulsion. The disease may also invade the cardiovascular system, resulting in cardiac failure, myocarditis, and distal gangrene. The most common sequelae resulting from aHUS are chronic renal failure and hypertension [bib_ref] Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment, Hofer [/bib_ref]. Upper respiratory tract symptoms are also commonly observed. aHUS may occur secondarily in patients with malignant hypertension, during pregnancy, after transplantation, with malignant diseases, or while using drugs such as anti-cancer chemotherapy or immunosuppressants [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref]. aHUS recurs frequently and its prognosis is poor, with death rates as high as 25% and progression to end-stage renal disease in 50% (3). Its rate of recurrence and prognosis vary depending on which particular complement mutation or environmental factors are present. ## Diagnosis ## Clinical diagnosis The diagnosis of complement-mediated aHUS is made by excluding other forms of TMA. Therefore, aHUS is suspected in patients with TMA without a secondary cause and ADAMTS13 activity > 10%, without evidence of STEC-HUS (grade 1B). aHUS is clinically defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI, which should not be related to coexisting diseases [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome (aHUS): making the diagnosis, Laurence [/bib_ref]. However, STEC infection can trigger an aHUS episode in approximately 1% of patients with a complement mutation (mostly MCP mutation in children) [bib_ref] Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series..., Fremeaux-Bacchi [/bib_ref] , and the alternative complement pathway can be transiently activated during the acute phase of STEC-HUS [bib_ref] Current evidence for the role of complement in the pathogenesis of Shiga..., Keir [/bib_ref] [bib_ref] Interaction of Shiga toxin 2 with complement regulators of the factor H..., Poolpol [/bib_ref]. The definitions of microangiopathic hemolytic anemia, thrombocytopenia, and AKI are summarized in [fig_ref] Table 2: Definitions of micro-angiopathic hemolytic anemia, thrombocytopenia, and AKI Presence of red blood... [/fig_ref] [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref] [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative..., Mehta [/bib_ref] [bib_ref] The definition of acute kidney injury and its use in practice, Thomas [/bib_ref]. However, regarding the urgency of the diagnosis and management of aHUS, a probable diagnosis of aHUS can be made with two essential criteria of microangiopathic hemolytic anemia and thrombocytopenia, without AKI, in which case the disease should not be related to Shiga toxins or TTP. The diagnostic sensitivity of aHUS would be increased if the data from multiple time points were evaluated, which would help in the early diagnosis and appropriate treatment of aHUS [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref]. Additionally, aHUS should also be strongly suspected if the following conditions are present in patients with HUS: very young age at onset (< 6 months); time point of HUS onset is not definite; recurrent HUS; recurrent HUS after renal transplantation; familial HUS; no history of diarrhea or bloody stools; and low C3 levels [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref]. ## Recommendations aHUS is suspected in patients with TMA without a secondary ## Distinguishing ahus from stec-hus: shiga toxin test STEC-HUS is accompanied by bloody diarrhea due to STEC infection. However, a diagnosis of STEC-HUS should not be made by the diarrhea symptom alone, because diarrhea can also be found in some patients with aHUS and asymptomatic shedding of STEC infection is possible [bib_ref] Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee..., Sawai [/bib_ref]. Therefore, tests for Shiga toxin/enterohemorrhagic Escherichia coli (EHEC) to exclude STEC-HUS should be performed for all patients suspected of having aHUS (grade 1B). Various methods can be used to confirm the presence of Shiga toxins in stool specimens. A stool or rectal swab should be performed at admission, and the specimens should be sent to the laboratory as soon as possible for STEC culture and Shiga toxin testing. If the stool specimens cannot be processed immediately, they should be refrigerated until they can be tested. A stool culture for STEC can be performed using sorbitol Mac-Conkey agar for O157:H7 and selective media for non-O157 STEC [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Nonculture assays can be performed to detect Shiga toxins such as STEC immunoassays using commercial kits, whereas real-time polymerase chain reaction (PCR) assays can be used to detect the stx1 and stx2 genes (61-63) and serum anti-lipopolysaccharides antibodies against common STEC serogroups [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Although sensitivity and specificity of immunoassays approved by the Food and Drug Administration (FDA) for the diagnosis of Shiga toxin producing STEC infection are 92%-100% and 98%-100%, respectively [bib_ref] Rapid detection of Shiga toxin-producing Escherichia coli by optical immunoassay, Teel [/bib_ref] [bib_ref] Evaluation of the duopath verotoxin test for detection of shiga toxins in..., Park [/bib_ref] [bib_ref] Evaluation of the premier EHEC assay for detection of Shiga toxin-producing Escherichia..., Kehl [/bib_ref] [bib_ref] Evaluation of performance and potential clinical impact of ProSpecT Shiga toxin Escherichia..., Gavin [/bib_ref] , one report demonstrated the superiority of PCR over EIA for the detection of STEC (68). It suggested that the level of detection for the EHEC enzyme immunoassays was 10 6 -10 7 CFU/mL of O157 STEC, but that PCR was able to detect STEC in a suspension of 10 2 CFU/mL [bib_ref] Comparison of three different methods for detection of Shiga toxin-producing Escherichia coli..., Vallières [/bib_ref]. ## Recommendations Tests for Shiga toxin/EHEC to exclude STEC-HUS should be performed for all patients suspected of having aHUS (grade 1B). ## Distinguishing ahus from ttp: the adamts13 test Because the central role of ADAMTS13 protease was discovered in the pathophysiology of acquired TTP [bib_ref] von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome, Furlan [/bib_ref] [bib_ref] Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, Tsai [/bib_ref] , several studies have assessed the clinical applicability of ADAMTS13 activity assay to attempt distinguishing aHUS from TTP [bib_ref] Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, Tsai [/bib_ref] [bib_ref] Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111..., Veyradier [/bib_ref]. The results of these studies support the hypothesis that a severe deficiency of ADMATS13 activity is more consistent with a diagnosis of acquired TTP than one of aHUS. Currently, in patients without a secondary cause of TMA, ADAMTS13 activity of < 10% is considered to be suggestive of TTP; otherwise, a diagnosis of aHUS is suggested [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] How I treat: the clinical differentiation and initial treatment of adult patients..., Cataland [/bib_ref] [bib_ref] Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on..., Sarode [/bib_ref] [bib_ref] Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update, Tsai [/bib_ref]. Therefore, tests for ADAMTS13 activity should be performed to exclude TTP in all patients suspected of having aHUS (grade 1B). However, because deficiency of ADAMTS13 activity could also be observed in a small number of patients with aHUS, if clinical findings are highly suggestive of aHUS, the diagnosis of aHUS should not be excluded only based on the result of ADAMTS13 activity test, especially in the patients who do not respond to the plasma exchange [bib_ref] Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. von Willebrand factor cleaving protease (ADAMTS13) is..., Remuzzi [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic..., Cataland [/bib_ref]. Currently, three kinds of assays are most widely used for evaluation of ADAMTS13 activity: immunoblotting-based assays, fluorescence resonance energy transfer (FRET)-based assays, and collagen-binding assays (CBA). To avoid erroneous results, the specimen for assaying ADAMTS13 activity should be collected before PEX or plasma infusion using sodium citrate as the anti-coagulant, not EDTA. The specimen should be packaged and shipped to the reference laboratory after freezing to preserve the enzyme activity [bib_ref] Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on..., Sarode [/bib_ref]. Biopsies may be helpful for difficult diagnostic situations. Regardless of whether they are clinically involved, gingiva, skin, and bone marrow are suggested sites for this purpose [bib_ref] Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108..., Bell [/bib_ref]. The thrombi of TTP are typically composed of platelets and VWF with minimal fibrin components. Vascular or perivascular infiltration of inflammatory cells is rare [bib_ref] Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted..., Mitra [/bib_ref] [bib_ref] Pathophysiology of thrombotic thrombocytopenic purpura, Tsai [/bib_ref]. In contrast, the micro-thrombi of aHUS are dominantly composed of fibrin, and infiltration of inflammatory cells in the perivascular area is usually observed [bib_ref] Pathophysiology of thrombotic thrombocytopenic purpura, Tsai [/bib_ref] [bib_ref] Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A..., Hosler [/bib_ref]. A recent study suggested that extensive microvascular deposition of C5b-9 supports the diagnosis of aHUS or TTP with concomitant complement dysregulation [bib_ref] Role of the skin biopsy in the diagnosis of atypical hemolytic uremic..., Magro [/bib_ref]. Therefore, the use of tissue biopsies could be considered on a case-by-case basis along with the ADMATS13 assay. ## Recommendations Tests for ADAMTS13 activity should be performed to exclude TTP in all patients suspected of having aHUS (grade 1B). ## Distinguishing ahus from cobalamin defect hus Because HUS can develop in hereditary defects in cobalamin metabolism, tests for plasma homocysteine, methionine, and methyl-malonic acid to exclude cobalamin defect HUS are recommended for all patients suspected of having aHUS (grade 2B). ## Recommendations Tests for plasma homocysteine, methionine, and methyl-malonic acid to exclude cobalamin defect HUS are recommended for all patients suspected of having aHUS (grade 2B). ## Proposed diagram to differentiate ahus among tmas In patients with thrombocytopenia and MAHA, TMA could be suspected clinically. MAHA could be identified by hemolytic anemia and the presence of schistocytes on the peripheral blood smear. In these patients, a thorough medical history investiga- tion and physical examination should be conducted for a differential diagnosis of TMAs. The first step is to exclude other causative clinical situations of TMA. Examples of TMA with a coexisting disease or condition are summarized in [fig_ref] Figure 2: Proposed diagram to differentiate atypical hemolytic uremic syndrome [/fig_ref]. Because TMA is a multisystem disease, the presence of any organ injury should be identified by physical examination and laboratory studies. The nervous, renal, and gastrointestinal systems are most frequently involved in patients with TMAs. First, the physical examination should be focused on neurological or gastrointestinal abnormalities. Previously, neurological abnormalities have been used to differentiate TTP from other TMAs, because the involvement of the nervous system was reported in up to 79% of patients with TTP (82-86). However, various degrees of neurological injury have also been observed in ADAMTS13 nondeficient aHUS patients [bib_ref] Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab, Gulleroglu [/bib_ref] [bib_ref] Reduced dose maintenance eculizumab in atypical hemolytic uremic syndrome (aHUS): an update..., Ohanian [/bib_ref] [bib_ref] Profound neurological injury in a patient with atypical hemolytic uremic syndrome, Salem [/bib_ref]. Therefore, the clinical utility of neurological symptoms is somewhat limited. Similarly, unexplained accompanying gastrointestinal symptoms are commonly observed in patients with TMAs [bib_ref] How I treat patients with thrombotic thrombocytopenic purpura: 2010, George [/bib_ref]. Nevertheless, it is noteworthy that patients with bloody diarrhea should be exam-ined for Shiga toxin-producing bacteria. Although renal injury requiring dialysis is the more frequent manifestation among aHUS patients, various degrees of renal impairment are also observed in patients with TTP [bib_ref] Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of..., Coppo [/bib_ref] [bib_ref] Survival and relapse in patients with thrombotic thrombocytopenic purpura, Hovinga [/bib_ref] [bib_ref] Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the..., Coppo [/bib_ref]. Other laboratory tests for rare conditions associated with TMAs may be helpful in differentiating the causes of TMAs. These include disseminated intravascular coagulation (DIC) panel (PT, aPTT, fibrinogen, FDP, d-dimer, and others), autoimmune serology (FANA, ANCA), paroxysmal nocturnal hemoglobinuria (PNH) screening by flow cytometry, and human immunodeficiency virus (HIV) screening. Therefore, the following laboratory tests for rare conditions associated with TMAs may be helpful in differentiating the causes of TMAs: DIC panel, autoimmune serology, PNH screening by flow cytometry, and HIV screening (grade 1B). In patients with TMA and any organ injury of the nervous, renal, or gastrointestinal system, an assay for ADAMTS13 activity and Shiga toxin/EHEC should be performed (grade 1B). Patients positive for Shiga toxin or EHEC have STEC-HUS diagnosed. Patients with severely deficient ADAMTS13 activity of In patients diagnosed with aHUS, the possibility of triggering factors should be investigated. Even in patients with a dysregulated complement system, the clinical syndrome may not develop until middle age [bib_ref] Atypical hemolytic-uremic syndrome, Noris [/bib_ref]. Certain clinical situations may promote the activation of the complement system and, consequently, the clinical manifestation of aHUS may develop in unaffected healthy carriers. Typical examples include infection, stress, active inflammation, surgery, pregnancy, and intravenous contrast agents [bib_ref] Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update, Tsai [/bib_ref]. Any identified triggering factor should be eradicated as soon as possible. To prevent recurrent episodes, patients with aHUS should be educated to avoid the identified triggering factors as much as possible after achieving clinical remission (grade 1C). ## Recommendations Genetic screening for complementary abnormalities is recommended for aHUS patients (grade 1B). To prevent recurrent episodes, patients with aHUS should be educated to avoid the identified triggering factors as much as possible after achieving clinical remission (grade 1C). ## Further investigation: genetic screening Abnormalities of the complement regulation system are the main causes of aHUS and include various kinds of mutations and copy number variations in the genes encoding C3, CFH, CFI, CD46 (MCP), CFB, THBD, and complement factor H-related proteins 1 through 5 (CFHR1-5) or anti-CFH antibodies [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. Currently, 60%-70% of patients with aHUS have identifiable mutations in complement genes or anti-CFH antibodies [bib_ref] Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to..., Ståhl [/bib_ref]. First, serum C3 and C4 levels should be measured for all patients presenting with clinical features of HUS. If those levels have decreased, then aHUS should be suspected, although the C3 and C4 levels may be normal in aHUS. If possible, one should measure factor H and factor I levels in serum and CD46 expression in PBMCs using FACS, if possible, for all patients presenting clinical features compatible with a diagnosis of aHUS, because the results guide the prognosis and transplantation options [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. Similarly, however, normal levels or expression of factor H, factor I, and MCP do not rule out the possibility of a normally expressed but functionally impaired mutant. Therefore, screening for complementary abnormalities by measuring serum levels (C3, C4, CFH, CFI, CFB, anti-CFH antibody) and expression of MCP in peripheral blood mononuclear cells using flow cytometry should be performed for aHUS patients (grade 2B). Eventually, the full genetic analysis is recommended for all patients with aHUS who show no causative disease, STEC infection, severe ADAMTS 13 deficiency, or hyperhomocysteinemia/methyl-malonic aciduria (grade 1B) [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Additionally, genetic screening should be performed without delay if the patients have an HUS relapse, a familial history of nonsynchronous HUS, pregnancy/postpartum HUS, or de novo post-transplant HUS [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Genetic screening is especially essential before renal transplantation for aHUS. However, genetic screening is not justified before transplantation for STEC-HUS, unless this diagnosis is uncertain or unproven [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. There are several reasons for performing a genetic analysis when the first episode of aHUS occurs. First, through genetic analysis, we can confirm whether aHUS is complement-dependent, which might predict prognosis, the risk of relapses, and progression to ESRD according to the results of genetic abnormalities and might guide the complement blockade treatment. Second, we can provide genetic counseling to parents and family. Third, we can make decisions for various renal transplantation situations, such as the choice of donor, treatment guidance for the prevention or treatment of post-transplant recurrence, and whether to opt for combined kidney and liver transplantation [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. For genetic analysis, screening for mutations in CFH, CFI, MCP, C3, CFB, THBD, and DGKE should be performed by direct Sanger sequencing analysis or next-generation sequencing (NGS), and screening for the CFH hybrid gene and copy number variation in CFH and CFHRs should be performed by multiplex ligation-dependent probe amplification (MLPA) [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref]. Additionally, because 6%-10% of aHUS patients have antibodies that bind to the C terminal region of factor H, and because the prevalence of anti-CFH in Korean children is higher than in other countries [bib_ref] Atypical hemolytic uremic syndrome: Korean pediatric series, Lee [/bib_ref] , autoantibodies against factor H should be performed in an appropriately accredited laboratory [bib_ref] Anti-factor H autoantibodies assay, Dragon-Durey [/bib_ref]. ## Recommendations Screening for complementary abnormalities measuring serum levels (C3, C4, CFH, CFI, CFB, anti-CFH antibody) and expression of MCP in peripheral blood mononuclear cells using flow cytometry should be performed for aHUS patients (grade 2B). ## Management ## Supportive treatment Any patient suspected of having aHUS should be transferred to a specialized center where dialysis and PEX facilities are available. Platelet transfusion is contraindicated unless the patient is bleeding or when a surgical procedure carrying a risk of bleeding is necessary. The protection of peripheral and central veins is important in patients with aHUS who need long-term vascular access for hemodialysis or PEX. Infections can trigger the relapse of aHUS, and appropriate treatment is necessary [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. ## Plasma therapy All patients who are clinically suspected of having aHUS should be offered a trial of PEX and/or plasma infusion (PI) as early as possible [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. Since the laboratory findings including complement and ADAMTS13 are usually not available when the patient presents with clinical symptoms of aHUS, the guidelines recommend plasma therapy to be started within 24 hours of presentations including renal insufficiency, unexplained thrombocytopenia and a microangiopathic hemolytic anemia with a normal international normalized ratio and partial thromboplastin time. PEX is an alternative option if eculizumab is not available, with an exchange of 1.5 plasma volumes (60-75 mL/ kg) per session and with fresh-frozen plasma (FFP) for compensation. When PEX cannot be performed, PI (10-20 mL/kg) should be administered. Patients receive PEX or PI daily from 5 days up to 2 weeks during the acute phase until the platelet count, lactate dehydrogenase (LDH), and hemoglobin levels have normalized and the renal function shows signs of improvement. When disease activity is controlled by daily PEX, the subsequent frequency is 5 times per week for 2 weeks, and then 3 times per week for the subsequent 2 weeks [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. The frequency may be reduced from weekly to every 2 to 4 weeks as a longterm maintenance therapy. A Recent study suggested that the risk of ESRD after the first episode of aHUS was similar in the group with low-intensity plasma therapy and those with the high-intensity plasma therapy. Although the intensity of plasma therapy remains questioned, there is a clinical need for a more efficient treatment in patients with aHUS because of severe renal outcomes [bib_ref] Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series..., Fremeaux-Bacchi [/bib_ref]. The further frequency of plasma therapy has to be decided according to the genetic information and clinical response to plasma therapy. In patients with an MCP/CD46 mutation, the withdrawal of plasma therapy is possible because MCP is not a circulating protein. An attempt to withdraw plasma therapy can be considered in patients without a relapse of HUS, despite tapering of PEX/PI to monthly administration [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. Although PEX/PI induced remission in 55%-80% of episodes in patients with aHUS in the Italian cohort, 48% of children and 67% of adults died or progressed to ESRD during the 3-year follow-up period [bib_ref] Relative role of genetic complement abnormalities in sporadic and familial aHUS and..., Noris [/bib_ref]. ## Recommendations All patients who are clinically suspected of having aHUS should be offered a trial of PEX and/or PI if eculizumab is not available (grade 1C). ## Kidney transplantation The risk of HUS recurrence after kidney transplantation varies according to the underlying genetic abnormality. Renal transplantation alone is not recommended for patients with a CFH or CFI mutation because of the poor outcome, with 80% of patients losing their graft due to a recurrence of the disease within 2 years. In patients with an MCP/CD46 mutation alone, the risk of recurrence post-transplantation is low. Patients with a C3 or CFB mutation show a significant risk of disease recurrence posttransplantation. No post-transplantation recurrence has been observed to date in patients with a DGKE mutation. Patients with an anti-factor H autoantibody should be treated with a PEX combination with Rituximab to minimize the antibody titer before proceeding to renal transplantation [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref]. Living-related renal transplantation alone should be avoided in cases of aHUS [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref]. PEX/PI for post-transplant recurrence usually failed to prevent graft loss, and prophylactic PEX/PI was recommended. According to the Consensus Study Group, one PEX with FFP (60-75 mL/kg) should be performed within 4-6 hours before graft reperfusion, FFP (10-20 mL/kg) should be infused during surgery, and PEX with FFP (60-75 mL/kg) should be continued daily for at least 5 days, followed by 5 sessions per week for 2 weeks, and then 3 sessions per week for 2 weeks, after which it should be tapered on a case-by-case basis. Recently, prophylactic eculizumab treatment for patients at high risk for post-transplant recurrence has been considered [bib_ref] Liver-kidney transplantation to cure atypical hemolytic uremic syndrome, Saland [/bib_ref]. ## Recommendations Patients should be informed that the risk of disease recurrence after renal transplantation varies according to the causative mutations. Patients with an anti-factor H autoantibody should be treated with a PEX combination with Rituximab to minimize the antibody titer before proceeding to renal transplantation. Living-related renal transplantation alone should be avoided in cases of aHUS (grade 1C). ## Liver transplantation Because CFH, CFI, CFB, and C3 are synthesized in the liver, an isolated liver transplantation or a combined liver and kidney transplantation may be an option for patients with preserved eGFR, despite a severe and/or relapsing course, and for patients with a CFH, CFI, CFB, or C3 mutation, complications, or no benefit from PEX/PI and no access to eculizumab treatment [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] Goodship TH; working party from the Renal Association, the British Committee for..., Taylor [/bib_ref] [bib_ref] Atypical hemolytic uremic syndrome. Orphanet, Loirat [/bib_ref] [bib_ref] Liver-kidney transplantation to cure atypical hemolytic uremic syndrome, Saland [/bib_ref]. ## Recommendations Isolated liver or combined liver-kidney transplantation may be performed for patients with a CFH, CFI, CFB, or C3 mutation (grade 2C). ## Terminal complement blockade (eculizumab) Eculizumab has been used successfully in patients with aHUS since 2009 [bib_ref] Eculizumab for atypical hemolytic-uremic syndrome, Nürnberger [/bib_ref] , and it received approval for the treatment of aHUS in the United States and Europe in late 2011. Eculizumab reduces terminal complement activation (C5b-9, membrane attack complex). Eculizumab therapy for patients with aHUS also reduces inflammation, endothelial damage, thrombosis, and renal injury. Therefore, eculizumab therapy reduces the ongoing risk of systemic TMA and progression to organ damage in patients with aHUS [bib_ref] Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers..., Cofiell [/bib_ref]. Eculizumab therapy for aHUS is usually delayed for several days because it takes several days to obtain baseline ADAMTS13 activity results, which are necessary for the differential diagnosis between aHUS and TTP. However, eculizumab therapy should be considered as a first-line therapy for patients who already have had aHUS diagnosed or who have had mutation results for aHUS [bib_ref] How I treat: the clinical differentiation and initial treatment of adult patients..., Cataland [/bib_ref]. Because TTP is less common in children, and because plasma exchange therapy is ineffective in patients with aHUS, it is also important to start eculizumab therapy as soon as possible in pediatric patients who are suspected of having aHUS [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Because eculizumab therapy increases the risk of meningococcal infections, patients should receive a meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab. However, eculizumab therapy usually cannot be delayed in patients with aHUS. Therefore, additional prophylactic antibiotics for 2 weeks (ciprofloxacin 500 mg twice daily, rifampin 600 mg twice daily, or penicillin VK 250 mg four times daily) should be considered for patients with aHUS who are beginning eculizumab therapy [bib_ref] How I treat: the clinical differentiation and initial treatment of adult patients..., Cataland [/bib_ref]. Eculizumab therapy is usually initiated intravenously at a dose of 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, and then 1,200 mg every other week thereafter. Dose adjustments should be considered for pediatric patients with body weight < 40 kg [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref] [bib_ref] How I treat: the clinical differentiation and initial treatment of adult patients..., Cataland [/bib_ref]. The recommended dosage and schedule are summarized in [fig_ref] Table 3: Recommended dosage and schedule of eculizumab in patients with aHUS kg to... [/fig_ref] [bib_ref] An international consensus approach to the management of atypical hemolytic uremic syndrome..., Loirat [/bib_ref]. Whereas improvement of thrombocytopenia and elevated LDH occur more quickly after eculizumab therapy, recovery of renal function and other end-organ injuries present may take longer. Therefore, recovery from thrombocytopenia is used as a surrogate marker for activity of complement-mediated TMA [bib_ref] Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome, Legendre [/bib_ref]. With continuous therapy, a time-dependent improvement of the estimated GFR is usually observed. Some patients eventually discontinued their previous dialysis. Patients with aHUS who undergo eculizumab therapy have an approximately 50% lower risk of reaching ESRD within 3 months of an aHUS episode compared with historical controls [bib_ref] Insights from the use in clinical practice of eculizumab in adult patients..., Fakhouri [/bib_ref]. Life-long eculizumab maintenance therapy is usually required for aHUS [bib_ref] Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome, Legendre [/bib_ref]. If aHUS patients discontinue eculizumab treatment, then they should be monitored closely for signs and symptoms of severe complications. Monitoring of the complement function test may allow a safe reduction of eculizumab therapy when patients remain in sustained remission [bib_ref] Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic..., Cugno [/bib_ref]. However, a continuation of eculizumab therapy is recommended for kidney transplant recipients with CFH mutations, for anti-CFH antibody-positive patients with an antibody titer < 2.5-times the upper limit of normal, and for patients with GFR < 20 mL/min/ 1.73 m 2 [bib_ref] Discontinuation of eculizumab treatment in atypical hemolytic uremic syndrome: an update, Ardissino [/bib_ref]. Because of another acute episode of aHUS after any complement-activating clinical event (infection, surgery, or pregnancy), careful monitoring and education should be emphasized for patients who have discontinued eculizumab. ## Recommendations Eculizumab is recommended for patients with symptomatic aHUS (grade 1C). All patients receiving eculizumab should receive a meningococcal vaccination prior to receiving the first dose of eculizumab (grade 1A). ## Recommendations for the diagnosis and management of ahus The Korean aHUS Working Group suggested the recommendations for the diagnosis and management of aHUS [fig_ref] Table 4: Recommendations for the diagnosis and management of atypical hemolytic uremic syndrome Diagnosis... [/fig_ref]. Although the guidelines are developed based on the current evidence, there are still many limitations to apply each recommendation in real clinical practice because of limited resources in Korea. The guidelines are not intended to limit, but improve current practice on the management of aHUS. Therefore, these guidelines intend to provide Korean physicians on the general information only and do not replace professional medical practice. [fig] Figure 1: Etiology of atypical hemolytic uremic syndrome (aHUS) in a Korean pediatric cohort. Group C (neither positive) n = 25 (49.0%) Group A (anti-CFH positive) n = 15 (29.4%): Group B (mutation positive) n = 11 (21.6%) CFH mutation 6 CD46/MCP mutation 2 CFI mutation 1 DGKE mutation 1 Dual gene mutations 1 (CFH and CFI mutations) n = 51 http://dx.doi.org/10.3346/jkms.2016.31.10.1516 [/fig] [fig] Figure 2: Proposed diagram to differentiate atypical hemolytic uremic syndrome (aHUS) among thrombotic micro-angiopathies. MAHA, microangiopathic haemolytic anaemia; TMA, thrombotic microangiopathy; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; CAPS, Catastrophic antiphospholipid syndrome; HELLP, hemolysis, elevated liver enzymes, and low platelet count syndrome; PNH, paroxysmal nocturnal hemoglobinuria; VEGF, vascular endothelium growth factor; U/A, urine analysis; HIV, human immunodeficiency virus; ADAMTS, A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13; EHEC, enterohemorrhagic Escherichia coli; STEC, Shiga toxin-producing Escherichia coli; HUS, hemolytic uremic symdrome; TTP, thrombotic thrombocytopenic purpura; aHUS, atypical hemolytic uremic symdrome. [/fig] [table] Table 1: Strength of recommendations and quality of evidence Weak recommendation: Medical and economic benefits are suggestive of some benefit; the evidence is not sufficient to make a strong recommendation Quality of evidence A High-quality evidence: Evidence from a meta-analysis of randomized controlled trials or at least one or more randomized controlled trial(s) B Moderate-quality evidence: Evidence from a randomized controlled study with a serious limitation or large-scale observational studies C Low-quality or very-low-quality evidence: Evidence from small-scale observa- [/table] [table] Table 2: Definitions of micro-angiopathic hemolytic anemia, thrombocytopenia, and AKI Presence of red blood cell fragments in a peripheral blood smear Thrombocytopenia Platelet count < 150 × 10 9 /L AKI Definition is suggested by international guidelines (KDIGO, RIFLE, and AKIN classifications) Definition of AKI in children: Serum creatinine should be increased to a level that is 1.5-fold higher than reference values, according to age and sex LDH, lactate dehydrogenase; AKI, acute kidney injury; KDIGO, kidney disease improving global outcomes classification; RIFLE, risk, injury, failure, loss, end-stage kidney disease classification; AKIN, acute kidney injury network classification. http://dx.doi.org/10.3346/jkms.2016.31.10.1516 cause and ADAMTS13 activity over 10%, without evidence of STEC-HUS (grade 1B). [/table] [table] Table 3: Recommended dosage and schedule of eculizumab in patients with aHUS kg to < 40 kg 600 mg/wk × 2 doses 900 mg during week 3, then 900 mg every 2 wk From 20 kg to < 30 kg 600 mg/wk × 2 doses 600 mg during week 3, then 600 mg every 2 wk From 10 kg to < 20 kg 600 mg/wk × 1 dose 300 mg during week 2, then 300 mg every 2 wk From 5 kg to < 10 kg 300 mg/wk × 1 dose 300 mg during week 2, then 300 mg every 3 wk aHUS, atypical hemolytic uremic syndrome. [/table] [table] Table 4: Recommendations for the diagnosis and management of atypical hemolytic uremic syndrome Diagnosis aHUS is suspected in patients with TMA without a secondary cause, ADAMTS13 activity > 10%, without evidence of STEC-HUS 1B Tests for ADAMTS13 activity should be performed for all patients with suspected aHUS 1B The specimen for testing ADAMTS13 activity should be packaged and shipped to the reference laboratory after freezing to preserve the enzyme activity 1B Tests for Shiga toxin/EHEC to exclude STEC-HUS should be performed for all patients suspected aHUS 1B Tests for plasma homocysteine, methionine, and methyl-malonic acid to exclude cobalamin defect HUS are recommended for all patients with suspected aHUS 2B Screening for complementary abnormalities measuring serum levels (C3, C4, CFH, CFI, CFB, anti-CFH antibody) and expression of MCP in peripheral blood mononuclear cells using flow cytometry abnormalities is recommended for aHUS patients 2B Genetic screening for complementary abnormalities is recommended for aHUS patients 2B Tissue biopsies could be considered on a case-by-case basis for patients with suspected aHUS 2C Other laboratory tests for rare conditions associated with TMAs may be helpful in differentiating the causes of TMAs: DIC panel, autoimmune serology, PNH screening by flow cytometry, and HIV screening 1B Management All patients who are clinically suspected of having aHUS should be offered a trial of PEX and/or plasma infusions if eculizumab is not available 1C Liver-related renal transplantation alone should be avoided in cases of aHUS 1C An isolated liver transplantation or a combined liver and kidney transplantation may be an option for patients with a CFH, CFI, CFB, or C3 mutation 2C Eculizumab is recommended as a first-line treatment for patients with symptomatic aHUS 1C All patients receiving eculizumab should receive a meningococcal vaccination prior to receiving the first dose of eculizumab 1A To prevent recurrent episodes, patients with aHUS should be educated to avoid the identified trigger factors as much as possible after achieving clinical remission 1C aHUS, atypical hemolytic uremic syndrome; CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; DIC, disseminated intravascular coagulation; EHEC, enterohemorrhagic Escherichia coli; HIV, human immunodeficiency virus; MCP, membrane cofactor protein; PEX, plasma exchange; PNH, paroxysmal nocturnal hemoglobinuria; STEC-HUS, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome; TMA, thrombotic micro-angiopathy. http://dx.doi.org/10.3346/jkms.2016.31.10.1516 [/table]	None	http://synapse.koreamed.org/Synapse/Data/PDFData/0063JKMS/jkms-31-1516.pdf	Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The major pathogenesis of aHUS involves dysregulation of the complement system. Eculizumab, which blocks complement C5 activation, has recently been proven as an effective agent. Delayed diagnosis and treatment of aHUS can cause death or end-stage renal disease. Therefore, a diagnosis that differentiates aHUS from other forms of thrombotic microangiopathy is very important for appropriate management. These guidelines aim to offer recommendations for the diagnosis and treatment of patients with aHUS in Korea. The guidelines have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population.
76327901b242373d040c05c092c387a3072ffdff	pubmed	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of intracerebral haemorrhage	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of intracerebral haemorrhage ## Classification of recommendations Class I: there are confirmed evidence or unanimously agreement that the procedure or treatment given is effective. ## Emergency management of vascular abnormalities related ich recommendation Surgery can be considered for the life-threatening secondary ICH. While surgically removing the hematoma, the treatment strategy may be weighed against the relative benefits and risks of saving the patient's life and eliminating the primary cause (Class IIa, Level of Evidence C). ## Section 3: surgical treatment for removal of haematoma The surgical treatment of patients with ICH is shown in. ## Minimally invasive surgery ## Cardiac complications Recommendation ECG and cardiac enzyme measurement is reasonable after cerebral haemorrhage to screen for cardiac complications (Class IIa, Level of Evidence C). ## Pulmonary infection and prevention recommendation Swallowing test is recommended before oral feeding to decrease the risk of pneumonia (Class I, Level of Evidence B). In patients with ICH with atrial fibrillation, the effectiveness of using dabigatran, rivaroxaban or apixaban to reduce the risk of recurrence is uncertain (Class IIb, Level of Evidence C). 3. In patients with anticoagulant-related ICH, the best timing to restore oral anticoagulant therapy is uncertain (Class IIb, Level of Evidence B). 4. If necessary, patients with ICH may consider antiplatelet monotherapy (Class IIa, Level of Evidence B). 5. The monotherapy of aspirin can be restored within a few days from the onset of ICH, but the best timing is not clear (Class IIa, Level of Evidence B). 6. Whether the use of statins should be restricted in patients with ICH is uncertain (Class IIb, Level of Evidence C). 7. All patients with ICH should control blood pressure (Class I, Level of Evidence A). 8. Blood pressure control measures should be started immediately after ICH onset (Class I recommendation, Level of Evidence A). It is reasonable to target BP <130/80 mm Hg for long-term blood pressure control (Class IIa, Level of Evidence B). 9. Smoking cessation, avoiding excessive drinking and treatment of obstructive sleep apnoea might be reasonable to reduce the risk of ICH (Class IIb, Level of Evidence B). ## Screening and prevention of deep vein thrombosis (dvt)	None	https://svn.bmj.com/content/svnbmj/5/4/396.full.pdf	Aim This evidence-based guideline aims to present current and comprehensive recommendations for the diagnosis and management of spontaneous intracerebral haemorrhage (ICH). Methods A formal literature search was conducted on MEDLINE (1 January 1990 to 30 June 2019). Data were synthesised using evidence tables. The members of the working group met by teleconference to update and formulate data-based recommendations. The recommendations are graded according to levels of evidence grading algorithm of the Chinese Stroke Association. The guideline draft has been reviewed by Chinese Stroke Association Stroke Council Guideline Writing Committee. Results Evidence-based guideline is proposed for the management of patients with ICH. The focus of the guideline is divided into the diagnosis and aetiology of ICH, management of ICH in emergency department, surgical treatment for removal of hematoma, management of complications and prevention of secondary ICH. Conclusions This guideline provides a framework for ICH management. Early active and reasonable treatment may improve the clinical outcome of patients.
86da497e077d203a14c9f294172b99c8b48d63c9	pubmed	BRAZILIAN GASTRIC CANCER ASSOCIATION GUIDELINES (PART 1): AN UPDATE ON DIAGNOSIS, STAGING, ENDOSCOPIC TREATMENT AND FOLLOW-UP	BRAZILIAN GASTRIC CANCER ASSOCIATION GUIDELINES (PART 1): AN UPDATE ON DIAGNOSIS, STAGING, ENDOSCOPIC TREATMENT AND FOLLOW-UP Background: The II Brazilian Consensus on Gastric Cancer by the Brazilian Gastric Cancer Association (ABCG) was recently published. On this occasion, several experts in gastric cancer expressed their opinion before the statements presented. Aim: To present the ABCG Guidelines (part 1) regarding the diagnosis, staging, endoscopic treatment and followup of gastric cancer patients. Methods: To forge these Guidelines, the authors carried out an extensive and current review regarding each statement present in the II Consensus, using the Medline/PubMed, Cochrane Library and SciELO databases with the following descriptors: gastric cancer, staging, endoscopic treatment and follow-up. In addition, each statement was classified according to the level of evidence and degree of recommendation. Results: Of the 24 statements, two (8.3%) were classified with level of evidence A, 11 (45.8%) with B and 11 (45.8%) with C. As for the degree of recommendation, six (25%) statements obtained grade of recommendation 1, nine (37.5%) recommendation 2a, six (25%) 2b and three (12.5%) grade 3. Conclusion: The guidelines presented here are intended to assist professionals working in the fight against gastric cancer with relevant and current information, granting them to be applied in the daily medical practice. HEADINGS -Gastric cancer. Guidelines. Staging. Endoscopic treatment. Consensus. Follow-up.RESUMO -Racional: O II Consenso Brasileiro de Câncer Gástrico da Associação Brasileira de Câncer Gástrico (ABCG) foi recentemente publicado. Nesta ocasião, inúmeros especialistas que atuam no tratamento desta doença expressaram sua opinião diante declarações apresentadas. Objetivo: Apresentar as Diretrizes da ABCG (Parte 1) quanto ao diagnóstico, estadiamento, tratamento endoscópico e seguimento dos pacientes com câncer gástrico. Métodos: Para formulação destas Diretrizes os autores realizaram extensa e atual revisão referente a cada declaração presente no II Consenso, utilizando as bases Medline/PubMed, Cochrane Library e SciELO com os seguintes descritores: câncer gástrico, estadiamento, tratamento endoscópico e seguimento. Ainda, cada declaração foi classificada de acordo com o nível de evidência e grau de recomendação. Resultados: Das 24 declarações, duas (8,3%) foram classificadas com nível de evidência A, 11 (45,8%) B e 11 (45,8%) C. Quanto ao grau de recomendação, seis (25%) declarações obtiveram grau de recomendação 1, nove (37,5%) grau 2a, seis (25%) 2b e três (12,5%) 3. Conclusão: As diretrizes aqui presentes têm a finalidade de auxiliar os profissionais que atuam no combate ao câncer gástrico com informações relevantes e atuais, permitindo que sejam aplicadas na prática médica diária. DESCRITORES -Câncer gástrico. Diretriz. Estadiamento. Tratamento endoscópico. Consenso. Seguimento. level of evidence and degree of recommendation adapted from the Brazilian Medical Association/Federal Council of Medicine (AMB/CFM) Guidelines represented in. Note that, in this first part, the ABCG Guidelines will only address issues related to diagnosis, staging, endoscopic treatment and follow-up. The ABCG Guidelines related to treatment itself will be addressed in a future publication. Note that the numbering of the statements is not in sequential order. They were divided according to the topic in question. Thus, many aspects related to diagnosis, staging, treatment and follow-up remain constantly changing. The Japanese Gastric Cancer Association recently published the 5 th English edition of the Japanese Gastric Cancer Treatment Guidelines. In this new edition, some evidence that recently emerged were presented, for instance: the new TNM staging classification of the Union for International Cancer Control (UICC) -8 th edition; the new classification of curability after endoscopic resection, the abandonment of lymph node dissection of the splenic hilus (station nº 10) in D2 lymphadenectomy in total gastrectomy; among others 2 . Furthermore, the Brazilian Gastric Cancer Association (ABCG) recently published the II Brazilian Consensus on Gastric Cancer 7 . In this study, 67 statements regarding the diagnosis, staging, treatment and prognosis of GC were presented to 57 specialists from all regions of the country. The experts were carefully selected considering the notorious knowledge and contribution of each one in the GC field. In this opportunity, the participants responded to the statements with only one possible answer among the alternatives "I totally agree"; "Partially agree"; "Undecided"; "I disagree"; "Strongly disagree". A consensus was adopted when at least 80% of the sum of the answers "fully agree" and "I partially agree" was reached. The results were presented at an ABCG event in Porto Alegre (RS). As mentioned in the II Consensus, Brazil is a country with a continental dimension, with many regional peculiarities that directly impact on the diagnosis, treatment and prognosis of GC patients. Therefore, it is pertinent that each region can act in the fight against GC in the best possible way, according to the local reality. Therefore, the aim of this study is to interpret the statements regarding the diagnosis, staging, endoscopic treatment and follow-up contained in the II Brazilian Consensus on Gastric Cancer through a review of the most recent medical literature. Again, it is important to note that the comments contained here are not absolute whatsoever. The idea is to provide new concepts and update old knowledge, which will certainly benefit GC patients. That said, each information presented here must be carefully analyzed and used in the best possible way according to the resources available at your place of work. # Methods During the elaboration of the methodology used in the II Consensus, some alternatives were presented in relation to the possibilities of the experts' responses to the statements displayed: the method used in the I Consensus published in 2013 could be repeated, in which there were only two possible answers ( "yes or no"); or else, offer the opportunity to the experts to agree wholly or in part, as well as disagree wholly or in part with the statements presented. Both options have already been used in the literature. The second option was chosen, since it can provide a greater amount of relevant information related to GC, when performing the comments presented in this study. In addition, as will be discussed below, there are many possibilities for managing GC, according to the situation in each region. To compose the comments for each statement, the authors used the Medline/PubMed, Cochrane Library and SciELO databases with the following descriptors: gastric cancer, staging, endoscopic treatment and follow-up. Preference was given to more recent articles with better statistical relevance. In addition, each statement was classified according to the OriginAl Article 2/8 negative biopsies collected by upper gastrointestinal endoscopy (including macrobiopsies), the diagnosis can be made through endoscopic resection or surgery. 94% Agreement (level of evidence C; degree of recommendation 2a) Comment Gastric biopsies must follow the Sydney Protocol (biopsy of the antrum, incisura angularis, small and greater curvature). It generally allows the diagnostic confirmation and the risk assessment for disease development. Anyhow, it is noteworthy that endoscopic mucosal resection or endoscopic submucosal dissection in suspected gastric lesions with dysplasia or early cancer are effective, with a high success rate and low recurrence. Another recommendation is enhanced image upper endoscopy and use of dyes, combined with biopsies is the best approach to accurately detect and stratify GC. Still, in cases where there is a high suspicion of GC, with repeated negative biopsies and highly suspicious imaging exams for GC, diagnostic laparoscopy can be performed 6 . # Statement 3 Ultrasound upper endoscopy is not indicated when there are clear endoscopic signs that the cancer is invasive. It should be used when there is any doubt about the early aspect of GC. It allows to evaluate the degree of tumor invasion in the gastric wall and the presence of suspicious lymph nodes for metastases. 96% Agreement (level of evidence C; degree of recommendation 2a) Comment According to a study published by, the ultrasound upper endoscopy is indicated in the following situations: diffuse GC with negative biopsies; to determine the proximal and distal limits of the tumor; for lymph nodes diagnosis; to assess the extent of the lesion and when there is an indication for neoadjuvant chemotherapy, as the method allows lymph node biopsies and ascites analysis (which positivity can modified the strategy adopted). In addition, they conclude that ultrasound upper endoscopy is not useful in T3/T4 tumors diagnosed by computed tomography (CT).analyzed 734 patients treated for GC to assess the agreement between ultrasound upper endoscopy and the pathological result. The agreement was considered moderate (stage T: 52% and stage N: 70%). The accurately estimated risk of invasion was 73%, overestimated in 19% and underestimated in 8%. It may be concluded with this report that ultrasound upper endoscopy should be used with caution and when necessary, always associated with another diagnostic imaging method. # Statement 4 The main staging method is computed tomography of the chest, abdomen and pelvis. 100% Agreement (level of evidence B; degree of recommendation 1) Comment Luo et al. (2017) published a meta-analysis to assess the value of CT in detecting lymph node metastases in GC. There were 27 studies enrolled, with 6,519 patients. They concluded that CT is adequate to assess lymph node metastases in the preoperative stage of serosa positive advanced GC. Nonetheless, it is insufficient to assess serosa negative GC (particularly early GC) due to its low sensitivity. Another meta-analysis corroborated these results, showing that CT is more sensitive than ultrasound and ultrasound upper endoscopy. Another advantage of CT is the possibility of detecting distant metastases (mainly liver and lung) and the possibility to diagnosis peritoneal carcinomatosis. # Statement 5 Positron emission tomography (PET-CT) and nuclear magnetic resonance (MRI) should be used only in selected cases. 100% Agreement (level of evidence C; degree of recommendation 2b) ## Comment Some studies have shown good results with the use of MRI (positive predictive values, negative predictive values, sensitivities and specificities ranging from 67 to 100%, 71 to 100%, 50 to 100% and 63-100%, respectively). Possibly, MRI would have an added value in detecting lymph node metastases and systemic diseases, in defining the volume of tumors and in predicting treatment response. Still, there is the fact that there is no ionizing radiation emission and yet the benefit for patients allergic to iodinated contrast.analyzed the use of PET-CT in GC staging and demonstrated its limited role in T stage evaluation. Considering its low level of spatial resolution, it provides limited information regarding gastric wall involvement or adjacent organs invasion. It is a method with lower sensitivity than isolated CT in detecting peritoneal lesions. Its sensitivity, specificity and precision for detecting lymph node metastases (N stage) varies from 41 to 74%, 75 to 100% and 51 to 76%, respectively. Whereas contrast CT scans vary from 70 to 83%, 62 to 92% and 67 to 80%, respectively. Possibly, the addition of PET-CT may assist in distant lymph nodes and bone metastases detection, which could significantly influence the treatment. After all, its use should be restricted to selected cases. # Statement 6 PET-CT can be used in well-differentiated tumors or in the proximal third. 74% Agreement (level of evidence C; degree of recommendation 2b) Commentevaluated the application of PET-CT in GC staging and found that it is associated with a low detection rate (around 55%), especially in early GC, as well as signet ring cells, mucinous and poorly differentiated adenocarcinomas, which are typically less metabolically active. Well-differentiated tumors may eventually present greater uptake of the radiopharmaceutical fluorodeoxyglucose (FDG-18 F) when compared to undifferentiated tumors. Notwithstanding, the variable and occasionally intense physiological uptake of FDG in the gastric wall is not uncommon and may mask the uptake by the primary tumor. Contrast uptake can often correspond to gastritis. As for proximal tumors, there is a benefit of using PET-CT in cardia tumors (mainly in Siewert's type I and II adenocarcinomas). These tumors have different metabolic and biological behavior from true stomach cancers. In fact, they behave more similarly to esophageal tumors and so, PET-CT can assist in lymph node metastases detection in the chest, which often occur in these types of tumors. # Statement 7 Staging laparoscopy should be performed in cases where there is uncertainty in computed tomography regarding the presence of peritoneal carcinomatosis or when multidisciplinary treatment is planned. 98% Agreement (level of evidence C; degree of recommendation 2a) Comment The staging laparoscopy with peritoneal washing cytology is recommended when CT fails to rule out the possibility of peritoneal carcinomatosis or radiologically occult metastatic disease. Recently, Li et al. (2020) conducted a study comparing CT with diagnostic laparoscopy in hidden peritoneal metastases detection. Among the 385 patients analyzed, diagnostic laparoscopy found hidden peritoneal metastases in 33 (8.5%). The main site was the greater omentum (38.6%), followed by the parietal and perihepatic peritoneum (22.8%). carried out a systematic review with meta-analysis including 240 patients. The authors found that most patients were already in advanced stages, with mean resectability of only 68.7% after staging laparoscopy. The sensitivity was 84.6% while specificity was 100%. Hence, based on the results of this meta-analysis, we can conclude that staging laparoscopy for BrAZiliAn gAStric cAncer ASSOciAtiOn gUiDelineS (PArt 1): An UPDAte On DiAgnOSiS, StAging, enDOScOPic treAtMent AnD FOllOW-UP ## 3/8 GC is a useful method for detecting peritoneal metastases, with good precision 32 . Currently, a Dutch multicenter prospective study is underway with the goal to compare PET-CT with staging laparoscopy in the preoperative resectable GC patients. The authors of this study hypothesize that there may be a 27% change in the treatment strategy, leading to an important cost reduction. In the era of neoadjuvant chemotherapy (NAC), staging laparoscopy is most needed. Despite great advances in imaging methods, laparoscopy allows a thorough evaluation of the tumor, adjacent organs and the peritoneal cavity. According to a study by, staging laparoscopy added important information in 65% of cases with NAC indication and changed the treatment strategy in 30% of them 8 . # Statement 8 Peritoneal washing with oncotic cytology should be performed in all cases during staging laparoscopy and / or surgery. It may be omitted if there is frank peritoneal carcinomatosis. 96% Agreement (level of evidence B; degree of recommendation 2a) Comment Some studies indicate an incidence between 7% and 10% of positive cytology in patients with GC without peritoneal metastases. This situation undoubtedly influences the type of treatment and the prognosis of these patients. In the meantime, peritoneal cytology may be omitted in patients whose lesions have a low risk for peritoneal dissemination (T1/T2, N0). It can also be avoided in those with clear peritoneal disease, in which a biopsy must be collected instead. Conventional peritoneal washing has low sensitivity and immunohistochemical and molecular techniques may be used to increase detection. Negativity cytology must be interpreted according to patient`s disease context and the surgeon`s impression. and 81.8% and for CA 19.9 was 55.0% and 93.7%, respectively. If these markers were elevated prior to surgery, the sensitivity of each marker was greater than 90%. Similar results were found by, in which the sensitivity for recurrence of CEA was 44%, for CA19.9 was 56% and for CA 72.4 was 51%. The combined sensitivity of the 3 markers was 87%. It is interesting to mention that the increase in these markers preceded the clinical diagnosis in most cases. For patients with elevated tumor markers preoperatively, sensitivity was 100%. On the other hand, false elevations of CEA, CA 19.9 and CA 72.4 in disease-free patients were 21%, 26% and 3%, respectively. Thus, the analysis of tumor markers should be performed in a combined manner, but only the CA 72.4 positivity should be considered as a specific indicator for GC recurrence during follow-up. # Preoperative care statements # Statement 11 Multidisciplinary therapeutic planning (surgeon, endoscopist, general clinician, oncologist, radiologist and pathologist) is recommended before starting any type of treatment. 90% Agreement (level of evidence B; degree of recommendation 1) Comment Although there are guidelines directing the therapeutic approach in different stages, the individualities of each patient demand a personalized treatment, adapting the treatment to the patients and tumors features. The association of therapeutic modalities, and the choice of the strategy to be used, require the involvement of several specialists. Therapeutic planning in the form of a multidisciplinary tumor board alters the diagnosis formulated, and the treatment planned when compared to a single physician in 18 to 27%, and in 23 to 41%, respectively. There are no randomized studies, yet there are prospective studies and systematic review acknowledging the contribution of multidisciplinary planning in the therapeutic decision of patients with gastric GC. # Statement 12 Patients who had weight lost greater than 10% of their usual weight in the past 6 months should receive some form of nutritional therapy before starting any treatment. 100% Agreement (level of evidence A; degree of recommendation 1) Comment The cachexia in cancer patients is often associated with decreased intake, catabolism, and exacerbated inflammatory response. It affects among 50-80% of patients, accounting for about 20% of deaths. Even with limitations of use as an isolated parameter to assess nutritional status, weight loss greater than 10% in 6 months is indicative of severe malnutrition. In patients with moderate and severe malnutrition, nutritional input is required before any type of treatment, for 7-14 days, in order to reduce morbidity and mortality. Patients initially submitted only to neoadjuvant treatment, also have indication of nutritional therapy, particularly those with food intake below 70% of estimated energy spent. # Staging statements # Statement 10 Currently, the staging that must be adopted is the UICC/ AJCC TNM 8 th edition. 100% Agreement (level of evidence A; degree of recommendation 2a) ## Comment The gastric cancer staging system, mainly with regard to the evaluation of the lymph node involvement (N), has undergone numerous changes in the last 20 years. The adoption of the numerical, quantitative system is due to the fact that it is simpler to be adopted in different centers of the world and has high precision. The last update of TNM -UICC / AJCC, 8th. edition, is consistent with the Japanese Gastric Cancer Association staging system, widely used in the East, and corrects the imperfections and disparities in the survival curves of stages IIIB and IIIC that existed in the 7th edition, since there was no separation between lymph node involvement between 7 and 15 and with more than 15 lymph nodes. Therepresents the TNM 8 th edition final staging.IIIC IIIC # Statement 18 The UICC / AJCC recommends a minimum of 15 harvested lymph nodes to allow correct staging. 92% Agreement (level of evidence B; degree of recommendation 2b) ## Comment The AJCC / UICC classification recommends at least 16 LN for correct lymph node staging analysis. In fact, some studies have shown the potential benefit of extended lymphadenectomy in this regard.found that limited lymphadenectomy (less than 16 LN removed) is associated with inadequate staging in 54.4% of patients. On the contrary, these rates decreased to 6.2% and 1.4%, respectively, in patients undergoing more extensive lymphadenectomy (D2 or D3), which are associated with adequate disease staging in most cases. # Statement 19 D2 lymphadenectomy recommends at least 25 harvested lymph nodes. 76% Agreement (level of evidence B; degree of recommendation 2b) Comment The lymphadenectomy does not concern the number of lymph nodes, but the locations (stations) dissected. This methodology for guiding the removal of lymph node stations is based on results of lymph node involvement studies in various types of tumor (location, degree of tumor penetration into the gastric wall and histological type), associating it with the survival observed according to the dissection pattern. Respecting this standardization, it is unlikely that the number of LN removed in D2 lymphadenectomy will be less than 25. In 2011, a new Japanese guideline was published to coincide with the standard AJCC/UICC TNM classification. The type of lymphadenectomy started to be considered depending on the type of gastrectomy to be performed (total or subtotal) . # Statement 20 It is recommended at the end of each operation that a member of the surgical team send the surgical specimen for the pathological analysis with all the separate and identified lymph node stations. 90% Agreement (level of evidence C; degree of recommendation 2b) Comment The wrong analysis of the number of lymph nodes removed after GC surgery can impair the correct staging for the presence of lymph node metastasis. This would certainly have a significant impact on the prognostic assessment and strategic formulation of adjuvant therapy. Under the premise of standard D2 lymphadenectomy, the number of lymph nodes collected depends mainly on the procedures that will examine the lymph nodes. Despite the fact that the current staging system consider only the number of lymph nodes involved, sending to the pathological evaluation the whole specimen, without dissection of the lymph node stations, could difficult this analysis, and furthermore, diminishes the quality of the surgery itself. ## Endoscopic treatment statements statement 13 Endoscopic resection is indicated in well-differentiated adenocarcinoma tumors, restricted to the mucosa (T1a), less than 2 cm in its longest axis and not ulcerated. 100% Agreement (level of evidence B; degree of recommendation 1) Comment These are tumors whose recommendation for endoscopic treatment is supported by the main medical societies involved in the treatment of early GC, including the International Gastric Cancer Association, due to low risk of lymph node metastasis, and high survival rates, similar to those achieved by standard gastrectomy. It presents as a potential advantage over surgical treatment, due to the possibility of a less invasive curative approach. However, it requires accurate endoscopic and histological diagnosis, and experienced professionals to perform the procedure. Despite this recommendation is widely accepted, there are no randomized studies, and the current recommendations are based on non-randomized and retrospective studies. # Statement 14 Early lesions with invasion of the submucosal layer, ulcerated, diffuse type and larger than 2 cm are exception criteria for endoscopic resection and should be adopted only in patients at high surgical risk. 92% Agreement (level of evidence B; degree of recommendation 2b) Comment The risk of lymph node metastases, incomplete resections, and recurrences make the above characteristics exception criteria for endoscopic resections. The endoscopic approach in these situations does not reproduce the results of radical surgical treatment, and should be reserved for peculiar situations, such as in patients who do not present performance for surgical treatment or refuse standard treatment. In the event of adoption of this approach, the need for exhaustive multidisciplinary discussion is emphasized, full clarification and agreement of the patient are mandatory, because the chance of complications, in such endoscopic procedure is not negligible, including perforations, which may result in possible surgical indication 2,29,30 . # Statement 15 Endoscopic submucosal dissection (ESD) is recommended as the treatment of choice for most superficial gastric tumors. 76% Agreement (level of evidence B; degree of recommendation 2a) ## Comment The submucosal dissections offer a higher probability of complete resections, excisions in a single fragment, obtaining free margins, and results in lower risk of recurrences than mucosal resections, especially in cases of tumors greater than 1cm. However, these are procedures of greater complexity than mucosal resections, and the risk of complications, especially perforations, is higher. They require high cost specialized instruments and the time necessary for performing such procedures is longer. Still, it represents a treatment modality with high curative potential, when formal clinical indications are observed (including cancer restricted to the mucosa non-ulcerated, regardless of tumor size, cancer restricted to the mucosa ulcerated maximum of 3 cm in diameter and cancer in the submucosal layer (<500 mm of the muscularis of the mucosa maximum of 3 cm in diameter non-ulcerated, all of the intestinal type and well differentiated.) In these situations, the possibility of lymph node metastases in early GC is practically nil. ## Follow-up statements statement 62 Patients with metastatic gastric cancer who have not responded to palliative chemotherapy or in poor clinical conditions, should receive only palliative care with best support of care. 96% Agreement (level of evidence C; degree of recommendation 1) Comment "Primum non nocere" (first, do not harm). In cases of patients with metastatic GC who do not respond to palliative chemotherapy or in poor clinical conditions, the goal of treatment is not to achieve a cure. It is essential to know when to stop. The medical assistant should seek to relieve symptoms, prevent complications and try to prolong life without impairing the quality of life 1 . # Statement 63 Patients undergoing radical surgery or after adjuvant therapy should not be followed due to the high cost and because there is no evidence that the follow-up improves survival. 18% Agreement (level of evidence C; degree of recommendation 3) ## Comment The periodic clinical follow-up of patients undergoing radical gastric surgery for GC is the subject of much controversy. BrAZiliAn gAStric cAncer ASSOciAtiOn gUiDelineS (PArt 1): An UPDAte On DiAgnOSiS, StAging, enDOScOPic treAtMent AnD FOllOW-UP ## 5/8 That is because the treatment options for relapse historically have always been very limited and also because there are no randomized trials that confirm the usefulness of follow-up. In 2012, the Italian Study Group on Gastric Cancer held a 3-month debate entitled "Rationale and limits of oncological follow-up after gastrectomy for cancer". This discussion involved 32 authors from 12 countries, including Brazil. Substantial differences emerged between the participants: authors from Japan, South Korea, Italy, Brazil, Germany and France perform routine followup with serial examinations, while authors from Eastern Europe, Peru and India do not. British and American surgeons carry out surveillance in a very limited way or in experimental studies. In addition to the physical examination, performance status, weight, tomography, endoscopy and laboratory tests are used, including tumor markers are requested. With the progressive increase in clinical and surgical therapeutic options for recurrence, this topic has been recently discussed. A propensity-score match analysis showed that standardized follow-up significantly increased overall survival. This work also suggests that imaging tests and relapse treatment were associated with better outcomes. In addition, this study recommends CT scans periodically, especially in the first three years. In fact, the possibility of recurrence is usually concentrated in the first 3 years in more than 90% of cases 9 . Other reasons for carrying out this postoperative follow-up are the possibility of diagnosing early and late gastrectomy complications; psychological support and surveillance of nutritional aspects of these patients. # Statement 64 Patients submitted to radical surgery can be followed through abdominal ultrasound, due to its accessibility and low cost. 38% Agreement (Level of Evidence C; degree of recommendation 3) Comment No evidence is available comparing imaging modalities performance in the diagnosis of recurrence during follow-up though. Nonetheless, the lack of efficacy regarding abdominal ultrasound in diagnosing some of the most common relapse sites of GC, such as peritoneal, regional and distant lymph nodes, or even small hepatic nodules, should be taken under consideration. Therefore, abdominal ultrasound should not be recommended routinely for GC follow-up 4 . # Statement 65 In the postoperative period of patients submitted to radical surgery, the upper endoscopy is indicated when there is clinical suspicion of recurrence and digestive symptoms. 78% Agreement (level of evidence C; degree of recommendation 2a) Comment The local recurrence in GC patients treated with adequate resection margins and lymph node dissection is not common. It is reported in up to 10% of patients from multicentric trials, such as the Dutch Trial. In the long term, among patients who had a subtotal gastrectomy, a recent Japanese study identified 5% risk of new tumors in the gastric stump. Although these are not very high numbers, they justify the performance of upper endoscopy as a strategy for GC patients follow-up. Two questions remain though: the time interval between each exam and its use among patients who underwent a total gastrectomy. There is no conclusive evidence on these questions. The most recent guidelines recommend and upper endoscopy one year after surgery and every two years after that. Regarding the use of upper endoscopy after a total gastrectomy, it could be implied that it would be more relevant for patients with tumors located in the cardia/fundus 2,41 . # Statement 66 The long-term follow-up should be offered to patients undergoing radical surgery or after the end of adjuvant therapy for nutritional and psychological control and support, early detection of recurrence, treatment of complications and data collection. 100% Agreement (level of evidence B; degree of recommendation 2b) Comment The main reason for monitoring patients operated for GC is the early diagnosis of recurrence, which usually occurs in the first 2 years after surgery with a curative intention. Of these patients, about 2/3 will have recurrence during followup. Despite the limited potential for treating recurrence, even when diagnosed early, other aspects influence the periodic surveillance of these patients. Among them, the treatment of complications related to gastrectomy, nutritional support, psychological support, diagnosis of other possible tumors, improvement in quality of life, data collection for institutional assessment of treatment outcomes 23 (see statement 63 for more information). # Statement 67 The attempt of surgical resection in patients with single local recurrence and low surgical risk can be considered in selected cases. 98% Agreement (level of evidence C; degree of recommendation 3) ## Comment The laparotomy with curative intent is an option for those patients with inadequate resections (for instance: positive gastric margin, immediate postoperative with gross macroscopic nodal disease, D0/D1 lymphadenectomy and local lymph node relapse). Few reports exist showing well succeed resection of local or liver recurrence. Mostly more disease than anticipated is found or resection is abandoned due to safety issues. The procedure should be reserved for patients with good clinical status 28 . # Discussion The statements conception that forged the II Brazilian Consensus on Gastric Cancer by ABCG was the subject of great debate (in the good sense of the word) among its authors. This is because some of the authors considered that the consensus should be succinct and concise and, therefore, with fewer statements. However, the understanding and perception of all forms of approach and management of GC require wide discussion. As previously mentioned extensively, the disease is complex and with different forms of behavior. In addition to this characteristic, is the fact that there is great social inequality in our country, causing enormous variability in the availability of human, diagnostic and technological resources between the different regions. For this reason, the simple adoption of foreign guidelines does not correspond to the needs found, requiring the positioning of ABCG for the best practices in our scenario. Hence, it was decided to build up the II Consensus composed of sufficient statements that could cover the different aspects of GC as fully as possible. However, publishing only the results could raise doubts about how would be the best way to manage a patient with GC according to each local reality. In fact, among the 67 statements performed, there was 100% agreement in just 10 (15%). Some aspects are still cause for much discussion among specialists, such as the routine use of drains in GC surgery, the role of neoadjuvant chemotherapy, the best form of surgical approach in cardia tumors, among others. Thus, the ABCG's main goal was to provide arguments based on the literature that could somehow support, or not, the guidelines contained in each statement. This will allow each professional to, as far as possible, offer adequate and effective treatment to the patient with GC. On the other hand, the literature review carried out on each statement made the II Consensus somewhat extensive. Therefore, it became opportune to publish the Brazilian Gastric Cancer OriginAl Article ## 6/8 Guidelines in two stages. In this first part are the statements regarding the diagnosis, staging, endoscopic treatment and follow-up. In the next stage (part 2) will be presented the statements about the treatment itself (surgical and multimodal). # Conclusion This publication contains comments and guidelines with reference to the diagnosis, staging, endoscopic treatment and follow-up of GC patients found on the II Brazilian Consensus on Gastric Cancer. The guidelines shown here are intended to assist professionals working in the fight against GC with relevant and current information, allowing them to be applied in daily medical practice.	None	http://www.scielo.br/pdf/abcd/v33n3/0102-6720-abcd-33-03-e1535.pdf	ABSTRACT Background: The II Brazilian Consensus on Gastric Cancer by the Brazilian Gastric Cancer Association (ABCG) was recently published. On this occasion, several experts in gastric cancer expressed their opinion before the statements presented. Aim: To present the ABCG Guidelines (part 1) regarding the diagnosis, staging, endoscopic treatment and follow-up of gastric cancer patients. Methods: To forge these Guidelines, the authors carried out an extensive and current review regarding each statement present in the II Consensus, using the Medline/PubMed, Cochrane Library and SciELO databases with the following descriptors: gastric cancer, staging, endoscopic treatment and follow-up. In addition, each statement was classified according to the level of evidence and degree of recommendation. Results: Of the 24 statements, two (8.3%) were classified with level of evidence A, 11 (45.8%) with B and 11 (45.8%) with C. As for the degree of recommendation, six (25%) statements obtained grade of recommendation 1, nine (37.5%) recommendation 2a, six (25%) 2b and three (12.5%) grade 3. Conclusion: The guidelines presented here are intended to assist professionals working in the fight against gastric cancer with relevant and current information, granting them to be applied in the daily medical practice.
beea90f372d4e4ab6b409eef279a7cd9250aee4a	pubmed	Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics	Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics Background: Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. # Introduction Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. To date, more than 943,000 cases have been diagnosed, with more than 41,192 deaths. Children accounted for around 2% of infections, with an estimated mortality rate of 0,2% [1]. These figures confirm the previous observation in China that children develop milder forms of the illness, compared to adults. Nonetheless, there is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, which has been named Pediatric Multisystem inflammatory Syndrome temporally associated with COVID-19 (PIMS-TS) in the UK and Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C) in the US. The latter term will be used in this paper. The clinical spectrum of MIS-C is wide, and children have been treated with a variable association of intravenous immunoglobulin (IV Ig), high-dose glucocorticoids, and anti-cytokine medications. To date, although diagnostic and therapeutic recommendations have been proposed by various pediatric societies, no universally agreed approach is available. After the first epidemic peak, which began in late February, the national lockdown policy in Italy led to a drastic reduction of cases, that, however, have restarted growing in the recent weeks. As MIS-C cases have been mostly observed in the regions with the highest impact of SARS-CoV-2 infection, we fear a recrudescence of the disease throughout Italy. We have, therefore, decided to prepare a report that helps clinicians to face this novel and challenging disease. Given the limited information currently available and the methodology employed, this document should not be seen as a guideline, but simply as a set of clinical suggestions based on the existing literature and the personal experience of the authors. ## Case definition There are multiple case definition criteria for MIS-C. We propose to consider MIS-C diagnosis in the presence of: A child or adolescent with Fever (> 38°C) lasting for more than 24 h. + Signs/symptoms of at least 2 organs involvement a + Laboratory work-up showing systemic inflammation (leukocytosis with neutrophilia, ESR and CRP (and PCT) increase, with or without lymphopenia + Exclusion of infection b b a recent exposure to SARS-CoV2 may be demonstrated in the majority of patients by means of nasal/ pharyngeal swabs or serology. In case of high clinical suspicion, MIS-C diagnosis and treatment should not be delayed by a negative swab or serology. A personal history of close SARS-CoV contact is present in the majority of cases and may be sufficient to substantiate MIS-C hypothesis. As many of the signs and symptoms listed are not specific, MIS-C diagnosis should rely on a high index of suspicion and cautious clinical judgement, taking into account the patient's history, the severity of organ involvement, the inflammatory markers level and other possible mimickers. LABORATORY WORK-UP ## Treatment To date, there is limited evidence to establish the optimal therapeutic approach to a child with MIS-C. Given the partial overlap of the clinical manifestations of MIS-C with those of Kawasaki disease, the majority of patients have been treated with the standard therapeutic protocols for the latter illness. It is important to consider that the spectrum of clinical manifestations and severity of MIS-C is is wide. Thus, the best treatment approach should be defined on an individual basis, and the following proposals are to be interpreted only as suggestions. Intravenous immunoglobulin 2 g/kg IV (up to 70-80 g) to be administered over at least 12 h. In patients with heart failure immunoglobulins should be administered over at least Since MIS-C is a post-infectious disease, it is conceivable to assume that symptoms have their onset when the viremic phase is ended. Nonetheless, it is difficult to clearly differentiate these two phases (viremic vs hyperinflammatory) in some clinical scenarios. We recommend to consider carefully the appropriate timing to start immunomodulatory treatment in such cases, to avoid interference with antiviral host response. # Conclusions Since there is a resurgence of COVID-19 cases throughout Italy, we expect a rise in MIS-C patients over the next weeks. Although MIS-C has variable severity, the majority of patients are seriously ill. The clinical experience indicates that prompt recognition and timely treatment are crucial to achieve good outcomes. Given the frequent overlap of clinical manifestations between MIS-C and Kawasaki disease, patients with the hyperinflammatory syndrome have generally been treated with the therapeutic protocols used in Kawasaki disease. Since the available information does not allow to formulate well-established guidelines or recommendations for MIS-C treatment, and the long-term sequelae of the illness are not yet known, we agree with the therapeutic regimens proposed and adopted so far. The final decision about the optimal management should be taken by the caring physician, based on the disease characteristics and severity of each individual patient.	None	https://ijponline.biomedcentral.com/counter/pdf/10.1186/s13052-021-00980-2	None
86eff293dbb2a9bb7e428dcee5ac4a32d3a4e84c	pubmed	APASL practical recommendations for the management of hepatocellular carcinoma in the era of COVID-19	APASL practical recommendations for the management of hepatocellular carcinoma in the era of COVID-19 Background COVID-19 has been giving the devastating impact on the current medical care system. There are quite many guidelines on COVID-19, but only a few on the management of hepatocellular carcinoma (HCC) during COVID-19 pandemic. Aims We develop these recommendations to preserve adequate clinical practice for the management of HCC. Methods Experts of HCC in the Asia-Pacific region exchanged opinions via webinar, and these recommendations were formed. Results Close contact should be minimized to reduce possible exposure of both medical staff and patients to the novel coronavirus. To prevent transmission of the virus, meticulous hygiene measures are important. With the decrease in regular medical service, the medical staff may be mobilized to provide COVID-19-related patient care. However, diagnosis and treatment of HCC should not be delayed because of COVID-19 pandemic. The management of HCC should be the same as in non-pandemic circumstances. HCC is highly malignant, thus it is recommended not to delay curative treatment such as surgery and ablation. However, a kind of triage is necessary even among patients with HCC when resources are insufficient for all to be treated. Curative treatments should be periodized and cytoreductive or non-curative treatment such as vascular interventions and systemic therapy may be postponed until it can be performed safely with sufficient resources. For patients with confirmed or suspected to be infected with the novel coronavirus, diagnosis and treatment should be postponed until the virus is eliminated or they are confirmed as not being infected with it. Conclusions These are collection of measures implemented by front-line medical professionals. We would evolve these recommendations over time as more real-world data becomes available. # Introduction Coronavirus disease 2019 (COVID-, an infectious disease caused by the novel coronavirus (SARS-CoV-2) has brought upon devastating stress on the current medical care system. The World Health Organization (WHO) recognized the outbreak of COVID-19 as a pandemic on 11 March 2020. As of 19th Aug 2020, COVID-19 pandemic has resulted in over 21.9 million confirmed cases globally, and over 775 thousand deaths. Approximately 250 thousand newly-confirmed cases are being reported daily. The pandemic has not settled down yet. The virus is mainly transmitted from personto-person through respiratory droplets and contact with contaminated surfaces or objects. There are also other modes of transmission (i.e. airborne and fecal-oral). The average incubation period is 5-6 days, ranging from 0 to 14 days. The clinical spectrum of COVID-19 ranges from mild disease with non-specific signs and symptoms of acute respiratory illness to severe pneumonia with respiratory failure and septic shock. There are also reports of asymptomatic cases. Currently, there is no vaccine against the novel coronavirus. The best way to prevent COVID-19 is to avoid being exposed to the coronavirus. It is recommended that we should keep distance of at least 2 m from other people. A new modeling study shows that intermittent periods of social distancing strategies will be needed till 2022 to avoid overloading of the medical system with its limited critical care capacity. Until the end of this COVID-19 pandemic, one needs to maintain high management standards of other diseases despite the shortage of medical resources, such as personnel, beds, personal protective equipment (PPE) and ventilators. There are a number of guidelines and recommendations on COVID-19. However, there are only few guidelines and recommendations on the management of hepatocellular carcinoma (HCC) on pandemic of COVID-19. Currently, liver cancer is the fourth most common cause of cancer-related death in the world, which caused 782 thousand deaths in 2018. More than 90% of liver cancer is hepatocellular carcinoma (HCC). The majority of cases of HCC are found in the Asian-Pacific region. Since Asia-pacific region has more experience both in HCC and in COVID-19 than anywhere else, experts of HCC exchanged opinions via webinar and developed these recommendations to preserve and sustain adequate clinical practice in the management of HCC in the era of COVID-19. APASL has presented clinical practice guidance for general hepatology and liver transplant providers during the COVID-19 pandemic which also includes HCC. Our article focuses specifically on HCC, presents more practical recommendations and elaborates on the different management needs. Our article does not have either grading of evidence or grading of recommendation as well as many recommendations concerning COVID-19. Since COVID-19 is a novel disease, guidance by scientific evidence is rarely available. The recommendations are the collection of measures implemented by front-line medical professionals and are revised through intense interaction via webinar. The presenter, the moderators and co-authors exchanged opinions and discussed the contents via emails and phones. These recommendations are likely to evolve over time as further data become available. ## Covid-19 and cancer Patients with cancer seem to be easier to be infected with the novel coronavirus than individuals without cancer. A prospective study in China revealed that 18 (1%) of 1590 COVID-19 patients had a history of cancer, which seems to be higher than the incidence of cancer in the overall Chinese population. They are also likely to be at an increased risk of progression to severe diseases with COVID-19, such as being admitted to the intensive care unit requiring invasive ventilation, and death, compared with patients without cancer. A retrospective study in Wuhan, China reported that 12 (0.79%) of 1524 patients with COVID-19 had cancer. It revealed that patients with cancer from the epicenter of COVID-19 had a higher risk of the novel coronavirus infection compared with the general population. Seven (58.3%) of 12 patients had non-small cell lung cancer. In a different retrospective study, there were 28 patients with cancer who were admitted for COVID-19 in three hospitals in Wuhan and who had received cancer therapy within 14 days. They were found to be associated with substantially higher risk of mortality. Patients with cancer may be susceptible to the infection and more likely to have higher morbidity and mortality than the general population. Several factors could account for an elevated risk for the infection and consequent complications among cancer patients, including systemic immunocompromised state caused by the malignancy and anticancer treatments, frequent hospital visits, advanced age, and poor performance status. Cancer is the second leading cause of death. An estimated 9.6 million people died of cancer globally in 2018, i.e., about 1 in 6 deaths was due to cancer. The five most common causes of cancer death were cancers of lung (1.76 million deaths), colorectal (862 thousand deaths), stomach (783 thousand deaths), liver (782 thousand deaths) and breast (627 thousand deaths). Cancer mortality can be reduced if cases are detected and treated without delay. When detected early, cancer is more likely to respond to effective treatment and can result in a greater probability of surviving, less morbidity, and less expensive treatment. Significant improvements can be made in the lives of cancer patients by detecting cancer early and avoiding delays in treatment. We should not delay the diagnosis and treatment of cancer in the era of COVID-19 pandemic. However, it would be necessary to tailor the management depending on available resources. Indication of any invasive procedure should be decided on a case-by-case basis with the consideration of the increased risk during the pandemic, the urgency of the procedure and the effect of the delayed intervention. ## 3 ## Covid-19 and chronic liver disease Most patients with HCC have underlying chronic liver disease, resulting from chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection, alcoholic liver disease, and non-alcoholic fatty liver disease. There have not been sufficient data on whether patients with chronic liver disease are at increased risk for getting COVID-19 or having severe COVID-19. CDC COVID-19 Response Team reported that 2692 (37.6%) of 7162 patients with full past history of illness had one or more underlying health condition or risk factor. They also reported that 41 (0.6%) had chronic liver disease, 17 (41%) of whom were hospitalized and 7 (17%) were treated in ICU. Incidentally, the most commonly reported conditions were diabetes mellitus, chronic lung disease, and cardiovascular disease. In other series of COVID-19 reported by Chinese centers, 2-11% of patients had comorbid chronic liver disease. There is a report that patients with non-alcoholic fatty liver disease were associated with COVID-19 progression. Infection with the novel coronavirus may impact existing chronic liver disease in three ways: first, the additional hepatic injury induced by COVID-19 could lead to hepatic decompensation in patients with compromised hepatic reserves. Second, the potential immunosuppressive properties induced by the novel coronavirus may lead to viral reactivation in patients with chronic viral hepatitis, although more data are required to confirm this hypothesis. Third, drugs used for the treatment of COVID-19 may produce hepatotoxicity, as suggested by histological features of moderate microvascular steatosis with mild hepatic inflammation. Many patients had antipyretic drugs for fever. Most antipyretic drugs contain acetaminophen, which has direct hepatotoxic potential. Furthermore, many patients with COVID-19 may be treated with novel, potentially hepatotoxic, antiviral drugs as well as antibiotics for bacterial superinfections. ## Hospital preparedness for covid-19 It is important to minimize exposure of both medical staff and patients to the novel coronavirus. Face-to-face consultation should be performed through web consultation or by telephone call whenever possible. Hospitals should adapt strategies for patients to minimize hospital visits and hospitalization. Routine follow-up visit of hospitals should be postponed as long as possible. If circumstances allow, the appointment registration system should be adapted. Pre-reception inspection should be set up including body temperature check and Questionnaire (symptoms, recent history of close contact with confirmed or suspected person infected with the novel coronavirus). It is important to maintain social safety distance of 2 m between individuals. In general, hospitals should not allow patients to be accompanied with others because they can be asymptomatically infected with the virus. There are various ways to screen individuals infected with the novel coronavirus. Reverse transcription polymerase chain reaction (RT-PCR) is the current standard test for COVID-19. In well-equipped hospitals, PCR assays have been conducted a few days prior to admission. Antigen test is another method of detecting the presence of the virus itself. Although it is less accurate, it offers results in about 15 min as opposed to hours for PCR. Both methods need a cumbersome swab to take samples from the cavity between the nose and mouth (nasopharyngeal swab). Another method is detection of antibodies (serological tests). Antibody tests show how many people have had the disease, including those whose symptoms are minor or who are asymptomatic. The serum antibody rises to certain level at an early period in patients infected with the virus. In general, chest CT is not recommended for detecting the novel coronavirus infection. CT should only be deployed in very specific conditions. One is in patients who have high risk of the novel coronavirus infection, because the sensitivity of PCR is not 100%. Another condition is in patients who are scheduled to be hospitalized and have abdominal CT, because it is not troublesome to take chest scan simultaneously. Chest CT screening for COVID-19 has a low pick up rate in asymptomatic patients infected with the novel coronavirus and a 20% false negative rate in symptomatic patients. Radiologic findings in COVID-19 are not specific. Typical features on CT initially include bilateral multilobar ground-glass opacities with a peripheral or posterior distribution. ## Covid-19 and hcc Generally, the diagnosis and treatment of HCC, which is a highly malignant tumor, should not be delayed because of pandemic of COVID-19. The indications and principles of management of HCC should be the same as in non-pandemic circumstances. However, a kind of triage may be necessary even among patients with HCC when resources are insufficient. With the decrease in regular medical service, staff may be mobilized to provide COVID-19-related patient care. This shift of staff should not have a negative impact on the ability to manage HCC patients. Patients with HCC who have symptoms suggestive of COVID-19 or other conditions of high risk of the novel coronavirus infection, such as close contact with infected people or people who come from a severely affected area, and have not been tested should undergo PCR. If available, chest CT should also be performed for those who have high risk of the novel coronavirus infection. For patients with confirmed or suspected to be infected with the novel coronavirus, diagnosis and treatment of HCC should be postponed until the virus is eliminated or they are confirmed as not being infected with it. It is supposed that the median time from onset to clinical recovery is approximately 2 weeks for mild cases and is 3-6 weeks for severe or critical disease cases. ## Surveillance for hcc Generally, surveillance with ultrasound (US) and serum alpha-fetoprotein (AFP) measurement are undertaken in high-risk groups of patients, such as those with chronic HBV or HCV hepatitis and those with liver cirrhosis of any etiology. US is widely practiced for surveillance of HCC since US is noninvasive and its cost is reasonable. However, in the era of COVID-19, surveillance using US should be limited because of the close contact with patients and US practitioner. Under normal circumstances, a 6-month surveillance interval is considered as a standard for high-risk subjects. Since COVID-19 decreases the regular medical service, it would be necessary to prioritize surveillance of super high-risk patients of developing HCC, such as those with HBV-or HCV-related liver cirrhosis. ## Diagnosis for hcc ## General principles in the era of covid-19 In the era of COVID-19 pandemic, the diagnosis of cancers as well as other diseases would not work smoothly in many hospitals because of their limited capacity. However, the diagnosis of HCC should be prioritized because HCC is highly malignant. Every patient should be considered as possibly infected with the novel coronavirus.summarizes recommendations for general principles and each examination for HCC. ## Us It is recommended to limit the usage of US, since US practitioners are in close contact with patients. Contrastenhanced US, which is very sensitive to detect hypervascularity in a nodule, should also be limited. As a protection for both US practitioners and patients, surgical facemasks are necessary for US practitioners. Examinees are also advised to wear facemasks. When examinees do not wear masks, US practitioners should have eye guards. Every patient should be considered as possibly infected with the novel coronavirus. To prevent transmission of the virus, meticulous hygiene measures are important. After each examination, thorough cleaning of a gel bottle and all touched surfaces should be performed using a disinfectant. ## Ct and mri In general, dynamic CT, dynamic MRI, or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOBDTPA)-enhanced MRI is recommended as a first-line diagnostic tool for HCC when a screening US shows a possible HCC nodule. As every patient possibly infected with the novel coronavirus, those who have an abdominal CT in their investigation may also have chest CT scan at the same time. It would not be troublesome to take chest scan additionally. However, chest CT should only be deployed in very specific circumstances, because CT screening for COVID-19 has a low pick up rate in asymptomatic patients infected with the novel coronavirus and a 20% false negative rate in symptomatic patients. After each examination, deep cleaning of equipment, surfaces and contact points is mandatory. If possible, ## Treatment for hcc ## General principles We need to decide whether we should perform, postpone or suspend treatment for each individual case by considering the situation in real time not only from medical but also from logistical viewpoint. Telemedicine is important in multi-disciplinary decision-making process on treatment and care plans. This technology would make it possible for HCC patients to get the right treatment at the right time without delay. HCC as well as most other cancers are considered as progressive diseases, thus it is recommended not to delay their curative treatment such as surgery and ablation. American College of Surgeons recommends Elective Surgery Acuity Scale, which would be useful to assist the decisionmaking process not only of surgery but also of other actions to triage non-emergent interventions. HCC as well as most other cancers may be categorized as "Tier 3a (high acuity)", thus action should not be postponed in general. However, a kind of triage is necessary even among patients with HCC when resources are insufficient for all to be treated without delay. Curative treatments should be more prioritized and cytoreductive or non-curative treatments may be postponed until they can be performed safely. The situation may be different from country to country and from institution to institution. During the intervention, minimum number of staff should be in the room and all staff in the room should wear appropriate PPEdepending on their role and risk. In some interventions without aerosol generation, PPE may be necessary only for operators who have close contact with patients possibly infected with the novel coronavirus. Procedure tasks are slower and more difficult when wearing full PPE.summarizes recommendations on general principles and each treatment for HCC. ## Liver resection Liver resection (LR) is a curative treatment for HCC among Child-Pugh class A patients, although recurrence develops in most cases even after radical resection. Its indication should be decided based on not only tumor condition but also liver function. Generally, liver resection with curative intent should not be delayed. However, in cases of high risk of decompensation or comorbidities that increase risk of severe COVID-19, surgical intervention should be postponed or alternative therapy such as ablation should be adapted. General principles Whether to perform, postpone or suspend treatment should be decided for each individual case not only from medical but also from logistical viewpoint It is recommended not to delay a curative treatment such as surgery and ablation Cytoreductive or non-curative treatment such as vascular interventions and systemic therapy may be postponed For patients with confirmed or suspected to be infected with the novel coronavirus, treatments should be postponed until the virus is eliminated or they are confirmed as not being infected with it Liver resection Generally, liver resection with curative intent should not be delayed However, in cases of high risk of decompensation or comorbidities, surgical intervention should be postponed or alternative therapy such as ablation should be adapted There has been some concern on the safety of surgery as surgery cannot be performed without aerosol generating procedures Liver transplantation Liver transplantation for patients with poor short-term prognosis should not be delayed Elective living donor transplantation may be suspended In patients with complete response to bridging therapy on transplant list, transplantation may be suspended Ablation Ablation with curative intent should not be delayed Ablation is an acceptable alternative to resection for cases of three or fewer tumors, each 3 cm or smaller, and of Child-Pugh class A or B liver dysfunction Vascular interventions Vascular interventions may be postponed because they are used as cytoreductive treatments in most cases Vascular interventions should be suspended in cases of risk of decompensation or comorbidities that increase the risk of severe COVID-19 Radiation therapy Radiation therapy for cases of symptoms control or at low risk of progression may be postponed However, radiation therapy for function-or life-threatening situation have to be treated without delay The course of radiation should be shortened when appropriate Systemic therapy Oral tyrosine kinase inhibitors would be better than infusional regimens during the pandemic The impact of immunotherapy on the course of COVID-19 is not known There has been some concern on the safety of surgery during COVID-19 pandemic as surgery cannot be performed without aerosol generating procedures, such as endotracheal incubation and energy device usage which produces surgical smoke. Laparoscopic or robotic surgery during the pandemic may contribute to decreased length of stay as compared with open surgery as well as minimizing the need for medical treatments. On the other hand, pneumoperitoneum, which is inevitable in laparoscopic or robotic surgery may bring higher risk of aerosol exposure to the surgeons and staff. ## Liver transplantation Liver transplantation, which is the best therapeutic option in some patients because it can be a treatment not only for HCC but also for cirrhosis. However, organ donor shortage restricts its indication. During COVID-19 pandemic, transplantation should be decided on case-by-case basis. Liver transplantation for patients with poor short-term prognosis, such as with high MELD score and HCC at the upper limits of the Milan criteria are in high priority and should not be delayedand for those with compensated liver disease and within the lower limits of Milan criteria have medium priority may be suspended to minimize the risk of the donor and the recipient. In patients with complete response to bridging therapy on transplant list, transplantation may also be suspended until it can be performed safely with sufficient resources. ## Ablation Image-guided percutaneous ablation, such as radiofrequency ablation, microwave ablation and others, are minimally invasive therapies for HCC. Ablation is a potentially curative treatment and easily repeatable for recurrence. Ablation with curative intent should not be delayed. In cases of three or fewer tumors, each 3 cm or smaller, and of Child-Pugh class A or B liver dysfunction, ablation is an acceptable alternative to resection. Ablation itself is not an aerosol generating procedure. Ablation is generally performed with local anesthesia. In some institutions, ablation is performed with general anesthesia, and general anesthesia is an aerosol generating procedure. When general anesthesia is performed, ablation rooms are considered as high-risk areas of infection. ## Vascular interventions Vascular interventions, such as transarterial chemoembolization and hepatic arterial infusion chemotherapy, are recommended for cases of unresectable, large/multifocal HCCs without vascular invasion nor extrahepatic spread. Vascular interventions are cytoreductive treatments in most cases. Therefore, they may be suspended until they can be performed safely with sufficient resources. Vascular interventions should be suspended in cases of risk of decompensation or comorbidities that increase the risk of severe COVID-19 because of reduced inpatient beds Vascular interventions, themselves are not aerosol generating procedures. ## Radiation therapy Radiation therapy, including proton beam and carbon ion beam therapies, can be used as an option for local control of HCC. Palliative care for cases receiving the therapy to control symptoms or at low risk of progression is better to delay the schedule of radiation. However, radiation therapy for patients with rapidly progressing HCC may outweigh the risks of the novel coronavirus infection. Radiation therapy for function-or life-threatening situation such as spinal cord compression and inferior vena cava syndrome have to be treated without delay. The course of radiation should be shortened, for example, single-fraction treatment for bone pain, and less fractionation when appropriate. ## Systemic therapy Systemic therapy is for advanced-stage HCC such as with macrovascular invasion or extrahepatic metastasis and with Child-Pugh class A liver function. For cases of advanced HCC treated with systemic therapy, oral tyrosine kinase inhibitors would be better than infusional regimens during the pandemic to protect both patients and medical staff. If available, video call should be used to manage common adverse events. Intravenous chemotherapy should be administered in a dedicated section of outpatient service. The impact of immunotherapy on the course of COVID-19 is not known since there is no sufficient data. Immunotherapy should be considered on a case-by-case basis. Clinical trial recruitment should be suspended until the COVID-19 pandemic settles down. During the COVID-19 pandemic, postponing of locoregional therapies may be necessary. Oral targeted drugs might be a substitute for some patients. ## Follow-up for hcc It is recommended to follow up the patients by telemedicine or online consultation to minimize hospital visits in the circumstances of COVID-19 pandemic. However, due to its high frequency of the recurrence in HCC, imaging examination to detect recurrence at the early stage should not be postponed. # Conclusions In these difficult times, it is our obligation to preserve high management standards of other diseases as well as to effectively handle the COVID-19 pandemic in spite of the shortage of medical resources, such as personnel, beds, PPE and others. To keep our patients and ourselves safe, we should share our experiences and strategies to manage our patients. The novel coronavirus infection will not settle down in the near future. We need to collect real-world data to mitigate the impact of COVID-19. It is mandatory to collect follow-up data of patients who recovered from COVID-19. There have not been any data available on COVID-19 from long-term viewpoint, since COVID-19 was first reported at the end of 2019. It is important to determine the symptomatic and asymptomatic incidence of the novel coronavirus infection by large-scale serological testing not only in the general population but also in patients with HCC and to survey their COVID-19-related morbidity and mortality to adjust management strategies of HCC. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. ## Compliance with ethical standards ## Conflict of interest	None	https://link.springer.com/content/pdf/10.1007/s12072-020-10103-4.pdf	None
6918bbd85207d2a727fb6a077781f13b3b584ea5	pubmed	KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease	KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease # Introduction preamble The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide as the obese and diabetic populations increase, and it has been estimated to be 20-30% in Korea. Considering the increased popularity of a westernized diet and lifestyle, lack of exercise, and the resulting increase in obesity and diabetes, NAFLD is predicted to become more prevalent in the future and to become a major cause of chronic liver disease. In some patients, NAFLD progresses to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC), and it is an independent cardiovascular risk factor. In 2013, the Korean Association for the Study of the Liver (KASL) enacted a clinical practice guideline for the diagnosis and treatment of NAFLD to improve understanding of the disease and provide useful clinical information and direction for healthcare providers. The research results that have accumulated since then necessitate a revision. Accordingly, the clinical practice guidelines committee began revising the guidelines to reflect the results of Korean and international research and develop new recommendations based on a systematic approach that reflects evidencebased medicine and expert opinions. However, evidence remains insufficient, and many studies are currently being conducted. As medical evidence and new findings accumulate in the future, these guidelines will require ongoing supplementation and revision. ## Target population Patients diagnosed with NAFLD based on clinical, biochemical, radiological, or pathological findings in the absence of significant alcohol consumption and liver diseases such as viral hepatitis were the primary research population involved in the development of these guidelines. These guidelines are also based on data from pediatric and adolescent NAFLD patients, whose unique findings distinguish them from adult NAFLD patients. ## Intended users The aim of these guidelines is to provide useful clinical information and direction to healthcare providers involved in the diagnosis and treatment of NAFLD patients. Moreover, these guidelines are intended to provide definite and practical information to resident physicians, practitioners, and trainers. ## Developer and funding information The Clinical Practice Guideline Committee for the Management of NAFLD (Committee) was organized in accordance with proposals by the approval of the KASL Board of Executives and consists of 16 gastroenterologists, one pathologist, one radiologist, and two pediatricians specializing in hepatology. All expenses were paid by KASL. Each committee member collected and analyzed the source data in his or her own field, and the members then wrote the manuscript together. http://www.e-cmh.org https://doi.org/10.3350/cmh.2021.0178 ies was elevated or lowered by accounting for the factors influencing the quality of the studies. Through follow-up studies, the level of evidence was defined as follows: A, indicating the highest level of evidence with the smallest possibility of any changes in the conclusion; B, indicating a moderate level of potential changes; and C, indicating the lowest level of evidence with the greatest possibility of any changes. The strength of each recommendation was suggested according to the GRADE system. In addition to the level of evidence, the results of studies were considered based on aspects of clinical multipliers and socio-economic factors, such as cost. Grading of the recommendations was performed as follows: 1, strong recommendation or 2, weak recommendation. A strong recommendation indicated, for example, that the interventions could be applied in most patients with strong certainty, there was a greater possibility of desirable effects, and there was high-quality evidence, as well as presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicated a suggestion made with less certainty but that could be considered favorable for many patients. Alternative interventions could be chosen for "weak recommendations", according to cost and the preferences of the patients or medical practitioners. These Clinical Practice Guidelines for the Management of NAFLD have been developed through the reviews of medical experts to be used practically for treatment, research, and education. These recommendations are not absolute standards for treatment, and adoption of these guidelines in clinical practice can differ for individual patients. ## List of key questions The committee considered the following clinical questions as key components to be covered in the guidelines. 1. What are the definition and categories? 2. What are the incidence rate and prevalence rate? 3. How does NAFLD progress? 4. What causes NAFLD-related deaths? 5. What are the risk factors of NAFLD?. What are NAFLD's comorbidities? 7. Who should be targeted for NAFLD screening, and how is screening conducted? 8. Which non-invasive surrogates are available to diagnose hepatic steatosis? 9. Which non-invasive surrogates are available to diagnose NASH? 10. Which non-invasive surrogates are available to assess liver fibrosis? 11. Which differential tests are available for advanced fibrosis? 12. What are the indications for liver biopsy?. What are the histopathological features of NAFLD? 14. Is surveillance for HCC necessary?. How can HCC be prevented?. Who should be treated, and what is the aim of the treatment? 17. What do lifestyle modifications include?. What is the effect of moderate or less alcohol consumption?. What are the types, indications, effects, and side effects of medications for NAFLD? 20. What are the indications for and post-operative manage- ## Release of the guidelines and plan for updates The Korean version of the KASL Clinical Practice Guideline for the Management of NAFLD was released at Liver Week 2021 (May , and published in the Clinical and Molecular Hepatology (July 2021). This guideline in Korean is available on the KASL website (http://www.kasl.org). Updates are planned when new reliable evidence has accumulated. Detailed plans for updates will be posted on the KASL website. ## Definition ## What are the definition and categories? NAFLD is a condition characterized by finding fat infiltration of the liver on radiological exams or biopsy without significant alcohol intake, viral hepatitis, medication intake that would cause a fatty liver, or other obvious cause. NAFLD is defined as a disease with findings suitable for clinical, biochemical, imaging, and pathological examinations. NAFLD is a generic term that encompasses the spectrum of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and NASH cirrhosis. The significant safe limits of daily alcohol intake that distinguish NAFLD from alcoholic fatty liver disease range from 10-40 g (pure alcohol), though that range varies between studies. Therefore, definite criteria are difficult to recommend. The Clinical Practice Guideline of the European Association for the Study of the Liver agreed to define the amount of significant alcohol consumption as weekly alcohol consumption ≥210 g in men and ≥140 g in women.No ethnic differences have been reported regarding safe alcohol limits that do not produce liver damage. The KASL Clinical Practice Guideline for NAFLD uses the amount of significant alcohol consumption stated above in clinical treatment and in studies for international comparison with the results of future studies. The term NAFLD was introduced by Schaffner in 1986.However, as information about the causes and mechanisms of the disease accumulated, an opinion emerged that the term NAFLD does not reflect the condition's heterogeneous pathogenesis and various courses. Furthermore, the overestimation of the exclusion of alcohol has sparked heated debate about the threshold of "signif- icant" alcohol consumption required for the diagnosis of NAFLD, and the potential (contradictory) role of alcohol consumption in these "non-alcohol" diseases has been repeatedly raised. In 2019, a consensus by 32 experts suggested alternative terminology, metabolic (dysfunction)-associated fatty liver disease (MAFLD), to more accurately reflect the pathogenesis of this disease.The diagnosis of MAFLD is based on evidence of fat accumulation in the liver in the presence of one of the following three criteria: overweight/obesity, type 2 diabetes mellitus (T2DM), and evidence of metabolic dysregulation. Further research results are needed to verify the validity of this term. ## Epidemiology What are the incidence rate and prevalence rate? ## Incidence In 2007, researchers published results from tracking 5,237 men for more than 4 years and reported for the first time that the annual incidence of NAFLD was 74.1 cases per 1,000 persons.The annual incidence rate of NAFLD diagnosed by abdominal ultrasonography in health screening examinees was about 48.2 cases per 1,000 persons (range, 13.4-77.7).As diagnosed by the hepatic steatosis index (HSI), the annual incidence rate was 21.1 cases per 1,000 persons.According to a meta-analysis in Asia, the annual incidence rate in Korea was 45.1 cases per 1,000 persons.Prevalence The prevalence of NAFLD varies depending on the study population, definition of NAFLD, and diagnostic modality. In 2002, the prevalence among 1,074 people receiving health checkups and diagnosed by abdominal ultrasound was 48.6%.The prevalence among 141,610 people receiving health checkups in the Seoul and Gyeonggi area and diagnosed by abdominal ultrasound was 25.2% (male, 34.4%; female, 12.2%),and the prevalence in other studies varied from 21% to 44%.In a meta-analysis, the prevalence in Korea, as diagnosed by ultrasonography, was 32.9%.The prevalence diagnosed using the fatty liver index (FLI) was 12.6-16.1%,and the prevalence diagnosed with transient elastography was 42.9%.The prevalence diagnosed by liver biopsy among 589 living liver donors in Korea was 51%.Lean/non-obese NAFLD People with normal body weight (body mass index [BMI; kg/m 2 ] of less than 23 kg/m 2 for Asians, less than 25 kg/m 2 for Westerners) or non-obese weight (BMI of less than 25 kg/m 2 for Asians, less than 30 kg/m 2 for Westerners) can also be diagnosed with NAFLD, but data on the incidence rate among those people in Korea are limited. In 2004, the prevalence of NAFLD was 16.1% among 460 people with a BMI between 18.5 kg/m 2 and 25 kg/m 2 who received domestic health checkups.In several domestic studies, the average prevalence of non-obese NAFLD was 18.8% .1%). ## Natural course and cause of death How does NAFLD progress? Because the natural course of NAFLD can only be confirmed through repeated liver biopsy, it has been reported only in small studies. The incidence of NASH was reported to vary from 8.5% to 64.0% over a 3.0-6.6 years follow-up period, a large variation that appears to result from differences in the number of patients, various follow-up periods, and diagnostic criteria.In a meta-analysis comparing NAFL and NASH, the percentage of patients who progressed to more than one stage of liver fibrosis were similar at 39.1% and 34.5%, respectively, but the time it took those patients to progress more than one stage was 14.3 years and 7.1 years, respectively. NASH thus showed faster progression.In a cohort study of NASH patients, the incidence of cirrhosis varied by race and region, with an average of 21-26% of patients progressing to cirrhosis in eight years.According to a study of an LT waitlist, the number of patients with end-stage liver disease because of NAFLD had tripled from 10 years previously, making NAFLD the second most common reason for needing LT.Recently, HCC caused by NAFLD has rapidly increased, becoming the third most common cause of HCC development in United States, and that number is expected to increase by 9% per year.This trend is believed to be due to the rapid increase in the prevalence of obesity, which is a risk factor for NAFLD. NAFLD is associated with a higher incidence of HCC than other etiologies of liver disease in the absence of advanced fibrosis or cirrhosis.What causes NAFLD-related deaths? According to data from the U.S. National Vital Statistics System, the mortality rate of NAFLD has increased in the past decade.In a meta-analysis, patients with NAFLD had a 1.6 times higher mortality rate than the general population. The major causes of death were cardiovascular disease (CVD), malignancy, and liver disease, and in the presence of steatohepatitis, liver disease-related deaths increased.In several cohort studies, the prognosis of patients with NAFLD was most closely related to the degree of liver fibrosis.In a large-scale cohort study based on liver biopsy, the mortality rate of NAFL patients was 1.7 times that of the normal control group; the mortality rate of patients who had steatohepatitis without hepatic fibrosis was 2.1 times that of the normal control group; patients with liver fibrosis had a mortality rate 2.4 times that of the normal control group; patients with cirrhosis had a mortality rate that was 3.8 times that of the normal control group. Thus, the mortality rate increased with the degree of liver fibrosis. 53 Summary 1. Liver fibrosis can progress faster in NASH than in NAFL. 2. The incidence of liver cirrhosis and HCC associated with NAFLD is increasing, and HCC can develop even in the absence of liver cirrhosis. 3. The main causes of death among patients with NAFLD are CVD, malignant tumors, and liver diseases, and liver diseaserelated mortality increases when steatohepatitis and liver fibrosis are present. ## What are the risk factors of nafld? NAFLD is closely related to obesity, diabetes, dyslipidemia, and metabolic syndrome. Obesity is a well-known risk factor for NAFLD, and the prevalence of NAFLD increases as BMI increases.Among obese patients who underwent bariatric surgery, the prevalence of NAFL, NASH, and significant liver fibrosis were 61-91%, 30-37%, and 29.3%, respectively.Metabolic syndrome, which consists of abdominal obesity, impaired fasting blood sugar, hypertriglyceridemia, low high-density cholesterolemia, and hypertension, is a major risk factor for NAFLD, just like obesity. In the presence of metabolic syndrome, the prevalence of NAFLD was 50%.The prevalence of NAFLD was also high in diabetic patients, 60-75%.In patients with dyslipidemia, another risk factor, the prevalence of NAFLD was 50%.In the presence of hypothyroidism, the prevalence of NAFLD increases by 1.6 times,and in the presence of polycystic ovary syndrome, the incidence increases by about 2.2 times.In addition, obstructive sleep apnea,hypopituitarism,hypogonadism,pancreatoduodenal resection,and psoriasis 67 increase the prevalence of NAFLD. Decreased physical activity and sarcopenia increase the risk of NAFLD.The prevalence and incidence of NAFL increased in the group with reduced physical activity.In the presence of sarcopenia, the risk of NAFLD increased by about four times regardless of obesity or metabolic syndrome.When sarcopenia was accompanied by NAFLD, the risk of advanced liver fibrosis increased by 1.8 times.Genetic factors play a major role in the occurrence of NAFLD. Typically, the patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily, member 2 (TM6SF2) single nucleotide polymorphisms affect the development and progression of the disease. In Korea, PNPLA3 and sorting and assembly machinery component 50 (SAMM50) were associated with the prevalence and severity of NAFLD. 73 Summary 1. Major risk factors for NAFLD include obesity, diabetes, dyslipidemia, and metabolic syndrome. ## What are nafld's comorbidities? NAFLD is closely related to systemic metabolic diseases,and it is an independent risk factor for the occurrence of various non- hepatic diseases, including CVD, T2DM, metabolic syndrome, chronic kidney disease (CKD), and malignant tumors.CVD In a retrospective cohort study of 1,804 patients with NAFLD in Denmark in the 2000s, the mortality rate from CVD was higher than that in the normal control group.Several cohort studies that followed also found NAFLD to be an independent risk factor for CVD.In a study that followed patients with histologically diagnosed NAFLD for an average of 26.4 years, the mortality rate increased by 1.3 times, and the risk of CVD increased by 1.6 times compared with the normal control group, with both increases associated with the degree of liver fibrosis.A meta-analysis of patients with NAFLD diagnosed histologically or radiologically concluded that the risk of CVD was increased by about 1.6 times compared with the normal control group. The risk of CVD also increased when liver fibrosis was assessed using the NAFLD fibrosis score (NFS) or liver biopsy.According to two Korean cohort studies, NAFLD was independently associated with the incidence of coronary artery calcification and atherosclerosis, which are direct causes of CVD.T2DM T2DM and NAFLD influence each other.In a large-scale cohort study of healthy Koreans, the prevalence and incidence of T2DM in patients with NAFLD (assessed using the NFS) increased with the degree of hepatic fibrosis.In a meta-analysis of Korean studies, the prevalence of diabetes in patients with NAFLD was 14.2%, higher than the 5.2% of the control group.The results of a meta-analysis of other studies also showed an increase of about 2.2 times in the incidence of T2DM. ## Metabolic syndrome Metabolic syndrome is a major risk factor for the occurrence of NAFLD and is a common comorbid disease. A prospective Korean cohort study of 46,874 men reported that patients with mild and moderate NAFLD (diagnosed by abdominal ultrasound) had a risk of metabolic syndrome 1.5 and 2 times higher, respectively, than the control group.In a meta-analysis of Korean studies, the incidence of metabolic syndrome was 40.7% in patients with NAFLD and 11.2% in the control group.CKD CKD and NAFLD share risk factors such as T2DM and hypertension,and CKD frequency increases in patients with NAFLD.In a meta-analysis of about 63,000 people, the prevalence of CKD increased by 2.1 times, and the incidence rate increased by 1.7 times compared with the control group.The prevalence and incidence of CKD were 2.5 times and 2.1 times higher in NASH than NAFLD. In a Korean cohort study, patients with NAFLD had a 1.2 times higher risk of developing CKD than the control group, and that risk increased with the stage of liver fibrosis. ## Other diseases Arrhythmia, osteoporosis, colon adenoma, colon cancer, and breast cancer all have increased incidence in patients with NAFLD.However, more follow-up studies are needed to confirm clear relationships between NAFLD and those diseases. ## Diagnosis ## Who should be targeted for nafld screening, and how is screening conducted? Screening for NAFLD should be considered in cases of persistent liver enzyme elevation. Because the cost effectiveness of screening in diabetic patients has been confirmed,patients with diabetes should receive screening tests for NAFLD regardless of their liver enzyme levels. In addition, subjects with metabolic syndrome (which is closely associated with insulin resistance), obesity, and other risk factors for NAFLD can be considered for screening tests.The primary screening test for NAFLD is ultrasonography. ## Non-invasive examinations Because the prognosis of NAFLD differs significantly depending on the histological findings, the diagnosis of hepatic steatosis and fibrosis and assessment of their severity are clinically crucial. To date, liver biopsy is the gold standard in assessing hepatic necroinflammation, steatosis, and fibrosis. However, liver biopsy is expensive, invasive, carries a risk of complications, is subject to intra-/inter-observer interpretational variability, and can suffer from sampling errors when an insufficient amount of liver tissue is collected.Therefore, noninvasive radiological surrogates such as ultrasonography and panels of serological tests are widely used. Which non-invasive surrogates are available to diagnose hepatic steatosis? ## Radiological surrogates Abdominal ultrasonography is the first-line imaging modality for screening asymptomatic patients with abnormal liver enzyme levels. However, it suffers from subjective interpretation, examination difficulties in obese patients, and low sensitivity when the amount of hepatic steatosis is less than 30%. Moreover, ultrasonography cannot distinguish NASH from NAFL.When hepatic steatosis assessed using MR spectroscopy (MRS) was used for reference, the diagnostic accuracy of ultrasonography was lower than that of non-contrast CT and MRI.However, ultrasonography is appropriate as a screening test, because it offers 1) robust diagnostic performance for moderate or severe steatosis, 2) the ability to evaluate the entire hepatobiliary system in addition to detecting the presence of hepatic steatosis, and 3) wide availability. Controlled attenuation parameter (CAP) is a feature of transient elastography that can quantify the degree of fat deposition in the liver parenchyma by measuring ultrasound attenuation.According to a recent Korean study enrolling people who received regular health checkups, the normal CAP range is 156-287 dB/m.The area under the receiver operating characteristic curve (AUC) of CAP used to diagnose a moderate to severe degree of steatosis was 0.88 (sensitivity, 83.3%; specificity, 81.6%), and the cutoff value was 276 dB/m in a Korean study of living LT donors.In another Korean study, the AUCs of CAP for mild, moderate, and severe degrees of steatosis in patients with chronic liver diseases, including NAFLD, were 0.885, 0.894, and 0.800, respectively, and the cutoff values were 250 dB/m, 299 dB/m, and 327 dB/m, respectively.In a recent meta-analysis, the AUCs of CAP for mild, moderate, and severe degrees of steatosis were 0.96, 0.82, and 0.70, respectively. 108 CAP can be used as a monitoring tool for hepatic steatosis, and it can be examined simultaneously with transient elastography.Other ultrasound-based methods, including image-based quantitative analysis of liver parenchymal echo texture and measuring the attenuation of ultrasound energy, are under investigation.Hepatic steatosis is associated with low attenuation on CT scans, which can be used for the quantitative assessment of hepatic steatosis. Because the attenuation of enhanced CT is affected mainly by the amount of blood flow, unenhanced CT is favored for the measurement of hepatic steatosis, and the attenuation of liver and spleen parenchyma are frequently compared. For moderate to severe steatosis, the specificity of CT was reported to be high, but its sensitivity and positive predictive value were low.Furthermore, its diagnostic performance for mild steatosis was suboptimal. The specificity and sensitivity of unenhanced CT for diagnosing moderate to severe steatosis were 100% and 53.8%, respectively, when CT attenuation of hepatic parenchyma was less than 48 HU.However, CT raises concerns about radiation hazards, and CT evaluations of hepatic steatosis are limited in patients with infiltrative liver diseases that deposit iron, copper, glycogen or amiodarone in the liver parenchyma because CT attenuation is affected by those materials.Dual energy CT, which adopts two different tube potentials for image acquisition, can perform material decomposition and has been used to quantify the degree of hepatic steatosis.MRI is superior to ultrasonography for measuring a small amount of fat in the liver, and it is the most precise imaging tool for evaluating NAFLD. Quantitative MRI measurements of hepatic fat deposition using the Dixon technique can be classified into MRS and MRI proton density fat fraction (MRI-PDFF).MRS can directly measure the signal from acryl groups of triglycerides, and MRS findings correlate closely with histological results and show high sensitivity to hepatic steatosis.map the entire liver for the degree of steatosis. Therefore, it can measure the degree of fat deposition in any part of the liver parenchyma. MRI-PDFF in different MRI units is in high agreement with histological findings, and its diagnostic performance in detecting severe steatosis (≥67%) was high (AUC, 0.95).In a recent meta-analysis, the AUCs for differentiating grade 1-3 steatosis, grade 2-3 steatosis, and grade 3 steatosis were 0.98, 0.91, and 0.90, respectively.MRI-PDFF showed superior diagnostic performance to CAP in assessing hepatic steatosis in a prospective study.MRS and MRI-PDFF can measure the degree of steatosis precisely, irrespective of iron deposition or fibrosis.Despite the superior diagnostic performance of MRS and MRI-PDFF, their limited availability and high cost remain problems. ## Panels In addition to radiological examinations, various panels of serological tests have been proposed to diagnose hepatic steatosis and assess its severity. These panels can be calculated using clinical information such as age, sex, and the results from serological tests. These panels do not directly diagnose hepatic steatosis, unlike ultrasonography, but they can help physicians who suspect the presence of hepatic steatosis to decide whether further assessments are justified. Large-scale studies frequently use these noninvasive panels to test for hepatic steatosis instead of ultrasonography, which has a high cost. The FLI was proposed by Bedogni et al.in an Italian study that examined 216 subjects with liver disease and 280 subjects with healthy livers. In that study, 228 patients had ultrasonography-defined NAFLD. The FLI is calculated based on triglycerides, gamma-glutamyl transpeptidase, BMI, and waist circumference. If the FLI is less than 30, NAFLD can be excluded (negative likelihood ratio, 0.2), and if the FLI is more than 60, NAFLD can be di-agnosed (positive likelihood ratio, 4.3). An FLI score of more than 60 has a positive predictive value of 99% and a negative predictive value of 15%. The AUC of the FLI was 0.84. The FLI showed acceptable accuracy among a Korean population.The NAFLD liver fat score (NLFS) was proposed by Kotronen et al.in a Finnish study comprising 470 subjects. That study used MRS to diagnose NAFLD. The NLFS is calculated based on metabolic syndrome, T2DM, fasting insulin, aspartate aminotransferase (AST), and the AST/alanine aminotransferase (ALT) ratio. Its cutoff is -0.640 (sensitivity, 86%; specificity, 71%). If the NLFS is less than -0.640, NAFLD can be excluded, and if it is more than -0.640, NAFLD can be diagnosed. The AUC of the NLFS was 0.86-0.87. NLFS showed acceptable accuracy in a Korean population.The HSI was proposed by Lee et al.in a Korean cohort study of 10,724 subjects (5,462 with ultrasonography-defined NAFLD). The HSI is calculated based on sex, BMI, AST, ALT, and T2DM. If the HSI is less than 30, NAFLD can be excluded (negative likelihood ratio of 0.2, sensitivity of 93.1%), and if it is more than 36, NAFLD can be diagnosed with high predictive accuracy (positive likelihood ratio of 6.1, specificity of 92.4%). The AUC of the HSI was 0.81. The HSI showed acceptable accuracy among a Korean population.The noninvasive surrogates just described show acceptable accuracy in most cross-section studies and have been used to trace changes in hepatic steatosis in certain studies. However, the usefulness of those noninvasive surrogates in monitoring disease progression and evaluating treatment response should be further investigated. Which non-invasive surrogates are available to diagnose NASH? NASH is significantly associated with liver fibrosis progression and HCC. Non-invasive modalities to diagnose NASH are limited, but a prediction model based on liver stiffness, CAP (assessed using transient elastography), and ALT levels was recently proposed by a Korean study.Some studies insist that NASH can be distinguished from NAFL using cytokeratin-18 fragments (sensitivity, 66%; specificity, 82%).A few studies claim that CT or MRI can be used to differentiate NASH from NAFLD, but no clear diagnostic criterion has been set.Based on the association between the viscosity shown in shear wave dispersion imaging and necroinflammation of the liver parenchyma, a recent study showed that shear wave dispersion imaging could be helpful in diagnosing NASH.The AUC of magnetic resonance elastography (MRE) alone and that for the combined use of MRE and MRI-PDFF in differentiating NASH from NAFL was 0.82-0.93.Recently, multiparametric MR indices, which score the results from various MRI techniques, have been under investigation. A recent Korean study found that a multiparametric MRI index using MRE, MRS, and T1 mapping to differentiate NASH from NAFL showed sensitivity of 80%, specificity of 85.2%, and an AUC of 0.883.In a meta-analysis that systematically reviewed all studies using MRI to differentiate NASH from NAFL, the pooled sensitivity and specificity were 87.4% and 74.3%, respectively. 110 ## [recommendations] 1. Non-invasive diagnosis of NASH remains limited, so it should be diagnosed by liver biopsy. (A1) Which non-invasive surrogates are available to assess liver fibrosis? The assessment of liver fibrosis is crucial in patients with NAFLD because the degree of liver fibrosis is significantly associated with long-term outcomes such as the development of HCC and liver-related death.Furthermore, it is important to noninvasively assess the regression or progression of liver fibrosis during the course of anti-fibrotic therapy. Radiological surrogates Ultrasound-based measurement techniques for liver fibrosis take advantage of shear wave elastography (SWE). They can be divided into two categories: 1) measuring the elasticity of the liver parenchyma using SWE without acquiring imaging data (transient elastography) and 2) image-based sonoelastography that acquires both elasticity and 2D image data (point SWE and 2D SWE). Transient elastography is widely used in clinical practice, and many researchers have reported its high performance in quantifying liver fibrosis in NAFLD patients. In a recent meta-analysis, transient elastography showed high sensitivity and specificity for evaluating the degree of liver fibrosis in NAFLD patients.However, the accuracy of transient elastography is limited in obese patients, who commonly have NAFLD, making it unavailable in 5-20% of patients.A recent study reported that using an XL probe rather than an M probe can significantly lower the failure rate of transient elastography.Image-based techniques have the advantage of acquiring both elasticity data and 2D images simultaneously. The failure rate is lower than that of transient elastography because operators can choose the area of the liver parenchyma to acquire elasticity data. The AUC of point SWE for quantifying liver fibrosis in NAFLD patients was higher than 0.8.The performance of point SWE for advanced liver fibrosis was excellent (100% sensitivity and 91% specificity).In a recent meta-analysis, the diagnostic performance of point SWE for liver fibrosis was similar to that of transient elastography.2D SWE can obtain elasticity data from a wider area than point SWE, and the reported failure rate of 2D SWE was lower than that of point SWE.In a prospective study, 2D SWE, MRE, and transient elastography had similar AUCs for advanced hepatic fibrosis (0.920, 0.929, and 0.915, respectively).MRE shows high diagnostic accuracy for liver fibrosis.In contrast to transient elastography, which can examine the elasticity of only a small portion of liver tissue, MRE can evaluate the entire liver parenchyma.MRE also has other advantages: operator non-dependency and no limitations for obese patients. MRE is the most accurate non-invasive test for liver fibrosis, with a diagnostic performance superior to that of transient elastography.In a meta-analysis, MRE correlated well with each stage of liver fibrosis, with AUCs for each stage of 0.84-0.93.The failure rate of MRE was less than 5%, which is significantly better than that of transient elastography. MRE was not significantly afhttp://www.e-cmh.org https://doi.org/10.3350/cmh.2021.0178 fected by the MRI manufacturer or the strength of the magnet.In addition, MRE showed robust reproducibility in repetitive examinations.However, the high cost of MRE limits its availability in clinical practice. In patients with iron deposition in the liver parenchyma, it is difficult to perform MRE, and the presence of other infiltrative diseases, such as profound hepatic steatosis, hepatic congestion, or acute inflammation, can attenuate the diagnostic accuracy of MRE.Panels In addition to radiological examinations, various panels of serological tests have been proposed to diagnose liver fibrosis. Well-validated panels are summarized here. Of the noninvasive panels for liver fibrosis, the NFS has been studied the most. The NFS was proposed in a US study by Angulo et al.that comprised 733 subjects with biopsy-proven NAFLD. Two cutoffs were proposed: <-1.455 (low probability, negative predictive value of 88-93%) and >0.676 (high probability, positive predictive value of 82-90%).A meta-analysis based on 13 studies with 3,064 subjects showed that the AUC of the NFS for advanced liver fibrosis was 0.85. If the NFS is less than -1.455, advanced liver fibrosis can be excluded with a sensitivity of 90% and a specificity of 60%, and if NFS is more than 0.676, advanced liver fibrosis can be diagnosed with a sensitivity of 67% and a specificity of 97%. 48,160-172 Among 412 Korean subjects with biopsy-proven NAFLD, an NFS of less than -1.455 allowed advanced liver fibrosis to be excluded with a high negative predictive value (86.6%), and an NFS of more than 0.676 allowed advanced liver fibrosis to be diagnosed with a positive predictive value of 50%.In another Korean study, which recruited 315 subjects with biopsy-proven NAFLD, the cutoff values (<-1.455 and >0.676) showed an AUC of 0.84 in diagnosing advanced liver fibrosis (negative predictive value of 89.3-95.7%).However, cases that fall between the cutoff values (indeterminate probability) still require a liver biopsy.The fibrosis-4 index (FIB-4) was proposed by Sterling et al. in a study comprising 832 subjects with human immunodeficiency virus/hepatitis C virus co-infection. FIB-4 is calculated using the platelet count, age, AST, and ALT. The AUC of FIB-4 for advanced liver fibrosis was 0.765. When the FIB-4 is less than 1.30, advanced liver fibrosis can be excluded (accuracy, 90%), and when FIB-4 is more than 2.67, advanced liver fibrosis can be diagnosed (accuracy, 80%).A recent study of subjects with biopsy-proven NAFLD showed that the diagnostic accuracy of the NFS and FIB-4 was significantly higher than that of other noninvasive panels for liver fibrosis and similar to that of MRE in diagnosing advanced liver fibrosis.However, because the diagnostic accuracy of FIB-4 was inferior to that of the NFS in a Korean study, further validation studies are required.The enhanced liver fibrosis (ELF) panel has recently been used to assess liver fibrosis in Europe. ELF was proposed by Guha et al.in a UK study comprising 192 subjects with biopsy-proven NAFLD. ELF is calculated based on three proteins associated with liver fibrosis: hyaluronic acid, tissue inhibitor of metalloproteinase 1, and amino terminal peptide of procollagen III. The cutoff value and AUC of ELF for advanced liver fibrosis were 0.3576 and 0.90, respectively (sensitivity, 80%; specificity, 90%; positive predictive value, 71%; negative predictive value, 94%).Other serological surrogates for liver fibrosis, such as M2BPGi and AsAGP, have been proposed.However, because few data for subjects with NAFLD are available, further validation studies are required. The noninvasive surrogates described above show acceptable accuracy and prognostic values in most crosssection studies. However, the usefulness of noninvasive surro- Which differential tests are available for advanced fibrosis? In NAFLD, liver fibrosis testing uses serologic tests, image tests, or liver biopsy. Because liver biopsy cannot be performed in all patients, an algorithm can be used to differentiate advanced fibrosis. Advanced fibrosis can be differentiated primarily using transient elastography, FIB-4, and the NFS.When subjects are classified as intermediate risk by transient elastography, FIB-4, or the NFS, additional tests such as M2BPGi, AsAGP, ELF, SWE, or MRE can be performed. If the algorithms suggest advanced fibrosis, additional tests to re-evaluate the liver fibrosis or a liver biopsy should be considered. ## Liver biopsy What are the indications for liver biopsy? Non-invasive tests to replace liver biopsy have been developed and shown high accuracy.However, liver biopsy remains the gold standard for diagnosing NAFLD.In practice, it is difficult to perform liver biopsy in all patients suspected of having NAFLD.However, liver biopsy can help with diagnosis, treatment planning, and distinguishing between NAFLD and other liver diseases (autoimmune hepatitis, drug-induced hepatitis, Wilson's disease, etc.). Liver biopsy is necessary when NASH or advanced liver fibrosis is suspected, as well as when other liver diseases cannot be excluded.Liver biopsy has several limitations. First, sampling error is a concern because only a small portion of the liver tissue is sampled during liver biopsy. Second, intra-and inter-observer variability occurs.Third, it carries the risk of complications such as bleeding and infection, as well as increased medical costs. There- fore, it is difficult to perform or repeat liver biopsy in all patients.To minimize discrepancies, it is recommended that a sufficient amount of tissue be collected, a thick needle (16-18 gauge) be used, and two or more samples of a sufficient length be collected. 97 [Recommendations] 1. Liver biopsy should be considered in patients suspected of having NASH or advanced liver fibrosis. (B1) 2. Liver biopsy should be considered when the presence or severity of coexisting chronic liver disease cannot be excluded. (B1) What are the histopathological features of NAFLD? The role of liver biopsy in NAFLD diagnosis lies in differentiating simple steatosis (NAFL) from NASH, evaluating the extent of fibrosis (stage), and excluding the possibility of other liver diseases. NAFL is defined as the presence of ≥5% steatotic hepatocytes without evidence of hepatocellular injury in the form of hepatocyte ballooning.The degree of steatosis is graded as 1+ (mild, 5-33%), 2+ (moderate, 34-66%), and 3+ (severe, ≥67%). NASH is diagnosed when there is evidence of hepatocellular injury (hepatocellular ballooning) and lobular inflammation in addition to steatosis.Fibrosis, when present, is staged as stage 1 (perivenular, perisinusoidal, or periportal fibrosis), stage 2 (both zone 3 and periportal fibrosis), stage 3 (bridging fibrosis), and stage 4 (cirrhosis). ## Hcc surveillance and prevention Is surveillance for HCC necessary? Because the incidence of liver cirrhosis and HCC associated with NAFLD is increasing rapidly, the risk of HCC should be assessed and surveillance should be established in all NAFLD patients. Because the incidence of HCC in patients with NAFLD-related cirrhosis is more than 1.5% per year,HCC surveillance is recommended if liver cirrhosis is clinically suspected.Although the incidence of HCC in patients with NAFLD was 10 times higher than that in the normal control group, 202 the incidence of HCC is very low in patients with early liver fibrosis (F0-2). However, when patients with early liver fibrosis have HCC risk factors (obesity, metabolic syndrome, diabetes, etc.), they become more likely to develop HCC. Thus, surveillance should be individualized.Abdominal ultrasound is the primary surveillance test for HCC. However, in overweight or obese patients, it can be difficult to perform accurately.In those cases, CT or MRI can be used instead. ## How can hcc be prevented? Smoking is associated with liver fibrosis and is known to be a risk factor for the development of HCC. In meta-analyses and cohort studies, smoking increased the risk of developing HCC by 1.5 and 1.8 times, respectively.Therefore, smoking cessation is recommended for NAFLD patients. The effect of alcohol consumption on the development of HCC varies between studies, but in a meta-analysis, drinking increased the incidence of HCC by 1.2-2.1 times. Patients with liver cirrhosis associated with NAFLD should abstain from alcohol because drinking it increases the risk of HCC and liver-related mortality.In a 32-year cohort study, diabetes increased the incidence of HCC by 4.6 times.A meta-analysis also showed that diabetes increased the incidence of HCC.Metformin decreased the incidence of HCC, but the use of sulfonylurea and insulin increased the incidence of HCC by 1.6 and 2.6 times, respectively.Peroxisome proliferator activated receptor gamma (PPAR-γ) agonist and glucagon-like peptide-1 (GLP-1) agonist were effective in the recovery of NASH, but they did not show a significant association with the development of HCC.Dyslipidemia is associated with NASH and CVD, but the relationship with liver disease-related mortality or HCC is still lacking. In a meta-analysis, statin use reduced the risk of developing HCC by 37%.However, results in patients with NAFLD remain insufficient.Obesity is associated with both liver fibrosis and HCC.Although weight loss and exercise improve both steatosis and fibrosis, there are insufficient studies showing that weight loss and exercise therapy reduce the incidence of HCC. Further research is thus needed on the association between weight loss and HCC incidence. [Recommendations] ## Treatment ## Who should be treated, and what is the aim of the treatment? NAFLD is commonly associated with metabolic diseases such as obesity, diabetes, and insulin resistance. Given that NAFLD is associated with increased mortality from CVD and liver-related complications, 225,226 NAFLD patients require management and treatment to improve their prognosis. Treatments for NAFLD aim to reduce the incidence and mortality of CVD and liver-related complications, and they include both pharmacologic and non-pharmacologic options to improve intrahepatic inflammation and fibrosis and treat comorbid metabolic diseases. Lifestyle modifications such as weight reduction, dietary control, and exercise and treatment of comorbidities such as diabetes, obesity, hypertension, and dyslipidemia are the cornerstones of treatment for NAFLD and should be applied to all NAFLD patients, regardless of the degree of inflammation or fibrosis. However, pharmacologic treatments should be applied selectively because NAFLD progresses slowly and encompasses a spectrum of conditions from NAFL to NASH cirrhosis. The most important histologic marker indicating long-term prognosis is the severity of fibrosis, 51,52,227 with stage 2 or more fibrosis (≥F2) being an independent predictor of liver-related complications and mortality.The most important factor in the progression of fibrosis is the presence of steatohepatitis. Fibrosis progresses more rapidly in patients with steatohepatitis than in those without it,and changes in steatohepatitis are associated with the progression of fibrosis.Therefore, patients with hepatic fibrosis or steatohepatitis can receive pharmacologic treatment to improve their long-term prognosis. ## Lifestyle modifications What do lifestyle modifications include? Weight reduction Among overweight or obese (BMI >25.0 kg/m 2 ) NAFLD pa-tients, weight loss through lifestyle changes significantly reduced their liver fat content as revealed by imagingor liver biopsy.In patients histologically diagnosed with NAFLD, weight loss of more than 5-7% resulted in decreased intrahepatic fat content and inflammation, 233,234 with greater weight loss correlating with greater histologic improvement.Liver fibrosis also improved in 45% of patients whose weight loss was more than 10%.In a meta-analysis of studies about weight loss through lifestyle modification, anti-obesity drugs, and surgical treatment, weight loss was associated with a decrease in intrahepatic fat, NAFLD activity score (NAS), and liver enzymes.Even in nonobese NAFLD patients, intrahepatic fat content improved with a weight loss of 3-5%.Therefore, weight loss is important in NAFLD patients regardless of the presence of obesity. In NAFLD patients with obesity, the rate of weight loss affects steatohepatitis. A study showed that weight reduction that targeted a gradual decrease (maximum of 1 kg/week of body weight) improved both NASH and NAS.However, a rapid decrease (more than 1.6 kg/week of body weight) worsened portal inflammation and fibrosis in some morbidly obese patients,and rapid weight loss through bariatric surgery can lead to acute hepatic failure.Therefore, progressive weight loss of less than 1 kg/week is recommended over rapid weight loss in NAFLD patients with obesity. ## Dietary therapy Reducing the intake of total energy and controlling food in take are crucial aspects of NAFLD treatment. In prospective, randomized, controlled studies, reductions in energy intake caused weight loss, decreased intrahepatic fat content, decreased liver enzyme levels, and decreased insulin resistance. 232,241,242 A daily intake of 1,500-1,800 kcal in men and 1,200-1,500 kcal in women can reduce total energy intake by more than 500 kcal/day.However, daily caloric intake should be optimally adjusted according to age, sex, weight, and physical activity. Recently, the association between the ratio of macronutrients (carbohydrates, fats, and proteins) and the development of obesity and NAFLD has been studied. Carbohydrate intake was associated with metabolic syndrome and the severity of intrahepatic inflammation.In Western studies, low-carbohydrate diets were more effective than low-fat diets in reducing liver fat content.In Korea, increased carbohydrate and fructose intake was associated with an increased prevalence of fatty liver and elevated liver enzymes,zymes and liver fat content.However, both low-fat and lowcarbohydrate diets effectively reduced liver fat content.The decrease in liver fat content did not differ depending on the type of diet; liver fat content decreased in patients who lost more than 7% of their body weight regardless of whether they ate a lowcarbohydrate or high-carbohydrate diet.In a meta-analysis comparing low-carbohydrate and low-fat diets, the two did not differ in reducing liver fat content.Therefore, total energy intake is a more important factor in NAFLD treatment than the composition ratio of macronutrients. The Mediterranean diet pattern emphasizes vegetables, fruits, whole grains, and legumes, and the principal source of dietary lipids is olive oil. It also includes the moderate consumption of fish and shellfish, white meat, eggs, and dairy products, with red meat and processed meats eaten rarely and in small quantities.It has a high content of monounsaturated fatty acids. The Mediterranean diet reduces liver fat content and makes insulin resistance significantly better than low-fat diets regardless of body weight,and adherence to the Mediterranean diet was more important than adherence to a low-fat diet.Dietary control along with weight loss can help reduce hepatic fat content. However, studies of specific nutrients and dietary habits have been conducted on only small numbers of patients, and few have shown histologic improvement to hepatic inflammation or fibrosis. It is difficult to maintain adherence to appropriate dietary habits in the long run. Therefore, it is necessary to study an appropriate diet to which patients can maintain adherence for a long time that produces histological improvement. In addition, dietary effects can vary depending on genetic predisposition,such as the presence of PNPLA3 or TM6SF2 variants, and dietary control needs to be individualized for each patient. Exercise NAFLD is associated with a low level of physical activity. In large-scale Korean cohort studies, prolonged sitting time and decreased physical activity were positively associated with the prevalence of NAFLD regardless of BMI,and moderate to vigorous exercise decreased the risk of developing a fatty liver or improved the resolution of an existing fatty liver.In biopsy-proven NAFLD patients, vigorous exercise (≥6 metabolic equivalents of task [METs]) was associated with a lower frequency of NASH and advanced fibrosis.Exercise itself decreases insulin resistance and reduces liver fat content regardless of body weight changes.In a meta-analysis, exercise was found to be effective in reducing the liver fat content.Aerobic exercise was mainly recommended at moderate or vigorous intensity (greater than 50-70% of maximal heart rate), and exercise for 30-60 minutes more than three times per week for at least 6 weeks was found to be effective.Resistance exercise was recommended at 50-70% of maximal strength (1-repetition maximum) for 30-60 minutes more than three times per week.According to the World Health Organization and United States Department of Health and Human Services, moderate-intensity physical activities include brisk walking, dancing, gardening, and carrying or moving an object of less than 20 kg, and vigorous-intensity physical activities include running, fast cycling, aerobics, fast swimming, and carrying or moving objects of more than 20 kg.It is unclear which exercise is most effective. Some randomized controlled studies comparing aerobic exercise and resistance exercise have shown that aerobic exercise more effectively reduces liv- er fat content than resistance exercise, 270 but some studies show similar effects from both exercise types.In recent systematic reviews, both aerobic and resistance exercise similarly reduced the liver fat content.However, resistance exercise could be more feasible than aerobic exercise for NAFLD patients with poor cardiorespiratory fitness or those who cannot tolerate aerobic exercise because it requires much lower energy consumption.Because exercise-mediated improvements in liver fat can be reversed to baseline levels after cessation, it is necessary to maintain exercise habits.Therefore, the selection of exercise needs to be individualized so that it can be maintained continuously considering each patient's preferences and cardiopulmonary fitness. [Recommendations] 1. In overweight or obese NAFLD patients, weight loss of more than 5-7% results in decreased intrahepatic fat content, and weight loss of more than 7-10% is required to improve hepatic inflammation and fibrosis. (A1) 2. To reduce intrahepatic fat content, a reduction in the total energy intake of more than 500 kcal/day is required. (A1) 3. To reduce intrahepatic fat content, at least moderate-intensity exercise for more than 30 minutes more than 3 times per week is required. (B1) What is the effect of moderate or less alcohol consumption? The effects of moderate or less alcohol consumption should be considered because NAFLD, by definition, includes patients whose alcohol consumption is insignificant. However, alcohol consumption is not easy to distribute randomly, so the effects of alcohol consumption on NAFLD can be evaluated only through longitudinal observational studies. Significant alcohol consumption (male ≥210 g/week, female ≥140 g/week) can cause alcohol-related liver disease and should be avoided. However, the effects of light or moderate drinking vary. In some studies, light or moderate drinking (male <210 g/week, female <140 g/week) appears to be protective against fatty liver and hepatic fibrosis,but in other studies it was associated with the progression of NAFLD.In a large cohort study in Korea, light drinking (less than 10 g/day) was associated with worsening in noninvasive markers of fibrosis,but further studies are needed. What are the types, indications, effects, and side effects of medications for NAFLD? ## Insulin sensitizers Pioglitazone Pioglitazone, a PPAR-γ agonist, reduces insulin resistance in the liver, muscle, and adipose tissue, and also reduces the amount of fat in the liver and hepatocellular injury by alleviating hepatic mitochondrial oxidative dysfunction.In four randomized controlled studies, histologic improvement of steatohepatitis was observed in patients with or without diabetes who were treated with pioglitazone (30 or 45 mg/day) compared to placebo-treated patients.However, no improvement was observed in liver fibrosis, a major indicator predicting the progression of liver disease.In the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, 247 nondiabetic NASH patients were randomized to pioglitazone (30 mg/day), vitamin E (800 IU/day), or placebo and followed for 96 weeks. The primary endpoint of this study was a ≥2 point reduction in the NAS (one or more point improvement in hepatocellular ballooning and one or more point improvement in either the lobular inflammation or steatosis scores). Compared with placebo, pioglitazone showed improvement in NASH (34% vs. 19%, P=0.04). This study concluded that the improvements observed with pioglitazone were not statistically significant because they did not reach the prespecified level of significance (P<0.025) for the primary outcome. However, there were discrepancies in the presence of hepatocellular ballooning between the results of pathological assessments performed locally and those performed centrally from deeper cuts prepared from the biopsy specimens obtained, and those classification errors were much higher in the subjects taking pioglitazone. The resolution of steatohepatitis, the secondary outcome, was higher in the pioglitazone group than the placebo group (47% vs. 21%, P =0.001). In conclusion, pioglitazone can be considered as a treatment option for NASH diagnosed by liver biopsy in patients with or without diabetes mellitus. However, weight gain 294 is a common side effect of pioglitazone treatment. Other potential side effects of long-term pioglitazone http://www.e-cmh.org https://doi.org/10.3350/cmh.2021.0178 use in NASH patients with diabetes mellitus include lower extremity edema, muscle cramps, as well as an increased risk of fractures,bladder cancer,and congestive heart failure.Metformin Metformin, a commonly prescribed drug for T2DM, was expected to be beneficial in treating NASH patients, as it reduces insulin resistance in the liver and muscles. Moreover, metformin inhibits hepatic fat accumulation and glucose excretion by activating adenosine monophosphate-activated protein kinase, and also decreases the expression of tumor necrosis factor-α.However, metformin has little or no effect on liver histology.Since metformin has a weight loss effect, it can compensate for the weight gain associated with pioglitazone when the two medications are used together. However, several studies, including randomized controlled studies, showed that the co-administration of metformin and pioglitazone did not improve histological findings in the liver, insulin resistance in the liver, or liver enzyme levels compared with controls.Only in a retrospective study, long-term use (more than 6 years) of metformin in patients with diabetes mellitus and histologically proven NASH or advanced fibrosis lowered the risk of overall mortality, LT, and HCC.Another retrospective study showed that diabetes mellitus increased the risk of death and liver-related complications such as HCC, and that metformin use lengthened the survival and decreased the risk of decompensated cirrhosis and HCC in 299 patients with NAFLD-associated Child-Pugh class A cirrhosis.GLP-1 agonist Liraglutide, a synthetic long-acting GLP-1 receptor agonist, has been approved to treat diabetes mellitus and obesity. In a small phase 2 clinical trial of 52 patients with biopsy-proven NASH, patients receiving subcutaneous injections of liraglutide (1.8 mg/day for 48 weeks) achieved greater weight loss and resolution of NASH than those receiving placebo.However, its development as a medication for NASH has been interrupted by its frequent gastrointestinal side effects such as diarrhea, constipation, and loss of appetite. In a phase 2 trial of semaglutide, a GLP-1 analogue, 320 patients with NASH were randomized to receive daily subcutaneous semaglutide (0.1 mg, 0.2 mg, or 0.4 mg) or placebo for 72 weeks. The proportions of patients who experienced NASH resolution without the exacerbation of hepatic fibrosis were 40%, 36%, and 59%, respectively, in the treatment groups and 17% in the placebo group (P<0.001, semaglutide of 0.4 mg vs. placebo).How-ever, the groups did not differ significantly with regard to fibrosis improvement. The mean percentage of weight loss was 13% for the 0.4 mg semaglutide group and 1% for the placebo group, with the semaglutide group reporting more frequent nausea, constipation, and vomiting than the placebo group. Based on those results, semaglutide is expected to prove its benefit as a treatment for NASH through additional phase 3 clinical trials. [Recommendations] 1. Pioglitazone is effective in improving steatohepatitis in NASH confirmed by liver biopsy, regardless of diabetes mellitus, but safety concerns about long-term treatment should be considered. (B1) 2. Metformin can be used as a first-line treatment for diabetes mellitus in patients with concomitant NAFLD who also have diabetes mellitus. (B1) ## Antioxidants Vitamin E (alpha-tocopherol) Vitamin E decreases oxidative stress (which worsens NASH) and improves liver inflammation.In the PIVENS study, which was a large-scale phase 3 trial, the administration of 96-week highdose vitamin E (800 IU/day) produced significant improve ment in liver histology compared to placebo (43% vs. 19%, P=0.001),but it did not improve liver fibrosis.The proportion of NASH resolution, a secondary endpoint, was 36% in the vitamin E group, which was higher than that in the control group (21%). Therefore, the use of vitamin E can be considered as biopsy-proven NASH treatment in patients without diabetes mellitus. However, the long-term use of vitamin E also carries safety concerns because of the increased risk of prostate cancer or hemorrhagic stroke.Although the finding is controversial, high doses of vitamin E (>400 IU/day) are associated with an increased mortality rate, requiring safety precautions.According to a retrospective study of 236 patients with biopsy-proven NASH with bridging fibrosis or compensated cirrhosis, the use of 800 IU/day of vitamin E for more than 2 years decreased the risk of death, LT and decompensated cirrhosis in patients both with and without diabetes mellitus. However, the incidence of HCC, vascular disease, and non-hepatic cancers did not differ between the vitamin E users and controls.1. High-dose vitamin E (800 IU/day) can improve NASH confirmed by liver biopsy in non-diabetic patients, but safety should be considered for long-term administration. (B1) ## Lipid-lowering drugs CVD is the most common cause of death for NAFLD patients, so it is important to modify its risk factors.An increase in plasma lipoprotein increases the carotid intima-media thickness and atherosclerotic plaques, which cause CVD, and thus it is necessary to prevent and treat dyslipidemia.Lipid lowering agents such as statins (hydroxy-methyl-glutaryl coenzyme A reductase inhibitors) 322 can be considered in NAFLD patients with dyslipidemia.In a post-hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study, statin use decreased aminotransferases and poor cardiovascular outcomes in NAFLD patients with aminotransferases up to three times higher than the upper normal limit. Less than 1% of patients (seven of 880 patients) withdrew from the study due to hepatotoxicity associated with the statin treatment; thus statin treatment seems to safely lower liver enzymes and reduce cardiovascular morbidity in patients with NAFLD.In a study using data from the National Health Information database of South Korea, statin treatment decreased not only the risk of NAFLD occurrence but also the development of fibrosis attributed to NALFD, regardless of diabetes mellitus.Strict control of low density lipoprotein cholesterol (LDL-C) is emphasized because many NAFLD patients treated with statins still did not meet their LDL-C treatment targets, which can itself increase the incidence of CVD.A common adverse effect of statins is the asymptomatic elevation of aminotransferases, which usually appears within 1 year of starting statins and recovers spontaneously.This increase in liver enzyme levels depends on the statin dose.However, because statin users and controls did not differ in terms of persistent and significant elevation of liver enzyme levelsor the incidence of liver and biliary tract disease,the administration of a statin is possible in chronic liver diseases, including NAFLD.However, the administration of statins to patients with decompensated cirrhosis or acute liver failure should be avoided.Statins can be used in NAFLD and NASH, and they are considered as a first-line treatment to lower LDL-C and prevent atherosclerotic CVD. If the response to the statin is insufficient, ezetimibe can be added.Omega-3 fatty acids are not recommended as a treatment for NASH because only some study results showed an effect on NASH,whereas others did not.However, they may be considered for use in hypertriglyceridemia with NAFLD.[Recommendations] 1. Because the incidence and mortality rate of CVD in NAFLD are high, it is necessary to actively control the risk factors of CVD. (A1) 2. In the case of dyslipidemia in NAFLD, a statin can be used to prevent CVD. (B1) 3. Omega-3 fatty acids are not recommended as a treatment for NASH, but they can be used in NAFLD with hypertriglyceridemia. (B1) ## New nash drugs in development The pathophysiology of NASH is complicated, and its interactions with other metabolic diseases have not been fully elucidated. Therefore, NASH treatments are currently under development for a wide range of targets. The main targets are changes in intestinal microflora and intestinal permeability, oxidative stress, insulin resistance, apoptosis, lipotoxicity, inflammation, bile acid metabolism, and liver fibrosis. At the time of this writing, six new drugs are in phase 3 clinical trials or have published intermediate results. Among them, the STELLAR-3, 4 trial of an apoptosis signal-regulating kinase 1 inhibitor (selonsertib) in NASH subjects with advanced liver fibrosis 344 and the RESOLVE-IT trial of a PPAR-α/δ agonist (elafibranor) in NASH patients with stages 1-3 of liver fibrosis have failed to demonstrate therapeutic efficacy in the interim results. Consequently, the development of both drugs was discontinued. In the REGENERATE trial in NASH subjects with hepatic fibrosis stage 1-3, the farnesoid X receptor agonist (obeticholic acid; Ocaliva ® ) showed dose-dependent primary treatment efficacy, an improvement in liver fibrosis of at least 1 stage, in the 10 mg and 25 mg treatment groups (18% and 23%) compared with the control group (12%) after 18 months of treatment.However, the US Food and Drug Administration rejected conditional approval of the drug as a treatment for NASH, judging that severe itching and the increased risk of CVD caused by increased LDL-C outweighed the benefits of treatment. To date, no drugs under development have met their efficacy targets in more than 50% of patients. Considering the complicated pathophysiology of NASH and the various treatment responses observed in clinical trials for individual drugs, it is highly likely that combination treatments or personalized treatments will become the standard. ## Bariatric surgery and lt What are the indications for and post-operative management of bariatric surgery? Bariatric surgery has been performed in NASH patients with obesity who did not respond to medical treatment for weight loss. In Western countries, bariatric surgery is considered to be indicated for patients with a BMI greater than 35 kg/m 2 that is accompanied by hypertension or diabetes mellitus or a BMI greater than 40 kg/m 2 .Several studies reported significant weight loss in addition to improvement in NAFLD.In Korea, the Health Insurance Review and Assessment Service allows bariatric surgery to be covered by the national health insurance for patients who have had no response to medical treatment and lifestyle modifications and whose BMI is greater than 35 kg/m 2 or 30 kg/m 2 and associated with hypertension, diabetes mellitus, or NAFLD. In a 5-year follow-up study of biopsy-confirmed NASH patients who underwent bariatric surgery, BMI, the amount of fat in the liver, and NAS were all found to be reduced, and histological improvement in the fibrosis stage was noted after surgery.Recent meta-analyses identified that bariatric surgery effectively reduced the amount of fat in the liver, inflammation, and fibrosis in NASH patients.However, histological worsening after surgery was observed in some patients. Therefore, well-designed, randomized controlled studies should be performed to confirm the benefits of bariatric surgery in NASH patients.The limitation of bariatric surgery is the risk of lethal liver failure that can be generated by rapid weight loss. Also, the safety of bariatric surgery for cirrhotic patients is still controversial, so a careful approach is needed.Before deciding to undertake bariatric surgery, intraoperative complications, long-term malnutrition, and other factors need to be considered comprehensively. ## What are the indications for lt and post-lt management? LT can be considered in patients with end-stage liver disease caused by NAFLD-associated cirrhosis, liver failure, or HCC, according to the clinical practice guideline for LT. NASH patients experience a high risk of mortality from cardiovascular complications, so a meticulous pretransplant cardiovascular evaluation is needed.Posttransplant outcomes for NAFLD patients, including 3-and 5-year survival, were comparable to those of non-NAFLD patients, whereas the risk of graft failure was lower.Overall survival was associated with BMI and the presence of diabetes mellitus. LT patients with a BMI greater than 35 kg/m 2 experienced a higher transplant failure rate and lower 1-year survival rate than LT patients with a BMI lower than 35 kg/m 2 .Posttransplant management is similar to that for other NASH patients. Maintaining a healthy weight and diet is important, especially given that weight gain is common following LT.Hepatic steatosis 367 or metabolic syndrome 368 is very common after LT, especially in patients with a history of NASH. Thus, careful attention should be paid to posttransplant management. [Recommendations] 1. Liver transplantation could be considered in NASH patients with end-stage liver disease or HCC, according to the clinical practice guideline for LT. (A1) ## Nafld in children and adolescents ## Epidemiology What is the prevalence rate? The National Health and Nutrition Survey conducted between 2015 and 2017 defined cases with ALT of 26 IU/L (boys) and 22 IU/L (girls) as NAFLD, and the estimated prevalence of this disease in children was 11.2% (14.7% for boys and 7.4% for girls).In 2001-2005, the prevalence was 7.8% (10.6% for boys and 4.6% for girls), so the prevalence is increasing, and 40-45% of obese adolescents have NAFLD.The obesity rate of children and adolescents aged 7-18 years increased from 8.4% in 2008 to 14.3% in 2016, so the prevalence of NAFLD is expected to increase rapidly in the future. 371,372 ## Summary ## The prevalence of nafld among children and adolescents in Korea is increasing as their obesity rate increases. ## How does nafld progress? The natural course and prognosis of NAFLD in children and adolescents are not well known. Unlike NAFL, NASH can progress to cirrhosis in children and adolescents.In a foreign study that followed 66 children and adolescents with NAFLD for 20 years, the exacerbation of liver disease and risk of early death increased by 14 times compared with the control group.There was also a case in which HCC occurred in a 7-year-old child diagnosed with NAFLD.In recent years, LT has increased in children, adolescents, and young adults due to end-stage liver disease related to NAFLD.Summary 1. NASH in children and adolescents can progress to end-stage liver disease, including cirrhosis, in young adults. What genetic diseases are associated with risk factors? The risk factors for NAFLD in children and adolescents are obesity, adolescent age, and being male.This disease is common in adolescence because the increased sex hormones that occur at puberty cause changes in insulin resistance and body composition, with the hormones of boys perhaps causing more NAFLD than those of girls. In patients with abdominal obesity and ob-structive sleep apnea, NAFLD is likely to be associated with acanthosis nigricans.Unlike in adults, in children and adolescents, steatosis sometimes appears as a phenotype of genetic disease. Therefore, through medical history, examination, and testing, Wilson's disease, Bardet-Biedl syndrome, polycystic ovary syndrome, Prader-Willi syndrome, Turner syndrome, Cohen syndrome, alpha1-antitrypsin deficiency, glycogen storage disease, genetic tyrosinemia type 1, homocystinuria, Refsum disease, citrullinemia, and lysosomal acid lipase deficiency should be differentiated. 373 Summary 1. Obesity, adolescent age, and being male are risk factors for nonalcoholic fatty liver disease in children and adolescents. 2. If steatosis is found in children and adolescents, potential accompanying genetic diseases should be considered. ## Genetic factors Is related NAFLD related to family history and genetic predisposition? Children and adolescents with a family history of NAFLD are at high risk of developing it. In children and adolescents diagnosed with NAFLD, 59% of their siblings and 78% of their parents also had NAFLD. On the other hand, in obese children and adolescent patients without NAFLD, NAFLD was found in only 17% of their siblings and 37% of their parents.NAFLD occurs from a variety of causes, but family outbreaks, twin studies, and differences in prevalence among races confirm that more than 50% of patients with this disease are likely to have a genetic predisposition to it.In a genome-wide association study, an increase in liver fat mass was associated with mutations in the PNPLA3, TM6SF2, LY-PLAL1, and GCKR genes.Genetic polymorphisms reported in children and adolescents include MBOAT7, PNPLA3, TM6SF2, and GCKR.Studies also showed an association with monoallelic ABHD5 mutations. 391 ## Summary ## Children and adolescents are at increased risk of nafld if there is a family history of it. 2. NAFLD in children and adolescents can be associated with genetic variations and genetic polymorphism. ## Screening and diagnosis Who should be targeted for NAFLD screening, and how is screening conducted? NAFLD is common in children and adolescents who are overweight (above the 85th percentile and below the 95th percentile of BMI) or obese (above the 95th percentile of BMI). Therefore, screening is necessary for those groups. Overweight and obesity are checked during school health checkups in the 4th and 6th grades of elementary school, the 1st grade of middle school, and the 1st grade of high school in Korea. In overweight young people, screening tests are performed using liver enzyme levels. ALT is used as a screening method for NAFLD in overweight and obese children and adolescents. In 2007, the US Expert Committee also recommended AST and ALT as screening tests.However, because the normal ranges of ALT by age and sex are unclear, European authorities recommended abdominal ultrasound along with ALT as a screening test.In the 2019 guidelines for obesity in children and adolescents, those who were overweight or obese and had an ALT of 26 IU/L (boys) or 22 IU/L (girls) or more were diagnosed with NAFLD and recommended for abdominal ultrasound when necessary.In 2017, the North American Society of Pediatric and Gastrointestinal Nutrition recommended ALT as a screening test for obese and overweight children aged 9-11 years with insulin resistance, pre-diabetes, diabetes, or dyslipidemia.Based on the limited research results available for the cost-effectiveness of screening tests in overweight and obese children and adolescents, the American Liver Association did not recommend screening for NAFLD using ALT in obese children and adolescents. 399 However, the 2019 guidelines for pediatric and adolescent obesity did recommend screening tests for NAFLD and other concomitant diseases in overweight and obese children and adolescents. What are the diagnostic methods? The standard test for diagnosing NAFLD is liver biopsy. However, because that method is invasive, its application to children and adolescents is limited. The pathologic findings of NAFLD in children and adolescents can differ from those found in adults. Representative differences are that steatosis is more widely observed, balloon degeneration of hepatocytes and hepatic lobular inflammation are milder, and inflammation and fibrosis of the portal region are often present. Sinusoid fibrosis in zone 3, which is commonly observed in adults, is relatively rare in NAFLD in children and adolescents. As a non-invasive method for diagnosing NAFLD, a method using cytokeratin-18, which is produced during hepatocyte death, can be used.In addition, various non-invasive panels are being studied, but they have not yet been recommended for clinical practice. Other additional methods include abdominal ultrasound, liver fibrosis scans, and MRI-PDFF. [Recommendations] 1. In addition to liver biopsy, non-invasive tests such as abdominal ultrasound, liver fibrosis scans, and MRI-PDFF can be performed. (B1) ## Treatment Who should be treated, and how? Overweight and obese children and adolescents with NAFLD are subject to treatment, and these patients are recommended to correct their lifestyle habits first. There are insufficient studies on the long-term prognosis of NAFLD in children and adolescents, and few prospective randomized controlled studies have been done. However, when the disease is diagnosed at an early age, the possibility of long-term complications is high. Most of children and adolescents with NAFLD are associated with obesity, so it is important to correct lifestyle habits to improve obesity. Various studies have been conducted on the correction of lifestyle habits. Based on randomized controlled studies, the North American Society of Pediatric Gastrointestinal Nutrition recommended in 2017 that simple sugar-added beverages be restricted, moderate physical activity be increased, and screen time (time exposed to the screens of electronic devices such as TVs, computers, and smartphones) be reduced to less than 2 hours per day.According to the TONIC trial, a large multicenter randomized controlled study comparing vitamin E, metformin, and placebo in NAFLD patients aged 8-17 years, the three groups did not differ in terms of a sustained decrease in ALT. In the vitamin E group, http://www.e-cmh.org https://doi.org/10.3350/cmh.2021.0178 Volume_27 Number_3 July 2021 histological improvement was observed. However, long-term use of high-dose vitamin E is not recommended because of concerns about side effects.In addition, a small randomized controlled study tested ursodeoxycholic acid, docosahexaenoic acid, and fish oil, and no significant effect was found.In conclusion, no drug treatment is currently recommended for NAFLD in children and adolescents. Although there is no guideline for surgical treatment of NAFLD, it can be performed in cases of severe obesity (BMI 97th percentile or higher) based on the results of research in adults.In the domestic guidelines for obesity in children and adolescents, obesity surgery is recommended when BMI is 40 or more, or 35 or more and accompanied by major complications related to obesity, and lifestyle improvements and drug treatment have produced no effects.Because children and adolescents are growing, growth should be considered when deciding on the timing of surgery. In general, surgery should be considered only when skeletal growth is almost complete (i.e., 13-14 years old for girls, 15-16 years old for boys), and it is recommended that surgery be performed when the Tanner stage (division stage considering the degree of development of male and female genitals according to the stage of puberty) is 4 or higher.Moon Young Kim is a speaker for Samjin and Gilead. He has received a research grant from Yuhan. ## Conflicts of interest Jin-Woo Lee has served as an advisory committee member of Abbvie and Novo Nordisk. He has received a research grant from Galectin Therapeutics Inc, BMS, MSD and Ipsen. The other authors declare that they have no competing interests.	None	https://www.e-cmh.org/upload/pdf/cmh-2021-0178.pdf	AGREE II, Appraisal of Guidelines for Research and Evaluation II; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the receiver operating characteristic curve; BMI, body mass index; CAP, controlled attenuation parameter; CKD, chronic kidney disease; CT, computed tomography; CVD, cardiovascular disease; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4 index; FLI, fatty liver index; GLP-1, glucagon-like peptide-1; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; GREACE, GREek Atorvastatin and Coronary-heart-disease Evaluation; HCC, hepatocellular carcinoma; HIS, hepatic steatosis index; KASL, the Korean Association for the Study of the Liver; LDL-C, low density lipoprotein cholesterol; LT, liver transplantation; MAFLD, metabolic (dysfunction)-associated fatty liver disease; METs, metabolic equivalents of task; MRE, magnetic resonance elastography; MRI-PDFF, MRI proton density fat fraction; MRI, magnetic resonance imaging; MRS, MR spectroscopy; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; NFS, NAFLD fibrosis score; NLFS, NAFLD liver fat score; PIVENS, Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis; PNPLA3, the patatin-like phospholipase domain–containing 3; PPAR-γ, peroxisome proliferator activated receptor gamma; SAMM50, sorting and assembly machinery component 50; SWE, shear wave elastography; T2DM, type 2 diabetes mellitus; TM6SF2, transmembrane 6 superfamily, member 2
99b7eae8427e0fc9e74ba3bad4c4da7367ba3d68	pubmed	Ultrasonography and the Ultrasound-Based Management of Thyroid Nodules: Consensus Statement and Recommendations	Ultrasonography and the Ultrasound-Based Management of Thyroid Nodules: Consensus Statement and Recommendations # Introduction Thyroid nodules are a common clinical problem and the incidence of thyroid nodules has increased with the recently increased use of thyroid ultrasonography . Several Yet the clinical importance of thyroid nodules lies in the detection of malignancy, and malignancy comprises approximately 5% of all thyroid nodules irrespective of the size [bib_ref] American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for..., Gharib [/bib_ref]. The risk factors associated with an increased likelihood of a malignancy in thyroid nodules include a previous history of irradiation, a family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) type II, patients who are younger than 20 years or older than 60 years, male patients, rapid growth of a nodule, a nodule with a fi rm and hard consistency, an inconspicuous margin of the nodule on palpation, the presence of enlarged cervical lymph nodes and the presence of a fi xed nodule [bib_ref] American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for..., Gharib [/bib_ref] [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. Among the modern imaging modalities, high-resolution US is the most sensitive diagnostic modality for the detection of the thyroid nodules and it is necessary to perform US for the nodules found after palpation [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. In addition, US can evaluate the size and characteristic of nonpalpable nodules, it can guide FNA for thyroid nodules and it can diagnose lymph node metastasis. Although thyroid US has been regarded as the mainstay for the management of the thyroid nodules, there has been no clear consensus on the US-based management such as follow-up for thyroid US and the selection of a nodule for FNA biopsies, as well as the standardized terminology for thyroid US. There are many different guidelines and recommendations for the management of thyroid nodules detected on US, and these recommendations and guidelines have been described by different organizations [bib_ref] American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for..., Gharib [/bib_ref] [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. The thyroid study group of the Korean Society of Radiology (TSGKSR) organized a task force group in 2005 and the task force members undertook a complete literature review in 2006 and 2009. The relevant articles from 1985 to 2009 were collected by searching MEDLINE using the following search terms: thyroid nodule, thyroid malignancy, thyroid carcinoma, US, aspiration biopsy, biopsy and follow-up. Since the TSGKSR fi rst organized the taskforce team to provide recommendations for thyroid US and to undertake a multicenter study [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref] , the thyroid study group published its recommendations for the US management of thyroid nodules in 2006and the group revised the recommendations in 2009. Meanwhile, the TSGKSR has been transformed into the Korean Society of Thyroid Radiology (KSThR). By the inclusion of new references (up to May 2010), we provide here this article for any radiologists who perform thyroid US. We have reviewed the standardized terminology for thyroid US as proposed by our task force, the US fi ndings of thyroid nodules and the strategy for US follow-up and US-FNA biopsies. We also discuss the current issues for the role of US screening for thyroid nodules. ## Analysis of the us findings of thyroid nodules the nodule size The size of a thyroid nodule is not helpful for distinguishing a malignant nodule from a benign nodule. The nodule size should be precisely documented for the purpose of follow-up. Although malignancy is believed to grow more prominently than benignancy, even benign nodules can grow with time and about 90% of benign nodules have demonstrated an increase in volume by 15% over a 5-year follow-up period [bib_ref] Importance of thyroid abnormalities detected at US screening: a 5-year follow-up, Brander [/bib_ref] [bib_ref] Fate of untreated benign thyroid nodules: results of long-term follow-up, Kuma [/bib_ref]. Cystic nodule showed slower growth than did solid nodule [bib_ref] Natural history of benign solid and cystic thyroid nodules, Alexander [/bib_ref]. The rapid growth of thyroid nodules can be seen for anaplastic thyroid carcinoma, lymphoma, sarcoma and rarely for high-grade carcinoma [bib_ref] US features of thyroid malignancy: pearls and pitfalls, Hoang [/bib_ref]. Although in principle the size of thyroid nodules should be measured in all three dimensions, only the maximal diameter of the nodule can be measured and documented. When measuring the nodule size, it is advisable to locate the calipers at the outer margin of the halo of the nodule (4). There has been no clear consensus on the defi nition of nodule growth. According to the American Thyroid Association (ATA) guideline, a reasonable defi nition of growth is a 20% increase in the nodule diameter with a minimum increase in two or more dimensions of at least 2 mm, which is roughly a 50% increase in volume [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. Some groups prefer a 15% increase in the nodule volume as a defi nition of nodule growth [bib_ref] Natural history of benign solid and cystic thyroid nodules, Alexander [/bib_ref] [bib_ref] Long-term changes in nodular goiter: a 5-year prospective randomized trial of levothyroxine..., Papini [/bib_ref]. Yet substantial interobserver bias has previously been observed, and especially for less than a 50% volume increase in small nodules [bib_ref] Interobserver variation for ultrasound determination of thyroid nodule volumes, Brauer [/bib_ref]. Accordingly, we recommend the defi nition of nodule growth as a 20% increase in the nodule diameter or a 50% increase in the nodule volume. ## Internal content Although a mainly cystic nodule is rare in thyroid carcinoma, a cystic component is found in 13-26% of all thyroid carcinomas [bib_ref] Common and uncommon sonographic features of papillary thyroid carcinoma, Chan [/bib_ref] [bib_ref] Role of ultrasound in the management of thyroid nodules, Watters [/bib_ref]. Approximately 5% of all partially cystic nodules have been reported to be malignant in a recent study [bib_ref] Partially cystic thyroid nodules on ultrasound: probability of malignancy and sonographic differentiation, Lee [/bib_ref]. In this case, the presence of a solid Consensus Statement and Recommendations for US-Based Thyroid Nodule Management component with vascularity, an eccentric location of the solid portion or microcalcifi cation may suggest malignant nodule and especially papillary thyroid carcinoma [bib_ref] Common and uncommon sonographic features of papillary thyroid carcinoma, Chan [/bib_ref] [bib_ref] Partially cystic thyroid nodules on ultrasound: probability of malignancy and sonographic differentiation, Lee [/bib_ref] [bib_ref] Cystic papillary carcinoma of the thyroid gland: a new sonographic sign, Hatabu [/bib_ref]. A nodule with multiple microcystic spaces separated by thin septae or intervening isoechoic parenchyma (a 'spongiform' appearance) is regarded as a benign nodule with a specifi city of 99.7-100% [bib_ref] Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules..., Bonavita [/bib_ref] [bib_ref] Are there any specifi c ultrasound fi ndings of nodular hyperplasia ("leave..., Moon [/bib_ref]. We suggest the following terminology for the internal content of a nodule. The internal content of a nodule is categorized in terms of the ratio of the cystic portion to the solid portion in the nodule: solid (≤ 10% of the cystic portion), predominantly solid (> 10% of the cystic portion and ≤ 50% of the cystic portion), predominantly cystic (> 50% of the cystic portion and ≤ 90% of the cystic portion) and cystic (> 90% of the cystic portion) (9) [fig_ref] Figure 1: Internal content of thyroid nodules [/fig_ref]. The defi nition of a spongiform appearance is the aggregation of multiple microcystic components in more than 50% of the volume of the nodule (9) . ## Nodule shape The shape of a nodule has gained diagnostic importance for the differentiation of benign and malignant nodules since this was fi rst described in a study by . and colleagues reported that a taller-than-wide shape showed a specifi city of 93% for the diagnosis of malignant nodules. In a larger multicenter study, a taller-than-wide shape was shown to be highly suggestive of a malignancy, with a specifi city of 89% and a positive predictive value of 86% [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref].These fi ndings refl ect that malignant nodules grow across the normal tissue plane in a centrifugal way, while benign nodules grow along the tissue plane in a parallel fashion [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref] [bib_ref] Thyroid nodule shape and prediction of malignancy, Alexander [/bib_ref] [bib_ref] Solid breast nodules: use of sonography to distinguish between benign and malignant..., Stavros [/bib_ref]. A nodule with an irregular shape is often seen in benign conditions such as focal thyroiditis as well as in malignant conditions [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. We suggest that the shape of a nodule is categorized as follows: ovoid to round (when the anteroposterior diameter of a nodule is equal to or less than its transverse diameter on a transverse or longitudinal plane), taller-than-wide (when the anteroposterior diameter of a nodule is longer than its transverse diameter on a transverse or longitudinal plane) or irregular (when a nodule is neither ovoid to round nor taller-than-wide) [fig_ref] Figure 3: Shape of thyroid nodules [/fig_ref]. ## Nodule margin Earlier studies have reported that both a spiculated or microlobulated margin and an ill-defi ned margin are suggestive of malignancy [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref] [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref]. With the development of high-frequency transducer US techniques, a previously described ill-defi ned margin could actually be a spiculated and jagged edge with sharp demarcation (a spiculated or microlobulated margin) or a poorly defi ned margin in which the tumor cannot be differentiated from the normal parenchyma (an ill-defi ned margin) [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. When the marginal tumor infi ltration is minimal, it can be seen as an ill-defi ned margin. In addition, benign thyroid nodules are known to be incompletely encapsulated and poorly marginated and they can merge with normal tissue [bib_ref] Sonography of thyroid nodules: a "classic pattern" diagnostic approach, Reading [/bib_ref]. Therefore, an illdefi ned margin is a nonspecifi c fi nding that is seen for both benign and malignant nodules. In contrast, a spiculated margin is a highly suggestive fi nding of malignancy with a A. Ovoid-to-round shape B. Taller-than-wide shape C. Irregular shape ## Fig. 2. us fi ndings of spongiform appearance are shown. transverse us image of benign nodular hyperplasia shows welldefi ned smooth isoechoic mass with a spongiform appearance (arrows). Consensus Statement and Recommendations for US-Based Thyroid Nodule Management specifi city of 92% and a positive predictive value of 81% [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. Accordingly, we suggest that the margin of a nodule is categorized as follows: smooth, spiculated/microlobulated or ill-defi ned [fig_ref] Figure 4: Margin of thyroid nodules [/fig_ref]. ## Echogenicity In terms of echogenicity, a solid component must be considered. When a solid component is heterogeneous, the nodular echogenicity is defi ned by that of the majority of the nodule. Marked hypoechogenicity is highly specifi c for malignant nodule with a specifi city of 92-94% [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref]. Although the parenchymal echogenicity of a thyroid gland can vary among individuals, it is used as a reference for nodule echogenicity. Another reference to defi ne nodule echogenicity is the strap muscles with low-echogenicity such as the sternothyroid muscle, the sternothyroid muscle and the sternocleidomastoid muscles [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref]. We suggest that nodule echogenicity is categorized according to the relative echogenicity compared to that of a reference as follows. Nodule echogenicity includes marked hypoechoic (when a nodule is hypoechoic relative to the adjacent strap muscle), hypoechoic (when a nodule is hypoechoic relative to the thyroid parenchyma), isoechoic (when a nodule has the same echogenicity as that of the thyroid parenchyma) and hyperechoic (when a nodule is echogenic relative to the thyroid parenchyma) [fig_ref] Figure 5: Echogenicity of thyroid nodules [/fig_ref]. ## Calcification Calcifi cations can be seen in both benign and malignant nodules. Calcifi cations may be microcalcifi cation, coarse or macrocalcifi cation or peripheral or rim calcifi cations in thyroid nodules. Pathologically, microcalcifi cation is a psammoma body that is comprised of 10-100 μm round, laminar, crystalline, calcifi c deposits, which is very specifi c for thyroid carcinoma, and especially for papillary thyroid carcinoma. Microcalcifi cations on US are fi ndings that are highly suggestive for malignancy with a specifi city of 86-95% and a positive predictive value of 42-94% [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref] [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref] [bib_ref] Thyroid calcifi cation and its association with thyroid carcinoma, Khoo [/bib_ref] [bib_ref] Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules?, Peccin [/bib_ref]. Large and irregular shaped dystrophic calcifi cations may develop secondarily due to tissue necrosis and these calcifi cations can be seen in both benign and malignant nodules. A solid nodule with macrocalcifi cation larger than 1 mm suggests the presence of a malignancy rather than a benign nodule [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. The meaning of peripheral, eggshell or rim calcifi cation is still being debated for making the differentiation between benign and malignant nodules. Recent reports have found that when a nodule has eggshell or rim calcifi cations, a hypoechoic halo and/or disruption of eggshell calcifi cations, these are fi ndings that suggest malignancy (9, 30-32). On US, a calcifi cation is defi ned as a prominent echogenic focus with or without posterior shadowing. The absence of posterior shadowing does not rule out the possibility of calcifi cation since some calcifi cations are too small to produce posterior shadowing. When punctuate echogenic foci are accompanied by reverberation artifacts, they should be due to colloid materials and they can be easily differentiated from calcifi cation on real-time US. We suggest that calcifi cation is categorized with respect to its size as follows. Calcifi cations include microcalcifi cations (when there are tiny, punctuate echogenic foci of 1 mm or less either with or without posterior shadowing), macrocalcifi cations (when punctuate echogenic foci are larger than 1 mm in size) and rim calcifi cations (when a nodule has peripheral curvilinear or eggshell calcifi cation) [fig_ref] Figure 6: Calcifi cations of thyroid nodules [/fig_ref]. ## Extracapsular invasion Extracapsular extension is observed in 36% of all thyroid [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref]. Aggressive local invasion is relatively common in anaplastic carcinoma, lymphoma and sarcoma. Radiologist should observe whether a nodule crosses the thyroid capsule and invades the adjacent structure such as the trachea, esophagus and thyroid cartilage. ## Other chracteristics The echotexture of a nodule may be homogeneous or heterogeneous. Echotexture is not a helpful fi nding in distinguishing malignant nodules from benign nodules [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. Sometimes a nodule show an accompanying hypoechoic thin or thick halo. A halo or hypoechoic rim surrounding a nodule is comprised of a pseudocapsule that is caused by fi brous connective tissue, compressed thyroid tissue and chronic infl ammatory change [bib_ref] The nonspecifi city of the thyroid halo sign, Propper [/bib_ref]. Although a completely even halo is a fi nding suggestive of benign nodule with a specifi city of 95% in one study [bib_ref] Ultrasonographic fi ndings of papillary thyroid carcinoma and their relation to pathologic..., Lu [/bib_ref] , more than a half of benign nodules lack a halo [bib_ref] Role of ultrasound in the management of thyroid nodules, Watters [/bib_ref] [bib_ref] The nonspecifi city of the thyroid halo sign, Propper [/bib_ref]. On the other hand, 10-24% of all papillary carcinomas have a complete or incomplete halo [bib_ref] US features of thyroid malignancy: pearls and pitfalls, Hoang [/bib_ref] [bib_ref] Common and uncommon sonographic features of papillary thyroid carcinoma, Chan [/bib_ref] [bib_ref] Role of ultrasound in the management of thyroid nodules, Watters [/bib_ref] [bib_ref] Ultrasonographic fi ndings of papillary thyroid carcinoma and their relation to pathologic..., Lu [/bib_ref]. ## Tumor vascularity Color Doppler US or power Doppler US can be used for the evaluation of the intratumoral vascularity of thyroid nodules. Although intratumoral hypervascularity is observed in 69-74% of thyroid carcinomas, it is a nonspecifi c fi nding [bib_ref] Common and uncommon sonographic features of papillary thyroid carcinoma, Chan [/bib_ref]. Though perinodular fl ow is mainly a characteristic fi nding for benign nodules, it is observed in 22% of malignant nodules [bib_ref] Common and uncommon sonographic features of papillary thyroid carcinoma, Chan [/bib_ref]. According to several recent studies, the resistive index, the maximal systolic velocity and the vascularity pattern on Doppler US did not help to differentiate benign and malignant nodules [bib_ref] Power Doppler US patterns of vascularity and spectral Doppler US parameters in..., Tamsel [/bib_ref] [bib_ref] Can vascularity at power Doppler US help predict thyroid malignancy?, Moon [/bib_ref]. Therefore, we do not recommend the routine use of color Doppler and power Doppler US for thyroid nodules. ## Us elastography US elastography is a new technique to measure the elasticity of tissue. The tissue of carcinoma is harder and fi rmer than that of the normal thyroid parenchyma or a benign nodule. Elastography quantifi es the fi rmness of the tissue and this is visualized as an elastography map. The strain index on elastography has been suggested as a good predictive factor for malignant thyroid nodules (37) . ## Us findings for benign and malignant nodules The known US fi ndings for malignant nodules are microcalcifi cations, the presence of hypoechoic nodule, an irregular margin, loss of the halo and the presence of a solid nodule as well as intratumoral vascularity [bib_ref] Thyroid nodule shape and prediction of malignancy, Alexander [/bib_ref] [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref] [bib_ref] Thyroid calcifi cation and its association with thyroid carcinoma, Khoo [/bib_ref] [bib_ref] Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules?, Peccin [/bib_ref] [bib_ref] Ultrasound-guided fi ne-needle aspiration biopsy in nonpalpable thyroid nodules: is it useful..., Kim [/bib_ref] [bib_ref] Sonographic features of benign thyroid nodules: interobserver reliability and overlap with malignancy, Wienke [/bib_ref] [bib_ref] Risk for malignancy of thyroid nodules as assessed by sonographic criteria: the..., Iannuccilli [/bib_ref]. However, the different use of terminology, the variable sample size of the previously published data, the use of US instruments with different qualities and the different range of experience of radiologists and even diagnostic overlap of these fi ndings cause variable results of the diagnostic accuracy [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref] [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref] [bib_ref] Thyroid calcifi cation and its association with thyroid carcinoma, Khoo [/bib_ref] [bib_ref] Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules?, Peccin [/bib_ref] [bib_ref] Can color Doppler sonography aid in the prediction of malignancy of thyroid..., Frates [/bib_ref]. In the multicenter retrospective study that applied standardized terminology for US fi ndings as proposed earlier in this report [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref] , the signifi cant fi ndings for malignant nodules were a taller than wide shape (sensitivity, 40%; specifi city, 91%), a spiculated margin (sensitivity, 48%; specifi city, 92%), marked hypoechogenicity (sensitivity, 41%; specifi city, 92%), microcalcifi cation (sensitivity, 44%; specifi city, 91%), and macrocalcifi cation (sensitivity, 10%; specifi city, 96%). The US fi ndings for benign nodules were isoechogenicity (sensitivity, 57%; specifi city, 88%) and a spongiform appearance (sensitivity, 10%; specifi city, 100%). Although hypoechogenicity is a suggestive fi nding for being malignancy in many reports [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref] [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref] [bib_ref] Sonographic features of benign thyroid nodules: interobserver reliability and overlap with malignancy, Wienke [/bib_ref] , marked hypoechogenicity is a more specifi c and more reliable criterion for a malignant nodule [bib_ref] New sonographic criteria for recommending fi ne-needle aspiration biopsy of nonpalpable solid..., Kim [/bib_ref]. In terms of the nodule size, a lower frequency of microcalcifi cation in microcarcinomas causes a lower sensitivity and this suggests that microcalcifi cation is not a major predictor of malignancy in nodules 1 cm or smaller. Although other fi ndings such as marked hypoechogenicity, a taller-thanwide shape and a spiculated margin are slightly more frequent in subcentimeter malignant nodules, and they are also more frequent in subcentimeter benign nodules than in the larger counterparts. Accordingly, the false positive rate of depiction of a malignant nodule could be increased in smaller nodules [bib_ref] The usefulness of sonographic features in selection of thyroid nodules for biopsy..., Popowicz [/bib_ref]. Although rim calcifi cation itself was not helpful for making a US diagnosis in a multicenter study, recent studies suggest that the presence of a hypoechoic halo and disruption of rim calcifi cation may be useful sonographic predictors of malignancy [bib_ref] Sonographic differentiation of thyroid nodules with eggshell calcifi cations, Kim [/bib_ref]. In addition, according to previous studies, the fi ndings of a complete cystic lesion and a cystic lesion containing comet tail artifacts are very specifi c for benignancy [bib_ref] Clinical signifi cance of the comet-tail artifact in thyroid ultrasound, Ahuja [/bib_ref]. Therefore, we suggest the US criteria for benign and malignant thyroid nodules as is shown in [fig_ref] Figure 8: Flowchart for strategy for follow-up US and US-guided fi ne needle aspiration [/fig_ref]. We divided thyroid nodules into A B . US elastography of thyroid nodules. A. Elastography shows nodule with hard consistency as blue relative to green background. B. Longitudinal US image shows same nodule with suspicious malignant US features. Nodule was proven to be papillary carcinoma. Consensus Statement and Recommendations for US-Based Thyroid Nodule Management three categories: suspicious malignant nodules, probably benign nodules and indeterminate nodules. A taller-thanwide shape, a spiculated margin, marked hypoechogenicity, microcalcifi cations and macrocalcifi cations are suggestive fi ndings for malignancy. The presence of at least one of the fi ndings for malignancy defi nes a nodule as a suspicious malignant nodule. In contrast, a simple cyst, a predominantly cystic or cystic nodule with reverberating artifacts and a nodule with a spongiform appearance (especially with intervening isoechoic parenchyma) are defi ned as probably benign nodules. Although a cystic nodule with more than a 90% cystic component is very rare for a thyroid malignancy, a mural solid component within the cystic nodule may be papillary thyroid carcinoma [bib_ref] Clinical signifi cance of the comet-tail artifact in thyroid ultrasound, Ahuja [/bib_ref]. Therefore, a small solid component in a predominantly cystic or cystic nodule should be carefully examined and it should be aspirated in the case with the presence of a suspicious malignant feature. Indeterminate nodules include nodules having US fi ndings with neither malignant nor benign features. The US fi ndings for an indeterminate nodule include isoechogenicity, hypoechogenicity, and hyperechogenicity, an ovoid-to-round or irregular shape, a smooth or ill-defi ned margin and a rim calcifi cation. Although, isoechogenicity is more suggestive of benignancy, 14% of the isoechoic nodules were malignant in one study [bib_ref] Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study, Moon [/bib_ref]. Although rim calcifi cation is classifi ed as an indeterminate factor for malignancy, the presence of a hypoechoic halo and rim disruption is more suggestive of malignancy [bib_ref] Sonographic differentiation of thyroid nodules with eggshell calcifi cations, Kim [/bib_ref]. The indeterminate category is currently a term for all nodules that are without clear evidence of being benign and malignant. The criteria for suspicious malignant nodules are identical to the US fi ndings for papillary carcinoma, which comprises most thyroid carcinomas. The US fi ndings for medullary carcinoma are almost the same as those for papillary carcinoma [bib_ref] Ultrasonographic fi ndings of medullary thyroid carcinoma: a comparison with papillary thyroid..., Kim [/bib_ref]. Yet these criteria have limited value in diagnosing thyroid carcinomas other than a subtype of papillary carcinoma. Relatively uncommon FTC and other histologic types of thyroid carcinoma can be eliminated by the use of these criteria [bib_ref] Evaluating the degree of conformity of papillary carcinoma and follicular carcinoma to..., Jeh [/bib_ref] [bib_ref] Sonographic features of follicular variant papillary thyroid carcinomas in comparison with conventional..., Kim [/bib_ref]. Along with an accumulation of evidence from further studies on thyroid US, the indeterminate category can be subclassifi ed into truly benign nodule or adenoma or malignant nodule. ## Indications for us-guided fine-needle aspiration biopsy according to the us criteria Our task force members established recommendations on the indications for US-guided fi ne-needle aspiration (USFNA) biopsy and follow-up for thyroid nodules fi rst in 2006and these were revised in 2009. In our recommendations, whether or not to perform a USFNA biopsy depends on the US fi ndings of a nodule [fig_ref] Figure 8: Flowchart for strategy for follow-up US and US-guided fi ne needle aspiration [/fig_ref]. When a single nodule is found on thyroid US, the presence of at least one malignant US fi ndings necessitates USFNA regardless of the size of the nodule. Evidence has shown that the mortality and rate of recurrence is directly proportional to the size of a thyroid tumor [bib_ref] Management of a solitary thyroid nodule, Mazzaferri [/bib_ref] [bib_ref] Long-term impact of initial surgical and medical therapy on papillary and follicular..., Mazzaferri [/bib_ref]. However, even a micropapillary thyroid carcinoma has a substantial number of lymph node metastases (8-50%) and a recurrence rate from 1% up to approximately 7% [bib_ref] Clinical features and therapeutic implication of papillary thyroid microcarcinoma, Pazaitou-Panayiotou [/bib_ref] [bib_ref] Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience, Baudin [/bib_ref] [bib_ref] Changes in clinical presentation, management and outcome in 1348 patients with differentiated..., Chow [/bib_ref] [bib_ref] An observation trial without surgical treatment in patients with papillary microcarcinoma of..., Ito [/bib_ref] [bib_ref] Small carcinomas of the thyroid. A long-term follow-up of 867 patients, Noguchi [/bib_ref]. The ATA guideline recommends that a subcentimeter nodule should be subjected to a biopsy only if the nodule has a suspicious fi nding or the patient has a personal history of radiation exposure or familial thyroid cancer [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. Among the subcentimeter cancers, a carcinoma smaller than 5 mm has a better survival rate and a better recurrence rate at 5 year (less than 3% versus 14% for carcinoma that is 6-10 mm in diameter). Regarding the size issue, recent studies have recommended not to biopsy nodules smaller than 5 mm in size because of a high rate of false positive US fi ndings as well as a high rate of inadequate cytology [bib_ref] Ultrasound-guided fi ne-needle aspiration biopsy of thyroid nodules: comparison in effi cacy..., Kim [/bib_ref] [bib_ref] Should all patients with subcentimeter thyroid nodules undergo fi ne-needle aspiration biopsy..., Mazzaferri [/bib_ref]. We recommend performing FNA for a nodule of any size that has suspicious malignant fi ndings if FNA is feasible and a nodule is larger than 5 mm in size. For a nodule smaller than 5 mm, selective FNA can be done according to patient's risk factors and the experience of the radiologists. This recommendation relies on the fact that there is still debate concerning the fate and prognosis of microcarcinomas, as was described above. If a nodule has indeterminate fi ndings on US and it is larger than 1 cm in diameter, then performing FNA is recommended due to the fact that the possibility of malignancy cannot be excluded. If a nodule has indeterminate fi ndings and it is 1 cm or less in size, then an FNA biopsy is not necessary and follow-up US would suffi ce. If a benign appearing nodule is larger than 1 cm, then we recommend performing follow-up US in two years and thereafter at 3-5 year intervals. If a benign appearing nodule (i.e., a spongiform nodule) is larger than 2 cm, then selective FNA biopsy can be done. Neither FNA nor follow up US is necessary for a spongiform nodule and a benign appearing nodule 1 cm or less in diameter. When multiple nodules are found on US, not all of the nodules have to be biopsied. The risk of malignancy for patients with multiple thyroid nodules is not greatly different from that for patients with a single thyroid nodule [bib_ref] Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and..., Papini [/bib_ref]. According to the ATA guideline [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref] , in the presence of two or more nodules 1-1.5 cm or more in size, a FNA biopsy is recommended for nodules with suspicious US fi ndings. If none of the nodules has suspicious US fi ndings, then FNA should be done for the largest one. Multifocality and bilaterality is not uncommon and even in thyroid microcarcinomas [bib_ref] Clinical features and therapeutic implication of papillary thyroid microcarcinoma, Pazaitou-Panayiotou [/bib_ref]. Furthermore, some investigators believe multifocality and bilaterality are linked to higher recurrence and higher mortality [bib_ref] Long-term impact of initial surgical and medical therapy on papillary and follicular..., Mazzaferri [/bib_ref] [bib_ref] Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience, Baudin [/bib_ref]. Therefore, multiple and bilateral nodules should not be regarded as a multinodular goiter consisting of benign nodules. In the case of multiple nodules of the thyroid, we choose the nodules to be biopsied according to the US fi ndings. We recommend aspirating one or more nodules that meet the US criteria of a nodule, but not to depend on the size criteria. We recommend aspirating at least one nodule for each lobe and at least one nodule (the largest) among multiple nodules that have similar US fi ndings. A nodule should not be chosen for a biopsy only on the size criteria alone. Some thyroid nodules may grow steadily as seen on follow-up US, even though they were diagnosed as being benign on the previous cytology. In these cases, a decision should be made on whether or not to perform a biopsy. The rate of nodule growth on US cannot distinguish benign from malignant nodules [bib_ref] The rate of tumour growth does not distinguish between malignant and benign..., Asanuma [/bib_ref]. In one study of 420 benign nodules, one-third of benign nodules showed growth of a 15-30% increase in volume, one-third of the benign nodules showed no change in growth and one-third showed a decrease in size [bib_ref] Natural course of benign thyroid nodules in a moderately iodine-defi cient area, Erdogan [/bib_ref]. The measurement of small nodule reportedly is not reliable as substantial interobserver bias has been observed in the measurement of small nodules, and especially for less than a 50% volume increase [bib_ref] Interobserver variation for ultrasound determination of thyroid nodule volumes, Brauer [/bib_ref]. Despite the debate concerning signifi cant size change, we advise to selectively biopsy a growing nodule according to the size change criteria adopted from the ATA guideline [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. We do recommend an FNA biopsy be performed if an indeterminate nodule is growing. If a benign nodule is growing, then we do not recommend performing an immediate FNA biopsy in every incidence. At least one more follow-up US exams can be selectively advised. When a malignant lymph node is suspected, it is necessary to biopsy any suspicious lymph node in the lateral neck area as well as a thyroid nodule regardless of the nodule's size and features. While central neck dissection is performed in almost all the patients with thyroid papillary carcinoma, lateral neck dissection (levels II-V) is selectively done for patients who have a preoperative diagnosis of lymphatic metastasis. Therefore, USFNA for suspicious lymph nodes in the lateral neck area (levels II-V) is important for making decisions about surgical management (8). ## Follow-up us and us fine-needle aspiration biopsy according to the us findings and cytology results When the initial US fi ndings are probably benign, a US-FNA biopsy is not necessary and follow-up US or clinical observation is advisory for a nodule's change. Among the probably benign nodules on US, a complete cystic or cystic nodule with reverberating artifacts and spongiform nodules can be placed under clinical observation alone. In contrast, the patients with a probably benign nodule larger than 1 cm are recommended to undergo follow-up by US in two years and thereafter at a 3-5 year interval. When the initial US fi ndings are suspicious for malignant or they are indeterminate, the fate of thyroid nodules is dependent on the adequately classifi ed cytology results [bib_ref] The Bethesda System for Reporting Thyroid Cytopathology, Cibas [/bib_ref]. If the cytology of the nodule results in nondiagnostic aspirates, then the presence of malignant US fi ndings determines the next step for the management of the Consensus Statement and Recommendations for US-Based Thyroid Nodule Management nodule. Non-diagnostic cytology results occur in 5-10% of cases under US guidance and these non-diagnostic cases are due to the operator's inexperience, aspiration of cystic fl uid and the presence of a bloody aspirate [bib_ref] Ultrasound-guided fi ne-needle aspiration biopsy in nonpalpable thyroid nodules: is it useful..., Kim [/bib_ref]. Five percent of nodules with nondiagnostic cytology after an initial biopsy are eventually diagnosed as malignant and approximately 18% of malignant nodules are diagnosed by at least two aspiration cytology examinations [bib_ref] Assessment of nondiagnostic ultrasoundguided fi ne needle aspirations of thyroid nodules, Alexander [/bib_ref] [bib_ref] The value of ultrasound-guided fi ne-needle aspiration cytology for thyroid nodules: an..., Ogawa [/bib_ref]. Therefore, thyroid nodules with non-diagnostic cytology and malignant US fi ndings should be followed by US-FNA biopsy at a 3-6 month interval. When a nodule does not have any malignant US fi ndings, but it has non-diagnostic cytology, it is recommended that the nodule should be followed up by US-FNA biopsy in 6-12 months. When the cytology result for a nodule is malignant, the patient should undergo surgery and follow-up by US [bib_ref] Revised American Thyroid Association management guidelines for patients with thyroid nodules and..., Cooper [/bib_ref]. When the cytology results of thyroid nodules are indeterminate (suspicious for a papillary carcinoma, atypical cells, follicular lesion or follicular neoplasm), the subtype of the indeterminate cytology and the presence of malignant US fi ndings determines the next step for the nodules' management. An indeterminate cytology fi nding, although the cytology results can vary as determined at different institutions, is responsible for approximately 15-30% of all the fi ne needle aspiration cytologies. The cytology results of a suspicious for papillary carcinoma or Hurthle cell neoplasm necessitates surgery (lobectomy or total thyroidectomy) followed by US. When the cytology of a nodule is indicative of a follicular neoplasm, it is recommended to consider surgery fi rst although repeated US-FNA biopsies are preferable in certain situations. When the cytology of a nodule is a follicular lesion of undetermined signifi cance or atypia of undetermined signifi cance (59), a nodule 1 cm or more is recommended to undergo a repeated US-FNA biopsy in 6-12 months in the case of malignant US fi ndings, while a nodule without malignant US fi ndings can be subjected to a repeated US-FNA in 1-1.5 years. When the cytology of a nodule is indicative of being benign, the follow-up strategy is as follows and according to the US fi ndings. A nodule with malignant US fi ndings is recommended to undergo repeat US-FNA in 6-12 months, while a nodule without malignant fi ndings is recommended to undergo repeat US in one year or to repeat US-FNA selectively. Since the false-negative rate of USFNA is low but not negligible, it is reasonable to repeat US-FNA in certain conditions, and especially for thyroid nodules with malignant US fi ndings [bib_ref] Value of US correlation of a thyroid nodule with initially benign cytologic..., Kwak [/bib_ref]. A nodule with a benign cytology and that has been subjected to at least two US-FNA biopsies is regarded as a benign nodule and it can be followed up in 3-5 years. ## Role of thyroid us as a screening test The role of a screening test for thyroid nodules is limited. Because of the very high prevalence of thyroid nodules and the very good prognosis and survival rate, the current consensus is that a screening test for thyroid malignancy cannot be justifi ed [bib_ref] American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for..., Gharib [/bib_ref]. As smaller malignant nodules can be detected on thyroid US, the survival rate and prognosis may improve regardless of the actual effect of the treatments, and even with an increasing prevalence of disease [bib_ref] Advances in diagnostic imaging and overestimations of disease prevalence and the benefi..., Black [/bib_ref]. Thyroid cancer detected by the use of an early screening test may tend to progress less rapidly than clinically detected disease. There may be cases that would regress, remain stable or progress too slowly to become clinically apparent during the lifetime of the patient (63). However, a screening test can be justifi ed in high-risk groups such as patients with a history of familial thyroid carcinoma, a history of MEN or a history of childhood irradiation of the head and neck area. # Conclusion US for thyroid nodules is the most sensitive diagnostic modality for making the diagnosis of thyroid carcinoma and this modality provides valuable guidance to perform an aspiration biopsy and follow-up. On the US of thyroid nodule, the size of the nodule, the internal texture, the shape, the echogenicity, the margin, the presence of calcifi cation and the presence of adjacent structures should be carefully scrutinized. The fi ndings for a suspicious malignant nodule include a tallerthan-wide shape, a spiculated or microlobulated margin, marked hypoechogenicity, microcalcifi cations and macrocalcifi cations. Presence of at least one of the malignant US fi ndings suggests the presence of a malignancy. According to these fi ndings and the resultant category of a nodule, the nodule should be aspirated or followed-up with US, or it should remain under clinical observation. [fig] Figure 1: Internal content of thyroid nodules. A. Solid B. Predominantly solid C. Predominantly cystic D. [/fig] [fig] Figure 3: Shape of thyroid nodules. Corresponding schematic drawings are shown in upper panel. [/fig] [fig] Figure 4: Margin of thyroid nodules. A. Smooth margin B. Spiculated or microlobulated margin (arrow) C. Ill-defi ned margin (arrows) [/fig] [fig] Figure 5: Echogenicity of thyroid nodules.A. Marked hypoechogenicity of nodule is shown. Note more hypoechoic nature of nodule (arrow) as compared to that of strap muscles (asterisk). B. Hypoechogenicity of nodule (arrows) C. Isoechogenicity of nodule (arrows) D. Hyperechogenicity of nodule (arrow) [/fig] [fig] Figure 6: Calcifi cations of thyroid nodules. A. Microcalcifi cation within nodule as echogenic focus B. Macrocalcifi cation (arrow) in center of nodule (white triangles) C. Rim calcifi cation in small nodule (calipers). [/fig] [fig] Figure 8: Flowchart for strategy for follow-up US and US-guided fi ne needle aspiration (USFNA) biopsy according to US fi ndings and cytology results of thyroid nodules.Dotted arrow means that surgery is not strongly recommended, but it can be considered according to individual situations. AUS = atypia of undetermined signifi cance, FLUS = follicular lesion of undetermined signifi cance. [/fig]	None	https://europepmc.org/articles/pmc3017873?pdf=render	The detection of thyroid nodules has become more common with the widespread use of ultrasonography (US). US is the mainstay for detecting and making the differential diagnosis of thyroid nodules as well as for providing guidance for a biopsy. The Task Force on Thyroid Nodules of the Korean Society of Thyroid Radiology has developed recommendations for the US diagnosis and US-based management of thyroid nodules. The review and recommendations in this report have been based on a comprehensive analysis of the current literature, the results of multicenter studies and from the consensus of experts.
52e1eae9c9dffde2ee51f753543d79772371b969	pubmed	Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology	Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology # Introduction Early in December 2019, the first cases of novel pneumonia from unknown etiology were described in the city of Wuhan, China. Subsequent studies have The recommendation panel was composed of 13 voting members, guideline methodologists (five members), and researchers responsible for the literature systematic review (nine members). The participants were indicated by the specialty societies or by the group methodologists, aiming to provide representativity and balance of technical competencies. Potential conflicts of interest data were collected with the standard WHO formulary. Members with a direct financial conflict of interest related to a given intervention had no right to vote for the related questions. A list of participants, their role in the guideline, and statement of conflicts of interest are provided in appendix 1. ## Research questions The questions were first proposed by the group of methodologists, and revised by the panel experts. The inclusion criteria were: a drug available for prescription in Brazil, and a clinical practice variability, or a clinically relevant doubt related to its use, being this last the prioritizing factor for clinical questions. Eight questions were prepared according to the acronym PICO (population, intervention, comparator, and outcome), considering six drug classes (aminoquinolines, antivirals, antibiotics, corticosteroids, anticoagulants, and immunobiologicals). Each research question could generate one or more recommendations. Remdesivir was not included in this document as, by the assessment time, it was not approved for prescription in Brazil. Were considered, but not prioritized, questions related to the use of nonsteroidal anti-inflammatory drugs and angiotensin receptor blockers (ARBs) or angiotensinconverting enzyme inhibitors. During the conduction of the recommendations panel, the question on the use of heparin was requested to be included, once it was not part of the initial scope. ## Evidence search and synthesis The searches were conducted on MEDLINE (via Pub-Med®), the Cochrane CENTRAL, and Embase databases, and also in the grey-literature bases, between April 22 and 30, 2020. Additionally searches on prepublication articles sources, such as OpenGrey (http://www.opengrey.eu), meDrxiv (https://www.medrxiv.org), and Biorxiv (www. biorxiv.org) were conducted; these articles were considered during the analyses, even though not peer-reviewed. The search strategies are shown in appendix 2. Additional evidence, emerging during the process and identified by members of the group, were considered during the discussions, although not included in the initial search results. Literature search, data extraction, and synthesis were performed by one single investigator and checked by a second revisor in case of doubts or inconsistencies. The synthesis was conducted in a qualitative model. First, titles and abstracts of the identified manuscripts were identified by the search strategy, and potentially eligible studies preselected. Second, the full text of the selected papers was assessed, to confirm eligibility. Considering the limited number of studies published so far, the following study designs were taken into consideration according to the evidence hierarchy: randomized clinical trials, quasi-randomized clinical trials, non-randomized clinical trials, cohort studies, casecontrol studies, series and case studies. The assessment of methodological quality and/or risk of bias of the included articles was conducted with tools appropriate for each study design: AMSTAR-2 for systematic reviews with and without metanalysis; Cochrane's risk of bias table for randomized clinical trials; ROBINS-I for non-randomized or quasi-randomized clinical trials; ROBINS-I or Newcastle-Ottawa for longitudinal comparative observational studies (case-control and cohort); the Joanna Briggs Institute case-series tool for phase I or phase II trials without a direct comparator and case-series and the Joanna Briggs Institute toll for cross-sectional studies. ## Assessment of certainty of the evidence and development of recommendations The GRADE system was used for the assessment of the quality of the evidence and the development of recommendations. Previously to the recommendations meetings, the certainty of the evidence was rated either as high, moderate, low, or very low. According to this methodology, recommendations may be either strong or weak (conditionals), favorable or against the intervention. The implication of the strength of the recommendation is shown in table 2. The data from the systematic review for each PICO question were compiled into evidence profiles and presented to the experts' panel. For the development of recommendations were considered: benefits, risks, quality of the evidence, costs, and variability of implementation. The recommendations were agreed upon by teleconferences held on May 5, May 8, and Whenever appropriate, the panel could provide recommendations according to subpopulations. A consensus was aimed for all the recommendations; if no consensus could be achieved, a voting procedure was conducted, and a simple majority required for approval of that specific recommendation. ## Population of interest The target population for the recommendations is constituted of patients either diagnosed or clinically suspected of SARS-CoV-2 infection. Clinical suspicion is when, based on epidemiological data, clinical history, signs, and symptoms, in addition to complementary tests, COVID-19 is the most likely diagnostic hypothesis. Information on diagnosis can be found elsewhere. The disease severity was grouped into five categories, in line with the National Institutes of Health (NIH) guidelines for the treatment of COVID-19. For the categorization of acute respiratory distress syndrome (ARDS) the Berlin's criteria were adopted as presented in table . # Results Eleven recommendations were issued. These recommendations are summarized in table 5. Detailed information on the evidence is shown in appendix 3, as GRADE evidence profiles, with complete references. ## Level definition implications High Strong confidence that the true effect lies close to that of the effect estimate. It is unlikely that additional trials will change the confidence in the estimated effect. Moderate Moderate confidence in the effect estimate. Future trials may modify the confidence in the effect estimate, and also can change the estimate. ## Low Limited confidence in the effect estimate. Future trials are likely to importantly impact our confidence in the effect estimate. Very Low Uncertain confidence in the effect estimate. Any effect estimate is uncertain. Source: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Updated October 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html. ## Policymakers The recommendation should be adopted as a healthcare policy in most of the situations. Substantial debate required and the involvement of stakeholders. ## Clinicians Most of the individuals would want the intervention to be indicated, and only a small number would reject the recommendation. A large portion of the individuals would want the intervention to be indicated; however, some individuals would reject the recommendation. ## Patients Most of the patients should receive the recommended intervention. The clinician should acknowledge that different choices are appropriate for each patient and choose consistently with his/her values and preferences. . Available from: https:// www.covid19treatmentguidelines.nih.gov/. ## Aminoquinolines (hidroxychloroquine and chloroquine) Recommendation 1 -we suggest against the routine use of hydroxychloroquine or chloroquine for treatment of COVID-19 patients (weak recommendation; Level of Evidence: low). Summary of the evidence: the systematic review identified three comparative clinical trials with available data on the effects of hydroxychloroquine (HCQ) in COVID-19 patients: two open randomized clinical trials in a patient population with mild to moderate disease, and one cohort study. No trials comparing chloroquine (CQ) to non-CQ therapy were found. The combined data from both clinical trials failed to show clinical-radiological improvement (relative risk -RR = 0.61; 95% confidence interval [95%CI] 0.26 -1.43), or improved viral negativation rates within seven days (RR = 2.00; 95%CI 0.02 -20.00), however, one of the studies prepublication version has shown on the raw data analysis an increased improvement rate with HCQ (80.6% versus 54.8%; p = 0.0476). Mortality and mechanical ventilation requirements, considered to be clinically relevant outcomes, were assessed in an observational study with 364 patients, showing an increased mortality rate with HCQ (HCQ: 27.8%; HCQ + azithromycin: 22.1%; standard therapy: 11.4%), with a significant association remaining after the propensity score-adjusted analysis comparing HCQ to the standard therapy (hazard ratio -HR = 2.61; 95%CI 1.10 -6.17). After the review date, an additional cohort study was identified involving 1,376 moderate to severe COVID-19 hospitalized patients. In this study, no association was found with death or invasive mechanical ventilation requirement (HR = 1.04; CI95% 0.82 -1.32). This trial was considered in the evidence analysis and because it was a well-designed observational study, with adjustment for confounders and appropriate sample size, the degree of confidence for the lack of benefit was increased from very low, to low. The association between HCQ and arrhythmias is well-known. An observational study has shown that seven out of 37 (19%) patients receiving HCQ monotherapy developed a QT interval ≥ 500ms. Additionally, in a randomized clinical trial that compared patients using high-dose (1,200mg CQ for 10 days; total dose 12g) versus a lower dose (900mg on the first day, followed by 450mg daily for four days; total dose 2.7g), a 13.5% (95%CI 6.9 -23.0%) overall mortality rate was found in association with the high-dose (in this trial both groups had a cointervention with ceftriaxone and azithromycin), suggesting a potential dose-response gradient. Comments: the recommendations panel interpreted that the available evidence suggests no clinically significant benefit of HCQ or CQ therapy. There was an agreement that the risk of cardiovascular adverse events is moderate, particularly regarding arrhythmias. So far, the existing comparative trials have only assessed hospitalized patients, therefore providing no basis for considerations on using or not these drugs in outpatients. The prescription of these products may be considered on a shared clinicianpatient decision, only for severe or critically ill patients, hospitalized, under constant QTc interval monitoring, and avoiding concomitant QTc prolonging therapies. Its use should preferably be under clinical trial protocols. ## Aminoquinolines (hydroxychloroquine and chloroquine) in association with azithromycin Recommendation 2 -we suggest against the routine use the hydroxychloroquine or chloroquine plus azithromycin combination for treatment of COVID-19 patients (weak recommendation; Level of Evidence very low). Summary of the evidence: no clinical trials were identified to assess azithromycin monotherapy. Azithromycin added to an HCQ regimen was assessed in one single trial, showing improved viral negativation in the group treated with the combination therapy (HQ + azithromycin 100%; n = 6/6 versus HQ 57%; n = 8/14; six-day negativation). No randomized clinical trials were identified for the comparison of HCQ + azithromycin versus standard therapy. Viral negativation was assessed by four studies, three from the same research group, showing viral negativation above 90% after five to 10 days therapy; in contrast, in one study treating ten patients with HCQ + azithromycin, negativation was found in only two patients (20%). (39) A total of six studies assessed mortality, with 35 deaths among 1,342 patients. Regarding adverse cardiovascular events, eight studies were identified. Five of them found a prolonged QT interval in some patients treated with HCQ/CQ plus azithromycin. A retrospective analysis of 130 thousand rheumatoid arthritis patients showed an increased risk of cardiovascular death with HCQ + azithromycin as compared with HCA + amoxicillin (HR = 2.19; 95%CI 1.22 -3.94; 30-day outcome). (44) The same analysis has also shown an increased risk of angina (HR = 1.15; 95%CI 1.05 -1.26) and heart failure (HR = 1.22; 95%CI 1.02 -1.45). In a non-comparative trial with 1,061 patients with HCQ + azithromycin, no patient has shown to have heart toxicity. Comments: the recommendations panel interpreted that the available evidence does not suggest a clinically significant benefit from the treatment with HCQ or CQ in combination with azithromycin. There was an understanding that there is an associated moderate increase of cardiovascular adverse events, especially arrhythmias, potentialized by the association of HCQ/ CQ with azithromycin, and additional care related to these adverse events is required. So far, the existing comparative trials have only assessed hospitalized patients, providing no basis for discussions on using or not this combination in outpatients. Its use may be considered in a shared clinician-patient decision, only in severe or critically ill patients, hospitalized, with frequent QTc interval monitoring and avoiding QTc prolonging concomitant therapy. Its use should be preferentially under clinical trial protocols. ## Oseltamivir Recommendation 3 -we recommend against the use of oseltamivir for the treatment of COVID-19 in patients with no suspected influenza coinfection (strong recommendation; Level of Evidence very low). Recommendation 4 -We suggest the use of empirical oseltamivir treatment in patients with Severe Acute Respiratory Syndrome (SARS) or flu-like syndrome with risk factors for complications when a diagnosis of influenza cannot be ruled out (weak recommendation; Level of Evidence very low). Summary of the evidence: no randomized clinical trial assessing the effectivity of oseltamivir in COVID-19 patients was identified. A cohort study with 504 COVID-19 hospitalized patients assessed the use of oseltamivir, lopinavir/ritonavir, and umifenovir. The mortality rate in the oseltamivir group (n = 66) was 12.2% versus 16.2% in the non-oseltamivir group (odds ratio -OR = 0.71; 95%CI 0.28 -1.59). Also, no difference was found regarding lung injury improvement as assessed by a chest CT scan (41.2% versus 43.3%). The study has important methodological issues, such as lacking randomization, sample representativity, and control for confounders. Comments: the recommendations panel interpreted that there is no evidence to support the use of oseltamivir for SARS-CoV-2 therapy; besides, there is no theoretical rationale to support this use. However, oseltamivir may be considered in cases of suspected influenza infection in patients with ARDS or flu-like syndrome with risk-factors for influenza complications (chronic diseases, immunosuppression, age ≥ 65 years, and pregnant women). (46) The usual dose for adults with appropriate renal function is 75mg twice daily for five days. Suspected influenza should take into consideration the patient's symptoms, radiological findings, as well as local epidemiology. A suspect may remain even in individuals with a history of immunization, once the vaccine's effectiveness is rarely above 80%. If testing for influenza is possible, oseltamivir may be stopped upon negative results, given the available test has appropriate sensitiveness for seasonal A, B, and H1N1 influenza. The decision on oseltamivir use was made based on indications for its use out of the context of the COVID-19 pandemic, with no appropriate information on the behavior of influenza in the scenery of a SARS-CoV-2 epidemics. (46) If well-developed local protocols are in place, we suggest them to be adhered to. ## Lopinavir/ritonavir Recommendation 5 -we suggest against the routine use lopinavir/ritonavir for treatment of COVID-19 (weak recommendation; Level of Evidence low). Summary of the evidence -two randomized clinical trials assessed the use of lopinavir/ritonavir in COVID-19 patients. (50,51) One of them assessed 90 patients in the lopinavir/ritonavir group and 100 patients with standard therapy. Patients in the intervention group had lower but not statistically significant mortality rates (19.2% versus 25%; 28-day mortality rate), and no clinically significant improvement within 14 days (45.5% with the intervention versus 30% in the control group; p < 0.05); the time to clinical improvement was reduced in one day (median: 15 days versus 16 days; HR = 1.39; 95%CI 1.00 -1.91; modified intention-to-treat analysis, excluding three early mortality patients). (50) Another randomized clinical trial included 21 patients in the lopinavir/ritonavir group and seven in the control group, with no statistically significant difference between the groups for outcomes such as fever, coughing relief rate, clinical condition deterioration rate, and CT scan improvement. (51) In both trials, there was no viral negativation difference between the groups. The adverse effects observed included anorexia, nausea, abdominal discomfort or diarrhea, acute gastritis, and reduced appetite; the lopinavir/ritonavir discontinuation rate was 13.8%. Comments: the recommendations panel interpreted that the available evidence suggests no clinically significant benefit from the lopinavir/ritonavir therapy. This therapy could be considered promising, and the lack of observed benefits may result from the small number of assessed patients. Despite the high discontinuation rate due to adverse events and potential drug interactions, lopinavir/ ritonavir is a relatively safe therapy for short term courses. This drug may be considered upon a clinician-patient shared decision, in hospitalized severe and critically ill patients, in centers with professionals experienced with this therapy. It should be preferably used under clinical trial protocols. ## Corticosteroids Recommendation 6 -we suggest against the routine use corticosteroids for COVID-19 patients' treatment (weak recommendation; Level of Evidence very low). Summary of the evidence: no clinical trials specifically assessing the use in COVID-19 patients were found. Four observational studies reported that the use of corticosteroids during hospitalization is associated with increased mortality; these studies combined hospitalized patients' populations, however, with heterogeneous clinical features. (52-55) One trial, however, suggests that the use of methylprednisolone reduced the risk of death in patients with ARDS (HR = 0.38; 95%CI 0.20 -0.72). (56) The outcomes for respiratory symptoms are variable in hospitalized patients. The studies' limitations include the lack of randomization and control groups, variable doses used, small samples, and retrospective analysis of the data. Despite the systematic review conducted did not involve other coronaviruses infections, indirect information on SARS and Mid-East respiratory syndrome (MERS) show an absence of impact on mortality (RR = 1.07; 95%CI 0.81 -1.42) and a prolonged time to viral negativation (3.78 days; 95%CI 1.16 -6.41 days). Comments: the recommendations panel interpreted that there is no evidence supporting the routine use of corticosteroids for COVID-19 patients. Corticosteroids should be avoided during the first seven to 10 days after the symptoms start, when the viral response is more relevant, as there is evidence that corticosteroids may delay viral negativation. Some evidence points out to a potential benefit for moderate to severe ARDS patients out of the viral infection context. (60) Its use may be considered for selected cases with moderate to severe ARDS, without suspected uncontrolled bacterial infection, 10 to 14 days after the COVID-19 symptoms start. The doses used in the studies ranged between 10mg and 20mg dexamethasone or 40mg to 120mg methylprednisolone daily, for five to 10 days. Their use should preferentially be under clinical research protocols. Patients with other indications for corticosteroids use (e.g.: asthma and exacerbated chronic obstructive pulmonary disease -COPD) should use these drugs according to the clinical indication, assessing other potential risks and benefits during COVID-19 infection. ## Tocilizumab (anti-interleukin-6) Recommendation 7 -we suggest against the routine use tocilizumab for COVID-19 treatment (weak recommendation; Level of Evidence very low). Summary of the evidence: no comparative trials evaluating tocilizumab effectiveness in COVID-19 patients were found; only two case series were identified. One of the series included 21 patients, all with chest CT changes, 20 on ventilatory support (45% with high-flow oxygen, 35% with a nasal cannula, 5% with an oxygen mask, 5% with non-invasive mechanic ventilation and 10% with invasive mechanical ventilation). Within five days, 75% of them had their ventilatory support requirements reduced; no deaths occurred during the follow-up period. (61) In another case series 15 patients were included, two moderately ill, six with severe disease, and seven in a very severe condition. Of the 15 patients, three died, two had increased severity, nine had clinical stabilization and one showed clinical improvement. Serum interleukin-6 (IL-6) was reduced in 10 patients after tocilizumab; increased IL-6 was found in the five patients with treatment failure, all of them with an initially very severe condition. Comments: the recommendation panel interpreted that no benefit and safety evidence was shown that would suggest the routine use of tocilizumab. Besides, this drug is costly, and especially during an epidemic, the use of resources should be rationalized, and the use of interventions with no benefit evidence avoided. This drug may be considered in a shared clinician-patient decision for severe and critically ill hospitalized patients, with a confirmed diagnosis of SARS-CoV-2 infection, and significantly increased markers or inflammation (e.g.: IL-6, D-dimer, C reactive protein, lactate dehydrogenase -LDH, and ferritin). The use of tocilizumab should be restricted to centers with professionals who are experienced in its use. Tocilizumab use should preferentially be under clinical trial protocols. ## Heparins Recommendation 8 -we recommend the routine use of venous thromboembolism prophylaxis in COVID-19 hospitalized patients (strong recommendation; Level of Evidence very low). Recommendation 9 -we suggest against the routine use therapeutic heparin doses for COVID-19 treatment (weak recommendation; Level of Evidence very low). Summary of the evidence: two retrospective cohorts were identified. (63,64) One of them assessed 449 severe or critically ill hospitalized COVID-19 patients; 99 of them were given heparin for at least seven days (94 enoxaparin 40mg -60mg daily and five unfractionated heparin 10,000 -15,000IU/daily), and 350 control patients (without any anticoagulant or heparin, or less than seven days of use). In this study, the 28-day mortality rate was similar (heparin 30.3% versus controls 29.7%). In the subgroup with an International Society on Thrombosis and Hemostasis -Sepsis-Induced Coagulopathy score (ISTH SIC) ≥ 4 (from one of the following features: platelets < 100,000, International Normalized Ratio -INR > 1.4 or a Sequential Organ Failure Assessment -SOFA -score ≥ 2), the mortality in the heparin group was lower (40% versus 64.2%; p = 0.029; n = 97). Increased effectiveness was also seen in patients with increased D-dimer, with a significantly reduced mortality in a group with D-dimer values above or equal to six-times the upper limit of the normal (32.8% versus 52.4%; p = 0.017). In a study that assessed 42 patients, all of them with an immunosuppressor or corticosteroids, and severe to moderate COVID-19, 21 patients were given low molecular weight heparin (13 enoxaparin 40mg daily, two enoxaparin 20mg daily, four nadroparin 4,100IU daily and two low molecular weight sodium heparin 5,000IU daily, median: 11 days) and 21 controls, D-dimer and IL-6 levels were significantly reduced, and lymphocytes counts were increased, with no hospital length of stay differences. Comments: the recommendations panel interpreted that there is no indication for therapeutic dose heparins (e.g.: enoxaparin 1mg/kg subcutaneously -SC -every 12 hours) for the treatment of COVID-19. The rationale for other anticoagulants is analogous. Anticoagulation is associated with an increased risk of bleeding events and should be restricted to patients with a clear indication (e.g.: atrial fibrillation, pulmonary thromboembolism, deep venous thrombosis, among others), according to appropriate protocols. COVID-19 patients apparently have an increased risk of thromboembolic events, and the assisting team should be aware of developing signs and symptoms. COVID-19 hospitalized patients should be given thromboembolism prophylaxis according to risk-stratification strategies, adhering to local hospital protocols. However, the use of prophylactic doses can be extended to all COVID-19 patients, as some SARS-CoV-2 patients appear to have a hypercoagulability state, with increased thromboembolic events rate as seen in observational clinical trials and post mortem examinations. (66,67) As an example, enoxaparin 40mg to 60mg SC oncedaily doses, or unfractionated heparin 5,000IU SC twice or three times a day, could be used. Although there is limited evidence for pharmacological prophylaxis in COVID-19 patients, this is a low-cost and well-tolerated intervention that may potentially prevent major clinical events. Heparin should not be used for cases with contraindications (e.g.: increased risk of bleeding, active bleeding, and severe thrombocytopenia); (68) low molecular weight heparin should be used carefully in renal dysfunction patients. ## Antibiotics Recommendation 10 -we suggest against the use prophylactic antibiotics in patients with a suspected or confirmed COVID-19 diagnosis (weak recommendation; Level of Evidence very low). ## Recommendation 11 -we recommend the use of antibiotics in covid-19 patients with suspected bacterial infection (non-rated recommendation). Summary of the evidence: no randomized clinical trials were found to assess the empirical antibiotics therapy effectiveness in COVID-19 patients without evidence of bacterial infections. Therefore, so far there is no clinical data enough to show benefits or risks of antibiotics in COVID-19 patients with no signs of bacterial infection. We did not access the evidence for bacterial infections therapy. Comments: the panel interpreted that considering the lack of evidence, there is no base for prophylactic antibiotic therapy in COVID-19 patients. In addition to the lack of benefit evidence, this could result in adverse events, increased antimicrobial resistance, and costs. There is no appropriate data on bacterial coinfection in COVID-19 patients, however, one should bear in mind that overlapping infections may occur. It is understood that those patients should be given antibiotics, similarly to COVID-19 patients, taking into consideration the local epidemiology and adhering to local protocols and guidelines from infection control services.shows a didactic summary of the recommendations according to the evaluated interventions, presenting their judgment regarding perceived benefits, risks, costs, availability, and evidence. Appendix 4 presents the most important drug interactions of potential COVID-19 therapies. # Discussion During epidemics, when consolidated effective therapies are not available, there is a trend to use therapies based on preclinical studies results, or based on observational studies with important limitations. (69) Experiences from other epidemics have shown that such interventions benefits may be far below the expected, as with oseltamivir during the influenza A (H1N1) epidemics in 2009. (60,70) During the Ebola virus epidemics in 2014, several interventions were tested, including CQ, HCQ, favipiravir, immunobiological agents, and convalescent plasma; none was proven effective. By the time when this guideline is publicized, we face a scenario where no specific COVID-19 proposed intervention is proven effective. Regarding safety, drugs such as HCQ (especially when combined with azithromycin) at the doses proposed for COVID-19 have been shown relevantly associated with cardiovascular events. In the absence of effective therapies, treatment under clinical trial protocols should be encouraged. In this context, healthcare professionals should seek information on therapeutic clinical trials, especially randomized clinical trials, already approved by regulatory agencies and ethical committees possibly ongoing in their institutions. Several other interventions are proposed, such as remdesivir, beta interferon, ivermectin, nitazoxandine, convalescent plasma, umifenovir, among others. This guideline chose to prioritize those interventions raising more clinical practice concerns in Brazil by the time of its development. Of note, the current speed of COVID-19 knowledge generation renders these recommendations prone to become outdated in a short frame of time. As most of the interventions are based on evidence from small observational or interventional trials, we understand that as new well-designed clinical trials, with appropriate sample sizes, are published, there is a huge potential that herein presented recommendations shall be changed. Therefore, it is of paramount importance that readers of this guideline keep this in mind as one of the most important limitations of this document. Also, it is necessary to understand that a clinical guideline aims to guide the clinical practice not necessarily applicable to every patient. The scarcity of evidence with appropriate methodology renders impossible to provide more categorical recommendations; we stress that a significant portion of the studies we evaluated was preliminary published in Ahead of Print bases, with no editorial board and peer review evaluations. Therefore, in this document we present suggested actions, to be contextualized according to features such as the patient's clinical profile, existing comorbidities, and risk of developing adverse effects, in addition to the assisting team's experience with the proposed interventions, patient's preferences, service structure, as well as costs and available resources. Regarding costs, in the context of public health, it is important to emphasize that, in a scenario of an epidemic, resource allocation should be prioritized to interventions more likely to be beneficial, such as Personal Protective Equipment and interventions related to the patient's ventilatory support. Therefore, under the light of the current COVID-19 knowledge, some investments in pharmacological therapies are debatable. However, the treatment of patients under clinical trial protocols, with appropriate study design and the potential to provide an answer to the society, should be encouraged. With this document we hope to guide clinical practice in a national context, therefore reducing the therapeutic variability. In addition to the evidence available in the scientific literature, the recommendations took into consideration some Brazilian specific features, such as the availability of some drugs (either because of lack of regulatory clearance or due to difficult access), population and healthcare professionals acceptance, and costs associated with their use. Also, most of this document's recommendations are in line with WHO therapeutic recommendations. This document consists of a joint positioning by three medical societies, taking into consideration the need for the development of encompassing recommendations and contextualization of different medical specialties regarding of the frailty of the available evidence, that may be an applicable tool both for physicians working in the public health system and the supplementary system. The developing group is committed to strive for periodically bring updates to this document, in a context of living guidelines, where recommendations are updated as new evidence becomes available. Additional interventions will be included as they become relevant doubts for COVID-19 therapy. OR "Bulbul coronavirus HKU11" OR "Thrush coronavirus HKU12" OR "novel coronavirus" OR "covid-19" OR "sarscov 2" OR "Betacoronavirus" [formula] X X Angela Bagattini - - X Bruno Tavares X X X Cassia Pagano X - X Cinara Stein X X X Clovis Cunha X X X Daniela Pachito - - - Débora Graf X - X Felipe Dal Pizzol X - X Flávia Medeiros - - X Gabriela Brito - - - Haliton Oliveira Júnior X X X Jessica Matuoka - - X José Chatkin - - - Lays Pires Marra - - - Leandro Fritscher X X X Luciano Azevedo X - - Maicon Falavigna X X X Marcelo Gazzana X X X Michele Nunes X X X Mirian Dalben X X Patrícia Parreira - - X Rachel Riera X X X Regis Rosa X X X Sergio Cimerman X X X Verônica Colpani X X X [/formula] #2 "Anti-Bacterial Agents" [mesh] OR "Anti-Bacterial Agents" OR "Agents, Anti-Bacterial" OR "Anti-Bacterial Agents" OR "Antibacterial Agents" OR "Agents, Antibacterial" OR "Anti-Bacterial Compounds" OR "Anti-Bacterial Compounds" OR "Compounds, Anti-Bacterial" OR "Bacteriocidal Agents" OR "Agents, Bacteriocidal" OR "Bacteriocides" OR "Anti-Mycobacterial Agents" OR "Agents, Anti-Mycobacterial" OR "Anti Mycobacterial Agents" OR "Antimycobacterial Agents" OR "Agents, Antimycobacterial" OR "Antibiotics" OR "Antibiotic" OR "antimicrobials" OR "antibacterials" OR "Azithromycin" [mesh] OR "Azythromycin" OR "Sumamed" OR "Toraseptol" OR "Vinzam" OR "CP-62993" OR "CP 62993" OR "CP62993" OR "Zithromax" OR "Azitrocin" OR "Azadose" OR "Ultreon" OR "Zitromax" OR "Azithromycin Dihydrate" OR "Dihydrate, Azithromycin" OR "Azithromycin Monohydrate" OR "Monohydrate, Azithromycin" OR "Goxal" OR "Zentavion" #5 "Enoxaparin"[Mesh] OR Enoxaparin OR Enoxaparine OR "PK-10,169" OR "PK 10,169" OR "PK10,169" OR "PK-10169" OR "PK 10169" OR "PK10169" OR "EMT-967" OR "EMT 967" OR "EMT967" OR Lovenox OR Clexane OR "EMT-966" OR "EMT 966" OR "EMT966" #6 "Nadroparin"[Mesh] OR Nadroparine OR "Nadroparin Calcium" OR "Calcium, Nadroparin" OR Fraxiparin OR Fraxiparine #7 "Dalteparin"[Mesh]" OR Tedelparin OR "Dalteparin Sodium" OR "Sodium, Dalteparin" OR Fragmin OR Fragmine #8 #2 OR #3 OR #4 OR #5 OR #6 OR #7 #9 #1 AND #8 OR "Bulbul coronavirus HKU11" OR "Thrush coronavirus HKU12" OR "novel coronavirus" OR "covid 19" OR "sarscov 2" OR "Betacoronavirus*" #2 "Anti-Bacterial Agents" [mesh] OR "Anti-Bacterial Agents" OR "Agents, Anti-Bacterial" OR "Anti-Bacterial Agents" OR "Antibacterial Agents" OR "Agents, Antibacterial" OR "Anti-Bacterial Compounds" OR "Anti-Bacterial Compounds" OR "Compounds, Anti-Bacterial" OR "Bacteriocidal Agents" OR "Agents, Bacteriocidal" OR "Bacteriocides" OR "Anti-Mycobacterial Agents" OR "Agents, Anti-Mycobacterial" OR "Anti Mycobacterial Agents" OR "Antimycobacterial Agents" OR "Agents, Antimycobacterial" OR "Antibiotics" OR "Antibiotic" OR "antimicrobials" OR "antibacterials" OR "Azithromycin" [mesh] OR "Azythromycin" OR "Sumamed" OR "Toraseptol" OR "Vinzam" OR "CP-62993" OR "CP 62993" OR "CP62993" OR "Zithromax" OR "Azitrocin" OR "Azadose" OR "Ultreon" OR "Zitromax" OR "Azithromycin Dihydrate" OR "Dihydrate, Azithromycin" OR "Azithromycin Monohydrate" OR "Monohydrate, Azithromycin" OR "Goxal" OR "Zentavion" OR "Vancomycin" [mesh] OR "Vancomycin" OR "Ceftriaxone" [mesh] OR "Ceftriaxone" OR "Cefepime" [mesh] OR "Cefepime" OR "Levofloxacin" [mesh] OR "Levofloxacin" OR "Fluoroquinolones" [mesh] OR "Fluoroquinolones" OR "Amoxicillin" [mesh] OR "Amoxicillin" OR "Ciprofloxacin" [mesh] OR "Ciprofloxacin" OR "Cephalexin" [mesh] OR "Cephalexin" OR " ## Pergunta 2 -hidroxicloroquina/cloroquina associada à azitromicina comparada a não utilizar em paciente com infecção por covid-19 Bibliografia: Borba et al., 2020 ; Million et al., 2020 ; Lane et al., 2020 ; Gautret et al., 2020 ; ; Chorin et al., 2020 ; Columbia University Kidney Transplant Program, 2020 ; ; ; Chang et al., 2020 ; Avaliação da certeza , , , Chorin et al., 2020 , Columbia University Kidney Transplant Program, 2020 , Borba et al., 2020 (7) ) mostrou ; § Borba, et al, 2020 avaliaram Pergunta 4 -Lopinavir associado a ritonavir comparado a cuidados padrão em paciente com infecção por COVID-19 Bibliografia: ; Li et al., 2020 ; ; Ye et al., 2020 ; Zhu et al., 2020 ; Shi et al., 2020 ; Liu et al., 2020 ; Sun et al., 2020 Avaliação da certeza ; Wu et al., 2020 ; Guan et al., 2020 ; Shang et al., 2020 ; Cao et al.,2020 ; Li et al., 2020 ; Xu et al. , 2020; Zha et al., 2020 ; Lu et al., 2020 ; Wang et al., 2020 ## Pergunta 6 -tocilizumabe comparado a não utilizar em paciente com infecção por covid-19 Bibliografia: Luo et al., 2020 ; Xu et al., 2020 Avaliação da certeza ## Pergunta 7 -heparinas comparadas a não utilizar em paciente com infecção por covid-19 Bibliografia: Shi et al., 2020 ; Tang et al., 2020 Avaliação da certeza	None	None	Introduction Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. Methods A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. Results Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. Conclusion So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.
c90def699a272a2ed524a5427c484cc380336476	pubmed	Recommendations of the 5th Canadian Consensus Conference on the diagnosis and treatment of dementia	Recommendations of the 5th Canadian Consensus Conference on the diagnosis and treatment of dementia Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD) have provided evidence-based dementia guidelines for Canadian clinicians and researchers. We present the results of the 5th CCCDTD, which convened in October 2019, to address topics chosen by the steering committee to reflect advances in the field, and build on previous guidelines. Topics included: (1) utility of the National Institute on Aging research framework for clinical Alzheimer's disease (AD) diagnosis; (2) updating diagnostic criteria for vascular cognitive impairment, and its management; (3) dementia case finding and detection; (4) neuroimaging and fluid biomarkers in diagnosis; (5) use of non-cognitive markers of dementia for better dementia detection; (6) risk reduction/prevention; (7) psychosocial and non-pharmacological interventions; and (8) deprescription of medications used to treat dementia. We hope the guidelines are useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to dementia. # Introduction Since # Methods The methodology was guided by the AGREE II collaboration 5 of which 20 of the 23 criteria were met. The steering committee chose the topics for CCCDTD5 based on a needs assessment and advances in the field. Working groups were formed, chosen by steering committee members. Overall representation was required for neurology, psychiatry, geriatric medicine, primary care, and experienced researchers in the field. Literature searches were tailored to the group needs depending on whether the recommendations were updates or de novo topics (described below). We attempted to follow, where possible, the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system in keeping with current recommendations for the conduct of consensus conferences.A semi-structured consensus building methodology was used, based on the Delphi process.Organizations relevant to the care of people with dementia representing industry, government, international experts, and other dementia guideline organizations had been invited to appoint nonvoting delegates as observers. Online voting closed 3 days before the conference assembly, which was held in Quebec on October 3, 2019. At the conference each topic was briefly summarized along with the results of the online voting. Recommendations requiring revision were discussed in detail followed by an anonymous vote. The same ≥80% threshold was required for revised recommendations. All endorsed recommendations are listed in the tables of this article, followed by GRADE of evidence and percentage endorsement in initial vote (and subsequent vote where relevant). ## Recommendations This summary paper lists the recommendations that reached consensus. Subsequent articles written by each working group will expand on the background work and describe in more depth the clinical impact of these recommendations. ## Nia research framework for ad diagnosis The NIA-AA Research Framework is proposing a biological definition of AD, intended for observational and interventional research, not routine clinical care.It is proposed that the diagnosis of AD is not based on the clinical consequences of the disease (ie, symptoms/signs), but on biomarkers of amyloid beta (Aß) deposition, pathologic tau, and neurodegeneration (ATN). The authors did emphasize that it was premature to use this research framework in general medical practice. ## Diagnosis and treatment of vci VCI is the second most important contributor to cognitive decline and dementia, after AD. Although recent VCI diagnostic criteria have not been validated neuropathologically in large samples, they do exhibit greater reliability than older criteria.Here we provide recommendations for neuroimaging, ,11 prevention,and management of stroke and stroke risk factors including hypertension,and pharmacological management of VCI . ## Dementia case finding and detection The goal was to use the most current evidence to provide practi- 3. Given that the presence of brain amyloid and/or tau in cognitively normal people is of uncertain significance, we discourage the use of amyloid and tau imaging without memory decline, outside of the research setting. The medical community should be clear in its discussion with patients, the media, and the general population that the presence of brain amyloid and/or tau in normal people is of unclear significance at the present time. 1A (100%) 3b. For patients with cognitive disorders in which a vascular contribution is known or suspected, antihypertensive therapy should be strongly considered for average diastolic blood pressure readings ≥90 mmHg and for average systolic blood pressure readings ≥140 mmHg. 1B (96%) 3c. In middle-aged and older persons being treated for hypertension who have associated vascular risk factors a systolic BP treatment target of <120 mmHg may be associated with a decreased risk of developing mild cognitive impairment and should be considered when deciding on the intensity of their therapy. 14 2C (83%) 4. All patients with cognitive symptoms or impairment should receive guideline-recommended treatments to prevent first-ever or recurrent stroke, as appropriate. 1B (98%) 5a. The use of aspirin is not recommended for patients with MCI or dementia who have brain imaging evidence of covert white matter lesions of presumed vascular origin without history of stroke or brain infarcts. 2C (96%) 5b. The effects of aspirin on cognitive decline in patients with MCI or dementia who have covert brain infarcts detected on neuroimaging without history of stroke has not been defined. The use of aspirin in this setting is reasonable, but the benefit is unclear. 2C (86%). Cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine may be considered for the treatment of vascular cognitive impairment in selected patients. 2B (89%) ## Ta b l e 3 dementia case finding and detection Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? 1. Cognitive testing to screen asymptomatic adults for the presence of mild cognitive impairment or dementia, including asymptomatic persons with risk factors such as family history or vascular risk factors, is not recommended. 1C (95%) 2. Primary care health professionals should be vigilant for potential symptoms of cognitive disorders in older or at-risk individuals, including but not limited to: reported cognitive symptoms by the patient or an informant, otherwise unexplained decline in instrumental activities of living, missed appointments or difficulty remembering or following instructions or taking medications, decrease in self-care, victimized by financial scams, or new onset later-life behavioral changes including new depression or anxiety (1C). If there is a clinical concern for a cognitive disorder (which may not always be shared by the patient due to anosognosia) then validated assessments of cognition, activities of daily living, and neuropsychiatric symptoms are indicated (see subsequent sections for suggestions for valid tools). 1A (95%). In persons at elevated risk for cognitive disorders (such as very advanced age, pre-existing brain diseases such as Parkinson's disease, a recent episode of delirium, or risk factors such as diabetes) it is reasonable to ask the patient (and an informant, if available) about concerns regarding memory (2C). If clinically significant memory concerns are elicited then further evaluation using validated assessments of cognition, behavior, and function is appropriate (see subsequent sections for suggestions for valid tools). 1B (98%) What tools can be used to evaluate patients in whom cognitive decline is suspected? 1. Routine screening of asymptomatic individuals has no evidence at this point. Cognitive testing to screen asymptomatic adults for the presence of mild cognitive impairment or dementia is not recommended. 1C (95%) 2. Primary care health professionals should stay vigilant for potential early symptoms of cognitive disorders in older individuals who may be less likely to report due their lack of insight, social isolation, or sociocultural beliefs, and in older individuals with warning signs, including but not limited to: reported cognitive symptoms by the patient or an informant, otherwise unexplained decline in instrumental activities of living, missed appointments, showing up to appointments at the incorrect time or day, difficulty remembering or following instructions or taking medications, decrease in self-care, or new onset of later-life behavioral changes including new depression or anxiety (1C). If there is a clinical concern for a cognitive disorder (which may not always be shared by the patient due to their lack of insight) then validated assessments of cognition, activities of daily living, and neuropsychiatric symptoms are indicated (see subsequent sections for suggestions for valid tools). 1A (95%) (Continues) ## Ta b l e 3 (continued) 3. In persons with elevated risk for cognitive disorders or with medical conditions associated with cognitive disorders such as 21 : (a) a history of stroke or transient ischemic attack (TIA); (b) late-onset depressive disorder or a lifetime history of major depressive disorder; (c) untreated sleep apnea; (d) unstable metabolic or cardiovascular morbidity; (e) a recent episode of delirium; (f) first major psychiatric episode at an advanced age (psychosis, anxiety, depression, mania); (g) recent head injury; (h) Parkinson's disease. It is reasonable to ask the patient and an informant about concerns regarding cognition and behavior (2C). If clinically significant cognitive concerns are elicited, then further evaluation using validated assessments of cognition, behavior, and function is appropriate (see subsequent sections for suggestions for valid tools). 1B (93%). The distinction between MCI and dementia is important and is currently made on the basis of clinical assessment of cognition and function. For screening purposes, examining the complaint with the patient and a family member and proceeding with an objective assessment of cognition and functional impairment should be done. 1A (88%) 5. An objective assessment of the patient's cognitive function could be achieved by using rapid psychometric screening tools such as the Memory Impairment Screen (MIS)+ clock drawing test (CDT),the Mini-Cog,the AD8,the four item version of the MoCA (Clock-drawing, Tap-at-letter-A, Orientation, and Delayed-recall),MMSE remains the most widely used instrument, with high sensitivity and specificity for separating moderate dementia from normal cognition and is recommended in many countries. However, it lacks sensitivity for the diagnosis of mild dementia or MCI. The MoCA 31 is more sensitive to MCI than the MMSE and its use is recommended when mild cognitive impairment is suspected or in cases where there is suspicion of cognitive impairment or concern about the patient's cognitive status, and the MMSE score is in the "normal" range (24+ out of 30). 1B (93%) 7. The use of longitudinal serial cognitive assessments like the QuoCo curves 32 might help optimize accuracy for distinguishing participants with dementia from healthy controls. 1C (80%). To obtain information in addition to that provided by the other psychometric screening tools, or if the patient is unable to answer the questions on the screening tools (lack of time or uncooperative), having the caregiver complete a questionnaire for identifying a cognitive and/or functional change, such as the Ascertain Dementia 8 (AD-8) questionnaire or the Informant Questionnaire on cognitive decline in the elderly (IQCODE)is recommended. 1B (93%). Combining cognitive tests with functional screens and informant reports may improve case-finding in people with cognitive difficulties. 1A (95%). Rapid screening of functional autonomy should be completed by an objective assessment with the patient and a family member using the Pfeffer Functional Activities Questionnaire (FAQ)or the Disability Assessment for Dementia (DAD). 35 1C (89%). If a personality, behavior, or mood change has been observed, an objective assessment of the behavioral and psychological symptoms of dementia (BPSD) with the patient and a family member using the short version of the Neuropsychiatric Inventory (NPI-Q),Mild Behavioural Impairment Checklist (MBI-C)or if a mood change has been observed with the Patient Health Questionnaire-9 (PHQ). 38 1A (93%) What important information can be gained from an informant, using which measures? 1. Due to variability in insight into cognitive, functional, and behavioral changes, report from a reliable informant is an essential component for the assessment of patients with suspected neurocognitive disorders at all settings. 1C (91%) 2. The use of standardized tools to obtain informant report on changes in cognition, function, and behavior increases the diagnostic accuracy when combined with patient-related measures and therefore is recommended. 1C (93%) 3. We recommend using one or more informant-based tools that cover cognitive, functional, and behavioral aspects. Specific tools can be selected based on the need for comprehensive assessment versus efficiency depending upon the setting. 1C (86%) 4. There is ongoing development of informant-based tools, and based on the current evidence we recommend tools that: measure informant's report of cognitive changes (eg, ECog)What instruments can be used to get more in-depth information to diagnose MCI or dementia? In addition to neuropsychological testing (if available), we make the following recommendations with regard to the instruments available for more in-depth cognitive evaluation of MCI and dementia: 1. A number of well-validated instruments exist to help in the process of MCI or dementia diagnosis. However, diagnosis of MCI or dementia should not be solely based on an impaired result on cognitive screening tests. 1B (100%) ## Ta b l e 3 (continued) What is the approach to those with cognitive concerns but without objective cognitive changes (ie, recommendations for subjective cognitive decline [SCD])? Functional and Ligand-Based Imaging 3a. For a patient with a diagnosis of a cognitive impairment who has undergone the recommended baseline clinical and structural brain imaging evaluation and who has been evaluated by a cognitive disorders specialist but whose underlying pathological process is still unclear, preventing adequate clinical management, an [ 18 F]-FDG PET scan is an effective and accurate tool for differential diagnosis purposes. 1A (88%) 3b. If such a patient cannot be practically referred for a FDG-PET scan, we recommend that a SPECT rCBF study be performed for differential diagnosis purposes. 1B(86%) 7. CSF analysis can also be considered in dementia patients with diagnostic uncertainty and predominance of language, visuospatial, dysexecutive, or behavioral features to rule out AD pathophysiology. 1C (78%; 100%) ## Ta b l e 5 non-cognitive markers of dementia 1a. There is strong evidence that slower gait speed is associated with future dementia, in population studies. When gait speed (cut-off gait speed below 0.8m/s) is coupled with cognitive impairment (subjective or objective) the risk is higher. We recommend testing gait speed in clinics in those patients with cognitive complaints/impairments if time/resources are available. 1B (62%, 100%) Note: Protocols on how to assess gait speed with stopwatch are available. Testing takes, on average, 3 minutes to perform. 91 1b. Dual-task gait impairment (lower speed or high cost) is associated with future incident dementia. In MCI samples, dual-task gait was shown to predict time to progression to dementia. Variability in the delivery of testing protocols is noted. We recommend that dual-task gait test may be used in specialized clinics (memory clinics) to help identify mild cognitive impairment (MCI) older adults at higher risk of progression to dementia if time/resources are available. 2B (60%, 100%) Note: Published protocols on how to assess Dual-Task Gait for dementia risk with just a stopwatch are available. (Continues) 5b. If symptoms of hearing loss are reported, then hearing loss should be confirmed by audiometry conducted by an audiologist meeting provincial regulations for the practice of audiology. If confirmed, audiologic rehabilitation may be recommended. This rehabilitation may include behavioral counselling and techniques, and may or may not include the recommended use of a hearing aid or other device. 1A (98%). ## Ta b l e 7 psychosocial interventions Individual Level 1. We recommend exercise (group or individual physical exercise) for people living with dementia.We cannot recommend any specific exercise duration or intensity at this time. 1B (93%) 2. Group cognitive stimulation therapy is an intervention for people with dementia which offers a range of enjoyable activities providing general stimulation for thinking, concentration, and memory usually in a social setting, such as a small group. We recommend considering group cognitive stimulation therapy for people living with mild to moderate dementia. 101-104 2B (96%) 3. Psychoeducational interventions for caregivers aim at the development of problem-focused coping strategies while psychosocial interventions address the development of emotion-focused coping strategies. These can include education, counseling, information regarding services, enhancing carer skills to provide care, problem solving, and strategy development. We recommend considering psychosocial and psychoeducational interventions for caregivers of people living with dementia.6. Deprescribing of ChEIs or memantine should occur gradually and treatment reinitiated if the individual shows clinically meaningful worsening of cognition, functioning, neuropsychiatric symptoms, or global assessment that appears to be related to cessation of therapy. 1B (98%). Dose reduction during deprescribing should follow general guidelines for deprescribing of medications with a reduction of dose by 50% every 4 weeks until the initial starting dose is obtained. After 4 weeks of treatment on the recommended starting dose, the cognitive enhancer could be discontinued. 2C (96%) 8. Cholinesterase inhibitors should not be discontinued in individuals who currently have clinically meaningful psychotic symptoms, agitation, or aggression until these symptoms have stabilized unless these symptoms appear to have been worsened by the initiation of a ChEI or an increase in ChEI dose. 2B (78%, 100%) 9. Individuals who have had a clinically meaningful reduction in neuropsychiatric symptoms (eg, psychosis) with cognitive enhancers should continue to be treated with the cognitive enhancer even if there is evidence of cognitive and functional decline. 2B (96%). Cholinesterase inhibitors and memantine should be deprescribed for individuals with mild cognitive impairment. 1B (89%) ## Use of neuroimaging and fluid biomarkers The imaging biomarkers groups extended the previous consensus work, . ## Non-cognitive markers of dementia Although cognitive impairment is the hallmark of AD and related dementias, non-cognitive markers may be early non-invasive biomarkers. ## Risk reduction As dementia prevention and fluid increasingly seems plausible,CCCDTD has addressed risk reduction in this iteration. We took the approach that most dementia occurs in late life and typically has multiple causes 96,97 building on updates from a 2017 comprehensive overview of dementia prevention.We supplemented information (when present) with updates, especially focusing on Canadian data. We offer recommendations on interventions that appear to have importance both across the life course and in primary, secondary, and sometimes tertiary prevention including: (1) nutrition, (2) physical exercise, (3) hearing loss, (4) sleep, (5) cognitive training and rehabilitation, (6) social engagement and education, (7) frailty,and medications . ## Psychosocial and non-pharmacological interventions The psychosocial and non-pharmacological interventions encompass a broad range of interventions and typically aim at improving cognition, symptoms, or well-being (including that of caregivers), or at adapting organizations and communities to the needs of people living with dementia and their caregivers. For the first time, the CCCDTD created a working group on these interventions. We synthetized published meta-analysis and reviews and provide five recommendations of both individual level and community level interventions, as both have the potential to improve outcomes for people living with dementia . ## Deprescription of medications used to treat dementia Acknowledging that many individuals who are affected by demen- . # Conclusions We hope that these evidence-based recommendations will be useful to clinicians and policy makers as well as the public at large. We do appreciate that within Canada, individual jurisdictions and access to care vary, and these recommendations are intended as guidelines for clinicians to implement in their practices based on available resources. The recommendations may also be useful to professional groups in other countries, taking into account local culture and resources. # Acknowledgments The CCCDTD5 meeting was supported financially by the Canadian Consortium on Neurodegeneration in Aging, the Réseau des cliniques mémoire du Québec, the Réseau Québecois de Recherche sur le Vieillissement. ## Participants The recommendations were prepared by the following working groups:	None	None	Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD) have provided evidence‐based dementia guidelines for Canadian clinicians and researchers. We present the results of the 5th CCCDTD, which convened in October 2019, to address topics chosen by the steering committee to reflect advances in the field, and build on previous guidelines. Topics included: (1) utility of the National Institute on Aging research framework for clinical Alzheimer's disease (AD) diagnosis; (2) updating diagnostic criteria for vascular cognitive impairment, and its management; (3) dementia case finding and detection; (4) neuroimaging and fluid biomarkers in diagnosis; (5) use of non‐cognitive markers of dementia for better dementia detection; (6) risk reduction/prevention; (7) psychosocial and non‐pharmacological interventions; and (8) deprescription of medications used to treat dementia. We hope the guidelines are useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence‐based approach to dementia.
da5b41ea945a646f70ebd27a974d0918e2685199	pubmed	Radiation Safety in Children With Congenital and Acquired Heart Disease	Radiation Safety in Children With Congenital and Acquired Heart Disease There is a need for consensus recommendations for ionizing radiation dose optimization during multimodality medical imaging in children with congenital and acquired heart disease (CAHD). These children often have complex diseases and may be exposed to a relatively high cumulative burden of ionizing radiation from medical imaging procedures, including cardiac computed tomography, nuclear cardiology studies, and fluoroscopically guided diagnostic and interventional catheterization and electrophysiology procedures. Although these imaging procedures are all essential to the care of children with CAHD and have contributed to meaningfully improved outcomes in these patients, exposure to ionizing radiation is associated with potential risks, including an increased lifetime attributable risk of cancer. The goal of these recommendations is to encourage informed imaging to achieve appropriate study quality at the lowest achievable dose. Other strategies to improve care include a patient-centered approach to imaging, emphasizing education and informed decision making and programmatic approaches to ensure appropriate dose monitoring. Looking ahead, there is a need for standardization of dose metrics across imaging modalities, so as to encourage comparative effectiveness studies across the spectrum of CAHD in children. Children with congenital and acquired heart disease (CAHD) represent a vulnerable patient population, many of whom will require life-long medical care. In these children, cardiac imaging using ionizing radiation is essential for accurate diagnosis and safe intervention. At the same time, exposure to ionizing radiation introduces radiation-related risks, including the potential development of cancer. Recent epidemiological studies evaluating childhood exposure to computed tomography (CT) scans have asserted an increased lifetime relative risk of cancer [bib_ref] Radiation exposure from CT scans in childhood and subsequent risk of leukaemia..., Pearce [/bib_ref] [bib_ref] Relationship between paediatric CT scans and subsequent risk of leukaemia and brain..., Berrington De Gonzalez [/bib_ref]. However, these and other reports have also highlighted the complexities and uncertainty associated with estimating long-term risks associated with the low-dose ionizing radiation exposures that are typically seen with medical imaging procedures, engendering continued debate [bib_ref] Radiation risks of medical imaging: separating fact from fantasy, Hendee [/bib_ref]. There continues to be a great deal of misunderstanding among the general public regarding radiation risks, often promulgated by the media [bib_ref] ALARA, image gently and CT-induced cancer, Cohen [/bib_ref] , as well as regarding which modalities utilize ionizing radiation [bib_ref] Parental knowledge of potential cancer risks from exposure to computed tomography, Boutis [/bib_ref] [bib_ref] Radioprotection (un)awareness in cardiologists, and how to improve it, Carpeggiani [/bib_ref] [bib_ref] Ionizing radiation knowledge among emergency department providers, Ditkofsky [/bib_ref] [bib_ref] Communicating potential radiationinduced cancer risks from medical imaging directly to patients, Lam [/bib_ref] [bib_ref] Physicians' and midlevel providers' awareness of lifetime radiation-attributable cancer risk associated with..., Puri [/bib_ref] [bib_ref] International Atomic Energy Agency study with referring physicians on patient radiation exposure..., Rehani [/bib_ref] [bib_ref] Radiation safety knowledge and perceptions among residents: a potential improvement opportunity for..., Sadigh [/bib_ref]. Despite uncertainty regarding the magnitude of risk, if any, there is universal agreement that every effort should be made to keep radiation exposure from medical imaging as low as reasonably achievable so long as diagnostic integrity and procedural safety are not compromised. A key strategy for radiation safety in cardiology is education, often through informed discussions of the benefits and potential risks of a given procedure among patients, parents and other caregivers, and clinical and imaging health care providers [bib_ref] Approaches to enhancing radiation safety in cardiovascular imaging: a scientific statement from..., Fazel [/bib_ref]. The education of providers-both those ordering studies and those performing and interpreting these studies-is critical. Principles of radiation protection include justification, to ensure that an imaging procedure is clinically necessary and appropriate and optimization, to ensure that radiation exposure is the appropriate amount and kept as low as reasonably achievable. Optimization does not imply dose reduction at any cost; misuse occurs both with too much and too little radiation dose. Optimization in medicine is "best described as management of the radiation dose to the patient to be commensurate with the medical purpose". The overarching aim of optimization within the medical context is to ensure that "the level of protection should be the best for the prevailing circumstances, maximizing the margin of benefit over harm". The purpose of this scientific statement is to provide expert consensus recommendations for optimization of medical imaging procedures commonly performed in children with CAHD, including cardiac CT, nuclear cardiology studies, and fluoroscopically guided diagnostic and interventional catheterization and electrophysiology procedures. These recommendations specifically focus on optimization approaches that, when properly implemented, will improve the radiation safety profile for children with heart disease, without compromising the diagnostic information provided by these valuable studies or other aspects of procedural safety. They are provided in the context of unique considerations in the care of children with CAHD [bib_ref] Sleeping with the enemy?' Expectations and reality in imaging children in the..., Frush [/bib_ref] , including the reality that performance of diagnostic and image-guided interventional care may differ among centers of pediatric focus, including children's hospitals and university practices, and community practices. ## Childhood heart disease, ionizing radiation, and associated risks Congenital heart disease is the most common birth defect, affecting an estimated 1 million children living in the United States [bib_ref] Congenital heart defects in the United States: estimating the magnitude of the..., Gilboa [/bib_ref] [bib_ref] The incidence of congenital heart disease, Hoffman [/bib_ref]. Cardiomyopathies and other forms of acquired heart disease affect an additional 1 of every 100,000 children and adolescents annually [bib_ref] The incidence of pediatric cardiomyopathy in two regions of the United States, Lipshultz [/bib_ref]. Children with CAHD often require complex medical care. They frequently have prolonged hospital stays and many require staged or repeated surgical interventions. The complexity of their care dictates that they are often exposed to a relatively high number of diagnostic medical imaging procedures involving ionizing radiation. In addition to diagnostic imaging, image-guided interventional procedures have become increasingly important in their care, with a substantial net increase in the average number of exposures per patient over the past 2 decades [bib_ref] Exposure to low-dose ionizing radiation from cardiac procedures in patients with congenital..., Beausejour Ladouceur [/bib_ref]. Although these diagnostic and therapeutic procedures have contributed greatly to improved outcomes in children with CAHD, several studies have demonstrated that these children can be exposed to relatively high cumulative doses of ionizing radiation [bib_ref] Cumulative exposure to medical radiation for children requiring surgery for congenital heart..., Glatz [/bib_ref] [bib_ref] Cumulative radiation exposure and cancer risk estimation in children with heart disease, Johnson [/bib_ref]. There is increasing awareness of the potential harmful effects of exposure to ionizing radiation from imaging procedures. Relatively high doses of ionizing radiation can cause tissue reactions (formerly referred to as deterministic effects) such as skin ulceration and hair loss, whereas stochastic effects such as cancer have been attributed to even relatively low doses. Tissue reactions result from radiation-induced cell death or damage and are only very rarely seen in children because individual procedural doses typically do not exceed threshold levels. By contrast, for stochastic effects, most expert panels have opined that the existing data best support a linear, no-threshold relationship to ionizing radiation dose, as a basis for radiation protection. Stochastic effects are due to ionizing radiationinduced mutations and occur more commonly in rapidly dividing cells and in higher cancer risk organ and tissue structures such as breast, bone marrow, stomach, colon, and lung tissues. Although mutations occur at the time of exposure, there is often a substantial time lag between exposure and onset of solid cancers which may be diagnosed decades later. Because children have more rapidly dividing cells within organs and tissues, and because there is typically a longer anticipated lifespan following exposure during which cancer can develop, exposures that occur at younger ages are associated with increased risk. Similarly, females are at increased risk due in large part to their increased risk of breast cancers. With increasing recognition of the lifetime risks associated with ionizing radiation exposure, and acknowledging the vital diagnostic and therapeutic role of medical imaging procedures that use ionizing radiation, it is critical to optimize these procedures so as to achieve sufficient diagnostic yield at reduced radiation doses when possible. percentage (from ~5% to >45%, depending on the study and imaging modality) of cardiac imaging studies has questionable justification (30-34). Similar appropriate use criteria have not been developed for pediatric cardiac imaging procedures that utilize ionizing radiation, and it is unclear what proportion of medical imaging procedures would generally be considered justified in these patients. Justification is an indispensable part of radiation protection in children, on the basis of the ethical principles of nonmaleficence and beneficence. As defined in the preceding text, optimization entails that the radiation dose to the patient is suitable for the intended medical purpose, and radiation that is clinically unnecessary or unproductive is avoided. Regardless of the imaging modality, optimization strategies almost always vary depending on the patient size or body habitus. Strategies for dose optimization in adults typically cannot simply be applied to children. For practitioners engaged in pediatric medical imaging procedures that use ionizing radiation, it is necessary to understand the unique needs of children and the challenges of optimized imaging across the spectrum of pediatric patients from the premature neonate to the adult-sized adolescent. ## Dose metrics A variety of metrics are used to quantify the radiation burden of cardiovascular procedures. These include both general terminology (2) and modality-specific metrics (35). One or more dose metrics should be recorded for all cardiovascular imaging procedures in children with CAHD. ## General metrics Ionizing radiation deposits energy in the human body, which creates charged particles (ionized tissue molecules) that have the potential to cause biological damage. The absorbed dose is an estimate of the energy deposited. Because less energy is carried by a fluoroscopic x-ray beam to deeper layers of tissue due to large deposits of energy in the superficial layers (attenuation), one should designate the location of a specified absorbed dose, for example, absorbed dose to a whole organ or tissue, skin entrance, midline, or exit plane. Today, absorbed dose is expressed in Système International units of grays (Gy, mGy, mGy, and so on), whereas, historically, it was expressed in units of rads or mrads, where 1 mGy = 100 mrad. A related concept is the equivalent dose, which weights absorbed dose to reflect the ability of the specific type of radiation to cause biological damage. For x-rays and gammarays, which are the types of radiation used in imaging children with CAHD, this weighting factor is 1, so absorbed and equivalent doses take equal values. However, equivalent dose is expressed in Système International units of sieverts (Sv, mSv, and so on), not grays. The historical unit was the rem, where 1 mSv = 100 mrem (2). Another general metric, used across modalities and facilitating comparisons between modalities, is the effective dose. Effective dose is a whole-body quantity representing a sum of organ equivalent doses, each weighted by a tissue weighting factor that reflects the radiation detriment from stochastic effects for that organ. These tissue weighting factors are prescribed in international standards and derive from synthesis of the extant worldwide radio-epidemiological data. Current tissue weighting factors for effective dose are age-and sex-averaged values, thus posing a limitation in characterizing a patient-specific stochastic radiation risk on the basis of effective dose, especially in children. Effective dose enables comparisons between exposure scenarios where different parts of the body receive different exposures, and is also expressed in units of sieverts. A dose expressed in units of sieverts could be either an effective or equivalent dose, and thus care should be taken to specify which quantity is being described. For example, if an effective dose is incorrectly interpreted as an equivalent dose, the dose to directly irradiated organs and their potential risk from a diagnostic examination could be significantly underestimated. ## Ct metrics Several related CT dose index quantities exist, which are calculated from dosimetric measurements performed in a cylindrical Plexiglas phantom (35). These include the volume CT dose index (CTDI vol ), the dose-length product (DLP), and the size-specific dose estimate (SSDE). CTDI vol , reported by current CT scanners, is calculated from both peripheral and central dosimetric measurements performed in a cylindrical phantom, as well as the pitch for a helical scan. It can be performed using a phantom of either 32 or 16 cm in diameter. DLP, also reported on current scanners, is calculated as CTDI vol multiplied by the scan length, and it reflects a total radiation burden from a scan, not just a dose at a single location. SSDE (36), a recently introduced CT dose metric not yet reported by CT scanners, normalizes CTDI vol to reflect patient size (effective diameter) (36). Published conversion factors (36) are multiplied by the displayed CTDI vol to calculate the SSDE. The size of the patient and size of the phantom used to calculate the displayed CTDI vol , are required to identify the correct published conversion factor for an individual patient. Conversion factors to estimate the effective dose from DLP in children are available [fig_ref] TABLE 2: Pediatric Average Cardiothoracic CT Conversion Factors Relating DLP to ED in Children [/fig_ref] , but SSDE cannot be converted to DLP (36) or effective dose. A consensus on a standard for radiation dose reporting for cardiovascular CT in pediatric patients has not been established, although California law requires physicians to record CTDI vol and DLP for all CT scans [bib_ref] International Commission on Radiological Protection. Radiation Dose to Patients from Radiopharmaceuticals. ICRP..., Accessed [/bib_ref]. Nonetheless, when CTDI vol , DLP, or SSDE is reported, the size of the phantom used in its determination should also be reported. If an effective dose estimate is calculated, the cardiac-or chest-specific conversion factor used in its estimation should be reported. Methodological specification is especially important in children because CT dose estimates can vary several fold depending on the method of calculation used, and dose comparisons between modalities should reflect similar adjustments to enable a valid comparison. ## Nuclear medicine metrics The activity of a radiopharmaceutical is the average number of nuclear decays per unit time. The Système International unit of activity is the Becquerel (Bq), which is used to refer to 1 decay per second. In the United States, the traditional unit of curies (Ci) is more commonly used, where 1 Ci = 3.7 × 10 10 Bq. For a given activity of a radiopharmaceutical, effective dose (as well as organ absorbed doses) can be estimated by multiplying the activity by a dose coefficient, determined on the basis of biokinetic models. Dose coefficients for many radiopharmaceuticals and children of a range of ages, can be found in publications of the International Commission on Radiological Protection (45-48) and the Society of Nuclear Medicine and Molecular Imaging [bib_ref] Primer for Absorbed Dose Calculations, Loevinger [/bib_ref] , as well as in radiopharmaceutical package inserts. Pediatric dose coefficients for commonly used cardiac radiopharmaceuticals are compiled in [fig_ref] TABLE 3: ED Coefficients [/fig_ref]. ## Fluoroscopy metrics Interventional fluoroscopic equipment used in the catheterization lab displays cumulative air kerma (K a,r ) in units of mGy from the procedure at an interventional reference point designed to approximate the entrance skin plane of an adult patient. This dose index can be used by a qualified medical physicist to estimate the skin dose to the patch of skin of the patient that received the largest radiation dose during the examination: the peak skin dose, which is typically less than the cumulative air kerma. Peak skin dose is an indicator of the likelihood that the patient will develop a tissue reaction as a result of the examination. This risk is greater in large adults than small children for whom a lower dose is required to achieve adequate image quality. Prototypes of real time feedback to the operator of the increasing peak skin dose during the examination are available on a limited number of vendors' equipment. When biplane interventional equipment is used for pediatric patients, the K a,r from the frontal and lateral planes should ideally not be added, given that each plane exposes a different area of skin. These same fluoroscopes also display the kerma-area product (KAP) or dose-area product to the patient from the examination. The KAP is the product of the air kerma and the crosssectional area of the x-ray beam. This quantity is constant at all distances from the source because the former falls, whereas the latter rises, both as the square of distance from the xray source. KAP is commonly measured using a special meter designed for this purpose that is built into the fluoroscopy unit, near the collimator. Analogously to DLP for CT, KAP reflects not just the kerma (dose) at the skin surface as does K a,r , but also the area of tissue that is irradiated, and as such, it better reflects the stochastic risk from a procedure than does K a,r . Thus, KAP is generally used as a surrogate of stochastic risk, whereas K a,r is used as a marker of deterministic risk, that is, risk of a tissue reaction. Although Monte Carlo simulations have been performed for anteroposterior and lateral exposures to relate K a,r and KAP to organ and effective dose in children, conversion factors enabling simple estimation of organ and effective doses from commonly performed pediatric cardiac fluoroscopic procedures have not yet been determined. ## Optimization strategies for cardiac computed tomography Cardiovascular CT is an increasingly common modality in children with CAHD (51-53). Modern cardiovascular multidetector CT (MDCT) scanner technology delivers detailed cardiac morphological imaging at the fast heart rates of children [bib_ref] Cardiovascular imaging trends in congenital heart disease: a single center experience, Han [/bib_ref] , reduces the need for sedation compared with magnetic resonance (MR) imaging [bib_ref] Computed tomography imaging in patients with congenital heart disease part i: rationale..., Han [/bib_ref] or cardiac catheterization, and can be performed at effective doses of <1 mSv [bib_ref] Evaluation of image quality and radiation dose of thoracic and coronary dualsource..., Saad [/bib_ref] [bib_ref] Radiation dose for thoracic and coronary stepand-shoot CT using a 128-slice dual-source..., Paul [/bib_ref] [bib_ref] Effective radiation dose in computed tomographic angiography of the chest and diagnostic..., Watson [/bib_ref]. Guidelines for advanced noninvasive cardiovascular imaging in children with CAHD do not include recommendations regarding cardiovascular CT (57), although cardiac imagers must be proficient in radiation dose management strategies to mitigate potential radiation risks for patients with cardiovascular disorders [bib_ref] Computed tomography imaging in patients with congenital heart disease, part 2: technical..., Han [/bib_ref] [bib_ref] The 'Image Gently' campaign: increasing CT radiation dose awareness through a national..., Goske [/bib_ref]. In addition, current variability (60) of radiation dose for cardiovascular CT in pediatric cardiovascular disorders could be reduced by universal application of radiation dose optimization techniques. Every cardiovascular CT scan performed in a patient with cardiovascular disorders should be tailored to the individual patient and clinical indication. This informed and individualized scan performance for pediatric CT can be separated into the 2 categories of patient preparation and scan acquisition. [fig_ref] TABLE 4: Approaches for Dose Optimization of Cardiac CT Procedures in Children [/fig_ref] and the Central Illustration summarize optimization strategies for patient preparation and scan performance. Patient preparation recommendations for dose optimization in cardiovascular CT include consultation with the referring cardiologist and surgeon when necessary. Heart rate-lowering medications, including beta-blockers, calcium channel blockers, and phenylephrine, should be considered for high-resolution coronary artery imaging [bib_ref] Evaluation of contraindications and efficacy of oral Beta blockade before computed tomographic..., De Graaf [/bib_ref] [bib_ref] Influence of heart rate and phase of the cardiac cycle on the..., Achenbach [/bib_ref] [bib_ref] Pediatric coronary CTA using phenylephrine to lower heart rate, Chelliah [/bib_ref]. The lowest radiation dose will be delivered with a slower and steady heart rate for electrocardiogram (ECG)gated/triggered scans [bib_ref] Impact of heart rate frequency and variability on radiation exposure, image quality,..., Weustink [/bib_ref]. For gated studies, heart rate-lowering medication will often allow use of a narrow acquisition window, that is, x-ray exposure during a shorter portion of the cardiac cycle. With faster acquisition (e.g., dual source or wide detector array scanning), nongated studies may give adequate evaluation of extracardiac structures such as the aorta and pulmonary veins at a lower radiation dose [bib_ref] High-pitch dual-source CT angiography of the aortic valveaortic root complex without ECG-synchronization, Karlo [/bib_ref] [bib_ref] High-pitch spiral computed tomography: effect on image quality and radiation dose in..., Lell [/bib_ref] [bib_ref] Dose modulated retrospective ECG-gated versus non-gated 64-row CT angiography of the aorta..., Schernthaner [/bib_ref] [bib_ref] Prospectively ECG gated CT pulmonary angiography versus helical ungated CT pulmonary angiography:..., Shuman [/bib_ref]. Sedation and/or anesthesia for suspended respiration in patients unable to cooperate may be needed when a protocol requiring several heart beats is used and patient motion may affect image quality. Examples include ECG-gated functional imaging or high-resolution coronary artery imaging at fast heart rates. Sedation and/or anesthesia can reduce overall heat rate and heart rate variability due to patient agitation. Rarely, pacemaker rate and mode should be adjusted for optimal imaging [bib_ref] Practical approaches to overcoming artifacts in coronary CT angiography, Lesser [/bib_ref]. Iodinated intravenous (IV) contrast media administration (including iodine concentration, dose, rate of administration, gauge, and location of IV access) should be planned to opacify all structures of interest. Optimally, all necessary information should be obtained in a single scan acquisition. For example, a 2-phase contrast injection can be used to opacify the right and left heart simultaneously, or a 2-phase contrast injection separated by a pause can be used to provide venous and arterial opacification in the same scan (58). Scanner-based optimization approaches include limiting the scan range to the anatomy requiring evaluation. The patient should be centered within the gantry [bib_ref] Automatic patient centering for MDCT: effect on radiation dose, Li [/bib_ref]. Scanner parameters such as tube current (mA) and tube potential (kVp) should be adjusted to patient size. Lower tube potential settings (e.g., 70 and 80 kVp for most children; 80 or 100 kVp in adolescents and small adults) should generally be selected [bib_ref] Automated low-kilovoltage selection in pediatric computed tomography angiography: phantom study evaluating effects..., Siegel [/bib_ref] [bib_ref] Feasibility of prospectively ECG-triggered high-pitch coronary CT angiography with 30 mL iodinated..., Zhang [/bib_ref]. Technique should also be adjusted to yield acceptable image quality that is tailored to the clinical indication. For example, a CT scan performed for evaluation of aortic coarctation after balloon angioplasty and stent placement typically can be fully diagnostic at a lower radiation dose than a scan performed for evaluation of coronary arterial anatomy. The scan mode chosen should provide the diagnostic image quality at the lowest practical radiation dose. Prospective ECG triggering rather than retrospective ECG gating should be used when possible. Retrospective gating, which results in a relatively higher radiation dose, should be reserved for highly irregular heart rates [bib_ref] Prospective electrocardiography-triggered CT angiography of the great thoracic vessels in infants and..., Pache [/bib_ref] [bib_ref] Prospective and retrospective ECG-gating for CT coronary angiography perform similarly accurate at..., Stolzmann [/bib_ref]. ECG-gated tube current modulation should typically be used for functional imaging. This limits the fully irradiated portion of the cardiac cycle to a narrow window and gives a reduced dose (typically 20%) through the remainder of the cardiac cycle [bib_ref] Left ventricular function can reliably be assessed from dual-source CT using ECG-gated..., Mahnken [/bib_ref]. The narrowest temporal acquisition window possible should be used for coronary imaging. For coronary artery origin and location, a narrow window will often provide adequate visualization [bib_ref] A prospective randomized trial comparing image quality, study interpretability, and radiation dose..., Leipsic [/bib_ref] , reserving a widened window for high resolution coronary imaging at high heart rates [bib_ref] A prospective randomized trial comparing image quality, study interpretability, and radiation dose..., Leipsic [/bib_ref] [bib_ref] High-pitch dual-source CT coronary angiography: systolic data acquisition at high heart rates, Goetti [/bib_ref]. Use of automated tube current [bib_ref] Pediatric cardiovascular CT angiography: radiation dose reduction using automatic anatomic tube current..., Herzog [/bib_ref] and tube potential (79) algorithms should be considered [bib_ref] Pediatric cardiovascular CT angiography: radiation dose reduction using automatic anatomic tube current..., Herzog [/bib_ref] [bib_ref] Cardiac computed tomography angiography with automatic tube potential selection: effects on radiation..., Ghoshhajra [/bib_ref]. Iterative reconstruction should be used on all scans [bib_ref] Assessment of an iterative reconstruction algorithm (SAFIRE) on image quality in pediatric..., Han [/bib_ref] [bib_ref] Paediatric cardiac CT examinations: impact of the iterative reconstruction method ASIR on..., Mieville [/bib_ref]. Collaboration among qualified cardiac imaging physicians, technologists, and medical physicists, as well as the CT vendor's product specialists should lead to more effective protocols. By virtue of using a combination of approaches, cardiac CT with good diagnostic image quality can be obtained using low radiation doses , and even without the most advanced technology. ## Optimization strategies for nuclear cardiac imaging Not only are children more sensitive to the effects of ionizing radiation than are adults, but also the radiation dose from a given activity of a radiopharmaceutical is greater for children than for adults. For example [fig_ref] TABLE 3: ED Coefficients [/fig_ref] , a 10 mCi dose of 99mTc sestamibi administered at exercise has an associated effective dose of 2.9 mSv in an adult, 3.7 mSv in a 15-year-old, 5.9 mSv in a 10-year-old, 8.5 mSv in a 5-year-old, and 16.7 mSv in a 1-year-old child (45,. This variability underscores the importance of radiation dose optimization when a nuclear cardiology procedure is clinically determined to be the right test for a child. Several approaches exist that can and should be used for dose optimization of nuclear cardiology procedures in children [fig_ref] TABLE 5: Approaches for Dose Optimization of Nuclear Cardiology Procedures in Children• Stress-first/stress-only imaging... [/fig_ref] , Central Illustration). Most nuclear cardiac studies in children are single-photon emission computed tomography (SPECT) myocardial perfusion studies. Thallium-201, which has a long half-life (3 days) and relatively high radiation dose, should be avoided. In general, a stress-first/stress-only approach using a technetium-99m-based radiopharmaceutical (sestamibi or tetrofosmin) should be performed. Here, stress testing and stress imaging is performed first, with stress images reviewed by an attending nuclear cardiology physician before any rest imaging, and rest imaging (with its attendant radiation dose) omitted if stress perfusion and left ventricular function, wall motion, and size are all normal [bib_ref] Estimating the reduction in the radiation burden from nuclear cardiology through use..., Mercuri [/bib_ref]. Multiple-position imaging, which for most cameras entails both supine and prone imaging, has been demonstrated to increase the normalcy rate of stress imaging and thus can increase the proportion of children not requiring subsequent rest imaging [bib_ref] Evaluating the role of routine prone acquisition on visual evaluation of SPECT..., Guner [/bib_ref]. In children, when rest imaging is needed, it should be performed on a later day than stress imaging, using the same administered activity (mCi), because same-day stress-rest myocardial perfusion imaging requires a rest activity of 3 to 4 times the stress dose to minimize the effect of residual stress activity on the rest study ("shine-through artifact") [bib_ref] Current worldwide nuclear cardiology practices and radiation exposure: results from the 65..., Einstein [/bib_ref]. Determination of administered activity should be tailored to the patient's size. North American consensus guidelines suggest Tc-99m sestamibi or tetrofosmin activity for children of 0.15 mCi/kg for the first scan in a given day, with a minimum of 2 mCi and a maximum of 10 mCi (87). These guidelines do not recommend activities for other radiopharmaceutials used in pediatric nuclear cardiology. However, several additional formulas exist that can be used to adjust the dose from a standard adult activity, on the basis of a child's age, weight, or body surface area. The recommended pediatric administered activity often varies widely among these formulas. For example, for an 11-year-old, 75-lb, 56-inch child undergoing exercise testing with Tc-99m sestamibi or tetrofosmin for evaluation of an anomalous coronary artery, North American consensus guidelines suggest an activity of 5.1 mCi, Clark's rule suggests an activity of 5.0 mCi, Young's rule, 4.8 mCi, Webster's formula, 6.7 mCi, a body-surface-area-based approach, 6.7 mCi, and the European Association of Nuclear Medicine (EANM) Dosage Card (88), 8.8 to 13.1 mCi. In practice, it may be useful to calculate recommended activity using several of these methods and then heuristically select within the range determined. When possible, technological advances in instrumentation-such as a high-efficiency cadmium-zinc-telluride camera or positron emission tomography (PET), or image reconstruction software incorporating iterative reconstruction, resolution recovery, and noise reduction-should be used to reduce administered activity and hence radiation dose. Such methodology can result in outstanding image quality using a lower administered activity, generally no more than 5 mCi of 99mTc, than that from any formula. It is desirable to obtain at least 1 million left ventricular region counts for each scan, with reconstruction filtering lowered to preserve resolution of the smaller heart walls (9). Because Tc-99m-based perfusion agents are "sticky" with adsorption of some radiopharmaceutical to the syringe and stopcock, when using low Tc-99m activity one should be careful to flush the syringe containing Tc-99m with saline after peak-exercise administration and inject this flush into the patient; to measure residual post-injection activity in the syringe and stopcock; and to prolong imaging time if net received activity is significantly lower than anticipated. Although overly low activity (e.g., <2 mCi) is not recommended a priori, it need not result in an uninterpretable study that might otherwise need to be repeated. In centers where PET myocardial perfusion imaging is available, it may be preferred versus SPECT due to lower radiation dose, higher spatial resolution, and higher accuracy. However, few centers perform exercise PET stress testing, and pharmacological vasodilator stress may not be adequate in simulating the effects of exercise for many children requiring myocardial perfusion imaging, for example, those with anomalous coronary arteries. If x-ray CT attenuation correction is used, the lowest possible tube current should be used to maintain accurate attenuation correction only, that is, diagnostic-quality CT is not required. The CT DLP should rarely exceed 15 mGy · cm. Three-dimensional (3D) PET acquisition mode should be used if possible with body habitus-or weight-based adjustment of the injected activity to minimize radiation exposure. For example, the combined effective dose for stress and rest imaging of a 10-year-old pediatric patient weighing 75 lbs (34 kg) is [fig_ref] TABLE 3: ED Coefficients [/fig_ref] approximately 2 mSv using 10 MBq/kg of Rb-82 or 5 MBq/kg of N-13 ammonia. The image reconstruction smoothing filter should be selected to optimize spatial resolution of the myocardial walls versus background noise. Stress-first imaging should be employed as described earlier in the text for SPECT, unless there is a specific request for assessment of stress/rest myocardial flow reserve, although relevant pediatric data are extremely limited. ## Optimization strategies for fluoroscopically guided procedures Fluoroscopically guided procedures, including diagnostic, interventional, and electrophysiological cardiac catheterization procedures, on average, account for more cumulative ionizing radiation to children with CAHD than all other medical imaging modalities combined [bib_ref] Cumulative exposure to medical radiation for children requiring surgery for congenital heart..., Glatz [/bib_ref] [bib_ref] Cumulative radiation exposure and cancer risk estimation in children with heart disease, Johnson [/bib_ref] [bib_ref] Cumulative patient effective dose and acute radiation-induced chromosomal DNA damage in children..., Ait-Ali [/bib_ref] [bib_ref] Cumulative radiation exposure in pediatric patients with congenital heart disease, Walsh [/bib_ref]. Radiation doses for individual procedures can vary widely depending on the size of the patient, complexity of the procedure, hardware and configuration of the fluoroscope, and the optimization practices of the proceduralist during the examination. Dose reduction strategies during fluoroscopy can be classified into 2 broad, but overlapping, categories: 1) aspects of the imaging equipment's hardware/configuration that must be selected to support pediatric imaging at the time the system is selected, installed, and/or configured; and 2) operator-dependent approaches to imaging that are often manipulated immediately before or during the procedure by the proceduralist or staff. Recommendations for management of patient dose while maintaining diagnostic quality images focused on hardware, configuration, and operator-dependent techniques are provided in [fig_ref] TABLE 7: Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children [/fig_ref] , respectively. These recommendations should be considered as guidelines rather than strict rules. Every imaging scenario requires an individualized approach, and dose management should never compromise image quality to the extent that diagnostic accuracy and/or procedural safety are adversely impacted. ## Hardware and configuration No currently marketed fluoroscope is designed solely for pediatric use. "Out of the box" new fluoroscopes are typically not configured for the unique challenges of pediatric imaging. Using a fluoroscope configured for adult patients on a child or infant can result in ionizing radiation doses that are orders of magnitude higher than needed [bib_ref] Optimization of a fluoroscope to reduce radiation exposure in pediatric imaging, Brown [/bib_ref] [bib_ref] Impact of imaging approach on radiation dose and associated cancer risk in..., Hill [/bib_ref] [bib_ref] Management of pediatric radiation dose using Philips fluoroscopy systems DoseWise: perfect image,..., Stueve [/bib_ref]. For these reasons, optimization of the fluoroscopic hardware and its configuration is critical. The process of hardware and software configuration should involve close collaboration among the physicians performing these procedures, the technologists, technicians, and physician extenders in the catheterization laboratory, the fluoroscope's design engineers and qualified medical physicists [bib_ref] Pediatric interventional radiography equipment: safety considerations, Strauss [/bib_ref] [bib_ref] Interventional suite and equipment management: cradle to grave, Strauss [/bib_ref]. ## Operator-dependent techniques Continuously managing doses during a complex imaging procedure requires an understanding of the capabilities and limitations of the fluoroscope, establishing good practice habits, and using all the appropriate features of the imaging equipment [bib_ref] The ALARA concept in pediatric cardiac catheterization: techniques and tactics for managing..., Justino [/bib_ref]. When effectively implemented, these approaches can reduce both the radiation dose per image and the number of images created during a procedure without compromising the quality of the study [bib_ref] Impact of imaging approach on radiation dose and associated cancer risk in..., Hill [/bib_ref]. In addition to the recommendations provided in Tables 7 to 9, further explanation is required regarding the use of anti-scatter grids . These grids are beneficial when there is significant scattered radiation. However, when scatter is reduced (i.e., in smaller patients), anti-scatter grids continue to attenuate some of the unscattered x-rays leading autoexposure controls to increase radiation output of the system, thereby contributing to increased dose to the patient with little benefit [bib_ref] Influence of the antiscatter grid on dose and image quality in pediatric..., Ubeda [/bib_ref]. Although the operator's tolerance for reduced contrast in the image (subjective) should determine when the grid is removed, for ease of implementation, we have provided a consensus recommendation for removal in children <20 kg. This is subject to reappraisal as newer technologies emerge and may require ongoing discussion with equipment vendors. Providers should note that if other imaging parameters are left unaltered, then removing the grid will always reduce the dose. In larger children or adults, this is detrimental to image quality. Therefore, individual practices may prefer to define the specific body habitus limits at which they feel image quality is sufficiently degraded to warrant using an anti-scatter grid. The air gap technique [fig_ref] FIGURE 5: Air Gap Technique [/fig_ref] is an alternate approach designed to limit the effects of scatter radiation on image quality without the dose penalty associated with an anti-scatter grid. With this technique the anti-scatter grid is removed, and the image receptor is moved approximately 15 cm from the patient, thereby creating an air gap. The geometry of the air gap causes most of the obliquely scattered x-rays emitted from the patient to "miss" the image receptor, whereas all the unscattered x-rays reach the image receptor. Without the grid in place, there is an increased dose rate to the image receptor, and the automatic exposure control system will respond by decreasing the dose rate delivered to the patient [bib_ref] Radiation dose reduction without compromise of image quality in cardiac angiography and..., Partridge [/bib_ref]. The increased receptor height also creates geometric magnification in the image. At 15 cm, this approximates a 1-step increase in electronic magnification, and users can maximize dose reductions by reducing the electronic magnification. However, as geometric magnification grows with increased air gap, perceptible image blur results in most cardiac systems with focal spots larger than 0.3 mm. Given the complexity of using geometric magnification properly, we recommend that practices work with qualified medical physicists to evaluate the impact of the air gap technique on the dose-image quality relationship with their fluoroscope. It is important to note that the air gap technique should not be used when the anti-scatter grid is in place. This redundancy needlessly increases overall dose to the patient due to auto-exposure control response to reduced signal intensity at the receptor. ## Use of fluoroscopy during electrophysiology procedures Advances in imaging techniques, specifically, 3D electroanatomic mapping (EAM) systems, have significantly reduced the use of fluoroscopy within the electrophysiology lab. These mapping systems, such as CARTO (Biosense Webster, South Diamond Bar, California) and Nav-X (St. Jude Medical, St. Paul, Minnesota), allow for the creation of 3D shells of intracardiac chambers and vessels, over which catheters can be visualized without the use of radiation. As EAM tools have advanced, the ability to perform safe and effective ablations using minimal radiation has been demonstrated in numerous studies [bib_ref] Exclusion of fluoroscopy during ablation treatment of right accessory pathway in children, Drago [/bib_ref] [bib_ref] The use of an integrated electroanatomic mapping system and intracardiac echocardiography to..., Mah [/bib_ref] [bib_ref] Nonfluoroscopic imaging systems reduce radiation exposure in children undergoing ablation of supraventricular..., Miyake [/bib_ref] [bib_ref] Radiofrequency ablation of accessory pathways in children and congenital heart disease patients:..., Papagiannis [/bib_ref] [bib_ref] Elimination of fluoroscopy use in a pediatric electrophysiology laboratory utilizing three-dimensional mapping, Smith [/bib_ref] [bib_ref] Significant reduction of fluoroscopy in pediatric catheter ablation procedures: long-term experience from..., Tuzcu [/bib_ref]. For these reasons, we encourage the use of 3D EAM during electrophysiology procedures in children. However, as electrophysiologists strive to perform zero-fluoroscopy studies, there is continued acknowledgment that fluoroscopy is still necessary for specific aspects of an electrophysiology procedure. This includes maneuvering long sheaths that cannot be seen on an EAM system and trans-septal needle punctures, although the latter could be addressed with intracardiac echocardiography and operator familiarity with intracardiac images. In addition, the financial costs of additional tools to allow nonfluoroscopic trans-septals and the need for an additional venous sheath should be weighed against the amount of fluoroscopy saved [bib_ref] The use of an integrated electroanatomic mapping system and intracardiac echocardiography to..., Mah [/bib_ref]. Lastly, some EAM systems, such as the CARTO UniVue platform, actually encourage a limited amount of fluoroscopy. Spot fluoroscopic pictures can be stored and used as background images on which electroanatomic shells can be superimposed. As such, the use of nonfluoroscopic imaging tools should go hand in hand with radiation reduction techniques. Even if the fluoroscopy time is minimal, electrophysiologists should not neglect the basic tenets of radiation reduction, as outlined in [fig_ref] TABLE 7: Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children [/fig_ref]. Moreover, consistent with our earlier recommendations, optimization of the fluoroscopic hardware and its configuration is important for electrophysiology procedures, just as it is for any procedure involving fluoroscopic guidance. Relative to cardiac catheterization procedures, electrophysiology procedures can potentially be safely performed using lower frame rates as well as lower a dose per frame for both acquisition and fluoroscopy imaging [bib_ref] Reducing patient radiation dosage during pediatric SVT ablations using an "ALARA" radiation..., Gellis [/bib_ref]. Providers should work with the fluoroscope's design engineers and/or qualified medical physicists to develop imaging protocols that meet the specific needs of the electrophysiology laboratory. ## Programmatic approaches to ensure sustained best practices Programmatic quality controls, including checklists and dose monitoring practices, can help sustain program-wide dose reduction efforts. These approaches track performance, motivate team members, and facilitate sustained, high performance. Several studies have demonstrated the benefits of implementing systematic approaches such as these [bib_ref] Characterization of radiation exposure and effect of a radiation monitoring policy in..., Verghese [/bib_ref] [bib_ref] Radiation dose from cardiac computed tomography before and after implementation of radiation..., Raff [/bib_ref]. Resources are available to guide institutions with implementation of quality improvement initiatives, including the Society for Cardiovascular Angiography and Interventions "Pediatric Radiation Safety Quality Improvement Toolkit" [bib_ref] Society for Cardiovascular Angiography and Interventions, Pediatric [/bib_ref]. The qualified medical physicist who performs periodic equipment compliance testing should be able to set up simple periodic tests to track the constancy of image quality and patient radiation dose rates of the x-ray equipment in the catheterization laboratory. ## The importance of patient/caregiver-centered imaging Public, patient, and caregiver (e.g., parent) knowledge of the risks of ionizing radiation is often relatively limited; some patients and caregivers are unaware of the potential for harmful effects, whereas others, sometimes heavily influenced by media misrepresentation, perceive risks far greater than those that actually exist [bib_ref] Parental knowledge of potential cancer risks from exposure to computed tomography, Boutis [/bib_ref] [bib_ref] Parental knowledge of radiation exposure in medical imaging used in the pediatric..., Hartwig [/bib_ref]. When surveyed, parents of children undergoing medical imaging procedures overwhelmingly state that they prefer to be informed of risks [bib_ref] Parental knowledge of potential cancer risks from exposure to computed tomography, Boutis [/bib_ref] [bib_ref] Informing parents about CT radiation exposure in children: it's OK to tell..., Larson [/bib_ref]. Moreover, communication of risk is a fundamental responsibility of professionalism, including patient autonomy [bib_ref] The role of CT in professionalism: accreditation, certification and the welfare of..., Frush [/bib_ref] [bib_ref] Disease prevention guidelines from the U.S. Preventive Services Task Force, Sox [/bib_ref]. We encourage involving families in the decision-making process by communicating anticipated risks and benefits of the planned procedure, including those associated with radiation exposure when these are anticipated to be sufficiently high [bib_ref] The communication of the radiation risk from CT in relation to its..., Westra [/bib_ref]. The method and extent of communication can be tailored to the risks and benefits of any given imaging scenario, such as potential cognitive deficits from general anesthesia (114) used for MR evaluation in young children, or IV contrast media for either CT or MR [bib_ref] Survey of gadolinium-based contrast agent utilization among the members of the Society..., Blumfield [/bib_ref] [bib_ref] Nonionic iodinated intravenous contrast material-related reactions: incidence in large urban children's hospital-retrospective..., Callahan [/bib_ref]. An offer to provide written or electronic materials may suffice for lower-dose procedures, whereas for procedures involving higher doses, direct verbal communication, with or without formal written consent, may be more appropriate. Radiation dose thresholds that dictate the level of discussion have been previously recommended for adult cardiac imaging. These recommendations, provided by an expert panel sponsored by the National Institutes of Health-National Heart, Lung, and Blood Institute/National Cancer Institute, specify that when there is an anticipated procedural effective dose of ≤3 mSv, the procedure is of very low risk and not warranting extensive discussion or written informed consent. By contrast, an anticipated effective dose of ≥20 mSv is considered at a level requiring either formal discussion or written informed consent [bib_ref] Patient-centered imaging: shared decision making for cardiac imaging procedures with exposure to..., Einstein [/bib_ref]. It is beyond the scope of this paper to recommend specific dose cutpoints for pediatric cardiac imaging; however, doses of >20 mSv have been reported for some pediatric cardiac imaging procedures, and these adult guidelines may be useful as a frame of reference [bib_ref] Cumulative exposure to medical radiation for children requiring surgery for congenital heart..., Glatz [/bib_ref] [bib_ref] Impact of imaging approach on radiation dose and associated cancer risk in..., Hill [/bib_ref]. Finally, it is necessary to acknowledge the importance of multidisciplinary communication, including the referring physician, imaging physician, and other members of the care team. This is paramount to ensure that the procedure is performed for appropriate indications with good understanding of the risks and benefits [bib_ref] The communication of the radiation risk from CT in relation to its..., Westra [/bib_ref] [bib_ref] Should we obtain informed consent for examinations that expose patients to radiation?, Nievelstein [/bib_ref]. ## Instituting a dose monitoring program Inherent in the accountability for ionizing radiation dose management across all ages and for any imaging specialty is that of auditing of clinical practice and modification of practice on the basis of the results as necessary [bib_ref] Radiation protection and dose monitoring in medical imaging: a journey from awareness,..., Frush [/bib_ref]. For imaging, this has been referred to as dose tracking or dose monitoring and has recently become a required component of practice accreditation for CT and nuclear medicine, as outlined in The Joint Commission's 2015 document Diagnostic Imaging Requirements. The major goal of a dose monitoring program is to improve individual patient care, as well as the performance across a population of patients within a practice or institution. The primary components of a dose monitoring program consist of: 1) definition of dose metrics to monitor; 2) access to these metrics across different equipment vendors within modalities, as well as between different modalities to enable consistent structured reporting; 3) quality and accuracy of the dose metrics, including the need for harmonious nomenclature for the examination (affording comparison within and between practices and over time); 4) clear analytics to summarize effectively the large amount of data that can be available; and 5) data access and display that are both user friendly and include appropriate security, encryption, and backup. A dose monitoring program is the responsibility of any imaging team and includes physicians and their delegates, including technologists and medical physicists with a heavy dependency on information technology specialists and administration. Information to monitor includes protocol-specific dose metrics that can serve in the establishment of standards of performance (also known as diagnostic reference levels [DRLs]) for the practice, as well as comparison to existing benchmarks, for example, through public registries such as the Dose Index Registry for x-ray CT (122) and the ImageGuide Registry for nuclear cardiology procedures. Methods should be established for identifying dose values outside of the defined reference range (e.g., between first and third quartiles) and for assessing system variability and trends over time, as well as discrepancies between the protocol definitions and protocols performed in clinical practice. One important consideration is whether past radiation history should impact decisions for current or future radiation use for an individual patient [bib_ref] International Atomic Energy Agency study with referring physicians on patient radiation exposure..., Rehani [/bib_ref]. Other challenges include large amounts of data to analyze, what to record, where to report dose metrics (e.g., patient report, PACS [picture archiving and communication system], other archive), inaccurate dose metrology (patient dose estimations), current lack of standardized DRLs (and thresholds for corrective actions), especially using fluoroscopy in the interventional suite, unclear frequency of interrogation, and establishment of authoritative program governance. ## Research needs and future directions Although there are many unmet research needs in terms of improving radiation safety in children with CAHD, several overarching objectives could serve as a framework to accelerate future advances. First, there is a critical need for dose metrics that are standardized and patient-centered, across the spectrum of imaging modalities. The current status quo, with differing metrics preferred depending on the imaging modality, can be confusing for patients and providers, and also poses challenges for comparative effectiveness evaluation. The ideal dose metric should endeavor to assess organ dose, because organ absorbed doses can be more readily compared across the wide spectrum of patient sizes in pediatrics and because organ absorbed doses are also the preferred metric for quantification of stochastic risks (the major radiation-related concern in children). To this end, there is a need to develop pediatric conversion factors to facilitate efficient conversion from standard modality-specific dose metrics (e.g., DLP, SSDE, KAP, and K a,r ) to metrics that reflect organ absorbed doses as well as effective dose. Standardization of dose metrics would also encourage our second identified overarching research need: a need for comprehensive (e.g., risk informed) comparative effectiveness evaluation across the spectrum of medical imaging in children with CAHD. Radiation exposure is one factor among many that can be assessed and compared between testing strategies in such a context. In adult cardiology, several completed and on-going randomized comparative effectiveness trials have evaluated specific clinical scenarios in which different imaging-based management strategies are considered. These trials are often particularly high yield as even negative trials can reduce the use of ionizing radiation and decrease population exposure. Examples of such studies include the DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial, studying screening nuclear stress testing in asymptomatic diabetic patients [bib_ref] Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with..., Young [/bib_ref] , the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) study, comparing initial anatomic imaging versus functional testing strategies in patients with new symptoms suggestive of coronary artery disease (125), the SCOTHEART (Scottish Computed Tomography of the Heart) trial, assessing the effect of added coronary CT angiography in patients with suspected angina [bib_ref] CT coronary angiography in patients with suspected angina due to coronary heart..., Investigators [/bib_ref] , and the PARR-2 (PET and the Recovery Following Revascularization-2) trial of standard versus PET-assisted management strategies in patients with left ventricular dysfunction being considered for coronary revascularization [bib_ref] F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular..., Beanlands [/bib_ref]. Similar trials should be considered in children with CAHD, for example, to consider accurate risks and benefits of screening cardiac catheterization procedures in single-ventricle patients or optimal modalities for coronary imaging (e.g., after arterial switch operations, in patients with Kawasaki disease, or anomalous coronary arteries). Registry-or trial-based comparative effectiveness evaluations contribute critical evidence that can be used to guide consensus guidelines focused on study justification or the development of appropriate use criteria. Finally, there is a need to evaluate the relative merits of cumulative dose monitoring in children. Patient passport models have been advocated by some as a means to monitor cumulative dose. Benefits include enhanced patient and provider awareness, and improved understanding of the long-term consequences of cumulative exposures. However, opponents to this position argue that there is currently an inherent uncertainty in dose and risk estimates and that dose passports can create undue anxiety with the potential to adversely influence medical decision making in the absence of guidelines for appropriate identification and management of patients exposed to high cumulative doses [bib_ref] ICRP and radiological protection in medicine, Cousins [/bib_ref]. [bib_ref] Radiation exposure from CT scans in childhood and subsequent risk of leukaemia..., Pearce [/bib_ref] , and 7 to 10 summarize consensus recommendations regarding strategies to optimize imaging during cardiac CT, nuclear cardiology, and fluoroscopically guided cardiac catheterization and electrophysiology procedures, respectively. These approaches are comprehensive, covering the spectrum of hardware and software features and configuration, as well as operator-dependent approaches to imaging. If broadly implemented by programs caring for children with CAHD, these recommendations could facilitate significant population-level reductions in cumulative ionizing radiation exposure while concomitantly ensuring high-quality imaging that does not compromise diagnostic integrity or procedural safety. Other measures, including a concerted effort to engage patients and caregivers in an informed decision making process related to medical imaging and efforts to develop program-wide dose monitoring procedures, are also recommended to improve patient care and to encourage informed imaging. The development of current cardiac imaging technologies has revolutionized the practice of cardiovascular medicine in children with CAHD by facilitating improved diagnosis and less-invasive intervention. It is now incumbent on the imaging community to ensure that these procedures are optimized to ensure image quality appropriate to the medical needs of the patient but at the lowest achievable dose. has received institutional research grants for other investigator-initiated studies from Philips Healthcare. Dr. Einstein has received research grants to Columbia University from GE Healthcare, Philips Healthcare, and Toshiba America Medical Systems. # Conclusions ## Abbreviat ions and acronyms ## Figure 1. case illustrating low-dose cardiac ct in children This CT scan was performed in a 1-day-old patient (2.8 kg) with an aortopulmonary (AP) window and aortic coarctation to further define great arterial anatomy. The patient was free breathing and without sedation (heart rate 145 beats/min). A total of 5.5 ml of iodinated contrast was mixed with an equivalent volume of saline and delivered via power injector through a 22-ga peripheral intravenous line placed in the left antecubital vein at a rate of 1 ml/s. The scan was performed on a third-generation dual source CT scanner (Somatom Force, Siemens Medical, Forchheim, Germany). Scan specifications included: 2 × 96 detector rows, 0.25-s gantry rotation time, 66-ms temporal resolution, 730-mm/s table acquisition speed. A prospectively ECG-triggered high-pitch (3.2) helical scan mode was used with 70-kVp tube voltage, automatic exposure control with online modulation (CARE Dose4D, Siemens Medical). The CT dose-volume index (CTDIvol) was 0.23 mGy, and the scan dose-length product (DLP) was 2.9 mGy · cm. Data were processed using a modelbased iterative reconstruction algorithm with a strength of 3. An isovolumetric 0.5-mm dataset was analyzed on a dedicated 3D workstation (Vitrea Enterprise Viewer, Vital Images, arrow), mid (70%; yellow arrow), and distal (90%; red arrow) left anterior descending artery, and a patent stent in the circumflex. He received a drug-eluting stent in the proximal vessel, and balloon angioplasty of the mid and distal segments. Images courtesy of Michael Collins MD, Ketan Bhattia CNMT, and Andrew J. Einstein MD, PhD, Columbia University Medical Center/New York-Presbyterian Hospital. ## Figure 3. effects of operator-dependent approaches to dose management In A, the image receptor is raised 20 cm from the patient (source-to-image distance [SID] = 113 cm), electronic magnification is increased (6-inch field of view [FOV]), and there is no collimation. In B, the image receptor is lowered to the patient (93 cm SID), electronic magnification is reduced 1 step (8-inch FOV), and the image is maximally collimated on all sides. The effective dose to the phantom (approximating a 3.5-kg, 51-cm neonate) for fluoroscopy in A was 0.74 mSv/min versus 0.27 mSv/min in B, a 2.7-fold reduction. Depending on the type of diagnostic or interventional procedure being performed, this reduced level of magnification may be adequate, and can achieve significant radiation reduction. With removal of the anti-scatter grid, the dose is further reduced to 0.14 mSv/min. ## Figure 4. anti-scatter grid removal The receptor from a Philips Allura XPER (Philips, Amsterdam, the Netherlands) system is demonstrated with the anti-scatter grid in place (A) and removed (B). On this particular system, the grid can be removed easily using the locking mechanism seen in A (asterisk). The anti-scatter grid has been removed, the receptor is raised 15 cm (SID = 106 cm), and the FOV has been increased to 10-inch (1-step reduction in electronic magnification). Both images are collimated on the periphery. On this particular fluoroscope, the air gap technique achieves a similar appearing image, but dose-area product for this 20-s acquisition is reduced from 3.76 mSv in A to 2.79 mSv in B. Abbreviations as in . ## Central illustration. key approaches for dose optimization of non-invasive cardiac imaging procedures in children Hill et al. ED is estimated by multiplying DLP by conversion factor. Bold type highlights cardiac-specific conversion factors determined using ICRP Publication 103 (2) definition of ED, which reflects optimal protocol and definition for estimation of ED for a cardiac CT scan. Average cardiothoracic conversion factors using ICRP 103 definition of ED are provided in [fig_ref] TABLE 2: Pediatric Average Cardiothoracic CT Conversion Factors Relating DLP to ED in Children [/fig_ref]. * For experiments performed with 16-cm phantom, the conversion factor here is normalized to 32-cm phantom by a factor of 2.0. † Using a factor of 1.9 which was determined on the CT scanner for this specific work, instead of a factor of 2.0, which would yield a normalized conversion factor of 0.087. ‡ Heart rate-lowering medications should be considered for coronary imaging. Pacemaker rate and mode should be adjusted for optimal imaging. Sedation and/or anesthesia for suspended respiration in patients unable to cooperate may be needed when patient motion may affect image quality. Contrast injection technique should be planned to simultaneously opacify all structures of interest in a single phase. ## Scanner-based approaches Scan range should be limited to the anatomy requiring evaluation. Center the patient within the gantry. Technique should be adjusted to: Yield acceptable image quality that is tailored to the clinical indication. Patient size: lower tube potential (kVp) settings can be used for most children. Use of automated tube current and tube potential algorithms should be considered. Scan mode chosen should provide diagnostic image quality at the lowest practical radiation dose. Prospective ECG triggering should be used when possible. ECG-gated tube current modulation should typically be used for functional imaging. Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children: Operator ## Approach rationale Select patient size and type of exam to manage acquisition parameters Purpose of anatomic programming is to select configurable parameters to manage patient dose and image quality during exam. Remove anti-scatter grid in children <20 kg Patient dose rate is reduced with limited loss of image quality. Remove extraneous body parts and other objects (e.g., arms, TEE probe) from the imaging FOV Imaging through extraneous body parts and objects causes autoexposure controls to increase dose, and image quality is degraded. Position patient at the imaging isocenter Prevents anatomy of interest from shifting out of FOV as projection angles are changed and provides reasonable distance between x-ray tube and entrance plane of the patient. Raise table to increase distance from radiation source (x-ray tube) to patient Dose to the patient's skin decreases according to the inverse square law. In a biplane laboratory, table height may be limited by the need to position the patient for imaging with the lateral camera. ## Minimize distance between patient and image receptor A gap between exit plane of patient and image receptor requires more radiation at the patient and increases radiation dose. An exception is the air gap technique where receptor distance is increased and the anti-scatter grid is removed. Start with a "low-dose" fluoroscopy mode selection and only increase (i.e., to moderate-or high-dose mode) if needed Standards require at least 2 operator-selectable dose modes at table side. Operators can select a higher-dose mode if needed. Pulsed fluoroscopy rates should not exceed 15 pulses/s The lowest pulse rate that provides adequatetemporal resolution reduces dose to the patient. Slower pulse rates (10, 7.5, 3.5 pulses per second) may be adequate. Acquisition (cineangiography) frame rates should not exceed 30 frames/s Lower fame rates (e.g., 15 or 7.5 frames per second) should be considered for slower heart rates or when imaging slow-moving structures (e.g., venous angiography) to reduce patient dose. Use collimation to reduce irradiated area. Include only necessary landmarks in image Collimation improves image contrast and quality by limiting scatter radiation and reduces the irradiated area (volume) of the patient's body. Use largest FOV (least electronic magnification) Dose rates increase proportionately to the inverse of the FOV change (e.g., changing FOV from 20 cm to 12 cm increases dose rate 1.6 fold. Use of electronic magnification should be limited to critical times during a procedure when a magnified image is needed (e.g., manipulating a guidewire into a small vessel). Avoid excessive use of oblique imaging angles Oblique imaging requires the x-ray beam to pass through more tissue. This degrades image quality and causes autoexposure controls to increase radiation dose rate. Limit beam "on" time: Beam "on" time is directly proportional to dose. Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children: Electrophysiology Procedures ## Approach rationale Use 3D EAM Purpose of anatomic programming is to select configurable parameters to manage patient dose and image quality during exam. Remove anti-scatter grid in children <20 kg Patient dose rate is reduced with limited loss of image quality. Remove extraneous body parts and other objects (e.g., arms, TEE probe) from the imaging field of view Imaging through extraneous body parts and objects causes autoexposure controls to increase dose and image quality is degraded. Position patient at the imaging isocenter Prevents anatomy of interest from shifting out of field of view as projection angles are changed and provides reasonable distance between x-ray tube and entrance plane of the patient. Raise table to increase distance from radiation source (x-ray tube) to patient Dose to the patient's skin decreases according to the inverse square law. In a biplane laboratory, table height may be limited by the need to position the patient for imaging with the lateral camera. ## Minimize distance between patient and image receptor A gap between exit plane of patient and image receptor requires more radiation at the patient and increases radiation dose. An exception is the air gap technique where receptor distance is increased and the anti-scatter grid is removed. Start with a "low-dose" fluoroscopy mode selection and only increase (i.e., to moderateor high-dose mode) if needed Standards require at least 2 operator-selectable dose modes at table side. Operators can select a higher-dose mode if needed. 3D EAM = 3-dimensional electroanatomic mapping; TEE = transesophageal echocardiography. JACC Cardiovasc Imaging. Author manuscript; available in PMC 2018 July 01. [fig] FIGURE 5: Air Gap Technique (A) Phantom imaging using a phantom representing a 3.5-kg, 51-cm neonate, is performed with a traditional setup including SID of 91 cm (image receptor 15 cm from phantom, lowest achievable), 8-inch FOV and the anti-scatter grid in place. (B) Phantom imaging using the air gap approach. [/fig] [table] Page 35 TABLE 1: Pediatric Cardiac and Chest CT Conversion Factors Relating DLP to ED in Children [/table] [table] TABLE 2: Pediatric Average Cardiothoracic CT Conversion Factors Relating DLP to ED in Children [/table] [table] TABLE 3: ED Coefficients (mSv/mCi) Relating ED (mSv) to Administered Activity (mCi) for Myocardial Perfusion Imaging in Children and AdultsAdult 15 Years 10 Years 5 Years 1 YearData from ICRP Publication 128(48), with the exception of N-13 ammonia, for which data are from ICRP Publication 80(46) in adults and ICRP Publication 53 (45) in children. To determine estimated effective dose (mSv), multiply administered activity (mCi) by appropriate coefficient in the table. ED = Effective dose. JACC Cardiovasc Imaging. Author manuscript; available in PMC 2018 July 01. [/table] [table] TABLE 4: Approaches for Dose Optimization of Cardiac CT Procedures in Children [/table] [table] TABLE 5: Approaches for Dose Optimization of Nuclear Cardiology Procedures in Children• Stress-first/stress-only imaging for SPECT and PET myocardial perfusion imaging • Multiple position imaging, to increase normalcy rate of stress-first imaging • Rest imaging, when needed, performed on later day than stress imaging • Avoidance of thallium-201 • Use of PET imaging tracers where available and appropriate • Administered activity based on patient's age and/or habitus • Use of advanced hardware (e.g., high-efficiency camera) or software (e.g., resolution recovery and noise reduction) technology to reduce administered activity • Minimization of x-ray CT tube current for PET attenuation correction • Use 3D acquisition mode for PET 3D = 3-dimensional; CT = computed tomography; PET = positron emission tomography; SPECT = single-photon emission computed tomography. JACC Cardiovasc Imaging. Author manuscript; available in PMC 2018 July 01. [/table] [table] TABLE 7: Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children: Hardware FeaturesApproach Rationale X-ray tube: High kW rating ensures adequate radiation output for pediatric patients that are adult or near adult sized Largest focal spot size: 0.8-1.0 mm; 80-90 kW Smallest focal spot size: ~0.3 mm; 12 kW 0.3-mm focal spot size is required to adequately support use of geometric magnification with minimal image blur Maximum kW rating of the x-ray tube and generator match Allows adequate penetration of adult or near adult-sized pediatric patients Programmable age-appropriate radiological acquisition settings for patient sizes from 2-125 kg Optimal settings vary depending on body habitus and region of body imaged Various filters, with atomic numbers greater than aluminum, inserted in the x-ray beam selectively remove low-energy, and pass high-energy x-rays to reduce skin dose Virtual collimation to indicate graphically the location of the collimator blades or partial wedge filters without requiring fluoroscopy Saves fluoroscopy time positioning collimators and wedge filters Size of image receptors should be appropriate to the clinical practice Although 23-cm image receptors are adequate for most adult cardiac catheterizations, larger format frontal plane image receptors (~35 cm) may be beneficial for pediatric imaging to visualize both lungs Last image hold and last fluoro loop store/playback features Allow images to be studied without further irradiation Radiotranslucent patient comfort and positioning pads Radio-opaque arm boards and other patient supports or pads can lead to artifacts in the image, increase scatter that reduces contrast in the image, reduce ability to penetrate large patients, and increase operator occupational dose from stray radiation [/table] [table] TABLE 8: Approaches for Dose Optimization of Fluoroscopically Guided Cardiac Procedures in Children: Software ConfigurationSelect settings based on type of exam and patient size Large patients may require maximum output of the fluoroscope. Small patients require different choices to manage dose and improve image quality Select focal spot automatically based on patient size Smallest focal spot size that provides adequate penetration improves visibility detail in the image Keep pulse width ≤5 ms in small children and ≤10 ms in adolescent or adult patients Short pulse widths freeze cardiac motion, which improves image sharpness of rapidly moving objects; longer pulse widths for adults improves penetration through thick body partsUse algorithms for small children to reduce tube current or pulse width to prevent reduction of voltage below 60 kV Voltages <70 kV do not improve contrast of iodine in the image but do unnecessarily increase patient dose rates relative to 70 kVSelect voltage and added filter thickness automatically as a function of patient mass Filter thickness and voltage determine average energy of x-ray beam impinging on patient, which balances diagnostic image quality against well-managed patient doses depending on patient mass Use AKIR α 1/(FOV) 0.5 or constant based on pulse rate KIR with flat panel detectors should follow AKIR α 1/(FOV) 0.5 to manage patient dose while maintaining image quality. To manage AKIR with image intensifiers, the relationship is AKIR α 1/(FOV). For example, as the FOV is reduced by a factor of 2, this results in an increase of patient dose rate by a factor of 1.4 and 2.0 for the flat panel detector and image intensifier, respectively. AKIR = air kerma rate at image receptor; FOV = field of view; KIR = kerma rate at image receptor. JACC Cardiovasc Imaging. Author manuscript; available in PMC 2018 July 01. [/table]	None	None	None
5e83cbf0c9967fc54340a98fc9b072b1583b135d	pubmed	Clinical practice guidelines for visualized percutaneous breast tissue clips: Chinese Society of Breast Surgery (CSBrS) practice guideline 2021	Clinical practice guidelines for visualized percutaneous breast tissue clips: Chinese Society of Breast Surgery (CSBrS) practice guideline 2021 ## Indications of tissue clips Level of evidence Strength of recommendation 1. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Indications for primary breast lesion 1.1. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Non-palpable suspicious breast lesion, for surgical biopsy [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] II A 1.1.2 Non-palpable breast cancer, for breastconserving surgery [bib_ref] Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical..., Rahusen [/bib_ref] [bib_ref] Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection..., Corsi [/bib_ref] I A ## 1.1.3 Breast cancer for neoadjuvant therapy and breastconserving surgery [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] I A 1.2 Indications for axilla lymph node 1.2. [bib_ref] A plea for the biopsy marker: how, why and why not clipping..., Thomassin-Naggara [/bib_ref] Pathologically confirmed metastatic axillary LN (pN1), for neoadjuvant therapy [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] I A # Discussion With the widespread screening for breast cancer, detected nonpalpable breast lesions have been increased. [bib_ref] Intraoperative margin management in breast-conserving surgery: a systematic review of the literature, Gray [/bib_ref] Clip placement in nonpalpable suspicious breast lesions could provide help in follow-up and surgical biopsy. [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] The expert panel recommended the clip placement in nonpalpable breast suspicious lesions as one indication. Accurate localization of nonpalpable breast cancer is a prerequisite for breast-conserving surgery, whereas clip placement and localization could increase negative margin rate to 90%, [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] and reduce the secondary resection. [bib_ref] Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical..., Rahusen [/bib_ref] [bib_ref] Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection..., Corsi [/bib_ref] The expert panel recommended the clip placement and perioperative poisoning in nonpalpable breast cancer intended for breast-conserving surgery as one indication. In breast cancer neoadjuvant therapy, the clinical complete remission rate could reach 20% to 57%. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] Therefore, residual lesion re-localization after neoadjuvant therapy is important. Retrospective studies showed that clip placement at primary breast cancer before neoadjuvant therapy helped localize tumor intraoperatively and improve the negative surgical margin rate. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] Besides, the 5-year local recurrence rate was lower in the clipped group than in the control. [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] The expert panel recommends the clip placement for primary breast cancer in neoadjuvant patients, especially planned for breast-conserving surgery. Functional axillary LN dissection has received increasing attention recently. The ACOSOG Z1071, MARI, and ILINA trials have shown the feasibility of the targeted axillary dissection (TAD) technique, suggesting that the removal of sentinel and clipped LNs could reflect the axillary LNs status (false negative rate/FNR 2%-7%) and reduce the incidence of postoperative upper limb lymphedema. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] [bib_ref] Improving the accuracy of axillary lymph node surgery in breast cancer with..., Plecha [/bib_ref] The expert panel recommends clip placement to label the pathologically confirmed metastatic axillary LN (pN1) before neoadjuvant therapy, providing an opportunity for TAD. The contraindications to US or MMG-guided clip placement for breast lesion and axillary LN should be based on the preoperative evaluation principles of breast lesion and regional LN biopsy, with reference to published exclusion criteria in clinical trials. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] The expert panel recommends the contraindications for clip placemen at Recommendation 2. US-guided clip placement has been reported to be more accurate than X-ray-guided placement. [bib_ref] Sonographically guided metallic clip placement after core needle biopsy of the breast, Phillips [/bib_ref] [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] The expert panel preferred US-guided clip placement, with X-rayguided placement as an optional method. Regarding the number of clips to be placed, which should balance localization accuracy and medical cost, [bib_ref] Intraoperative ultrasound guidance with an ultrasound-visible clip: a practical and cost-effective option..., Konen [/bib_ref] [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] the expert panel recommended one clip for each primary breast lesion or metastatic axillary LN. Due to the small size of clips, intraoperative position failure and loss of clips have been reported in 5% to 20% of cases. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] Considering the clinical operability and accessibility in China, the expert panel recommended the use of guide wires or dyes for preoperative assisted clip localization, and isotopic tracers could be used when available. Intraoperative resected specimens need to be reexamined, and the expert panel recommends the use of radiographic imaging for intraoperative clip confirmation. Regarding the timing of clip placement, delayed clip placement in primary breast lesions after 2-cycle of effective neoadjuvant therapy may achieve some health- [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A 2.2 Concomitant severe bleeding or coagulation disorders [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A ## 2.3 The presence of breast local infection or adjacent to the breast prosthesis [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A Number of clips placed 3.1.1 One placed in the center of primary breast lesion [bib_ref] Intraoperative ultrasound guidance with an ultrasound-visible clip: a practical and cost-effective option..., Konen [/bib_ref] [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] II A 3.1.2 One placed in the center of metastatic axillary LN [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A 3.2 Imaging-guided approaches for clip placement 3.2.1 Ultrasound-guided placement [bib_ref] Surgical benefits conveyed by biopsy site marking system using ultrasound localization, Nurko [/bib_ref] [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] [bib_ref] Ultrasound-guided segmental mastectomy and excisional biopsy using hydrogel-encapsulated clip localization as an..., Gentile [/bib_ref] I A 3.2.2 X-ray-guided placement [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] I A ## 3.3 Preoperative clip localization methods 3.3.1 Guide wire [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] [bib_ref] Wire guided localisation for targeted axillary node dissection is accurate in axillary..., Balasubramanian [/bib_ref] I A 3.3.2 Dye [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] I A 3.3.3 Isotopic tracer [bib_ref] Radio-guided and clip-guided preoperative localization for malignant microcalcifications offer similar performances in..., Corsi [/bib_ref] I A 3.4 Intraoperative clip confirmation 3.4.1 Intraoperative radiography [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] I A ## 3.5 Timing of clip placement in neoadjuvant therapy 3.5.1 Before neoadjuvant therapy following pathological confirmation of primary breast cancer lesion [bib_ref] Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy..., Oh [/bib_ref] I A 3.5.2 Before neoadjuvant therapy following pathological confirmation of metastatic axillary LN [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] I A LN: Lymph nodes. Chinese Medical Journal 2021;134 [bib_ref] Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip..., Kim [/bib_ref] www.cmj.org economics advantages, [bib_ref] Influencing factors of placement and removal of breast tissue marker clips in..., Yizhou [/bib_ref] but further confirmation is needed from prospective studies. For metastatic axillary LN, published studies indicated that clip placement needed before neoadjuvant therapy. [bib_ref] Identification and resection of the clipped node decreases the false negative rate..., Boughey [/bib_ref] [bib_ref] Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer..., Caudle [/bib_ref] [bib_ref] Intraoperative ultrasound-guided excision of axillary clip in patients with node-positive breast cancer..., Siso [/bib_ref] The expert panel recommends clip placement in pathologically confirmed primary breast cancer and metastatic axillary LN before neoadjuvant therapy. Appendix 1: Technical guidelines for visualized percutaneous breast tissue clip placement, http://links.lww.com/ CM9/A624. ## Conflicts of interest The expert committee for these guidelines declares no conflict of interest. These guidelines are a reference for breast disease specialists in clinical practice. However, the guidelines are not to be used as the basis for medical evaluation, and do not play an arbitrating role in the handling of any medical disputes. The guidelines are not a reference for patients or nonbreast specialists. The Chinese Society of Breast Surgery assumes no responsibility for results involving the inappropriate application of these guidelines and reserves the right to interpret and revise the guidelines. List of Committee members (In alphabetical order by surname): Zhong-Wei Cao, Yuan-Jia Cheng, De-Tian	None	None	Breast tissue clip is a kind of tissue marker visible under ultrasound (US), mammogram (MMG), and magnetic resonance imaging (MRI) and could be used to precisely mark the breast lesions and axillary lymph nodes (LN) under US or MMG guidance. In order to standardize the clinical application of tissue clip, the Chinese Society of Breast Surgery (CSBrS) identified key clinical issues and developed this clinical practice guideline after evaluating the evidence with reference to the GRADE (ie, Grading of Recommendations Assessment, Development, and Evaluation) system and the accessibility in clinical practice.
91575fc2e7993cd9e1e04c68aef49894d08655b6	pubmed	MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy	MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy # Introduction Mucositis refers to mucosal damage secondary to cancer therapy occurring in the oral cavity; pharyngeal, laryngeal, and esophageal regions; and other areas of the gastrointestinal tract. Mucositis can be caused by chemotherapy and=or radiation therapy. It occurs in approximately 20% to 40% of patients receiving conventional chemotherapy, 80% of patients receiving high-dose chemotherapy as conditioning for hematopoietic stem cell transplantation (HSCT), and nearly all patients receiving head and neck radiation therapy (H&NRT). [bib_ref] Epidemiology of treatment-associated mucosal injury after treatment with newer regimens for lymphoma,..., Jones [/bib_ref] [bib_ref] Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with..., Vera-Llonch [/bib_ref] [bib_ref] Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma, Vera-Llonch [/bib_ref] Oral mucositis presents as erythema and=or ulceration of the oral mucosa. In addition, the pharyngeal, laryngeal, and esophageal mucosa are also at risk for mucositis, particularly in patients undergoing H&NRT. It is typically very painful, requiring opioid analgesics, and impairs nutritional intake and quality of life. [bib_ref] Patterns of mucositis and pain in patients receiving preparative chemotherapy and bone..., Mcguire [/bib_ref] [bib_ref] Quality of life, mucositis, and xerostomia from radiotherapy for head and neck..., Duncan [/bib_ref] Gastrointestinal mucositis presents with debilitating symptoms such as pain, nausea=vomiting, and diarrhea. [bib_ref] Intestinal mucositis: mechanisms and management, Keefe [/bib_ref] Severe mucositis can necessitate a reduction in the chemotherapy dose or a treatment break in RT, which can negatively influence prognosis. [bib_ref] The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis, Elting [/bib_ref] [bib_ref] Mucositis incidence, severity and associated outcomes in patients with head and neck..., Trotti [/bib_ref] In addition, mucositis has a considerable economic impact, due to costs associated with symptom management, nutritional support, management of secondary infection, and hospitalization. [bib_ref] The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis, Elting [/bib_ref] [bib_ref] Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck..., Elting [/bib_ref] Thus, mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. Although direct cell damage from chemotherapy and=or RT initiates the process, evidence suggests that the pathogenesis of mucositis is more complex. [bib_ref] New thoughts on the initiation of mucositis, Sonis [/bib_ref] A 5-stage model has been proposed. [bib_ref] The pathobiology of mucositis, Sonis [/bib_ref] Reactive oxygen species, second messengers, proinflammatory cytokines and pathways, and metabolic byproducts of colonizing microorganisms are all believed to play a role in amplifying the tissue injury. [bib_ref] Emerging evidence on the pathobiology of mucositis, Al-Dasooqi [/bib_ref] As a result, a large number of diverse interventions have been tested for mucositis. Although many of these interventions are available over the counter or for off-label use or marketed as devices, to the best of our knowledge only 1 agent to date has been approved by the US Food and Drug Administration as a drug for mucositis, albeit in a relatively restricted population. Studies of many interventions range widely in quality, sometimes with conflicting results. Therefore, there is a need for evidence-based clinical practice guidelines for mucositis to guide clinicians on which interventions are truly effective. In 2004, the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology published what to our knowledge were the first evidencebased clinical practice guidelines for mucositis.The first update of these guidelines was published in Cancer in 2007. [bib_ref] Updated clinical practice guidelines for the prevention and treatment of mucositis, Keefe [/bib_ref] Over the last decade, other organizations have also published guidelines for mucositis. The guidelines published by the European Society for Medical Oncology are a direct adoption of the MASCC=ISOO guidelines. [bib_ref] ESMO Guidelines Working Group. Management of oral and gastrointestinal mucositis: ESMO Clinical..., Peterson [/bib_ref] The guidelines published by the US National Comprehensive Cancer Network are an adaptation of the MASCC=ISOO guidelines, combined with expert opinion. [bib_ref] NCCN Task Force Report. Prevention and management of mucositis in cancer care, Bensinger [/bib_ref] Thus, the MASCC=ISOO mucositis guidelines are the leading clinical practice guidelines for this toxicity. Due to the large volume of additional literature published since the last update, we undertook the second revision of these guidelines, which is presented here. # Materials and methods Our methods and the underlying considerations have been described in detail in 2 recent publications.In brief, we developed evidence-based guidelines based on systematic reviews of the evidence for various interventions. A research librarian constructed search strategies and conducted literature searches through the OVID interface to Medline. Inclusion criteria were English language publications reporting testing of an intervention for mucositis in humans, published in a peer-reviewed journal, and indexed in Medline on or before December 31, 2010. We excluded articles that did not report the effects of an intervention on mucositis or mucositis-related outcomes (such as pain), animal or in vitro studies, and literature reviews. Due to the large number and diverse range of interventions, the reviewers and articles were organized into 8 clinical sections. One section focused on gastrointestinal mucositis and 7 sections examined the following classes of interventions for oral mucositis: 1) basic oral care; 2) growth factors and cytokines; 3) antiinflammatory agents; 4) antimicrobials, coating agents, anesthetics, and analgesics; 5) laser and other light therapy; 6) cryotherapy; and 7) natural and miscellaneous agents. Each of the 8 sections had a section head, 1 co-section heads, and 5 to 10 reviewers. All participants were calibrated to ensure consistency in the application of the review criteria. In addition, reviewers and section heads were provided with role-specific written instructions and a manual detailing the procedures. Each article was independently reviewed by 2 reviewers. Each reviewer extracted and entered up to 66 fields of data per article into an electronic reviewer form. The quality of the reviewed literature was assessed by identifying major and minor flaws as per the criteria published by Hadorn et al (see online supporting information). [bib_ref] Rating the quality of evidence for clinical practice guidelines, Hadorn [/bib_ref] These criteria specify major and minor flaws for 8 study design variables: selection of patients, allocation to groups, therapeutic regimen, study administration, Review Article withdrawals, blinding, outcome measurement, and statistical analysis. The section heads finalized the reviews of each article and adjudicated discrepancies between the 2 reviewers. Then the overall body of evidence for each intervention, in each treatment setting, was evaluated and assigned a level of evidence, based on criteria published by Somerfield et al [fig_ref] TABLE 1: Criteria for Each Level of Evidence [/fig_ref]. [bib_ref] ASCO clinical practice guidelines: process, progress, pitfalls, and prospects, Somerfield [/bib_ref] These criteria allocate levels of evidence based on the type of study and according to whether a study is well designed. To minimize subjectivity, we defined a "well-designed study" as a study with no major flaws, as per the criteria of Hadorn et al. [bib_ref] Rating the quality of evidence for clinical practice guidelines, Hadorn [/bib_ref] The level of evidence for each intervention was then translated into a provisional guideline, based on criteria published by Somerfield et al [fig_ref] TABLE 2: Criteria for Each Guideline Category [/fig_ref]. [bib_ref] ASCO clinical practice guidelines: process, progress, pitfalls, and prospects, Somerfield [/bib_ref] There were 3 possible categories: "recommendation," "suggestion," or "no guideline possible." Level I or II evidence was required to support a recommendation, which could only be achieved by 1 randomized controlled trials without any major flaws. A suggestion was possible for lower-level evidence but only with consistent evidence from multiple studies and panel consensus on the interpretation of this evidence. When adequate evidence demonstrated the lack of efficacy of an agent, a guideline "against" the use of that agent was developed. The provisional guidelines were discussed and finalized at a full-day, in-person guidelines meeting attended by > 60 members of the panel and 2 independent observers. # Results The literature search identified 8279 articles, 1032 of which were retrieved for detailed evaluation based on titles and abstracts; of these, 570 articles qualified for final inclusion in the systematic reviews (see online supporting information). Less than 5% of all studies reviewed were determined to have no major flaws, as per the criteria of Hadorn et al. [bib_ref] Rating the quality of evidence for clinical practice guidelines, Hadorn [/bib_ref] Summary results for each section are presented below and in [fig_ref] TABLE 3: MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis [/fig_ref] , which also list the specifics of each guideline (whether for the prevention or treatment of mucositis and the specific patient population it applies to). For more detailed results of each section, including tables listing the details of every article reviewed, please refer to the recently published articles from the individual sections. [bib_ref] Systematic review of agents for the management of gastrointestinal mucositis in cancer..., Gibson [/bib_ref] [bib_ref] Systematic review of cytokines and growth factors for the management of oral..., Raber-Durlacher [/bib_ref] [bib_ref] Systematic review of amifostine for the management of oral mucositis in cancer..., Nicolatou-Galitis [/bib_ref] [bib_ref] Systematic review of anti-inflammatory agents for the management of oral mucositis in..., Nicolatou-Galitis [/bib_ref] [bib_ref] Systematic review of laser and other light therapy for the management of..., Migliorati [/bib_ref] [bib_ref] Systematic review of oral cryotherapy for management of oral mucositis caused by..., Peterson [/bib_ref] [bib_ref] Systematic review of natural agents for the management of oral mucositis in..., Yarom [/bib_ref] [bib_ref] Systematic review of miscellaneous agents for the management of oral mucositis in..., Jensen [/bib_ref] [bib_ref] Systematic review of basic oral care for the management of oral mucositis..., Mcguire [/bib_ref] Gastrointestinal Mucositis (Not Including the Oral Cavity) The previous version of the MASCC=ISOO guidelines for gastrointestinal mucositis included guidelines in favor of amifostine, octreotide, sucralfate enemas, and sulfasalazine in specific treatment settings [fig_ref] TABLE 3: MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis [/fig_ref]. In addition, it included guidelines against the use of 5-acetyl salicylic acid and related compounds and oral sucralfate. Based on the present systematic review, these prior guidelines were able to be continued with no changes. One previous guideline, which was against the use of systemic glutamine for the prevention of gastrointestinal mucositis in patients receiving standard-dose and high-dose chemotherapy, was changed to "No guideline possible," based on the incorporation of newer evidence. In addition, 3 new guidelines were developed:1) a suggestion in favor of hyperbaric oxygen to treat radiation-induced proctitis; 2) a suggestion for probiotic agents containing Lactobacillus species for the prevention of chemotherapy and radiation-induced diarrhea in patients with pelvic malignancy; and 3) a recommendation against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis [fig_ref] TABLE 3: MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis [/fig_ref]. [bib_ref] Systematic review of agents for the management of gastrointestinal mucositis in cancer..., Gibson [/bib_ref] Due to inadequate and=or conflicting evidence, no guideline was possible for several agents reviewed, including activated charcoal, balasalazide, budesonide, cefixime, celecoxib, cholestyramine=levofloxacin, chrysin, circadian rhythm, formalin, heater probes, leucovorin, metronidazole, neomycin, palifermin, physical activity, and sodium butyrate. Oral Mucositis ## Basic oral care The results of the current systematic review indicated that most studies examining the use of oral care protocols for the prevention of oral mucositis reported a beneficial effect. These protocols typically included a combination of toothbrushing, flossing, and 1 mouth rinses to maintain oral hygiene. Although the evidence was not strong enough to support a recommendation, there was adequate positive evidence to support a suggestion in favor of using oral care protocols for the prevention of oral mucositis across all cancer treatment modalities . The evidence also supported a suggestion against the use of chlorhexidine mouthwash for the prevention of oral mucositis in patients receiving H&NRT. No guideline was possible regarding the use of oral care protocols for the treatment of oral mucositis. In addition, no guideline was possible related to the individual use of the following mouth rinses: saline, sodium bicarbonate, mixed medication mouthwashes, calcium phosphate, and chlorhexidine in patients receiving chemotherapy, due to inadequate and=or conflicting evidence. 31 ## Growth factors and cytokines To the best of our knowledge, palifermin (keratinocyte growth factor-1) is the only agent that has been approved as a drug by the US Food and Drug Administration and the European Medicines Agency for oral mucositis. Evidence included a large, well-designed, randomized controlled trial and other supporting studies. [bib_ref] Palifermin for oral mucositis after intensive therapy for hematologic cancers, Spielberger [/bib_ref] The previous version of the MASCC=ISOO guidelines for oral mucositis included a recommendation in favor of this agent for the prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. Based on the current systematic review, this recommendation was continued with no change in the target population . The evidence reviewed also continued to support a suggestion against the use of granulocyte-macrophage-colony-stimulating factor mouthwash for the prevention of oral mucositis in patients undergoing autologous or allogeneic HSCT. Furthermore, the use of granulocyte-colony-stimulating factor during H&NRT has been associated with reduced local tumor control. [bib_ref] Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy-results of..., Staar [/bib_ref] Due to inadequate and=or conflicting evidence, no guideline was possible for the following agents reviewed: palifermin and granulocyte-macrophage-colony-stimulating factor in treatment settings other than that listed above, fibroblast growth factor-20, keratinocyte growth factor-2, granulocyte-colony-stimulating factor, transforming growth factor-b, epidermal growth factor, milk-derived growth factor extract, interleukin-11, ATL-104, and recombinant human intestinal trefoil factor. 23 ## Antiinflammatory agents Benzydamine hydrochloride is a nonsteroidal antiinflammatory drug that can inhibit the production of proinflammatory cytokines such as tumor necrosis factor-a and interleukin-1b. The previous version of 1. The panel suggests that intravenous amifostine be used to prevent esophagitis induced by concomitant chemotherapy and radiation therapy in patients with non-small cell lung carcinoma (III). 2. The panel suggests that sucralfate enemas be used to treat chronic radiation-induced proctitis in patients with rectal bleeding (III). 3. The panel suggests that systemic sulfasalazine, at a dose of 500 mg administered orally twice a day, be used to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis (II). 4. The panel suggests that probiotics containing Lactobacillus species be used to prevent diarrhea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy (III). 5. The panel suggests that hyperbaric oxygen be used to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumor (IV). the MASCC=ISOO mucositis guidelines included a recommendation for the use of benzydamine mouthwash to prevent oral mucositis in patients with head and neck cancer who were receiving moderate-dose RT based on evidence from studies indicating a benefit in radiation doses up to 50 grays in patients not receiving concomitant chemotherapy. For the present systematic review, the entire body of evidence, including 2 additional studies in this patient population, was reviewed. These studies did not allow the extension of this recommendation to patients receiving > 50 grays of radia-tion. A new suggestion was developed against the use of misoprostol mouth rinse for the prevention of oral mucositis in patients receiving H&NRT . Although we reviewed 30 studies related to amifostine use for the prevention of oral mucositis in various settings, no guideline was possible due to conflicting evidence. [bib_ref] Systematic review of amifostine for the management of oral mucositis in cancer..., Nicolatou-Galitis [/bib_ref] Additional agents reviewed for which no guideline was possible included diphenhydramine, prostaglandin E2, immunoglobulins, corticosteroids, indomethacin, azelastine, mesalazine, aspirin, orgotein, flurbiprofen, histamine, colchicine, and Placentrex. [bib_ref] Systematic review of anti-inflammatory agents for the management of oral mucositis in..., Nicolatou-Galitis [/bib_ref] ## Table 4. mascc/isoo clinical practice guidelines for oral mucositis a ## Recommendations in favor of an intervention (ie, strong evidence supports effectiveness in the treatment setting listed): 1. The panel recommends that 30 min of oral cryotherapy be used to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy (II). 2. The panel recommends that recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) be used to prevent oral mucositis (at a dose of 60 lg/kg per day for 3 days prior to conditioning treatment and for 3 days after transplant) in patients receiving high-dose chemotherapy and total body irradiation, followed by autologous stem cell transplantation, for a hematological malignancy (II). 3. The panel recommends that low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm 2 ), be used to prevent oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy, with or without total body irradiation (II). 4. The panel recommends that patient-controlled analgesia with morphine be used to treat pain due to oral mucositis in patients undergoing HSCT (II). 5. The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with head and neck cancer receiving moderate dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (I). SUGGESTIONS IN FAVOR OF AN INTERVENTION (ie, weaker evidence supports effectiveness in the treatment setting listed): 1. The panel suggests that oral care protocols be used to prevent oral mucositis in all age groups and across all cancer treatment modalities (III). 2. The panel suggests that oral cryotherapy be used to prevent oral mucositis in patients receiving high-dose melphalan, with or without total body irradiation, as conditioning for HSCT (III). 3. The panel suggests that low-level laser therapy (wavelength around 632.8 nm) be used to prevent oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer (III). 4. The panel suggests that transdermal fentanyl may be effective to treat pain due to oral mucositis in patients receiving conventional or high-dose chemotherapy, with or without total body irradiation (III). 5. The panel suggests that 2% morphine mouthwash may be effective to treat pain due to oral mucositis in patients receiving chemoradiation for head and neck cancer (III). 6. The panel suggests that 0.5% doxepin mouthwash may be effective to treat pain due to oral mucositis (IV). 7. The panel suggests that systemic zinc supplements administered orally may be of benefit to prevent oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation (III). RECOMMENDATIONS AGAINST AN INTERVENTION (ie, strong evidence indicates lack of effectiveness in the treatment setting listed): 1. The panel recommends that PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin) antimicrobial lozenges and PTA paste not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (II). 2. The panel recommends that iseganan antimicrobial mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II), or in patients receiving radiation therapy or concomitant chemoradiation for head and neck cancer (II). 3. The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (I) or concomitant chemoradiation (II) for head and neck cancer. 4. The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (II) for head and neck cancer. 5. The panel recommends that intravenous glutamine not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II). SUGGESTIONS AGAINST AN INTERVENTION (ie, weaker evidence indicates lack of effectiveness in the treatment setting listed): 1. The panel suggests that chlorhexidine mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (III). 2. The panel suggests that granulocyte-macrophage-colony-stimulating factor mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, for autologous or allogeneic stem cell transplantation (II). 3. The panel suggests that misoprostol mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (III). 4. The panel suggests that systemic pentoxifylline, administered orally, not be used to prevent oral mucositis in patients undergoing bone marrow transplantation (III). 5. The panel suggests that systemic pilocarpine, administered orally, not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (III), or in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II). Abbreviations: Gy, grays; HSCT, hematopoietic stem cell transplantation; MASCC/ISOO, Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology; mW, milliwatt; nm, nanometers. a Level of evidence for each guideline is in brackets after the guideline statement. ## Antimicrobials, coating agents, anesthetics, and analgesics Several topical antimicrobial agents have been examined for the treatment of oral mucositis with either negative or mixed results. The evidence reviewed supported the continuation of a recommendation against the use of lozenges containing polymyxin, tobramycin, and amphotericin and bacitracin, clotrimazole, and gentamicin as well as polymyxin, tobramycin, and amphotericin paste for the prevention of oral mucositis in patients receiving H&NRT. A new recommendation was developed against the use of iseganan mouthwash in patients receiving HSCT or H&NRT. We reviewed 20 studies examining the use of the mucosal coating agent sucralfate in various settings. The evidence supported recommendations against the use of sucralfate for the prevention or treatment of oral mucositis in patients receiving chemotherapy and also in patients receiving H&NRT. No guideline was possible for any anesthetic agent reviewed due to inadequate evidence. Guidelines were developed in favor of the use of patient-controlled analgesia with morphine, transdermal fentanyl, morphine mouth rinse, and doxepin mouth rinse for the management of oral mucositis pain in specific treatment settings . Agents for which no guideline was possible included acyclovir, clarithromycin, nystatin, kefir, povidone-iodine, fluconazole, sodium hyaluronate topical, tetracaine, dyclonine, MGI-209 (with benzocaine), cocaine, amethocaine, capsaicin, methadone, ketamine, nortryptyline, and gabapentin. 26 ## Laser and other light therapy We reviewed 24 studies evaluating the effects of laser or other light therapy on oral mucositis. The evidence supported the development of 2 new guidelines: a recommendation in favor of low-level laser therapy (LLLT) for the prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT with or without total body irradiation, [bib_ref] A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy..., Schubert [/bib_ref] and a suggestion for LLLT in the prevention of oral mucositis in patients receiving H&NRT without concomitant chemotherapy . [bib_ref] Low-energy He=Ne laser in the prevention of radiation-induced mucositis. A multicenter phase..., Bensadoun [/bib_ref] No guideline was possible related to the use of LLLT in any other treatment setting, or related to the use of other emerging light modalities such as lightemitting diodes and visible light. [bib_ref] Systematic review of laser and other light therapy for the management of..., Migliorati [/bib_ref] Cryotherapy A total of 22 eligible studies examined the placement of ice chips in the mouth during the delivery of chemotherapy. The evidence supported the continuation of a recommendation for the use of cryotherapy for the prevention of oral mucositis in patients receiving bolus dosing of 5-fluorouracil. A suggestion for the use of cryotherapy in patients receiving high-dose melphalan as conditioning for HSCT was revised to clarify that this applies regardless of the use of concomitant total body irradiation. No guidelines related to cryotherapy were possible in other treatment settings due to inadequate evidence. 28 ## Natural and miscellaneous agents Zinc is an essential trace element that is required for some tissue repair processes. Zinc also has an antioxidant effect. We reviewed 3 discrete studies testing zinc supplementation in patients receiving H&NRT, all of which found a positive effect. A new suggestion was developed in favor of zinc in patients with oral cancer undergoing RT or chemoradiation. [bib_ref] Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for..., Lin [/bib_ref] However, there is some evidence indicating that the use of antioxidants in smokers during H&NRT may reduce the efficacy of the RT. 38 The evidence reviewed supported the continuation of a recommendation against the use of intravenous glutamine for the prevention of oral mucositis in patients receiving high-dose chemotherapy for HSCT . Due to inadequate and=or conflicting evidence, no guideline was possible in relation to other agents of natural origin reviewed, including glutamine in other treatment settings, the antioxidants vitamin A and E, honey, aloe vera, chamomile, Kamillosan, Chinese herbals, indigowood root, manuka and kanuka oils, oral gel wafers, Rhodiola algida, traumeel S, and Wobe-Mugos E. [bib_ref] Systematic review of natural agents for the management of oral mucositis in..., Yarom [/bib_ref] Pilocarpine is a cholinergic agonist that stimulates salivary secretion. The present systematic review supported 2 new suggestions against the use of systemic pilocarpine specifically for the prevention of oral mucositis: during H&NRT and in patients receiving high-dose chemotherapy, with or without total body irradiation, before HSCT . It should be noted that these guidelines apply only to the use of pilocarpine for the prevention of mucositis. Pilocarpine can be beneficial to increase salivary flow, particularly in patients treated with H&NRT who are experiencing hyposalivation. The evidence also supported the continuation of a suggestion against the use of the phosphodiesterase inhibitor pentoxifylline for the prevention of oral mucositis in patients undergoing bone marrow transplantation. Due to inadequate and=or conflicting evidence, no guideline was possible in relation to other miscellaneous agents=modalities reviewed including allopurinol, midline mucosa-sparing radiation blocks, payayor, timing of RT, bethanechol, chewing gum, propantheline, and tetrachlorodecaoxide. [bib_ref] Systematic review of miscellaneous agents for the management of oral mucositis in..., Jensen [/bib_ref] # Discussion To ensure consistency in the application of review criteria and guideline development, we reviewed the entire body of evidence for each intervention, not just the new publications since the last guidelines update. Our methodology provides confidence that the evaluation of the literature and subsequent guidelines development across various interventions are based on uniform and transparent criteria. The present systematic review resulted in the development of 16 new guidelines for or against the use of various interventions in specific treatment settings. Thus, the clinical usefulness of these guidelines should continue to increase. However, it is recognized that there are many clinical situations faced by the practitioner that are not addressed by these guidelines, due to inadequate and=or conflicting evidence. This constitutes a limitation of such strictly evidence-based guidelines. Therefore, symptom management (such as pain control and nutritional support) continues to be an important part of any mucositis management strategy. An important new guideline developed in the present update is the new recommendation (based on level II evidence) in favor of LLLT for the prevention of oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy. In addition, a new suggestion (based on level III evidence) was developed in favor of LLLT for the prevention of oral mucositis in patients undergoing H&NRT, without concomitant chemotherapy. However, patients now typically receive H&NRT with concomitant chemotherapy, and no guideline was possible in that population due to inadequate evidence. Although the majority of studies of LLLT demonstrate a benefit, the variable quality of the studies and the wide variation in laser parameters used complicates the evaluation of the evidence. [bib_ref] Systematic review of laser and other light therapy for the management of..., Migliorati [/bib_ref] Animal studies indicate that LLLT promotes wound healing and has an antiinflammatory effect. Barriers to the acceptance of this technology include the cost of laser equipment and the laborintensiveness of this modality (because many regimens involve the daily treatment of patients). In addition, a modality such as LLLT can only act on mucosa by direct contact. It will not be useful for areas such as pharyngeal, laryngeal, or esophageal mucosa, which are also at risk of mucositis in patients receiving H&NRT, but are difficult to directly access. Sucralfate is a generically available mucosal coating agent. We reviewed 20 studies that clearly demonstrated a lack of benefit for sucralfate in the prevention or treatment of oral mucositis secondary to chemotherapy or RT.Although it appears theoretically feasible that such a protective coating can protect the exposed nerve endings and thus reduce pain, the data regarding sucralfate did not provide support for such a beneficial effect. Recently, several proprietary mucosal coating agents have been marketed as devices for oral mucositis. Our literature search identified only 1 eligible published study of one of these agents, on the basis of which no guideline was possible. The goal of such clinical practice guidelines is to improve clinical outcomes by facilitating evidence-based care. To achieve this, it is important for the guidelines to be widely disseminated and, most importantly, adopted into routine practice. Strategies to facilitate guidelines uptake can include open-access publication of the guidelines-related articles and translations into other languages, as well as online resources, including a version suitable for viewing on a smartphone. MASCC=ISOO is also in discussions with relevant organizations to determine how we can work together to minimize duplication of effort and promote the clinical use of supportive care guidelines. The motto of the MASCC=ISOO is "Supportive care makes excellent cancer care possible." In keeping with this, MASCC=ISOO is committed to enhancing the supportive care of oncology patients, with the goal of improving the patient experience and allowing for the delivery of optimal cancer treatment. # Funding support The Guidelines Update Meeting was supported by BioAlliance Pharma and Helsinn Healthcare, SA. No honorarium or travel support was provided to the reviewers for participation in the guidelines update effort. No industry representatives attended the guidelines update meeting or participated in the guidelines update effort in any way. ## Conflict of interest disclosures Dr. Lalla received grants from Evolife Laboratories and BioAlliance Pharma, as well as personal fees from iNova Pharmaceuticals, Sucampo, Cangene, and Ingalpharma outside of the current study. Dr. Elting received a grant from Helsinn Research funding for work outside of the current study. Dr. Epstein received a grant from 3M-Riker Canada for participation in a phase 3 study related to the current work. Dr. Keefe received grants from Helsinn Healthcare, GlaxoSmithKline, and Nestec for work outside of the current study. Dr. Sonis is an employee of Biomodels LLC, has acted as a consultant for Clinical Assistance Programs, acted as a member of the advisory board for Actogenix, acted as an advisor for Avaxia, acted as a biomodels consultant for BioAlliance, acted as a member of the advisory board for Galera, acted as a consultant for Izun, acted as an advisor for PolyMedix, acted as a biomodels consultant for Piramal, received fees as a founderconsultant for Inform Genomics, acted as a member of the advisory boards of Synedgen and Soligenix, acted as a member of the advisory board of and as a consultant for Pfizer, acted as a member of the advisory board of Reata, acted as a consultant for Access, and acted as a biomodel consultant for Novartis and Merck for work outside of the current study. Dr. Sonis also holds the following patents that are broadly relevant to the current work: US Patent 6458777, US Patent 6663850, US Patent 6713463, US Patent 6841578B2, and US Patent 7297123. [table] TABLE 1: Criteria for Each Level of Evidence [/table] [table] TABLE 2: Criteria for Each Guideline Category [/table] [table] TABLE 3: MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis (Not Including the Oral Cavity) a RECOMMENDATIONS IN FAVOR OF AN INTERVENTION (ie, strong evidence supports effectiveness in the treatment setting listed): 1. The panel recommends that intravenous amifostine be used, at a dose of 340 mg/m 2 , to prevent radiation proctitis in patients receiving radiation therapy (II). 2. The panel recommends that octreotide, at a dose of 100 lg subcutaneously twice daily, be used to treat diarrhea induced by standard-or highdose chemotherapy associated with HSCT, if loperamide is ineffective (II). SUGGESTIONS IN FAVOR OF AN INTERVENTION (ie, weaker evidence supports effectiveness in the treatment setting listed): [/table]	None	https://europepmc.org/articles/pmc4164022?pdf=render	Mucositis is a highly significant, and sometimes dose‐limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis.
beeb7dd7d78a31a6e40a06aee6c01192a6d6b9e7	pubmed	Advancing the NIH Strategic Plan and Health Care Needs During the COVID-19 Pandemic	Advancing the NIH Strategic Plan and Health Care Needs During the COVID-19 Pandemic ## Advancing the nih strategic plan and health care Needs During the COVID-19 Pandemic Congress passed and the President signed the 2020 Coronavirus Aid, Relief, and the Economic Security (CARES) Act on March 27, incorporating several public health provisions, including $945 million for the National Institutes of Health (NIH). In the midst of a pandemic, resources must be mobilized quickly and effectively to help save lives. The race to develop therapeutics and a vaccine for COVID-19 and provide support to survivors to live with the potential long-term health consequences requires research and infrastructure. Nurses play critical roles in advancing public health in terms of disease prevention and wellness, supporting people through acute illness, managing long-term chronic consequences, addressing health inequities, and providing palliative care. Nowhere are these needs more evident than in the many health concerns that are emerging in the COVID-19 pandemic being experienced by diverse people across the lifespan and the world. As nurse scientists, we will continue to leverage our scientific knowledge and expertise to address these and other needs as they emerge. In these uncertain times, science and facts must drive health care practice and policy, to include the care that nurses provide. The Council for Advancement of Nursing Science (CANS), dedicated to promoting better health through nursing science, is a national voice for nursing science that leverages the many strengths of our members to guide the work of our discipline and health policy, in collaboration with the American Academy of Nursing. Our work was recently exemplified in our response to a Request for Information (RFI) from the National Institutes of Health (NIH), seeking feedback on the proposed framework for the NIH-Wide Strategic Plan for Fiscal Years (FYs) 2021-2025. The NIH Strategic Plan, approved by Congress every five years, is designed to guide how the NIH will "advance its mission to support research in pursuit of fundamental knowledge about the nature and behavior of living systems, and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability" (National Institute of Health, 2015). The NIH RFI sought feedback on the framework for the strategic plan including cross-cutting themes and overarching objectives. CANS and the Academy acted swiftly and decisively to prepare comments that directly relate to several of the current challenges with COVID-19, as well as the many other health challenges facing society. We convened a series of calls and email communications with CANS leaders and experts, including myself; Robin Dail, PhD, RN, FAAN; Holli DeVon, PhD, RN, FAHA, FAAN; Ann Marie McCarthy, PhD, RN, FAAN; Rita Pickler, PhD, RN, PNP, APRN-BC, FAAN; Susan Rawl, PhD, RN, FAAN; and Therese Richmond, PhD, CRNP, FAAN, to evaluate the strategic plan draft and consider ways to bolster it to assure that it maximized its impact on the health of the population. We prepared and submitted our response with the collaboration of the Academy senior staff and board members. Our group of senior scientists reviewed the proposed cross-cutting themes included in the NIH framework: "Optimizing Data Science and the Development of Technologies and Tools." To safeguard our future, the wellness and safety of every individual, in any location, during all health stages is foundational. Innovation and emerging practices must be tested and advanced for heightened impact and improved outcomes. [formula] Increasing [/formula] To help increase the impact of the plan, we made two recommendations related to the cross-cutting themes: Health equity, and the incredible impact of improving it for the nation, should be added as its own crosscutting theme. Increased access to not only health services, but also all the factors that affect the social determinants of health, will improve the health of a nation as a whole. This language is also in line with that used in the Healthy People 2030 Guidelines. The framework also addresses the overarching objectives to guide NIH's work for the next five years. We recommended amending the following: We also requested that NIH provide some clarifying language around the word "cultivating." Like much of the scientific community, CANS has been monitoring and sharing concerns about the slow growth in the research workforce. This is a particular issue for the preparation of nurses with research doctorates and the diversity represented within, especially since individuals from diverse backgrounds represent the fastest growing group of the US population. In addressing this objective, we requested clarification about whether partnerships referred specifically, to NIH partnerships or external opportunities? We also suggested the need to address the areas of ethics, accountability, and the regulatory burdens faced by scientists. In addition, we suggested more collaboration between the institutes at NIH and between the intraand extramural programs to avoid duplication in research areas and facilitate team science. Ways to promote public engagement in setting research priorities and in research itself should also be investigated. The process of refining the NIH strategic plan will ultimately include the input of many stakeholders. As we await the final document, there are numerous innovations and research needs that are emerging and will require further study, especially as they pertain to the COVID-19 pandemic. The most obvious and acute need is for an effective vaccine and curative treatments. However, there are many other areas that are emerging and will likely be the focus of future research to inform practice and policy, to include research conducted by nurse scientists. Some examples are listed below. These are by no means meant to be exhaustive: The COVID-19 pandemic has led to widespread use of telehealth due to the loosening of regulatory restrictions that help protect frontline healthcare providers, as well as patients, during emergencies (Centers for Medicare and Medicaid Services, 2020). However, much remains to be known about best practices and outcomes of this innovation in diverse populations with varying health care needs and differing levels of access to technology. Emerging evidence suggests that the COVID-19 pandemic disproportionately affects low income and minority group members. There is a need to better understand the social determinants for this inequity and to study ways to improve community health and policy to address this problem now and in the future. The shortage of personal protective equipment (PPE) is leading to the need for improved understanding of potential ways for recycling PPE (or new forms of PPE) to ensure the safety of health care providers and our patients. Emerging reports suggest that, similar to other survivors of critical illness, COVID-19 survivors who require critical care may have long term needs for rehabilitation, extending well beyond the acute care period. There is a need to know who is at highest risk for negative long-term outcomes, the nature and duration of these needs, and best ways to address them. Palliative care is a critically important service for people who are dying. The pandemic has been especially challenging, given the large number of people in need. Yet, the risk of infection has limited the ability of families to be present at the bedside. There is a need to evaluate the impact of this practice and ways to anticipate and address this problem in the future. Anxiety, trauma symptoms, and social isolation are increasingly common as the pandemic progresses. Research is needed to understand the trajectory and risk factors for these problems and ways to prevent long term negative health outcomes. Nurses play a vital role in addressing health care needs and in developing health care innovations. In the spring of 1918, when the Spanish Flu (H1N1) first appeared in the United States, the country's nursing resources were already spread thin due to deployments associated with World War I. Despite these shortages, "excellent nursing care was the primary treatment for influenza. The disease was not well understood, and there were no antiviral medications to inhibit its progression or antibiotics to treat the complicating pneumonia that often followed" [bib_ref] Alert to the Necessities of the Emergency": U.S. Nursing during the 1918..., Keeling [/bib_ref]. As was the case 100 years ago, today we see our nurse colleagues stepping up to the challenge to serve our patients and protect the health of our nation. As scientists, we know that nursing and health care, when supported by nursing science, make a tremendous impact on the health of the public. We look forward to seeing the 2021 NIH Strategic Plan and contributing to the important scientific work of advancing the health of individuals, families, communities, and society through the COVID-19 pandemic and beyond. [table] Objective 3: Exemplifying and Promoting the Highest Level of Scientific Integrity, Public Accountability, and Social Responsibility in the Conduct of Science [/table]	None	http://www.nursingoutlook.org/article/S0029655420302967/pdf	None
85f786beb175099d8878fe0dd8d5261162138ac5	pubmed	2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19	2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19 ## Preamble The American College of Cardiology (ACC) and the American Heart Association (AHA) support their members' goal to improve the prevention and treatment of cardiovascular diseases (CVDs) through professional education, research, the development of guidelines and standards, and by fostering policy that supports optimal patient care and outcomes. The ACC and AHA also recognize the importance of using clinical data standards for patient management, assessment of outcomes, and conduct of research, as well as the importance of defining the processes and outcomes of clinical care, whether in randomized trials, observational studies, registries, or quality improvement initiatives. Clinical data standards aim to identify, define, and standardize data elements relevant to clinical topics in cardiovascular medicine, with the primary goal of assisting data collection and use by providing a corpus of data elements and definitions applicable to various conditions. Broad agreement on common vocabulary and definitions is needed to pool or compare data from the electronic health records (EHRs), clinical registries, administrative datasets, and other databases and to assess whether these data are applicable to clinical practice and research endeavors. The clinical data standards can, therefore, serve as a guide to develop administrative data sets, and complementary administrative or quality assurance elements can evolve from these core clinical concepts and elements. Thus, rather than forcing the clinical data standards to harmonize with existing administrative codes, such as ICD-10-CM or CPT codes, we envision the For example, a longitudinal clinic database may contain these elements because access is restricted to the patient's health care team. In clinical care, health care providers communicate with each other through a common vocabulary. In an analogous manner, the integrity of clinical research depends on firm adherence to prespecified procedures for patient enrollment and follow-up; these procedures are guaranteed through careful attention to definitions enumerated in the study design and case report forms. Harmonizing data elements and definitions across studies facilitates comparisons and enables the conduct of pooled analyses and meta-analyses, thus deepening our understanding of individual study results. The recent development of quality performance measurement initiatives, particularly those for which the comparison of health care providers and institutions is an implicit or explicit aim, has further raised awareness about the importance of clinical data standards. Indeed, a wide audience, including nonmedical professionals such as payers, regulators, and consumers, may draw conclusions about care and outcomes from these comparisons. To understand and compare care patterns and outcomes, the data elements that characterize them must be clearly defined, consistently used, and properly interpreted. Different diagnostic terminologies are being used for overlapping conditions such as "myocardial injury," "myocarditis," "type II myocardial infarction," "stress cardiomyopathy," or "inflammatory cardiomyopathy." These data standards will help standardize definitions and set the framework to capture and better understand how COVID-19 impacts cardiovascular health. This document is intended for use by researchers, registry developers, and clinicians and is proposed as a framework for ICD-10 code development of COVID-19-related cardiovascular conditions. Specifically, COVID-19 cardiovascular data standards are of great importance to patients, providers, investigators, scientists, administrators, public health officials, policy makers, and payers. The ACC/AHA Writing analysis or meta-analysis is anticipated n Public health policy, health insurance coverage, and legislation development n Health system administrators for estimation of necessary resources such as protective personal equipment (PPE), testing, space and staffing needs, isolation, sanitation, or quarantine requirements n Alternative models of health care such as telemedicine, virtual visits, and point-of-care diagnostic platforms. The data element tables are also included as an Excel file in the Online Data Supplement. ## Special considerations In this document, data elements were not differentiated for specific encounters, such as for inpatients versus outpatients, dates of encounter, number of encounters, baseline or repeated data elements. Databases can be built and customized according to users' needs to capture such information. The intent of this writing committee was not to provide recommendations regarding COVID-19 treatment, and the writing committee recommends that readers follow prevailing COVID-19 management guidelines. ## Abbreviations # Methodology ## Writing committee composition The Task Force selected the members of this writing committee. The writing committee consisted of 15 individuals with domain expertise in cardiomyopathy, infectious disease, CVD, myocarditis, cardiovascular registries, outcomes assessment, medical informatics, health information management, and health care services research and delivery. ## Relationships with industry and other entities The Task Force made every effort to avoid actual or potential conflicts of interest because of personal, professional, or business interests or relationships of any member of the writing committee. Specifically, all members of the writing committee were required to disclose all such relationships that could be perceived as real or potential conflicts of interest in writing. The included documentation was updated when any changes occurred. Authors' and peer reviewers' relationships with industry and other entities pertinent to this data standards document are disclosed in Appendixes 1 and 2, respectively. In addition, for complete transparency, the disclosure information of each writing committee member-including relationships not pertinent to this document-is available in a Supplemental Appendix. The work of the writing committee was supported exclusively by the AHA and ACC without commercial support. Writing committee members volunteered their time for this effort. Meetings of the writing committee were confidential and attended only by committee members and staff. ## Review of literature and existing data definitions ## Development of terminology concepts The writing committee aggregated, reviewed, harmonized, and extended these terms to develop a controlled, semantically interoperable, machine computable terminology set that would be usable in as many contexts as Also referred to as "postacute COVID-19 syndrome" or "long COVID." Not well characterized currently. ## Multisystem inflammatory syndrome in children (mis-c) The occurrence of fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization with multisystem ($2) organ involvement AND No plausible alternative diagnoses AND Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test OR exposure to a suspected or confirmed COVID-19 case within 4 wk prior to symptom onset in an individual aged <21 y ## Covid-19 reinfection New discrete episode of acute COVID-19 in person with a prior history of probable/ confirmed COVID-19. Other information can provide supporting but not definitive evidence for reinfection, such as culture or subgenomic mRNA analysis (to detect the presence of replication-competent virus) or serology, which could be useful to document a serological response to SARS-CoV-2. HF can be subclassified according to LVEF as HF with preserved EF (LVEF $50), HF with reduced EF (LVEF <40%), HF with mildly reduced EF (LVEF 41%-49%), or HF with improved EF (HF with a baseline LVEF #40%, a $10-point increase from baseline LVEF, and a second measurement of LVEF >40%). See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc ischemic cardiomyopathy Reduced LV function with LVEF <50% in a patient with history of suspected or confirmed myocardial ischemia or ACS with confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc nonischemic cardiomyopathy Reduced LV function with LVEF <50% without evidence of myocardial ischemia that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc inappropriate sinus tachycardia Inappropriate sinus tachycardia at rest with heart rate >100 bpm that cannot be explained by any identifiable cause, including anemia, hypoxia, hypotension, or fever that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. ## Pasc pots PASC POTS is a clinical syndrome that started during probable or confirmed acute COVID-19 and lasts $3 mo. POTS is defined as 1) sustained heart rate increment $30 bpm within 10 min of standing or head-up tilt (for individuals who are age 12-19 y, the required heart rate increment is $40 bpm); 2) absence of orthostatic hypotension (ie, no sustained systolic blood pressure drop of $20 mm Hg); 3) frequent symptoms of orthostatic intolerance during standing, with rapid improvement on return to a supine position. Symptoms may include lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, and fatigue; 4) duration of symptoms for at least 3 mo; and 5) absence of other conditions explaining sinus tachycardia such as anorexia nervosa, primary anxiety disorders, hyperventilation, anemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (eg, sympathomimetics, anticholinergics) or severe deconditioning caused by prolonged bed rest. See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. PASC AF or atrial flutter AF or atrial flutter in a patient without prior history of atrial tachyarrhythmias that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. implications for long-term surveillance and outcomes in survivors. Heart See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. PASC supraventricular tachyarrhythmia other than AF or atrial flutter Supraventricular tachycardia other than AF or atrial flutter in a patient without prior history of atrial tachyarrhythmias that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. n Yes n No n Unknown Mitrani RD, Dabas N, Goldberger JJ. COVID-19 cardiac injury: implications for long-term surveillance and outcomes in survivors. Heart See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc pericarditis/ pericardial effusion Pericarditis characterized by chest pain, electrocardiographic changes or pericardial effusion, that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. ## Pasc cardiac structural abnormalities Cardiac structural changes or abnormalities characterized by myocardial systolic dysfunction or myocardial edema or fibrosis on noninvasive cardiac imaging that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. ## Pasc deep venous thrombosis Formation of $1 blood clots or thrombi in large veins of the body, diagnosed with Doppler ultrasound, occurring most frequently in lower extremities or upper extremities that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc pulmonary thromboembolic disease Intravascular migration of a venous thrombus or embolus to the pulmonary arterial circulation, microvascular thrombosis in the pulmonary capillaries, or pulmonary artery thrombus in situ diagnosed by a positive pulmonary angiogram, an unequivocally positive helical CT scan, a high-probability ventilation-perfusion scan, or autopsy that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. See Appendix 3 for the definition of a probable or confirmed acute COVID-19 case. ## Pasc neurovascular disorder Disorder of the nervous system related to a vascular etiology that started during probable or confirmed acute COVID-19 and persisted beyond 4 wk after the initial diagnosis of COVID-19. Preexisting cardiovascular conditions, or those that did not develop until after COVID-19 had resolved, should not be listed here. Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute MI or by autopsy findings showing recent MI or recent coronary thrombosis. Death resulting from a procedure to treat an MI (PCI, CABG), or to treat a complication resulting from MI, should also be considered death attributable to acute MI. Death resulting from an elective coronary procedure to treat myocardial ischemia (ie, chronic stable angina), or death attributable to an MI that occurs as a direct consequence of a cardiovascular investigation/procedure/operation, should be considered as a death attributable to a cardiovascular procedure. ## Sudden cardiac death Death that occurs unexpectedly and suddenly without ROSC in a patient with probable or confirmed acute COVID-19 and not within 30 d of an acute MI. Sudden cardiac death includes the following scenarios: a. Death witnessed and occurring without new or worsening symptoms b. Death witnessed within 60 min of the onset of new or worsening cardiac symptoms, unless the symptoms suggest acute MI c. Death witnessed and attributed to an identified arrhythmia (eg, captured on an ECG recording, witnessed on a monitor, with asystole, pulseless electrical activity, ventricular tachycardia, or ventricular fibrillation, or unwitnessed but found on implantable cardioverter-defibrillator review) d. Unwitnessed death in a subject seen alive and clinically stable #24 h prior to being found dead without any evidence supporting a specific noncardiovascular cause of death (information regarding the patient's clinical status preceding death should be provided, if available) ## Death attributable to stroke Death after a stroke that is either a direct consequence of the stroke or a complication of the stroke in a patient with probable or confirmed acute COVID-19. Acute stroke should be verified to the extent possible by the diagnostic criteria outlined for stroke. Cytokine release syndrome was also observed in patients with SARS-CoV and MERS-CoV and may also be referred to as cytokine storm syndrome. For patients with both distributive and cardiogenic shock, both should be coded. ## Acute kidney injury with renal replacement therapy Abrupt reduction in kidney function in a patient with probable or confirmed COVID-19, measured by urine output and renal biomarkers requiring any renal replacement therapy Only for patients who were not previously on chronic renal replacement therapy for end-stage kidney disease Acute liver injury with fulminant failure Acute liver injury manifested by abnormalities in liver enzymes in a patient with probable or confirmed COVID-19. A minority of patients experience severe liver injury that can result in hepatic failure, defined as rapid loss of liver function during acute COVID-19, which is associated with coagulopathy or encephalopathy, and often multiorgan failure. Coagulopathy may occur in acute COVID-19 in the absence of disseminated intravascular coagulation. ## Rhabdomyolysis Destruction or degeneration of muscle tissue accompanied by the release of breakdown products from muscle cells into the bloodstream (eg, creatine kinase, aldolase) that may lead to acute kidney injury in a patient with probable or confirmed COVID-19 The presumed mechanism is cerebral hypoperfusion. There should not be clinical features of other nonsyncopal causes of loss of consciousness, such as septic shock, seizure, antecedent head trauma, or apparent loss of consciousness (ie, pseudosyncope). ## Presyncope The symptoms before syncope. These symptoms could include extreme lightheadedness; visual sensations, such as "tunnel vision" or "graying out"; and variable degrees of altered consciousness without complete loss of consciousness. Presyncope could progress to syncope, or it could abort without syncope. The presumed mechanism is cerebral hypoperfusion. There should not be clinical features of other nonsyncopal causes of loss of consciousness, such as septic shock, seizure, antecedent head trauma, or apparent loss of consciousness (ie, pseudosyncope). ## Presyncope The symptoms before syncope. These symptoms could include extreme lightheadedness, visual sensations, such as "tunnel vision" or "graying out," and variable degrees of altered consciousness without complete loss of consciousness. Presyncope could progress to syncope, or it could abort without syncope. ## Rhythm Presence of: n Sinus rhythm: an electrocardiographic finding of a cardiac rhythm that originates in the sinoatrial node n AF: an arrhythmia characterized by uncoordinated atrial myocardium attributable to multiple reentry circuits with consequent deterioration of atrial mechanical function. Instead of intermittently contracting, the atria quiver continuously in a chaotic pattern, causing a totally irregular often tachycardic ventricular rate n Atrial flutter: a disorder characterized by an electrocardiographic finding of an organized, regular atrial rhythm with atrial rate of 240-340 bpm. Multiple P waves typically appear in the inferior leads in a sawtooth-like pattern between the QRS complexes. n Ventricular arrhythmia: a disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathological process in the cardiac ventricles n Supraventricular tachycardia: a disorder characterized by an electrocardiographic finding of a tachycardia that does not originate in the ventricles or His Purkinje system n Paced rhythm: an electrocardiographic finding that the cardiac rhythm is initiated by an electrical impulse from a mechanical cardiac pacemaker n Other NCI Pulmonary infiltrates Imaging-defined opacification and consolidation of lungs suggesting injury and substance denser than air, such as pus, blood, or protein, within the parenchyma of the lungs during acute COVID-19 Pulmonary vascular redistribution Distension of the pulmonary veins, particularly in the upper lung fields during acute COVID-19 Pulmonary congestion Imaging findings consistent with increased intravascular blood volume in the lungs during acute COVID-19 NCI PAPi Pulse pressure across pulmonary artery divided by RA (calculated systolic pulmonary arterial pressurediastolic pulmonary pressure)/right atrial pressure) n Numeric ## Mean pulmonary capillary wedge pressure The pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch n Numeric, mm Hg NCI Thesaurus Code: C129955 63 May be recorded with or without V-wave. ## Cardiac output The total volume of blood pumped by the heart over a set period of time, conventionally 1 min; it is calculated as heart rate times stroke volume and is additionally dependent on preload and afterload for functional output. n Numeric, L/min NCI Thesaurus Code: C119246 63 ## Cardiac index The measure of an individual's cardiac output as divided by their body surface area). This calculation is a useful function to determine an individual's cardiac performance in relation to their body size, providing an overview of global cardiovascular function. n Numeric, L/min/m 2 NCI Thesaurus Code: C119245 63 ## Transpulmonary gradient Difference between mean pulmonary artery pressure and mean pulmonary capillary wedge pressure n Numeric, mm Hg ## Pulmonary vascular resistance Pulmonary vascular resistance is calculated as (mean PA pressure minus mean pulmonary capillary wedge pressure) divided by cardiac output. Norepinephrine Norepinephrine is a sympathomimetic drug that increases blood pressure and enhances ventricular contractility. ## Epinephrine Epinephrine is a sympathomimetic drug that increases blood pressure and enhances ventricular contractility. ## Dopamine Dopamine is a sympathomimetic drug that increases blood pressure and enhances ventricular contractility. ## Vasopressin Vasopressin is a vasoactive hormone used synergistically with another sympathomimetic drug (typically norepinephrine) to increase and maintain peripheral vascular tone in patients with distributive shock. ## Phenylephrine Phenylephrine is a sympathomimetic drug whose primary activity results from stimulation of the alpha receptors of the vasculature, resulting in vasoconstriction while producing comparatively mild direct cardiac effects. ## Other None IV inotropic agent IV positive inotropic agents are a group of medicines that stimulate and increase the force of contraction of the heart muscle. ## Milrinone Milrinone is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility, decrease pulmonary vascular resistance, and as a systemic vasodilator. ## Dobutamine Dobutamine is a direct-acting inotropic agent whose primary activity results from stimulation of the b receptors of the heart while producing comparatively mild chronotropic, hypertensive, arrhythmogenic, and vasodilative effects. Other None COVID-19-specific intermediate-or full-dose anticoagulation (heparin, lowmolecular-weight heparin, DOAC, warfarin) Intermediate-or full-dose anticoagulation used to prevent VTE complications attributable to SARS-CoV-2 specifically and not because of documented VTE or another noninfectious indication. Note that this excludes the low-dose prophylactic anticoagulation often given to inpatients for VTE prophylaxis (see below). Note that "low-dose" anticoagulation is specifically excluded from this element (see below). ## Full dose standard treatment dose Intermediate dose Intermediate dose is defined here as a dosing strategy targeting levels of anticoagulation less than standard treatment doses but greater than standard VTE prophylaxis doses. ## Unknown A proper value is applicable but not known. Heparin is an indirect thrombin inhibitor composed of a mixture of heterogeneous mucopolysaccharides with a molecular weight of 5-30 kDa. ## Anticoagulation for vte prophylaxis Low-molecularweight heparin Low-molecular-weight heparin compounds are fractions of heparin that primarily act by inhibiting the activated clotting factor X. Examples include enoxaparin and dalteparin. ## Fondaparinux Fondaparinux is a synthetic anticoagulant based on the pentasaccharide sequence that makes up the minimal antithrombin-binding region of heparin. ## Bivalirudin Bivalirudin is a semisynthetic derivative of hirudin and is a highly specific inhibitor of thrombin. Other Unknown A proper value is applicable but not known. ## Renal replacement therapy Use of renal replacement therapy during hospitalization for COVID-19 in a patient without end-stage renal disease prior to such hospitalization. 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Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008;36:1330-1349. [/fig] [fig] 139: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. 140. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/ AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68:1476-1488. 141. 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January CT, Wann LS, Calkins H, et al. 2019 AHA/ ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019;74:104-132. 145. Julia S, James U. Direct oral anticoagulants: a quick guide. Eur Cardiol. 2017;12:40-45. 146. Centers for Disease Control and Prevention. Different COVID-19 vaccines. Accessed March 4, 2022. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines.html 147. Piazza G, Morrow DA. Diagnosis, management, and pathophysiology of arterial and venous thrombosis in COVID-19. JAMA. 2020;324:2548-2549. 148. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/ AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776-803. 149. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019;74:e51-e156. [/fig] [table] 123: World Health Organization. Diarrhoeal disease. Accessed March 4, 2022. https://www.who.int/en/ news-room/fact-sheets/detail/diarrhoeal-disease 124. Hauser WA, Beghi E. First seizure definitions and worldwide incidence and mortality. Epilepsia. 2008;49(Suppl 1):8-12. 125. 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Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489-495. 133. Douglas PS, Carabello BA, Lang RM, et al. 2019 ACC/AHA/ASE key data elements and definitions for transthoracic echocardiography: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Transthoracic Echocardiography) and the American Society of Echocardiography. J Am Coll Cardiol. 2019;74:403-469. 134. Cury RC, Abbara S, Achenbach S, et al. CAD-RADS TM Coronary Artery Disease -Reporting and Data System. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NASCI). J Cardiovasc Comput Tomogr. 2016;10:269-281. 135. Dehmer GJ, Badhwar V, Bermudez EA, et al. 2020 AHA/ACC key data elements and definitions for coronary revascularization: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Coronary Revascularization). J Am Coll Cardiol. 2020;75:1975-2088. 136. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53:1475-1487. 137. National Institute of Neurological Disorders and Stroke. Common data elements. Cardiac magnetic resonance imaging (MRI). Accessed March 4, 2022. https://www.commondataelements.ninds.nih.gov/cde_ detailed_report/23564/Imaging%20Diagnostics/ Assessments%20and%20Examinations/Stroke/ Cardiac%20Magnetic%20Resonance%20Imaging% 20%28MRI%29 138. Powers WJ, Rabinstein AA, Ackerson T, et al.Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344-e418. [/table] [table] 150: Cannon CP, Brindis RG, Chaitman BR, et al. 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). J Am Coll Cardiol. 2013;61:992-1025. 151. Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/ AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol. 2015;66:403-469. 152. Fried TR, Redding CA, Robbins ML, et al. Stages of change for the component behaviors of advance care planning. J Am Geriatr Soc. 2010;58:2329-2336. 153. Sudore RL, Lum HD, You JJ, et al. Defining advance care planning for adults: a consensus definition from a multidisciplinary Delphi panel. J Pain Symptom Manage. 2017;53:821-832. KEY WORDS ACC/AHA Clinical Data Standards, cardiogenic shock, cardiovascular diseases, coronavirus infections, COVID-19, extracorporeal membrane oxygenation, medical informatics, myocarditis, SARS-CoV-2 APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)-2022 AHA/ACC KEY DATA ELEMENTS AND DEFINITIONS FOR CARDIOVASCULAR AND NONCARDIOVASCULAR COMPLICATIONS OF COVID-19 Prathit A. Kulkarni Baylor College of Medicine-Assistant Professor, Infectious Diseases; Michael E. DeBakey VA Medical Center-Assistant Chief of Medicine Erin D. Michos Johns Hopkins University School of Medicine-Associate Professor of Medicine and Epidemiology; Director, Women's Cardiovascular Health; and Associate Director, Preventive Cardiology This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity, or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document or makes a competing drug or device addressed in the document; or c) the person or a member of the person's household, has a reasonable potential for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document. Significant relationship. †Kathleen LaPoint is an ACC/AHA joint staff member and acts as the Clinical Healthcare Data Manager for the "2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19." No relevant relationships to report. Not included/counted in the RWI balance for this committee. ACC indicates American College of Cardiology; AHA, American Heart Association; COVID-19, coronavirus disease-2019; UT, University of Texas; and VA, Veterans Affairs. University of Pennsylvania-Professor of Medicine, Vice Chair of Medicine for Informatics, and Section Chief, Advanced Heart Failure and Cardiac Transplant St. Charles Health System-Chief of Cardiology, and Director, Structural Cardiology This table represents all relationships of committee members with industry and other entities that were reported at the time of peer review, including those not deemed to be relevant to this document at the time this document was under review. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity, or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to https://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC/AHA Disclosure Policy for Writing Committees. Significant relationship. †No financial benefit. ‡This disclosure was entered under the Clinical Trial Enroller category in the ACC's disclosure system. To appear in this category, the individual acknowledges that there is no direct or institutional relationship with the trial sponsor as defined in the (ACCF or ACC/AHA) Disclosure Policy for Writing Committees.Being in close contact, as defined by the CDC, with a person with a probable or confirmed acute COVID-19 case while the person was in the presumptive infectious period [/table]	None	None	None
f00e198452bf0911359d0a50d14ba463f8db92b5	pubmed	Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma	Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC. # Introduction For more than 20 years, immunotherapy using IL-2 or IFN has been a primary treatment for patients with metastatic RCC (mRCC) [bib_ref] The treatment of renal cell carcinoma with human leukocyte alpha-interferon, Dekernion [/bib_ref] [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref] [bib_ref] Complete response to interferon-alpha in a patient with metastatic renal cell carcinoma..., Yamamoto [/bib_ref]. The toxicity of high-dose (HD) IL-2 therapy, in particular, has restricted its use to patients with adequate organ function and treated at institutions experienced in the management of side effects. Multiple studies over many years have tried to identify biologic and immunologic parameters to pre-select patients for sensitivity to HD IL-2, but to date there is no biomarker for response related to the tumor itself or to the patient's immune profile that has been prospectively validated. The most recent prospective study demonstrated that clinico/pathologic parameters such as excellent performance status and clear cell histology remain as the best predictors of HD IL-2 responsiveness [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. Investigations have also clarified prognostic groups, and those for whom immunotherapy is not useful. The identification of biomarkers predictive of response or resistance to immunotherapy continues to be the focus of active research. Over many years of evaluation, it has become apparent that RCC is comprised of a number of different histologic subtypes, now shown to have different genomic profiles [bib_ref] Genetic basis of cancer of the kidney: disease-specific approaches to therapy, Linehan [/bib_ref]. It has also been noted in multiple clinical trials and registry experiences that nonclear cell RCC is much less likely to respond to IL2 or IFN. The treatment approach for non-clear cell RCC continues to be explored with optimal subtype-specific strategies yet to be developed. Since 2005, ten agents have been approved for the treatment of patients with metastatic clear cell RCC (which continues to be 75-85 % of mRCC). These include six agents that target the tyrosine kinase of receptors of VEGF (sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib [in combination with everolimus]) [bib_ref] Sorafenib in advanced clear-cell renal-cell carcinoma, Escudier [/bib_ref] [bib_ref] Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall..., Motzer [/bib_ref] [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a..., Sternberg [/bib_ref] , two that target mTOR (temsirolimus, everolimus) [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] [bib_ref] Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled..., Motzer [/bib_ref] , and a monoclonal antibody that binds VEGF before it engages its receptor (bevacizumab) [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]. These agents have brought treatment options to greater numbers of patients with metastatic clear cell RCC. The selection of patients for different treatment options as well as the sequencing of these targeted agents relative to each other continue to be topics of clinical investigation. Despite an abundance of newer agents, there continues to be a role, albeit more limited, for cytokine-based immunotherapy. In addition, new immunotherapeutic agents are entering the clinical arena, notably nivolumab, an immune checkpoint inhibitor for programmed death 1 (PD-1) (nivolumab) [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref]. Therefore, optimal sequencing becomes even more important in order to provide patients with the greatest chance of durable disease control and survival that is free from symptoms of disease or treatment. In the era of anti-angiogenesis therapy, with agents that are available to nearly all patients with mRCC, SITC has convened a panel of RCC/immunotherapy experts to consider the current data and to provide treatment recommendations to practicing clinicians caring for patients with RCC, outlining the current and potential future role of immunotherapy for this disease. # Methods # Consensus statement policy SITC has adopted a process and standards, initially outlined by the Institute of Medicine, to develop clinical practice guidelines for the use of immunotherapy [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref]. This paper is the result of this process in delineating guidelines for the use of immunotherapy in the treatment of renal cell cancer. SITC convened a multi-disciplinary panel of renal cancer/immunotherapy experts in October 2014 to produce an evidence-based guideline document, transparent with regard to funding as well as the reporting and management of conflicts of interest. The resulting document is designed to provide guidance only. The panel focused on drugs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients in the U.S. The final consensus statement and was made available to the entire SITC membership for open comment. This feedback received during the comment period were considered for the final manuscript (Additional file 1). Due to the approval of two agents and release of phase III data since the convened meeting, additional edits, approved by all authors, were also incorporated. ## Renal cancer consensus task force and conflicts of interest The Task Force consisted of 17 health care providers, all specializing in the treatment of patients with RCC (12 medical oncologists, 3 urologic oncologists, and 2 oncology nurses), as well as 2 patient advocates and 1 patient (Additional file 2). The providers were particularly experienced in the management of patients with either advanced or local/regional disease. More than 80 % had experience with HD IL-2 and with anti-angiogenesis agents, and more than 75 % had experience with mTOR inhibitors. In addition, more than 85 % had experience with RCC clinical trials. Clinical trial participation among the [fig_ref] Table 1: Task Force criteria for HD IL-2 therapy [/fig_ref] , anti-PD-L1 (59 %), allogeneic bone marrow transplantation (29 %), RCC vaccines , and cabozantinib, a VEGF and MET inhibitor (65 %). Thus, the Task Force was a highly selected group of experts with long-standing experience in RCC treatment and clinical research and reflects the forefront of individuals conducting clinical trials with the newer agents for RCC over the past decade. Several Task Force members were also involved in the development and conduct of adjuvant clinical trials in patients with high risk RCC. All Task Force members were required to disclose any conflicts of interest related to the treatment of RCC and the agents to be discussed during the conference. This included full financial disclosure of relationships with commercial sponsors of these agents. No commercial funding was provided for any aspect of the process, including the literature search, support of the meeting, or preparation of the manuscript. ## Literature review The database selected for the literature review was MEDLINE. The search terms that were utilized included "kidney cancer or renal cancer and immunotherapy" with subtopics of "BMT" and "other/vaccine," "kidney cancer or renal cancer and interferon," "cytokine monotherapy" with subtopics "Bev/interferon" and "Peg-IFN," "kidney cancer or renal cancer and IL2," and "kidney cancer or renal cancer and anti-PD-1." The literature search was supplemented with additional papers identified by the Task Force at the time of the consensus meeting. This resulted in a 290-item bibliography (Additional file 3). The level of evidence reported in the literature was placed into one of three levels. Level A was considered the strongest supportive evidence, demonstrated by randomized, controlled trials and/or by meta-analyses as well as by long-term follow-up of prospective, uncontrolled trials in the case of HD IL-2. Level B was considered moderate evidence supported by more recent prospective, uncontrolled trials, and level C was considered weak evidence, derived from case reports and retrospective reviews. ## Task force consensus meeting agenda Topics discussed with respect to immunotherapy of RCC were the following: 1) the current role and place of HD IL-2 therapy; 2) the selection of patients for IL-2-based regimens and the criteria for those choices; 3) the current role of IFN and its use in conjunction with bevacizumab; 4) the identification of biomarkers of response to immunotherapy; 5) the sequencing of immunotherapy with the anti-VEGF agents; 6) the management of patients with central nervous system (CNS) metastases; 7) the potential role and sequencing of new immunotherapy agents including the PD-1/PD-L1 pathway inhibitors; 8) future opportunities and the role of immunotherapy-based combination therapies for RCC. The pre-meeting survey questions and Task Force responses are also available in full (Additional file 4). It was agreed that the data supporting the use of IL-2 originates from older studies, rather than phase III comparative trials, and therefore, the basis for recommendations regarding this agent reflects decades of clinical experience. Because of the need for careful selection of patients for HD IL-2, historical data must be the basis for recommendations. More recently, a prospective phase II clinical trial of HD IL-2 suggested that in the current era of alternative treatment options, patients felt to be appropriate for HD IL2 treatment experience a higher response rate than in the initial reports (25 vs. 14 %) [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. Additionally, registry data from treatment centers in the current era demonstrate enhanced activity and reduced severe toxicity for this treatment approach [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref] [bib_ref] High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes, Lowder [/bib_ref]. ## Consensus recomendations What is the role of systemic therapy for resected stage II/ III renal cell cancer? Although clinical trials of HD IL-2 and of IFN were conducted as adjuvant therapy, results did not support their use in this setting [bib_ref] Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a..., Clark [/bib_ref] [bib_ref] Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal..., Messing [/bib_ref]. VEGFR tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib did not demonstrate benefit relative to placebo in the E2805 ASSURE trial [bib_ref] Dose analysis of ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal..., Haas [/bib_ref]. However, recent preliminary data from S-TRAC indicate a relapse-free survival benefit to sunitinib over placebo in patients with resected high-risk RCC. Full details regarding this trial including overall survival and relative toxicity are awaited to determine if sunitinib will be a new standard of care in this setting. Other ongoing adjuvant clinical trials awaiting results include: EVEREST (S0931, NCT01120249), a phase III comparison of everolimus versus placebo in the North American Cooperative Groups, which will complete accrual shortly and SORCE, a randomized phase III trial of one year of sorafenib versus three years of sorafenib versus observation conducted in Europe, which completed accrual and is pending analysis [bib_ref] Patients' preferences for adjuvant sorafenib after resection of intermediate or highrisk renal..., Blinman [/bib_ref]. In addition, two industrysponsored trials (PROTECT and ATLAS) are ongoing. ## Literature review and analysis The earliest adjuvant trials in patients with completely resected RCC were with IFN. The North American Cooperative Groups conducted an intergroup study, enrolling from 1987-1992, in which 283 patients with pT3-4a and/or lymph node positive patients were randomized to observation or to IFN alfa-NL, administered daily for 5 days, every 3 weeks, for up to 12 cycles [bib_ref] Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal..., Messing [/bib_ref]. At a median follow-up of 10.4 years, the median survival was 7.4 years in the observation group, and 5.1 years in the IFN group (log rank p = 0.9). Median recurrence-free survival (RFS) was 3.0 years for the observation group and 2.2 years in the IFN group (p = .33). The investigators concluded that adjuvant treatment with IFN did not contribute to survival or RFS [bib_ref] Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal..., Messing [/bib_ref]. The Cytokine Working Group (CWG) conducted an adjuvant study in a mixed population of 69 resected locally advanced or metastatic patients, comparing HD IL-2 to observation [bib_ref] Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a..., Clark [/bib_ref]. Early closure was recommended after an interim analysis determined that the goal of a 30 % improvement in 2-year disease-free survival (DFS) could not be achieved with further accrual. As stated above, a number of randomized, placebocontrolled adjuvant trials utilizing anti-VEGF agents or anti-mTOR agents are being completed and/or undergoing analysis. The first report was of ASSURE in 2015, demonstrating no difference in RFS comparing sunitinib to placebo or sorafenib to placebo [bib_ref] Dose analysis of ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal..., Haas [/bib_ref]. Ongoing genomic studies may provide insights into differing populations among the patients in this trial. Considerable enthusiasm is developing for adjuvant trials of checkpoint inhibitors in resected RCC and such trials are in development. ## Consensus recommendations The entire Task Force agreed that the current standard of care in the adjuvant setting is either observation or enrollment in a clinical trial based on Level A evidence for cytokines [bib_ref] Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a..., Clark [/bib_ref] [bib_ref] Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal..., Messing [/bib_ref] and Level A evidence from the ASSURE clinical trial [bib_ref] Dose analysis of ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal..., Haas [/bib_ref]. The panel was supportive of initiation of studies utilizing PD-1 pathway blocking agents in the neoadjuvant and/or adjuvant setting and such trials are in development [fig_ref] Table 2: Select immunotherapy agents and ongoing immunotherapy clinical trials in RCC Ongoing clinical... [/fig_ref]. The preliminary S-TRAC data release, which occurred after the meeting, may impact both the standard of care and the control arms of future clinical trials in this setting. What is the role of surgery for stage IV renal cell cancer? Initial assessment of a patient with mRCC Patients with mRCC should be evaluated for histologic subtype and extent of metastatic disease, including evaluation of the CNS. In the presence of small volume metastatic disease, relative to the tumor volume in the primary site, cytoreductive nephrectomy is often recommended prior to systemic therapy [bib_ref] Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma, Fallick [/bib_ref] [bib_ref] Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis, Flanigan [/bib_ref] [bib_ref] Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic..., Flanigan [/bib_ref] [bib_ref] Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic..., Mickisch [/bib_ref]. Data suggest improved survival associated with cytoreductive nephrectomy in the cytokine era [bib_ref] Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma, Fallick [/bib_ref] [bib_ref] Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis, Flanigan [/bib_ref] [bib_ref] Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic..., Flanigan [/bib_ref] [bib_ref] Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic..., Mickisch [/bib_ref] and preliminarily also with VEGFR pathway targeted therapy [bib_ref] Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in..., Mathieu [/bib_ref]. If there are isolated distant metastases, these may be considered for resection as data support this approach [bib_ref] Survival after complete surgical resection of multiple metastases from renal cell carcinoma, Alt [/bib_ref] [bib_ref] The role of surgery in advanced renal cell carcinoma: cytoreductive nephrectomy and..., Karam [/bib_ref]. Systemic therapy is not indicated after metastasectomy in the absence of residual disease except as part of a research study. There is an ongoing cooperative group clinical trial evaluating pazopanib versus placebo in the setting of resected metastatic disease (E2810, NCT01575948). However, if patients have a large tumor burden outside of the kidney, particularly symptomatic distant metastases, or poor performance status/co-morbidities, then initiating therapy without nephrectomy may be appropriate and should be strongly considered as part of a multidisciplinary discussion. ## Literature review and analysis Early studies demonstrated improved survival in patients presenting with metastatic disease, who subsequently underwent nephrectomy and were then treated with IFN, compared in randomized trials with those only treated systemically [bib_ref] Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis, Flanigan [/bib_ref] [bib_ref] Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic..., Flanigan [/bib_ref] [bib_ref] Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic..., Mickisch [/bib_ref]. Similarly, nephrectomy prior to HD IL-2 confers benefit [bib_ref] Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma, Fallick [/bib_ref]. A more recent report suggests that this benefit may be limited to selected patients, with survival being primarily improved in patients with favorable Memorial-Sloan Kettering Cancer Center (MSKCC) or Eastern Cooperative Oncology Group (ECOG) prognostic features among patients treated with VEGF-targeted therapies [bib_ref] Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in..., Mathieu [/bib_ref]. Several reports also describe survival benefit from resection of concurrent or recurrent metastatic disease, again in highly selected patients [bib_ref] Survival after complete surgical resection of multiple metastases from renal cell carcinoma, Alt [/bib_ref] [bib_ref] The role of surgery in advanced renal cell carcinoma: cytoreductive nephrectomy and..., Karam [/bib_ref]. ## Consensus recommendations These comments were discussed as part of the general discussion and were not voted on. In general, the Task Force agreed that nephrectomy remains an important component of management of patients with mRCC based on Level A evidence for IFN and IL-2 [bib_ref] Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma, Fallick [/bib_ref] [bib_ref] Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis, Flanigan [/bib_ref] [bib_ref] Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic..., Flanigan [/bib_ref] [bib_ref] Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic..., Mickisch [/bib_ref] and Level C evidence for VEGF-targeted agents [bib_ref] Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in..., Mathieu [/bib_ref] [bib_ref] The role of surgery in advanced renal cell carcinoma: cytoreductive nephrectomy and..., Karam [/bib_ref]. The resection of oligometastases is supported by Level C evidence [bib_ref] Survival after complete surgical resection of multiple metastases from renal cell carcinoma, Alt [/bib_ref] [bib_ref] The role of surgery in advanced renal cell carcinoma: cytoreductive nephrectomy and..., Karam [/bib_ref]. It is unclear how novel immunotherapy may impact these surgical approaches. ## Immunotherapy for mrcc In the setting of residual metastatic disease, following nephrectomy, or recurrent metastatic disease, the Task Force discussed the role of first-line treatment with immunotherapy versus VEGF or mTOR targeted therapy for metastatic disease. The outcome of this discussion is outlined below and summarized in a treatment algorithm for patients with stage IV RCC [fig_ref] Figure 1: Stage IV renal cell carcinoma [/fig_ref]. What is the current role of HD IL-2 in the treatment of mRCC? IL-2 is a cytokine that was initially called "T cell growth factor" [bib_ref] T-cell growth factor, Smith [/bib_ref] that activates both effector and regulatory T cells. It has shown clinical antitumor activity in preclinical models and clinical trials leading to its FDA approval in patients with advanced RCC in 1992 and melanoma in 1998 [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref]. The FDA approval for HD IL-2 was based on the potential for a small subset of treated patients to achieve durable complete responses, which may last for decades. Therefore, centers that treat patients with mRCC frequently screen for HD IL-2 candidates prior to considering other types of agents as initial treatment. Research to develop biomarkers of responsiveness has been ongoing. However, criteria for patient selection remain clinical at this time. Many IL-2 treatment centers recommend HD IL-2 as initial treatment for patients with mRCC, depending upon the patient's clinical condition and perceived ability to tolerate this therapy. Others recommend clinical trials since some, especially those evaluating frontline use of checkpoint inhibitors, preclude patients with prior therapy of any kind including HD IL-2. ## Literature review and analysis HD IL-2 was approved for treatment of mRCC in 1992, based on summarized data from 7 clinical trials consisting of 255 patients [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref]. The overall response rate (ORR) was 15 % (37/255), including 17 complete (CR) and 20 partial responses (PR). Sixty percent of the PRs had more than 90 % reduction in tumor burden, and some were rendered complete responders by further surgery. The median duration of response was 54 months, including a median of 20 months for PR patients and median not reached for CR patients. The median survival for all 255 patients was 16 months [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref]. Subsequent reports with data from a median of 10 years follow-up showed that 60 % of CR patients remained in complete remission. Additionally, 4 PR patients who underwent surgery of residual disease to achieve CR remained alive and disease-free at more than 65 + months [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref]. More recently, the CWG conducted a prospective, biomarker validation study entitled "SELECT" in which clinical and some biologic features were evaluated as potential selection factors for best response [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. This study again demonstrated that HD IL-2 therapy yielded durable remission and prolonged survival in patients with mRCC. These results were achieved in patients considered both "poor" risk and "favorable" based on retrospectively derived criteria [bib_ref] Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma, Motzer [/bib_ref]. Clinico/pathologic criteria appeared to select for better outcome, such as clear cell histology (96 % of subjects) and prior nephrectomy (99 % of subjects), and these reflected selection prior to enrollment in the trial, based on previous clinical experience. This study demonstrated improved results compared to the historical studies postulated to be based primarily on better patient selection. One hundred and twenty eligible patients were enrolled, 70 % of them being intermediate risk based on MSKCC criteria. The independently evaluated ORR was 25 %, with 3 CRs and 27 PRs. Thirteen patients (11 %) remained progression-free at 3 years from treatment, and the median overall survival (OS) was 42.8 months [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. Biomarkers that were evaluated and not found to be predictive of response were histologic subtype and CA-IX score by immunohistochemistry. Positive expression of PD-L1 in the tumor (18 patients) did significantly correlate with response, but this result requires validation. Additional new data on outcomes with HD IL-2 treatment has been derived from single institution reports and the development of a national database registry of initially retrospective patients and now ongoing prospective collection of treatment and outcome data for HD IL-2 (PROCLAIM NCT 01415167,) [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref] [bib_ref] High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes, Lowder [/bib_ref]. PROCLAIM data on the retrospective cohort of 97 patients with mRCC treated between 2007 and 2012 at 13 sites was presented in 2015. The ORR was 22 % (8 % CR and 14 % PR). The median OS was 51 months for the entire cohort. For those patients achieving CR, PR or stable disease (SD) > 6 months, the median OS has not been reached [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref]. The median OS for those patients who directly progressed after IL-2 therapy was 37.9 months. There were no deaths due to IL-2 related toxicity among the 97 patients. Additionally, the median OS for those patients treated with HD IL-2 as first-line therapy was 61.8 months (n = 82) compared with a median OS of [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref] [bib_ref] Interferon-alfa as a comparative treatment for clinical trials of new therapies against..., Motzer [/bib_ref]. 2) For patients with small-volume, indolent metastases, an initial period of observation can be considered accounting for patient age/comorbidities, patient preference, and toxicity of available therapy. 3) A clinical trial, including those that are immunotherapy-based, should be considered in all RCC patients in all lines of therapy. 4) As noted in the manuscript, HD IL2 should be considered and discussed with mRCC patients with clear cell histology and good performance status. 5) For patients with advanced non-clear cell renal cell carcinoma (RCC), if available a clinical trial is the preferred initial treatment option, including trials of checkpoint inhibitors for which limited data exists regarding efficacy in non-clear cell RCC. If unavailable, then a VEGFR tyrosine kinase inhibitor (TKI) is preferred given results from two small randomized trials showing a slight advantage over mTOR inhibitors in this setting [bib_ref] Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma..., Tannir [/bib_ref] [bib_ref] Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma..., Armstrong [/bib_ref]. 6) Nivolumab is an appropriate initial recommendation in refractory RCC in the absence of contraindications given the overall survival benefit and tolerability. Other options (TKI, HD IL-2 and mTOR inhibitors) can be considered depending on patient performance status, comorbidities, prior therapy received and preference. Figure adapted from 15.3 months for those treated with IL-2 as second-line therapy (n = 15) [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref]. Additional single institution data have been published, demonstrating similarly improved ORR and survival in the modern era [bib_ref] Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and..., Payne [/bib_ref]. ## Consensus recommendations The Task Force was divided about the degree of the role that HD IL-2 has in initial treatment of patients with mRCC. The overall opinion was that appropriate patients with mRCC who have undergone nephrectomy, either in the past or as a cytoreductive intervention, should have a discussion about IL-2 and be referred to centers of excellence for further discussion when appropriate. Sixty-seven percent recommended that all such patients have a discussion regarding IL-2, whereas 33 % preferred to select the patients for that discussion. This recommendation was based on Level A evidence from long-term follow-up of multiple clinical trials [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref] and Level B as well as C evidence from more recent prospective, uncontrolled clinical trials and clinical experience as noted in the literature review [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref] [bib_ref] High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes, Lowder [/bib_ref] [bib_ref] Patients' preferences for adjuvant sorafenib after resection of intermediate or highrisk renal..., Blinman [/bib_ref] [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref]. What are the criteria for considering IL-2 therapy? The Task Force discussed in detail the clinical and biological criteria required for consideration of treatment with HD IL-2 [fig_ref] Table 1: Task Force criteria for HD IL-2 therapy [/fig_ref]. These are specific to HD IL-2, but some criteria may also be applicable to emerging immunotherapy. ## Literature review and analysis Several clinical studies have demonstrated poorer outcomes of patients with non-clear cell RCC compared with those having clear cell RCC, after treatment with cytokines such as IL-2 or IFN [bib_ref] Genetic basis of cancer of the kidney: disease-specific approaches to therapy, Linehan [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref]. A retrospective review of histology showed markedly improved outcome among patients with clear cell RCC after IL-2 therapy, compared with those with mixed histology or those with extensive granular features [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref]. In this study, among patients with clear cell and favorable features (alveolar but no papillary or granular features) the ORR was 39 % (n = 36), and in patients with clear cell with < 50 % granular features, ORR was 19 % (n = 146). Among others including non-clear cell, the ORR was 6 % [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref]. This report provided preliminary data that led to the evaluation of tumor histology that was prospectively evaluated in the renal SELECT clinical trial [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. With respect to sarcomatoid differentiation, studies describe rapid clinical deterioration and report poorer outcomes overall among patients whose tumors have these features, regardless of treatment approach [bib_ref] Impact of histology on the treatment outcome of metastatic or recurrent renal..., Wu [/bib_ref] [bib_ref] Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current..., Shuch [/bib_ref]. Wu et al. described 7 patients with sarcomatoid histology, none of which responded to treatment with HD IL-2. Median survival among these patients was 13 months compared with a median survival of 39 months in 63 patients with clear cell RCC treated with HD IL-2. All were treated in the pre-VEGF pathway inhibitor era in a single institution [bib_ref] Impact of histology on the treatment outcome of metastatic or recurrent renal..., Wu [/bib_ref]. Evaluations of potential biomarkers of response to HD IL-2 have been ongoing but have not provided guidance for specific populations who are more likely to respond. The prospective SELECT trial evaluated several biomarkers, such as tumor CA-IX expression, but this did not predict response. Further exploration of expression of PD-L1 as a biomarker of disease behavior and/or response to immunotherapy is ongoing. Clinical selection by the above criteria remained the strongest predictors along with clear cell histology [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. ## Consensus recommendations In terms of biology, the histology of the renal tumor should be the first consideration [bib_ref] Genetic basis of cancer of the kidney: disease-specific approaches to therapy, Linehan [/bib_ref] [bib_ref] Impact of histology on the treatment outcome of metastatic or recurrent renal..., Wu [/bib_ref]. The majority of the Task Force felt that only patients with clear cell histology should be considered for HD IL-2. The Task Force discussed whether patients with tumors having sarcomatoid features should receive IL-2, and 40 % of participants would exclude such patients. Others would consider such patients, depending upon the proportion of sarcomatoid features noted and the biologic behavior of the disease (rapid or indolent). Thirteen percent would exclude patients with extensive granular features or Fuhrman grade 4 histology based on retrospective data [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref]. PD-L1 expression versus a marker for aggressive RCC or a combination of both were discussed as biomarkers to predict sensitivity to IL-2 as suggested in the SELECT trial. However, this will need to be further verified [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. The level of evidence supporting the recommendations related to pathology are considered Level C, based on retrospective reviews [bib_ref] Genetic basis of cancer of the kidney: disease-specific approaches to therapy, Linehan [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] [bib_ref] Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, Upton [/bib_ref] [bib_ref] Impact of histology on the treatment outcome of metastatic or recurrent renal..., Wu [/bib_ref] [bib_ref] Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current..., Shuch [/bib_ref] and Level B, based on a prospective, uncontrolled trial [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. Clinical and physiologic criteria should also be evaluated prior to recommending HD IL-2. The following have long been established as criteria for patients to undergo HD IL-2 treatment: adequate heart and lung function; ECOG performance status 0-1, preferably 0; age (physiologic versus chronologic), but the upper limit for both is usually in the upper 70s; and absence of CNS metastases (or treated metastases, with no residual edema) [bib_ref] Guidelines for the safe administration of high-dose interleukin-2, Schwartzentruber [/bib_ref] [bib_ref] High dose interleukin-2 (Aldesleukin) -expert consensus on best management practices-2014, Dutcher [/bib_ref]. The Task Force agreed upon these and established a series of criteria and rated their level of importance [fig_ref] Table 1: Task Force criteria for HD IL-2 therapy [/fig_ref]. This was based on Level A evidence from long-term follow-up in multiple trials . What is the role of immunotherapy in mRCC patients with CNS metastases? The development of CNS metastases is not rare in mRCC and remains a criterion for exclusion from clinical trials. However, there are multiple modalities for treatment of small volume CNS lesions, including surgery and stereotactic radiation. When these modalities are successful, the previous CNS metastases do not alone preclude proceeding with systemic treatment of mRCC, including immunotherapy. The concern with HD IL-2 is the risk of increasing brain edema when administered to patients with untreated CNS metastases, and therefore, most clinicians screen for CNS involvement prior to starting HD IL-2. However, occasionally small lesions are not identified and such patients have been treated. ## Literature review and analysis Retrospective reports from the early decades of therapy with HD IL-2 have described treatment of patients with either treated or untreated CNS metastatic disease [bib_ref] Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival, Shuch [/bib_ref] [bib_ref] Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases, Guirguis [/bib_ref] [bib_ref] Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating..., Samlowski [/bib_ref]. A report from University of California, Los Angeles (UCLA) described the outcome of 138 patients with mRCC who developed CNS metastases from 1989 to 2006 [bib_ref] Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival, Shuch [/bib_ref]. In this study, those with symptomatic and asymptomatic lesions as well as the total number of lesions were characterized. The results illustrated that patients with solitary lesions were less likely to develop additional CNS lesions. In addition, selected patients were able to proceed with HD IL-2 and experienced prolonged survival [bib_ref] Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival, Shuch [/bib_ref]. In this series, the median survival after diagnosis of CNS metastases was 10.7 months, and the 5-year survival was 12 %. Patients receiving HD IL-2 after CNS treatment had a response rate of 17 %. Retrospective data from the National Cancer Institute consisted of more than 1000 patients with either melanoma or mRCC who were treated with HD IL-2 with or without other therapy from 1985 to 2000 [bib_ref] Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases, Guirguis [/bib_ref]. Patients with previously treated CNS metastases (n = 27) had an ORR of 18.5 %, and those with no brain metastases (n = 1005) had an ORR of 19.8 % [bib_ref] Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases, Guirguis [/bib_ref]. Two of 36 patients with untreated CNS lesions demonstrated objective response of both intracranial and extracranial disease. This report stated that there were no differences in toxicity profile or reasons for stopping IL-2 among those with CNS lesions and those without. A third retrospective report described the management of CNS metastases in patients with mRCC, with the use of stereotactic radiation therapy (SRS) from 2000 to 2006 [bib_ref] Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating..., Samlowski [/bib_ref]. Among 32 patients with 71 CNS lesions, local control was achieved in 22 patients and 42 lesions. Whereas the median survival of all patients with CNS metastases was 10 months, 16 % achieved 3 year survival. In addition, these patients were able to proceed to systemic immunotherapy, including HD IL-2 and IFN [bib_ref] Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating..., Samlowski [/bib_ref]. Two later reports of patients with melanoma also describe the objective response of intracranial metastases to immunotherapy (HD IL-2 and adoptive cell therapy), confirming the ability of immunotherapy to induce regressions of intracranial tumors [bib_ref] Single-institution outcome of high-dose interleukin-2 (HD IL-2) therapy for metastatic melanoma and..., Powell [/bib_ref] [bib_ref] Successful treatment of melanoma brain metastases with adoptive cell therapy, Hong [/bib_ref]. ## Consensus recommendations Given the heterogeneous and retrospective nature of the information available regarding management of CNS metastases in patients with mRCC, the Task Force felt that proceeding with HD IL-2 in this setting is individualized and relies on clinical judgment. With respect to patients presenting with CNS metastasis, 47 % of the Task Force preferred the use of a VEGFR TKI after local treatment of the CNS disease. However, 40 % would treat the CNS lesion(s) with either surgery of stereotactic RT first, and then consider proceeding with HD IL2, if other criteria are met. The level of evidence for the recommendation for use of IL-2 was considered Level A, based on long-term follow-up [bib_ref] Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival, Shuch [/bib_ref] [bib_ref] Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases, Guirguis [/bib_ref] and Level C based on short-term, retrospective data [bib_ref] Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating..., Samlowski [/bib_ref]. What is the role of evaluation of risk factor prognostic categories in deciding treatment approach? Several groups have evaluated clinical and laboratory features of patients with mRCC and have developed algorithms that define prognosis and survival. The initial report was developed retrospectively among patients treated with IFN [bib_ref] Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma, Motzer [/bib_ref] , and additional retrospective studies demonstrated similar delineations of patients into favorable, intermediate (majority of mRCC) and poor risk groups [bib_ref] Use of the University of California Los Angeles integrated staging system to..., Patard [/bib_ref] [bib_ref] Prognostic model for survival in patients with metastatic renal cell carcinoma: results..., Manola [/bib_ref]. Subsequent evaluations have assessed risk criteria among patients treated with VEGF pathway inhibitors and have demonstrated consistent results [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref]. The evaluation of such prognostic information has become useful in evaluating outcome of clinical trials by strata, as well as adding information when considering treatment options for patients. ## Literature review and analysis In the prospective SELECT trial, HD IL-2 produced durable remissions and prolonged survival in both good and poor risk patients according to MSKCC criteria; however, the poor risk patients were few in number [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. Reports in clinical trials [bib_ref] Sorafenib in advanced clear-cell renal-cell carcinoma, Escudier [/bib_ref] [bib_ref] Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall..., Motzer [/bib_ref] [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a..., Sternberg [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] and in the modern prognostic factor analyses with immune and targeted therapy [bib_ref] Use of the University of California Los Angeles integrated staging system to..., Patard [/bib_ref] [bib_ref] Prognostic model for survival in patients with metastatic renal cell carcinoma: results..., Manola [/bib_ref] [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref] demonstrate the greatest treatment benefit for patients with mRCC to be among those with favorable and intermediate risk. ## Consensus recommendations Regarding the use of the prognostic categories that have been developed for predicting survival of patients with mRCC, the consensus of the Task Force was that these criteria are used for treatment decisions. Poor risk patients, with expected shortened survival are not considered initial candidates for HD IL-2, and the majority (53 %) would proceed with anti-VEGFR TKI, 20 % with temsirolimus, and 27 % with clinical trials, if available, in the setting of poor risk patients. These recommendations are based on Level B evidence from long-term retrospective reviews [bib_ref] Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma, Motzer [/bib_ref] [bib_ref] Use of the University of California Los Angeles integrated staging system to..., Patard [/bib_ref] [bib_ref] Prognostic model for survival in patients with metastatic renal cell carcinoma: results..., Manola [/bib_ref] [bib_ref] Prognostic factors for overall survival in patients with metastatic renal cell carcinoma..., Heng [/bib_ref] and Level B evidence from a prospective trial with IL-2 [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref] as well as Level C evidence from retrospective evaluations of risk categories in studies of targeted therapies [bib_ref] Sorafenib in advanced clear-cell renal-cell carcinoma, Escudier [/bib_ref] [bib_ref] Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall..., Motzer [/bib_ref] [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a..., Sternberg [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] [bib_ref] Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled..., 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]. What are considerations of duration of treatment with HD IL-2 and when to change therapy? There was discussion regarding retreatment of patients following the first course of HD IL-2. Although chemotherapy treatment in oncology utilizes repetitive treatment cycles, the necessary treatment duration for immunotherapy continues to be evaluated. It is conceivable that once activation of the immune system occurs, additional treatment does not result in additional benefit. ## Literature review and analysis Based on the SELECT trial and PROCLAIM data, SD may be a therapeutic effect of IL-2. In SELECT, there was an ORR of 25 %, with 3 CRs and 27 PRs. The median duration of response was 20.6 months, and 13 patients progression-free at 3 years. There were 9 patients with SD lasting more than 6 months. The median OS was 43 months for all 120 patients [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. In the retrospective and prospective PROCLAIM registry, which is still accumulating patient data, the response rate is 20 %, and the median OS has not been reached for the prospective category of patients [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref]. The survival of stable patients aligned with the responders and was considerably better that that of the progressing patients [bib_ref] High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the..., Aung [/bib_ref]. ## Consensus recommendations There were different opinions as to whether more than one course of HD IL-2 should be given to those patients who respond or are stable. In patients with responding or SD 12 weeks following HD IL-2, 80 % would give a second two week course of therapy. Thirteen percent would continue to observe, especially in patients with SD, until progression is documented, and then start another treatment. Anecdotal patients were discussed who achieved a durable CR with one course of HD IL-2. It has not been prospectively evaluated whether patients who have SD as their best response to the first course of HD IL-2 can achieve either a better response or delayed progression with additional courses of therapy. However, if no contraindication existed, the majority of the Task Force would proceed with a second course before changing treatment. The level of evidence was considered Level C, based on retrospective data and case anecdotes. What options are recommended at progression following HD IL-2? For many years additional immunotherapy or clinical trials were the only treatment options. In initial exploratory clinical trials of VEGF and mTOR pathway inhibitors, most of the patients had progressed on prior immunotherapy, which did not have a negative effect on outcome [bib_ref] Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic..., Ratain [/bib_ref] [bib_ref] Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor..., Motzer [/bib_ref]. Therefore, data and clinical experience exist to inform the management of patients following HD IL-2. This decision clearly depends on the timing of progression (immediate vs years later), type and degree of progression, rate of progression, and previous experience with HD IL-2 treatment. ## Literature review and analysis Data for proceeding with additional HD IL-2 come from experience in patients for whom this had been their only option. Anecdotal experience has demonstrated subsequent responses to HD IL-2, after a hiatus of time from the initial treatment. Also, long-term follow-up data from IL-2 studies show patients with surgically completed complete responses continue to demonstrate long term remission [bib_ref] Surgical resection of metastatic renal cell carcinoma and melanoma after response to..., Sherry [/bib_ref]. Subsequent treatment with anti-angiogenesis agents or mTOR inhibitors has likewise demonstrated benefit in patients who progressed on cytokines [bib_ref] Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled..., Motzer [/bib_ref] [bib_ref] Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic..., Ratain [/bib_ref] [bib_ref] Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor..., Motzer [/bib_ref]. There are limited data on activity of checkpoint pathway inhibitors following treatment with HD IL-2. ## Consensus recommendations There was a difference of opinion regarding options at progression, even if response to IL-2 lasted at least 6 months: 73 % would proceed to another therapy, whereas 13 % would recommend another course of HD IL-2. Another 13 % would recommend resection of residual disease if possible to remove all such disease. In a follow-up discussion, the consensus was that patients who have major response to 2 courses of IL-2, who have residual oligometastatic disease should be managed with surgical resection of residual disease (73 %), another course of IL-2 (20 %), or switch to TKI (7 %). All data was considered anecdotal, and therefore, clinical judgment is the deciding factor at this time. What is the role of Low dose IL-2 or low dose IL-2 combined with IFN? Low dose regimens have been studied in the past, including low dose intravenous (IV) administration on the same schedule as HD IL-2, low dose subcutaneous (SQ) administration, 5 days/week for indeterminate time frame, a decrescendo dosing schedule of SQ IL2, and SQ administration of both low dose IL-2 and IFN, among others. Although durable complete responders have been documented with all of these regimens, the ORR is lower than with HD IL-2 in the IV bolus dose and the SQ injection schedule [bib_ref] Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal..., Yang [/bib_ref] [bib_ref] Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon..., Mcdermott [/bib_ref]. ## Literature review and analysis A low dose IV regimen of IL-2 was noted to yield durable CRs in some patients, albeit in smaller numbers, and this regimen was safe in patients with organ dysfunction [bib_ref] Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal..., Yang [/bib_ref] [bib_ref] Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon..., Mcdermott [/bib_ref] [bib_ref] A Cytokine Working Group (CWG) phase II study of intermediate dose bolus..., Logan [/bib_ref]. Additionally, studies have been reported in which alternate schedules of HD IL-2 have been utilized, and appear to be more tolerable with similar efficacy [bib_ref] Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen..., Acquavella [/bib_ref] [bib_ref] Changes in dendritic cell phenotype after a new high-dose weekly schedule of..., Finkelstein [/bib_ref]. These should be further evaluated, particularly in the context of combinations. ## Consensus recommendations All agreed that there is limited to no role of either low dose IL-2 regimen as a single agent treatment, with the possible exception of patients with impaired organ function based on a prospective, uncontrolled trial (Level B evidence) [bib_ref] A Cytokine Working Group (CWG) phase II study of intermediate dose bolus..., Logan [/bib_ref]. Level A efficacy data favoring HD IL-2 compared to low dose IL-2 was based on two randomized, comparative studies [bib_ref] Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal..., Yang [/bib_ref] [bib_ref] Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon..., Mcdermott [/bib_ref]. Level B data on new schedules was derived from prospective, uncontrolled trials [bib_ref] Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen..., Acquavella [/bib_ref] [bib_ref] Changes in dendritic cell phenotype after a new high-dose weekly schedule of..., Finkelstein [/bib_ref]. Investigation of low dose regimens in conjunction with new immunotherapies is a research consideration, given that check point pathway inhibitors are being studied at much lower doses in combination than those used in the original single agent trials. Alternative schedules should also be explored in the context of combination immunotherapy or immunotherapy with targeted agents. What is the role of HD IL-2 as second-line therapy after anti-VEGF TKI in a patient who met eligibility criteria for HD IL-2 and was not progressing rapidly? More commonly in the past 10 years, patients with mRCC are started on an anti-VEGF TKI and upon progression are referred for consideration of immunotherapy with HD IL-2 to an institution with such a treatment program. The Task Force was asked to consider the pros and cons of this approach in terms of optimizing treatment options for patients, as well as tolerability of this approach. ## Literature review and analysis Cho et al. reported a small experience in which 40 % of 15 patients treated with prior TKI treatment had unexpected cardiac toxicity upon treatment with HD IL-2 [bib_ref] Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted..., Cho [/bib_ref]. They noted that patients generally had very brief "wash out" periods after completing treatment with anti-VEGF TKIs. Lam et al. subsequently reported the successful administration of HD IL-2 after anti-VEGF TKIs have recommended doing so in the setting of a prolonged break between therapies [bib_ref] Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior..., Lam [/bib_ref]. They did, in fact, note unexpected grade 3 cardiac events in 6/40 patients who were treated after a short interval. Both reports recommend 8-12 weeks before initiating HD IL-2 therapy [bib_ref] Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted..., Cho [/bib_ref] [bib_ref] Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior..., Lam [/bib_ref]. ## Consensus recommendations Sixty-seven percent of the Task Force felt that anti-PD-1 agents will be the preferred second-line immunotherapy in this setting, following initial anti-VEGF TKI. This is not based on comparative data with other immunotherapy, but it is based on the logistics of outpatient therapy of anti-PD-1 and less stringent eligibility criteria. This second-line position of anti-PD-1 agents is now supported by Level A data from the recently published randomized phase III trial of nivolumab versus everolimus in the second-line setting [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref]. Currently, if anti-PD-1 agents are not available for use, then HD IL-2 should be considered as second-line therapy after a washout period in appropriate patients based on Level C data [bib_ref] Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted..., Cho [/bib_ref] [bib_ref] Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior..., Lam [/bib_ref]. Such patients should be evaluated carefully with a cardiac echo and show adequate cardiac function prior to initiation of IL-2 therapy. What is the role of HD IL-2 after investigational treatment with an anti-PD-1 agent? Data are only now being compiled by the PROCLAIM registry for centers treating with HD IL-2 and thus no substantial data are yet available. ## Literature review and analysis There are no prospective studies. However, there is a single abstract reporting the outcome of patients treated with HD IL-2 after progression on anti-PD-1 checkpoint inhibitors. A small report using the PROCLAIM database and a single institution reported on 11 patients, 7 of whom had mRCC. All developed ongoing SD or response with a median follow-up of 15 months [bib_ref] A retrospective analysis of high-dose aldesleukin (HD IL-2) following immune checkpoint blockade..., Gunturi [/bib_ref]. ## Consensus recommendations There was no formal vote on this topic. However, the Task Force's assessment was that HD IL-2 could follow anti-PD-1 agents based on their lower toxicity profile, which is associated with fewer persistent immunerelated adverse events compared with other checkpoint inhibitors (e.g., anti-CTLA-4 agents). Informally, 73 % felt that this sequence is a consideration, as the two immunotherapy approaches work by different mechanisms of immune activation and that anti-PD-1 and IL-2 could potentiate the activity of each other. Some of the Task Force members have done this successfully. The level of evidence for sequencing is currently Level C. A prospective trial of HD IL-2 following anti-PD-1 therapy was felt to be worth consideration. ## Summary of hd il-2 recommendation Eligible patients (clear cell histology with adequate organ reserve, s/p nephrectomy, with few adverse risk features) should be considered for IL-2 therapy at centers with adequate experience. The utility and role of IL-2 prior to or after checkpoint inhibitors is unknown and requires further study. What is the role of IFN in the treatment of RCC? IFN has been a mainstay in the treatment of RCC for more than 20 years and has been the control arm for the initial clinical trials that led to the approval of anti-VEGF and mTOR targeted therapies [bib_ref] The treatment of renal cell carcinoma with human leukocyte alpha-interferon, Dekernion [/bib_ref] [bib_ref] Complete response to interferon-alpha in a patient with metastatic renal cell carcinoma..., Yamamoto [/bib_ref] [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref]. IFN has anti-proliferative activity, as well as immune stimulatory activity, with activation of cellular immunity. Continued research provides insight into interactions with signaling pathways for gene transcription, apoptosis, and immune interactions with Toll-like receptors among others [bib_ref] Alphainterferon and its effects on signal transduction pathways, Caraglia [/bib_ref] [bib_ref] Interferons at age 50: past, current and future impact on biomedicine, Borden [/bib_ref]. IFN has produced CRs in patients with mRCC, both in the cytokine era and more recently, following anti-VEGF therapy [bib_ref] The treatment of renal cell carcinoma with human leukocyte alpha-interferon, Dekernion [/bib_ref] [bib_ref] Complete response to interferon-alpha in a patient with metastatic renal cell carcinoma..., Yamamoto [/bib_ref]. Nevertheless, it is a difficult drug to use because of the chronic administration as well as the severity and chronicity of side effects. ## Literature review and analysis IFN is currently approved in combination with bevacizumab for treatment of patients with mRCC, based on the results of two phase III trials comparing the combination to IFN alone [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] Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy..., Rini [/bib_ref] [bib_ref] A multinational phase II trial of bevacizumab with low-dose interferon-alpha2a as first-line..., Melichar [/bib_ref]. In these studies, the combination had a better response rate (26-31 %) compared to IFN alone (13 %) and a prolonged progressionfree survival (PFS) compared with IFN (8.5-10.4 months versus 5.2-5.4 months). OS was prolonged in both arms, and approached 2 years. The lack of difference in OS between arms was thought to be in part due to subsequent therapy given to patients in both arms after progression. A subsequent multicenter, phase II trial was conducted, built on the initial phase III bevacizumab/IFN data, taking into account the frequent dose reductions of IFN observed in those studies [bib_ref] A multinational phase II trial of bevacizumab with low-dose interferon-alpha2a as first-line..., Melichar [/bib_ref]. This study utilized a reduced dose of IFN (3 MIU 3×/week versus 9 MIU 3×/week). Compared with the data from the initial phase III trials, there was reduced IFN-related toxicity without compromising efficacy [bib_ref] A multinational phase II trial of bevacizumab with low-dose interferon-alpha2a as first-line..., Melichar [/bib_ref]. The response rate was 28 %, the median PFS was 15.3 months, and OS was 30.7 months. There appears to be additive benefit for IFN in combination with bevacizumab, and studies of lower dose IFN appear to provide a manageable regimen in combination. There is wider IFN usage outside of North America. ## Consensus recommendations Most members of the Task Force do not use IFN, even in combination with bevacizumab (60 %) and even at lower IFN doses, which evolved in the randomized trials and then was formally evaluated [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] Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy..., Rini [/bib_ref] [bib_ref] A multinational phase II trial of bevacizumab with low-dose interferon-alpha2a as first-line..., Melichar [/bib_ref] [bib_ref] Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic..., Escudier [/bib_ref]. The efficacy recommendation for single agent IFN is level A, based on prospective, randomized trials showing that anti-VEGF receptor and mTOR inhibitor targeted therapies have superior PFS compared to single agent IFN [bib_ref] Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, Motzer [/bib_ref] [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref]. The level of evidence for IFN in combination with bevacizumab being superior to IFN alone is Level A, based on two randomized, controlled clinical trials [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] Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy..., Rini [/bib_ref] [bib_ref] Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic..., Escudier [/bib_ref]. Among the members of the Task Force, only 13 % would use IFN as a single agent. What is the role of PD-1 blockade (either with anti-PD-1 or anti-PD-L1)? The PD-1 pathway is a checkpoint for immune regulation and suppression at the level of the tumor and immune cell interaction [bib_ref] PD-1 and its ligands in tolerance and immunity, Keir [/bib_ref]. Inhibition of this pathway leads to immune activation. Agents that are under investigation include antibodies to PD-1 and PD-L1 [fig_ref] Table 2: Select immunotherapy agents and ongoing immunotherapy clinical trials in RCC Ongoing clinical... [/fig_ref] , and clinical trials have demonstrated anti-tumor benefit including in mRCC [bib_ref] Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors:..., Brahmer [/bib_ref] [bib_ref] Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, Brahmer [/bib_ref] [bib_ref] Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, Topalian [/bib_ref]. Two such agents have been approved for the treatment of melanoma (nivolumab and pembrolizumab) and more recently for non-small cell lung cancer, RCC (nivolumab), urothelial cancer (atezolizumab), Hodgkin Disease (nivolumab). Nivolumab was approved for mRCC following progression on a VEGFR targeted therapy by the FDA in 2015. This approval was based on Level A evidence in a randomized, phase III controlled trial demonstrating an OS benefit of nivolumab compared with everolimus following progression on anti-VEGFR TKI. There are no comparative data between immunotherapies at this time. The approval of PD-1 pathway blockers in RCC will necessitate further study of sequencing and combination therapy approaches in this disease, involving immunotherapies and VEGF pathway targeted therapies. Many such trials are ongoing. ## Literature review and analysis Current longitudinal data for anti-PD-1 agents in mRCC include a phase II trial of nivolumab, evaluating 3 different dose levels. There did not appear to be a dose response in this study, and responses were observed at all three dose levels with an ORR of 21 % and median PFS of 4 months [bib_ref] Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II..., Motzer [/bib_ref]. Another report provided long-term follow-up of the expansion cohort of mRCC patients treated with nivolumab in the initial phase I study, in which 34 treatment-refractory mRCC patients were enrolled [bib_ref] Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors:..., Brahmer [/bib_ref] [bib_ref] Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal..., Mcdermott [/bib_ref]. The response rate was 29 % with a median response duration of 12.9 months, and there were 9 additional patients (27 %) with stable disease lasting beyond 24 weeks. The median OS of all patients was 22.4 months [bib_ref] Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal..., Mcdermott [/bib_ref]. In a recent update, 3 and 5-year survival for this patient population was reported to be 41 and 34 % respectively [bib_ref] Long-term overall survival (OS) with nivolumab in previously treated patients with advanced..., Mcdermott [/bib_ref]. This data led to a phase II trial (NCT01354431), which enrolled 167 patients with VEGR TKI refractory advanced RCC and randomized them to 3 different dose levels of nivolumab administered every 3 weeks [bib_ref] Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II..., Motzer [/bib_ref]. Response rates were 20-22 % for each dose level and median OS ranged from 18 to 25 months. Updated data were recently presented at ASCO 2016. At a minimum follow-up of 38 months ORR was 21 % and the median duration of response was 22 months. In addition, the 3-year OS rate was 35 % [bib_ref] Long-term overall survival (OS) with nivolumab in previously treated patients with advanced..., Mcdermott [/bib_ref]. Recently, results of the phase III clinical trial of nivolumab versus everolimus in second-line treatment of mRCC were released [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref]. The study was stopped early in July 2015 because data demonstrated a median OS benefit in patients receiving nivolumab at 25 months compared with everolimus at 19 months, hazard ratio 0.73, p = 0.002 [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref]. Additionally, the objective response rate for nivolumab was 25 % compared to 5 % for everolimus (p < 0.001). Median PFS was 4.6 months with nivolumab and 4.4 months with everolimus, p = .11. Grade 3 or 4 adverse events deemed related to treatment occurred in 19 % of nivolumab-treated patients and in 37 % of everolimus-treated patients. This study also evaluated tumor expression of PD-L1 as a potential biomarker of treatment effect, with cut-off values at ≥ 1 % and ≥ 5 %. While expression of PD-L1 correlated with poorer outcome, it did not predict better response to or survival with nivolumab compared with everolimus, as patients with both high and low PD-L1 expressing tumors appeared to benefit from nivolumab relative to everolimus [bib_ref] Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, Motzer [/bib_ref]. This report led to FDA approval of nivolumab for mRCC as second line therapy following a VEGFR inhibitor. A phase I study of the anti-PD-L1 agent, atezolimuzab reported increased anti-tumor activity in patients whose tumor-infiltrating lymphocytes demonstrated PD-L1 expression. Additionally, this study showed a response rate of 22 % among patients with clear cell RCC with Fuhrman grade 4 or sarcomatoid features [bib_ref] Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term..., Mcdermott [/bib_ref]. It should be noted, however, that given the low expression of PD-L1 in RCC, 5 out of 9 responders had low PD-L1 expression, highlighting the limited value of assessment of PD-L1 expression for clinical decision making in patients with mRCC. Combination studies of anti-CTLA-4 and anti-PD-1 have been reported in melanoma with high response rate and high toxicity rate [bib_ref] Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, Postow [/bib_ref] [bib_ref] Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma, Larkin [/bib_ref]. This approach is currently undergoing considerable modification in terms of dose and schedule and clinical trials of combinations are ongoing in a variety of diseases, including mRCC [fig_ref] Table 2: Select immunotherapy agents and ongoing immunotherapy clinical trials in RCC Ongoing clinical... [/fig_ref]. Studies of combinations of PD-1 pathway blockers and anti-VEGF pathway agents are also ongoing [fig_ref] Table 2: Select immunotherapy agents and ongoing immunotherapy clinical trials in RCC Ongoing clinical... [/fig_ref]. ## Consensus recommendations At the time of the meeting, phase III studies were not yet reported and the Task Force discussed the role of PD-1 pathway blockade in mRCC in light of the available phase I and II data. There was enthusiasm for this approach as a single agent, as well as for investigation in combination with other checkpoint pathway inhibitors (anti-CTLA-4) and with activating cytokines (IL-2). The Task Force did vote on their preferred treatment for patients who have progressed on anti-VEGF TKI therapy, in the setting of a patient who had received sunitinib for one year, pazopanib for 8 months, and who remained with ECOG performance status 1. Sixty-seven percent preferred anti-PD-1 agents in clinical trials or as a commercial agent, if available. Thirteen percent would choose IL-2 in appropriate patients after TKIs, and 6.7 % would recommend either axitinib or everolimus. Due to their more favorable toxicity profiles, many patients as well as physicians would likely prefer immunotherapy with anti-PD-1 agents compared to HD IL-2. There was considerable enthusiasm for enrolling patients into ongoing clinical trials of anti-PD-1 agents in combination therapy. This was preferred even in the first-line setting where several clinical trials are available [fig_ref] Table 3: Ongoing phase III studies in front-line advanced/metastatic RCC Study Primary endpoint Sample... [/fig_ref]. The utilization of expression of PD-L1 as a biomarker of potential activity of these agents is still under investigation and not established. Critical questions regarding checkpoint inhibitor therapy include the value (risk/benefit ratio) of combination therapy over single agent use, the ability to stop and restart therapy (i.e., the need for ongoing treatment), the development of biomarkers to select patients, and optimizing toxicity management. What treatment is recommended for metastatic non-clear cell RCC? ## Literature review and analysis Historically, patients with non-clear cell RCC did not frequently respond to treatment with HD IL-2 [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref]. The HD IL-2 "SELECT" trial included 5 patients with non-clear cell RCC, and none responded [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref]. In an unplanned analysis of the outcome of patients in the phase III trial of temsirolimus versus IFN, patients with non-clear cell carcinoma treated with temsirolimus had a major survival advantage compared to those treated with IFN, demonstrating either the effectiveness of temsirolimus or the lack thereof of IFN in non-clear cell subtypes [bib_ref] Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma, Hudes [/bib_ref] [bib_ref] Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal..., Dutcher [/bib_ref]. Although expanded access trials and small studies of targeted therapy suggested some response to anti-VEGF directed therapy, large database reviews report lower response rates and poorer median survival among patients with metastatic non-clear cell RCC compared with clear cell RCC [bib_ref] Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization..., Kroeger [/bib_ref] [bib_ref] Targeted therapies and the treatment of non-clear cell renal cell carcinoma, Bellmunt [/bib_ref] [bib_ref] Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and..., Vera-Badillo [/bib_ref]. There is a recently opened NCIsponsored clinical trial for patients with papillary RCC to evaluate a variety of MET-inhibitors, thus targeting a known genomic feature of some papillary RCC tumors (S1500). Whether the newer immunotherapies will have a role in non-clear cell RCC remains to be determined. A case report describes a dramatic and rapid response of a single patient with papillary RCC with sarcomatoid and rhabdoid features to nivolumab [bib_ref] Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic..., Geynisman [/bib_ref]. ## Consensus recommendations The majority of the Task Force felt that HD IL-2 should be reserved for patients with clear cell renal cancer, based on Level A [bib_ref] The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models..., Mcdermott [/bib_ref] and Level B evidence [bib_ref] Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell..., Fisher [/bib_ref] [bib_ref] Results of treatment of 255 patients with metastatic renal cell carcinoma who..., Fyfe [/bib_ref] [bib_ref] Durability of complete responses in patients with metastatic cancer treated with high-dose..., Rosenberg [/bib_ref]. Data are insufficient regarding the use of checkpoint pathway inhibitors in the non-clear cell RCC population, since very few such patients were entered into the clinical trials of these agents. There was lack of consensus on the initial treatment recommendation for patients with metastatic non-clear cell RCC. Essentially, the Task Force voted for clinical trials as initial therapy for such patients, provided new agents or approaches have strong rationale for the specific subtype. If a clinical trial is unavailable, then a VEGFR TKI is preferred given results from two small randomized trials showing a slight advantage over mTOR inhibitors in this setting [bib_ref] Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma..., Tannir [/bib_ref] [bib_ref] Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma..., Armstrong [/bib_ref]. # Conclusions Immunotherapy remains an established modality for the treatment of patients with mRCC and continues to produce durable responses in a subset of patients. Patient selection for HD IL2 remains based on clinical criteria. Outcome for HD IL-2 continues to be the gold standard insofar as there are durable complete remissions. The approval of nivolumab in previously treated patients with mRCC and clinical trials with nivolumab and other PD1 pathway blockers are providing new directions for immunotherapy in patients with mRCC and will likely expand the cohort of patients eligible for such therapy. It is not yet clear whether this approach will provide an increased number of responders, although the suggestion of response in patients with more aggressive tumors with anti-PD-L1 therapy is perhaps evidence that HD IL-2 and PD-1 pathway blockade may have some complementary anti-tumor efficacy. However, further research is ongoing, including exploration of combinations, dose and schedule, and potential consideration of studies in the adjuvant setting. The further development of immunotherapy in patients with RCC will provide meaningful benefit, and the goal should be durable CRs comparable to those observed with HD IL-2. Recent data showing substantial 3-5 year survival rates with nivolumab suggest that this goal may quickly become a reality. ## Additional files [fig] Figure 1: Stage IV renal cell carcinoma (RCC) immunotherapy treatment algorithm. All treatment options shown may be appropriate. The final selection of therapy should be individualized based on patient eligibility and the availability of each therapy at the treating physician's discretion. 1) "Risk" refers to prognostic risk group per Memorial Sloan Kettering Cancer Center (MSKCC) and/or International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification [/fig] [fig] Additional file 1: Comments Received during Review. (DOCX 17 kb) Additional file 2: Task Force Roster. (DOCX 12 kb) Additional file 3: Annotated Biobliography. (DOCX 225 kb) Additional file 4: Task Force Pre-meeting Survey Questions. (DOCX 34 kb) Abbreviations CNS: Central nervous system; CR: Complete response; CWG: Cytokine working group; DFS: Disease-free survival; ECOG: Eastern Cooperative Oncology Group; FDA: U.S. Food and Drug Administration; HD IL-2: High dose interleukin-2; IFN: Interferon-alpha; IL-2: Interleukin-2; mRCC: Metastatic RCC; MSKCC: Memorial-Sloan Kettering Cancer Center; mTOR: Mammalian target of rapamycin; ORR: Overall response rate; OS: Overall survival; PD-1: Programmed death receptor 1; PD-L1: Programmed death ligand 1; PR: Partial response; RCC: Metastatic renal cell cancer; RFS: Recurrence-free survival; SD: Stable disease; SITC: Society for immunotherapy of cancer; SQ: Subcutaneous; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor [/fig] [table] Table 1: Task Force criteria for HD IL-2 therapy [/table] [table] Table 2: Select immunotherapy agents and ongoing immunotherapy clinical trials in RCC Ongoing clinical trials for check point inhibitorsAbbreviations: Ipi ipilimumab, nivo nivolumab, atezo atezolimumab, bev bevacizumab, pembro pembrolizumab, len lenvatinib, HQ hydroxychloroquine, SBRT stereotactic body radiation therapy, RT radiation therapy [/table] [table] Table 3: Ongoing phase III studies in front-line advanced/metastatic RCC Study Primary endpoint Sample size National clinical trial identifier Start time/status [/table]	None	https://jitc.biomedcentral.com/track/pdf/10.1186/s40425-016-0180-7	None
caf404418ad8b3f429cf80a7c2d537d53392fdeb	pubmed	Guidelines for the prevention and management of children and adolescents with COVID-19	Guidelines for the prevention and management of children and adolescents with COVID-19 Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.Conclusion: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged.What is Known: - Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. - We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. What is New:- The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. # Introduction The worldwide spread of coronavirus disease 2019 (COVID- represents a serious threat to the health of children. As of June 30, 2022, nearly 13.8 million children have tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection since the onset of the pandemic, and children comprised [bib_ref] Guidelines International Network: principles for disclosure of interests and management of conflicts..., Schünemann [/bib_ref].7% of all cases. Omicron has rapidly replaced the Delta variant and become the dominant SARS-CoV-2 variant responsible for most infections, since it was first detected in November 2021 [bib_ref] Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2, Antonelli [/bib_ref]. Since the emergence of the Omicron variant, the number of COVID-19 cases in children has dramatically increased, reigniting concerns about how to appropriately manage SARS-CoV-2 infection in children. Since the beginning of the COVID-19 outbreak, close to 100 international and national clinical practice guidelines (CPGs) for the management of adult COVID-19 patients have been developed . However, there are so far only few evidence-based guidelines specifically focusing on pediatric COVID-19. The management of pediatric patients differs in many aspects from that of adults [bib_ref] Clinical care of children and adolescents with COVID-19: recommendations from the National..., Navarro [/bib_ref]. For example, COVID-19 is usually milder in children than adults [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref]. Interventions used to treat adults may not be effective and safe in children. In addition, there are topics such as breastfeeding during the pandemic that are specific to children and, although mentioned in some guidelines [bib_ref] Clinical care of pregnant and postpartum women with COVID-19: living recommendations from..., Vogel [/bib_ref] [bib_ref] Breastfeeding of infants born to mothers with COVID-19: a rapid review, Yang [/bib_ref] , not necessarily covered by most adult or general guidelines. In response to these issues, we published the first international Rapid Advice Guidelines for Management of Children with COVID-19 in May 2020 [bib_ref] Rapid advice guidelines for management of children with COVID-19, Liu [/bib_ref]. We provided ten recommendations addressing the most common questions in the diagnosis and management of children with COVID-19, based on the knowledge of the disease at the time of the guideline publication. Along with the emergence of new evidence related to the management of COVID-19 in children and adolescents over the last years, more information about COVID-19-related clinical syndromes has become available [bib_ref] Multisystem inflammatory syndrome in U.S. children and adolescents, Feldstein [/bib_ref] [bib_ref] Coronavirus disease 2019 (COVID-19) and mental health for children and adolescents, Golberstein [/bib_ref]. According to the World Health Organization (WHO) guideline development methodology, a standard (instead of a rapid) guideline is recommended for public health emergencies that have lasted over 6 months [bib_ref] Developing WHO rapid advice guidelines in the setting of a public health..., Garritty [/bib_ref]. We updated the original guideline [bib_ref] Rapid advice guidelines for management of children with COVID-19, Liu [/bib_ref] following methodological handbooks , and reported the contents according to the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist and the Checklist for the Reporting of Updated Guidelines (CheckUp) [bib_ref] A reporting tool for practice guidelines in health care: the RIGHT statement, Chen [/bib_ref] [bib_ref] Reporting items for updated clinical guidelines: checklist for the reporting of updated..., Vernooij [/bib_ref]. We registered the guideline at the International Practice Guidelines Registry Platform (http:// guide lines-regis try. org/, registration No. IPGRP-2020CN101) and published the guideline protocol [bib_ref] Guidelines for the Management of Children and Adolescent with COVID-19: protocol for..., Zhou [/bib_ref]. ## Guideline working group Building on the panel of the previous version of the guideline, two chairs (EL, RLS) invited and recruited more new panelists in developing this guideline, with the aim of enhancing the diversity in expertise, geographical origin, and gender among the panel members. The updated panel comprised 18 specialties including pediatric respiratory medicine, pediatric infectious diseases, pediatric critical care medicine, neonatology, pediatric nephrology, pediatric immunology, general pediatrics, pulmonary and critical care medicine, infectious diseases, nursing, radiology, epidemiology, global health, health technology assessment, health policy, health economics, law, and statistics. The newly added methodologists (GG, IDF) have rich experience in updating guidelines and using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and the Appraisal of Guidelines for Research & Evaluation (AGREE) instrument. The newly added pulmonary physician (BC) has experience in clinical trials on drugs for COVID-19. We also considered gender balance, nearly half of the panelists were female. The international guideline working group comprised 69 members: 45 members of the original guideline working group and 24 new members. Members were allocated to four specific groups: (1) a steering group comprised of five members, including the chair (EL) and co-chair (RLS), a chief methodologist (YC), and two chief clinical experts (QL and ZL); (2) a consensus group comprised of 41 members; (3) an evidence synthesis and evaluation group comprised of 20 members with experience conducting systematic reviews; and (4) a patient partner group with two guardians of children and a child patient. Appendix 1 [fig_ref] Table 1: Grading of certainty of evidence and strength of recommendations * * According... [/fig_ref] presents detailed information about the guideline working group. ## Declaration and management of conflict of interests (cois) Our competing interest procedures adhered to the principles of the Guidelines International Network [bib_ref] Guidelines International Network: principles for disclosure of interests and management of conflicts..., Schünemann [/bib_ref]. Before starting the updating process, all members of the guideline working group and the external reviewers declared their financial and intellectual interests. Each member completed and signed the form for declaration of interests (DOI). Two chairs (EL, RLS) and one methodologist (YC) who themselves had no COI reviewed all DOI forms and decided upon the final list of participants. Appendix 1 presents a summary of the DOI statements and information on how conflicts of interest were managed. Appendix 2 includes all DOI forms filled by the group members. ## Scope of the guideline The guideline focuses on the prevention and management of COVID-19. The target population of the updated guideline is children and adolescents younger than 18 years old infected, or at risk of infection, by SARS-CoV-2. The target audience includes clinicians, pediatricians, clinical pharmacists, general practitioners, nurses, and other health workers in general and children's hospitals, primary clinics, and communities worldwide, as well as families involved in the care of children with COVID-19. # Methodology ## Formulating clinical questions To identify a preliminary set of clinical questions, we first performed a systematic review of existing CPGs for managing COVID-19 in childrenand noted the research gaps they identified, as well as existing clinical trials for COVID-19 in children. Second, we conducted semi-structured interviews with three experienced pediatricians. The steering group then drafted an initial list of preliminary clinical questions. All questions used the PICO format, which describes the population (P), intervention (I), comparison (C), and outcomes (O). Panelists used a seven-point Likert scale to rate whether each question should be included in the guideline . The guideline included clinical questions achieving high total scores without substantial dissent and approved by all steering group members. 1 3 [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. We also provided "good practice statements (GPS)" proposed by the GRADE Working Group in our guideline [bib_ref] Guideline panels should seldom make good practice statements: guidance from the GRADE..., Guyatt [/bib_ref]. ## Formulation of the recommendations We drafted preliminary recommendations based on the evidence for each question, balance of benefits and harms, patients' values and preferences, and cost considerations [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. The consensus group and patient representatives participated in two rounds of Delphi survey and voted for the preliminary recommendations and gave their comments. Recommendations were taken to have reached a consensus when 70% of the voters agreed on the recommendation. ## External review Two external experts (Dr Yu-Lung Lau, Chair Professor of Pediatrics, University of Hong Kong and Dr Anthony Que, Clinical pharmacist, Lanzhou University) reviewed the final draft guideline. The two chairs (EL, RLS) and one methodologist (YC) discussed feedback from the external reviews and revised the guideline based on their comments and suggestions. # Results We initially identified eight clinical questions. We subsequently added a clinical question on COVID-19 vaccination for children because the issue has recently received significant attention from physicians, the public, and policymakers. All panelists agreed and approved the new question. We found two existing living systematic reviews to support clinical questions on high-flow oxygen by nasal cannula (HFNC) or non-invasive ventilation (NIV) and breastfeeding [bib_ref] Ventilation techniques and risk for transmission of coronavirus disease, including COVID-19: a..., Schünemann [/bib_ref] [bib_ref] Update alert 3: ventilation techniques and risk for transmission of coronavirus disease,..., Muti-Schüenemann [/bib_ref] [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. We conducted four systematic reviews to support the other clinical questions [bib_ref] Risk factors for poor prognosis in children and adolescents with COVID-19: a..., Shi [/bib_ref] [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref] [bib_ref] Use of non-steroidal antiinflammatory drugs and adverse outcomes during the COVID-19 pandemic:..., Zhou [/bib_ref]. We present the summary of recommendations in [fig_ref] Figure 1: Structure and modifications of recommendations in the updated guideline [/fig_ref] , including the new items and the changes to the previous guideline recommendations. Appendix 1 [fig_ref] Table 3 A: summary of vaccines that have been validated in clinical trials in children [/fig_ref] presents the process of formulating clinical questions, Appendix 1 presents the final list of PICO questions, and Appendix 1 presents a detailed overview of the new recommendations, previous recommendations, and the rationale for changes. ## Recommendations We display the final list of the recommendations along with their strength and the certainty of the supporting evidence in . Each recommendation is labelled as new, modified, or unchanged. The following sections describe the details of each question and the summary of the evidence and consensus process that support each recommendation. ## Clinical question 1: what are the main prognostic factors for death or pediatric intensive care unit (picu) admission in children and adolescents with covid-19? RecommendationWe suggest that pediatricians and other guideline users should identify the presence of prognostic factors for death or PICU admission in children and adolescents with COVID-19 at an early stage. The main prognostic factors for death are multisystem inflammatory syndrome in children (MIS-C) complications and acute kidney injury (AKI); the prognostic factors for PICU admission include AKI, Acute Respiratory Distress Syndrome (ARDS), MIS-C complications, chronic pulmonary disease, and congenital heart disease (Conditional recommendation, very low certainty of evidence) (New). Explanation Most children with COVID-19 have milder clinical symptoms and better prognosis than adults [bib_ref] Systematic review of COVID-19 in children shows milder cases and a better..., Ludvigsson [/bib_ref]. However, as the number of SARS-CoV-2-infected children and adolescents continues to rise globally, the number of children with severe forms of the disease, including complications such as respiratory failure and multiple organ failure, also increases. Therefore, identifying the prognostic factors for unfavorable outcomes is crucial to identify the children at highest risk early, and to allow hierarchical management and prevention of disease progression. Only a few guidelines that focus on prognosis of COVID-19 in children exist. The guidelines of the Centers for Disease Control and prevention (CDC) indicate that the risk of developing severe COVID-19 for children was higher if pre-existing conditions, such as obesity, diabetes, asthma, chronic lung disease, or immunosuppression, were present. One consensus statement mentioned that increased respiratory rate, poor mental response or lethargy, progressive elevation of lactate levels, bilateral or multiple lobar infiltrates, pleural effusion or rapid progression of pulmonary lesions in the short term, and age less than 3 months were predictors for developing severe or critical COVID-19 [bib_ref] Expert consensus on imaging diagnosis and infection control for COVID-19, Tian [/bib_ref]. A systematic review showed that male sex, elevated inflammatory markers (including C-reactive protein [CRP], procalcitonin, ferritin, and D-dimer), and decreased lymphocyte count were associated with various indicators of poor prognosis including death, PICU admission, progression to Summary of the recommendations and good practice statements Unchanged, the main content and the strength of recommendation remain unchanged from the original recommendation; modified, the main content or strength of the recommendation has changed compared to the original recommendation; new, the recommendation that was not included in the original version of the guideline has been added in the updated guideline. Abbreviations and acronyms: COVID-19, coronavirus disease 2019; IVIG, intravenous immunoglobulin; MIS-C, multisystem inflammatory syndrome in children; PICU, pediatric intensive care unit; HFNC, high-flow oxygen by nasal cannula; NIV, non-invasive ventilation; CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome critical disease, progression to MIS-C, need of respiratory support, organ dysfunction, and hospitalization in children with COVID-19 [bib_ref] Risk factors for severity in children with coronavirus disease 2019: a comprehensive..., Tsabouri [/bib_ref]. ## Clinical question 2: should remdesivir be used to treat children and adolescents with covid-19? Recommendation 2 We suggest standard care without remdesivir to treat children and adolescents with COVID-19 (Conditional recommendation, very low certainty of evidence) (Modified). Evidence summary Our systematic review identified three single-arm cohort studies with 112 children and adolescents with COVID-19, with data collected between January 2020 and August 2021 [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref]. In one of these studies, all patients had severe COVID-19 [bib_ref] Compassionate use of remdesivir in children with severe COVID-19, Goldman [/bib_ref] ; in another study, 75% of the patients were admitted to the pediatric intensive care unit (PICU) [bib_ref] Compassionate use of remdesivir in children with COVID-19, Méndez-Echevarría [/bib_ref] ; and in the third study, 22% of the patients received mechanical ventilation. The pooled results showed that among those treated with remdesivir, 5.9% (95% confidence interval [CI]: 1.5 to 10.2%) died, 37.2% (95% CI: 0.0 to 76.0%) needed extra-corporeal membrane oxygenation (ECMO) or invasive mechanical ventilation (IMV), 37.1% (95% CI: 0.0 to 74.5%) experienced adverse events, and 16.2% (95% CI: 1.8 to 30.5%) experienced serious adverse events. One published living systematic review of four clinical trials with 3826 hospitalized adults with COVID-19 found little to no difference between patients receiving or not receiving remdesivir in the main outcomes: mortality (odds ratio [OR] 0.90, 95% CI: 0.72 to 1.11), mechanical ventilation (OR 0.75, 95% CI: 0.52 to 0.98), viral clearance at 7 days (OR 1.06, 95% CI: 0.35 to 3.20), and time to symptom resolution (ratio of mean days with symptoms between remdesivir and standard care 0.82, 95% CI: 0.64 to 1.06) [bib_ref] Drug treatments for covid-19: living systematic review and network meta-analysis, Siemieniuk [/bib_ref]. Explanation Remdesivir is a broad-spectrum antiviral agent that can integrate into the ribonucleic acid (RNA) strand of SARS-CoV-2 and prematurely terminate the RNA replication process [bib_ref] To investigate the application value of remdesivir in the treatment of COVID-19..., Wang [/bib_ref]. On October 22, 2020, the US Food and Drug Administration (FDA) approved remdesivir for the treatment of COVID-19 in children and adolescents aged at least 12 years and weighing at least 40 kg requiring hospitalization. Now, it expanded the approval of using Note: Unchanged recommendation, the main content and the strength of recommendation remain unchanged relative to the original recommendation; modified recommendation, the main content or strength of the recommendation has been changed from the original recommendation; new recommendation, the recommendation that was not included in the original version of the guideline has been added during the update; unpreserved recommendation, the recommendation in the original version of the guideline has not been preserved in the updated guideline. Abbreviations and acronyms: COVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; HFNC, high-flow oxygen by nasal cannula; NIV, non-invasive ventilation; AHRF, acute hypoxemic respiratory failure remdesivir to treat pediatric patients 28 days of age and older weighing at least 3 kg with SARS-CoV-2 infection, who are hospitalized, or not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19. Only a few single-arm cohort studies of remdesivir for the treatment of COVID-19 in children have been published [bib_ref] Compassionate use of remdesivir in children with severe COVID-19, Goldman [/bib_ref] [bib_ref] Compassionate use of remdesivir in children with COVID-19, Méndez-Echevarría [/bib_ref]. Its efficacy and safety for treating children and adolescents with COVID-19 is currently uncertain. The recommendations for remdesivir therapy vary greatly among different countries and organizations [bib_ref] A living WHO guideline on drugs for covid-19, Rochwerg [/bib_ref] [bib_ref] Should remdesivir be used for the treatment of patients with COVID-19? Rapid,..., Qaseem [/bib_ref] [bib_ref] Multicenter interim guidance on use of antivirals for children with coronavirus disease..., Chiotos [/bib_ref]. Given the uncertainty of the effectiveness and safety of remdesivir in children, as well as the situation that the drug was not licensed for use in most countries and regions, the panelists made the final decision not to recommend its use under standard care after consulting two patient members of the panel for their preferences. ## Clinical question 3: should antipyretics (ibuprofen or paracetamol) be used to treat children and adolescents with covid-19? Recommendation We suggest that antipyretics (ibuprofen or paracetamol) can be used to relieve fever and pain in children and adolescents with COVID-19 (Conditional recommendation, very low certainty of evidence) (New). Evidence summary Our systematic review included 40 studies (37 retrospective cohort studies and three prospective cohort studies) with 4,881,423 adults with COVID-19, with data collected between January 2020 and November 2021 [bib_ref] Use of non-steroidal antiinflammatory drugs and adverse outcomes during the COVID-19 pandemic:..., Zhou [/bib_ref]. During the COVID-19 pandemic, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to potentially reduce mortality (OR 0. [bib_ref] Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions, Favas [/bib_ref] Explanation Ibuprofen and paracetamol are commonly used as antipyretic drugs in children [bib_ref] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents:..., Castagnoli [/bib_ref]. Their effectiveness for reducing fever or pain is undisputed. However, concerns exist that the use of NSAIDs could worsen COVID-19 symptoms. In vitro experiments confirmed that SARS-CoV-2 virus can invade human cells by binding to angiotensin-converting enzyme-2 (ACE2), and ibuprofen can increase the bioavailability of ACE2 to a certain extent, thereby enhancing the viral replication process [bib_ref] Structural basis of receptor recognition by SARS-CoV-2, Shang [/bib_ref] [bib_ref] Are patients with hypertension and diabetes mellitus at increased risk for COVID-19..., Fang [/bib_ref]. Therefore, ibuprofen might exacerbate the progression of the disease [bib_ref] A pneumonia outbreak associated with a new coronavirus of probable bat origin, Zhou [/bib_ref]. However, the evidence we collected shows that the drug is safe for adults with COVID-19. Despite the indirectness of the evidence for this result for children with COVID-19, the panel remains somewhat confident that the use of ibuprofen is relatively safe for children with COVID-19. Therefore, panelists suggest that ibuprofen can still be used if necessary. Recommendations for ibuprofen in other guidelines are also consistent with ours . ## Clinical question 4: should systemic glucocorticoids be used to treat children and adolescents with severe covid-19? RecommendationWe suggest low-dose short-course dexamethasone therapy for children and adolescents with severe COVID-19 (Conditional recommendation, low certainty of evidence) (Modified). Evidence summary Our systematic review, which included one prospective cohort study and one case series with a total of 69 children and adolescents with COVID-19, with data collected between January 2020 and August 2021, did not find statistically significant impact of glucocorticoid therapy on the critical outcomes mortality (OR 2.79, 95% CI: 0.13 to 60.87), mechanical ventilation (OR 2.83, 95% CI: 0.78 to 10.30), or duration of PICU admission (weighted mean differences [WMD] 2.0, 95% CI: − 0.95 to 4.95) when compared with no glucocorticoid therapy [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref]. One published systematic review included fourteen RCTs on glucocorticoid therapy with over 2000 adult COVID-19 patients [bib_ref] Drug treatments for covid-19: living systematic review and network meta-analysis, Siemieniuk [/bib_ref]. Compared with standard care, corticosteroids probably reduce mortality (risk difference [RD] 20 fewer deaths per 1000 patients, 95% CI: 36 fewer to 3 fewer) and mechanical ventilation (RD 25 fewer per 1000, 95% CI: 44 fewer to 1 fewer), and increase the number of days free from mechanical ventilation (RD 2.6 more, 95% CI: 0.3 more to 5.0 more). Another published systematic review included seven RCTs with 1703 critically ill adult COVID-19 patients [bib_ref] Association between administration of systemic corticosteroids and mortality among critically ill patients..., Sterne [/bib_ref]. The 28-day all-cause mortality was lower in patients receiving dexamethasone than in patients receiving usual care or placebo (OR 0.64, 95% CI: 0.50 to 0.82); mortality did not differ between patients receiving hydrocortisone (OR 0.69, 95% CI: 0.43 to 1.12 compared with usual care or placebo) and patients receiving methylprednisolone (OR 0.91, 95% CI: 0.29 to 2.87 compared with usual care than placebo). Explanation Glucocorticoids are the most widely used, effective anti-inflammatory and immunosuppressive agents in clinical practice, and they can reduce the severity of inflammatory lung injury in patients with severe COVID-19 [bib_ref] Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy:..., Carsana [/bib_ref]. Although there are so far no high-quality clinical trials confirming the efficacy of glucocorticoid therapy for COVID-19 in children and adolescents, the efficacy of dexamethasone has been demonstrated in adult patients. Dexamethasone is inexpensive, easy to administer, and readily available globally. A short course of dexamethasone therapy is generally safe and does not increase the risk of adverse events among critically ill patients [bib_ref] Association between administration of systemic corticosteroids and mortality among critically ill patients..., Sterne [/bib_ref]. Although our direct evidence from children, due to the small sample size, does not yet prove its effectiveness, glucocorticoid therapy is becoming routine in the treatment of adult patients with COVID-19. After balancing the potential risks and benefits of the drug in children, the panel believed that it may potentially be associated with lower mortality. The panel therefore suggested to use low-dose (0.15 to 0.3 mg/kg/dose once daily, maximum 6 mg) and short-course (generally 3-5 days, up to 10 days) dexamethasone therapy for children and adolescents with severe COVID-19. When dexamethasone is not available, equivalent dosage of alternative glucocorticoids (hydrocortisone and methylprednisolone) could be considered. Of note, direct evidence from pediatric patients is very limited and the evidence is extrapolated from adult patients. Therefore, systemic glucocorticoids are suggested to be used for pediatric COVID-19 patients with caution, preferring dexamethasone over other glococorticoids if available. ## Clinical question 5: should intravenous immunoglobulin (ivig) be used to treat children and adolescents with mis-c? Recommendation 5.We suggest IVIG for children and adolescents with MIS-C (Conditional recommendation, very low certainty of evidence) (New). ## Recommendation 5.2 We suggest using glucocorticoids in combination with IVIG for children and adolescents with MIS-C who have a severe clinical presentation at the time of diagnosis (acute left ventricular dysfunction, immediate admission to PICU care, or hemodynamic support requirement) (Conditional recommendation, very low certainty of evidence) (New). Evidence summary Our systematic review identified four cohort studies of children and adolescents with MIS-C with data collected between January 2020 and August 2021 [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref]. The review showed that 64 patients receiving IVIG (2 g/kg) as the only first-line therapy had a treatment success rate of 62% (treatment failure was defined as the persistence of fever 2 days after the introduction of first-line therapy or recrudescence of fever within 7 days after the beginning of the first-line therapy treatment). One published systematic review of 27 case series with 917 MIS-C patients (mean age 9.3 years, 95% CI: 8.4 to 10.1) found that 81.0% (95% CI: 75.0 to 86.9%) of MIS-C patients received IVIG treatment; overall mortality was 1.9% (95% CI: 1.0 to 2.8%) [bib_ref] COVID-19 and multisystem inflammatory syndrome in children: a systematic review and meta-analysis, Yasuhara [/bib_ref]. One of the cohort studies included in our systematic review [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref] found that 32 MIS-C patients with a severe initial clinical presentation at the time of diagnosis (acute left ventricular dysfunction, admission to PICU care, or need of hemodynamic support) who received a combination of IVIG and methylprednisolone (0.8-1 mg/kg/12 h for 5 days; or 15-30 mg/kg/day for 3 days) as first-line therapy had lower odds of treatment failure (OR 0.25, 95% CI: 0.09 to 0.70), need of second-line treatment (OR 0.19, 95% CI: 0.06 to 0.61) and hemodynamic support (OR 0.21, 95% CI: 0.06 to 0.76), and occurrence of secondary acute left ventricular dysfunction (OR 0.20, 95% CI: 0.06 to 0.66) compared with 64 MIS-C patients who received IVIG alone (2 g/kg, single dose) as first-line therapy [bib_ref] Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of..., Ouldali [/bib_ref]. One study (n = 40) showed that 22 MIS-C patients who received a combination of IVIG and methylprednisolone (0.8 mg/kg/d for 5 days) had a shorter time to recovery of left ventricle ejection fraction (2.9 vs. 5.4 days, p = 0.002) than the remaining 18 patients who received IVIG alone (2 g/kg, single dose) as first-line therapy [bib_ref] Addition of corticosteroids to immunoglobulins is associated with recovery of cardiac function..., Belhadjer [/bib_ref]. Another study with larger sample size (103 patients in the IVIG plus glucocorticoids group and 103 in the IVIG group after propensity score matching) also indicated that IVIG plus glucocorticoids was associated with a lower risk of the composite outcome of cardiovascular dysfunction on or after day 2 than IVIG alone (17% vs. 31%; RR = 0.56, 95%CI: 0.34 to 0.94) [bib_ref] Multisystem inflammatory syndrome in children -initial therapy and outcomes, Son [/bib_ref]. Explanation MIS-C is a newly discovered clinical syndrome associated with SARS-CoV-2 infection and characterized by fever, systemic inflammation, and multiple organ dysfunction. Similar to Kawasaki disease, MIS-C patients can develop severe manifestations including coronary artery dilation, coronary aneurysms, toxic shock syndrome, sepsis, and macrophage activation syndrome [bib_ref] COVID-19 and multisystem inflammatory syndrome in children: a systematic review and meta-analysis, Yasuhara [/bib_ref]. IVIG produces a general anti-inflammatory effect. Direct evidence supporting the use of IVIG in MIS-C is very limited. A few case series found that the majority of MIS-C patients treated with IVIG had their condition improved and very low mortality [bib_ref] COVID-19 and multisystem inflammatory syndrome in children: a systematic review and meta-analysis, Yasuhara [/bib_ref]. A vast body of indirect evidence supporting IVIG use is available in patients with Kawasaki disease, where IVIG has been found to reduce abnormalities of the coronary artery and myocarditis in patients and is the recommended first-line therapy [bib_ref] Intravenous immunoglobulin for the treatment of Kawasaki disease in children, Oates-Whitehead [/bib_ref]. Given the similarity of the two diseases, we therefore recommend IVIG to treat MIS-C. However, due to the indirectness of the evidence, we gave a conditional recommendation. High-dose IVIG (2 g/kg, single dose) can be used if the cardiac function and fluid status are normal; otherwise, IVIG should be given as divided doses (1 g/kg/ day, for 2 days). For MIS-C patients who have more severe initial clinical presentation (shock, severe cardiac dysfunction or other severe end-organ involvement, or requiring PICU care and hemodynamic support), methylprednisolone (1-2 mg/kg/day for 5 days) may be added because the combination therapy is more effective and causes only minor adverse events when used for a short period of time [bib_ref] Potentially effective drugs for the treatment of COVID-19 or MIS-C in children:..., Wang [/bib_ref] [bib_ref] Association between administration of systemic corticosteroids and mortality among critically ill patients..., Sterne [/bib_ref]. [bib_ref] Ventilation techniques and risk for transmission of coronavirus disease, including COVID-19: a..., Schünemann [/bib_ref]. The mean ± standard deviation age of the hospitalized patients was 40.5 ± 15.6 years. Mortality was lower in hospitalized patients who received HFNC or NIV compared to those who received conventional oxygen therapy (OR 0.21, 95% CI: 0.09 to 0.47). However, health care workers (HCWs) who performed HFNC or NIV for COVID-19 patients had higher odds of being infected than those who did not perform these procedures (OR 3.10, 95% CI: 1.40 to 6.80). Thirty-five percent of HCWs exposed to COVID-19 patients treated with HFNC and NIV developed respiratory symptoms and 2.5% were tested positive for SARS-CoV-2 with polymerase chain reaction. This living systematic review has been updated three times and the search date of the last update is June 21, 2021 [bib_ref] Update alert 3: ventilation techniques and risk for transmission of coronavirus disease,..., Muti-Schüenemann [/bib_ref]. The new evidence from the latest update did not change the original finding that HFNC may reduce mortality compared with conventional oxygen therapy [bib_ref] Update alert 3: ventilation techniques and risk for transmission of coronavirus disease,..., Muti-Schüenemann [/bib_ref]. Moreover, NIV was not found to increase the risk of mortality in patients with COVID-19 compared with invasive mechanical ventilation (OR 0.74, 95% CI: 0.46 to 1.18) [bib_ref] Update alert 3: ventilation techniques and risk for transmission of coronavirus disease,..., Muti-Schüenemann [/bib_ref]. Explanation Low-certainty evidence suggests that HFNC and NIV (CPAP and BiPAP) can ameliorate hypoxemia, and reduce the need of early intubation and rate of complications associated with mechanical ventilation for patients with acute respiratory failure [bib_ref] Ventilation techniques and risk for transmission of coronavirus disease, including COVID-19: a..., Schünemann [/bib_ref]. However, both HFNC and NIV may cause propagation of aerosol particles containing the virus, which may increase the risk of transmission of SARS-CoV-2 to HCWs [bib_ref] Recommendations on the clinical management of the COVID-19 infection by the «new..., Calvo [/bib_ref]. Recommendations on the use of HFNC and NIV as the initial modality of therapy for treating COVID-19 patients with acute hypoxic respiratory failure are currently inconsistent across different guidelines. Appropriate use of personal protective equipment can minimize the risk for infections to HCWs from aerosols [bib_ref] Ventilation techniques and risk for transmission of coronavirus disease, including COVID-19: a..., Schünemann [/bib_ref] [bib_ref] Personal protective equipment for preventing highly infectious diseases due to exposure to..., Verbeek [/bib_ref]. Therefore, HFNC or NIV can be used to treat acute hypoxic respiratory failure in children and adolescents with COVID-19 if appropriate precautions are taken. Cooperation from the patients is crucial for successful ventilation and therefore should be a consideration when performing HFNC and NIV [bib_ref] Noninvasive ventilation in children, Nørregaard [/bib_ref]. After providing HFNC or NIV, the condition of the patients must be monitored every 1 to 2 h with clinical and arterial blood gas evaluation to ensure the efficacy and safety of the ventilation. If there are signs of rapid deterioration, the patients should be intubated promptly. ## Clinical question 7: should mothers with covid-19 continue to breastfeed their babies? Recommendation [bib_ref] Clinical care of pregnant and postpartum women with COVID-19: living recommendations from..., Vogel [/bib_ref] We recommend that mothers with COVID-19 continue to breastfeed their babies if their health condition permits, while taking appropriate precautions (Strong recommendation, low certainty of evidence) (Unchanged). Evidence summary One living systematic review included 427 studies with 28,952 mothers with COVID-19 and 18,237 babies, with data collected between December 2019 and August 2021 [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. The overall rate of SARS-CoV-2 positivity in babies born to mothers with COVID-19 was 1.8% (95% CI: 1.2 to 2.5%). Of the 592 SARS-CoV-2 positive babies with test data, 14 had confirmed mother-to-child transmission (seven in utero, two intrapartum, and five during the early postpartum period). Of the 800 SARS-CoV-2 positive babies with outcome data, 749 babies were alive at the end of follow-up. Mother with severe COVID-19 (OR 2.4, 95% CI: 1.3 to 4.4), maternal death (OR 14.1, 95% CI: 4.1 to 48.0), maternal admission to an ICU (OR 3.5, 95% CI: 1.7 to 6.9), and maternal postnatal infection (OR 5.0, 95% CI: 1.2 to 20.1) were associated with SARS-CoV-2 positivity in babies. Explanation Breastfeeding is recognized as the best source of nutrition for infants, benefiting their neurological and immune system development, while reducing the risk of breast cancer, ovarian cancer, and type 2 diabetes in mothers. The WHO and the Rapid Advice Guidelines for Management of Children with COVID-19 currently recommend that mothers with suspected or confirmed COVID-19 continue breastfeeding while taking the necessary protective measures [bib_ref] Rapid advice guidelines for management of children with COVID-19, Liu [/bib_ref]. However, there are concerns that mothers with COVID-19 could transmit the virus to their babies while breastfeeding. Although in utero, intrapartum, and early postpartum transmission of SARS-CoV-2 is possible, the vertical transmission rate is very low [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. Current evidence shows the overall rate of SARS-CoV-2 positivity in babies born to mothers with COVID-19 is less than 2% [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. In addition, the mortality of SARS-CoV-2 positive babies is very low [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. As the benefits of breastfeeding for the infant outweigh the risk of SARS-CoV-2 infection, the panelists agreed that breastfeeding should be continued as long as the health conditions of the mother and infant permit. However, mothers need to take appropriate protective measures (e.g., washing hands before contact with the infant and wearing a mask during close contact), especially those with severe COVID-19, admitted to ICU, or having a postnatal infection, who seem to have an elevated risk of SARS-CoV-2 positivity in their babies [bib_ref] SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review..., Allotey [/bib_ref]. ## Clinical question 8: should children and adolescents be vaccinated against covid-19? ## Recommendation 8 we suggest covid-19 vaccination for children and adolescents aged 3-17 years if a covid-19 vaccine is available and approved by local health authorities for their age and health condition, while closely monitoring for potential side effects after vaccination (Conditional recommendation, moderate certainty of evidence) (New). Evidence summary One systematic review, which is an updated version of a previous systematic review we conducted [bib_ref] Safety, Immunogenicity, and efficacy of COVID-19 vaccines in children and adolescents: a..., Lv [/bib_ref] , included six RCTs with 9962 children aged 3-17 years, with data collected until November 2021. As for the safety of vaccines, the overall risk of unsolicited adverse reactions (RR 1.21, 95% CI: 1.07 to1.36) was significantly higher in the vaccine group than in the control group within 28 to 30 days after vaccination. However, no significant difference was found in severe (RR 2.35, 95% CI: 0.78 to 7.03) or life-threatening (RR 1.00, 95% CI: 0.06 to 15.94) adverse reactions between the two groups. No significant differences were found after receiving the first and the second dose (RR 1.00, 95% CI 0.99 to 1.02). Compared with mRNA vaccines and adenovirus vector vaccines, inactivated vaccines have a more satisfactory safety profile, both after the first (RR 1.40, 95% CI: 1.04 to 1.90) and the second (RR 1.84, 95% CI: 1.20 to 2.81) dose. As for the immunogenicity of vaccines, seroconversion rate after the first dose injection increased significantly for receptor binding domain (RBD)binding antibodies (RR 99.48, 95% CI: 6.31 to 1559.12) compared with the unvaccinated. After booster vaccination, the immunogenicity of vaccines was further enhanced; seroconversion rate for RBD-binding antibodies (RR 101.50, 95% CI: 6.44 to 1600.76) and pseudovirus neutralizing antibodies (RR 144.80, 95% CI: 44.97 to 466.24) were further increased compared with the unvaccinated, and reached optimal levels. As for the efficacy of vaccines, three RCTs with mRNA vaccine as the intervention found that the risk of diagnosing COVID-19 after mRNA vaccination was low (RR 0.10, 95% CI: 0.05 to 0.21) compared with the unvaccinated. Other RCTs with inactivated vaccines or adenovirus vector vaccines as interventions did not assess vaccine efficacy. Explanation Some international and national guidelines recommend vaccination for children, but the recommendations vary between guidelines . The WHO guideline recommends two doses of the COVID-19 vaccine for children aged 5 to 15 to protect against COVID-19. CDC recommends COVID-19 vaccines for children aged 6 months and older. The National Institute for Health and Care Excellence recommends vaccination for children over 5 years old who meet certain conditions, such as immunosuppression . The COVID-19 vaccines which have so far been validated in completed clinical trials in children include BNT162b2, mRNA-1273, CoronaVac, BBIBP-CorV, Ad5-nCoV, and ZyCov-D, with an overall age range of 3 to 17 years [fig_ref] Table 3 A: summary of vaccines that have been validated in clinical trials in children [/fig_ref]. None of the vaccines increased the risk of severe or life-threatening adverse reactions, and all generated immune response to SARS-CoV-2 [bib_ref] Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents, Frenck [/bib_ref] [bib_ref] Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years..., Walter [/bib_ref] [bib_ref] Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents, Ali [/bib_ref] [bib_ref] Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (Corona-Vac) in healthy..., Han [/bib_ref] [bib_ref] Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger..., Xia [/bib_ref] [bib_ref] Safety and immunogenicity of a recombinant adenovirus type-5-vectored COVID-19 vaccine with a..., Zhu [/bib_ref] [bib_ref] Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim..., Khobragade [/bib_ref]. We also observed the interim findings from two ongoing clinical trials of the BNT162b2 and mRNA-1273 that included children 6 months through 3 years of age. The findings of these clinical trials showed that both vaccines may prevent children aged 6 months to 3 years against COVID-19 without increasing the risk of serious adverse events. However, we have serious concern about the short duration of follow-up (median = 35 days), limiting the ability to detect severe adverse events that might occur specifically after dose 3. We also concern about the small study size. These clinical trials may be not adequately powered to detect rare adverse events and efficacy against severe disease in young children. Therefore, more studies are needed to demonstrate the efficacy and safety of COVID-19 vaccine in children aged 6 months to 3 years. Based on the currently available evidence on COVID-19 vaccines for children and a consideration of the patients' values and preferences, the panel believes that the benefits of administering vaccines to children aged 3-17 years would outweigh the harms. It should be noted that the overall age of vaccination has been extended to 3-17 years old in the current clinical trials, but different types of vaccines are approved for different age groups [fig_ref] Table 3 A: summary of vaccines that have been validated in clinical trials in children [/fig_ref]. In addition, there are substantial differences across countries and regions in the types of vaccines that are available and the age pain, headache, fever, and fatigue at which children are eligible to be vaccinated. Therefore, decisions related to COVID-19 vaccination should be made in accordance with local regulations and local research data. Cases of myocarditis and pericarditis were found in children and adolescents, especially in male adolescents, after receiving mRNA (BNT162b2 or mRNA-1273) vaccines, which requires close monitoring [bib_ref] Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients:..., Gargano [/bib_ref]. Myocarditis and pericarditis occurred more often after the second dose, and usually within a week of vaccination [bib_ref] Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients:..., Gargano [/bib_ref]. The conditions of most patients with myocarditis or pericarditis improved quickly after treatment and they could return to their normal daily activities [bib_ref] Epidemiology and clinical features of myocarditis/pericarditis before the introduction of mRNA COVID-19..., Park [/bib_ref]. Although the short-term risks of adverse outcomes among children with myocarditis after mRNA vaccination were low, the long-term risks associated with myocarditis and pericarditis remain unknown. Besides, the evidence on the effects of COVID-19 vaccination for children below 3 years is very limited. Larger studies with longer follow-up are needed to inform recommendations for COVID-19 vaccination in this population. ## Clinical question 9: how should the mental health of children and adolescents with covid-19 be managed? Good practice statement We suggest pediatricians, parents, and caregivers should explore possible mental health problems among children and adolescents with COVID-19 and provide them with the optimal support feasible in the local setting (New). Evidence summary Our systematic review did not identify studies that met the requirements. Explanation Managing mental health of patients with COVID-19 during the pandemic is important, especially in the context of a pandemic where the huge social-psychological impact brought by the COVID-19 epidemic may exceed the role of the disease itself [bib_ref] Covid-19: pandemic has disproportionately harmed children's mental health, report finds, Iacobucci [/bib_ref]. People with COVID-19 are at increased risk for mental health problems [bib_ref] Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions, Favas [/bib_ref]. Anxiety and depression appear to be the main symptoms among children and adolescents in the context of COVID-19 [bib_ref] Exploring the impact of COVID-19 on mental health outcomes in children and..., Nearchou [/bib_ref] , especially among hospitalized COVID-19 patients [bib_ref] Psychological distress and its correlates among COVID-19 survivors during early convalescence across..., Cai [/bib_ref] [bib_ref] The effects of psychological intervention on anxiety symptoms of COVID19-positive patients isolated..., Sun [/bib_ref]. Possible reasons include the isolation from family members and friends which can lead to helplessness and loneliness [bib_ref] Timely mental health care for the 2019 novel coronavirus outbreak is urgently..., Xiang [/bib_ref] , and the fear of being stigmatized and discriminated because of being infected. Apart from the high incidence of short-term mental disorders, some studies have indicated that survivors may develop psychological sequelae after recovering from COVID-19, such as anxiety and/or depression, post-traumatic stress disorder, and cognitive deficits [bib_ref] World Health Organization (WHO) (2021) Basic psychosocial skills: a guide for COVID-19..., Schou [/bib_ref]. Therefore, we suggest that children and adolescents with COVID-19 should be monitored for possible mental health problems. The symptoms of mental disorders in children and adolescents are atypical and vary across different ages. Young children may experience fussiness and irritability, startling and crying more easily, and difficulties in consolation. Older children and adolescents may show symptoms such as changes in mood, ongoing irritability, and feelings of hopelessness or rage. Out of consideration for children's mental health, the panel proposed a statement on psychological interventions based on the concept of a good practice statement according to the GRADE framework. The panel suggested that pediatricians, parents, and caregivers should observe whether the children have features of anxiety, depression, or other psychological symptoms. The optimal mental health support feasible in the local setting should be provided for children and adolescents with COVID-19 [96]. # Discussion Children are the future of the world, but in the context of the pandemic, their health and future are facing great uncertainty [bib_ref] Pediatrics and COVID-19, Christakis [/bib_ref]. The attention paid to children with COVID-19 globally is far from enough. There also exist clearly less clinical evidence and fewer practice guidelines related to children with COVID-19 than for adults. The guideline working group has been concerned about SARS-CoV-2 infections in children as early as the beginning of the outbreak in 2020 and continues to assemble evidence and conduct research on children with COVID-19. After publishing the first version of the evidence-based rapid advice guideline for children, the panel has updated the guideline by including additional stakeholders in the panel and through a comprehensive search of the latest evidence. This guideline can assist pediatricians in clinical decision-making, support policy makers in developing relevant policies, and inspire researchers in prioritizing clinical trials. In addition, the guideline will help children and their guardians access and understand up-to-date evidence-based knowledge of COVID-19. # Strengths and limitations Our guideline has several strengths. First, to our knowledge, this is one of the few guidelines for children with COVID-19 that is registered and has a published protocol. Second, we strictly followed methodological handbooks to update our guideline and report its contents. Third, all recommendations were supported by systematic reviews and solicited suggestions from patient representatives. The guideline has however also limitations. First, we comprehensively searched the literature and used systematic reviews to support recommendations. However, very few clinical studies have been conducted specifically on children and the study quality was not optimal. The weakness of the evidence may cause some bias and lead to low certainty of evidence. Therefore, it was difficult for panelists to make strong recommendations. However, we still provide specific recommendations on key clinical questions, such as the application of IVIG for treating MIS-C, the use of systemic glucocorticoids in children with severe COVID-19, and the vaccination of children, based on scientific consensus. Caution is nevertheless needed when translating these recommendations into clinical practice. More reliable evidence about the management of children with COVID-19 is urgently needed. Another limitation is that while the guideline can be used at different levels of healthcare facilities, some recommendations, such as those for HFNC or NIV, may be difficult to implement in resource-limited settings. Finally, the guideline development group did not include any general practitioners, who nevertheless constitute a target audience group for our guideline. ## Updating This guideline has been last updated in July 2022. The evidence synthesis group will systematically search for evidence on children with COVID-19 every 3 months. The trigger for updating or producing specific recommendations is based on the following criteria (the fulfillment of any of the three may initiate the process): (1) practice-changing evidence is identified; (2) the evidence can be incorporated in our systematic review and is sufficient to change the certainty of evidence; and (3) new clinical issues arise that may attract interest on an international level. ## Suggestions for future research There is an urgent need for clinical trials on children with COVID-19. The research gaps for future research identified by the panelists are listed in . Zhili Wang, Liangqin Yi, Shuai Peng). We thank the patient representatives (Maryam Yasser Sami Amer, Jianping Peng, Lei Shi) for giving comments to the initial guideline and voting for consensus. We thank Professor Rafael González Cortés, Professor Saurabh Mehta, Professor Shariful Islam, and Gilead Sciences Inc for providing us their unpublished data. We thank Dr Sayada Zartasha Kazmi for helping the panelists fill out the questionnaire and check emails. # Authors' contributions All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Enmei Liu, Zhengxiu Luo, Qinyuan Li, Qi Zhou, and Yaolong Chen. The first draft of the manuscript was written by Enmei Liu, Rosalind Louise Smyth, Qinyuan Li, Qi Zhou, and Yaolong Chen and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding This work was supported by grants from the National Clinical Research Center for Child Health and Disorders (Children's Hospital of Chongqing Medical University, Chongqing, China) (grant number NCRCCHD-2020-EP-01), the Fundamental Research Funds for the Central Universities (grant number lzujbky-2021-ey13), and Chongqing "Bayu Scholar" program. The sponsors did not have any influence in the content of the guideline. What is the effectiveness and safety of systemic glucocorticoids for the treatment of children with COVID-19? What is the effectiveness and safety of IVIG and combination of IVIG and glucocorticoids in the treatment of children and adolescents with MIS-C? Which ventilation mode (HFNC, CPAP or BiPAP) is the most efficient and has the lowest risk of SARS-COV-2 transmission, and should be the primary intervention option for acute hypoxemic respiratory failure in children and adolescents with COVID-19? How can mental disorders such as obsessive-compulsive disorder in children who have been subject to lockdown measures, or in children and adolescents with COVID-19, be managed? Should children younger than three years old be vaccinated against COVID-19? What are the long-term sequelae (such as lung function and growth and development) in children who recovered from COVID-19? What are the impacts of new variants (e.g., Omicron variant and possible future variants) on children and adolescents? What is the effectiveness and safety of paxlovid for the treatment of children with COVID-19? What is the effectiveness and safety of sotrovimab for the treatment of children with COVID-19? What is the effectiveness and safety of tocilizumab and other immunomodulatory medication for the treatment of children with COVID-19? [fig] Figure 1: Structure and modifications of recommendations in the updated guideline. [/fig] [fig] Clinical question 6: Should high-flow oxygen by nasal cannula (HFNC) or non-invasive ventilation (NIV) including continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) be used as the initial modality of therapy to treat acute hypoxemic respiratory failure in hospitalized children and adolescents with COVID-19? Recommendation 6 We suggest HFNC or NIV (CPAP or BiPAP) as the initial modality of therapy for acute hypoxic respiratory failure in hospitalized children and adolescents with COVID-19 (Conditional recommendation, low certainty of evidence) (New). Evidence summary One published living systematic review on HFNC or NIV including CPAP and BiPAP identified 123 studies (45 on COVID-19, 70 on severe acute respiratory syndrome [SARS], and eight on Middle East Respiratory Syndrome [MERS]) published until May 2020, without any direct evidence in children with COVID-19 [/fig] [fig] 4: Priority research gaps on COVID-19 in children and adolescents COVID-19, coronavirus disease 2019; IVIG, intravenous immunoglobulin; MIS-C, multisystem inflammatory syndrome in children; HFNC, high-flow oxygen by nasal cannula; CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure [/fig] [table] Table 1: Grading of certainty of evidence and strength of recommendations * * According to the GRADE Working Group[24] [/table] [table] Table 3 A: summary of vaccines that have been validated in clinical trials in children [/table]	None	https://link.springer.com/content/pdf/10.1007/s00431-022-04615-4.pdf	None
a652d4763b5a21672ce18c8a40c43f2da1f57795	pubmed	Obesity and COVID-19. A necessary position statement	Obesity and COVID-19. A necessary position statement I. Bretón).1Have contributed equally to the development of this manuscript.2530-0180/ It is our intention to demonstrate that obese patients belong to a vulnerable group that requires greater emphasis on the prevention of infection, close monitoring in case of infection and caring for their health and psychological needs, and therefore, that they should be considered a priority group in the recently started vaccination campaign. People with obesity are not only affected by the pandemic due to the fact that they constitute a risk group, but also because of the consequences to their physical and psychological health derived from the mobility restriction measures, the disruptions and delays in healthcare, as with other chronic diseases, and the difficulty of access to bariatric surgery, among others. In this context, the COVID-19 pandemic collides with the obesity pandemic, amplifying the deleterious effects of each of them in a bidirectional way, as will be explained below. ## Obesity as a risk factor for worse progression of covid-19 People with obesity have a 46% higher risk of infection by SARS-CoV-2, compared to people of normal weight. In the event they contract COVID-19, they present twice the risk of requiring hospitalisation. In addition, the risk of severity also increases in people with excess weight, ICU admissions increase by 73% and the need for assisted mechanical ventilation by 69%. [bib_ref] Individuals with obesity and COVID-19: a global perspective on the epidemiology and..., Popkin [/bib_ref] It has been proven that worse prior conditions regarding cardiorespiratory training (cardiorespiratory fitness), nutritional status and muscular functional status (sarcopaenia), contribute to a worse evolution of COVID-19. [bib_ref] Moderate physical activity as predictor of weight loss after bariatric surgery, Mundi [/bib_ref] Unhealthy dietary habits and less physical activity in people with obesity condition a worse immune response and a greater risk of malnutrition and sarcopaenia in the event of coronavirus infection. The chronic inflammatory situation caused by obesity and aggravated by COVID-19 worsens respiratory muscle function and capacity to respond to hypoxia. [bib_ref] COVID-19: a major cause of cachexia and sarcopenia?, Morley [/bib_ref] If in addition to the situation of sarcopaenia associated with age and obesity we add the conditions derived from COVID-19 infection, such as anorexia, anosmia, dysgeusia, nausea, vomiting and diarrhoea, it facilitates a progressive malnutrition related to the disease. Thus, the unfavourable combination of sarcopaenia and malnutrition is much more common (and easily overlooked) in people with obesity, which undoubtedly contributes to increasing the severity of COVID-19 infection. [bib_ref] Coronavirus disease 2019 (COVID-19) and nutritional status: the missing link?, Silverio [/bib_ref] [bib_ref] Sarcopenia during COVID-19 lockdown restrictions: long-term health effects of short-term muscle loss, Kirwan [/bib_ref] Other conditioning factors associated with obesity, such as the increased risk of thrombosis, poor control of metabolic comorbidities such as diabetes, hypertension or dyslipidaemia, contribute to a worse progression of COVID-19. 6 ## Effects of restricted mobility on the health of people with obesity During the lockdown, between April and May 2020, the combination of a higher food intake and a sedentary lifestyle was the most common rationale for the weight gain that affected almost half of the Spanish population, which ranged between 1 and 3 kg. Among the risk factors associated with the weight gain during the lockdown, female sex, younger age, previous excess weight and having been locked down in southern Spain should be highlighted. Furthermore, living in small apartments, having a lower level of education and low income are associated with a greater probability of gaining weight. A ''halo effect'' was also observed, in that there was a weight increase in 44.6% of the people around those who had gained weight. After the first few weeks, the purchase of high calorie products such as alcoholic beverages, sweets and snacks increased by more than 50%. Additionally, the lockdown limited access to sports centres and made it difficult to do physical activity outdoors, which together with the lack of routine exercising at home, greatly hindered the ability to maintain an active lifestyle. [bib_ref] Ganancia de peso durante el confinamiento por la COVID-19; encuesta de la..., López De La Torre [/bib_ref] Finally, not knowing that obesity is a poor prognostic factor in COVID-19 is also related to having limited knowledge about the harmful health consequences of excess weight. This lack of knowledge is greater in young people under 24 years of age, in those who have gained more than 3 kg and in people with fewer financial resources. Although children and adolescents are groups at lower risk of developing serious illness from COVID-19, they are affected by the familial, educational and social repercussions of the pandemic that ultimately promote obesity. ## Psychological impact of the pandemic on patients with obesity The association between obesity and mental health disorders is a well-known phenomenon. The prevalence of depression is at least 25% higher among people with obesity, who also have a higher risk of anxiety and eating disorders. There is a two-way relationship between obesity and depression. Therefore, obesity, especially severe obesity, is a predisposing factor for mental illness. [bib_ref] Psychiatric disorders and obesity: a review of association studies, Rajan [/bib_ref] In this context, the outbreak of the COVID-19 pandemic, with particularly harmful effects in people with obesity, has heightened mood disturbances. These disturbances translate into social isolation, stress, sleep deprivation and chronodisruption, sedentary lifestyle and eating disorders, including increased alcohol intake and the appearance of other addictions, all of which are factors that are also implicated in the development of obesity. Fear of infection for oneself and for close relatives over the course of outbreaks has a relevant effect on mental stress. Isolation is especially impactful in elderly people, and even more so if they have dementia, as they feel disconnected from their family environment and from their usual health monitoring, which increases the risk of physical and mental deterioration. The changes in work activity caused by the pandemic increase unemployment and stress, with the consequent increase in the socioeconomic gap that contributes to the obesogenic environment. [bib_ref] Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for..., Holmes [/bib_ref] [bib_ref] Obesity and COVID-19: the two sides of the coin, Dicker [/bib_ref] Impact of delayed access to bariatric surgery on people with obesity During the current situation arising from COVID-19, many surgical procedures have been suspended, among them, bariatric surgery. In addition to the need to reorganise resources to cope with the pandemic, surgery in patients with COVID-19 presents a high risk of complications. Reorganisation of healthcare services should include planning for bariatric surgery, as delays can have serious or fatal consequences. [bib_ref] Bariatric and metabolic surgery during and after the COVID-19 pandemic: DSS recommendations..., Rubino [/bib_ref] [bib_ref] Obesity and SARS-CoV-2: considerations on bariatric surgery and recommendations for the start..., Santos [/bib_ref] Up to 50% of patients on the bariatric surgery waiting list develop a new complication of obesity and 1.5% die while waiting for the surgery. [bib_ref] Cause of death in patients awaiting bariatric surgery, Lakoff [/bib_ref] Furthermore, weight loss and the improvement of complications associated with obesity after bariatric surgery can reduce the risk of severe illness if they contract COVID-19. [bib_ref] Bariatric and metabolic surgery can prevent people with obesity from COVID-19 infection, Parmar [/bib_ref] Thus, in addition to the need to treat cases of complications from a previous bariatric surgery, it is recommended that priority be given to patients with poor control of comorbidities (diabetes, sleep apnoea, etc.) and to those in whom obesity contraindicates performing another vital treatment, such as a transplant. [bib_ref] Obesity and SARS-CoV-2: considerations on bariatric surgery and recommendations for the start..., Santos [/bib_ref] In general, a waiting list time of no more than six months should be guaranteed for surgeries for benign pathologies. However, in the case of bariatric surgery, this time is much longer. [bib_ref] Bariatric surgery waiting lists in Spain, Arteaga-González [/bib_ref] The restart of bariatric surgery has been relegated to the bottom of the list of elective surgical procedures, indicating inequity, systematic bias and discrimination towards people with obesity. It is also possible that the drop in health monitoring has also affected patients previously treated with bariatric surgery, who are at high risk of nutritional deficiencies. Furthermore, the COVID-19 pandemic has led to the cancellation and/or delay of consultations planned for the evaluation and treatment of obesity, both in primary and specialised care. As a consequence, the exposure time to obesity and its metabolic and non-metabolic complications will increase. ## People with obesity, a priority group for vaccination against covid-19 For all the reasons stated above, people with obesity, especially those with higher degrees (BMI ≥35 kg/m 2 ), should be considered a priority group for vaccination against COVID-19. # Funding No funding was received for drafting this position paper.	None	None	None
34c38d4f9a2e7865706729c69ea12f818c935394	pubmed	Caring for children and adolescents with type 1 diabetes mellitus: Italian Society for Pediatric Endocrinology and Diabetology (ISPED) statements during COVID-19 pandemia	Caring for children and adolescents with type 1 diabetes mellitus: Italian Society for Pediatric Endocrinology and Diabetology (ISPED) statements during COVID-19 pandemia # Introduction In December 2019 a new RNA betacoronavirus infection emerged in Wuhan, China [bib_ref] Epidemiological characteristics and prevention and control measures of Corona Virus Disease 2019..., Jiatong [/bib_ref]. It has been recognized as causative factor of severe pneumonia and other systemic complications [bib_ref] Epidemiological characteristics and prevention and control measures of Corona Virus Disease 2019..., Jiatong [/bib_ref]. At the end of January 2020, the WHO named this betacoronavirus infection COVID-19 and defined it as a global epidemic communicable form of pneumonia. The disease spread rapidly worldwide and by March 11 the COVID-19 outbreak was classified as a pandemic disease. Compared with other previous coronavirus epidemics [i.e Severe Acute Respiratory Syndrome (SARS) in 2003, and Middle East Respiratory Syndrome (MERS) in 2014], COVID-19 has spread more rapidly, probably because of increased globalization, inadequate risk assessment and other unknown environmental factors [bib_ref] The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest..., Peeri [/bib_ref]. The most recognized form of COVID-19 transmission is through large respiratory droplets. The virus has been also found in tears, urine and stool of affected individuals [bib_ref] COVID-19-New insights on a rapidly changing epidemic, Rio [/bib_ref]. The clinical features of the COVID-19 infection vary from being asymptomatic to fever, dry cough and fatigue up to acute respiratory distress syndrome with multiorgan involvement and death [bib_ref] Risk Factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref]. Other symptoms include sore throat, headache, abdominal pain, and diarrhea. Median age of infected individuals is in 50s, with a prevalence of male gender [bib_ref] COVID-19-New insights on a rapidly changing epidemic, Rio [/bib_ref]. Infected adult patients who developed acute respiratory distress syndrome were usually affected by other comorbidities [bib_ref] Risk Factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref]. The aim of our study was to analyze available data about COVID-19 infections and type 1 diabetes mellitus, and to formulate recommendations for children and adolescents with or who may develop type 1 diabetes mellitus in the time of Covid-19 infection. # Methods A literature search was carried out in the guideline databases, Medline and Embase and in Diabetes Societies websites until May 21st, 2020 for guidelines and recommendations on type 1 diabetes mellitus management during COVID-19 pandemic. The search terms used were: COVID or COVID-19 or coronavirus or SARS-CoV2, and type 1 diabetes mellitus, and children, and adolescents, and recommendations. The searches were limited to papers published in English. A descriptive analysis was performed. # Results ## Covid-19 in pediatric patients COVID-19 infection in pediatric patients seems to be clinically less severe than in adults; children have so far accounted for 1-5% of diagnosed cases, with a median age of 6.7 years (1 day-15 years) and better prognosis [bib_ref] Are children less susceptible to COVID-19?, Lee [/bib_ref] [bib_ref] Systematic review of covid-19 in children shows milder cases and a better..., Ludvigsson [/bib_ref]. The hypothesis that children are less susceptible to COVID-19 is intriguing, since newborn and infants can be infected, even if vertical transmission has not been certainly ruled out [bib_ref] Novel coronavirus infection in hospitalized infants under 1 year of age in..., Wei [/bib_ref] [bib_ref] Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and..., Hong [/bib_ref] ; a lower risk has been recently ascribed to an age-dependent expression of Angiotensin-Converting Enzyme 2 (ACE2). ACE2 in nasal epithelium is the first point of contact for SARS-CoV-2 and the human body [bib_ref] Evidence and possible mechanisms of rare maternal-fetal transmission of SARS-CoV-2, Egloff [/bib_ref]. Incubation period is about 1-14 days, up to 24 days. Children affected by COVID-19 infection are generally asymptomatic increasing the risk of prolonged spreading of the outbreak. In fact, in more than 90% of affected children, the infection is clinically silent or is characterized by mild to moderate disease, while, in 5.2% of cases, severe form and in 0.6% critical illness have been described [bib_ref] Systematic review of covid-19 in children shows milder cases and a better..., Ludvigsson [/bib_ref]. Otherwise, different clinical presentations have been described, including low fever, dry cough, wheezing, fatigue, nasal congestion, abdominal pain, nausea, vomiting, and diarrhea. Clinical manifestations include mild, moderate, severe disease up to critical illness, including severe pneumonia, septic shock, refractory metabolic acidosis, coagulation dysfunction [bib_ref] Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19)..., Qiu [/bib_ref]. No chest abnormalities have been reported in 20% of affected children; in the remaining cases chest computed tomography imaging have revealed unilateral or bilateral sub pleural ground glass opacities, and consolidation with surrounding halo sign, without pleural effusion [bib_ref] Clinical and CT features in pediatric patients with COVID-19 infection: different points..., Xia [/bib_ref]. COVID-19 pneumonia can be superimposed with other types of pathogens, particularly in children with other comorbidities, therefore imaging data might be more complex. Household contact with affected family members seems the main route of transmission. Moreover, the more active innate immune response, the healthier respiratory tract and the fewer comorbidities as compared to adults, as well as the different distribution, maturation, and functioning of viral receptors might partially explain the relative resistance to COVID-19 infection [bib_ref] Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins..., Lu [/bib_ref]. Recently the Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) study has been published. It involved a cohort of 100 Italian children younger than 18 years of age with confirmed Covid-19 infection, who referred to pediatric emergency departments between March 3 and March 27. The peculiarity of this work lies in having identified, in addition to the common symptoms (44% of the patients presented with cough), also other more specific symptoms of early childhood, such as no feeding or feeding difficulties (23% of children). In this cohort 9 patients received respiratory support. ## Diabetes mellitus and infectious diseases Previous observations report an increased susceptibility to infections among patients with both type 1 and type 2 diabetes mellitus, responsible of increased morbidity and mortality [bib_ref] Increased risk of common infections in patients with type 1 and type..., Muller [/bib_ref] [bib_ref] Glycemic control and risk of infections among people with type 1 or..., Critchley [/bib_ref] [bib_ref] The mortality in infectious in patients with type 2 diabetes compared with..., Ma [/bib_ref] [bib_ref] Mortality from infectious diseases in diabetes, Zoppini [/bib_ref]. Hyperglycemia may increase the virulence of different pathogens by enhancing bacterial replication and facilitating their attachment to epithelial cells favoring immune system dysfunction [bib_ref] Infections in patients with diabetes mellitus: a review of pathogenesis, Casqueiro [/bib_ref] [bib_ref] Outcomes of hyperglycemia in patients with and without diabetes hospitalized for infectious..., Akirov [/bib_ref] [bib_ref] Poorly regulated blood glucose in diabetic patients-predictor of acute infections, Burekovic [/bib_ref]. A study aimed to evaluate humoral factors in pediatric patients with type 1 diabetes showed lower IgG and C3 levels in poorly controlled disease as compared to patients with satisfactory degree of metabolic control [bib_ref] Is immunity in diabetic patients influencing the susceptibility to infections? Immunoglobulins, complement..., Roio [/bib_ref]. Moreover, several viral infections have been considered as possible triggers of the autoimmune process leading to clinically overt type 1 diabetes mellitus, and infectious diseases may accelerate the clinical onset in at risk subjects [bib_ref] Viruses in type 1 diabetes, Hyö Ty [/bib_ref] [bib_ref] Enteroviral infections as a trigger for type 1 diabetes, Rodriguez-Calvo [/bib_ref] [bib_ref] The diabetes pandemic and associated infections: suggestions for clinical microbiology, Toniolo [/bib_ref] [bib_ref] Type 1 diabetes and measles, mumps and rubella childhood infections within the..., Ramondetti [/bib_ref]. Several case reports describe severe infections both in affected children and adults and underline the importance of considering infectious diseases prompt diagnosis, treat-ment and, when available, prevention as goal for good management of the disease [bib_ref] Iliopsoas abscess in adolescents with type 1 diabetes mellitus, Maines [/bib_ref] [bib_ref] Helicobacer pylori infection in children with type 1 diabetes: a case control..., Bazmamoun [/bib_ref] [bib_ref] Frequency of urinary tract infection and antibiotic sensitivity of uropathogens in patients..., Zubair [/bib_ref] [bib_ref] Patients with type 1 diabetes mellitus have impaired IL-1b production in response..., Lachmandas [/bib_ref]. Similarly, diabetic ketoacidosis recovery may be delayed by concomitant infectious disease [bib_ref] Difficulties or mistakes in diagnosing type 1 diabetes in children?-demographic factors influencing..., Pawłowicz [/bib_ref]. A US study in 77% type 1 and 23% type 2 diabetes adolescents reported that respiratory infections were the most common kind of infections, responsible for emergency care, hospitalization, increased economic impact, and health care cost [bib_ref] The burden of common infections in children and adolescents with diabetes mellitus:..., Korbel [/bib_ref]. American Diabetes Association Clinical Practice Recommendations consider vaccinations mandatory for patients, especially for seasonal influenza and pneumococcal infection. Despite several evidence suggests the importance of vaccination in patients with diabetes mellitus, and the lack of association between vaccinations and autoimmunity [bib_ref] Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies, Morgan [/bib_ref] , global coverage is still lower than expected [bib_ref] Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture..., Verger [/bib_ref] [bib_ref] Hepatitis B vaccination coverage in patients with diabetes mellitus, Arrelias [/bib_ref] [bib_ref] Antibody responses to immunizations in children with type 1 diabetes mellitus: a..., Eisenhut [/bib_ref] [bib_ref] Children with type 1 diabetes mellitus: access to special immunobiological and child..., Wolkers [/bib_ref] [bib_ref] TEDDY Study Group. PandemrixÒ vaccination is not associated with increased risk of..., Elding Larsson [/bib_ref] [bib_ref] Italian Pneumococcal Study Group on Diabetes. Streptococcus pneumoniae oropharyngeal colonization in school-age..., Principi [/bib_ref]. As regards previous MERS and SARS outbreaks, to our knowledge no data are available regarding clinical course and sequelae in pediatric patients. On the other hand vaccination against H1N1 virus was not associated with increased risk of islet autoimmunity or type 1 diabetes, and in a group of Italian patients we did not report an increased risk of hospitalization due to H1N1 infection in pediatric patients with type 1 diabetes [bib_ref] Pandemic influenza vaccination coverage in children with type 1 diabetes: analysis from..., Rabbone [/bib_ref]. ## 3.3. Quantifying COVID-19-related risks for patients with diabetes mellitus Adult patients with diabetes are included in high risk group for COVID-19 infection with high mortality and morbidity rate. Diabetes mellitus and COVID-19 infection might share more links than expected. Both diseases represent a severe pandemics and are characterized by multiorgan involvement, even if with peculiar differences: chronic versus acute condition, communicable versus non communicable, both with unknown, at present, and known long-term complications. Even if common opinion associates diabetes with higher morbidity and mortality due to infections, it is still unknown if and how it represents a risk factor for prognosis of COVID-19. Diabetes mellitus is indeed one of the most frequent comorbidities observed in patients with COVID-19 infection. Some authors described that patients with severe disease, as compared with subjects with more mild infection, had diabetes as a common comorbidity [bib_ref] Diabetes and Covid-19: a global health challenge, Shenoy [/bib_ref]. On the other hand, since in patients with diabetes any infectious disease worsens the degree of metabolic control with a negative effect on the recovery, also COVID-19 infection may generate a vicious circle that would be detrimental for a better prognosis. It is also important to consider that COVID-19 receptors ACE2 are expressed on several organs and tissues, with a consequent risk of multiorgan failure other than lung involvement [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref]. A recent study aimed to establish if diabetes is a risk factor influencing the outcome and prognosis of COVID-19 reported that adult patients without other comorbidities were at higher risk of severe pneumonia, showed higher tissue enzyme levels indicating multiorgan involvement, uncontrolled inflammatory response and hypercoagulable state together with dysregulation of metabolic control, even if insu-d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 6 8 ( 2 0 2 0 ) 1 0 8 3 7 2 lin requirement increased after infection [bib_ref] Diabetes is a risk factor for the progression and prognosis of COVID-19, Guo [/bib_ref]. Worsening of metabolic control affects severity of pneumonia, together with the coexistence of comorbidities. Therefore, diabetes should be considered as a risk factor for the inflammatory storm leading to rapid worsening of COVID-19 infection. Potential mechanisms increasing the risk of COVID-19 among patients with diabetes are higher affinity cellular binding and efficient virus entry into the cells, decreased virus clearance, reduced T cell function, increased susceptibility to cytokine storm [bib_ref] Perspective COVID-19 pandemic, coronaviruses, and diabetes mellitus, Muniyappa [/bib_ref]. Increased expression of ACE2 has been observed in the lung, kidney, heart, pancreas in animal models of diabetes [bib_ref] ACE and ACE2 activity in diabetic mice, Wysocki [/bib_ref]. Moreover, higher levels of furin, a cellular protease facilitating virus entry, have been observed in patients with diabetes mellitus [bib_ref] Plasma levels of the proprotein convertase furin and incidence of diabetes and..., Fernandez [/bib_ref]. As for the impact of diabetes among adults COVID-19 infected Italian patients, it has been reported that the prevalence of pre-existing diabetes was 8.9%, and the ratio of diabetes in patients who died for COVID-19 infection as compared to general population was 1.75. The authors concluded that diabetes does not increase the risk of COVID-19 infection, but can worsen the outcome of the disease, as reported for other infections, as Pandemic Influenza A in 2009, SARS and MERS. In reverse, a Chinese report of 72,314 cases of COVID-19 patients showed a increase mortality rate of 7.3% in patients with pre existing diabetes as compared to 2.3% mortality rate that has been observed globally [bib_ref] Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. At present, COVID-19 infection in children and adolescents with type 1 diabetes is clinically different as compared to adults, without increased morbidity and mortality. Young patients with type 1 diabetes and COVID-19 infection usually don't need hospitalization, and careful management of glycometabolic assessment is required. The localization of ACE2 receptors in the endocrine pancreas raises the question if COVID-19 infection is a risk factor for development of dysglycemia. A previous report showed that patients infected with SARS coronavirus -and not treated with glucocorticoids -showed transient hyperglycemia due to acute damage of beta cells induced by the virus, occurring within 3 days and 2 weeks after hospitalization [bib_ref] Binding of SARS coronavirus to its receptor damages islets and causes acute..., Yang [/bib_ref]. Conflicting results have been reported about the role of ACE-inhibitors in COVID-19 infection: on one hand, ACE inhibitors may worsen the prognosis of severe pneumonia, on the other hand ACE inhibitors might reduce the severity of lung inflammation [bib_ref] Coronavirus disease (COVID-19) infection and renin angiotensin system blockers, Bavishi [/bib_ref]. As for H1N1 viral infection as possible risk factor for diabetes, it has been reported that H1N1 strains are able to infect and replicate in mammalian pancreatic cells both in vitro and in vivo, but are not associated with clinical onset of diabetes mellitus [bib_ref] Study of 2009 H1N1 pandemic influenza virus as a possible causative agent..., Capua [/bib_ref]. At present, there is no association between COVID-19 infection and the increased risk of type 1 diabetes: future studies are needed to better define the role of COVID-19 and autoimmunity. The COVID-19 infection seems to be unusual among patients with type 1 diabetes mellitus, although they are considered a fragile population. It has been hypothesized that the peculiar immune condition that leads to the destruction of the beta cells might play an important role [bib_ref] The CoV-19 infection appears to be unusual among patients with type 1..., Tatti [/bib_ref]. On the other hand, the risk of increased frequency of severe ketoacidosis in new-onset type 1 diabetes due to delayed diagnosis -because of fear of contracting COVID-19 in a hospital setting, or inability to contact a medical provider for timely evaluationshould be considered [bib_ref] Unintended consequences of COVID-19: Remember general pediatrics, Cherubini [/bib_ref]. Similarly, parents of patients with poor glycemic control requiring closer follow-up might postpone the appointments for the same reasons. [fig_ref] Table 1 -: Summary of reviewed papers looking at the impact of COVID-19 infections and... [/fig_ref] reports a summary of data extracted from studies looking at clinical characteristics of COVID-19 infection and its impact in patients affected by diabetes mellitus. ## Adaptation of standard-of-care treatment regimens Several pediatric diabetes centers have developed and implemented telemedicine services, thus allowing patients to remain in close contact with the team, to share glycemic data and insulin dosage, and to adapt disease management without close person-to-person contact, thus minimizing the risk of infection and of metabolic decompensation [bib_ref] Telemedicine consultations and diabetes technology during COVID-19, Nørgaard [/bib_ref]. Benefit of telemedicine included prevention of ketoacidosis in longstanding patients thanks to remote monitoring [bib_ref] The silver lining to COVID-19: Avoiding diabetic ketoacidosis admissions with telehealth, Peters [/bib_ref]. In fact remote glycemic monitoring through cloud platforms has enabled pediatric diabetologists to obtain a closer interaction with patients during the pandemic lockdown. Thanks to telemedicine patients are now evaluated safely and more frequently, every week or two according to the degree of metabolic control. Telehealth is not only limited to glycemic control, but needs to be extended to all diabetic team, including diabetes educators, dieticians, psychologists [bib_ref] Inpatient transition to virtual care during covid-19 pandemic, Jones [/bib_ref]. Several pediatric teams with a dedicated dietician have prepared specific weekly food plans in order to prevent inappropriate excessive caloric intake, especially in this period of reduced physical exercise. On the other hand, promotion of physical exercise even during quarantine was followed by Don't interrupt vaccination program. -ISPED practical recommendations for children and adolescents with type 1 diabetes. ## Reassure patients and families that consultations are available Maintain a good metabolic control, increase the glucose monitoring also by means of technological devices (i.e. pumps, continuous glucose monitoring, CGM) Improve telemedicine consultations for each component of the team Increase the use of CGM and remote monitoring Albeit outpatient section have reduced their activity, emergency section is always available in case of metabolic decompensation Promote adherence healthy nutrition, avoiding excessive caloric intake as well as minerals and oligoelements deficiency by increasing fruit and vegetable i ntake and reducing high-calorie food intake ## Patients treated with angiotensin converting enzyme (ace)-inhibitors deserve attention In case of suspected symptoms, including difficult breathing or shortness of breath, persistent pain and chest pressure, immediately contact general practitioner and the hospital. Intensify blood glucose measurements and don't miss insulin administration, otherwise increase administration and corrective boluses as for other intercurrent illnesses Continue regular physical activity an improvement of metabolic control [bib_ref] Glycemic control in type 1 diabetes mellitus during covid-19 quarantine and the..., Tornese [/bib_ref]. Moreover, periodical teleconsult with psychologist has been guaranteed to help patients and families to cope with this stressful period and has been well accepted by both patients and families. ## Patient education and psychological care Type 1 diabetes is a chronic condition requiring complex clinical care and lifelong involvement, and may have significant influence not only on the physical and psychological but also on the emotional state in children, adolescents, and their caregivers. Intensive insulin treatment and new technological devices require patients and family engagement and significant modifications of daily life. Adequate food plan and exercise plan are mandatory to achieve and maintain good metabolic control. The observations based on the large number of infected people that were exposed and the evidence of person-to-person transmission of COVID-19 infection led to the social isolation of patients. Special attention and efforts to protect or reduce transmission have been applied in susceptible populations including children, especially if affected by chronic conditions like type 1 diabetes, health care providers, and fragile people. Elevated levels of stress, anxiety and depression have been reported during the outbreak, together with the fear of being infected, or infecting parents and relatives [bib_ref] Immediate psychological responses and associated factors during the initial stage of the..., Wang [/bib_ref]. Even if COVID-19 infection in young patients with type 1 diabetes has been rarely encountered, patients experienced the awareness of being considered as a risk group. Moreover forced sedentary behavior might negatively influence exercise programs and degree of glycemic control [bib_ref] A tale of two pandemics: How will COVID-19 and global trends in..., Hall [/bib_ref]. Chewing and spitting out food as a compensatory behavior should be taken into account particularly if associated with weight gain and increased insulin requirement. Deterioration of metabolic control might also impair quality of life and resilience levels [bib_ref] Health-related Quality of Life of adolescents with type 1 diabetes in the..., Luká Cs [/bib_ref]. ## Covid-19 and pediatric diabetes: isped practical recommendations Besides general recommendations for pediatric patients [fig_ref] Table 2 -: General recommendations [/fig_ref] , ISPED has proposed specific measures for patients with diabetes . Moreover, in case of COVID-19 infection, careful sick day management program proposed by International Society for Pediatric and Adolescents Diabetes (ISPAD) must be followed, together with specific treatment for the infection [bib_ref] ISPAD clinical practice consensus guidelines 2018: Sick day management in children and..., Laffel [/bib_ref]. In case of hospitalization, a multidisciplinary management of the affected patients by strict cooperation between pediatric diabetologist and other physicians is mandatory. For adolescents with type 2 diabetes treated with metformin or other antidiabetic drugs, oral agents may need to be stopped, and insulin treatment considered for glucose control when hospitalized [bib_ref] Clinical considerations for patients with diabetes in times of COVID-19 epidemic, Gupta [/bib_ref]. COVID-19 outbreak has removed many long-standing regulatory burdens to telehealth, and it is now assumed that telemedicine is a new safe and effective way for remote diabetes management [bib_ref] Managing newonset type 1 diabetes during the COVID-19 pandemic: challenges and opportunities, Garg [/bib_ref]. Future research are needed to evaluate the impact of COVID-19 in type 1 diabetes mellitus patients, regarding not only its hypothetical role in disease epidemiology, but also the implementation of new management strategies, the short-and long-term impact of telemedicine as current tool for diabetes care. ## 6. Organizational strategy for future scenarios At present the recovery from COVID-19 pandemia is unpredictable, therefore the development of new alternative approaches to manage patients with diabetes is mandatory. The pandemia has removed several burdens to telehealth, and the use of universal digital platforms for continuous glucose monitoring download, as well as connectivity to electronical medical records deserve implementation. Telemedicine consultation improvement represents a new task for each component of the team, including physicians, nurses, dieticians, and psychologists. COVID-19 pandemia represents a challenge for diabetologists in order to evaluate the consequences of this unpredictable scenario in diabetes mellitus, in particular regarding epidemiology, etiopathogenesis, management, psychological burden, quality of life. Multicenter studies are needed to increase the knowledge and to establish new prevention and therapeutic strategies. ## 7. Critical research priorities 1. Collect national real-data on the effects of lockdown and 2020 year infection rate on the metabolic and psychological outcomes of patients with type 1 diabetes 2. Determine the impact of the time of infection on weight, exercise activity and treatment regimens 3. Develop an epidemiological model to estimate the cumulative incidence of COVID-19 for patients with type 1 diabetes as well as the impact of the infection environment into the development of type 2 diabetes 4. Determine the COVID-19 morbidity in pregnant woman with long-term effects on glucose metabolism and prevalence of diabetes mellitus. # Conclusions (sharing experience) There is currently no evidence suggesting a higher risk of COVID-19 infection in children with diabetes than in unaffected peers. In addition, contrary to adult patients with diabetes, there are no reports suggesting that diabetes is a comorbidity associated with poor outcomes in children and adolescents. Despite the risk that the COVID-19 infection may develop into a more severe form seems to be lower if diabetes is well controlled, several practical recommendations may be useful. Children and adolescents affected by type 1 diabetes, as for other chronic conditions, need uninterrupted access to drugs, supplies, technology and care, especially in stressful situations. Since the lockdown reduced the access to outpatient clinics, pediatric diabetologists rescheduled all routine checks as telephone consultations and video-link consultations. In this stressful moment, patients and their families need to be reassured that a close link with the pediatric team is and will be available, and the medical care is maintained and reinforced. Since strict glycometabolic control is mandatory to prevent short-and long-term complications, pediatric diabetologists realized the need to develop new and alternative routes for disease management. The reduction of direct contacts among patients and healthcare team might be responsible for the worsening of metabolic control, with an increased risk of severe decompensation, even if in absence of COVID-19 infection. In Italy, both adult and pediatric scientific societies have obtained from the Italian Agency of Drugs (Agenzia Italiana del FArmaco, AIFA) that all patients with type 1 and type 2 diabetes can have access to drugs and self management without having to present the annual request form, that is usually released by diabetologists, limiting in this way the need to access hospitals. ## Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. [table] Table 1 -: Summary of reviewed papers looking at the impact of COVID-19 infections and diabetes mellitus. [/table] [table] Table 2 -: General recommendations. Wash your hands, don't touch eyes, nose and mouth Cover mouth and nose with bent elbow or tissue when coughing or sneezing Avoid contacts with other persons, particularly if affected by COVID-19 [/table]	None	http://www.diabetesresearchclinicalpractice.com/article/S0168822720306252/pdf	None
1f62fc682b0150ff50fcade5fb438ea6e99ee6e8	pubmed	Post-natal follow-up for women and neonates during the COVID-19 pandemic: French National Authority for Health recommendations	Post-natal follow-up for women and neonates during the COVID-19 pandemic: French National Authority for Health recommendations Introduction: In the context of the stage 3 SARS-Cov-2 epidemic situation, it is necessary to put forward a method of rapid response for an HAS position statement in order to answer to the requests from the French Ministry of Solidarity and Health, healthcare professionals and/or health system users' associations, concerning post-natal follow-up for women and neonates during the COVID-19 pandemic. Methods: A simplified 7-step process that favours HAS collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. A short and specific dissemination format, which can be quickly updated in view of the changes in available data has been chosen. # Introduction On 14th March 2020, France entered stage 3 of the COVID-19 epidemic outbreak. In a letter dated 27th March 2020, the French Direction Générale de la Santé (DGS) referred the matter to the French National Authority for Health (Haute Autorité de Santé; HAS), with a view to drawing up general recommendations designed to ensure continuity of care for pregnant women during lockdown and travel restrictions. Given the very limited data available, the French High Council for Public Health considered pregnant women in the third trimester of pregnancy to be at risk of developing a severe form of COVID-19. Rare cases of vertical transmission of the virus have been identified (even though no placental viremia, or presence of the virus in amniotic fluid or in cord blood has been published to date) [bib_ref] Clinical characteristics of pregnant women with Covid-19 in Wuhan, Chen [/bib_ref] [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref] [bib_ref] Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn, Dong [/bib_ref] [bib_ref] Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19..., Yu [/bib_ref]. The extension of lockdown and the role and workload of healthcare professionals, lead to re-interviewing organizations for the follow-up of pregnant women in terms of prevention and care. These rapid responses focus on the conditions and organization of the return home of mothers and their children during the lockdown period and the management of cases of women with COVID-19 (without signs of severity) and their newborns returning home. They should be adapted according to the geographical particularities of the epidemic outbreak and access to local resources. These rapid responses are based on the knowledge available at the time of publication and are subject to change as new information becomes available. # Methods In the context of the stage 3 SARS-Cov-2 epidemic situation, it is necessary to put forward a method of rapid response for a HAS position statement in order to answer to the requests from the French Ministry of Solidarity and Health, healthcare professionals and/or health system users' associations. A simplified 7-step process that favours HAS collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. A short and specific dissemination format, which can be quickly updated in view of changes in available data has been chosen. Step 1) Selection of requests and identification of issues requiring a rapid response by the President of the HAS College. Step 2) Data selection and analysis by the HAS teams in close collaboration with experts named by the National Professional Councils (Conseils Nationaux Professionnels -CNP) and French scientific societies. Data selection has been restricted to the best levels of evidence and in descending order: High Council for Public Health recommendations and French health agencies Recommendations of French and International scientific societies WHO guidelines Recommendations from international health agencies (NICE, INESS, etc.) Literature reviews and recent 2019 and 2020 scientific literature with rapid critical analysis Step 3) Drafting of provisional rapid responses by a select working group: HAS team, previously appointed experts and patient associations Step 4) Review and consultation / information of stakeholders. Available online at ScienceDirect www.sciencedirect.com Health Directorate, High Council for Public Health). These reviews are carried out electronically and allow a response within a short time frame. Step 5) Finalization of the rapid responses by the previously appointed working group. Step 6) Validation and dissemination of the rapid responses by the HAS. The texts are then published in a short format on the website of the HAS, scientific societies and associations involved. A warning is included in the text: "These recommendations, drawn up on the basis of the knowledge available at the date of their publication, are subject to change and are likely to be updated in light of new available data". The experts' ties of interest are analysed by the HAS ethics officer and the legal department, on the basis of the information available in the "DPI-HEALTH and TRANSPARENCY-HEALTH" databases, and are provided to the members of the HAS College for their information Step 7) Regular update of the rapid responses taking into account the developments in the scientific literature and the recommendations from scientific societies. This document was drawn up jointly by the HAS and experts appointed by the Collège National des Gynécologues et Obstétriciens Français (CNGOF), the Collège National des Sages-femmes de France (CNSF), the Collège de la Médecine Générale (CMG), the Société Française de Néonatalogie (SFN), the Société française de pédiatrie (SFP), the Fédération Française des Réseaux de Santé en Périnatalité (FFRSP), the Association Française de Pédiatrie Ambulatoire (AFPA). The rapid responses were reviewed by the Collectif Interassociatif Autour de la Naissance (CIANE). ## Recommendations Discharge after childbirth: conditions and organization of the return home of mothers and their newborns during the COVID-19 pandemic As the hospital is considered a COVID-19 cluster, early discharge for mothers and children at low medical, psychological and social risk is recommended : When possible, within 48 h of the newborn's life for a woman giving birth by vaginal delivery. If discharge from the maternity ward is planned before 48 h of life, the HAS recommendations apply, with regard to the criteria for reinforced surveillance of the newborn and the organization of neonatal screening. When possible, within 96 h of the newborn's life for a woman giving birth by caesarean section. Before any early discharge from the maternity ward, the newborn is examined by a paediatrician according to the situations mentioned above: before 48 h, at 48 h of life and after 96 h. It is advisable that a post-natal care consultant accompanies women, particularly those in precarious situations or those in vulnerable psychological or social situations, in order to: Carry out screening, prevent complications and identify them early in order to refer the patient to another professional if necessary Identify a need for follow-up or additional assistance or referral via the appropriate channels. Anticipate possible infection of the newborn to organize return home Newborns of a COVID + mother should be considered carriers of the virus. Routine screening of newborns of COVID-or nonÀCOVID + suspected mothers is not currently recommended. The American Academy of Pediatrics (AAP) and Society of Obstetricians and Gynecologists (SOGC) recommend that newborns of a COVID + mother be considered suspect for COVID-19. The authors suggest that the value of a screening test is to organize postpartum care and to provide close monitoring of the newborn. In the French context, the HAS considers it more prudent to consider any newborn of a COVID + mother as a carrier of the virus. Testing the newborn is therefore not justified. The precautions to be taken are to stay confined at home with the child, to avoid too close contact with family members (especially siblings and people at risk), to wear a surgical mask and to have strict hand hygiene. Temperature and appearance of symptoms of respiratory infection should be monitored in both mother and child. A systematic review of 23 studies (20 Chinese, 1 Korean, 1 American, and 1 from Honduras) evaluated that of a total of 122 infants tested out of 162 infants born to mothers with COVID-19, 10 % were found to be positive for SARS-CoV-2 by RT-PCR (with one stillborn and one perinatally deceased child with no specified link to COVID-19) [bib_ref] Pregnancy outcomes, newborn complications and Maternal-Fetal Transmission of SARS-CoV-2 in women with..., Gajbhiye [/bib_ref]. The French Society of Neonatology (SFN) stresses that the results of a test would not influence maternity unit practices (no separation of mother and child and possible breastfeeding) or the implementation of protection and surveillance measures in the event of an infected mother or child (while nevertheless protecting the other children in the household). Indeed, since the beginning of the COVID-19 epidemic outbreak, children, especially newborns, are a more protected group, as evidenced by the low proportion of children among the total number of infected persons (between 1 and 5%) and the more benign nature of their infection. Post-natal follow-up for women and neonates during COVID-19 pandemic: HAS recommendations. Rapid Response #1: Rare cases of vertical transmission of SARS-CoV-2 have been identified and there is no evidence of transmission during breastfeeding. After birth, the newborn is likely to be infected. Lockdown and barrier measures must be followed and reinforced if the mother is infected with COVID-19. Rapid Response #2: Encourage early discharge, from the 48 th hour of life of the newborn, by promoting communication and town/hospital organization. Rapid Response #3: Have a physical examination of the newborn between the 6 th and 10 th day after birth carried out by a paediatrician or a general practitioner within the framework of an organized care system. Rapid Response #4: Propose follow-up by remote consultation or face-to-face based on the assessment of the clinical situation, but also on the woman's social and psychological context. Rapid Response #5: Ensure the physical and mental well-being of the mother, maintain psychological support for women, including remotely, and accompany the mother or couple in their parenting practices Rapid Response #6: Reinforce follow-up in case of very early discharge (before 48 h of life) Rapid Response #7: Pay particular attention to the jaundice risk monitoring circuit and follow-up in the maternity ward in case of confirmed jaundice Rapid Response #8: Modulate organization of postnatal monitoring according to the geographical particularities of the epidemic outbreak and access to local resources Current data, feedback from professionals in the field on the impact of carrying out screening tests on maternity practices, the conditions of return home and findings on child health do not make it possible to systematically recommend a screening test for children. If the mother's COVID status is known, that of the newborn must in fact be considered to be identical. In case of the slightest symptom, both mother and child should be tested. Adapt the conditions and organization of postnatal follow-up at home for mothers and their newborns The conditions and organization of the return home follow the HAS recommendations while adapting to the context of the epidemic. A first routine visit is carried out by a midwife ideally within 24 h after leaving the maternity unit. The mother leaves the maternity unit with this appointment. A second visit can be scheduled if decided by the midwife, by remote consultation or face-to-face depending on the situation. If necessary, she will contact the obstetrician and/or the paediatrician and/or the general practitioner. Other visits can be planned according to the medical aspects to be monitored, the mother's vulnerabilities or social or psychological context, and/or if the mother or the couple feel they need them; they can be carried out by remote consultation. For at-risk women, if hospitalization at home is indicated, it should be preferred depending on the resources available locally. The first health certificate "to be drawn up within the first eight days of life" is systematically issued by a doctor (paediatrician or general practitioner). It can be filled in when leaving the maternity unit. Given the shorter length of stay in the maternity unit, it is recommended that a newborn child be examined in person between the 6th and 10th day after the birth, preferably by a paediatrician or a general practitioner. The newborn's visit planned during the second week (close medical supervision of the infant) is left, during an outbreak of COVID-19, to the decision of the paediatrician or general practitioner who examined the child between the 6th and 10th day postpartum. ## Maternal monitoring parameters Bleeding, infectious, thromboembolic, urinary, digestive, scarring and pain risk Signs of physical and psychological distress (quantity and quality of sleep, state of fatigue, mood); postpartum depression (which can occur within two weeks of birth or later), especially in women who have shown signs of depression since pregnancy and/or express excessive concern about their maternal capacity; situation of domestic violence in the context of lockdown. Psychological support may be necessary. Breastfeeding difficulties, adapted response to newborn crying. Risk of child abuse, especially Shaken Baby Syndrome: the quality of support from family and friends is essential, as is recourse to psychological support. In a context of lockdown and family isolation, it is essential to reinforce postnatal monitoring by remote consultation, particularly for monitoring breastfeeding, screening for postnatal depression, and support for the mother or couple in their parenting practices (especially for first time mothers): two postnatal remote consultations can be conducted by a midwife between the 8th day after delivery and the postnatal visit. The postnatal visit is maintained at the hospital/practice six weeks after delivery: gynaecological examination, method of contraception, vaccinations, screening smears, pelvic floor physiotherapy, experience of childbirth and the aftermath of childbirth, assessment of signs of distress or depression, relationship with the child and within the couple. Pelvic floor physiotherapy sessions, usually started six weeks after delivery, can be arranged remotely. ## Child monitoring parameters Risk of jaundice (focus on Risk of heart disease: if there is any doubt as to the cardiac auscultation, or if the femoral pulses are not perceived or there are any other signs of heart failure, a special telephone help line must be set up to reach the maternity ward paediatrician, with a line through to the paediatric cardiology department. Risk of dehydration/undernutrition: weight, monitoring of effective feeding (well established breastfeeding or artificial breastfeeding): urine output at each nappy change, spontaneous and regular bowel function (three to four stools/day). Infectious risk (COVID-19 and others): temperature (hypo or hyperthermia), respiratory rate, hemodynamic disorders (longer capillary refill time), diarrhoea. ## Reinforce surveillance in case of very early discharge, before 48 h This can only be possible if local resources and organization permit it, including the organization of neonatal screening tests : Focus on how to organize discharge for jaundice and the prevention of severe hyperbilirubinemia. The jaundice risk assessment must be integrated into the reasoning leading up to the decision for discharge from the maternity unit. For each child, compilation of a jaundice profile based on the normogram [bib_ref] Management of Hyperbilirubinemia in the newborn infant 35 or more weeks of..., Hyperbilirubinemia [/bib_ref] , combined with the recognition of risk factors for severe hyperbilirubinemia, ensures that the child is discharged in optimal safety conditions and thus reduces the risk of readmission to hospital for hyperbilirubinemia. Jaundice follow-up procedures should: be effective within 24 h of early discharge from the maternity unit. enable quantification of jaundice. enable physical evaluation of the child (weighing) and breastfeeding (observation of a feed). identify a possible return route (if necessary) to a care facility. Parents must be informed of the warning signs and of who to contact in the event of an emergency prior to discharge. It is recommended that jaundice data be recorded in the child's health record, or that this information (risk factors, profile outcome, diagnosis and test results) be mentioned on the immediate post-partum liaison sheet for the professional(s) providing follow-up. In practice, if the midwife does not have a bilirubinometer, she should be able to arrange for a bilirubin test at the maternity ward. As part of early discharge during the COVID-19 pandemic, it is important to monitor clinical signs and arrange for bilirubin monitoring at a private practice or at the hospital if necessary. In the event of jaundice, phototherapy must be organized via secure channels in the maternity unit where the woman gave birth. and timely completion of those tests. Screening for metabolic diseases must be carried out between 48 and 72 h of life with transmission of blotters within 24 h to guarantee reliability. Communication and town/hospital organization is essential for the appropriate care of the mother and child. Early examination of the newborn by the paediatrician in the maternity ward before discharge in the same way as for discharge at 48 h has to be considered, as well as early and rapid follow-up by the midwife at home. Monitoring by bilirubinometer should take place after 24 h according to the local organization. ## Points of caution regarding neonatal screening tests The results of neonatal screening tests should be routinely recorded in the child's health record. Systematic neonatal screening for metabolic diseases: In view of the lockdown measures taken by the post office, which have an impact on the delivery of "blotting paper" tests to neonatal screening reference centres, discharge from the maternity ward after 48 h will ensure that neonatal screening can be carried out in good conditions. Hearing screening: If hearing screening could not be carried out in the maternity ward (at the earliest after 24 h) or if a check-up is necessary, schedule this screening or obtain diagnostic confirmation once the epidemic situation has passed. Screening for critical congenital cardiopathies: measurement of right upper limb and lower limb saturation between 6 h and 24 h before leaving the maternity hospital: definition of the action to be taken in liaison with the referring maternity hospital paediatric cardiologist. Screening for congenital hip dislocation: repeated physical examination at each routine newborn and infant visit. In case of abnormal physical examination (abduction limitation, instability), an ultrasound should be performed and treatment should be implemented further to orthopaedic assessment. If risk factors are present, a hip ultrasound should be performed before the age of 3 months. ## Support for ambulatory care The implementation of these rapid responses implies essential support for the care offer, which is currently below standard in the context of the COVID-19 epidemic (closure of some day care structures, few personal protection measures in terms of equipment for midwives, less post-natal home follow-up by midwives). The day care structures (Maternal and child welfare in France is the name of the protection system for mothers and children) have an important role to play in the continuity of care and must participate in the follow-up of women and their children (doctor, home-visiting nursery nurse) by restricting their activities, while following barrier measures. The organization of postnatal monitoring should be modulated according to the geographical particularities of the epidemic outbreak and access to local resources, perinatal health networks playing a major role. In the context of COVID-19, teamwork, communication and information sharing must be strengthened between the hospital and town to increase efficiency and safety. The methods are determined jointly by the healthcare professionals involved in caring for women (midwives, obstetricians, paediatricians, general practitioners, etc.). Given the midwives' role outside the hospital in monitoring women and their children after birth, it is essential to ensure they have all the appropriate personal protective equipment they need (masks, overalls, gloves, etc.). Institutions must draw up a list of midwives outside the hospital who can provide follow-up care for women and their children after birth to reinforce the town/hospital link. The role of perinatal networks is essential in the epidemic context. All of these measures aim to step up ambulatory care and facilitate the management of patients with COVID-19 by obstetrical teams in health facilities. Ambulatory care is defined as medical care carried out by any health non-hospital personnel (midwife, general practitioner and gynaecologistobstetrician) who work in the city. Women and their newborns returning home with COVID-19 (without signs of severity) The general practitioner and all home-visiting healthcare professionals must be informed of the mother's infection. Newborns without comorbidities can stay with their COVID-19 + mother and be breastfed (unless the mother asks to be separated from her child). The French Society of Neonatology (SFN) and the Paediatric Infectious Pathology Group (GPIP) do not currently recommend separation of mother and child and do not contraindicate breastfeeding. ## Mother and child monitoring parameters A mother with COVID-19 and her child are monitored by their general practitioner and, if necessary, the paediatrician for the newborn. At the same time, the midwife can ensure postnatal supervision of the mother and the child in liaison with the referring obstetrical team. Any woman or child with signs of severe COVID-19 or aggravating comorbidities should be taken to a health care facility. Monitoring and follow-up for a COVID-19+ mother Active monitoring of her temperature and onset of symptoms of respiratory infection (fever, cough, breathing difficulty, sensation of suffocation etc.). Strict lockdown with the child. Too close contact with family members should be avoided. A mask (surgical mask) should be worn. Strict hand hygiene: hands should be washed before taking care of the child. The general practitioner or the nurse should contact the mother every 24 h to follow-up on the infection (tracing the results to be recovered and calls made), giving priority to remote consultation or remote care when possible. Postnatal monitoring of mother and child by the midwife in liaison with the referring obstetrical team. Exit from isolation after recovery as in the general population.Consultation with a doctor three weeks after discharge. ## Monitoring and precautions for infants born to mothers with covid-19 Active monitoring of temperature and the onset of symptoms of respiratory infection (fever, cough, breathing difficulties, etc.), diarrhoea. Strict lockdown with the mother. It is not recommended for newborns to wear masks First consultation within 24 h of arrival at home with the midwife, then a consultation between the 6th and 10th day postpartum, preferably at the paediatrician's or general practitioner's practice, in accordance with the safety protocol in place (for example at the end of a consultation with a paediatrician at a special clinic for newborns or small infants). Although compulsory, in the event of a COVID-19 epidemic, examination of the newborn planned during the second week (close medical supervision of the infant) is decided by the paediatrician or general practitioner who examined the child between the 6th and 10th postpartum. Any symptoms in the newborn should be reported to the health care professional who looks after the child and should give rise to a consultation, and determine the frequency of follow-up. In case of emergency: go to the paediatric emergency department of the reference hospital having first called the emergency services. No data are available on the impact of early maternal infection during pregnancy on child development: close monitoring of the child at each visit [bib_ref] Maternal and Perinatal Outcomes with COVID-19: a systematic review of 108 pregnancies, Zaigham [/bib_ref]. ## Lockdown at home As with any person confirmed to be COVID-19+, self-isolation at home for 14 days after the onset of the first symptoms is recommended and special precautions should be taken. The precautions applicable to women with COVID-19 are the same as for the general population (barrier measures, social distancing, lockdown) to reduce the risk of transmission. Specific recommendations also apply. Monitoring instructions and hygiene precautions to be observed must be given and explained to the woman or couple before leaving the maternity unit. Mother and child organization at home after leaving the maternity unit At home, the mother is advised to isolate with the child, if possible, in a separate room, avoiding contact with the other occupants, and to air the room regularly. A hotel room is available if the mother prefers (COVISAN system in Paris, or equivalent elsewhere). The cot should be placed about six feet from the mother's bed or chair. All occupants should wash their hands frequently after using the bathroom and toilet, which must be cleaned regularly with bleach or disinfectant. Surfaces touched regularly (door handles, mobile phones, etc.) are cleaned daily and disinfected). It is not advisable to receive visits unless they are essential, such as visits from a midwife, nurse, childcare worker or home help. ## Breastfeeding Studies show that the viral genome is not found in the breast milk of COVID-19-infected mothers [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref] [bib_ref] Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know, Rasmussen [/bib_ref] [bib_ref] Experience of clinical management for pregnant women and newborns with novel coronavirus..., Wang [/bib_ref]. Breastfeeding therefore does not appear to be contraindicated. A COVID-19+ mother, or suspected to have COVID, and symptomatic, should take all the necessary precautions to avoid transmitting the virus to her infant. She should wash her hands before touching the infant, wear a face mask, and if possible, during breastfeeding. If the mother is expressing milk with a manual or electric breast pump, or feeds her child with baby formula, she should wash her hands before touching any part of the breast pump or bottle and follow the recommendations for proper cleaning of the breast pump or bottle after each use. Implement protective measures during examination and care of the newborn child During examination or care of the newborn, during the first month of life, it is recommended to wear a mask and to wash hands beforehand (using soap or had sanitizer) The newborn must be seen again for the first month visit in person. Mandatory vaccinations must be administered at two months of life (possible from 6 weeks).	None	None	None
5a0d31d6f8d563fbbbfbe04cd1b8cffb74c2f838	pubmed	Application of the Updated CDC Isolation Guidelines for Health Care Facilities	Application of the Updated CDC Isolation Guidelines for Health Care Facilities indicates that continuing education contact hours are available for this activity. Earn the contact hours by reading this article and taking the examination on pages 543-544 and then completing the answer sheet and learner evaluation on pages 545-546. You also may access this article online at http://www.aornjournal.org. © AORN, Inc, 2008 T he Centers for Disease Control and Prevention (CDC) has published updated guidelines that outline how health care workers can prevent the transmission of infectious agents to their patients as well as to one another. 1 During the past 11 years since the previous guidelines were published, 2 research has expanded, and effective interventions Application of the Updated CDC Isolation Guidelines for Health Care Facilities SHAUNA ELY TARRAC, RN, MSN, CIC, CNOR, CPANTHE CENTERS FOR DISEASE CONTROL and Prevention has published updated guidelines for isolation precautions that outline how health care workers can prevent the transmission of infectious agents to their patients and to themselves.THE GUIDELINES RE-EMPHASIZEstandard precautions, which guide clinicians in the use of appropriate personal protective equipment (PPE), depending on the expected type of exposure. Respiratory hygiene/ cough etiquette is incorporated into infection control practices as a new component of standard precautions. THE ARTICLE PROVIDES information on the new guidelines as well as information on newly emerging patho gens and methods to prevent disease transmission in health care settings. AORN J 87 (March 2008) 534--542. © AORN, Inc, 2008. This article highlights some of the changes in the updated "Guidelines for isolation precautions: preventing transmission of infectious agents in healthcare settings." 1 Particularly, the article guides clinicians in the appropriate application of standard precautions and prepares clinicians to incorporate respi-ratory hygiene/cough etiquette into infection control practices, which has been added as a component of standard precautions. It is important to note that several terms have been changed. The term nosocomial infections has been replaced with the term healthcare-associated infections (HAIs) and the term negative pressure room has been replaced with the term airborne infection isolation room. ## Re-emphasis on standard precautions Standard precautions, previously known as universal precautions, have become one of the first-line tools for decreasing transmission of disease from patient-to-patient or patient-tohealth care worker. The key elements of standard precautions include performing hand hygiene; using appropriate personal protective equipment (PPE) depending on the expected type of exposure (ie, gowns for exposure to blood or diarrheal drainage, mask and eye protection for cough-producing procedures); employing safe injection practices; and adhering to respiratory etiquette. Standard precautions are "based on the principle that all blood, body fluids, secretions, and excretions . . . may contain transmissible infectious agents." 1(p66) These infection prevention practices apply to all patients, regardless of suspected or confirmed infection status, in any setting in which health care is delivered. One component of standard precautions is using safe injection practices.These guidelines mirror the Occupational Safety and Health Administration guidelines for health care worker protection from blood and body fluid pathogens.The precautions include - using a sterile, disposable needle and syringe with a protective device for each injection and discarding all items intact in an appropriate sharps container after use; - using single-dose medication vials, prefilled syringes, and ampules when possible; - not using bags of IV solution as a common source of supply for multiple patients; and - using aseptic technique to avoid contamination of sterile injection equipment. Another concern is the potential for contamination of patient care equipment with infectious body fluids. Health care personnel must handle equipment in a manner that prevents transmission of infectious agents. Recommendations include wearing gloves during direct contact with contaminated equipment; containing heavily soiled equipment; and properly cleaning, disinfecting, and sterilizing equipment before use on another patient. In the surgical setting, a patient may be admitted for emergency surgery but also may be harboring an unknown bacterial or viral infection. By consistently applying standard precautions, the possibility of infection transmission is decreased greatly. These precautions may include hand hygiene and use of gloves, eye protection or a face shield, a mask, or a gown depending on the anticipated exposure. For example, when the circulating nurse assists with intubation and extubation, he or she should wear the appropriate PPE (eg, gloves, mask, eye protection). Precautions are necessary for invasive procedures involving the insertion of catheters or in-jection of material into spinal or epidural spaces via lumbar puncture (eg, myelogram, spinal or epidural anesthesia). 1 Although most elements of standard precautions evolved from universal precautions that were developed for protection of health care personnel, these new elements of standard precautions focus on protection of patients. Staff members now are advised to wear masks during these invasive procedures. [bib_ref] Surgical face masks are effective in reducing bacterial contamination caused by dispersal..., Philips [/bib_ref] [bib_ref] Guidelines for the prevention of intravascular catheter-related infections, O'grady [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, Jensen [/bib_ref] The strategy to contain respiratory infectious diseases has been termed respiratory hygiene/cough etiquette [bib_ref] Foundations of the severe acute respiratory syndrome preparedness and response plan for..., Srinivasan [/bib_ref] and should be incorporated into infection control practices as a new component of standard precautions. The strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections and applies to any person who enters a health care facility with signs of illness, including cough, congestion, rhinorrhea, or increased production of respiratory secretions. [bib_ref] Nosocomial pertussis: possible spread by a hospital visitor, Valenti [/bib_ref] ## Respiratory hygiene/cough etiquette ## Disease transmission Disease transmission can occur through direct contact (eg, the hands of a health care worker who is a carrier of the disease); indirect contact (eg, patient care devices, the hands of a health care worker who has touched a contaminated item, shared toys, medical instruments that have not been cleaned or disinfected adequately); and airborne and droplet routes [fig_ref] TABLE 1: Types of Standard PrecautionsDepending on the Routes of Disease Transmission 1 [/fig_ref]. The envi-ronment also has been implicated in infections via contaminated food, water, IV fluids, and dust or debris on the outside of sterile supply packages. For transmission to occur, a source must exist, a mode of transmission must be present, and a susceptible host must be exposed. DIRECT CONTACT TRANSMISSION. Transmission via direct contact remains the most common source of microorganism transmission. Direct contact refers to transmission from one person directly to another. Sources include peoples' hands and coughing or sneezing. Susceptible hosts include very old people; the very young; and any patient with chronic diseases, especially diseases involving the immune system. INDIRECT CONTACT TRANSMISSION. Indirect transmission occurs when an intermediate object (eg, a contaminated needle or instrument, the hands of a health care worker) transfers microorganisms to a susceptible host. Sources that are particularly unsanitary are referred to as "high touch surfaces" (eg, elevator buttons, telephones, door handles). Another example of indirect disease transmission is that of vectorborne illnesses that are propagated by mosquitoes, flies, rats, deer, and squirrels. Diseases in this category include Lyme disease, plague, tickborne relapsing fever, tularemia, Eastern equine and West Nile encephalitis, and yellow fever. [bib_ref] The role of the intestinal tract as a reservoir and source for..., Donskey [/bib_ref] [bib_ref] Acquisition of nosocomial pathogens on hands after contact with environmental surfaces near..., Bhalla [/bib_ref] AIRBORNE TRANSMISSION. Airborne transmission occurs when a person inhales an infectious agent. The infectious particles are small enough to be suspended in the air and to move along air currents. Patients with airborne infectious diseases must be placed in an airborne infection isolation room (ie, previously known as negative pressure room) with negative pressure in relation to the corridor. All staff members providing care for the patient should wear a National Institute of Occupational Safety and Health (NIOSH)-certified N95 respirator. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, Jensen [/bib_ref] Patients with airborne infections should not be removed from their rooms unless a procedure cannot be performed in a patient room (eg, nonportable x-rays) or is deemed an emergent situation (eg, emergency surgical interventions). When patients do require transport outside of their rooms, the patient is required to wear a surgical mask. Transmission of Aspergillus spores between patients have been noted in an intensive care unit where a patient required frequent wound debridement and extensive dressing changes. [bib_ref] Cluster of cases of invasive Aspergillosis in a transplant intensive care unit:..., Peques [/bib_ref] Transmission was thought to have occurred via aerosolization of the spore. DROPLET TRANSMISSION. Diseases can be transmitted via the respiratory system from one person to another directly or indirectly. When an infected person sneezes, coughs, or speaks, droplet particles can be generated, can stay suspended for long periods of time, and can be inhaled or swallowed by another person, usually within a distance of 3 ft. 1(p132) Experimental studies performed with smallpox and observations during the SARS outbreak in 2003 indicate that these two infections may be transmitted up to 6 ft from the source patient. [bib_ref] Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission..., Seto [/bib_ref] In addition, some people are considered "shedders" (ie, nasal carriers) exhibiting "cloud baby syndrome" or "cloud adult syndrome." For these syndromes, transmission of microorganisms that are not normally transmitted by the airborne route have been documented. This phenomenon has been noted in outbreak cases with the transmission of Staphylococcus aureus from colonized patients or health care workers. [bib_ref] Dispersal of Staphylococcus aureus into the air associated with a rhinovirus infection, Bassetti [/bib_ref] [bib_ref] The "cloud baby:" an example of bacterial-viral interaction, Eichenwald [/bib_ref] [bib_ref] A cloud adult: the Staphylococcus aureus-virus interaction revisited, Sheretz [/bib_ref] ## Organisms of interest "Any infectious agent transmitted in health care settings may, under defined conditions, become targeted for control." 1(p21) Clinicians at each health care facility must monitor the endemic rate of these infections to determine a baseline threshold for that organism. Surveillance then continues, and an unexplained increase over and above the endemic rate, with or without an increase in the severity of disease, requires investigation and the institution of control measures. MDROS. Resistant organisms refer to certain bacterial pathogens that have proven resistant to any first-line therapy medication. Any organism that is resistant to more than two antibiotics generally is considered to be an MDRO. Transmission is from patient to patient, usually via the hands of health care workers. [bib_ref] Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination..., Wilcox [/bib_ref] [bib_ref] Environmental control to reduce transmission of Clostridium difficile, Mayfield [/bib_ref] This disease usually is related to recent or prolonged antibiotic therapy. In addition, a relatively new strain made its appearance in England, Canada, and the United States beginning in 2001. [bib_ref] Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003:..., Pépin [/bib_ref] This strain-toxinotype III, North American PFGE (pulsed-field gel electrophor esis) type 1-has been shown to produce 16 times more toxin A and 23 times more toxin B than has been observed historically with Clostridium difficile. [bib_ref] Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003:..., Pépin [/bib_ref] Prevention focuses on - instituting contact precautions for any patient with diarrhea; - increasing the environmental cleaning of surfaces, especially patient rooms, bathrooms, and commodes; and - ensuring consistent hand hygiene with soap and water for mechanical removal of the spores. Some facilities have noted a decrease in Clostridium difficile transmission when a bleachcontaining disinfectant is used for environmental cleaning. [bib_ref] Environmental control to reduce transmission of Clostridium difficile, Mayfield [/bib_ref] ## Creutzfeldt-jakob disease (cjd). Creutzfeldt-Jakob disease is a progressive neurological disorder involving an infection with a prion.A prion is thought to be a transmissible, proteinaceous agent. In the United States, CJD occurs in one person per million per year. Prion diseases also can infect sheep (ie, scrapie), cattle (ie, bovine spongiform encephalopathy), and deer and elk (ie, chronic wasting disease). Transmission has been linked to treatment with - human cadaveric pituitary-derived hormone; - human dura mater grafts; - corneal transplants; and - contaminated neurosurgical instruments, including stereotactic electroencephalogram electrodes. Bloodborne transmission has been linked to two infections in patients with variant CJD. [bib_ref] Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion, Llewelyn [/bib_ref] Standard precautions are recommended when caring for patients infected with CJD.Special processes are required when handling tissue in the histology laboratory or when performing an autopsy. It is essential that a very specific method be used for disinfecting surgical equipment and instruments. [bib_ref] Creutzfeldt-Jakob disease and related transmissible spongiform encephalo pathies, Johnson [/bib_ref] [bib_ref] Potential epidemic of Creutzfeldt-Jakob disease from human growth hormone therapy, Brown [/bib_ref] [bib_ref] Clinical review 58: Creutz feldt-Jakob disease in recipients of pituitary hormones, Frasier [/bib_ref] Processing any CJD-suspect equipment includes soaking the item in sodium hydroxide solution (ie, 1N NaOH) and after removing the item from the solution, steam sterilizing it at 134° C (273° F) for 18 minutes. Alternatively, the item may be soaked in 1N NaOH and, after removal from the solution, steam sterilized at 121° C (250° F) for 30 minutes. Recent studies have indicated that the temperature for steriliza-tion must be exact. If the temperature is above the recommendation, prion growth may occur. [bib_ref] Putative neurosurgical transmission of Creutzfeldt-Jakob disease with analysis of donor and recipient:..., El Hachimi [/bib_ref] [bib_ref] Evidence for case-to-case transmission of Creutzfeldt-Jakob disease, Will [/bib_ref] [bib_ref] Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery, Bernoulli [/bib_ref] [bib_ref] Creutzfeldt-Jakob disease: recommendations for disinfection and sterilization, Rutala [/bib_ref] SARS. According to the World Health Organization, a total of 8,098 people worldwide became sick with SARS during the 2003 outbreak. [bib_ref] The severe acute respiratory syndrome, Peiris [/bib_ref] [bib_ref] Transmission of the severe acute respiratory syndrome on aircraft, Olsen [/bib_ref] Of those infected, 774 died. As of February 2003, a total of 418 patients were thought to be infected with SARS in the United States. Of those patients 344 were classified as having "suspected" and 74 as having "probable" SARS cases.All of these people had traveled to other parts of the world where SARS was prevalent. Disease transmission has been documented during endotracheal intubation; noninvasive positive pressure (eg, continuous positive airway pressure, bilevel positive airway pressure); and cardiopulmonary resuscitation. [bib_ref] SARS among critical care nurses, Loeb [/bib_ref] [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] [bib_ref] Illness in intensive care staff after brief exposure to severe acute respiratory..., Scales [/bib_ref] [bib_ref] Possible SARS coronavirus transmission during cardio pulmonary resuscitation, Christian [/bib_ref] The incubation period of SARS CoV is two to 10 days, and symptoms include generalized upper respiratory infections, temperature greater than 38° C (100.4° F), chills, rigors, headache, and rapidly progressing dyspnea. [bib_ref] The severe acute respiratory syndrome, Peiris [/bib_ref] [bib_ref] Transmission of the severe acute respiratory syndrome on aircraft, Olsen [/bib_ref] [bib_ref] In-flight transmission of severe acute respiratory syndrome (SARS): a case report, Wilder-Smith [/bib_ref] [bib_ref] Detection of airborne severe acute respiratory syndrome (SARS) coronavirus and environmental contamination..., Booth [/bib_ref] Outbreaks in health care settings have been documented with health care workers becoming ill with the disease after caring for infected patients. [bib_ref] In-flight transmission of severe acute respiratory syndrome (SARS): a case report, Wilder-Smith [/bib_ref] [bib_ref] Centers for Disease Control and Prevention. Cluster of severe acute respiratory syndrome..., Yu [/bib_ref] AVIAN FLU. Usually, the term avian influenza virus refers to influenza A viruses found most predominantly in birds, but infections with these viruses can and have occurred in humans. [bib_ref] Avian influenza in Hong Kong, Sims [/bib_ref] [bib_ref] Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong..., Guan [/bib_ref] Confirmed cases of human infection from several subtypes of avian influenza have been reported since 1997.Most cases of avian influenza in humans have resulted from contact with infected poultry (eg, domesticated chicken, ducks, turkeys) or surfaces contaminated with secretion or excretions from infected birds. [bib_ref] Reemerging H5N1 influenza viruses in Hong Kong in 2002 are highly pathogenic..., Sturm-Ramirez [/bib_ref] [bib_ref] Re-emergence of fatal human influenza A subtype H5N1 disease, Peiris [/bib_ref] [bib_ref] Microbial adaptation and change: avian influenza, Webster [/bib_ref] [bib_ref] Characterization of an avian influenza A (H5N1) virus isolat, Subbarao [/bib_ref] The spread of avian influenza virus from one ill person to another has been reported very rarely and has been limited, inefficient, and unsustained. [bib_ref] Reemerging H5N1 influenza viruses in Hong Kong in 2002 are highly pathogenic..., Sturm-Ramirez [/bib_ref] [bib_ref] Re-emergence of fatal human influenza A subtype H5N1 disease, Peiris [/bib_ref] [bib_ref] Microbial adaptation and change: avian influenza, Webster [/bib_ref] [bib_ref] Characterization of an avian influenza A (H5N1) virus isolat, Subbarao [/bib_ref] Symptoms of avian influenza in humans have ranged from typical human influenzalike symptoms (eg, fever, cough, sore throat, muscle aches) to eye infections, pneumonia, and severe respiratory diseases (eg, acute respiratory distress) and other severe and lifethreatening complications. The symptoms of avian influenza may depend on which type of avian influenza virus caused the infection. When the virus is documented in humans in the United States, all patients who present to a health care setting with fever and respiratory symptoms should be managed according to CDC recommendations, including respiratory etiquette. Patients and visitors should be questioned regarding their recent travel history. Patients with a history of travel in the previous 10 days to a country with avian influenza activity and who are hospitalized with a severe febrile respiratory illness, [bib_ref] Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong..., Guan [/bib_ref] or are otherwise being evaluated for avian influenza, should be managed using isolation precautions identical to those recommended for patients with known SARS. These include the following: - Standard precautions-health care personnel should pay careful attention to hand hygiene before and after all patient contact or contact with items potentially contaminated with respiratory secretions. - Contact precautions-health care personnel should - wear gloves and a gown for all patient contact and - use dedicated equipment (eg, stethoscopes, disposable blood pressure cuffs, disposable thermometers) whenever possible. - Airborne precautions-health care personnel should use a fit-tested respirator, at least as protective as a NIOSH-approved N-95 filtering mask (ie, disposable) respirator, when entering the room. The patient should be placed in an airborne infection isolation room - with monitored negative air pressure in relation to the corridor, - with six to 12 air exchanges per hour, and - that exhausts air directly outside or recirculates air filtered by a high-efficiency particulate air (HEPA) filter. If an airborne infection isolation room is unavailable, the health care facility engineer should be contacted to assist or obtain portable HEPA filters to initiate the number of air exchanges per hour. NOROVIRUS. This virus, formerly known as "Norwalk-like" virus, 60-62 is transmitted via contaminated food and water and person-to-person via fecal-oral contamination. Infection with this disease can reach epidemic proportions quickly, especially in hospitals, nursing homes, cruise ships, hotels, and schools, [bib_ref] Public health consequences and outbreak management, Parashar [/bib_ref] [bib_ref] A norovirus outbreak at a long-term-care facility: the role of environmental surface..., Wu [/bib_ref] [bib_ref] Impact of an outbreak of norovirus infection on hospital resources, Zingg [/bib_ref] [bib_ref] A large-scale gastroenteritis outbreak associated with Norovirus in nursing homes, Calderon-Margalit [/bib_ref] [bib_ref] An outbreak of acute gastroenteritis in a geriatric long-term care facility: combined..., Marx [/bib_ref] possibly because the minimal infecting dose required for infection to occur is extremely low (ie, less than 100 viral particles). The incubation period is 12 to 48 hours, and symptoms last 12 to 60 hours. Patients report nausea, vomiting, abdominal cramps, and diarrhea. Although transmission is primarily fecal-oral, there have been reports of transmission via aerosolization of infectious particles from vomitus or fecal material. It has been suggested that health care workers may inhale and then swallow the virus. ## Managing health care environments The definition of isolation was the mainstay on which hospital isolation protocols were established. In recent years, however, the term isolation has evolved to characterize a process designed to manage the health care environment. Modern isolation techniques incorporate a broad-based theory that addresses the needs of both patients and employees to ensure that the safest possible environment is maintained throughout the health care facility. The term isolation has changed from meaning a special "set of precautions" performed by a few health care providers for a select few patients to a safety system that is practiced by virtually everyone in the course of routine patient care. These changes have evolved in stages during the past few years. Early isolation standards required that patients be placed under isolation protocols when an infectious process was diagnosed or strongly suspected. Patients were assigned isolation protocols based on a system that categorized them according to the type of disease and its primary method of transmission. ## Modern isolation techniques incorporate a broad-based theory that addresses the needs of both patients and The concept and re-emphasis of standard precautions is creating a need for health care professionals to change the way they think about infection and the way they interact with 6. An inpatient is scheduled for a liver biopsy and resection of a mass identified on computed tomography scan. The patient also has lesions in the right upper lobe of the lung. All sputum samples have been negative. Frozen section staining of the hepatic lesion indicates acidfast bacillus and probable Mycobacterium tuberculosis. What type of precautions are appropriate? a. airborne b. contact c. droplet 7. Some facilities have noted a decrease in Clostridium difficile transmission when a. antibiotics are administered for an extended period of time. b. airborne precautions are instituted immediately when the symptoms are first noted. c. a bleach-containing disinfectant is used for environmental cleaning. ## 8. Processing equipment that is suspected of having been exposed to Creutzfeldt-Jakob disease (CJD) includes soaking the item in sodium hydroxide solution and, after removing the item from the solution, [table] TABLE 1: Types of Standard PrecautionsDepending on the Routes of Disease Transmission 1 [/table] [table] TABLE 2: Summary of the Updated Centers for Disease Control and Prevention Isolation Guidelines1 Mask/goggles/face shield During procedures and patient-care activities likely to generate splashes or sprays of • blood, • body fluid, or • secretions (eg, suctioning, endotracheal intubation) 1. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings 2007. Centers for Disease Control and Prevention. http://www.cdc.gov /ncidod/dhqp/pdf/guidelines/Isolation2007.pdf. Accessed January 3, 2008. [/table]	None	https://europepmc.org/articles/pmc7111080?pdf=render	None
8da3f3346400170269de398ce959143c63b143c5	pubmed	AGA Clinical Practice Update on The Management of Refractory Helicobacter pylori Infection: Expert Review	AGA Clinical Practice Update on The Management of Refractory Helicobacter pylori Infection: Expert Review The purpose of this CPU Expert Review is to provide clinicians with guidance on the management of H. pylori after an initial attempt at eradication therapy fails, including best practice advice on specific regimen selection, and consideration of patient and systems factors that contribute to treatment efficacy. This Expert Review is not a formal systematic review, but is based upon a review of the literature to provide practical advice. No formal rating of the strength or quality of the evidence was carried out. Accordingly, a combination of available evidence and consensus-based expert opinion were used to develop these best practice advice statements. # Introduction Helicobacter pylori (H. pylori) infection is recognized as one of the most common chronic bacterial infections worldwide, infecting approximately half of the global population. [bib_ref] Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis, Hooi [/bib_ref] H. pylori is a World Health Organization (WHO)-designated carcinogen and the strongest known risk factor for noncardia gastric adenocarcinoma, the most prevalent form of gastric cancer. It is also causally linked to peptic ulcer disease. Even though only 1-3% of infected individuals will develop malignant complications, H. pylori accounts for 15% of the total cancer burden globally, with up to 89% of all gastric cancer attributable to H. pylori infection. Accordingly, all major gastroenterological societies recommend that H. pylori be eradicated in individuals who test positive. This manuscript version is made available under the CC-BY-NC-ND 4.0 license. Downstream consequences of failed treatment include clinical complications related to persistent H. pylori infection and repeated exposure to antibiotics and high-dose acid suppression, generation of antibiotic resistance in H. pylori and other organisms, as well as the associated direct and indirect costs to the healthcare system. Because the likelihood of successful eradication decreases with each subsequent therapeutic attempt, every effort should be made to address factors that might contribute to eradication failure. Several guidelines exist to help providers choose regimens to eradicate H. pylori on the first attempt; they also include advice on management after initial treatments fail. However, these guidelines are backed by limited high-quality evidence. In general, they rely heavily on trials conducted in populations that are relatively homogenous within geographic borders, albeit ethnically distinct (e.g. Asian-Pacific populations). In contrast, the United States (US) population comprises individuals with diverse ancestral backgrounds, with correspondingly diverse H. pylori strains. [bib_ref] An African origin for the intimate association between humans and Helicobacter pylori, Linz [/bib_ref] In the US, the lack of recent comparative clinical trials is coupled with limited knowledge of locoregional H. pylori antibiotic resistance patterns and of regimen-specific local cure rates, as well as limited contemporary data on temporal trends and relevant demographic details (e.g. age, race and ethnicity). Current national and international guidelines provide limited guidance on how to approach factors other than H. pylori antibiotic resistance which might also underlie eradication failure, such as host-and systems-related factors. Collectively, these issues contribute to persistent H. pylori infection [fig_ref] Figure 1: Factors impacting failure to eradicate H [/fig_ref]. The primary objectives of this Clinical Practice Update (CPU) Expert Review are to 1) provide a salient overview of determinants of H. pylori eradication treatment failure, including host-, microbe-, and systems-related factors as they are currently understood; and, 2) leverage these data to provide clinical practitioners with evidence-and consensus-based multimodal best practice advice for treating H. pylori after the first treatment failure. We include a clinically relevant synthesis of contemporary data on the appropriateness and efficacy, or lack thereof, of specific antimicrobial treatment regimens and adjunctive therapeutic agents for this purpose. The terms "salvage" and "rescue" therapy are commonly used in the literature to describe treatment courses following the initial eradication therapy, but without a consistent definition. As such, we avoid the use of these terms. Additionally, to the extent possible, we focus on evidence from North America in order to ensure that this article is most relevant for US practitioners. ## Definition of refractory infection For the purpose of this CPU Expert Review, refractory H. pylori infection is defined by a persistently positive non-serological H. pylori test (i.e., a breath-, stool-, or gastroscopybased test), at least 4 weeks following one or more completed course(s) of current guidelinerecommended first-line H. pylori eradication therapy, and off of any medications that might impact the test sensitivity (e.g. proton-pump inhibitors (PPI)). Refractory H. pylori infection should be differentiated from recurrent infection-that is, a non-serological test which was initially negative after eradication therapy, but then subsequently positive at a later interval-as the latter might be the result of ongoing intrafamilial exposure and may be best addressed by testing household members and treating those who test positive. The causes of H. pylori eradication treatment failure [fig_ref] Figure 1: Factors impacting failure to eradicate H [/fig_ref] Failure to eradicate H. pylori results from the complex interaction of host-, microbial-and systems-related factors. Antibiotic resistance (microbial and systems) and patient nonadherence (host and systems) are the two most commonly cited reasons for eradication failure. However, because primary eradication failure still occurs despite confirmed antibiotic sensitivity and patient adherence, potentially with higher frequency in refractory H. pylori specifically, additional factors are likely also relevant. Providers should attempt to identify all contributing etiologies before simply prescribing alternative antibiotics. (BPA#1) These factors, along with antibiotic resistance and nonadherence, are described herein. ## Antibiotic resistance: mechanisms and rates Resistance to several of the antibiotics commonly used in eradication regimens has risen globally over the last 20 years. Rising rates have been linked to prior use of that specific antibiotic, or others within the same class, by the individual, as well as with widespread antibiotic consumption at the population level. [bib_ref] Effect of Previous Nitroimidazole Treatment on Helicobacter pylori Eradication Success, Boltin [/bib_ref] [bib_ref] Impact of Previous Exposure to Macrolide Antibiotics on Helicobacter pylori Infection Treatment..., Boltin [/bib_ref] [bib_ref] Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic..., Megraud [/bib_ref] Predictably, eradication failure is more likely when an antibiotic to which H. pylori demonstrates in vitro resistance is included in the regimen. Combining studies of both treatment naïve and refractory H. pylori infection, in vitro resistance to clarithromycin and levofloxacin are associated with a 7.0-fold (95% CI, 5.2-9.3) and 8.2-fold (95% CI, 3.8-17.6) significantly higher likelihood of treatment failure, respectively, in regimens containing these drugs; whereas in vitro nitroimidazole resistance has relatively less clinical impact, increasing the odds of treatment failure by 2.5-fold (95% CI, 1.8-3.5). [bib_ref] Prevalence of antibiotic resistance in helicobacter pylori: a systematic review and meta-analysis..., Savoldi [/bib_ref] Importantly, selecting eradication therapies based on prior antibiotic exposure is not inferior to selecting therapy based on in vitro antibiotic susceptibility 9,10 , and bypasses the many logistical barriers to obtaining in vitro testing. Accordingly, providers should conduct a thorough review of the medical/pharmacy record and discuss previous medication exposures with the patient and also a pharmacist [bib_ref] A randomized controlled trial of an enhanced patient compliance program for Helicobacter..., Lee [/bib_ref] , if available. This should be done prior to the initial eradication attempt, but is especially critical for successfully treating refractory H. pylori infection.(BPA #2) A national US survey reported that only 38% of participating providers asked patients about prior antibiotic exposure 12 ; thus, there is considerable room for improvement. The dominant molecular mechanisms responsible for antibiotic resistance in H. pylori are well established for clarithromycin (usually due to one of three point mutations in the 23S ribosomal subunit), levofloxacin (mutations in DNA gyrase subunit A), amoxicillin (mutations in penicillin binding protein 1), tetracycline (mutations in genes encoding binding site for ribosomal 16S subunit, or increased efflux), and rifabutin (mutations in rpoB, the beta subunit of RNA polymerase gene). [bib_ref] Resistance mechanisms of Helicobacter pylori and its dual target precise therapy, Gong [/bib_ref] Nitroimidazole resistance is more complicated. It is usually related to mutations within rdxA, a gene encoding a nitroreductase that normally activates nitroimidazoles (e.g. metronidazole) from the prodrug state, though changes in drug uptake and efflux may also play a role. The complexity of rdxA mutations reported and possible synergy with other redox-associated H. pylori genes precludes phenotypic (culture-based) methods are not well standardized for metronidazole resistance testing and can vary by method used. This may contribute to the relatively low predictive value of in vitro metronidazole resistance testing to treatment outcome. Based on a comprehensive systematic review and meta-analysis, including data from over 50,000 patients from 45 countries, overall primary resistance rates by global region ranged from 10-34% for clarithromycin, 11-30% for levofloxacin and 23-56% for metronidazole. [bib_ref] Prevalence of antibiotic resistance in helicobacter pylori: a systematic review and meta-analysis..., Savoldi [/bib_ref] After unsuccessful H. pylori treatment (secondary resistance) rates increased to 15-67% for clarithromycin, 19-30% for levofloxacin and 30-65% for metronidazole. In contrast, resistance rates were low for amoxicillin and tetracycline, generally occurring in less than 5% of strains, usually in the 1-2% range. [bib_ref] Prevalence of antibiotic resistance in helicobacter pylori: a systematic review and meta-analysis..., Savoldi [/bib_ref] H. pylori also demonstrates low primary and secondary resistance to rifabutin, based on other reports. [bib_ref] Rifabutin-Based Triple Therapy (RHB-105) for Helicobacter pylori Eradication: A Double-Blind, Randomized, Controlled..., Graham [/bib_ref] [bib_ref] Review article: rifabutin in the treatment of refractory Helicobacter pylori infection, Gisbert [/bib_ref] Estimating H. pylori resistance rates is particularly challenging in the US because measuring resistance has been uncommon in clinical practice, ultimately equating to very limited contemporary data to guide treatment considerations. In a prospective multi-center US study of 347 strains collected from 1998 to 2002, overall H. pylori resistance rates (treatment naïve and previously treated combined) were 13% for clarithromycin and 25% for metronidazole. [bib_ref] Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States, Duck [/bib_ref] In 128 strains cultured from patients at the Houston Veterans Affairs Medical Center from 2009-2013, resistance rates in the 110 treatment-naïve patients were 15% for clarithromycin, 17% for metronidazole, and 29% for levofloxacin, with 15% of strains resistant to more than one antibiotic. [bib_ref] Antibiotic Resistance of Helicobacter pylori Among Male United States Veterans, Shiota [/bib_ref] Most recently, primary resistance rates of 345 strains collected during a multi-center clinical trial were 17% for clarithromycin and 44% for metronidazole. 14 It should be recognized, however, that because H. pylori infection is most often acquired in childhood, immigrants from countries where H. pylori is endemic might exhibit antimicrobial resistance patterns characteristic of their native, as opposed to host country; this again underscores the need for robust surveillance registries that include host demographics. ## Nonadherence The level of adherence to therapy above which there is negligible incremental benefit for eradication success in refractory H. pylori is not known; however, studies demonstrate that adherence to >60% to >90% of the prescribed course might be sufficient for successful eradication, at least in primary H. pylori infection. [bib_ref] A randomized controlled trial of an enhanced patient compliance program for Helicobacter..., Lee [/bib_ref] [bib_ref] Factors influencing the eradication of Helicobacter pylori with triple therapy, Graham [/bib_ref] The threshold likely varies depending on individual factors and might plausibly be higher for refractory H. pylori. Prior to prescribing therapy, barriers to adherence should be explored and addressed, and the regimen thoroughly discussed. Common barriers include complexity of eradication regimens, associated high pill burden, physical intolerance of medications, poor provider communication, and overall lack of understanding of why therapy is indicated. [bib_ref] A randomized controlled trial of an enhanced patient compliance program for Helicobacter..., Lee [/bib_ref] [bib_ref] Discontinuation rates of Helicobacter pylori treatment regimens: a meta-analysis, Buring [/bib_ref] Based on these considerations, providers who treat H. pylori infection should provide their patients with anticipatory guidance to help ensure maximum adherence. This specifically includes explaining the rationale for therapy, dosing instructions, expected adverse events and the importance of completing the full therapeutic course (BPA #3) Recently, two large RCTs from China demonstrated that the use of an interactive smartphone medical application 20 and text-based reminders 21 during treatment improved adherence to primary therapy. These adjunctive systems are worthy of further investigation in the US for refractory H. pylori infection, and would provide information on which approaches might be more effective in certain populations compared to others, for example, based on characteristics such as age, race and ethnicity, educational level, access, and language. Pillboxes, medication calendars, medication and counseling from pharmacists may also augment patient adherence. [bib_ref] A randomized controlled trial of an enhanced patient compliance program for Helicobacter..., Lee [/bib_ref] Systems-related factors that contribute to refractory H. pylori infection additionally include lack of robust eradication surveillance registries, lack of widely accessible antibiotic sensitivity testing, practice pattern variability among practitioners with respect to adherence to guideline-recommended therapies [bib_ref] Management of Helicobacter Pylori in the United States: Results from a national..., Murakami [/bib_ref] , as well as little progress in developing novel anti-H. pylori therapies. ## Host genetics Host genetics are also implicated in refractory H. pylori infection. Polymorphisms that affect intragastric pH, including those of CYP2C19, IL-1B and MDR1, are especially relevant to successful H. pylori eradication. H. pylori is most susceptible to antibiotics when intragastric pH is consistently between 6-8, since this is the optimal pH range for H. pylori replication. Some antibiotics, including clarithromycin and amoxicillin, also require intragastric acid suppression for maximum efficacy and sustained activity. For example, for gastric pH <2, the half-lives of amoxicillin and clarithromycin are approximately 15.2 (+/−0.3) hours and 1.0 (+/− 0.04) hours respectively, while for gastric pH>7, the half-lives of both antibiotics are >68 hours. [bib_ref] The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to..., Erah [/bib_ref] Hence, in the absence of adequate and sustained acid suppression, H. pylori can persist despite exposure to antibiotics to which it is otherwise susceptible in vitro. [bib_ref] Pharmacologic aspects of eradication therapy for Helicobacter pylori Infection, Furuta [/bib_ref] The largest body of literature for host genetics contributing to H. pylori eradication failure is focused on CYP2C19, the cytochrome P450 gene responsible for the majority of metabolism of the earlier-generation PPIs. CYP2C19 polymorphisms giving rise to poor metabolizer phenotypes result in high plasma PPI drug concentrations. [bib_ref] Update on the pharmacogenomics of proton pump inhibitors, Hagymási [/bib_ref] The metabolism-enhancing phenotypes of CYP2C19 are associated with higher rates of eradication failure when PPIs that are heavily metabolized by CYP2C19 (e.g. omeprazole, lansoprazole) are used. [bib_ref] CYP2C19 polymorphism influences Helicobacter pylori eradication, Kuo [/bib_ref] Because PPIs also have a direct antimicrobial effect and impact H. pylori bacterial load, CYP2C19-induced PPI metabolism also influences H. pylori persistence independently of intragastric pH. [bib_ref] CYP2C19 polymorphism influences Helicobacter pylori eradication, Kuo [/bib_ref] There are far less data on non-CYP2C19 genetic determinants of intragastric pH (e.g. MDR1, IL-1B) and other host genetic variants, which might contribute to refractory H. pylori infection through other mechanisms, such as H. pylori bacterial load regulation and dysregulation, evasion or alteration of mucosal immunity. Studies evaluating CYP2C19 genotype-guided PPI selection and dosing in refractory H. pylori infection have been conducted in Asian-Pacific populations, but analogous studies in US populations are lacking. This is an important deficit since there are substantive racial and ethnic differences in the prevalence of CYP2C19 variant alleles and genotypes in the US. [bib_ref] Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes, Martis [/bib_ref] [bib_ref] Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine, El Rouby [/bib_ref] Caucasians, non-Hispanic African Americans, and Hispanics have a significantly higher prevalence (57%−71%) of metabolism-enhancing CYP2C19 phenotypes compared to Asian American ethnic groups (45%), even in population studies of asymptomatic individuals. [bib_ref] Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied..., Ishizaki [/bib_ref] Asian Americans also have the highest prevalence of the poor metabolism genotype. [bib_ref] Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes, Martis [/bib_ref] Furthermore, Caucasians with extensive metabolizer phenotypes might have even higher clearance of omeprazole compared to some Asian ethnic groups with the same CYP2C19 genotype 28 , suggesting additional genetic or gene-environment interaction determinants might be relevant. Despite these considerations, current data are insufficient to support genetic polymorphism testing for guiding therapeutic selection in refractory (or primary) eradication therapy. Given the high population prevalence of metabolism-enhancing phenotypes of CYP2C19 at least in non-Asian groups, empiric selection of strategies that achieve greater intragastric acid suppression might be reasonable in the management of refractory H. pylori infection. These include higher dosing and/or increased frequency of first-generation PPIs; the use of later generation, more potent PPIs; and selecting potent non-PPI gastric acid suppressors, such as vonoprazan, if available. However, further population-specific data are needed, including comparisons of cost. ## Other host factors Non-genetic host-related and lifestyle factors, such as age and smoking, are also associated with eradication treatment failure. In one meta-analysis, patients who smoked vs. did not smoke were nearly twice as likely to have persistent H. pylori infection following therapy (OR 1.95, 95% CI, 1.55-2.45). [bib_ref] Smoking increases the treatment failure for Helicobacter pylori eradication, Suzuki [/bib_ref] Biological plausibility underlies this association, since smoking increases gastric acid secretion and impairs mucous secretion and gastric blood flow, thus decreasing local antibiotic delivery. Whether smoking cessation, at least while taking eradication therapy, improves eradication success in refractory H. pylori infection is not established. The data are less consistent for other host factors, such as comorbid obesity and diabetes, but are important areas for focused research. ## H. pylori strain diversity The high level of H. pylori strain-specific genetic diversity engenders microbial mechanisms that promote H. pylori persistence to variable extents. These mechanisms include manipulation and evasion of host immune responses, alteration of the gastric environment, increased bacterial load, enhanced virulence and consequent adverse gastric histopathology, as well as resistance to antimicrobials. [bib_ref] Immune Evasion Strategies and Persistence of Helicobacter pylori, Mejías-Luque [/bib_ref] [bib_ref] Effect of smoking on failure of H. pylori therapy and gastric histology..., Camargo [/bib_ref] Except for antimicrobial resistance, other H. pylori genetic constituents (e.g. cytotoxin-associated gene A, vacuolating cytotoxin A) have not been leveraged in the management of refractory H. pylori infection, but deserve attention. [bib_ref] Unsuccessful treatment results in survival of less virulent genotypes of Helicobacter pylori..., Correa [/bib_ref] [bib_ref] Systematic review and meta-analysis: importance of CagA status for successful eradication of..., Suzuki [/bib_ref] Proposed treatment algorithm An algorithm for regimen considerations in refractory H. pylori cases is illustrated in [fig_ref] Figure 2: Figure 2. [/fig_ref] , and is based on the initial therapy used and the presence or absence of true penicillin allergy. Of these regimens, only PBMT is FDA-approved for refractory H. pylori infection. If bismuth-based quadruple therapy failed as a first-line treatment, shared decision-making between providers and patients should guide selection between a) levofloxacin-or rifabutin-based triple therapy regimens with high-dose dual proton pump inhibitor (PPI) and amoxicillin, or b) an alternative bismuth-containing quadruple therapy, as second-line options. (BPA #4) Due to rising rates of levofloxacin resistance, levofloxacin should not be considered for treatment unless the H. pylori strain is known to be sensitive to it, or if the population levofloxacin resistance rates are known to be <15% (analogous to the longstanding "rule" regarding clarithromycin usage in triple therapies). However, it is reasonable to consider rifabutin in a triple regimen without prior sensitivity testing since rifabutin and amoxicillin resistance are rare. A recent study demonstrated that the addition of rifabutin to the high dose amoxicillin, PPI dual regimen improves eradication rates significantly. 14 Although the referenced study used this regimen as first-line therapy, based on these data it is reasonable to consider PAR usage with high-dose and/or high-potency PPI and amoxicillin 750mg TID over high-dose dual therapy alone. Optimal dosing of PPIs is provided in and is described in text below. We have not included in [fig_ref] Figure 2: Figure 2. [/fig_ref] several other potential regimens (such as concomitant, sequential or hybrid therapies) due to extremely limited data on their use for refractory H. pylori infection specifically. 4 ## Considerations in regimen selection for refractory h. pylori There is no shortage of guidelines from international authorities advising on H. pylori management. Some of the most prominent recent releases are listed in . [bib_ref] The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults, Fallone [/bib_ref] [bib_ref] Fifth Chinese National Consensus Report on the management of Helicobacter pylori infection, Liu [/bib_ref] [bib_ref] Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report, Malfertheiner [/bib_ref] Overall, the guidance for the management of refractory infection are relatively consistent among the expert groups. However, it should be emphasized that the body of evidence underlying their conclusions reflects the general low quality and heterogeneity of clinical studies conducted on refractory H. pylori infection. Furthermore, most of the trials included in metanalyses of second-line treatment have investigated treatment after failure of a firstline regimen with clarithromycin-based triple therapy, a regimen that we now appreciate should no longer be used in most regions of the world, including the US. [bib_ref] Systematic review, meta-analysis, and metaregression: Successful second-line treatment for Helicobacter pylori, Muñoz [/bib_ref] [bib_ref] Systematic review and network meta-analysis: Comparative effectiveness of therapies for second-line Helicobacter..., Yeo [/bib_ref] Lastly, even though incorporation of antibiotic susceptibility testing has been advocated by the Maastricht expert consensus group since the first iteration of their guidelines in 1997, the slow uptake of resistance testing around the world persists and continues to propagate empiric selection of eradication therapy for most refractory H. pylori infections, especially in the US. Nevertheless, several important themes have emerged for guiding treatment of refractory H. pylori infection. First, given the high resistance rates to clarithromycin and levofloxacin, these antibiotics or others in their class (macrolides, fluoroquinolones respectively) should not be repeated in subsequent treatment attempts. Based on the premise that secondary H. pylori resistance may have ensued as collateral damage, an antibiotic history of usage of any of these drug classes for other indications should be considered when selecting subsequent therapy. Because primary and secondary resistance to amoxicillin, tetracycline, and rifabutin are very low, these can be used in repeated regimens, even if they have been used previously for H. pylori eradication or other therapy.(BPA #2) Age, comorbidities, and concomitant medications should also guide therapeutic selection and factor into shared decision-making. Second, resistance to nitroimidazoles, either based on in vitro testing or suspected due to prior nitroimidazole exposure, should not be considered as an 'absolute' preclusion for reuse of this antibiotic class for refractory H. pylori therapy, since, for reasons described above, in vitro resistance does not reliably correlate with H. pylori eradication failure associated with using this drug. Nitroimidazole resistance might be potentially overcome with dose adjustments and addition of bismuth. [bib_ref] Effect of Previous Nitroimidazole Treatment on Helicobacter pylori Eradication Success, Boltin [/bib_ref] Higher doses of metronidazole, at least in the 1.5-2 g/day range, are also associated with significantly improved eradication rates. [bib_ref] Meta-analysis: High-dose vs. low-dose metronidazole-containing therapies for Helicobacter pylori eradication treatment, Ji [/bib_ref] These higher doses might be poorly tolerated due to gastrointestinal and other side effects; thus patients should be advised to consume metronidazole in divided doses (TID to QID) with food and to avoid alcohol for the therapeutic duration due to a disulfuram-like reaction. (BPA #5) Third, it is now increasingly appreciated that consistently achieving adequate threshold levels of amoxicillin and intragastric acid suppression are important for successful H. pylori eradication, both individually as well as concomitantly since intragastric pH affects the efficacy and half-life of amoxicillin. Drug dose, frequency, and, for acid suppression, drug potency are relevant, especially with respect to their efficacy as a dual regimen, as well as in other regimens for refractory H. pylori infection. [fig_ref] Figure 2: Figure 2. [/fig_ref] Amoxicillin was originally given twice daily in clarithromycin-based triple therapy; however, it is now recognized that dividing 2-3g amoxicillin into at least three doses daily avoids low trough levels and improves the efficacy of eradication therapy. [bib_ref] Effect of dosing schemes of amoxicillin on eradication rates of Helicobacter pylori..., Furuta [/bib_ref] (BPA #6) Given its value in treating refractory H. pylori infection, in the absence of anaphylaxis, penicillin allergy testing should be considered to delist penicillin allergy and potentially enable the use of amoxicillin.(BPA #6) Despite relatively prevalent chart documentation of penicillin allergy, true anaphylaxis to penicillin is rare. Inadequate acid suppression may undermine eradication efforts through a variety of mechanisms, as detailed above. To this end, optimal dosing of PPIs is frequently overlooked when prescribing eradication therapy, but similar fine-tuning of the acid suppressive prescription may improve eradication outcomes in refractory H. pylori infection.(BPA #7) Providers should also confirm that patients are taking the PPI in a manner that maximizes absorption and activation; factors such as timing of PPI administration in relation to food (and types of foods) and the impact on absorption, as well as the impact of concomitant medications such as histamine H 2 receptor blockers on PPI activation should be studied further. Higher dosing, greater frequency (e.g. TID or QID PPI dosing), and the use of more potent PPIs (e.g. esomeprazole or rabeprazole) may be beneficial in cases of refractory H. pylori infection and similarly warrant further investigation. Vonoprazan, a first-in-class potassium-competitive acid blocker, is a potent intragastric acid suppressor that also bypasses CYP2C19-dependent metabolism. Although ## Author manuscript Author Manuscript Author Manuscript ## Author manuscript After multiple failed eradication attempts, the potential benefits of H. pylori eradication should be weighed carefully against the likelihood of adverse effects and inconvenience of repeated high-dose acid suppression and antibiotic exposure, particularly among individuals who are not at identifiably higher risk of complications from persistent H. pylori infection (e.g. gastric cancer, peptic ulcer disease); in such scenarios, a shared decision-making approach should be seriously considered, especially in the elderly, those with frailty, and those with intolerance to antibiotics (BPA #9) ## Antibiotic susceptibility-based approach Unlike most infectious diseases where therapy is guided by knowledge of antibiotic sensitivity profiling of the target organism, or at least by knowledge of strains within the relevant geographical region, H. pylori treatment has remained largely empiric. For refractory cases, it may seem obvious that sensitivity testing should be considered after two failed attempts at treatment. [bib_ref] Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report, Malfertheiner [/bib_ref] (BPA #10) However, in practice the situation is complicated by the logistical challenges of obtaining resistance profiles for H. pylori, as well as the lack of convincing data demonstrating superiority of selecting treatment based on sensitivity testing compared to empirically selecting treatment based on prior antibiotic exposure, as further discussed below. Standard methodology to test for antibiotic sensitivity involves promptly transporting gastric biopsies in sterile containers at room temperature to the receiving microbiology laboratory where they undergo a relatively labor-intensive process to grow up the microbial colonies in micro-aerophilic conditions over several days. Once it is confirmed that the bacteria are indeed H. pylori, for example, based on morphology, urease, catalase and oxidase activity, the bacteria are then tested for viability in the presence of the relevant antibiotics. Because few hospitals or endoscopy centers in the US offer this service in-house, the biopsy specimens for sensitivity testing are instead usually sent in refrigerated packaging to a commercial laboratory. It should be emphasized, though, that in practice the success rates of obtaining a useful result are much lower than the 80-95% success usually reported in research studies. The reasons for the very low success rates outside of a clinical protocol are multifactorial and include delays and errors in sample processing and transport, compounded with the fact that H. pylori is a fastidious organism and the success rates of culturing H. pylori are further decreased by the recent use of PPIs or antibiotics. As an alternative, molecular resistance testing (using a variety of platforms) is simpler, more likely to yield results, and can also be performed on archival specimens including the formalinfixed paraffin-embedded gastric biopsy tissue remaining after routine diagnostic histopathological testing. This obviates the need for specialized tissue handling by the endoscopist. [bib_ref] Review of current diagnostic methods and advances in Helicobacter pylori diagnostics in..., Pohl [/bib_ref] Apart from the practicalities of obtaining H. pylori antibiotic sensitivity testing, especially in the US, a note of caution is still warranted when embarking on therapy directed by susceptibility testing (also referred to as "tailored therapy"); the published literature in this area, which derives almost entirely from studies conducted in the Western Pacific, provides little to no evidence that sensitivity-based treatment selection actually results in significantly improved rates of successful H. pylori eradication over empirically selected second-line regimens. [bib_ref] The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults, Fallone [/bib_ref] [bib_ref] Efficacies of Genotypic Resistance-Guided vs Empirical Therapy for Refractory Helicobacter pylori Infection, Liou [/bib_ref] [bib_ref] Systematic review and meta-analysis: susceptibilityguided versus empirical antibiotic treatment for Helicobacter pylori..., López-Góngora [/bib_ref] High quality clinical trials of tailored versus empiric therapy after two or more failed attempts at eradication are unfortunately lacking in the US and should be prioritized for future research. Cost-effectiveness analyses will also be valuable, especially if non-endoscopic modalities for susceptibility testing become a viable option, such as molecular testing of stool samples. In the absence of such data, the Maastricht strategy of susceptibility testing after two unsuccessful therapies should be considered in most cases [fig_ref] Figure 1: Factors impacting failure to eradicate H [/fig_ref]. ## Strategies to advance the field and potential adjunctive therapies The most effective strategy for managing refractory H. pylori is preventing refractory H. pylori infection by improving success rates of primary eradication therapy. Personalizing the initial H. pylori eradication therapy by incorporating individual host genetic, host non-genetic, and, microbial factors [fig_ref] Figure 1: Factors impacting failure to eradicate H [/fig_ref] might help achieve this by shifting the paradigm away from empiric therapy alone. Population-specific research with particular attention to race, ethnic, and age groups, can indicate determinants that impact eradication success in the US. Regional information of local success rates would further refine regimen selection. The Pan-European Registry on H. pylori management 44 is one prototype to emulate. Ideally, such a model would encompass systematic collection and reporting, together with periodic updates of regimen-specific local eradication ratesincluding regimens for primary and refractory infection-along with relevant nonidentifiable individual-level data such as demographics, smoking history, prior antibiotic exposure, and antibiotic sensitivity data if available. Aggregated data should be made publicly available to guide local selection of H. pylori eradication therapy. (BPA #11) This information could be utilized for both initial and refractory treatment choices. Non-invasive H. pylori antibiotic sensitivity testing on stool, to supplant the current sensitivity testing using endoscopically obtained samples, would overcome many ratelimiting barriers precluding widespread uptake of sensitivity testing. Molecular testing of stool for the small number of known mutations responsible for clarithromycin of levofloxacin resistance is relatively straightforward, as there are several commercial kits for these purposes that utilize PCR. However, next generation sequencing technology offers the potential to detect the resistance footprint of all antibiotics considered in H. pylori therapy. While the clinical utility of utilizing stool-based predictions to guide antibiotic therapy remains to be fully determined, collecting this information would galvanize a data pipeline to accelerate the establishment of surveillance registries, which are immediately needed. Hand-in-hand, implementation and adherence to standard quality metrics based on current clinical guidelines, including appropriate eradication confirmation testing in all individuals treated for H. pylori would simultaneously advance surveillance programs and ideally attenuate the high practice pattern variability observed in the management of refractory H. pylori infection. Despite rising rates of resistance, the global impact of antibiotic overuse, as well as the exorbitant cost associated with treatment failure (estimated to be at least $33 billion in the US alone [bib_ref] Helicobacter pylori: friend or foe?, Malnick [/bib_ref] , no truly novel anti-H. pylori therapies are visible on the horizon. Development of newer antimicrobial agents against H. pylori should be fostered, as should investigation into repurposing already available antimicrobials with alternative mechanisms of action against H. pylori. For example, the addition of clavulanic acid to amoxicillin-based regimens has been associated with a 10-20% increase in eradication success [bib_ref] Clavulanic Acid in the Scope of Helicobacter pylori Treatment: A Literature Review..., Alrabadi [/bib_ref] , although more rigorous studies are needed. There are also some promising data for non-antibiotic adjuncts, such as statins [bib_ref] Atorvastatin in combination with conventional antimicrobial treatment of Helicobacter pylori eradication: A..., Sarkeshikian [/bib_ref] [bib_ref] Simvastatin improves the eradication rate of Helicobacter pylori: upper Egypt experience, Hassan [/bib_ref] [bib_ref] Statin Decreases Helicobacter pylori Burden in Macrophages by Promoting Autophagy, Liao [/bib_ref] and probiotics [bib_ref] Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori..., Feng [/bib_ref] [bib_ref] Probiotics improve the efficacy of standard triple therapy in the eradication of..., Lau [/bib_ref] [bib_ref] The effect of probiotics supplementation on Helicobacter pylori eradication rates and side..., Dang [/bib_ref] [bib_ref] Systematic review and meta-analysis: Multistrain probiotics as adjunct therapy for Helicobacter pylori..., Mcfarland [/bib_ref] [bib_ref] Meta-analysis of the efficacy and safety of Lactobacilluscontaining and Bifidobacterium-containing probiotic compound..., Wang [/bib_ref]. Regarding the latter, there is an increasing body of data supporting a benefit of probiotics containing Lactobacillus and Bifidobacterium on H. pylori eradication success via an inhibitory effect as well as enhanced patient tolerance of H. pylori eradication therapy resulting in improved adherence. To date, at least twenty clinical trials and several metaanalyses have evaluated the effect of probiotics on H. pylori eradication (albeit not necessarily refractory H. pylori) [bib_ref] Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori..., Feng [/bib_ref] [bib_ref] Probiotics improve the efficacy of standard triple therapy in the eradication of..., Lau [/bib_ref] [bib_ref] The effect of probiotics supplementation on Helicobacter pylori eradication rates and side..., Dang [/bib_ref] [bib_ref] Systematic review and meta-analysis: Multistrain probiotics as adjunct therapy for Helicobacter pylori..., Mcfarland [/bib_ref] [bib_ref] Meta-analysis of the efficacy and safety of Lactobacilluscontaining and Bifidobacterium-containing probiotic compound..., Wang [/bib_ref] ; these are mostly positive, but there is significant trial heterogeneity and concerns over study quality. Collectively, there are limited data to guide optimal timing, formulation, dosage, duration, and appropriate patient selection for these adjunctive therapies, and their use should therefore be considered experimental. (BPA#12) Further rigorous investigation in US populations and specifically in refractory H. pylori infection would be valuable, particularly given the generally favorable side effect and cost profiles of these agents. # Conclusion H. pylori management has become increasingly challenging due to declining eradication success rates coupled with increasing antibiotic resistance, resulting in more H. pylori infections that are now refractory to first-line therapies. Accordingly, this CPU was developed to provide practitioners with practical advice on how to manage patients whose initial H. pylori treatment was unsuccessful. When considering the major public health implications associated with persistent H. pylori infection with respect to disease-and treatment-related complications and cost, there is a clear need to prioritize systematic approaches to improve rates of successful H. pylori eradication with the least number of therapeutic attempts. ## Rct ## 2. Providers should conduct a thorough review of prior antibiotic exposures. If there is a history of any treatment with macrolides or fluoroquinolones, then clarithromycin-or levofloxacin-based regimens, respectively, should be avoided given the high likelihood of resistance. By contrast, resistance to amoxicillin, tetracycline and rifabutin is rare and these can be considered for subsequent therapies in refractory H. pylori infection. ## 3. Eradication regimens for H. pylori are complex and might not be fully comprehended by patients. Barriers to adherence should be explored and addressed prior to prescribing therapy. Providers should explain the rationale for therapy, dosing instructions, expected adverse events and the importance of completing the full therapeutic course. ## 4. If bismuth quadruple therapy failed as a first-line treatment, shared decisionmaking between providers and patients should guide selection between a) levofloxacin-or rifabutin-based triple therapy regimens with high-dose dual proton pump inhibitor (PPI) and amoxicillin, or b) an alternative bismuthcontaining quadruple therapy, as second-line options. ## 5. When using metronidazole-containing regimens, providers should consider adequate dosing of metronidazole (1.5-2 g daily in divided doses) with concomitant bismuth therapy, as this may improve eradication success rates irrespective of observed in vitro metronidazole resistance. ## 6. 6. In the absence of a history of anaphylaxis, penicillin allergy testing should be considered in a patient labelled as having this allergy in order to delist penicillin as an allergy and potentially enable its use. Amoxicillin should be used at a daily dose of at least 2g divided TID or QID to avoid low trough levels. ## 7. Inadequate acid suppression is associated with H. pylori eradication failure. The use of high-dose and more potent PPIs, PPIs not metabolized by CYP2C19 or potassium-competitive acid blockers if available, should be considered in cases of refractory H. pylori infection. ## 8. Longer treatment durations provide higher eradication success rates compared to shorter durations (e.g. 14 days vs 7 days). Whenever appropriate, longer treatment durations should be selected for treating refractory H. pylori infection. ## 9. In some cases, there should be shared decision-making regarding ongoing attempts to eradicate H. pylori. The potential benefits of H. pylori eradication should be weighed carefully against the likelihood of adverse effects and inconvenience of repeated exposure to antibiotics and high-dose acid suppression, particularly in vulnerable populations, such as the elderly. ## 10. After two failed therapies with confirmed patient adherence, H. pylori susceptibility testing should be considered to guide the selection of subsequent regimens. ## 11. Compiling local data on H. pylori eradication success rates for each regimen, along with patient demographic and clinical factors (including prior non-H. pylori antibiotic exposure) is important. Aggregated data should be made publicly available to guide local selection of H. pylori eradication therapy. ## 12. Proposed adjunctive therapies, including probiotics, are of unproven benefit as treatment for refractory H. pylori infection and, thus, their use should be considered experimental. Treatment algorithm for refractory H. pylori infection. [bib_ref] Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis, Hooi [/bib_ref] Limited evidence guiding therapy in individuals with true penicillin allergy 2 With high-dose or high-potency PPI, amoxicillin 750 mg TID 3 High-dose metronidazole (1.5-2g divided) Only if clarithromycin sensitive strain [bib_ref] Effect of Previous Nitroimidazole Treatment on Helicobacter pylori Eradication Success, Boltin [/bib_ref] Second-line therapies for H. pylori eradication, based on selected international guidelines * ## Regimen failures Maastricht V/Florence Consensus Report [fig] Figure 1: Factors impacting failure to eradicate H. pylori infection. CagA cytotoxin-associated antigen A; IL, interleukin; VacA, vacuolating cytotoxin A. Author manuscript; available in PMC 2022 April 01. [/fig] [fig] Figure 2: Figure 2. [/fig]	None	http://www.gastrojournal.org/article/S001650852100319X/pdf	The purpose of this CPU Expert Review is to provide clinicians with guidance on the management of H. pylori after an initial attempt at eradication therapy fails, including best practice advice on specific regimen selection, and consideration of patient and systems factors that contribute to treatment efficacy. This Expert Review is not a formal systematic review, but is based upon a review of the literature to provide practical advice. No formal rating of the strength or quality of the evidence was carried out. Accordingly, a combination of available evidence and consensus-based expert opinion were used to develop these best practice advice statements.
61e2f9b75b832e0e4ea680b3d8ca86a78b2f1cd1	pubmed	2015 ESC Guidelines for the diagnosis and management of pericardial diseases	2015 ESC Guidelines for the diagnosis and management of pericardial diseases ## Table of contents ## Preamble Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk-benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/ Writing-ESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk -benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2. The experts of the writing and reviewing panels provided declarations of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http:// www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC Guidelines covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement all guidelines, condensed pocket guidelines versions, summary slides, booklets with essential messages, summary cards for non-specialists, and an electronic version for digital applications (smartphones, etc.) are produced. These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available on the ESC website. The National Societies of the ESC are encouraged to endorse, translate and implement the ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. # Introduction The pericardium (from the Greek p1ri´, 'around' and kárdion, 'heart') is a double-walled sac containing the heart and the roots of the great vessels. The pericardial sac has two layers, a serous visceral layer (also known as epicardium when it comes into contact with the myocardium) and a fibrous parietal layer. It encloses the pericardial cavity, which contains pericardial fluid. The pericardium fixes the heart to the mediastinum, gives protection against infection and provides lubrication for the heart. Pericardial diseases may be either isolated disease or part of a systemic disease. The main pericardial syndromes that are encountered in clinical practice include pericarditis (acute, subacute, ## Level of evidence b Data derived from a single randomized clinical trial or large non-randomized studies. ## Level of evidence c Consensus of opinion of the experts and/ or small studies, retrospective studies, registries. ## Class iia weight of evidence/opinion is in should be considered Class IIb established by evidence/opinion. ## May be considered Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Is not recommended chronic and recurrent), pericardial effusion, cardiac tamponade, constrictive pericarditis and pericardial masses. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] All medical therapies for pericardial diseases are off-label, since no drug has been registered until now for a specific pericardial indication. ## What is new in pericardial diseases? Pericardial diseases are relatively common in clinical practice and new data have been published since the publication of the 2004 ESC Guidelines on pericardial diseases. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] New diagnostic strategies have been proposed for the triage of patients with pericarditis and pericardial effusion and allow the selection of high-risk patients to be admitted as well as when and how additional diagnostic investigations are to be performed. Moreover, specific diagnostic criteria have been proposed for acute and recurrent pericarditis in clinical practice. Multimodality imaging for pericardial diseases has become an essential approach for a modern and comprehensive diagnostic evaluation. Both the American Society of Echocardiography and the European Association of Cardiovascular Imaging have provided recommendation documents in recent years. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] The aetiology and pathophysiology of pericardial diseases remain to be better characterized, but new data supporting the immunemediated pathogenesis of recurrences and new forms related to autoinflammatory diseases have been documented, especially in paediatric patients. [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] The first epidemiological data have become available. [bib_ref] Myopericarditis versus viral or idiopathic acute pericarditis, Imazio [/bib_ref] [bib_ref] Clinical profile and influences on outcomes in patients hospitalized for acute pericarditis, Kytö [/bib_ref] Age and gender issues are now more evident and clear, including specific recommendations for patients during pregnancy. Major advances have occurred in therapy with the first multicentre randomized clinical trials. Colchicine has been demonstrated as a first-line drug to be added to conventional antiinflammatory therapies in patients with a first episode of pericarditis or recurrences in order to improve the response to therapy, increase remission rates and reduce recurrences. Specific therapeutic dosing without a loading dose and weight-adjusted doses have been proposed to improve patient compliance. [bib_ref] Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis..., Imazio [/bib_ref] New therapeutic choices have become available for refractory recurrent pericarditis, including alternative immunosuppressive therapies (e.g. azathioprine), intravenous immunoglobulins (IVIGs) and interleukin-1 (IL-1) antagonists (e.g. anakinra). Pericardiectomy has been demonstrated as a possible valuable alternative to additional medical therapies in patients with refractory recurrent pericarditis. [bib_ref] Pericardiectomy vs medical management in patients with relapsing pericarditis, Khandaker [/bib_ref] The first large prospective and retrospective studies (.100 patients) have investigated the prognosis and complication risk in patients with acute and recurrent pericarditis. Imaging techniques for the detection of pericardial inflammation [e.g. cardiac magnetic resonance (CMR)] may identify forms of initial reversible constrictive pericarditis, allowing a trial of medical antiinflammatory therapy that may reduce the need for surgery. In conclusion, significant new data have become available since 2004, and a new version of guidelines has become mandatory for clinical practice. Nevertheless, in the field of pericardial diseases there are a limited number of randomized controlled trials (RCTs). Therefore the number of class I level A indications are limited. ## Epidemiology, aetiology and classification of pericardial diseases 2.1 epidemiology Despite the relative high frequency of pericardial diseases, there are few epidemiological data, especially from primary care. Pericarditis is the most common disease of the pericardium encountered in clinical practice. The incidence of acute pericarditis has been reported as 27.7 cases per 100,000 population per year in an Italian urban area. [bib_ref] Myopericarditis versus viral or idiopathic acute pericarditis, Imazio [/bib_ref] Pericarditis is responsible for 0.1% of all hospital admissions and 5% of emergency room admissions for chest pain. [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Clinical practice. Acute pericarditis, Lewinter [/bib_ref] Data collected from a Finnish national registry (2000-9) showed a standardized incidence rate of hospitalizations for acute pericarditis of 3.32 per 100,000 person-years. [bib_ref] Clinical profile and influences on outcomes in patients hospitalized for acute pericarditis, Kytö [/bib_ref] These data were limited to hospitalized patients and therefore may account for only a minority of cases, as many patients with pericarditis are commonly not admitted to hospital. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Clinical practice. Acute pericarditis, Lewinter [/bib_ref] [bib_ref] Treatment of acute and recurrent idiopathic pericarditis, Lilly [/bib_ref] Men ages 16 -65 years were at higher risk for pericarditis (relative risk 2.02) than women in the general admitted population, with the highest risk difference among young adults compared with the overall population. Acute pericarditis caused 0.20% of all cardiovascular admissions. The proportion of caused admissions declined by an estimated 51% per 10-year increase in age. The in-hospital mortality rate for acute pericarditis was 1.1% and was increased with age and severe co-infections (pneumonia or septicaemia). [bib_ref] Clinical profile and influences on outcomes in patients hospitalized for acute pericarditis, Kytö [/bib_ref] However, this is a study based on hospital admissions only. Recurrences affect about 30% of patients within 18 months after a first episode of acute pericarditis. 10,11 ## Aetiology A simple aetiological classification for pericardial diseases is to consider infectious and non-infectious causes [fig_ref] Table 3: Aetiology of pericardial diseases [/fig_ref]. [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Aetiological diagnosis in acute and recurrent pericarditis: when and how, Imazio [/bib_ref] [bib_ref] Forgotten cardiovascular diseases in Africa, Sliwa [/bib_ref] The aetiology is varied and depends on the epidemiological background, patient population and clinical setting. In developed countries, viruses are usually the most common aetiological agents of pericarditis, [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] whereas tuberculosis (TB) is the most frequent cause of pericardial diseases in the world and developing countries, where TB is endemic. In this setting, TB is often associated with human immunodeficiency virus (HIV) infection, especially in sub-Saharan Africa. [bib_ref] Forgotten cardiovascular diseases in Africa, Sliwa [/bib_ref] ## Pericardial syndromes Pericardial syndromes include different clinical presentations of pericardial diseases with distinctive signs and symptoms that can be grouped in specific 'syndromes'. The classical pericardial syndromes include pericarditis, pericardial effusion, cardiac tamponade and constrictive pericarditis. Pericardial effusion and cardiac tamponade may occur without pericarditis and will be considered in separate chapters. Specific considerations apply to cases with pericarditis and concomitant myocardial inflammatory involvement, usually referred to in the literature as 'myopericarditis'. ## Acute pericarditis Acute pericarditis is an inflammatory pericardial syndrome with or without pericardial effusion. The clinical diagnosis can be made with two of the following criteria [fig_ref] Table 4: Definitions and diagnostic criteria for pericarditis [/fig_ref] : 2,4 -15 (i) chest pain (.85 -90% of cases)-typically sharp and pleuritic, improved by sitting up and leaning forward; (ii) pericardial friction rub (≤33% of cases)-a superficial scratchy or squeaking sound best heard with the diaphragm of the stethoscope over the left sternal border; (iii) electrocardiogram (ECG) changes (up to 60% of cases)-with new widespread ST elevation or PR depression in the acute phase (Web; and (iv) pericardial effusion (up to 60% of cases, generally mild) (Web [fig_ref] Figure 2: Therapeutic algorithm for acute and recurrent pericarditis [/fig_ref]. Additional signs and symptoms may be present according to the underlying aetiology or systemic disease (i.e. signs and symptoms of systemic infection such as fever and leucocytosis, or systemic inflammatory disease or cancer). [bib_ref] Pericardial involvement in systemic inflammatory diseases, Imazio [/bib_ref] Widespread ST-segment elevation has been reported as a typical hallmark sign of acute pericarditis (Web. However, changes in the ECG imply inflammation of the epicardium, since the parietal pericardium itself is electrically inert. Typical ECG changes have been reported in up to 60% of cases. [bib_ref] Colchicine in addition to conventional therapy for acute pericarditis: results of the..., Imazio [/bib_ref] The temporal evolution of ECG changes with acute pericarditis is highly variable from one patient to another and is affected by therapy. Major differential diagnoses include acute coronary syndromes with ST-segment elevation and early repolarization. [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Aetiological diagnosis in acute and recurrent pericarditis: when and how, Imazio [/bib_ref] [bib_ref] Differential diagnosis of acute pericarditis from normal variant early repolarization and left..., Bhardwaj [/bib_ref] Elevation of markers of inflammation [i.e. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as elevation of the white blood cell count] is a common and supportive finding in patients with acute pericarditis and may be helpful for monitoring the activity of the disease and efficacy of therapy. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Prevalence of C-reactive protein elevation and time course of normalization in acute..., Imazio [/bib_ref] Patients with concomitant myocarditis may present with an elevation of markers of myocardial injury [i.e. creatine kinase (CK), troponin]. [bib_ref] Myopericarditis versus viral or idiopathic acute pericarditis, Imazio [/bib_ref] [bib_ref] Good prognosis for pericarditis with and without myocardial involvement: results from a..., Imazio [/bib_ref] Early onset (rare): - Direct injury (penetrating thoracic injury, aesophageal perforation). - Indirect injury (non-penetrating thoracic injury, radiation injury). Delayed onset: Pericardial injury syndromes (common) such as postmyocardial infarction syndrome, postpericardiotomy syndrome, posttraumatic, including forms after iatrogenic trauma (e.g. coronary percutaneous intervention, pacemaker lead insertion and radiofrequency ablation). Drug-related (rare): Lupus-like syndrome (procainamide, hydralazine, methyldopa, isoniazid, phenytoin); antineoplastic drugs (often associated with a cardiomyopathy, may cause a pericardiopathy): doxorubicin, daunorubicin, hypersensitivity pericarditis with eosinophilia; amiodarone, methysergide, mesalazine, clozapine, minoxidil, dantrolene, practolol, phenylbutazone, thiazides, streptomycin, thiouracils, streptokinase, p-aminosalicylic acid, sulfadrugs, cyclosporine, bromocriptine, several vaccines, GM-CSF, anti-TNF agents. Other (common): Amyloidosis, aortic dissection, pulmonary arterial hypertension and chronic heart failure. Other (uncommon): congenital partial and complete absence of the pericardium. ## Traumatic and iatrogenic: CMV ¼ cytomegalovirus; EBV ¼ Epstein-Barr virus; GM-CSF ¼ granulocyte-macrophage colonystimulating factor; HHV ¼ human herpesvirus; spp ¼ species; TNF ¼ tumor necrosis factor. ## Incessant Pericarditis lasting for >4-6 weeks but <3 months without remission. Recurrent episode of acute pericarditis and a symptom-free interval of 4-6 weeks or longer a . ## Chronic Pericarditis lasting for >3 months. [formula] CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; ECG ¼ electrocardiogram. a [/formula] Usually within 18 -24 months but a precise upper limit of time has not been established. A chest X-ray is generally normal in patients with acute pericarditis since an increased cardiothoracic ratio only occurs with pericardial effusions exceeding 300 ml. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] In the case of pleuropulmonary diseases, signs of pleuropericardial involvement may be found in patients with pericarditis. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] Recommendations for diagnosis of acute pericarditis ## Clinical management and therapy It is not mandatory to search for the aetiology in all patients, especially in countries with a low prevalence of TB, because of the relatively benign course associated with the common causes of pericarditis and the relatively low yield of diagnostic investigations. [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Aetiological diagnosis in acute and recurrent pericarditis: when and how, Imazio [/bib_ref] [bib_ref] Acute pericardial disease: approach to the aetiologic diagnosis, Permanyer-Miralda [/bib_ref] Specific final identifiable causes (non-viralnon-idiopathic) as well as high-risk features in the context of acute pericarditis have been identified as being associated with an increased risk of complications during follow-up (tamponade, recurrences and constriction). [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Aetiological diagnosis in acute and recurrent pericarditis: when and how, Imazio [/bib_ref] [bib_ref] Treatment of acute and recurrent idiopathic pericarditis, Lilly [/bib_ref] [bib_ref] Medical therapy of pericardial diseases: part I: idiopathic and infectious pericarditis, Imazio [/bib_ref] The major risk factors associated with poor prognosis after multivariate analysis include high fever [.388C (.100.48F)], subacute course (symptoms over several days without a clear-cut acute onset), evidence of large pericardial effusion (i.e. diastolic echo-free space .20 mm), cardiac tamponade and failure to respond within 7 days to non-steroidal antiinflammatory drugs (NSAIDs). [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Treatment of acute and recurrent idiopathic pericarditis, Lilly [/bib_ref] [bib_ref] Medical therapy of pericardial diseases: part I: idiopathic and infectious pericarditis, Imazio [/bib_ref] Other risk factors should also be considered (i.e. 'minor risk factors'); these are based on expert opinion and literature review, including pericarditis associated with myocarditis (myopericarditis), immunodepression, trauma and oral anticoagulant therapy. On this basis a triage for acute pericarditis is proposed, Web [fig_ref] Table 6: Commonly prescribed anti-inflammatory therapies for recurrent pericarditis [/fig_ref]. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Treatment of acute and recurrent idiopathic pericarditis, Lilly [/bib_ref] Any clinical presentation that may suggest an underlying aetiology (e.g. a systemic inflammatory disease) or with at least one predictor of poor prognosis (major or minor risk factors) warrants hospital admission and an aetiology search. On the other hand, patients without these features can be managed as outpatients with empiric antiinflammatories and short-term follow-up after 1 week to assess the response to treatment. [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] Recommendations for the management of acute pericarditis [formula] Recommendations Class a Level b Ref. c [/formula] Hospital admission is recommended for high-risk patients with acute pericarditis (at least one risk factor d ) [formula] I B 8,9 [/formula] Outpatient management is recommended for low-risk patients with acute pericarditis [formula] I B 8,9 [/formula] Evaluation of response to anti-inflammatory therapy is recommended after 1 week In patients identified with a cause other than viral infection, specific therapy appropriate to the underlying disorder is indicated 49,51 and the epidemiological background (high vs. low prevalence of TB) should be considered. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Aetiological diagnosis in acute and recurrent pericarditis: when and how, Imazio [/bib_ref] [bib_ref] Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in..., Mayosi [/bib_ref] The first nonpharmacological recommendation is to restrict physical activity beyond ordinary sedentary life until resolution of symptoms and normalization of CRP for patients not involved in competitive sports. [bib_ref] Pericarditis: diagnosis, management, and return to play, Seidenberg [/bib_ref] Athletes are recommended to return to competitive sports only after symptoms have resolved and diagnostic tests (i.e. CRP, ECG and echocardiogram) have been normalized. [bib_ref] Pericarditis: diagnosis, management, and return to play, Seidenberg [/bib_ref] [bib_ref] Recommendations for participation in competitive sport and leisure-time physical activity in individuals..., Pelliccia [/bib_ref] A minimal restriction of 3 months (after the initial onset of the attack) has been arbitrarily defined according to expert consensus. [bib_ref] Recommendations for participation in competitive sport and leisure-time physical activity in individuals..., Pelliccia [/bib_ref] We suggest applying this restriction only to athletes, while a shorter period (until remission) may be suitable for non-athletes. Aspirin or NSAIDs are mainstays of therapy for acute pericarditis. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] International collaborative systematic review of controlled clinical trials on pharmacologic treatments for..., Lotrionte [/bib_ref] [bib_ref] Individualized therapy for pericarditis, Imazio [/bib_ref] Different anti-inflammatory drugs have been proposed [fig_ref] Table 5: Commonly prescribed anti-inflammatory therapy for acute pericarditis [/fig_ref]. The choice of drug should be based on the history of the patient (contraindications, previous efficacy or side effects), the presence of concomitant diseases (favouring aspirin over other NSAIDs when aspirin is already needed as antiplatelet treatment) and physician expertise. [bib_ref] Individualized therapy for pericarditis, Imazio [/bib_ref] Colchicine is recommended at low, weight-adjusted doses to improve the response to medical therapy and prevent recurrences. Tapering of colchicine is not mandatory but may be considered to prevent persistence of symptoms and recurrence. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Individualized therapy for pericarditis, Imazio [/bib_ref] Corticosteroids should be considered as a second option in patients with contraindications and failure of aspirin or NSAIDs because of the risk of favouring the chronic evolution of the disease and promoting drug dependence; in this case they are used with colchicine. If used, low to moderate doses (i.e. prednisone 0.2 -0.5 mg/kg/day or equivalent) should be recommended instead of high doses (i.e. prednisone 1.0 mg/kg/day or equivalent). [bib_ref] Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation, Imazio [/bib_ref] The initial dose should be maintained until resolution of symptoms and normalization of CRP, then tapering should be considered. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] ## Prognosis Most patients with acute pericarditis (generally those with presumed viral or idiopathic pericarditis) have a good long-term prognosis. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] Cardiac tamponade rarely occurs in patients with acute idiopathic pericarditis, and is more common in patients with a specific underlying aetiology such as malignancy, TB or purulent pericarditis. Constrictive pericarditis may occur in ,1% of patients with acute idiopathic pericarditis, and is also more common in patients with a specific aetiology. The risk of developing constriction can be classified as low (,1%) for idiopathic and presumed viral pericarditis; intermediate (2 -5%) for autoimmune, immunemediated and neoplastic aetiologies; and high (20-30%) for bacterial aetiologies, especially with TB and purulent pericarditis. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] Approximately 15-30% of patients with idiopathic acute pericarditis who are not treated with colchicine will develop either recurrent or incessant disease, while colchicine may halve the recurrence rate. 10,11,13 -15 ## Incessant and chronic pericarditis The term 'incessant' has been adopted for cases with persistent symptoms without a clear-cut remission after the acute episode. The term 'chronic' generally refers-especially for pericardial effusions-to disease processes lasting .3 months. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] The Task Force suggests that the term 'acute' should be adopted for new-onset pericarditis, 'incessant' for pericarditis with symptoms persisting for .4 -6 weeks (that is generally the approximate length of conventional anti-inflammatory therapy and its tapering), [bib_ref] Relapsing pericarditis, Soler-Soler [/bib_ref] and 'chronic' for pericarditis lasting .3 months. ## Recurrent pericarditis Recurrent pericarditis is diagnosed with a documented first episode of acute pericarditis, a symptom-free interval of 4 -6 weeks or longer and evidence of subsequent recurrence of pericarditis [fig_ref] Table 4: Definitions and diagnostic criteria for pericarditis [/fig_ref]. 11,13 -15 Diagnosis of recurrence is established according to the same criteria as those used for acute pericarditis. CRP, 2,47 computed tomography (CT) and/or CMR may provide confirmatory findings to support the diagnosis in atypical or doubtful cases showing pericardial inflammation through evidence of oedema and contrast enhancement of the pericardium. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Usefulness of cardiac magnetic resonance-guided management in patients with recurrent pericarditis, Alraies [/bib_ref] The recurrence rate after an initial episode of pericarditis ranges from 15 to 30%, [bib_ref] Colchicine in addition to conventional therapy for acute pericarditis: results of the..., Imazio [/bib_ref] and may increase to 50% after a first recurrence in patients not treated with colchicine, particularly if treated with corticosteroids. In developed countries, the aetiology is often not identified in most immunocompetent patients, and it is generally presumed to be immune-mediated. A common cause of recurrence is inadequate treatment of the first episode of pericarditis. In up to 20% of cases, when additional virological studies have been conducted on pericardial fluid and tissue, a viral aetiology is detected. [bib_ref] Viral genomes in the pericardial fluid and in peri-and epicardial biopsies from..., Pankuweit [/bib_ref] ## Therapy Recurrent pericarditis therapy should be targeted at the underlying aetiology in patients with an identified cause. Aspirin or NSAIDs remain the mainstay of therapy [fig_ref] Table 6: Commonly prescribed anti-inflammatory therapies for recurrent pericarditis [/fig_ref] , Web Box, Web [fig_ref] Table 1: Classes of recommendations [/fig_ref]. Colchicine is recommended on top of standard anti-inflammatory therapy, without a loading dose and using weight-adjusted doses (i.e. 0.5 mg once daily if body weight is ,70 kg or 0.5 mg twice daily if it is ≥70 kg, for ≥6 months) [fig_ref] Table 6: Commonly prescribed anti-inflammatory therapies for recurrent pericarditis [/fig_ref] , Web Table 1B) in order to improve the response to medical therapy, improve remission rates and prevent recurrences. In cases of incomplete response to aspirin/NSAIDs and colchicine, corticosteroids may be used, but they should be added at low to moderate doses to aspirin/NSAIDs and colchicine as triple therapy, not replace these drugs, in order to achieve better control of symptoms. Corticosteroids at low to moderate doses (i.e. prednisone 0.2 -0.5 mg/kg/day) should be avoided if infections, particularly bacterial and TB, cannot be excluded and should be restricted to patients with specific indications (i.e. systemic inflammatory diseases, post-pericardiotomy syndromes, pregnancy) or NSAID contraindications (true allergy, recent peptic ulcer or gastrointestinal bleeding, oral anticoagulant therapy when the bleeding risk is considered high or unacceptable) or intolerance or persistent disease despite appropriate doses. [bib_ref] Colchicine for the prevention of pericarditis: what we know and what we..., Imazio [/bib_ref] Although corticosteroids provide rapid control of symptoms, they favour chronicity, more recurrences and side effects. [bib_ref] Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation, Imazio [/bib_ref] [bib_ref] International collaborative systematic review of controlled clinical trials on pharmacologic treatments for..., Lotrionte [/bib_ref] [bib_ref] Longterm outcomes in difficult-to-treat patients with recurrent pericarditis, Brucato [/bib_ref] If corticosteroids are used, their tapering should be particularly slow. A critical threshold for recurrences is a 10 -15 mg/day dose of prednisone or equivalent. At this threshold, very slow decrements as small as 1.0 -2.5 mg at intervals of 2-6 weeks are useful. In cases of recurrence, every effort should be made not to increase the dose or to reinstate corticosteroids (Tables 6 and 7). [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation, Imazio [/bib_ref] [bib_ref] Longterm outcomes in difficult-to-treat patients with recurrent pericarditis, Brucato [/bib_ref] After obtaining a complete response, tapering should be done with a single class of drug at a time before colchicine is gradually discontinued (over several months in the most difficult cases). Recurrences are possible after discontinuation of each drug. Each tapering should be attempted only if symptoms are absent and CRP is normal. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Prevalence of C-reactive protein elevation and time course of normalization in acute..., Imazio [/bib_ref] [bib_ref] Individualized therapy for pericarditis, Imazio [/bib_ref] The Task Force does not recommend influenza vaccine as a preventive measure for pericarditis in patients with recurrent pericarditis, since the influenza virus is not a usual cause of pericarditis. The influenza vaccine should be administered according to specific indications beyond pericarditis; moreover, recurrences are generally immune mediated, and inappropriate or unwanted stimulation of the immune system may trigger or worsen an episode of pericarditis. An alternative effective approach to minimize systemic side effects related to corticosteroids may be intrapericardial administration of non-absorbable corticosteroids, [bib_ref] Intrapericardial treatment of autoreactive pericardial effusion with triamcinolone: the way to avoid..., Maisch [/bib_ref] [bib_ref] Intrapericardial triamcinolone administration for autoreactive pericarditis, Frasiolas [/bib_ref] but this technique requires further investigation. For those patients who require unacceptably high long-term doses of corticosteroids (e.g. prednisone 15 -25 mg/day) or who do not respond to anti-inflammatory therapies, several drugs have been used, including azathioprine, 28 IVIG (immunomodulatory but also anti-viral) [bib_ref] Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis, Moretti [/bib_ref] [bib_ref] Intravenous human immunoglobulin for refractory recurrent pericarditis. A systematic review of all..., Imazio [/bib_ref] and anakinra, a recombinant IL-1b receptor antagonist, 31,32 but strong evidence-based data are lacking (Web [fig_ref] Table 2: Levels of evidenceData derived from multiple randomized clinical trials or meta-analyses [/fig_ref]. Other immunosuppressive drugs [i.e. cyclophosphamide, cyclosporine, methotrexate, hydroxychloroquine, anti-tumour necrosis factor (TNF) agents] have been only anecdotally reported. Less toxic agents might be preferred, and eventually combined, with the therapy being tailored to the individual patient and physician experience [fig_ref] Figure 2: Therapeutic algorithm for acute and recurrent pericarditis [/fig_ref]. Azathioprine is mainly a slow-acting corticosteroid-sparing agent, useful to control the disease for a long-term follow-up, while anakinra and IVIG are effective during the acute phase, though recurrences may occur after discontinuation. Drugs such as IVIG, anakinra and azathioprine may be considered in cases of proven infectionnegative, corticosteroid-dependent, recurrent pericarditis not responsive to colchicine after careful assessment of the costs, risks and eventually consultation by multidisciplinary experts, including immunologists and/or rheumatologists, in the absence of a specific expertise. It is also mandatory to educate the patient and his/her caregivers about the clinical risks related to immunomodulatory/immunosuppressive drugs and the safety measures to adopt during the treatment. As a last resort, pericardiectomy may be considered, but only after a thorough trial of unsuccessful medical therapy, and with referral of the patient to a centre with specific expertise in this surgery. [bib_ref] Pericardiectomy vs medical management in patients with relapsing pericarditis, Khandaker [/bib_ref] The physical activity restrictions in acute pericarditis apply also to recurrences. [bib_ref] Pericarditis: diagnosis, management, and return to play, Seidenberg [/bib_ref] [bib_ref] Recommendations for participation in competitive sport and leisure-time physical activity in individuals..., Pelliccia [/bib_ref] If ischaemic heart disease is a concern or antiplatelet therapy is required, aspirin should be considered, at medium high doses (1-2.4 g/day)* (Web box) ## Prognosis Severe complications are uncommon in idiopathic recurrent pericarditis. [bib_ref] Prognosis of idiopathic recurrent pericarditis as determined from previously published reports, Imazio [/bib_ref] [bib_ref] Relapsing pericarditis, Soler-Soler [/bib_ref] [bib_ref] Longterm outcomes in difficult-to-treat patients with recurrent pericarditis, Brucato [/bib_ref] Cardiac tamponade is rare and generally occurs at the beginning of the disease. Constrictive pericarditis has never been reported in these patients, despite numerous recurrences, and the overall risk is lower than that recorded after a first episode of acute pericarditis (,1%). [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] [bib_ref] Prognosis of idiopathic recurrent pericarditis as determined from previously published reports, Imazio [/bib_ref] [bib_ref] Longterm outcomes in difficult-to-treat patients with recurrent pericarditis, Brucato [/bib_ref] Thus it is important to reassure patients about their prognosis, explaining the nature of the disease and its likely course. The complication rates are related to the aetiology and not to the number of recurrences. Drug treatment should take into account this favourable outcome to avoid more toxic agents. However, quality of life can be severely affected in patients with repeated recurrences, subacute or incessant pericarditis and glucocorticoid dependence. ## Pericarditis associated with myocardial involvement (myopericarditis) Pericarditis and myocarditis share common aetiologies, and overlapping forms may be encountered in clinical practice. [bib_ref] Good prognosis for pericarditis with and without myocardial involvement: results from a..., Imazio [/bib_ref] [bib_ref] Management of myopericarditis, Imazio [/bib_ref] Pericarditis with known or clinically suspected concomitant myocardial involvement should be referred to as 'myopericarditis', while predominant myocarditis with pericardial involvement should be referred to as 'perimyocarditis', according to Task Force consensus. The classical presentation is chest pain associated with other signs of pericarditis (pericardial rubs, ST-segment elevation and pericardial effusion) plus the elevation of markers of myocardial damage (i.e. troponins). Limited clinical data on the causes of myopericarditis suggest that viral infections are among the most common causes in developed countries, while other infectious causes are more common in developing countries (especially TB). Cardiotropic viruses can cause pericardial and myocardial inflammation via direct cytolytic or cytotoxic effects and/or subsequent immune-mediated mechanisms. Such mechanisms are especially involved in cases associated with connective tissue diseases, inflammatory bowel diseases and radiation-induced, drug-induced or vaccinia-associated myopericardial involvement. Many cases of myopericarditis are subclinical. In other patients, cardiac symptoms and signs are masked by pronounced systemic manifestations of infection or inflammation. [bib_ref] Management of myopericarditis, Imazio [/bib_ref] In many cases, myopericarditis manifestations are preceded by or are sometimes concomitant with an acute respiratory illness (especially acute tonsillitis, pneumonia) or gastroenteritis. The increased sensitivity of troponin assays and contemporary widespread use of troponins has greatly increased the reported number of cases. 7,34,66 -68 ## Definition and diagnosis The diagnosis of predominant pericarditis with myocardial involvement, or 'myopericarditis', can be clinically established if patients with definite criteria for acute pericarditis show elevated biomarkers of myocardial injury (troponin I or T, CK-MB fraction) without newly developed focal or diffuse impairment of left ventricular function in echocardiography or CMR. [bib_ref] Good prognosis for pericarditis with and without myocardial involvement: results from a..., Imazio [/bib_ref] The term myopericarditis indicates a primarily pericarditic syndrome with minor myocardial involvement, which describes the majority of combined pericarditis and myocarditis cases encountered in clinical practice. [bib_ref] Myopericarditis versus viral or idiopathic acute pericarditis, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Good prognosis for pericarditis with and without myocardial involvement: results from a..., Imazio [/bib_ref] [bib_ref] Clinical presentation and long-term follow-up of perimyocarditis, Buiatti [/bib_ref] On the other hand, evidence of new-onset focal or diffuse reduction of left ventricular function in patients with elevated myocardial biomarkers and clinical criteria for acute pericarditis suggests predominant myocarditis with pericardial involvement ('perimyocarditis'). [bib_ref] Good prognosis for pericarditis with and without myocardial involvement: results from a..., Imazio [/bib_ref] [bib_ref] Management of myopericarditis, Imazio [/bib_ref] Definite confirmation of the presence of myocarditis will require endomyocardial biopsy according to the Myocardial and Pericardial Diseases Working Group position statement. [bib_ref] European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current..., Caforio [/bib_ref] However, the benign prognosis of patients with suspected concomitant myocardial involvement in predominant pericarditis (myopericarditis), with absent or mild left ventricular dysfunction, and no symptoms of heart failure does not clinically require endomyocardial biopsy. In cases of pericarditis with suspected associated myocarditis, coronary angiography (according to clinical presentation and risk factor assessment) is recommended in order to rule out acute coronary syndromes. CMR is recommended for the confirmation of myocardial involvement and to rule out ischaemic myocardial necrosis in the absence of significant coronary disease; this has clinical and therapeutic implications. 34,66 ## Management Hospitalization is recommended for diagnosis and monitoring of patients with myocardial involvement and differential diagnosis, especially with acute coronary syndromes. In the setting of myopericarditis, management is similar to that recommended for pericarditis. Empirical anti-inflammatory therapies (i.e. aspirin 1500 -3000 mg/day) or NSAIDs (ibuprofen 1200 -2400 mg/day or indomethacin 75 -150 mg/day) are usually prescribed to control chest pain, while corticosteroids are prescribed as a second choice in cases of contraindication, intolerance or failure of aspirin/NSAIDs. [bib_ref] Management of myopericarditis, Imazio [/bib_ref] In the setting of myopericarditis, some authors recommend reducing dosages, as compared with pure pericarditis, because in animal models of myocarditis, NSAIDs have been shown to be non-efficacious and may enhance inflammation, increasing mortality. [bib_ref] European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current..., Caforio [/bib_ref] [bib_ref] Pericarditis with troponin elevation: is it true pericarditis and a reason for..., Imazio [/bib_ref] [bib_ref] Enhancement of coxsackievirus B4 virulence by indomethacin, Khatib [/bib_ref] [bib_ref] Myopericarditis: etiology, management, and prognosis, Imazio [/bib_ref] However, the application of these findings from animal models to humans may be questionable. [bib_ref] Management of myopericarditis, Imazio [/bib_ref] In addition, there are insufficient data to recommend the use of colchicine, which is a well-established adjunctive treatment for acute and recurrent pericarditis. [bib_ref] Colchicine for the prevention of pericarditis: what we know and what we..., Imazio [/bib_ref] Despite the lack of specific therapies for most cases, several non-specific recommendations are important. Rest and avoidance of physical activity beyond normal sedentary activities is recommended in all patients with myopericarditis. [bib_ref] Pericarditis: diagnosis, management, and return to play, Seidenberg [/bib_ref] [bib_ref] Recommendations for participation in competitive sport and leisure-time physical activity in individuals..., Pelliccia [/bib_ref] [bib_ref] Management of myopericarditis, Imazio [/bib_ref] Sudden cardiac death cases have been reported in military personnel after strenuous exertion and also in male athletes without prodromic symptoms [football (soccer) players, swimming]. [bib_ref] Pericarditis: diagnosis, management, and return to play, Seidenberg [/bib_ref] [bib_ref] Recommendations for participation in competitive sport and leisure-time physical activity in individuals..., Pelliccia [/bib_ref] [bib_ref] Management of myopericarditis, Imazio [/bib_ref] While in isolated pericarditis, return to exercise is permissible when there is no further evidence of active disease in non-athletes, or after 3 months in athletes, the presence or suspicion of myocardial involvement leads to contraindication of physical exercise for at least 6 months from the onset of the illness according to expert opinion and previous recommendations for participation in competitive sports. 53,54,66 ## Prognosis Myocardial involvement in pericarditis has a good prognosis, and several observational series have demonstrated no evolution to heart failure or mortality in patients with myopericarditis. Recommendations for the diagnosis and management of pericarditis associated with myocarditis ## Pericardial effusion The normal pericardial sac contains 10 -50 ml of pericardial fluid as a plasma ultrafiltrate that acts as a lubricant between the pericardial layers. Any pathological process usually causes an inflammation with the possibility of increased production of pericardial fluid (exudate). An alternative mechanism of accumulation of pericardial fluid may be decreased reabsorption due to a general increase in systemic venous pressure as a result of congestive heart failure or pulmonary hypertension (transudate). [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] Pericardial effusion may be classified according to its onset (acute or subacute vs. chronic when lasting .3 months), distribution (circumferential or loculated), haemodynamic impact (none, cardiac tamponade, effusive-constrictive), composition (exudate, transudate, blood, rarely air, or gas from bacterial infections) and, in particular, by its size [fig_ref] Table 8: Classification of pericardial effusion [/fig_ref] based on a simple semiquantitative echocardiographic assessment as mild (,10 mm), moderate (10 -20 mm) or large (.20 mm) (Web [fig_ref] Figure 2: Therapeutic algorithm for acute and recurrent pericarditis [/fig_ref]. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] This semiquantitative assessment has also proven to be useful in estimating the risk of specific aetiology and complications during follow-up in the setting of pericarditis. [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusion and..., Imazio [/bib_ref] In the last 20 years, five major surveys have been published on the characteristics of moderate to large pericardial effusions (Web [fig_ref] Table 3: Aetiology of pericardial diseases [/fig_ref]. A significant proportion of patients with pericardial effusion are asymptomatic and pericardial effusion constitutes an incidental and unexpected finding on X-ray or echocardiogram performed for other reasons. According to these series, many cases remain idiopathic in developed countries (up to 50%), while other common causes include cancer (10 -25%), infections (15 -30%), iatrogenic causes (15 -20%) and connective tissue diseases (5-15%), whereas TB is the dominant cause in developing countries (.60%), where TB is endemic. [bib_ref] Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in..., Mayosi [/bib_ref] [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] In the setting of pericarditis with pericardial effusion, the prevalence of malignant or infectious aetiologies ranges from 15 to 50% depending on the published series. 6,9 ## Clinical presentation and diagnosis The clinical presentation of pericardial effusion varies according to the speed of pericardial fluid accumulation. If pericardial fluid is rapidly accumulating, such as after wounds or iatrogenic perforations, the evolution is dramatic and even small amounts of blood may cause an increase in intrapericardial pressure within minutes and overt cardiac tamponade. On the other hand, a slow accumulation of pericardial fluid allows the collection of a large effusion in days to weeks before a significant increase in pericardial pressure causes symptoms and signs (Web . [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Pericardial effusion: haemodynamic spectrum, Shabetai [/bib_ref] [bib_ref] Acute cardiac tamponade, Spodick [/bib_ref] Classic symptoms include dyspnoea on exertion progressing to orthopnoea, chest pain and/or fullness. Additional occasional symptoms due to local compression may include nausea (diaphragm), dysphagia (oesophagus), hoarseness (recurrent laryngeal nerve) and hiccups (phrenic nerve). Non-specific symptoms include cough, weakness, fatigue, anorexia and palpitations, and reflect the compressive effect of the pericardial fluid on contiguous anatomic structures or reduced blood pressure and secondary sinus tachycardia. Fever is a non-specific sign that may be associated with pericarditis, either infectious or immune mediated (i.e. systemic inflammatory diseases). [bib_ref] Pericardial involvement in systemic inflammatory diseases, Imazio [/bib_ref] Physical examination may be absolutely normal in patients without haemodynamic compromise. When tamponade develops, classic signs include neck vein distension with elevated jugular venous pressure at bedside examination, pulsus paradoxus and diminished heart sounds on cardiac auscultation in cases of moderate to large effusions. Pericardial friction rubs are rarely heard; they can usually be detected in patients with concomitant pericarditis. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] The diagnosis of pericardial effusion is generally performed by echocardiography, which also enables semiquantitative assessment of the pericardial effusion size and its haemodynamic effects. Although echocardiography remains the primary diagnostic tool for the study of pericardial diseases because of its widespread availability, portability and limited costs, CT and CMR provide a larger field of view, allowing the detection of loculated pericardial effusion and pericardial thickening and masses, as well as associated chest abnormalities. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristić [/bib_ref] Recommendations for the diagnosis of pericardial effusion ## Triage and management When a pericardial effusion is detected, the first step is to assess its size, haemodynamic importance (especially the presence of cardiac tamponade) and possible associated diseases (either cardiovascular or systemic diseases). Pericardial effusion is often associated with known or unknown (e.g. hypothyroidism) medical conditions (up to 60% of cases). [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Clinical clues to the causes of large pericardial effusions, Sagrista-Sauleda [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] If inflammatory signs are present, the clinical management should be that of pericarditis. Cardiac tamponade without inflammatory signs is associated with a higher risk of a neoplastic aetiology (likelihood ratio 2.9), whereas a severe effusion without cardiac tamponade and inflammatory signs is usually associated with a chronic idiopathic aetiology (likelihood ratio 20). [bib_ref] Clinical clues to the causes of large pericardial effusions, Sagrista-Sauleda [/bib_ref] A practical routine evaluation for triage of pericardial effusion is presented in . [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] Recommendations for the initial management of pericardial effusion [formula] Recommendations Class a Level b Ref. c [/formula] Admission is recommended for high-risk patients with pericardial effusion d ## I c A triage of patients with pericardial effusion is recommended as in I C. In chronic effusion with no definite aetiology, there are no data on non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids. If markers of inflammation are elevated, a trial of NSAIDs and/or colchicine and/or low-dose corticosteroids may be tried. ## Therapy Therapy of pericardial effusion should be targeted at the aetiology as much as possible. In about 60% of cases, the effusion is associated with a known disease and the essential treatment is that of the underlying disease. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Clinical clues to the causes of large pericardial effusions, Sagrista-Sauleda [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] When pericardial effusion is associated with pericarditis, management should follow that of pericarditis. When a pericardial effusion becomes symptomatic without evidence of inflammation or when empiric anti-inflammatory drugs are not successful, drainage of the effusion should be considered. Pericardiocentesis with prolonged pericardial drainage of up to 30 ml/24 h may be considered in order to promote adherence of pericardial layers and prevent further accumulation of fluid; however, evidence to support this indication is based on case reports, retrospective studies and expert opinion. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristić [/bib_ref] Unfortunately, there are no proven effective medical therapies to reduce an isolated effusion. In the absence of inflammation, NSAIDs, colchicine and corticosteroids are generally not effective. [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Colchicine for pericarditis: hype or hope?, Imazio [/bib_ref] Pericardiocentesis alone may be necessary for the resolution of large effusions, but recurrences are also common, and pericardiectomy or less invasive options (i.e. pericardial window) should be considered whenever fluid reaccumulates, becomes loculated or biopsy material is required. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] Recommendations for the therapy of pericardial effusion ## Prognosis and follow-up The prognosis of pericardial effusion is essentially related to the aetiology. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with..., Frö Hlich [/bib_ref] The size of the effusion is correlated with the prognosis, as moderate to large effusions are more common for specific aetiologies such as bacterial and neoplastic conditions. 9,48 Idiopathic pericardial effusion and pericarditis have an overall good prognosis with a very low risk of complications, especially if the effusion is mild to moderate. In contrast with these observations, a recently published prospective study has shown that even with mild pericardial effusion the overall prognosis may be worse than in age-and sexmatched controls. [bib_ref] A small pericardial effusion is a marker of increased mortality, Mitiku [/bib_ref] Large idiopathic chronic effusions (.3 months) have a 30 -35% risk of progression to cardiac tamponade. [bib_ref] Long-term followup of idiopathic chronic pericardial effusion, Sagrista-Sauleda [/bib_ref] Also, subacute (4-6 weeks) large effusions not responsive to conventional therapy and with echocardiographic signs of collapse of the right chambers may have an increased risk of progression according to some authors, who recommend preventive drainage in such cases. [bib_ref] Pericardial disease, Little [/bib_ref] Documented idiopathic pericarditis has a very low risk of constrictive pericarditis despite several recurrences: here the risk is related to the aetiology and not the number of recurrences. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] The followup of pericardial effusion is mainly based on the evaluation of symptoms and the echocardiographic size of the effusion, as well as additional features such as inflammatory markers (i.e. CRP). [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] Cardiac tamponade or suspected bacterial or neoplastic aetiology? A simplified algorithm for pericardial effusion triage and management. ## Esc guidelines A mild idiopathic effusion (,10 mm) is usually asymptomatic, generally has a good prognosis and does not require specific monitoring. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] Moderate to large effusions (.10 mm) may worsen, and especially severe effusions may evolve towards cardiac tamponade in up to one-third of cases. For idiopathic moderate effusions, an appropriate timing for echocardiographic follow-up may be an echocardiogram every 6 months. For a severe effusion, an echocardiographic follow-up may be every 3 -6 months. A tailored followup is also warranted considering the relative stability or evolution of the size. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] Specific considerations on pericardial effusion in the postoperative setting are discussed in the section on post-cardiac injury syndromes (section 5.5). ## Cardiac tamponade Cardiac tamponade is a life-threatening, slow or rapid compression of the heart due to the pericardial accumulation of fluid, pus, blood, clots or gas as a result of inflammation, trauma, rupture of the heart or aortic dissection. [bib_ref] Acute cardiac tamponade, Spodick [/bib_ref] [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristić [/bib_ref] Clinical signs in a patient with cardiac tamponade include tachycardia, hypotension, pulsus paradoxus, raised jugular venous pressure, muffled heart sounds, decreased electrocardiographic voltage with electrical alternans and an enlarged cardiac silhouette on chest X-ray with slow-accumulating effusions. A key diagnostic finding is pulsus paradoxus (conventionally defined as an inspiratory decrease in systolic arterial pressure of .10 mmHg during normal breathing). Pulsus paradoxus is due to exaggerated ventricular interdependence occurring in cardiac tamponade, when the overall volume of cardiac chambers becomes fixed and any change in the volume of one side of the heart causes the opposite changes in the other side (i.e. inspiratory increase of venous return and right chambers with decreased volume of left chambers and reduced systemic blood pressure). The magnitude of clinical and haemodynamic abnormalities depends on the rate of accumulation and amount of pericardial contents, the distensibility of the pericardium and the filling pressures and compliance of the cardiac chambers (Web . Various causes for cardiac tamponade are listed in [fig_ref] Table 9: Causes of cardiac tamponade [/fig_ref]. The stiffness of the pericardium determines fluid increments precipitating tamponade, as illustrated by characteristic pericardial pressure-volume (strain-stress) curves: there is an initial slow ascent, followed by an almost vertical rise (Web . This steep rise makes tamponade a 'last-drop' phenomenon: the final increment produces critical cardiac compression and the first decrement during drainage produces the largest relative decompression. In a patient with clinical suspicion of cardiac tamponade, several diagnostic tools are required. An ECG may show signs of pericarditis, with especially low QRS voltages and electrical alternans. Both ECG signs are generally considered to be an expression of the damping effect of pericardial fluid and swinging heart. Echocardiography is the single most useful diagnostic tool to identify pericardial effusion and estimate its size, location and degree of haemodynamic impact. Also, echocardiography is used to guide pericardiocentesis with excellent safety and efficacy. Signs of tamponade can be identified by echocardiography: swinging of the heart, early diastolic collapse of the right ventricle, late diastolic collapse of the right atrium, abnormal ventricular septal motion, exaggerated respiratory variability (.25%) in mitral inflow velocity, inspiratory decrease and expiratory increase in pulmonary vein diastolic forward flow, respiratory variation in ventricular chamber size, aortic outflow velocity (echocardiographic pulsus paradoxus) and inferior vena cava plethora. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Triage and management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristić [/bib_ref] CT and CMR are often less readily available and are generally unnecessary unless Doppler echocardiography is not feasible. Cardiac catheterization is rarely used to diagnose cardiac tamponade. It will show equilibration of average diastolic pressure and characteristic respiratory reciprocation of cardiac pressures, i.e. an inspiratory increase on the right and a concomitant decrease on the left-the proximate cause of pulsus paradoxus. Except in low-pressure tamponade, diastolic pressures throughout the heart are usually in the range of 15-30 mmHg. The treatment of cardiac tamponade involves drainage of the pericardial fluid, preferably by needle pericardiocentesis, with the use of echocardiographic or fluoroscopic guidance, and should be performed without delay in unstable patients. Alternatively, drainage is performed by a surgical approach, especially in some situations such as purulent pericarditis or in urgent situations with bleeding into the pericardium. A triage system (Web has been proposed by the ESC Working Group on Myocardial and Pericardial Diseases in order to guide the timing of the intervention and the possibility of transferring the patient to a referral centre. [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristić [/bib_ref] This triage system is essentially based on expert consensus and requires additional validation in order to be recommended in clinical practice. ## Constrictive pericarditis Constrictive pericarditis can occur after virtually any pericardial disease process, but only rarely follows recurrent pericarditis. [bib_ref] Prognosis of idiopathic recurrent pericarditis as determined from previously published reports, Imazio [/bib_ref] The risk of progression is especially related to the aetiology: low (,1%) in viral and idiopathic pericarditis, intermediate (2 -5%) in immune-mediated pericarditis and neoplastic pericardial diseases and high (20 -30%) in bacterial pericarditis, especially purulent pericarditis. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] A few large historical series of patients with constrictive pericarditis have been described from tertiary referral centres (Stanford, Mayo Clinic, Cleveland Clinic and Groote Schuur Hospital) reporting cases after pericardiectomy (Web [fig_ref] Table 4: Definitions and diagnostic criteria for pericarditis [/fig_ref]. The most common reported causes in developed countries were idiopathic or viral (42-49%), post-cardiac surgery (11-37%), postradiation therapy (9-31%) (mostly for Hodgkin's disease or breast cancer), connective tissue disorder (3-7%), post-infectious causes (TB or purulent pericarditis in 3 -6%) and miscellaneous causes (malignancy, trauma, drug-induced, asbestosis, sarcoidosis, uraemic pericarditis in ,10%). TB is now only a rare cause of constrictive pericarditis in developed countries, while it is a major cause in developing countries. [bib_ref] Constrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Mutyaba [/bib_ref] However, this disorder may be increasing among immigrants from underdeveloped nations and patients with HIV infection. ## Clinical presentation Constrictive pericarditis is characterized by impaired diastolic filling of the ventricles due to pericardial disease. The classic clinical picture is characterized by signs and symptoms of right heart failure with preserved right and left ventricular function in the absence of previous or concomitant myocardial disease or advanced forms. Patients complain about fatigue, peripheral oedema, breathlessness and abdominal swelling. The delay between the initial pericardial inflammation and the onset of constriction is variable and is possibly a direct evolution from subacute/chronic pericarditis to constrictive pericarditis. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] Venous congestion, hepatomegaly, pleural effusions and ascites may occur. Haemodynamic impairment of the patient can be additionally aggravated by a systolic dysfunction due to myocardial fibrosis or atrophy in more advanced cases. Although classic and advanced cases show prominent pericardial thickening and calcifications in chronic forms, constriction may also be present with normal pericardial thickness in up to 20% of the cases. [bib_ref] Constrictive pericarditis in 26 patients with histologically normal pericardial thickness, Talreja [/bib_ref] Pericardiectomy is equally successful in those with and without increased pericardial thickness. ## Diagnosis A diagnosis of constrictive pericarditis is based on the association of signs and symptoms of right heart failure and impaired diastolic filling due to pericardial constriction by one or more imaging methods, including echocardiography, [bib_ref] Echocardiographic diagnosis of constrictive pericarditis: Mayo Clinic criteria, Welch [/bib_ref] CT, CMR, and cardiac catheterization. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Constrictive pericarditis in the modern era: novel criteria for diagnosis in the..., Talreja [/bib_ref] The main differential diagnosis is with restrictive cardiomyopathy [fig_ref] Table 1: Classes of recommendations [/fig_ref]. Recommendations for the diagnosis of constrictive pericarditis ## Therapy Although the mainstay of treatment of chronic permanent cases is surgery, medical therapy may have a role in at least three conditions. First, medical therapy of specific aetiologies (i.e. tuberculous pericarditis) may be useful to prevent the progression to constriction. Antituberculosis antibiotics may significantly reduce the risk of constriction from .80% to ,10%. [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] [bib_ref] Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis, Mayosi [/bib_ref] Second, medical therapy (generally based on anti-inflammatory drugs) may solve the transient constriction occurring in 10 -20% of cases within a few months, generally as a temporary phenomenon during the resolution of pericarditis. [bib_ref] Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusion and..., Imazio [/bib_ref] [bib_ref] Transient cardiac constriction: an unrecognized pattern of evolution in effusive acute idiopathic..., Sagrista-Sauleda [/bib_ref] [bib_ref] Transient constrictive pericarditis: causes and natural history, Haley [/bib_ref] The detection of elevated CRP and imaging evidence of pericardial inflammation by contrast enhancement on CT and/or CMR may be helpful to identify patients with potentially reversible forms of constriction where empiric anti-inflammatory therapy should be considered and may prevent the need for pericardiectomy. [bib_ref] Constrictive pericarditis-a curable diastolic heart failure, Syed [/bib_ref] Third, medical therapy is supportive and aimed at controlling symptoms of congestion in advanced cases and when surgery is contraindicated or at high risk. In these cases, medical therapy should never delay surgery, if this option is feasible, because advanced cases have a higher mortality and a worse prognosis if surgery is delayed. [bib_ref] Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusion and..., Imazio [/bib_ref] ## Specific forms The classic description of chronic permanent constrictive pericarditis has been challenged by specific forms of constrictive syndromes (i.e. transient constriction, effusive-constrictive forms). Definitions, main differential diagnoses and treatment of the main constrictive pericardial syndromes are summarized in [fig_ref] Table 1: Classes of recommendations [/fig_ref]. 51 3.7.4.1 Transient constrictive pericarditis A temporary form of constriction usually develops with pericarditis and mild effusion and resolves with anti-inflammatory therapy within several weeks. [bib_ref] Transient cardiac constriction: an unrecognized pattern of evolution in effusive acute idiopathic..., Sagrista-Sauleda [/bib_ref] [bib_ref] Transient constrictive pericarditis: causes and natural history, Haley [/bib_ref] The typical clinical course implies the presence of acute inflammatory pericarditis with constriction due to inflammation, which resolves once the inflammatory process is treated. [bib_ref] Transient cardiac constriction: an unrecognized pattern of evolution in effusive acute idiopathic..., Sagrista-Sauleda [/bib_ref] [bib_ref] Transient constrictive pericarditis: causes and natural history, Haley [/bib_ref] Thus, in the absence of evidence that the condition is chronic (e.g. cachexia, atrial fibrillation, hepatic dysfunction or pericardial calcification), patients with newly diagnosed constrictive pericarditis who are haemodynamically stable may be given a trial of conservative management for 2 -3 months before recommending pericardiectomy. Since the inflamed pericardium is enhanced on CT and/or CMR, Failure of the right atrial pressure to fall by 50% or to a level below 10 mmHg after pericardiocentesis. May be diagnosed also by non-invasive imaging. Pericardiocentesis followed by medical therapy. Surgery for persistent cases. Chronic constriction (d.d. transient constriction, restrictive CMP). Persistent constriction after 3-6 months. Pericardiectomy, medical therapy for advanced cases or high risk of surgery or mixed forms with myocardial involvement. [formula] CMP ¼ cardiomyopathy; d.d. ¼ differential diagnosis. [/formula] ## Effusive-constrictive pericarditis The pericardial cavity is typically obliterated in patients with constrictive pericarditis. Thus even the normal amount of pericardial fluid is absent. However, pericardial effusion may be present in some cases. In this setting, the scarred pericardium not only constricts the cardiac volume, but can also put pericardial fluid under increased pressure, leading to signs suggestive of cardiac tamponade. This combination is called effusive-constrictive pericarditis. [bib_ref] Effusive-constrictive pericarditis, Sagrista-Sauleda [/bib_ref] Effusive-constrictive pericarditis appears to be relatively uncommon in developing countries, with only limited published data. [bib_ref] Effusive-constrictive pericarditis, Sagrista-Sauleda [/bib_ref] Most cases of effusive-constrictive pericarditis in developed countries are idiopathic, reflecting the frequency of idiopathic pericardial disease in general. However, TB is the most common cause in developing countries.Other reported causes include radiation, neoplasia, chemotherapy, infection (especially TB and purulent forms) and post-surgical pericardial disease.Patients with effusive-constrictive pericarditis usually have clinical features of pericardial effusion or constrictive pericarditis, or both. The diagnosis of effusive-constrictive pericarditis often becomes apparent during pericardiocentesis in patients initially considered to have uncomplicated cardiac tamponade. [bib_ref] Effusive-constrictive pericarditis, Sagrista-Sauleda [/bib_ref] For these reasons, it is recommended that intrapericardial pressures, right heart pressures and systemic arterial blood pressure are monitored during elective pericardiocentesis whenever possible. A persistently elevated right atrial pressure after efficient pericardiocentesis may also be due to right heart failure or tricuspid regurgitation. However, non-invasive imaging may be equally useful for the diagnosis of effusive-constrictive pericarditis.The epicardial layer of pericardium, which is responsible for the constrictive component of this process, is not typically thickened to a degree that is detectable on imaging studies. Nevertheless, careful detection of Doppler findings of constriction can be reported following pericardiocentesis for cardiac tamponade, and effusive-constrictive pericarditis can also be suspected in these cases without haemodynamic monitoring. Useful data may also be provided by CMR. The utility of CMR in constrictive pericardial disease is well established, providing the opportunity not only to evaluate pericardial thickness, cardiac morphology and function, but also for imaging intrathoracic cavity structures, allowing the differentiation of constrictive pericarditis from restrictive cardiomyopathy. Assessment of ventricular coupling with real-time cine magnetic resonance during free breathing allows an accurate evaluation of ventricular interdependence and septal bounce. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] Since it is the visceral layer of pericardium and not the parietal layer that constricts the heart, visceral pericardiectomy must be performed. However, the visceral component of the pericardiectomy is often difficult, requiring sharp dissection of many small fragments until an improvement in ventricular motion is observed. Thus pericardiectomy for effusive-constrictive pericarditis should be performed only at centres with experience in pericardiectomy for constrictive pericarditis. [bib_ref] Effusive-constrictive pericarditis, Sagrista-Sauleda [/bib_ref] ## Chronic constrictive pericarditis Pericardiectomy is the accepted standard of treatment in patients with chronic constrictive pericarditis who have persistent and prominent symptoms such as NYHA class III or IV. However, surgery should be considered cautiously in patients with either mild or very advanced disease and in those with radiation-induced constriction, myocardial dysfunction or significant renal dysfunction. Surgical removal of the pericardium has a significant operative mortality ranging from 6 to 12%. Pericardiectomy must be as complete as is technically feasible and should be performed by experienced surgeons. Referral to a centre with a special interest in pericardial disease may be warranted in centres with limited experience in this surgery. Patients with 'end-stage' constrictive pericarditis derive little or no benefit from pericardiectomy, and the operative risk is inordinately high. Manifestations of end-stage disease include cachexia, atrial fibrillation, a low cardiac output (cardiac index ,1.2 l/m 2 /min) at rest, hypoalbuminaemia due to protein-losing enteropathy and/or impaired hepatic function due to chronic congestion or cardiogenic cirrhosis. Prior ionizing radiation is associated with a poor long-term outcome, because it induces cardiomyopathy as well as pericardial disease. Predictors of poor overall survival are prior radiation, worse renal function, higher pulmonary artery systolic pressure, abnormal left ventricular systolic function, lower serum sodium level and older age. Pericardial calcification had no impact on survival. Survival after radical pericardiectomy in patients with Child -Pugh (CP) B or C (CP score ≥7) was reported to be significantly worse than in patients with CP-A. In multivariable analysis, a CP score ≥7, mediastinal irradiation, age and end-stage renal disease (ESRD) identified an increased risk of death after radical pericardiectomy. [bib_ref] Child-Pugh score predicts survival after radical pericardiectomy for constrictive pericarditis, Komoda [/bib_ref] On this basis, it seems appropriate to apply the CP scoring system for the prediction of mortality after radical pericardiectomy in patients with constrictive pericarditis. ## Recommendations for therapy of constrictive pericarditis ## Chest x-ray Although chest X-ray can detect pericardial calcifications, presenting as a curvilinear density at the extreme margin of the silhouette, particularly on the lateral view, [bib_ref] Cardiac and pericardial calcifications on chest radiographs, Ferguson [/bib_ref] other techniques (i.e. echocardiography, CT) yield much greater accuracy in assessing the heart and lungs, providing information with regard to cardiac size and the presence of pulmonary pathology (e.g., pulmonary congestion, pneumonia, TB, lung cancer), pleural effusion and hilar and mediastinal enlargement. ## Echocardiography Transthoracic echocardiography is the first-line imaging test in patients with suspected pericardial disease, because it accurately detects pericardial effusion and cardiac tamponade, as well as ventricular dysfunction due to myocardial involvement. 2,3 Although patients with purely fibrinous acute pericarditis may have a normal echocardiogram, the presence of a pericardial effusion is consistent with acute pericarditis and is one of the criteria for its diagnosis. [bib_ref] American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients..., Klein [/bib_ref] [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Colchicine in addition to conventional therapy for acute pericarditis: results of the..., Imazio [/bib_ref] Echocardiography may help to differentiate acute pericarditis from myocardial ischaemia by excluding wall motion abnormalities consistent with coronary flow distribution in the setting of patients with acute chest pain. However, 5% of patients with acute pericarditis and myocardial involvement may demonstrate wall motion abnormalities. Clinically, two-dimensional echocardiography with Doppler provides the most cost-effective way of diagnosing pericardial effusion and assessing its haemodynamic significance. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] The size of pericardial effusion on two-dimensional echocardiography is qualitatively assessed by the end-diastolic distance of the echo-free space between the epicardium and parietal pericardium: small (,10 mm), moderate (10-20 mm), large (.20 mm) (Web [fig_ref] Figure 2: Therapeutic algorithm for acute and recurrent pericarditis [/fig_ref]. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] In order to allow follow-up studies, it is recommended that the images be documented digitally and the effusion size described in a detailed way in the echocardiographic report, including not only the extent, but also the location of each measurement. However, the haemodynamic tolerance is more related to the rapidity of appearance of the effusion than to its total volume. [bib_ref] Management of pericardial effusion, Imazio [/bib_ref] [bib_ref] Pericardial effusion: haemodynamic spectrum, Shabetai [/bib_ref] Loculated pericardial effusions or pericardial effusions that contain clots (e.g. after cardiac surgery) may be difficult to diagnose using a transthoracic approach and may require transoesophageal echocardiography. [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] Specific findings in pericardial syndromes are discussed in the pertinent paragraphs. ## Computed tomography CT should be regarded as a valuable complementary imaging modality to echocardiography. [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Multimodality imaging of pericardial disease, Yared [/bib_ref] [bib_ref] The role of multimodality imaging in the management of pericardial disease, Verhaert [/bib_ref] [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] CT is the most accurate technique to image calcified tissue. 2,3 Current multidetector CT scanners combine acquisition speed, high contrast and spatial resolution with volumetric scanning to provide excellent anatomical detail of the heart and pericardium. The anatomical region of interest covered by CT can be limited to the heart and pericardium ('cardiac CT'), although in patients with neoplastic, inflammatory or aortic disease it may encompass the chest entirely and possibly also include the abdomen and pelvis. [bib_ref] The role of multimodality imaging in the management of pericardial disease, Verhaert [/bib_ref] [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] Low-radiation cardiac CT is feasible using prospective electrocardiographic triggering. [bib_ref] The role of multimodality imaging in the management of pericardial disease, Verhaert [/bib_ref] [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] Although the functional consequences of pericardial disease on the heart can be evaluated by CT-at the expense of significantly higher radiation doses-echocardiography and CMR are more appropriate for assessing this feature. Intravenous administration of iodinated contrast material is recommended to increase the density of blood and to depict pericardial inflammation. The normal pericardium is visible as a thin curvilinear structure surrounded by the hypodense mediastinal and epicardial fat, and has a thickness ranging from 0.7 to 2.0 mm. The pericardial sinuses and their respective recesses are visible, in particular when they contain small amounts of pericardial fluid. The main CT findings in pericardial effusion and pericarditis are summarized in [fig_ref] Table 2: Levels of evidenceData derived from multiple randomized clinical trials or meta-analyses [/fig_ref]. [bib_ref] Multimodality imaging of pericardial disease, Yared [/bib_ref] [bib_ref] The role of multimodality imaging in the management of pericardial disease, Verhaert [/bib_ref] [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] In patients with neoplastic disease, pericardial involvement may occur by direct tumour invasion or metastatic spread. CT is important in treatment planning and patient follow-up. The diagnosis of (congenital) pericardial cysts-presenting as well-defined, fluiddense structures along the left or right heart border-as well as the differential diagnosis with other cystic structures, such as bronchogenic or duplication cysts, is usually straightforward. Finally, CT can be helpful to establish the diagnosis in congenital absence of the pericardium by showing displacement of cardiac structures through the pericardial defect. CT is also essential in the preoperative workup of some patients with constrictive pericarditis, especially to depict the extension of calcifications and for those with a history of prior cardiothoracic surgery. [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] ## Cardiac magnetic resonance Over the years, CMR has shifted from a morphologic imaging modality towards a comprehensive one, allowing visualization and tissue characterization of the pericardium (and heart) in patients with pericardial disease and appraisal of the consequences of pericardial abnormalities on cardiac function and filling patterns. [bib_ref] Magnetic resonance imaging evaluation of myocardial and pericardial disease, Frank [/bib_ref] [bib_ref] Assessment of ventricular coupling with real-time cine MRI and it value to..., Francone [/bib_ref] As such, it is probably the preferred imaging modality to optimally assess pericardial disease. [bib_ref] Cardiovascular magnetic resonance in pericardial diseases, Bogaert [/bib_ref] [bib_ref] MR imaging of the pericardium, Misselt [/bib_ref] Cardiac and pericardial morphology are evaluated by dark-blood T1-weighted fast spin-echo and bright-blood cine steady-state free-precession (SSFP) imaging. Cine SSFP imaging has become the reference sequence to assess and quantify cardiac volumes, myocardial mass and ventricular function. When acquired in real-time, this sequence can be used to assess ventricular coupling by assessing the changes in ventricular septal shape and motion over the respiratory cycle. [bib_ref] Pericardial disease: value of CT and MR imaging, Bogaert [/bib_ref] [bib_ref] Magnetic resonance imaging evaluation of myocardial and pericardial disease, Frank [/bib_ref] Tissue characterization of the heart and pericardium is achieved by darkblood T1-weighted and dark-blood T2-weighted, short-tau inversion-recovery (STIR) spin-echo imaging, cine SSFP imaging and T1-weighted contrast-enhanced and/or late contrast-enhanced (LCE) imaging following intravenous administration of paramagnetic gadolinium chelates. [bib_ref] Lancellotti P; on behalf of the European Association of Cardiovascular Imaging (EACVI)..., Cosyns [/bib_ref] [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] MR, CT, and PET imaging in pericardial disease, Alter [/bib_ref] The LCE sequence uses an inversionrecovery pre-pulse to increase image contrast and is well suited to visualize pericardial inflammation. [bib_ref] MR, CT, and PET imaging in pericardial disease, Alter [/bib_ref] [bib_ref] Detection of pericardial inflammation with late-enhancement cardiac magnetic resonance imaging: initial results, Taylor [/bib_ref] Ventricular inflow and venous flow patterns can be evaluated using phase contrast imaging. [bib_ref] Assessment of ventricular coupling with real-time cine MRI and it value to..., Francone [/bib_ref] Similar to CT, the normal pericardium appears on T1-weighted imaging as a thin hypointense ('dark') curvilinear structure surrounded by hyperintense ('bright') mediastinal and epicardial fat. Normal pericardial thickness ranges from 1.2 to 1.7 mm. The imaging characteristics of pericardial effusion and pericarditis at CMR are shown in [fig_ref] Table 2: Levels of evidenceData derived from multiple randomized clinical trials or meta-analyses [/fig_ref]. It should be emphasized that CMR can accurately distinguish between mixed myopericardial diseases such as mixed inflammatory forms (e.g. myopericarditis or perimyocarditis) and post-myocardial infarction pericardial injury. [bib_ref] Contemporary imaging of the pericardium, Dawson [/bib_ref] [bib_ref] Value of MRI in patients with a clinical suspicion of acute myocarditis, Yelgec [/bib_ref] In patients with constrictive pericarditis, CMR is particularly important in the diagnosis of atypical presentations, such as those with minimally thickened pericardium or effusive-constrictive pericarditis, and those with potentially reversible or transient forms of constrictive pericarditis, showing enhancement of the pericardial layers at LCE imaging. [bib_ref] Detection of pericardial inflammation with late-enhancement cardiac magnetic resonance imaging: initial results, Taylor [/bib_ref] [bib_ref] Cardiac magnetic resonance imaging pericardial late gadolinium enhancement and elevated inflammatory markers..., Feng [/bib_ref] [bib_ref] Pericardial delayed hyperenhancement with CMR imaging in patients with constrictive pericarditis undergoing..., Zurick [/bib_ref] Compared with CT, CMR has the advantage of providing information with regard to the haemodynamic consequences of the non-compliant pericardium on cardiac filling, and has the potential of showing fibrotic fusion of pericardial layers. [bib_ref] Diagnosis of constrictive pericarditis by tagged cine magnetic resonance imaging, Kojima [/bib_ref] In patients with congenital pericardial pathology and pericardial malignancy, CMR shares the advantages of CT, but allows better tissue characterization and the possibility of evaluating the functional consequences. [bib_ref] Functional MRI of congenital absence of the pericardium, Psychidis-Papakyritsis [/bib_ref] Moreover, novel techniques, such as diffusionweighted and dynamic contrast-enhanced magnetic resonance imaging, open perspectives for improved tissue characterization in patients with pericardial tumours. [bib_ref] Malignant pleural disease: diagnosis by using diffusion-weighted and dynamic contrast-enhanced MR imaging-initial..., Coolen [/bib_ref] ## Nuclear medicine In selected cases, positron emission tomography (PET) alone, or preferably in combination with CT (PET/CT), can be indicated to depict the metabolic activity of pericardial disease. Pericardial uptake of 18 F-fluorodeoxyglucose (FDG) tracer in patients with solid cancers and lymphoma is indicative of (malignant) pericardial involvement, thus providing essential information on the diagnosis, staging and assessment of the therapeutic response. [bib_ref] Spectrum of physiological and pathological cardiac and pericardial uptake of FDG in..., Lobert [/bib_ref] The uptake is usually intense and often associated with a focal soft tissue mass. [bib_ref] Utility of FDG PET/CT in inflammatory cardiovascular disease, James [/bib_ref] PET/CT is also of value in identifying the nature of inflammatory pericarditis. In particular, tuberculous pericarditis yields higher FDG uptakes than idiopathic forms. [bib_ref] )F-FDG PET/CT in differentiating acute tuberculous from idiopathic pericarditis: preliminary study, Dong [/bib_ref] However, differentiation between benign and malignant pericardial disease, as well as differentiation between physiological and pathological cardiac FDG uptake by PET/CT, remains challenging. [bib_ref] Spectrum of physiological and pathological cardiac and pericardial uptake of FDG in..., Lobert [/bib_ref] ## Cardiac catheterization Cardiac catheterization is not routinely used for the diagnosis of pericardial disease, as current non-invasive techniques are usually able to solve the differential diagnosis of a patient with the suspicion of heart disease involving the pericardium. However, right heart catheterization may be useful in certain circumstances. Early recognition of abnormal haemodynamics related to cardiac tamponade during invasive procedures (i.e. epicardial ablation, percutaneous aortic valve implantation, complex angioplasty or complex procedures involving trans-septal punctures, among others) may help avoid serious consequences for the patient. In addition, the differentiation between constrictive pericarditis and restrictive cardiomyopathy is sometimes difficult and may require an invasive test. In cardiac tamponade, the right atrial pressure waveform has an attenuated or an absent Y-descent. Absent Y-descent is secondary to diastolic equalization of pressures in the right atrium and right ventricle and lack of effective flow across the tricuspid valve in early ventricular diastole. Also, equalization of mean right atrial, right ventricular and pulmonary artery diastolic pressures and mean pulmonary capillary wedge pressures can be present. Other haemodynamic abnormalities include elevation of filling pressures in all four cardiac chambers, right ventricle and left ventricle peak systolic pressures out of phase, peak aortic pressure varying more than 10 -12 mmHg and a decrease in cardiac output. [bib_ref] Right heart catheterization and hemodynamic profiles, Crossman [/bib_ref] [bib_ref] Cardiac tamponade, Meltser [/bib_ref] The differentiation of constrictive pericarditis from restrictive cardiomyopathy remains difficult. Visualization of the pericardium by CT or CMR may help in detecting an abnormal pericardium. But these tests provide anatomical information and do not necessarily reflect the pathophysiological abnormality present. Also, patients with surgically proven constrictive pericarditis may have a normalappearing pericardium on imaging studies. Alternatively patients may have abnormal pericardial thickness in the absence of constriction, especially after radiation therapy or prior cardiac surgery. Classically, direct measurements of pressures show M-or W-shaped atrial pressure waveforms and 'square root' or 'dip-and-plateau' right ventricular pressure waveforms, reflecting impaired ventricular filling. End-diastolic pressure equalization (typically within 5 mmHg) occurs between these cardiac chambers in constrictive pericarditis because of the fixed and limited space within the thickened and stiff pericardium. Pulmonary artery systolic pressures are usually normal in pericardial constriction; higher pulmonary pressures suggest a restrictive cardiomyopathy. [bib_ref] Right heart catheterization and hemodynamic profiles, Crossman [/bib_ref] Recently a novel haemodynamic parameter has been tested to differentiate both entities. [bib_ref] Constrictive pericarditis in the modern era: novel criteria for diagnosis in the..., Talreja [/bib_ref] Specifically, the ratio of the right ventricular to left ventricular systolic pressure-time area during inspiration versus expiration (systolic area index) was used as a measurement of enhanced ventricular interaction. In patients with surgically documented constrictive pericarditis, during inspiration there is an increase in the area of the right ventricular pressure curve compared with expiration. The area of the left ventricular pressure curve decreases during inspiration as compared with expiration. In contrast, patients with restrictive myocardial disease documented by endomyocardial biopsy usually present a decrease in the area of the right ventricular pressure curve during inspiration as compared with expiration. The area of the left ventricular pressure curve is unchanged during inspiration as compared with expiration. This systolic area index presented a 97% sensitivity and 100% predictive accuracy for identifying patients with surgically proven constrictive pericarditis. [bib_ref] Constrictive pericarditis in the modern era: novel criteria for diagnosis in the..., Talreja [/bib_ref] ## Multimodality imaging Echocardiography, cardiac CT and CMR are often used as complementary imaging modalities [fig_ref] Table 1: Classes of recommendations [/fig_ref]. The choice of one or multiple imaging modalities is driven by the clinical context or condition of the patient. A modern approach for the management of pericardial diseases should include the integration of different imaging modalities in order to improve the diagnostic accuracy and clinical management of patients. 2,3 ## Proposal for a general diagnostic work-up In the management of pericardial syndromes, a major controversy is the role of an extensive aetiological search and admission for all patients with pericarditis or pericardial effusion. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] [bib_ref] Contemporary management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusion and..., Imazio [/bib_ref] The epidemiological background is essential to develop a rational cost-effective management programme and the clinician should especially identify causes that require targeted therapies. The approach may be different for research, when we attempt to reduce the number of 'idiopathic' cases. The diagnosis of idiopathic cases is essentially an exclusion diagnosis, supported by a typical clinical course. On this basis, auscultation, ECG, echocardiography, chest X-ray, routine blood tests, including markers of inflammation (i.e., CRP and/or ESR) and myocardial lesions (CK, troponins), are recommended in all cases of suspected pericarditis. Additional testing should be related to the suspected origin and clinical presentation. The major specific causes to be ruled out are bacterial pericarditis (especially TB), neoplastic pericarditis and pericarditis associated with a systemic disease (generally an autoimmune disease) (Web [fig_ref] Table 5: Commonly prescribed anti-inflammatory therapy for acute pericarditis [/fig_ref]. 9,77,129 -131 Each of these specific causes has a frequency of 5% of all unselected cases of pericarditis from developed countries (Web [fig_ref] Table 5: Commonly prescribed anti-inflammatory therapy for acute pericarditis [/fig_ref] , 9,77,129 -131 while frequencies increase in moderate to large pericardial effusions (Web [fig_ref] Table 3: Aetiology of pericardial diseases [/fig_ref]. 8,74 -78 Emerging additional causes include iatrogenic ones (percutaneous coronary interventions, pacemaker insertion, catheter ablation). [bib_ref] Post-cardiac injury syndromes. An emerging cause of pericardial diseases, Imazio [/bib_ref] The aetiological spectrum is different in developing countries with a high prevalence of TB (e.g. 70 -80% of pericarditis in sub-Saharan Africa, and often associated with HIV infection). [bib_ref] Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in..., Mayosi [/bib_ref] [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] Certain clinical features at presentation may be associated with an increased risk of specific aetiologies (non-viral or nonidiopathic) and complications during follow-up (recurrences, tamponade, constriction) and are suggested as 'high-risk features' useful for the triage of pericarditis to establish the need for a full aetiological search and admission in a single patient, Web [fig_ref] Table 6: Commonly prescribed anti-inflammatory therapies for recurrent pericarditis [/fig_ref]. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] Factors indicated as 'major' have been validated by multivariate analysis, while factors indicated as 'minor' are based on expert opinion and literature review: 9 they are essentially theoretical risk factors for complications and suggest the indication for admission and close monitoring of the evolution. Major risk factors include fever .388C [hazard ratio (HR) 3.56], subacute course (symptoms developing over several days or weeks; HR 3.97), large pericardial effusion (diastolic echo-free space .20 mm in width) or cardiac tamponade (HR 2.15) and failure of aspirin or NSAIDs (HR 2.50). [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] Large effusion and tamponade (HR 2.51) and aspirin or NSAIDs failure (HR 5.50) also identify an increased risk of complications during follow-up (recurrences, tamponade, constriction). [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] Minor risk factors are pericarditis associated with myocarditis, immunodepression, trauma and oral anticoagulant therapy. For patients with predictors of poor prognosis, major or minor, hospitalization and a full aetiological search are warranted. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Triage and management of acute pericarditis, Imazio [/bib_ref] In contrast, when these negative predictors are absent, patients are at low risk of specific causes and complications, and outpatient management may be considered. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] This approach is safe without an excess of complications and new unexpected diagnoses requiring a specific therapy. [bib_ref] Day-hospital treatment of acute pericarditis: a management program for outpatient therapy, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Triage and management of acute pericarditis, Imazio [/bib_ref] The often presents as a self-limited disease, with most patients recovering without complications. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] However, as a consequence of acute viral pericarditis, cardiac tamponade, recurrent pericarditis and, more rarely, constrictive pericarditis may also develop. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] ## Pathogenesis Cardiotropic viruses can cause pericardial and myocardial inflammation via direct cytolytic or cytotoxic effects (e.g. enteroviruses) and/ or via T and/or B cell -driven immune-mediated mechanisms (e.g. herpesviruses). Persistence of viral nucleic acid without virus replication in the peri(myo)cardium is known to sustain ongoing inflammation and effusions via (auto)immune processes directed against specific cardiac proteins by molecular mimicry. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] ## Diagnosis The definite diagnosis of viral pericarditis requires a comprehensive workup of histological, cytological, immunohistological and molecular investigations in pericardial fluid and peri-/epicardial biopsies obtained in conjunction with pericardioscopy, permitting the evaluation of possible algorithms for a causative therapy. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] In contrast, serological tests were found to be futile in the diagnosis of viral pericarditis. Whereas no up-regulation of pro-inflammatory cytokine expression is noted in the serum, TNF-a, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), IL-6, IL-8 and interferon-gamma (IFN-g) are increased in the pericardial effusions of patients with pericarditis, indicating the presence of local inflammatory reactions. [bib_ref] Cytokine activation in pericardial fluids in different forms of pericarditis, Pankuweit [/bib_ref] [bib_ref] Pericardial cytokines in neoplastic, autoreactive, and viral pericarditis, Ristic [/bib_ref] Accordingly, there is no correlation of antiviral antibodies in the serum or virus isolation from throat or rectal swabs with positive molecular polymerase chain reaction (PCR)/in situ hybridization analyses for the detection of cardiotropic viruses in pericardial tissue and fluid. [bib_ref] Virus serology in patients with suspected myocarditis: utility or futility?, Mahfoud [/bib_ref] ## Identification of viral nucleic acids Mainly by quantitative PCR techniques, nucleic acids of different cardiotropic RNA and DNA viruses have been detected in epicardial and pericardial biopsies and the pericardial fluid of children and adults with acute pericarditis, but also in patients with recurring and constrictive pericarditis. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] and human herpesvirus 6 (HHV-6)], are present in pericardial biopsies and pericardial fluid at greater frequencies and higher viral DNA copy numbers. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Whereas parvovirus B19, with up to 7 × 10 6 GE/lg DNA was predominantly detected in epicardial tissue, EBV was most frequently found in pericardial fluid. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] DNA of varicella zoster virus, herpes simplex virus and adenoviruses is only rarely detected in pericarditis patients. Cytomegalovirus (CMV)-associated pericarditis is mainly found in immunocompromised and HIV patients. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] In developing countries with a delayed rollout of antiretroviral therapy, HIV-associated inflammatory reactions (often related to TB) of the pericardium and myocardium are common complications. [bib_ref] HIV and the heart: the impact of antiretroviral therapy: a global perspective, Thienemann [/bib_ref] However, at present these investigations are usually not performed because of their complexity, cost, invasive nature and low availability. ## Therapy Acute viral pericarditis often presents as a self-limiting disease that responds well to a short course of treatment with NSAIDs, with the adjunct of colchicine, especially for prevention of recurrences. The identification of specific viral signatures aids in understanding the pathogenetic mechanisms in pericarditis, and might enable an individualized aetiologically driven specific treatment approach to be established by distinguishing a viral aetiology from autoreactive inflammation. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Some experts suggest antiviral treatment similar to that for myocarditis (IVIG therapy in acute systemic enteroviral, CMV, EBV and parvovirus B19 infection, oral valganciclovir in HHV-6 perimyocarditis, IFN-a for enteroviral pericarditis). [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] However, these treatments are still under evaluation and rarely used. Involvement of infectious disease specialists is recommended. So far, no therapy is available to solve the problem of virus persistence and consecutive inflammation, particularly when induced by herpesviruses and parvovirus B19 infections. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Importantly, corticosteroids are generally not indicated in viral pericarditis, as they are known to reactivate many virus infections and thus lead to ongoing inflammation. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Recommendations for the diagnosis and therapy of viral pericarditis ## Bacterial pericarditis Bacterial pericarditis is relatively uncommon in clinical practice in developed countries with a low prevalence of TB. Tuberculous pericarditis is the most common form all over the world and the most common cause of pericardial diseases in developing countries. We will discuss this form and also purulent pericarditis, which is less common. ## Tuberculous pericarditis Tuberculous pericarditis accounts for ≤4% of pericardial disease in the developed world. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] [bib_ref] Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in..., Mayosi [/bib_ref]. In contrast, TB is the cause of clinically significant pericardial effusion in .90% of HIV-infected and 50 -70% of non-HIV-infected individuals who live in developing countries where TB is endemic. [bib_ref] Epidemiology of pericardial effusions at a large academic hospital in South Africa, Reuter [/bib_ref] The disease can occur at any age, and men are affected more frequently than women. [bib_ref] Clinical characteristics and initial management of patients with tuberculous pericarditis in the..., Mayosi [/bib_ref] Clinical evidence of chronic cardiac compression mimicking congestive heart failure is the most common presentation. [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] [bib_ref] Constrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Mutyaba [/bib_ref] Clinical presentations are pericardial effusion, effusive-constrictive pericarditis and constrictive pericarditis. [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] Tuberculous pericarditis has a mortality rate of 17-40% at 6 months after diagnosis. [bib_ref] Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa, Mayosi [/bib_ref] It should be emphasized that the majority of the information on tuberculous pericarditis comes from endemic areas in underdeveloped countries and immunodepressed patients. The applicability of this information to the Western world is questionable. ## Diagnosis A 'definite' diagnosis of tuberculous pericarditis is based on the presence of tubercle bacilli in the pericardial fluid or on histological section of the pericardium, by culture or by PCR (Xpert MTB/RIF) testing; a 'probable' diagnosis is made when there is proof of TB elsewhere in a patient with unexplained pericarditis, a lymphocytic pericardial exudate with elevated unstimulated interferon-gamma (uIFN-g), adenosine deaminase (ADA) or lysozyme levels and/or an appropriate response to antituberculosis chemotherapy in endemic areas. [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] uIFN-g offers superior accuracy for the diagnosis of microbiologically confirmed tuberculous pericarditis compared with the ADA assay and the Xpert MTB/RIF test. [bib_ref] Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to..., Pandie [/bib_ref] A protocol for the evaluation of suspected tuberculous pericardial effusion is proposed in [fig_ref] Table 1: Classes of recommendations [/fig_ref]. ## Management A regimen consisting of rifampicin, isoniazid, pyrazinamide and ethambutol for at least 2 months followed by isoniazid and rifampicin (total of 6 months of therapy) is effective in treating extrapulmonary TB. Treatment for ≥9 months gives no better results and has the disadvantages of increased cost and increased risk of poor compliance. [bib_ref] Interventions for treating tuberculous pericarditis, Mayosi [/bib_ref] The evolution towards constrictive pericarditis is a serious potential complication. Constriction generally develops within 6 months of presentation with effusive pericarditis (effusive-constrictive pericarditis). [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] Tuberculous pericardial constriction is almost always associated with pericardial thickening. Prior to the introduction of effective TB chemotherapy, up to 50% of patients with effusive tuberculous pericarditis progressed to constriction. Rifampicin-based antituberculosis treatment reduced the incidence of constriction to 17 -40%. Appropriate antibiotic therapy is essential to prevent this progression. [bib_ref] Tuberculous pericarditis, Mayosi [/bib_ref] [bib_ref] The management of tuberculous pericardial effusion: experience in 233 consecutive patients, Reuter [/bib_ref] In addition, two interventions may reduce the incidence of constriction: the first is intrapericardial urokinase [bib_ref] Prevention of pericardial constriction by transcatheter intrapericardial fibrinolysis with urokinase, Cui [/bib_ref] and second, the Investigation of the Management of Pericarditis (IMPI) trial has shown that high-dose adjunctive prednisolone reduces the incidence of constrictive pericarditis by 46% regardless of HIV status. [bib_ref] Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis, Mayosi [/bib_ref] Adjunctive corticosteroid therapy with prednisolone for 6 weeks had a neutral effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or pericardial constriction; however, this therapy was associated with an increased risk of HIV-associated malignancies in the prednisolone- ≥6 based on the following criteria is highly suggestive of tuberculous pericarditis in people living in endemic areas: fever (1), night sweats (1), weight loss (2), globulin level >40 g/L (3) and peripheral leucocyte count <10x10 9 /L (3). ## Stage 2: pericardiocentesis - Therapeutic pericardiocentesis is absolutely indicated in the presence of cardiac tamponade. - Diagnostic pericardiocentesis should be considered in all patients with suspected tuberculous pericarditis, and the following tests perf 1. Dir culture for M. tuberculosis. 2. Quantitative polymerase chain reaction (Xpert MTB/RIF) testing for nucleic acids of M. tuberculosis. 3. Biochemical tests to distinguish betw 4. White cell analysis and count, and cytology: a lymphocytic exudate favours tuberculous pericarditis. 5. Indirect tests for tuberculous infection: interferon-gamma (IFN-y), adenosine deaminase (ADA), or lysozyme assay. ## Stage 3: pericardial biopsy - "Therapeutic" biopsy: as part of surgical drainage in patients with cardiac tamponade relapsing after pericardiocentesis or requiring open drainage of pericar medical therapy. - Diagnostic biopsy: In areas where tuberculosis is endemic, a diagnostic biopsy is not required prior to commencing empiric antituberculosis treatment. In areas where tuberculosis is not endemic, a diagnostic biopsy is recommended in patients with >3 weeks of illness and without aetiologic diagnosis having been reached by other tests. ## Stage 4: empiric antituberculosis chemotherapy - Tuberculosis endemic in the population: trial of empiric antituberculosis chemotherapy is recommended for exudative pericardial effusion, after excluding other causes such as malignancy, uraemia, trauma, purulent pericarditis, and auto-immune diseases. - Tuberculosis not endemic in the population: when systematic investigation fails to yield a diagnosis of tuberculous pericarditis, there or starting antituberculosis treatment empirically. ADA ¼ adenosine deaminase; CT ¼ computed tomography; LDH ¼ lactate dehydrogenase; MRI ¼ magnetic resonance imaging; TB ¼ tuberculosis. treated group. [bib_ref] Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis, Mayosi [/bib_ref] Adjunctive steroid therapy was associated with a reduced incidence of pericardial constriction and hospitalization. The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients. On this basis, it may be reasonable to use adjunctive corticosteroids in patients with tuberculous pericarditis without HIV infection and to avoid them in HIV-infected individuals because of the increased risk of malignancy. [bib_ref] Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis, Mayosi [/bib_ref] Recommendations for the diagnosis and treatment of tuberculous pericarditis and effusion ## Purulent pericarditis ## Epidemiology Purulent pericarditis is rare, accounting for ,1% of cases. [bib_ref] Diagnosis and treatment of pericarditis, Imazio [/bib_ref] [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] In Western series, the most common organisms have been staphylococci, streptococci and pneumococci, while the predominant associated lesions were empyema (50%) or pneumonia (33%). [bib_ref] Purulent pericarditis: review of a 20-year experience in a general hospital, Sauleda [/bib_ref] In immunosuppressed patients or following thoracic surgery, Staphylococcus aureus (30%) and fungi (20%) are more common. [bib_ref] microbiologic and therapeutic aspects of purulent pericarditis, Rubin [/bib_ref] Also, anaerobes originating from the oropharynx have been reported. [bib_ref] Microbiology of acute purulent pericarditis. A 12-year experience in a military hospital, Brook [/bib_ref] Seeding may be haematogenous or by contiguous spread from the retropharyngeal space, cardiac valves and below the diaphragm. [bib_ref] Purulent pericarditis, Goodman [/bib_ref] Neisseria meningitidis may involve the pericardium either through initiating an immunemediated sterile effusion or by direct infection and purulent reaction. The modern era of iatrogenic and HIV-associated immunosuppression has witnessed more unusual organisms. ## Diagnosis Purulent pericarditis is rare and generally manifested as a serious febrile disease. The underlying sepsis may predominate the illness. Suspicion of purulent pericarditis is an indication for urgent pericardiocentesis, 1,5,12 which is diagnostic. The fluid may be frankly purulent. A low pericardial:serum glucose ratio (mean 0.3) and elevated pericardial fluid white cell count with a high proportion of neutrophils (mean cell count 2.8/ml, 92% neutrophils) differentiate purulent from tuberculous (glucose ratio 0.7, count 1.7/ml, 50% neutrophils) and neoplastic (glucose ratio 0.8, count 3.3/ml, 55% neutrophils) pericarditis. [bib_ref] Diagnostic value of the biochemical composition of pericardial effusions in patients undergoing..., Ben-Horin [/bib_ref] Fluid should be sent for bacterial, fungal and tuberculous studies, with blood for cultures and other samples being taken as guided by the clinical presentation. 12 ## Management Purulent pericarditis should be managed aggressively, as death is inevitable if untreated, whereas with comprehensive therapy 85% of cases have been reported to survive the episode and have a good long-term outcome. [bib_ref] Medical therapy of pericardial diseases: part I: idiopathic and infectious pericarditis, Imazio [/bib_ref] [bib_ref] Purulent pericarditis: review of a 20-year experience in a general hospital, Sauleda [/bib_ref] Intravenous antimicrobial therapy should be started empirically until microbiological results are available. Drainage is crucial. Purulent effusions are often heavily loculated and likely to rapidly reaccumulate. Intrapericardial thrombolysis is a possible treatment for cases with loculated effusions in order to achieve adequate drainage before resorting to surgery. [bib_ref] Clinical review: intrapericardial fibrinolysis in management of purulent pericarditis, Augustin [/bib_ref] Subxiphoid pericardiostomy and rinsing of the pericardial cavity should be considered. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] This allows more complete drainage of the effusion, as loculations can be manually lysed. ## Recommendations for the diagnosis of purulent pericarditis ## Pericarditis in renal failure Renal disease and overall ESRD are associated with possible pericardial involvement. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] Three different pathologies are found in uraemic patients: uraemic pericarditis-before renal replacement therapy or within 8 weeks of its initiation; dialysis pericarditis-after being stabilized on dialysis (usually ≥8 weeks after its initiation) [bib_ref] Pericarditis and renal failure, Renfrew [/bib_ref] and, very rarely, constrictive pericarditis. The global incidence of pericarditis in ESDR patients has declined to 5% in those patients starting dialysis. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] The reported frequency of dialysis pericarditis ranges from 2 to 21%, but recent data are lacking. Pericardial involvement in ESRD is manifested most commonly as acute pericarditis and chronic pericardial effusion and infrequently as chronic constrictive pericarditis. Typical features of this form of pericarditis include a lower rate of pleuritic chest pain (up to 30% of patients are asymptomatic) and the absence of ECG abnormalities in most cases, probably due to the lack of myocardial inflammation. Patients with ESRD are more likely to develop chronic pericardial effusion due to continuous volume overload. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] Not all pericardial effusions result from inflammation, and the normal volume of pericardial fluid is larger in stable haemodialysis patients than in normal controls. [bib_ref] Changing patterns of pericardial disease in patients with end-stage renal disease, Banerjee [/bib_ref] With the advent of advanced renal replacement therapy, the incidence of haemodynamically significant effusions has decreased. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] [bib_ref] Pericardial tamponade and large pericardial effusions: causal factors and efficacy of percutaneous..., Kabukcu [/bib_ref] [bib_ref] Pericarditis associated with renal failure. Evolution and management, Wood [/bib_ref] The most probable cause of uraemic pericarditis is the retention of toxic metabolites. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] [bib_ref] Pericarditis associated with renal failure. Evolution and management, Wood [/bib_ref] Since pericardial effusion is often bloody in uraemic patients, anticoagulation should be carefully considered or avoided in patients starting dialysis. [bib_ref] Pericardial involvement in end-stage renal disease, Alpert [/bib_ref] [bib_ref] Pericarditis associated with renal failure. Evolution and management, Wood [/bib_ref] Recommendations for the management of pericarditis in renal failure ## Pericardial involvement in systemic autoimmune and autoinflammatory diseases Pericardial involvement in systemic autoimmune diseases may be symptomatic (pericarditis and symptomatic pericardial effusion) or asymptomatic (usually pericardial effusion) and generally reflects the degree of activity of the underlying disease. [bib_ref] Pericardial involvement in systemic inflammatory diseases, Imazio [/bib_ref] Approximately 5 -15% of patients with acute or recurrent pericarditis may have a systemic autoimmune disease, either overt or underlying [fig_ref] Table 1: Classes of recommendations [/fig_ref]. 9,77,129 -131 Pericardial involvement is common in systemic lupus erythematosus, Sjö gren's syndrome, rheumatoid arthritis and scleroderma, but may also be present in systemic vasculitides, Behçet's syndrome, sarcoidosis and inflammatory bowel diseases. Pericardial involvement rarely occurs as the first manifestation of these diseases. In most patients the underlying disease has already been diagnosed by classical symptoms and signs. Concomitant myocardial inflammatory involvement may complicate the presentation and should be ruled out. If clinical features suggest a possible systemic autoimmune disease, a targeted aetiological search is warranted in cooperation with specialist consultation. The treatment is especially targeted at control of the systemic underlying disease. [bib_ref] Pericardial involvement in systemic inflammatory diseases, Imazio [/bib_ref] A specific subset of patients includes those with periodic fevers. These are genetic disorders characterized by mutations of genes involved in the regulation of the inflammatory response, without involvement of specific T cells or autoantibodies. These disorders are usually detected in the paediatric population, although some patients experience disease onset during adulthood. The most common autoinflammatory syndromes include familial Mediterranean fever (FMF), in which serositis episodes last only 1 -3 days, and tumour necrosis factor receptor-associated periodic syndrome (TRAPS), in which the episodes last for weeks. Mutations associated with these disorders are rare in recurrent pericarditis. These conditions may be characterized by an exaggerated expression of IL-1. [bib_ref] Role of autoimmunity and autoinflammation in the pathogenesis of idiopathic recurrent pericarditis, Cantarini [/bib_ref] A 10% rate of familial occurrence of pericarditis has been reported among the relatives of these patients. These data suggest a genetic predisposition in at least a subset of patients; counselling may be warranted in these cases. A positive family history for pericarditis or periodic fevers, a poor response to colchicine, as well as the need for immunosuppressive agents are clues to the possible presence of an auto-inflammatory disease; 160 particularly in these conditions, anti-IL-1 or anti-TNF agents may be considered. 31,32,160 ## Post-cardiac injury syndromes The term post-cardiac injury syndromes (PCIS) is an umbrella term indicating a group of inflammatory pericardial syndromes including post-myocardial infarction pericarditis, post-pericardiotomy syndrome (PPS) and post-traumatic pericarditis (either iatrogenic or not). [bib_ref] Post-cardiac injury syndromes. An emerging cause of pericardial diseases, Imazio [/bib_ref] Such syndromes are presumed to have an autoimmune pathogenesis triggered by initial damage to pericardial and/or pleural tissues caused by either myocardial necrosis (late post-myocardial infarction pericarditis or Dressler syndrome), surgical trauma (PPS), accidental thoracic trauma (traumatic pericarditis) or iatrogenic trauma with or without bleeding (pericarditis after invasive cardiac interventions). [bib_ref] Etiology of pericarditis in a prospective cohort of 1162 cases, Gouriet [/bib_ref] The immune-mediated pathogenesis is supported by a latent period generally of a few weeks until the appearance of the first manifestations and the response to antiinflammatory drugs (NSAIDs, corticosteroids, colchicine) with the possibility of recurrences. Pericardial bleeding and pleura incision are triggers for the syndrome. [bib_ref] The post-pericardiotomy syndrome, Imazio [/bib_ref] Some forms, such as Dressler syndrome, have become rare with early reperfusion therapy of myocardial infarction; however, it may occur especially in cases of even minor bleeding into the pericardium. [bib_ref] Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by..., Imazio [/bib_ref] ## Definition and diagnosis According to proposed diagnostic criteria for PPS, 168 -170 the diagnosis of PCIS may be reached after a cardiac injury following clinical criteria: (i) fever without alternative causes, (ii) pericarditic or pleuritic chest pain, (iii) pericardial or pleural rubs, (iv) evidence of pericardial effusion and/or (v) pleural effusion with elevated CRP. At least two of five criteria should be fulfilled. The rationale for proposing specific criteria instead of adopting the same for pericarditis is that these syndromes may have concomitant pleuropericardial involvement and possible pulmonary infiltrates, and are not simply pericarditis. [bib_ref] Postpericardiotomy syndrome: a proposal for diagnostic criteria, Imazio [/bib_ref] Moreover, it is sometimes difficult to differentiate PCIS from the simple mechanical consequences of surgery (such as pericardial or pleural effusion). The demonstration of inflammatory activity should be essential to establish the diagnosis. Basic diagnostic evaluation of a patient with a suspected PCIS includes physical examination, ECG, echocardiogram, thoracic echography and/or chest X-ray. [bib_ref] Post-cardiac injury syndromes. An emerging cause of pericardial diseases, Imazio [/bib_ref] [bib_ref] The post-pericardiotomy syndrome, Imazio [/bib_ref] On this basis, echocardiography is recommended when an iatrogenic complication is suspected after a cardiovascular intervention. 2,3,132 ## Management Treatment of PCIS is essentially based on empiric anti-inflammatory therapy, and may improve remission rates and reduce the risk of recurrences. [bib_ref] The effective treatment of postpericardiotomy syndrome after cardiac operations. A randomized placebo-controlled..., Horneffer [/bib_ref] The same therapeutic scheme adopted for pericarditis is efficacious for all these forms, including post-myocardial infarction pericarditis [fig_ref] Table 3: Aetiology of pericardial diseases [/fig_ref]. Colchicine is not recommended for postoperative effusions in the absence of systemic inflammation. Similarly NSAIDs are generally not indicated in asymptomatic post-surgical effusions, and this therapy may be associated with an increased risk of side effects related to NSAIDs. 173,174 ## Prevention Different preventive strategies have been examined in a few studies regarding aspirin, 175 methylprednisone, 176 dexamethasone 177 and colchicine. [bib_ref] Colchicine for the prevention of postpericardiotomy syndrome, Finkelstein [/bib_ref] [bib_ref] COlchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS): a multicentre, randomized,..., Imazio [/bib_ref] [bib_ref] for the COPPS-2 Investigators. Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative..., Imazio [/bib_ref] Four controlled clinical trials for primary prevention of PPS were included in a systematic review on 894 patients; three studies were double-blind RCTs. Treatment comparisons were colchicine vs. placebo (two RCTs enrolling 471 patients), methylprednisolone vs. placebo (one RCT involving 246 paediatric patients) and aspirin vs. historical controls (one non-randomized study involving 177 paediatric patients). Meta-analytic pooling showed that only colchicine was associated with decreased risk of PPS [odds ratio (OR) 0.38]. Data on methylprednisolone (OR 1.13) and aspirin (OR 1.00) were negative. [bib_ref] Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome, Imazio [/bib_ref] The Colchicine for Prevention of the Post-pericardiotomy Syndrome and Postoperative Atrial Fibrillation (COPPS-2) trial confirmed the overall efficacy of perioperative use of colchicine, but it was also found to be associated with an increased risk of gastrointestinal side effects 172 compared with postoperative use of colchicine. [bib_ref] COlchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS): a multicentre, randomized,..., Imazio [/bib_ref] Colchicine is not recommended for the perioperative treatment and prevention of postoperative effusions in the absence of systemic inflammation. [bib_ref] for the COPPS-2 Investigators. Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative..., Imazio [/bib_ref] In another trial, 177 high-dose dexamethasone (1 mg/kg as a single intraoperative dose) was not efficacious in preventing PPS or complicated PPS. ## Prognosis Despite limited published data, the prognosis of PPS is generally good. [bib_ref] Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome, Imazio [/bib_ref] There are very few available data on other forms of postpericardial injury syndromes. In the largest published series on PPS patients after cardiac surgery, 166 complication rates were low: ,4% for recurrences, ,2% for cardiac tamponade and no cases of constriction, although hospital stay may be prolonged in these patients. However, the development of constrictive pericarditis has been reported in 3% of cases. [bib_ref] Risk of constrictive pericarditis after acute pericarditis, Imazio [/bib_ref] ## Post-myocardial infarction pericarditis Following an acute myocardial infarction (AMI), three major pericardial complications may occur: (i) pericardial effusion, (ii) early infarct-associated pericarditis (often called early post-infarction pericarditis, typically a few days after AMI) and (iii) late pericarditis or post-cardiac injury (Dressler) syndrome (typically 1 -2 weeks after AMI). Early post-infarction pericarditis usually occurs soon after the AMI and is transient. This complication is rare in the primary percutaneous coronary intervention era and is especially related to late reperfusion or failed coronary reperfusion. [bib_ref] Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by..., Imazio [/bib_ref] Diagnostic criteria do not differ from those for acute pericarditis. ECG changes are usually overshadowed by changes due to the myocardial infarction. However, ST segments may remain elevated, with persistence of upright T waves, as T waves may become upright again after having been inverted. Echocardiography should be performed in patients suspected of having post-AMI to evaluate for the presence of a pericardial effusion. CMR can be used to show the presence of concomitant pericardial inflammation. [bib_ref] Assessment of early post-infarction pericardial injury using cardiac magnetic resonance (CMR), Doulaptsis [/bib_ref] Patients with a post-AMI pericardial effusion .10 mm in thickness should be investigated for a possible subacute rupture. [bib_ref] Nature and progression of pericardial effusion in patients with a first myocardial..., Figueras [/bib_ref] [bib_ref] Hospital outcome of moderate to severe pericardial effusion complicating ST-elevation acute myocardial..., Figueras [/bib_ref] The treatment is generally supportive, as most cases are self-limited. However, a minority of patients may have persistent symptoms that require more than supportive care. For these patients, aspirin plus colchicine may be considered. Late post-AMI pericarditis (Dressler syndrome) is rare (,1%) in the era of primary percutaneous coronary intervention and may reflect a larger size of AMI and/or late reperfusion. [bib_ref] Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by..., Imazio [/bib_ref] Diagnosis and treatment are similar to that generally recommended for PCIS. Although pericarditis is associated with a larger infarct size, inhospital and 1-year mortality and major adverse cardiac events were similar in patients with and without pericarditis. Timely primary percutaneous coronary intervention may reduce the occurrence of post-AMI pericarditis. Early post-AMI pericarditis remains a marker of larger infarct size, but without independent prognostic significance. [bib_ref] Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by..., Imazio [/bib_ref] ## Postoperative effusions Postoperative pericardial effusions are relatively common after cardiac surgery. They usually disappear in 7 -10 days, but sometimes they persist for longer and can be dangerous. Early post-cardiac surgery pericardial collections must be interpreted in the clinical context of the patient. They have been reported as asymptomatic in 22% of patients 2 weeks after cardiac surgery. [bib_ref] Evolution of the postoperative pericardial effusion after day 15: the problem of..., Meurin [/bib_ref] The prognosis is good for mild effusions occurring in two of three cases, but moderate to large effusions (one of three) may progress to cardiac tamponade in 10% of cases 1 month after cardiac surgery. [bib_ref] Evolution of the postoperative pericardial effusion after day 15: the problem of..., Meurin [/bib_ref] [bib_ref] Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes..., Tsang [/bib_ref] Treatment of these asymptomatic effusions by diclofenac was shown to be useless in the Post-Operative Pericardial Effusion (POPE) trial and may be associated with an increased risk of side effects related to NSAID use. [bib_ref] Nonsteroidal anti-inflammatory drug treatment for postoperative pericardial effusion: a multicenter randomized, double-blind..., Meurin [/bib_ref] In contrast, cardiac tamponade occurring in the first hours after cardiac surgery is usually due to haemorrhage in the pericardial space, and surgical reintervention is mandatory in this situation. There are no data for or against the use of higher doses in this setting. ## Recommendations for the management and prevention of post-cardiac injury syndromes ## Traumatic pericardial effusion and haemopericardium Any cardiac intervention (e.g. percutaneous coronary intervention, pacemaker lead insertion, radiofrequency ablation) may be responsible for haemopericardium and cardiac tamponade due to coronary or cardiac chamber perforation. Pericardial effusion induced by trauma is included in the more expanded concept of PCIS. [bib_ref] Post-cardiac injury syndromes. An emerging cause of pericardial diseases, Imazio [/bib_ref] However, in the event of overt chest trauma complicated by cardiac tamponade, the magnitude of the trauma is the main cause of the syndrome. Diagnosis includes the presence of a prior history of chest trauma as a trigger for the syndrome plus the signs and symptoms of pericarditis (i.e. chest pain, pericardial rub, dyspnoea, lowgrade fever) and markers of inflammatory reaction (i.e. elevated CRP, leucocytosis, ESR). ECG is normally used to rule out AMI as a possible cause of pericarditis. Chest X-ray may help to detect cardiomegaly and pleural effusions. Transthoracic echocardiography is used to detect the presence, size and haemodynamic importance of the pericardial effusion. A recent randomized trial demonstrated that the use of limited transthoracic echocardiography improved the time from the trauma bay to the operating room and reduced the mortality rate. [bib_ref] Findings of a randomized controlled trial using limited transthoracic echocardiogram (LTTE) as..., Ferrada [/bib_ref] Therefore treatment differs according to the severity of the syndrome. For those with post-traumatic pericarditis with no haemodynamic compromise, treatment is essentially based on empirical anti-inflammatory therapy and adjunctive colchicine, which has been shown to be safe and efficacious for the prevention of pericarditis. [bib_ref] Colchicine for pericarditis: hype or hope?, Imazio [/bib_ref] For those life-threatening cases of penetrating trauma to the heart and chest, emergency thoracotomy is recommended to improve survival as opposed to the classic strategy of initial pericardiocentesis as a bridge to surgery. [bib_ref] Pericardiocentesis in trauma: a systematic review, Lee [/bib_ref] [bib_ref] American College of Surgeons' Committee on Trauma, International ATLS Working Group, Atls Subcommittee [/bib_ref] This is usually done through left anterolateral thoracotomy that makes pericardiotomy possible with effective relief of cardiac tamponade and direct cardiac massage if needed. In the setting of aortic dissection with haemopericardium and suspicion of cardiac tamponade, emergency transthoracic echocardiography or a CT scan should be performed to confirm the diagnosis. In such a scenario, controlled pericardial drainage of very small amounts of the haemopericardium can be attempted to temporarily stabilize the patient in order to maintain blood pressure at 90 mmHg. [bib_ref] Impact of controlled pericardial drainage on critical cardiac tamponade with acute type..., Hayashi [/bib_ref] Recommendations for the management of traumatic pericardial effusion and haemopericardium in aortic dissection ## Pericardial involvement in neoplastic disease The differential diagnosis between malignant processes and other causes of pericarditis is particularly relevant and generally is accomplished by imaging, e.g. CT scan, cytology of pericardial fluid and eventually biopsies. Primary tumours of the pericardium, either benign (lipomas and fibromas) or malignant (mesotheliomas, angiosarcomas, fibrosarcomas), are very rare. [bib_ref] Evaluation and management of pericardial effusion in patients with neoplastic disease, Maisch [/bib_ref] [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] Mesothelioma, the most common malignant tumour, is almost always incurable. The most common secondary malignant tumours are lung cancer, breast cancer, malignant melanoma, lymphomas and leukaemias. Malignant pericardial effusions may be small, medium or large, with an imminent tamponade (frequent recurrences) or constriction; they may even be the initial sign of malignant disease. [bib_ref] Relation of acute pericardial disease to malignancy, Imazio [/bib_ref] The diagnosis is based on confirmation of the malignant infiltration within the pericardium. [bib_ref] Evaluation and management of pericardial effusion in patients with neoplastic disease, Maisch [/bib_ref] [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] Of note, in almost two-thirds of patients with documented malignancy, pericardial effusion is caused by non-malignant diseases, e.g. radiation pericarditis, other therapies or opportunistic infections. [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] Chest X-ray, CT, PET and CMR may reveal mediastinal widening, hilar masses and pleural effusion. Analyses of pericardial fluid and pericardial or epicardial biopsies are essential for the confirmation of malignant pericardial disease. The diagnostic yield of the concentrations of tumour markers in pericardial fluid remains controversial: carcinoembryonic antigen (CEA), CYFRA 21 -1, neuron-specific enolase (NSE), CA-19 -9, CA-72-4, SCC, GATA3 and VEGF may be useful, but none of these tumour markers has been proven to be accurate enough for distinguishing malignant from benign effusions. [bib_ref] Diagnostic value of biochemical biomarkers in malignant and non-malignant pericardial effusion, Karatolios [/bib_ref] Epidermal growth factor receptor (EGFR) mutation should be evaluated and has prognostic indications in patients with malignant pericardial effusion in the course of lung adenocarcinoma 194 in order to tailor the treatment. Treatment of cardiac tamponade is a class I indication for pericardiocentesis. The following steps are recommended in large suspected neoplastic pericardial effusion without tamponade: (i) systemic antineoplastic treatment as baseline therapy, [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] (ii) pericardiocentesis to relieve symptoms and establish a diagnosis and (iii) intrapericardial instillation of cytostatic/sclerosing agents to prevent recurrences. Pericardial drainage is recommended in all patients with large effusions because of the high recurrence rate (40 -70%). Prevention of recurrences may be achieved by intrapericardial instillation of sclerosing and cytotoxic agents. Intrapericardial treatment should be tailored to the type of tumour: cisplatin was most effective in pericardial involvement in the course of lung cancer [bib_ref] Neoplastic pericardial disease in lung cancer: impact on outcomes of different treatment..., Lestuzzi [/bib_ref] [bib_ref] Neoplastic pericardial effusion: efficacy and safety of intrapericardial treatment with cisplatin, Maisch [/bib_ref] and thiotepa was more effective in breast cancer pericardial metastases. [bib_ref] Malignant cardiac tamponade in women with breast cancer treated by pericardiocentesis and..., Bishiniotis [/bib_ref] [bib_ref] Intracavitary chemotherapy with thiotepa in malignant pericardial effusion: an active and well..., Colleoni [/bib_ref] Tetracyclines as sclerosing agents also control malignant pericardial effusion in 85% of cases, but side effects and complications are quite frequent: fever (19%), chest pain (20%) and atrial arrhythmias (10%). [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] [bib_ref] Pericardiocentesis and intrapericardial sclerosis: effective therapy for malignant pericardial effusion, Girardi [/bib_ref] Radiation therapy is very effective (93%) in controlling malignant pericardial effusion in patients with radiosensitive tumours such as lymphomas and leukaemias. However, radiotherapy of the heart can cause myocarditis and pericarditis. [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] Pericardiotomy is indicated when pericardiocentesis cannot be performed. [bib_ref] Retrospective comparison of outcomes, diagnostic value, and complications of percutaneous prolonged drainage..., Patel [/bib_ref] The procedure can be carried out under local anaesthesia, but complications include myocardial laceration, pneumothorax and mortality. [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] [bib_ref] Retrospective comparison of outcomes, diagnostic value, and complications of percutaneous prolonged drainage..., Patel [/bib_ref] Surgical pericardiotomy does not improve clinical outcomes over pericardiocentesis and is associated with a higher rate of complications. [bib_ref] Catheter drainage followed by the instillation of bleomycin to manage malignant pericardial..., Maruyama [/bib_ref] Pleuropericardiotomy allows drainage of malignant pericardial fluid into the pleural space. It is associated with a higher complication rate and offers no advantage over pericardiocentesis or pericardiotomy. Pericardiectomy is rarely indicated, mainly for pericardial constriction or complications of previous procedures. [bib_ref] Treatment of malignant pericardial effusion, Vaitkus [/bib_ref] Percutaneous balloon pericardiotomy creates a pleuropericardial direct communication, which allows fluid drainage into the pleural space: in large malignant pericardial effusions and recurrent tamponade it seems to be effective (90 -97%) and safe. [bib_ref] Neoplastic pericardial effusion: efficacy and safety of intrapericardial treatment with cisplatin, Maisch [/bib_ref] Pericardial window creation via left minithoracotomy is a safe and effective approach in the surgical treatment of malignant cardiac tamponade. [bib_ref] Retrospective comparison of outcomes, diagnostic value, and complications of percutaneous prolonged drainage..., Patel [/bib_ref] In clinical practice, management is often palliative at late stages with advanced disease; it is aimed only at the relief of symptoms rather than treatment of the underlying disease, taking into account prognosis and the overall quality of life of the patients.Recommendations for the diagnosis and management of neoplastic involvement of the pericardium Prior chest radiation is an important cause of pericardial disease. Most cases are secondary to radiation therapy for Hodgkin's lymphoma or breast or lung cancer. Serious radiation-induced pericardial disease was most often due to radiation therapy of Hodgkin's lymphoma, although the incidence of the condition has decreased with lower doses and modern radiation therapy techniques (shielding and dose calculation). As an example, the incidence of pericarditis decreased from 20 to 2.5%. [bib_ref] Radiation injury to the heart, Stewart [/bib_ref] Less commonly, radiation exposure can cause other conditions (e.g. oesophageal cancer) or can occur in association with nuclear accidents. Soon after radiation the patient may develop acute pericarditis with or without effusion. [bib_ref] Radiation injury to the heart, Stewart [/bib_ref] Late onset of pericardial disease is common; it has been observed in up to 20% of patients within 2 years following irradiation,with a latency of up to 15-20 years, and is not necessarily preceded by acute pericarditis. [bib_ref] Cardiac disease after radiation therapy for Hodgkin's disease: analysis of 48 patients, Applefeld [/bib_ref] Late pericardial disease may consist of effusive-constrictive pericarditis or classical constrictive pericarditis (4-20% of patients) and appears to be dose dependent and related to the presence of pericardial effusion in the delayed acute phase.Alternatively, radiation damage may result in a large pericardial effusion, with or without tamponade. The effusion may be serous or haemorrhagic and has a high probability of developing fibrous adhesions. Therapies are similar to those employed in pericarditis and pericardial effusion. Therapeutic radiation may cause other types of cardiac injury as well. The most serious is radiation-induced cardiomyopathy, but the coronary arteries and the cardiac valves may also be affected; this probably explains why pericardiectomy for radiation-induced disease is associated with a worse outcome than when performed for constrictive pericarditis resulting from most other causes. Recommendations for the prevention and management of radiation pericarditis ## Chylopericardium Chylopericardium is a pericardial effusion composed of chyle, the normal content of the lymphatic vessels. It is a rare disorder that may be primary or, more often, secondary to injury to the thoracic duct, which carries chyle from the intestinal tract to the blood at the junction of the left internal jugular and left subclavian veins. [bib_ref] Thoracoscopic direct clipping of the thoracic duct for chylopericardium and chylothorax, Wurnig [/bib_ref] It is often associated with chylothorax. Cardiac complications are cardiac tamponade, acute pericarditis and chronic constriction. Causes are trauma, surgery (especially for congenital heart disease), congenital lymphangiomatosis, radiotherapy, subclavian vein thrombosis, infection (e.g. TB), mediastinal neoplasms and acute pancreatitis. Primary chylopericardium is less common and is a diagnosis by exclusion. CT with and without contrast enhancement or combined with lymphangiography/lymphangioscintigraphy (rarely performed) can be used to identify injury or blockage of the thoracic duct. Chylopericardium should not be confused with cholesterol pericarditis, in which the fluid is clear and occurs in tuberculous pericarditis, rheumatoid pericarditis and trauma. The concentration of cholesterol equals or exceeds that of the blood. Pericardiocentesis is seldom effective and optimal therapy is radical pericardiectomy plus treatment of the underlying cause. [bib_ref] The management of chylothorax/chylopericardium following pediatric cardiac surgery: a 10-year experience, Nguyen [/bib_ref] [bib_ref] Use of octreotide in the treatment of chylopericardium, Szabados [/bib_ref] Recommendations for the diagnosis and management of chylopericardium ## Drug-related pericarditis and pericardial effusion Pericardial reactions to drugs are rare [fig_ref] Table 1: Classes of recommendations [/fig_ref]. Pericardial damage has also been associated with polymer fume inhalation, 'serum sickness' by blood products or foreign antisera, venoms (scorpion fish sting), foreign substance reactions by direct pericardial application (e.g. talc, magnesium silicate), silicones, tetracyclines, sclerosants, asbestos and iron in b-thalassaemia. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] Management is based on discontinuation of the causative agent and symptomatic treatment. The use of heparin and anticoagulant therapies is often perceived as a possible risk factor for the development of a worsening or haemorrhagic pericardial effusion that may result in cardiac tamponade, but a multivariable analysis of nearly 500 consecutive cases of acute pericarditis did not show this to be the case. [bib_ref] Indicators of poor prognosis of acute pericarditis, Imazio [/bib_ref] Similarly in another study of 274 patients with acute pericarditis or myopericarditis, the use of heparin or other anticoagulants was not associated with an increased risk of cardiac tamponade. [bib_ref] Myopericarditis versus viral or idiopathic acute pericarditis, Imazio [/bib_ref] On the other hand, in the setting of iatrogenic pericardial effusion, full anticoagulation may be a risk factor for tamponade and complications. [bib_ref] Iatrogenic pericardial effusion and tamponade in the percutaneous intracardiac intervention era, Holmes [/bib_ref] ## Pericardial effusion in metabolic and endocrine disorders The main cause of pericardial diseases in this setting is represented by hypothyroidism. Pericardial effusion may occur in 5 -30% of patients with hypothyroidism, but recent data are lacking; 218,219 it may be quite large, but tamponade occurs rarely. It is diagnosed by a high thyroid stimulating hormone (TSH) level, and clinically is characterized by relative bradycardia and low QRS voltage in the ECG. ## Pericardial involvement in pulmonary arterial hypertension Pericardial effusion in the setting of pulmonary artery hypertension (PAH) is common (25 -30%) and typically small in size, but rarely causes haemodynamic compromise. Pericardial effusion development in PAH appears to relate to right ventricular failure and a subsequent increase in right-sided filling pressures along with right atrial hypertension and increased pressure in the thebesian veins and coronary sinus. These processes result in increased filtration and lymphatic obstruction, resulting in pericardial effusion. [bib_ref] Pericardial effusions in pulmonary arterial hypertension: characteristics, prognosis, and role of drainage, Fenstad [/bib_ref] Diagnosis of cardiac tamponade in a patient with severe PAH is challenging. Determining the haemodynamic significance of pericardial effusions in PAH requires increased attention since high rightsided pressures can mask many of the typical right-sided clinical and echocardiographic findings of tamponade. Because there is elevation in right-sided intracardiac chamber pressures, right-sided chamber collapse is uncommon. In contrast, left atrial pressure is typically lower in PAH and therefore left atrial early diastolic collapse is more commonly seen. Exaggerated ventricular interdependence, such as a decrease in left ventricular filling with early inspiration, may also be present. The presence of pericardial effusion has been associated with connective tissue disease, shorter 6-minute walk distance and an elevated B-type natriuretic peptide level. Even a small quantity of excess pericardial fluid in a patient with PAH portends a poor prognosis. Pericardial effusions in PAH appear to be a marker of co-morbidity with either concomitant connective tissue disease or high venous pressure; these two factors are recognized to confer an adverse risk. [bib_ref] Pericardial effusions in pulmonary arterial hypertension: characteristics, prognosis, and role of drainage, Fenstad [/bib_ref] ## Pericardial cysts Pericardial cysts are rare mediastinal masses with an incidence of 1 in 100,000 patients 131,221 that have been described as diverticulae or cystic formations when an abnormal chest X-ray was obtained. They represent 6% of mediastinal masses and 33% of mediastinal cysts. Other cysts in the mediastinum are bronchogenic (34%), enteric (12%), thymic and others (21%). [bib_ref] Etiology of pericarditis in a prospective cohort of 1162 cases, Gouriet [/bib_ref] They are often found in either one of the cardiophrenic angles. [bib_ref] Etiology of pericarditis in a prospective cohort of 1162 cases, Gouriet [/bib_ref] Cysts do not communicate with the pericardial space, whereas diverticulae do. They may be uni-or multiloculated. Inflammatory cysts comprise pseudocyst as well as encapsulated or loculated pericardial effusions caused by rheumatic disorders, bacterial infection, trauma or cardiac surgery. Echinococcal cysts usually originate from ruptured hydatid cysts in the liver and the lungs. The differential diagnosis comprises loculated pericardial effusions of unknown origin and malignant pericardial masses. The diagnostic workup includes echocardiography, CT and eventually CMR to define the size, density and neighbouring structures. [bib_ref] Etiology of pericarditis in a prospective cohort of 1162 cases, Gouriet [/bib_ref] They are mostly asymptomatic and detected incidentally, but can also present with chest discomfort, dyspnoea or palpitations due to cardiac compression. The first treatment for symptomatic congenital and inflammatory cysts is percutaneous aspiration, 206,222 possibly associated with ethanol sclerosis. [bib_ref] Alcohol ablation of pericardial cysts under pericardioscopical control, Maisch [/bib_ref] If the diagnosis is not completely established by imaging or the cyst recurs after drainage, surgical resection may be necessary. For echinococcal cysts, percutaneous aspiration and instillation of ethanol or silver nitrate after pre-treatment with albendazole (800 mg/day for 4 weeks) has been proposed. [bib_ref] Task Force on the Diagnosis and Management of Pericardial Diseases of the..., Maisch [/bib_ref] 6. Age and gender issues in pericardial diseases [bib_ref] Controversial issues in the management of pericardial diseases, Imazio [/bib_ref] ## .1 paediatric setting Pericarditis accounts for 5% of all children who present with chest pain to a paediatric emergency department. [bib_ref] Conditions leading to pediatric cardiology consultation in a tertiary academic hospital pediatrics, Geggel [/bib_ref] Children may be affected by the same syndromes that affect adults. [bib_ref] Idiopathic pericarditis and pericardial effusion in children: contemporary epidemiology and management, Shakti [/bib_ref] Diagnostic criteria are the same and the risk of recurrence is similar (15 -30%). The aetiology is similar to that in adults, with PPS more often described, particularly after interatrial defect correction. [bib_ref] Recurrent pericarditis in children and adolescents, Raatikka [/bib_ref] Compared with adults, children often have a marked inflammatory clinical pattern, with more commonly fever, pleuropulmonary involvement and raised CRP and less commonly anti-nuclear antibody (ANA) positivity. This might imply activation of inflammatory pathways with release of IL-1. [bib_ref] Recurrent pericarditis in children and adolescents: etiology, presentation, therapies, and outcomes. A..., Imazio [/bib_ref] No RCT has been done in children. NSAIDs remain the mainstay, at high dosages (Web. Most paediatricians avoid aspirin in children. Colchicine halved recurrences in children. [bib_ref] Recurrent pericarditis in children and adolescents: etiology, presentation, therapies, and outcomes. A..., Imazio [/bib_ref] Corticosteroid use should be restricted in children even more than in adults, given that their side effects (striae rubre and growth impairment) are particularly deleterious in growing children; the minimal effective dose should be sought. Severe physical restriction is bothersome in children and may further worsen their quality of life and that of their family. Anakinra (anti-IL-1 receptor) is a new option for children, especially if they are corticosteroid-dependent. The long-term prognosis in children is good; however, quality of life can be severely affected with repeated recurrences, glucocorticoid dependence and severe physical restriction. [bib_ref] Recurrent pericarditis in children and adolescents: etiology, presentation, therapies, and outcomes. A..., Imazio [/bib_ref] Recommendations for therapy of acute and recurrent pericarditis in children ## Pregnancy, lactation and reproductive issues The most common form of pericardial involvement in pregnancy is hydropericardium, usually as a benign mild effusion by the third trimester, which is found in up to 40% of women, often occasionally. The effusion is usually silent and clinical examination and ECG are generally normal. In a few cases, slightly elevated blood pressure and/or aspecific ST-T changes have been documented. [bib_ref] Pericardial disease in pregnancy, Ristić [/bib_ref] [bib_ref] Medical treatment of pericarditis during pregnancy, Brucato [/bib_ref] The most common disease to require medical therapy is acute pericarditis; diagnosis is made using the usual criteria. No specific aetiology is usually identified. Nowadays the general outcomes of pregnancies in these women when followed by dedicated multidisciplinary teams are similar to those expected in the general population. [bib_ref] Medical treatment of pericarditis during pregnancy, Brucato [/bib_ref] A proposed treatment scheme for pericarditis during pregnancy is described in Web [fig_ref] Table 8: Classification of pericardial effusion [/fig_ref]. Pregnancy in women with recurrent pericarditis should be planned during a phase of disease quiescence. Classic NSAIDs (ibuprofen, indomethacin) may be considered during the first and second trimesters; 25 -27 most experts prefer high-dose aspirin, since it is regularly used in antiphospholipid syndrome in pregnancy and is moderately effective in the prevention of pre-eclampsia in high-risk obstetric patients. [bib_ref] Anti-inflammatory and immunosuppressive drugs and reproduction, Østensen [/bib_ref] [bib_ref] Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic..., Henderson [/bib_ref] After gestational week 20, all NSAIDs (except aspirin ≤100 mg/day) can cause constriction of the ductus arteriosus and impair foetal renal function, and they should be withdrawn in any case at gestational week 32. [bib_ref] Anti-inflammatory and immunosuppressive drugs and reproduction, Østensen [/bib_ref] [bib_ref] Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic..., Henderson [/bib_ref] The lowest effective doses of prednisone may be used throughout pregnancy and breastfeeding (with supplementation with calcium and vitamin D). Paracetamol is allowed throughout pregnancy and breastfeeding, as are anti-histamine H2 blockers or proton pump inhibitors. [bib_ref] The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis, Gill [/bib_ref] During pregnancy, tapering of therapies should be extremely cautious. Normal vaginal delivery is possible and should be considered in the absence of contraindications. Ibuprofen, indomethacin, naproxen and prednisone may be considered in women who are breastfeeding. After discontinuation of breastfeeding, gradual tapering of prednisone should be considered, eventually resuming colchicine. Colchicine is considered contraindicated during pregnancy and breastfeeding, even though no adverse events during pregnancy and foetal or child development have been reported in women with FMF treated with colchicine during pregnancy and breastfeeding. 227 -229 ## The elderly Most guidelines have not discussed the applicability of their recommendations to older patients with multiple co-morbidities. [bib_ref] Medication non-adherence among elderly patients newly discharged and receiving polypharmacy, Pasina [/bib_ref] No paper has specifically addressed pericardial diseases in the elderly, so only expert opinion exists. Therapy adherence and compliance may be problematic in the elderly because of cognitive impairment, poor vision or hearing and cost, but the strongest predictor of nonadherence is the number of medications. [bib_ref] Medication non-adherence among elderly patients newly discharged and receiving polypharmacy, Pasina [/bib_ref] Indomethacin is not indicated, the colchicine dose should be halved and particular care should be taken to evaluate renal impairment and drug interactions. ## Interventional techniques and surgery The aetiology of pericardial diseases remains unresolved in many cases because the full spectrum of diagnostic methods is not used in many institutions. The gold standard remains surgical by the subxiphoid approach, allowing collection of fluid samples and performing pericardial biopsy and pericardial drainage. Interventional techniquesinclude the combined use of imaging by pericardioscopy first described in combination with diagnostic molecular, histological and immunohistological methods to assess the aetiology and pathogenesis of pericardial and epicardial disease manifestations [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] and the option to intervene therapeutically by instillation of drugs into the pericardial sac. [bib_ref] Viral genomes in the pericardial fluid and in peri-and epicardial biopsies from..., Pankuweit [/bib_ref] [bib_ref] Neoplastic pericardial effusion: efficacy and safety of intrapericardial treatment with cisplatin, Maisch [/bib_ref] ## Pericardiocentesis and pericardial drainage For pericardial drainage and biopsy, the surgical approach remains the gold standard. The classical approach is by subxiphoid incision, through which it is easy to take fluid samples and perform a pericardial biopsy. The operation is completed by leaving a small drain in place to evacuate remaining effusion. This technique using a subxiphoid approach is straightforward for a thoracic or cardiovascular surgeon, if such a team is close to the cardiology team. In clinical practice, pericardial fluid is aspirated by pericardiocentesis. State-of-the-art pericardiocentesis must be guided either by fluoroscopy or echocardiography 206 under local anaesthesia. Blind procedures must be not be used to avoid the risk of laceration of the heart or other organs, except in very rare situations that are immediately life threatening. An experienced operator and staff should perform pericardiocentesis in a facility equipped for radiographic, echocardiographic, haemodynamic and ECG monitoring. For echo-guided pericardiocentesis, the ideal entry site is the point on the body surface where the effusion is closest to the transducer and the fluid collection is maximal. The needle trajectory is defined by the angulation of the handheld transducer and should avoid vital structures such as the liver, myocardium, lung, internal mammary artery (3 -5 cm away from the parasternal border) and the vascular bundle at the inferior margin of each rib. The intended point of entry is marked on the skin and the direction of the ultrasound beam is carefully noted (see Web supplemental material). An additional technique is the echo-guided approach followed by echomonitoring of the procedure. For fluoroscopic-guided pericardiocentesis, a polytef-sheathed needle with an attached saline-filled syringe is advanced under moderate suction until the pericardial sac is reached.When using the more common subxiphoid route for pericardiocentesis, a Tuohy-17, blunt-tip introducer needle is advanced to the left shoulder at a 30-degree angle to the skin, thus avoiding coronary, pericardial and internal mammary arteries. The lateral angiographic view provides the best visualization of the puncturing needle and its relation to the diaphragm and pericardium. The needle is slowly advanced towards the heart shadow and the epicardial halo phenomenon, under moderate suction and with injection of small amounts of diluted contrast medium, until pericardial fluid is aspirated. If haemorrhagic fluid is freely aspirated, a few millilitres of contrast medium may be injected under fluoroscopic control to verify the position of the needle. A soft J-tip guidewire is then introduced and after dilatation is exchanged for a multihole pigtail catheter, through which the fluid is evacuated under the control of intrapericardial pressure.Pericardiocentesis should be performed by experienced operators and carries a risk of complications ranging from 4 to 10% depending on the type of monitoring, the skill of the operator and the setting (emergency vs. urgent vs. elective). [bib_ref] Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes..., Tsang [/bib_ref] Most common complications include arrhythmias, coronary artery or cardiac chamber puncture, haemothorax, pneumothorax, pneumopericardium and hepatic injury (Web [fig_ref] Table 9: Causes of cardiac tamponade [/fig_ref]. Pericardiocentesis may have additional limitations/dangers when pericardial fluid is not free and when located in a lateral or posterior position or ,10 mm. In these cases a surgical approach might be safer, depending on local expertise and availability. ## Pericardioscopy Pericardioscopy permits visualization of the pericardial sac with its epicardial and pericardial layers. Macroscopic views show a clustering of protrusions, haemorrhagic areas and neovascularization in malignant pericardial effusion, which are often haemorrhagic, in contrast to radiogenic or viral and autoimmune effusions. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Pericardioscopy enables the performing physician to take targeted biopsy specimens from epicardial and pericardial layers, avoiding epicardial vessels and increasing the probability of obtaining diseasespecific results. For safety reasons it is important to have a second wire in place. The safety wire allows a quick exchange with a pigtail catheter and allows autotransfusion in the case of relevant bleeding. By selecting the biopsy site, less informative white areas of fibrin can be avoided and dark spots of inflammation, malignancy or haemorrhagic imbibitions can be selected, which can be identified best in the blue-light mode. Pericardial biopsy can even be taken under radiologic control alone. The open jaws of the bioptome are advanced gently until the silhouette of the pericardial sac is reached. Then the jaws are closed and the biopsy sample is taken. Seven to 10 samples should be taken to reduce sampling error. The most meaningful diagnostic yield from pericardial biopsies can be obtained by multiple pericardioscopically guided tissue acquisitions. This technique is quite demanding and can be performed in only a limited number of experienced tertiary referral centres. Pericardioscopy may be considered as a diagnostic method for inspection of the pericardium and epicardium in experienced centres. It permits safe tissue acquisition in pericardial diseases of unknown origin. ## Pericardial fluid analysis, pericardial and epicardial biopsy Serosanguinous or haemorrhagic fluid can be found in malignant as well as post-pericardiotomy, rheumatologic and traumatic effusions or can be caused by iatrogenic lesions during pericardiocentesis, but also in idiopathic and viral forms. In cases of sepsis, TB or in HIVpositive patients, bacterial cultures can be diagnostic. Fluid cytology can separate malignant from non-malignant effusions, which is important for effusions in tumour patients after radiotherapy of the mediastinum. Discriminative signatures between malignant and autoreactive effusions are higher levels of tumour markers in neoplastic pericardial effusion. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] Cytology and assessment of bacterial cultures of the fluid, histological/immunohistological evaluation of biopsy specimens and molecular analysis (PCR for microbial agents of fluid and tissue) allow a definite aetiological diagnosis in many cases, which permits further treatment. [bib_ref] Pericardioscopy and epi-and pericardial biopsy-a new window to the heart improving etiological..., Maisch [/bib_ref] ## Intrapericardial treatment In patients with a larger effusion of unknown origin, prolonged pericardial drainage may allow subsequent intrapericardial treatment. In neoplastic pericardial effusion, most frequently due to bronchus carcinoma or breast cancer, intrapericardial cisplatin or thiotepa therapy have been proposed in combination with systemic antineoplastic treatment, which should be tailored in collaboration with the oncologist. [bib_ref] Neoplastic pericardial effusion: efficacy and safety of intrapericardial treatment with cisplatin, Maisch [/bib_ref] In autoreactive and lymphocytic pericardial effusion diseasespecific intrapericardial crystalloid triamcinolone (300 mg/m 2 body surface) may be considered. [bib_ref] Intrapericardial treatment of autoreactive pericardial effusion with triamcinolone: the way to avoid..., Maisch [/bib_ref] Viral pericarditis may be excluded by PCR in fluid and tissue specimens, but such investigations are not usually performed in uncomplicated cases in clinical practice. In cases of uraemic pericardial effusion, intrapericardial therapy with triamcinolone may be considered, apart from intensified haemo-or peritoneal dialysis and fluid evacuation. [bib_ref] Intrapericardial treatment of autoreactive pericardial effusion with triamcinolone: the way to avoid..., Maisch [/bib_ref] [bib_ref] Intrapericardial triamcinolone administration for autoreactive pericarditis, Frasiolas [/bib_ref] In rare cases of recurrent effusion, balloon pericardiotomy is an option that allows a (transient) pericardio(-pleural-)abdominal window for drainage. This approach should be avoided in neoplastic or purulent effusions. ## Pericardial access for electrophysiology First reported in 1996, [bib_ref] A new technique to perform epicardial mapping in the electrophysiology laboratory, Sosa [/bib_ref] pericardial access has been used for the mapping and ablation of epicardial substrates of ventricular tachyarrhythmias with improved success rates and avoidance of a surgical procedure [bib_ref] Transthoracic epicardial catheter ablation. Indications, techniques and complications, Yamada [/bib_ref] [bib_ref] Epicardial ventricular tachycardia ablation a multicenter safety study, Sacher [/bib_ref] (see supplemental Web material and Web [fig_ref] Table 9: Causes of cardiac tamponade [/fig_ref] for complications of the procedure). 7.6 Surgery for pericardial diseases 7.6.1 Pericardial window A pericardial window is a cardiac surgical procedure to create a communication, or 'window', from the pericardial space to the pleural cavity. The purpose of the window is to allow a pericardial effusion (usually malignant) to drain from the space surrounding the heart into the chest cavity in order to prevent a large pericardial effusion and cardiac tamponade. The window is usually performed by a cardiac surgeon, but a pericardial window may be created by video-assisted thoracoscopy or balloon pericardiotomy by a percutaneous intervention. The main indication is represented by recurrent large effusions or cardiac tamponade when a more complex operation such pericardiectomy is a high risk or the life expectancy of the patient is reduced (e.g. neoplastic pericardial disease) and the intervention is palliative. The results of a pericardial window are less definitive since the communication may close and recurrent effusions, especially loculated, are common and may require additional interventions compared with pericardiectomy, which is a more complex but complete operation. [bib_ref] Completion pericardiectomy for recurrent constrictive pericarditis: importance of timing of recurrence on..., Cho [/bib_ref] ## Pericardiectomy In constrictive pericarditis the treatment is pericardectomy. The decortications should remove as much of the pericardium as possible with all constricting parietal and epicardial layers, 103 -105 but taking care of perserving the phrenic nerves bilaterally. Only by using sternotomy can all the constricting pericardial layers be removed. Therefore, left anterolateral thoracotomy should be avoided since it permits only a partial resection. It is also necessary to liberate all of the right atrium, the superior vena cava and especially the inferior vena cava and the inferior part of the right ventricle adjacent to the diaphragm as far as possible. Only when the constricting peel is adherent and calcified is it necessary to leave behind a few islands of the pericardium. To avoid bleeding, cardiopulmonary bypass should be employed only in cases of co-existent cardiac surgical lesions, but cardiopulmonary bypass may be needed in stand-by, in case of the occurrence of haemorrhagic lesions during the procedure. By applying these principles, the controversy over the type of operation (complete or radical or only anterior pericardiectomy) is not an issue. In recurrent constrictive pericarditis, a repeated operation has to be done as soon as possible, ideally during the first postoperative year. Rare patients with relapsing pericarditis can also benefit from pericardiectomy. [bib_ref] Pericardiectomy vs medical management in patients with relapsing pericarditis, Khandaker [/bib_ref] ## Perspective and unmet needs Despite a large amount of new data and the first clinical trials that allow clinical management to be on the road to evidencebased medicine, there are several issues that require additional research and clarification. The main issues and unsolved questions include (1) Pathophysiology and risk factors for recurrent pericarditis. What is really 'idiopathic recurrent pericarditis'? (2) How is it possible to prevent pericarditis beyond colchicine? (3) Is drug tapering useful for patients with pericarditis? (4) What is the best treatment duration for patients with pericardial diseases? (5) New and individualized therapies for refractory recurrent pericarditis. Are they really available and useful? (6) Is exercise restriction really needed for patients with acute and recurrent pericarditis? (7) Given the high risk of constrictive pericarditis in infective pericarditis (i.e. tuberculous and purulent) and the promising effect of intrapericardial fibrinolysis in case reports and small trials, is intrapericardial fibrinolysis in exudative pericarditis really safe and efficacious? And when should it be considered in the clinical management of patients? (8) What interventions are required to reduce the high mortality of tuberculous pericarditis treated with antituberculosis medication? (9) What actually is pericarditis with myocarditis? [bib_ref] Colchicine in addition to conventional therapy for acute pericarditis: results of the..., Imazio [/bib_ref] What are the long-term outcomes of patients with myopericarditis and perimyocarditis? (11) Aetiology and pathophysiology of isolated pericardial effusion. What is 'idiopathic pericardial effusion'? (12) Is diagnosis and treatment necessary for all moderate to large pericardial effusions? [bib_ref] Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine..., Imazio [/bib_ref] What are the indications for invasive diagnostic techniques and their diagnostic yield in clinical practice? [bib_ref] Adler Y; CORP (COlchicine for Recurrent Pericarditis) Investigators. Colchicine for recurrent pericarditis..., Imazio [/bib_ref] What is the role, value and application of intrapericardial therapies? (15) Is pericardiectomy really useful and indicated in refractory recurrent pericarditis? [bib_ref] Clinical profile and influences on outcomes in patients hospitalized for acute pericarditis, Kytö [/bib_ref] What are the causes and risk factors for constrictive pericarditis? [bib_ref] Idiopathic pericarditis and pericardial effusion in children: contemporary epidemiology and management, Shakti [/bib_ref] What is the best timing for surgical therapies in pericardial diseases? Ongoing basic and clinical research is warranted and needed to address all these issues and provide additional diagnostic and therapeutic tools for individualized management of each patient and to improve the prognosis. Hospital admission is recommended for high-risk patients* with acute pericarditis I B Colchicine use (0.5 mg twice or once daily for patients ,70 kg or intolerant to higher doses) is recommended as first-line therapy for acute pericarditis as an adjunct to aspirin/NSAIDs therapy (3 months) and is also recommended for recurrent pericarditis (6 months) ## I a Corticosteroids are not recommended as first-line therapy for acute pericarditis III C CRP should be considered to guide the treatment duration and assess the response to therapy IIa C ## Recommendation for management and therapy of pericardial effusion Pericardiocentesis or cardiac surgery is indicated for cardiac tamponade or for symptomatic moderate to large pericardial effusions not responsive to medical therapy and for suspicion of unknown bacterial or neoplastic aetiology ## I c A triage of patients with pericardial effusion is recommended (see I C It is recommended to target the therapy of pericardial effusion according to the aetiology I C Recommendation for diagnosis and therapy of constrictive pericarditis CT and/or CMR are indicated as second-level imaging techniques (after echocardiography and chest X-ray) to assess calcifications (CT), pericardial thickness, degree and extension of pericardial involvement I C Cardiac catheterization is indicated when non-invasive diagnostic methods do not provide a definite diagnosis of constriction ## I c The mainstay of treatment of chronic permanent constriction is pericardiectomy I C ## Recommendation for diagnostic work-up of pericardial diseases In all cases of suspected pericardial disease first diagnostic evaluation is recommended, with auscultation, ECG, transthoracic echocardiography, chest X-ray and routine blood tests, including markers of inflammation (i.e. CRP and/or ESR), WBC count with differential, renal function, liver tests and myocardial damage (creatine kinase, troponin) ## I c CT and/or CMR are second-level testing for diagnostic workup in pericarditis I C Further testing is indicated in high-risk patients* according to the clinical conditions I C ## Management of tuberculous pericarditis and effusion In patients living in endemic areas, empiric anti-TB chemotherapy is recommended for exudative pericardial effusion, after excluding other causes ## I c In patients living in non-endemic areas, empiric anti-TB treatment is not recommended when systematic investigation fails to yield a diagnosis of tuberculous pericarditis ## Iii c Standard anti-TB drugs for 6 months is recommended for the prevention of tuberculous pericardial constriction ## I c Pericardiectomy is recommended if the patient's condition is not improving or is deteriorating after 4-8 weeks of antituberculosis therapy I C ## Management of neoplastic pericardial disease Cytological analyses of pericardial fluid are recommended for the confirmation of malignant pericardial disease ## I b Pericardial or epicardial biopsy should be considered for the confirmation of malignant pericardial disease ## Iia b Tumour marker testing should be considered for distinguishing malignant from benign effusions in pericardial fluid ## Iia b Systemic antineoplastic treatment is recommended in confirmed cases of neoplastic aetiology ## I b Extended pericardial drainage is recommended in patients with suspected or definite neoplastic pericardial effusion in order to prevent effusion recurrence and provide intrapericardial therapy ## I b Intrapericardial instillation of cytostatic/sclerosing agents should be considered since it may prevent recurrences in patients with malignant pericardial effusion ## Iia b CMR ¼ cardiac magnetic resonance; CRP ¼ C-reactive protein; CT ¼ computed tomography; ECG ¼ electrocardiogram; ESR ¼ erythrocyte sedimentation rate; NSAID ¼ non-steroidal anti-inflammatory drug; TB ¼ tuberculosis; WBC ¼ white blood cell. *High risk when there is at least one risk factor among the following: high fever (.388C), subacute course without a clear-cut acute onset, large pericardial effusion (i.e. diastolic echo-free space .20 mm), cardiac tamponade, failure to respond to NSAID therapy, myopericarditis, immunodepression, trauma or oral anticoagulant therapy. a Class of recommendation. b Level of evidence. ## Web addenda All Web figures and Web tables are available in the online addenda at: http://www.escardio.org/Guidelines-&-Education/ Clinical-Practice-Guidelines/Pericardial-Diseases-Guidelines-onthe-Diagnosis-and-Management-of [fig] Figure 1: (both major and minor predictors of poor prognosis). [/fig] [fig] Figure 2: Therapeutic algorithm for acute and recurrent pericarditis (see text for explanation). [/fig] [table] 1: Clinical presentation . . . . . . . . . . . . . . . . . . . . .2937 3.7.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . .2937 3.7.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2937 3.7.4 Specific forms . . . . . . . . . . . . . . . . . . . . . . . Multimodality imaging . . . . . . . . . . . . . . . . . . . . . . .2940 4.1.1 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . .2940 4.1.2 Echocardiography . . . . . . . . . . . . . . . . . . . . . . .2940 4.1.3 Computed tomography . . . . . . . . . . . . . . . . . . .2940 4.1.4 Cardiac magnetic resonance . . . . . . . . . . . . . . . .2940 4.1.5 Nuclear medicine . . . . . . . . . . . . . . . . . . . . . . .2942 Proposal for a general diagnostic workup . . . . . . . . . .2943 5. Specific aetiologies of pericardial syndromes . . . . . . . . . . .2944 5.1 Viral pericarditis . . . . . . . . . . . . . . . . . . . . . . . . . .2944 5.1.2 Definition and clinical spectrum . . . . . . . . . . . . .2944 5.1.3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . .2945 5.1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . .2945 5.1.5 Identification of viral nucleic acids . . . . . . . . . . . .2946 5.1.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .2946 5.2 Bacterial pericarditis . . . . . . . . . . . . . . . . . . . . . . .2946 5.2.1 Tuberculous pericarditis . . . . . . . . . . . . . . . . . .2946 5.2.1.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . .2947 5.2.1.2 Management . . . . . . . . . . . . . . . . . . . . . .2947 5.2.2 Purulent pericarditis . . . . . . . . . . . . . . . . . . . .2948 5.2.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . .2948 5.2.2.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . .2948 5.2.2.3 Management . . . . . . . . . . . . . . . . . . . . . .2948 5.3 Pericarditis in renal failure . . . . . . . . . . . . . . . . . . .2949 5.4 Pericardial involvement in systemic autoimmune and autoinflammatory diseases . . . . . . . . . . . . . . . . . . . . . .2949 5.5 Post-cardiac injury syndromes . . . . . . . . . . . . . . . . .2950 5.5.1 Definition and diagnosis . . . . . . . . . . . . . . . . . .2950 5.5.2 Management . . . . . . . . . . . . . . . . . . . . . . . . .2950 5.5.3 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . .2950 5.5.4 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . Pericardial involvement in neoplastic disease . . . . . . .2952 5.8 Other forms of pericardial disease . . . . . . . . . . . . . .2953 5.8.1 Radiation pericarditis . . . . . . . . . . . . . . . . . . Pericardial effusion in metabolic and endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2954 5.8.5 Pericardial involvement in pulmonary arterial hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2954 5.8.6 Pericardial cysts . . . . . . . . . . . . . . . . . . . . . . .2955 6. Age and gender issues in pericardial diseases . . . . . . . . . . .2955 6.1 Paediatric setting . . . . . . . . . . . . . . . . . . . . . . . Interventional techniques and surgery . . . . . . . . . . . . . . . .2956 7.1 Pericardiocentesis and pericardial drainage . . . . . . . . .2956 7.2 Pericardioscopy . . . . . . . . . . . . . . . . . . . . . . . . . . .2957 7.3 Pericardial fluid analysis, pericardial and epicardial biopsy 2957 7.4 Intrapericardial treatment . . . . . . . . . . . . . . . . . . . . .2957 7.5 Pericardial access for electrophysiology . . . . . . . . . . . .2957 7.6 Surgery for pericardial diseases . . . . . . . . . . . . . . . . .2957 7.6.1 Pericardial window . . . . . . . . . . . . . . . . . . . . . .2957 7.6.2 Pericardiectomy . . . . . . . . . . . . . . . . . . . . . . . .2957 8. Perspective and unmet needs . . . . . . . . . . . . . . . . . . . . . .2958 9. To do and not to do messages from the pericardium guidelines 2958 10. Web addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2959 11. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2959 12. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2960 [/table] [table] Table 2: Levels of evidenceData derived from multiple randomized clinical trials or meta-analyses. [/table] [table] Table 3: Aetiology of pericardial diseases. The pericardium may be affected by all categories of diseases, including infectious, autoimmune, neoplastic, iatrogenic, traumatic, and metabolic A. Infectious causes: Viral (common): Enteroviruses (coxsackieviruses, echoviruses), herpesviruses (EBV, CMV, HHV-6), adenoviruses, parvovirus B19 (possible overlap with aetiologic viral agents of myocarditis). Bacterial: Mycobacterium tuberculosis (common, other bacterial rare), Coxiella burnetii, Borrelia burgdorferi, rarely: Pneumococcus spp, Meningococcus spp, Gonococcus spp, Streptococcus spp, Staphylococcus spp, Haemophilus spp, Chlamydia spp, Mycoplasma spp, Legionella spp, Leptospira spp, Listeria spp, Providencia stuartii. Fungal (very rare): Histoplasma spp (more likely in immunocompetent patients), Aspergillus spp, Blastomyces spp, Candida spp (more likely in immunocompromised host). erythematosus, Sjögren syndrome, rheumatoid arthritis, scleroderma), systemic vasculitides (i.e. eosinophilic granulomatosis with polyangiitis or allergic granulomatosis, previously named Churg-Strauss syndrome, Horton disease, Takayasu disease, Behçet syndrome), sarcoidosis, familialNeoplastic:Primary tumours (rare, above all pericardial mesothelioma). Secondary metastatic tumours (common, above all lung and breast cancer, lymphoma).Metabolic: Uraemia, myxoedema, anorexia nervosa, other rare. [/table] [table] Table 4: Definitions and diagnostic criteria for pericarditis (see text for explanation) [/table] [table] Table 5: Commonly prescribed anti-inflammatory therapy for acute pericarditis [/table] [table] Table 6: Commonly prescribed anti-inflammatory therapies for recurrent pericarditis (for further details see Web Tables 1A and 1B) [/table] [table] Table 8: Classification of pericardial effusion [/table] [table] Table 9: Causes of cardiac tamponade [/table]	None	https://academic.oup.com/eurheartj/article-pdf/36/42/2921/23488748/ehv318.pdf	ADA : adenosine deaminase AMI : acute myocardial infarction ANA : anti-nuclear antibody bFGF : basic fibroblast growth factor CK : creatine kinase CMR : cardiac magnetic resonance CMV : cytomegalovirus CP : Child–Pugh CRP : C-reactive protein CT : computed tomography EBV :
e9b311ae59f8d099b10f179f676573afced64c6f	pubmed	COVID-19 and schools. Guidelines of the French Pediatric Society☆	COVID-19 and schools. Guidelines of the French Pediatric Society☆ # Introduction In France, the COVID-19 epidemic was accompanied by a lockdown involving the total closure of schools on March 13, 2020. Schools reopened very gradually from May 11, 2020 until the summer break. The French Pediatric Society (SFP) and various societies of pediatric specialties have firmly supported the return of children to school, including those with chronic illnesses. The back-to-school period, set for September 2, 2020, is taking place in the context of an increase in viral spread and requires strict adherence to health measures to limit the risk of outbreaks in communities. It is crucial to recall that the educational and social benefits provided by school far outweigh the risks of a possible COVID-19 contamination of children in school environments or in daycare centers (DCC). In line with the position taken by pediatric authorities in many countries, the SFP proposes a practical management of COVID-19 infections in schools, compatible with regular in-person teaching and without imposing on children repeated screening tests, which is of no benefit for epidemic control (Appendix 1). # Methods These guidelines are based on an exhaustive search of studies concerning the role of children in the transmissibility of the infection and of children's susceptibility to infection. The PubMed and medRxiv databases were searched, with a particular focus on publications from the past 3 months. The following keywords were used: children, pediatric, COVID-19, SARS-CoV-2, schools, transmission, susceptibility, outbreak, household. This review of recent publications was organized around four themes: (a) the role of children in transmission, (b) susceptibility to infection, (c) expression of the disease in children, and (d) the benefits of school. The established recommendations were also compared with the different positions taken by pediatric societies or governmental health organizations in Europe. The educational and social benefits provided by school far outweigh the risks of a possible COVID-19 contamination of children in school environments or in daycare centers. Following summer break, the back-to-school period in France is taking place in the context of an increasing viral spread and requires strict adherence to health measures to limit the risk of outbreaks in communities. Based on a critical update of the role of children in the transmission of the infection, and of children's susceptibility to infection, the French Pediatric Society published practical guidelines for school re-entry and the management of COVID-19 infections in schools. The secondary attack rate from children is very low, and clusters initiated by a pediatric case are rare There are now many observational studies from several countries, models, or meta-analyses that allow us to assert the low transmitter status of children compared with adults. In Irish schools, no secondary cases were found among the 1,001 children who came into contact with three pediatric cases (10-15-year-old children) and three adult cases [bib_ref] No evidence of secondary transmission of COVID-19 from children attending school in..., Heavey [/bib_ref]. In England, national surveillance following the reopening of educational settings in June and July 2020 showed that only 70 children were affected out of more than 1 million children attending preschool and primary school. Only 0.01% of open educational settings had an outbreak. Importantly, staff members had an increased risk of SARS-CoV-2 infections compared with students in any educational setting, and the majority of cases linked to outbreaks were in staff. In Guangzhou (China), a retrospective study of 195 intrafamily clusters showed that the lowest risk of infection was in contacts under 20 years of age (OR = 0.23 [0.11-0.46]) compared with contacts over 60 years of age. Transmission was highest during the incubation period [bib_ref] Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China:..., Jing [/bib_ref]. In Switzerland, the evaluation of 111 intrafamily contacts around 40 cases of infected children under 16 years of age showed that a pediatric case was suspected to be the first intrafamily case in only 8% of cases [bib_ref] COVID-19 in children and the dynamics of infection in families, Posfay-Barbe [/bib_ref]. In Australia, testing of contacts linked to 12 children and 15 adults in 15 schools (children aged 6 years and older) and 10 kindergartens/nurseries (children aged 6 weeks to 5 years) showed a child-to-child attack rate of 0.3%, a child-to-adult attack rate of 1%, an adult-to-child attack rate of 1.5%, and an adult-to-adult attack rate of 4.4%. Only one daycare center experienced an outbreak with six adults and seven children infected out of 35 contact cases; transmissions were adult-to-adult and adult-to-child. In France, 80 schoolchildren were tested in three classes attended by a 9-year-old infected boy. No secondary cases were observed [bib_ref] Cluster of Coronavirus Disease 2019 (COVID-19) in the French Alps, Danis [/bib_ref]. In Korea, the reports for contacts of 5706 index cases were analyzed. Children between 0 and 9 years of age represented only 29 index cases (0.5%) and those between 10 and 19 years of age only 124 index cases (2.2%). The number of infected people was much higher in the home than outside the home (11.8% vs. 1.9%, respectively). The rate of cases linked to the index case was the lowest among children aged 0-9 years (5.3% at home vs. 1.1% outside the home). This rate was high among adolescents aged 10-19 years (18.6% at home vs. 0.9% outside the home). However, it was not known whether the index case, defined as the first identified case, was actually the transmitter [bib_ref] Contact tracing during Coronavirus disease outbreak, Park [/bib_ref]. In Rhode Island, strict surveillance was implemented after the reopening of 666 communities for children (0-12 years), with adults wearing masks. Reports of infections were rare: 25 situations with one case without secondary transmission; four situations with possible secondary transmission [bib_ref] Limited Secondary Transmission of SARS-CoV-2 in Child Care Programs -Rhode Island, Link-Gelles [/bib_ref]. This reduced ability of children to transmit the infection appears to be independent of the viral load measured by polymerase chain reaction (PCR), which seems to be the same in symptomatic children and adults [bib_ref] Culture-competent SARS-CoV-2 in nasopharynx of symptomatic neonates, children, and adolescents, L'huillier [/bib_ref] , or is even higher in young children. ## 3.2. Epidemiological data suggest that a child exposed to an infectious case is less likely to become infected than an adult In a recent general review on the effect of age on the transmission of SARS-CoV-2 in households, schools, and the community, Golstein et al. concluded that there was evidence that susceptibility to infection in children under the age of 10 years was significantly lower compared with adults. This conclusion is indeed supported by epidemiological data from many countries. In Iceland, targeted screening of at-risk individuals showed a 6.7% positivity rate in children under 10 years of age compared with 13.7% in those older than 10. In population-based screening without risk factors, the positivity rate was 0% in children under 10 years of age compared with 0.8% in those older than 10 [bib_ref] Spread of SARS-CoV-2 in the Icelandic population, Gudbjartsson [/bib_ref]. Current French epidemiological data are consistent with this. In week 33, the lowest incidence rate (per 100,000 inhabitants) was in the 0-14 age group (8.4), compared with 43.1 in the 15-44 age group, 19.5 in the 45-64 age group, 10.1 in the 65-74 age group, and 11.4 in the 75 and over age group. Data from the French GPIP-ACTIV pediatric network showed that the risk of PCR positivity during the epidemic period (March-April 2020) was 3 times higher in adults than in children [bib_ref] Changes in RT-PCR-positive SARS-CoV-2 rates in adults and children according to the..., Levy [/bib_ref]. The UK experience is identical to the one in France. Children under 16 years of age represented 1.1% of proven cases. The rate of positive tests was very low in children compared with adults [bib_ref] COVID-19 in children: analysis of the first pandemic peak in England, Ladhani [/bib_ref]. Data from the United States confirmed a low prevalence of SARS-CoV-2 infection in children who were asymptomatic and who were tested by PCR before surgery, clinic visits, or hospital admissions [bib_ref] Prevalence of SARS-CoV-2 infection in children without symptoms of coronavirus disease 2019, Sola [/bib_ref]. The pooled prevalence of infection was 0.65% (95% CI: 0.47-0.83), but varied from 0 to 2.2% in a linear relationship with the mean weekly incidence of COVID-19 for the entire population of the same geographical area. Prevalence in asymptomatic children remained below 1% as long as the weekly incidence in the general population remained below 70/100,000. It reached 1.5% if this incidence rose to 120/100,000 (asymptomatic pediatric prevalence = 1.07 Â weekly incidence [no. per 1000 general population] + 0.23) [bib_ref] Prevalence of SARS-CoV-2 infection in children without symptoms of coronavirus disease 2019, Sola [/bib_ref]. In an intrafamily transmissibility study analyzing 105 index patients and 392 home contacts, the secondary attack rate was 2.3% in children aged 0-5 years, 5.4% in those aged 6-17 years, and 17.1% in adults [bib_ref] The characteristics of household transmission of COVID-19, Li [/bib_ref]. In Greece, the analysis of 23 family clusters showed that the adult was the first identified case in 91.3% of cases. Adult-to-adult transmissions were identified in 12 clusters, and adult-to-child transmissions in 19 clusters. There was no evidence of child-tochild or child-to-adult transmission [bib_ref] Transmission dynamics of SARS-CoV-2 within families with children in Greece: a study..., Maltezou [/bib_ref]. In Hunan (China), retrospective analysis of 210 clusters showed that only 8 of 210 clusters (3.5%) were linked to asymptomatic patients. The risk of transmission was increased at home. Susceptibility to infection increased with age. The number of infected contacts from index cases under 20 years of age was very low. In a model based on multinational data, the susceptibility to infection in children was estimated to be half that of adults (0.40 [0.25-0.57] in 0-9-yearolds vs. 0.88 [0.70-0.99] in 60-69-year-olds) [bib_ref] Age-dependent effects in the transmission and control of COVID-19 epidemics, Davies [/bib_ref]. In the most recent meta-analysis, the average rate of secondary attack at home (10 studies) was 31.0% (95% CI: 19.4-42.7%) for adults and 15.7% (9.9-21.5%) for children under 18 years of age. Only one recent study showed a strong pediatric transmission [bib_ref] SARS-CoV-2 transmission and infection among attendees of an overnight camp -Georgia, Szablewski [/bib_ref]. After exposure to a teenage staff member in a camp without any particular prevention measures, the attack rate was 51% in children aged 6-10 years and 44% in those aged 11-17 years; 26% of the infections were asymptomatic. This study gave few details on the epidemiological links, but suggested avoiding situations of very close exposure without appropriate measures. Somewhat similar to this study, an outbreak was described in a high school in Israel, during the reopening of schools, with an attack rate of 13.2% among teenagers and 16.6% among teachers [bib_ref] A large COVID-19 outbreak in a high school 10 days after schools'..., Stein-Zamir [/bib_ref]. This study was, however, not very informative because the conditions of the outbreak were very particular (no prevention measures, heatwave, air conditioning), the modes of transmission were not described, and intrafamily screening was not reported. Like the experience of the Georgian camp, it nevertheless suggests avoiding situations of close exposure in high school without appropriate prevention measures. 3.3. Infected children are more likely to be asymptomatic, and hospitalization of severe forms is rare In the intrafamily transmission study conducted in Switzerland, 57% of infected children were asymptomatic, compared with only 15% of infected adults [bib_ref] COVID-19 in children and the dynamics of infection in families, Posfay-Barbe [/bib_ref]. Similarly, the intrafamily transmission study carried out in Greece showed that 40% of infected children were asymptomatic, compared with 10.5% of infected adults [bib_ref] Transmission dynamics of SARS-CoV-2 within families with children in Greece: a study..., Maltezou [/bib_ref]. In France, studies conducted in Cré py-en-Valois schools showed that 41.4% of seropositive children reported no symptoms, compared with only 9.9% of seropositive adults. In a model based on multinational data, the fraction of symptomatic infections was 21% (12-31%) in children aged 10-19 years, compared with 69% (57-82%) in people over 70 years of age [bib_ref] Age-dependent effects in the transmission and control of COVID-19 epidemics, Davies [/bib_ref]. In France, children aged 0-14 years account for 1% of hospitalized patients (1033/83,756, on 18/08/2020). Pediatric deaths are exceptional [bib_ref] COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study, Gotzinger [/bib_ref] [bib_ref] Severe and fatal forms of COVID-19 in children, Oualha [/bib_ref]. ## The educational and social benefits provided by school far outweigh the risks of a possible sars-cov-2 contamination of children in school environments The consequences of school closures during the lockdown imposed in many countries are multiple and concern numerous aspects: educational, economic, health, family, and abuse. The most vulnerable children were the most affected by school closures. Preexisting vulnerabilities have been exacerbated, and inequalities have worsened, particularly in access to high-quality distance education. The reopening of schools with the physical presence of pupils is therefore an objective shared by all pediatric societies around the world. A recent editorial made a strong case for schools reopening [bib_ref] Reopening primary schools during the pandemic, Levinson [/bib_ref]. The admission of children to school should be made on the condition that transmissibility in the population is reduced, or better still eliminated, through testing and supervision. The number of pediatric cases in the community will be lower if the viral circulation in the population is low, intrafamily transmission being predominant. It is particularly crucial to set up a rapid screening strategy around adult cases, targeting as a priority the circle of close relatives. The risk of an epidemic in a community of children will also be lower if adult staff in the establishments follow strict health measures, since transmission in communities is mainly from adults to adults or from adults to children. ## 4. Guidance for school re-entry: Guidelines of the French Pediatric Society 4.1. Back-to-school is possible for every child, under mitigation strategies (e.g., hand hygiene practices, social distancing, and cloth face coverings when indicated). Children without comorbidities must be able to go back to school normally. All children with chronic diseases must be able to go back to school normally, unless an exception is validated by the child's referring specialist. In primary, middle, and high schools, soap or hand sanitizer distribution stations should be provided at least at the entrances of schools classrooms, and education about their regular use should be provided. For children < 6 years of age, education about regular handwashing is essential. All adult staff in schools must wear masks at all times. Wearing a mask by middle and high school students is useful. It can be less restrictive in classes where physical distancing is possible. . Decision tree for COVID testing by PCR of children under 6 years of age. Signs of severity; Do not forget the differential diagnosis of severe bacterial infection; *For example, diagnosis of acute pyelonephritis without associated respiratory signs, strep throat, chicken pox. ## Indications for pcr testing should be proportionate to children's small contribution to the transmission of infection (figs. 1 and 2) Apart from any notion of contact, systematic screening for asymptomatic forms in children in the community is useless, because of the weak transmission role of children. Any child exposed in his or her home to a COVID+ person must be tested before returning to the community. If the child is asymptomatic, he or she may return to the community if the test result is negative. This return must not compromise the isolation of infected persons in the home. Any symptomatic child of at least 6 years of age or adolescent (with cough, and/or fever, and/or digestive disorders) must be screened before returning to the community unless a diagnosis of another infectious disease is made with certainty (e.g., scarlet fever, streptococcal tonsillopharyngitis, clinical enteroviral entities such as herpangina or foot hand mouth syndrome, urinary tract infections, etc.). In symptomatic children under 6 years of age (nurseries/daycare centers and kindergartens), the high frequency of viral infections during the autumn and winter, combined with the low transmissibility of COVID-19 by young children, should reserve the indications for COVID PCR to: patients requiring hospitalization or those severe enough to warrant further investigations; children who have had contact with a COVID+ proven case; children in contact at home with persons considered at risk for severe forms of COVID-19; children whose symptoms do not improve within the usual timeframe for respiratory infections (e.g., more than 3 days for fever). Screening of an entire class is only warranted if one teacher in the class is COVID+ or if at least two children in the class are symptomatic and COVID+. The rarity of child-to-child transmission does not justify initiating a whole class screening based on an isolated case of symptomatic or asymptomatic children. ## Limit school absenteeism by targeting temporary exclusions of infected children All COVID+ children should be excluded from class for 7 days, and possibly longer if symptoms persist. PCR monitoring is not necessary for a return to school or to DCC, as transmissibility is now shown to be maximal during the pre-symptomatic period and low 7 days after the beginning of symptoms. If a child tests positive for COVID-19 (intrafamily or community screening) and is asymptomatic, the 7-day exclusion rule applies. A negative PCR test is not required for return to school or to DCC. Any child who is symptomatic, but without an indication for a COVID PCR, is excluded from school or DCC for the duration of the symptoms. A COVID PCR is only required if symptoms persist beyond day 3. Class closure is justified only if at least three children are infected with COVID-19 in the same class. Limit the other causes of digestive and/or respiratory symptoms by developing a policy to encourage vaccination against influenza and rotavirus. # Disclosure of interest The authors declare that they have no competing interest. ## Appendix a. supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.arcped.2020.09.001. Decision tree for COVID testing by PCR of children over 6 years of age. Signs of severity: signs of sepsis, severity of respiratory distress; Do not forget the differential diagnosis of severe bacterial infection; For example, diagnosis of acute pyelonephritis without associated respiratory signs, strep throat, chicken pox. [fig] .: Children, and especially those under 10 years of age, do not contribute significantly to the dynamics of the SARS-CoV-2 epidemic: [/fig] [fig] Figure 2: Fig. 2. Decision tree for COVID testing by PCR of children over 6 years of age. Signs of severity: signs of sepsis, severity of respiratory distress; Do not forget the differential diagnosis of severe bacterial infection; *For example, diagnosis of acute pyelonephritis without associated respiratory signs, strep throat, chicken pox. [/fig]	None	None	None
69878c69e40f7104eaff4f5482b6c99b7abb7eb9	pubmed	CONSORT-SPI 2018 Explanation and Elaboration: guidance for reporting social and psychological intervention trials	CONSORT-SPI 2018 Explanation and Elaboration: guidance for reporting social and psychological intervention trials Background: The CONSORT (Consolidated Standards of Reporting Trials) Statement was developed to help biomedical researchers report randomised controlled trials (RCTs) transparently. We have developed an extension to the CONSORT 2010 Statement for social and psychological interventions (CONSORT-SPI 2018) to help behavioural and social scientists report these studies transparently.Methods: Following a systematic review of existing reporting guidelines, we conducted an online Delphi process to prioritise the list of potential items for the CONSORT-SPI 2018 checklist identified from the systematic review. Of 384 international participants, 321 (84%) participated in both rating rounds. We then held a consensus meeting of 31 scientists, journal editors, and research funders (March 2014) to finalise the content of the CONSORT-SPI 2018 checklist and flow diagram.Results: CONSORT-SPI 2018 extends 9 items (14 including sub-items) from the CONSORT 2010 checklist, adds a new item (with 3 sub-items) related to stakeholder involvement in trials, and modifies the CONSORT 2010 flow diagram. This Explanation and Elaboration (E&E) document is a user manual to enhance understanding of CONSORT-SPI 2018. It discusses the meaning and rationale for each checklist item and provides examples of complete and transparent reporting. Conclusions: The CONSORT-SPI 2018 Extension, this E&E document, and the CONSORT website (www.consortstatement.org) are helpful resources for improving the reporting of social and psychological intervention RCTs. # Background ## Consort-spi 2018 explanation and elaboration The CONSORT (Consolidated Standards of Reporting Trials) Statement was developed to help authors report randomised controlled trials (RCTs) [bib_ref] Improving the quality of reporting of randomized controlled trials. The CONSORT statement, Begg [/bib_ref]. It has improved the quality of reports in medicine [bib_ref] Use of the CONSORT statement and quality of reports of randomized trials:..., Moher [/bib_ref] [bib_ref] Does the CONSORT checklist improve the quality of reports of randomised controlled..., Plint [/bib_ref] [bib_ref] Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of..., Turner [/bib_ref] [bib_ref] The reporting of methodological factors in randomized controlled trials and the association..., Devereaux [/bib_ref] , and has been officially endorsed by over 600 journals and prominent editorial groups [bib_ref] Update on the endorsement of CONSORT by high impact factor journals: a..., Shamseer [/bib_ref]. A smaller number of journals have implemented CONSORT-particularly its extension statements-as a requirement for the manuscript submission, peer-review, and editorial decision-making process [bib_ref] Update on the endorsement of CONSORT by high impact factor journals: a..., Shamseer [/bib_ref] [bib_ref] Endorsement of the CONSORT statement by high impact factor medical journals: a..., Hopewell [/bib_ref]. There are extensions of the CONSORT Statement (http:// www.consort-statement.org/extensions) for specific trial designs [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] [bib_ref] Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010..., Piaggio [/bib_ref] [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref] [bib_ref] CONSORT extension for reporting N-of-1 trials (CENT) 2015 statement, Vohra [/bib_ref] , types of data (e.g. patient-reported outcomes, harms, and information in abstracts) [bib_ref] Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension, Calvert [/bib_ref] [bib_ref] CONSORT for reporting randomised trials in journal and conference abstracts, Hopewell [/bib_ref] [bib_ref] Better reporting of harms in randomized trials: an extension of the CONSORT..., Ioannidis [/bib_ref] , and interventions [bib_ref] Methods and processes of the CONSORT group: example of an extension for..., Boutron [/bib_ref] [bib_ref] Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement, Gagnier [/bib_ref] [bib_ref] Revised STandards for reporting interventions in clinical trials of acupuncture (STRICTA): extending..., Macpherson [/bib_ref]. Several reviews have shown that RCTs of social and psychological interventions are often not reported with sufficient accuracy, comprehensiveness, and transparency to replicate these studies, assess their quality, and understand for whom and under what circumstances the evaluated intervention should be delivered [bib_ref] Reporting quality of social and psychological intervention trials: a systematic review of..., Grant [/bib_ref] [bib_ref] Developing and evaluating complex interventions: the new Medical Research Council guidance, Craig [/bib_ref] [bib_ref] Specifying and reporting complex behaviour change interventions: the need for a scientific..., Michie [/bib_ref] [bib_ref] Reporting implementation in randomized trials: proposed additions to the consolidated standards of..., Mayo-Wilson [/bib_ref] [bib_ref] What is missing from descriptions of treatment in trials and reviews?, Glasziou [/bib_ref]. Moreover, behavioural and social scientists may be prevented from reproducing or synthesising previous studies because trial protocols, outcome data, and the materials required to implement social and psychological interventions are often not shared [bib_ref] Promoting an open research culture, Nosek [/bib_ref] [bib_ref] Replication and contradiction of highly cited research papers in psychiatry: 10-year followup, Tajika [/bib_ref] [bib_ref] Behaviour change techniques: the development and evaluation of a taxonomic method for..., Michie [/bib_ref]. These inefficiencies contribute to suboptimal dissemination of effective interventions [bib_ref] Reducing waste from incomplete or unusable reports of biomedical research, Glasziou [/bib_ref] [bib_ref] Increasing value and reducing waste in biomedical research: Who's listening?, Moher [/bib_ref] , overestimation of intervention efficacy [bib_ref] Does publication bias inflate the apparent efficacy of psychological treatment for major..., Driessen [/bib_ref] , and research waste [bib_ref] Reducing waste from incomplete or unusable reports of biomedical research, Glasziou [/bib_ref]. Transparent and detailed reporting of social and psychological intervention RCTs is needed to minimise reporting biases and to maximise the credibility and utility of this research evidence [bib_ref] Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention, Ioannidis [/bib_ref] [bib_ref] Improving transparency and reproducibility through registration: the status of intervention trials published..., Cybulski [/bib_ref]. We developed an extension of the CONSORT 2010 Statement for Social and Psychological Interventions (CONSORT-SPI 2018) [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Mayo-Wilson [/bib_ref]. To delineate the scope of CONSORT-SPI 2018, we defined interventions by their mechanisms of action. We define social and psychological interventions as actions intended to modify processes and systems that are social and psychological in nature (such as cognitions, emotions, behaviours, norms, relationships, and environments) and are hypothesised to influence outcomes of interest [bib_ref] Development of a CONSORT extension for social and psychological interventions, Grant [/bib_ref]. Social and psychological interventions may be offered to individuals who request them or as a result of policy, may operate at different levels (e.g., individual, group, place), and are usually "complex" [bib_ref] Developing and evaluating complex interventions: the new Medical Research Council guidance, Craig [/bib_ref]. CONSORT-SPI 2018 is designed primarily for reports of RCTs, though some parts of this guidance may be useful for researchers conducting other types of clinical trialsor who are interested in developing and evaluating complex interventions [bib_ref] Criteria for reporting the development and evaluation of complex interventions in healthcare:..., Möhler [/bib_ref]. In addition, although terms in this report are most appropriate for parallel-group trials, the guidance is designed to apply to other designs (e.g. stepped wedge and N of 1). # Methods We previously reported the methods used to develop CONSORT-SPI 2018 [bib_ref] Protocol for CONSORT-SPI: an extension for social and psychological interventions, Montgomery [/bib_ref]. In summary, we first conducted systematic reviews of existing guidance and quality of trial reporting [bib_ref] Reporting quality of social and psychological intervention trials: a systematic review of..., Grant [/bib_ref]. Second, we conducted an international online Delphi process between September 2013 and February 2014 to prioritise the list of potential items for the CONSORT-SPI 2018 checklist and flow diagram that were identified in the systematic review. Survey items can be accessed at the project's ReShare site: 10.5255/UKDA-SN-851981. Third, we held a consensus meeting to finalise the content of the checklist and flow diagram. The meeting was held in March 2014 and comprised 31 scientists, journal editors, and research funders. A writing group drafted CONSORT-SPI 2018, and consensus group participants provided feedback and agreed to the final manuscript for the CONSORT-SPI 2018 Extension Statement, and this Explanation and Elaboration (E&E) document (Additional file 1: [fig_ref] Table 1: The CONSORT-SPI 2018 checklist [/fig_ref]. The CONSORT-SPI 2018 checklist extends 9 of the 25 items (incorporating 14 sub-items) found in CONSORT 2010 [fig_ref] Table 1: The CONSORT-SPI 2018 checklist [/fig_ref] ; new items are in the 'CONSORT-SPI 2018' column) and includes a modified flow diagram. Participants also voted to add a new item about stakeholder involvement, and they recommended modifications to existing CONSORT 2010 checklist items . This E&E document briefly summarises the content from the CONSORT 2010 E&E document for each CONSORT 2010 item [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref] , tailored to a behavioural and social science audience, and it provides an explanation and elaboration for the new items in CONSORT-SPI 2018. Specifically, for each item from CONSORT 2010 and CONSORT-SPI 2018, this E&E provides the rationale for the checklist item and examples of reporting for a behavioural and social science audience (Additional file 2: . Throughout this article, we use the term 'participants' to mean 'participating units' targeted by interventions, which might be individuals, groups, or places (i.e. settings or locations) [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref]. While we include a brief statement about each item in the CONSORT 2010 checklist, readers can find additional information about these items on the CONSORT website (www.consort-statement.org) and the CONSORT 2010 E&E [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref]. # Results and discussion Explanation and elaboration of the CONSORT-SPI Title and abstract Item 1a: identification as a randomised trial in the title Placing the word 'randomised' in the title increases the likelihood that an article will be indexed correctly in bibliographic databases and retrieved in electronic searches. Authors should consider providing information in the title to assist interested readers, such as the name of the intervention and the problem that the trial addresses. We advise authors to avoid uninformative titles (e.g. catchy phrases or allusions) because they reduce space that could be used to help readers identify relevant manuscripts. # Introduction Item 2a: scientific background and explanation of rationale A structured introduction should describe the rationale for the trial and how the trial contributes to what is known [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. In particular, the introduction should describe the targeted problem or issue [bib_ref] Evaluating the quality of reporting occupational therapy randomized controlled trials by expanding..., Moberg-Mogren [/bib_ref] and what is already know about the intervention, ideally by referencing systematic reviews. Item 2b: specific objectives or hypotheses The objectives summarise the research questions, including any hypotheses about the expected magnitude and direction of intervention effects [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref] [bib_ref] The ClinicalTrials. gov results database-update and key issues, Zarin [/bib_ref]. For social and psychological interventions that have multiple units of intervention and multiple outcome assessments (e.g. individuals, groups, places), authors should specify to whom or to what each objective and hypothesis applies. CONSORT-SPI 2018 item 2b: if pre-specified, how the intervention was hypothesised to work Describing how the interventions in all groups (i.e. all experimental and comparator groups) were expected to affect outcomes provides important information about the theory underlying the interventions. For each intervention evaluated, authors should describe the 'mechanism of action' [bib_ref] Process evaluation of complex interventions: Medical Research Council guidance, Moore [/bib_ref] , also known as the 'theory of change' [bib_ref] Using theory of change to design and evaluate public health interventions: a..., Breuer [/bib_ref] , 'programme theory' [bib_ref] Demystifying theory and its use in improvement, Davidoff [/bib_ref] , or 'causal pathway' [bib_ref] A taxonomy of behavior change techniques used in interventions, Abraham [/bib_ref]. Authors should state how interventions were thought to affect outcomes prior to the trial, and whether the hypothesised mechanisms of action were specified a priori, ideally with reference to the trial registration and protocol [bib_ref] SPIRIT 2013 statement: defining standard protocol items for clinical trials, Chan [/bib_ref]. Specifically, authors should report: how the components of each intervention were expected to influence modifiable psychological and social processes, how influencing these processes was thought to affect the outcomes of interest, the role of context, facilitators of and barriers to intervention implementation, and potential adverse events or unintended consequences [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref] [bib_ref] Dark logic': theorising the harmful consequences of public health interventions, Bonell [/bib_ref]. Graphical depictionssuch as a logic model or analytic framework-may be useful [bib_ref] Developing and evaluating complex interventions: the new Medical Research Council guidance, Craig [/bib_ref]. [fig_ref] Table 1: The CONSORT-SPI 2018 checklist [/fig_ref] Identification as a randomised trial in the title § Mechanism used to implement the random allocation sequence, describing any steps taken to conceal the sequence until interventions were assigned § Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions § Awareness of assignment 11a Who was aware of intervention assignment after allocation (for example, participants, providers, those assessing outcomes), and how any masking was done 11b If relevant, description of the similarity of interventions Analytical methods 12a Statistical methods used to compare group outcomes § How missing data were handled, with details of any imputation method 12b Methods for additional analyses, such as subgroup analyses, adjusted analyses, and process evaluations # Methods: trial design Item 3a: description of trial design (such as parallel, factorial) including allocation ratio Unambiguous details about trial design help readers assess the suitability of trial methods for addressing trial objectives, and clear and transparent reporting of all design features of a trial facilitates reproducibility and replication [bib_ref] What does research reproducibility mean?, Goodman [/bib_ref]. Authors should explain their choice of design (especially if it is not an individually randomised, two-group parallel trial) [bib_ref] Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010..., Piaggio [/bib_ref] ; state the allocation ratio and its rationale; and indicate whether the trial was designed to assess the superiority, equivalence, or noninferiority of the interventions [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref] [bib_ref] Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT..., Piaggio [/bib_ref]. Randomising at the cluster level (e.g. schools) has important implications for trial design, analysis, inference, and reporting. For cluster randomised trials, authors should follow the CONSORT Extension to Cluster Randomised Trials. Because many social and psychological interventions are cluster randomised, we provide the extended items from this checklist in Tables 4 and 5 [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref]. Authors should also report the unit of randomisation, which might be social units (e.g. families), organisations (e.g. schools, prisons), or places (e.g. neighbourhoods), and specify the unit of each analysis, especially when the unit of analysis is not the unit of randomisation (e.g. randomising at the cluster level and analysing outcomes assessed at the individual level). Item 3b: important changes to methods after trial commencement (such as eligibility criteria), with reasons Deviations from planned trial methods are common, and not necessarily associated with flawed or biased research. Changes from the planned methods are important for understanding and interpreting trial results. A trial report should refer to a trial registration (Item 23) [bib_ref] Trial reporting in ClinicalTrials. gov-the final rule, Zarin [/bib_ref] [bib_ref] Toward a new era of trust and transparency in clinical trials, Hudson [/bib_ref] and protocol (Item 24) developed in advance of assigning the first participant [bib_ref] SPIRIT 2013 statement: defining standard protocol items for clinical trials, Chan [/bib_ref] , and to a pre-specified statistical analysis plan [bib_ref] False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything..., Simmons [/bib_ref]. The report should summarise all amendments to the protocol and statistical analysis plan, when they were made, and the rationale for each amendment. Because selective outcome reporting is pervasive [bib_ref] Is mandatory prospective trial registration working to prevent publication of unregistered trials..., Scott [/bib_ref] , authors should state any changes to the outcome definitions during the trial. # Methods: participants Item 4a: eligibility criteria for participants Eligibility criteria should describe how participants (i.e. individuals, groups, or places) were recruited. Readers need this information to understand who could have entered the trial and the generalisability of findings. Authors should describe all inclusion and exclusion criteria used to determine eligibility, as well as the methods used to screen and assess participants to determine their eligibility [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. CONSORT-SPI 2018 item 4a: when applicable, eligibility criteria for settings and those delivering the interventions In addition to the eligibility criteria that apply to individuals, social and psychological intervention trials often have eligibility criteria for the settings where participants will be recruited and interventions delivered, as well as intervention providers [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref]. Authors should describe these criteria to help readers compare the trial context with other contexts in which interventions might be used [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref] [bib_ref] Intervention description is not enough: evidence from an in-depth multiple case study..., Wells [/bib_ref]. Item 4b: settings and locations of intervention delivery and where the data were collected Information about settings and locations of intervention delivery and data collection are essential for understanding trial context. Important details might include the geographic location, day and time of trial activities, space required, and features of the inner setting (e.g. implementing Noteworthy changes to CONSORT 2010 items in the CONSORT-SPI 2018 checklist - Item 6a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Item 11. 'Blinding' has been changed to 'Awareness of assignment and 'masking' in the section heading and item wording, respectively. These changes address concerns about the use of the term 'blinding' as well as the need to emphasise the issue of awareness of assignment by providers and participants in social and psychological intervention trials. - Item 12. The section heading 'Statistical methods' has been changed to 'Analytical methods' because some methods may be qualitative in social and psychological intervention RCTs. - Item 12a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Item 12b. Process evaluations are specifically highlighted. - Item 13a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Items 13a and 16. The wording 'number of participants' has been changed to 'number' because the term 'participants' is not appropriate for RCTs in which the unit of intervention is a geographic area. While social and psychological interventions may target individual participants or groups of individuals such as families or schools, they may also involve place-based techniques that target geographic units and examine area-level effects. However, for convenience and consistency with the CONSORT 2010 guidance [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref] , the CONSORT-SPI 2018 checklist and E&E will refer to the unit targeted by the intervention as 'participants', though 'participants' throughout this guidance is meant to stand for 'participating units', or the unit being targeted by the intervention [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref] , which may include geographic units. - Item 15. The words 'clinical and demographic' have been removed because this checklist targets interventions that may not be medical in nature or have health outcomes, and thus to emphasise the need to report important baseline characteristics irrespective of their nature. - Item 16. The parenthetical '(denominator)' has been removed. The term implied the use of dichotomous outcomes, whereas continuous outcomes are extremely prevalent in social and psychological intervention RCTs. - Item 17a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Items 23-25. The section 'Other Information' has been changed to 'Important Information' because consensus meeting participants had concerns that 'Other' makes the requested information appear to be of secondary importance to previous sections. - Item 25. The phrase 'such as supply of drugs' has been removed because drug trials are not in the purview of this extension by definition. [formula] - Item 26: New item. A new sub-section in 'Important Information' [/formula] called 'Stakeholder Involvement' has been added because consensus meeting participants thought such a sub-section would best fit the three sub-items currently allocated to it organisation) and outer setting (e.g. external context and environment) that might influence implementation [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref]. Authors should refer to the mechanism of action when deciding what information about setting and location to report. # Methods: interventions Item 5: the interventions for each group with sufficient details to allow replication, including how and when they were actually administered Complete and transparent information about the content and delivery of all interventions in all groups (experimental and comparator) [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref] is vital for understanding, replicating, and synthesising intervention effects [bib_ref] A taxonomy of behavior change techniques used in interventions, Abraham [/bib_ref] [bib_ref] The Oxford implementation index: a new tool for incorporating implementation data into..., Montgomery [/bib_ref]. Essential information includes: naming the interventions, what was actually delivered (e.g. materials and procedures), who provided the interventions, how, where, when, and how much [bib_ref] Better reporting of interventions: template for intervention description and replication (TIDieR) checklist..., Hoffmann [/bib_ref]. Details about providers should include their professional qualifications and education, expertise or competence with the interventions or area in general, and training and supervision for delivering the interventions [bib_ref] Journal article reporting standards for quantitative research in psychology: the APA publications..., Appelbaum [/bib_ref]. Tables or diagrams showing the sequence of intervention activities, such as the participant timeline recommended in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement [bib_ref] SPIRIT 2013 statement: defining standard protocol items for clinical trials, Chan [/bib_ref] , are often useful [bib_ref] Graphical method for depicting randomised trials of complex interventions, Perera [/bib_ref]. Authors should avoid the sole use of labels such as 'treatment as usual' or 'standard care' because they are not uniform across time and place [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. CONSORT-SPI 2018 item 5a: extent to which interventions were actually delivered by providers and taken up by participants as planned Frequently, interventions are not implemented as planned. Authors should describe the actual delivery by providers and uptake by participants of interventions for all groups, including methods used to ensure or assess whether the interventions were delivered by providers and taken up by participants as intended [bib_ref] The Oxford implementation index: a new tool for incorporating implementation data into..., Montgomery [/bib_ref]. Quantitative or qualitative process evaluations [bib_ref] Process evaluation of complex interventions: Medical Research Council guidance, Moore [/bib_ref] may be used to assess what providers actually did (e.g. recording and coding sessions), the amount of an intervention that participants received (e.g. recording the number of sessions attended), and contamination across intervention groups [bib_ref] Contamination in trials: is cluster randomisation the answer?, Torgerson [/bib_ref] [bib_ref] Process evaluation in complex public health intervention studies: the need for guidance, Moore [/bib_ref]. Authors should distinguish planned systematic adaptations (e.g. tailoring) from modifications that were not anticipated in the trial protocol. When this information cannot be included in a single manuscript, authors should use online supplements, additional reports, and data repositories to provide this information. CONSORT-SPI 2018 item 5b: where other informational materials about delivering the interventions can be accessed Authors should indicate where readers can find sufficient information to replicate the interventions, such as intervention protocols [bib_ref] Providing full manuals and intervention descriptions: addiction policy, West [/bib_ref] , training manuals [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref] , or other materials (e.g. worksheets and websites) [bib_ref] A taxonomy of behavior change techniques used in interventions, Abraham [/bib_ref]. For example, new online platforms such as the Open Science Framework allow researchers to share some or all of their study materials freely (https://osf.io). CONSORT-SPI 2018 item 5c: when applicable, how intervention providers were assigned to each group Some trials assign specific providers to different conditions to prevent expertise and allegiance from confounding the results. Authors should report whether the same people delivered the experimental and comparator interventions, whether providers were nested within intervention groups, and the number of participants assigned to each provider. # Methods: outcomes Item 6a: completely define pre-specified outcomes, including how and when they were assessed All outcomes should be defined in sufficient detail for others to reproduce the results using the trial data [bib_ref] The ClinicalTrials. gov results database-update and key issues, Zarin [/bib_ref] [bib_ref] Multiple outcomes and analyses in clinical trials create challenges for interpretation and..., Mayo-Wilson [/bib_ref]. An [bib_ref] The ClinicalTrials. gov results database-update and key issues, Zarin [/bib_ref]. In addition, authors should report the methods and persons used to collect outcome data, properties of measures or references to previous reports with this information, methods used to enhance measurement quality (e.g. training of outcome assessors), and any differences in outcome assessment between trial groups. Authors also should indicate where readers can access materials used to measure outcomes [bib_ref] Promoting an open research culture, Nosek [/bib_ref]. When a trial includes a measure (e.g. a questionnaire) that is not available publicly, authors should provide a copy (e.g. through an online repository or as an online supplement). Item 6b: any changes to trial outcomes after the trial commenced, with reasons All outcomes assessed should be reported. If the reported outcomes differ from those in the trial registration (Item 23) or protocol (Item 24), authors should state which outcomes were added and which were removed. To allow readers to assess the risk of bias from outcome switching, authors should also identify any changes to level of importance (e.g. primary or secondary) [bib_ref] Harms of outcome switching in reports of randomised trials: CONSORT perspective, Altman [/bib_ref]. Authors should provide the rationale for any changes made and state whether these were done before or after collecting the data. # Methods: sample size Item 7a: how sample size was determined Authors should indicate the intended sample size for the trial and how it was determined, including whether the sample size Specification that allocation was based on clusters rather than individuals and whether allocation concealment (if any) was at the cluster level, the individual participant level, or both Implementation 10a Who generated the random allocation sequence, who enrolled clusters, and who assigned clusters to interventions 10b Mechanism by which individual participants were included in clusters for the trial (such as complete enumeration, random sampling) 10c From whom consent was sought (representatives of the cluster, individual cluster members, or both) and whether consent was sought before or after randomisation Analytical methods 12a How clustering was taken into account # Results Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of clusters that were randomly assigned, received the intended treatment, and were analysed for the primary outcome was determined a priori using a sample size calculation or due to practical constraints. If an a priori sample size calculation was conducted, authors should report the effect estimate used for the sample size calculation and why it was chosen (e.g. the smallest effect size of interest, from a meta-analysis of previous trials). If an a priori sample size calculation was not performed, authors should not present a post hoc calculation, but rather the genuine reason for the sample size (e.g. limitations in time or funding) and the actual power to detect an effect for each result (Item 17). Item 7b: when applicable, an explanation of any interim analyses and stopping guidelines Multiple statistical analyses can lead to false-positive results, especially when using stopping guidelines based on statistical significance. Any interim analyses should be described, including which analyses were conducted (i.e. the outcomes and methods of analysis), when they were conducted, and why (particularly whether they were pre-specified [bib_ref] Family-focused cognitive behaviour therapy versus psycho-education for chronic fatigue syndrome in 11-to..., Chalder [/bib_ref]. Authors should also describe the reasons for stopping the trial, including any procedures used to determine whether the trial would be stopped early (e.g. regular meetings of a data safety monitoring board) [bib_ref] Data safety and monitoring boards, Slutsky [/bib_ref]. # Methods: randomisation-sequence generation Item 8a: method used to generate the random allocation sequence In a randomised trial, participants are assigned to groups by chance using processes designed to be unpredictable. Authors should describe the method used to generate the allocation sequence (e.g. a computer-generated random number sequence), so that readers may assess whether the process was truly random. Authors should not use the term 'random' to describe sequences that are deterministic (e.g. alternation, order of recruitment, date of birth). Item 8b: type of randomisation; details of any restriction (such as blocking and block size) Some trials restrict randomisation to balance groups in size or important characteristics. Blocking restricts randomisation by grouping participants into 'blocks' and by assigning participants using a random sequence within each block. When blocking is used, authors should describe how the blocks were generated, the size of the blocks, whether and how block size varied, and if trial staff became aware of the block size. Stratification restricts randomisation by creating multiple random allocation sequences based on site or characteristics thought to modify intervention effects. When stratification is used, authors should report why it was used and describe the variables used for stratification, including cut-off values for categories within each stratum. When minimisation is used, authors should report the variables used for minimisation and include the statistical code. When there are no restrictions on randomisation, authors should state that they used 'simple randomisation' [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref]. ## Methods: randomisation-allocation concealment mechanism Item 9: mechanism used to implement the random allocation sequence, describing any steps taken to conceal the sequence until interventions were assigned In addition to generating a truly random sequence (Item 8a), researchers should conceal the sequence to prevent foreknowledge of the intervention assignment by persons enrolling and assigning participants. Otherwise, recruitment and allocation could be affected by knowledge of the next assignment. Authors should report whether and how allocation was concealed [bib_ref] Allocation concealment in randomised trials: defending against deciphering, Schulz [/bib_ref] [bib_ref] How to prove that your therapy is effective, even when it is..., Cuijpers [/bib_ref]. When allocation was concealed, authors should describe the mechanism and how this mechanism was monitored to avoid tampering or subversion (e.g. centralised or 'third-party' assignment, automated assignment system, sequentially numbered identical containers, sealed opaque envelopes). While masking (blinding) is not always possible, allocation concealment is always possible. # Methods: randomisation-implementation Item 10: who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions In many individually randomised trials, staff who generate and conceal the random sequence are different from the staff involved in implementing the sequence. This can prevent tampering or subversion [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. Other procedures may be used to ensure true randomisation in trials in which participants (e.g. groups, places) are recruited and then randomised at the same time. Authors should indicate who carried out each procedure (i.e. generating the random sequence, enrolling participants, and assigning participants to interventions) and the methods used to protect the sequence. ## Methods: awareness of assignment Item 11a: who was aware after assignment to interventions (for example, participants, providers, those assessing outcomes), and how any masking was done Masking (blinding) refers to withholding information about assigned interventions post-randomisation from those involved in the trial. Masking can reduce threats to internal validity arising from an awareness of the intervention assignment by those who could be influenced by this knowledge. Authors should state whether and how (a) participants, (b) providers, (c) data collectors, and (d) data analysts were kept unaware of intervention assignment. If masking was not done (e.g. because it was not possible), authors should describe the methods, if any, used to assess performance and expectancy biases (e.g. masking trial hypotheses, measuring participant expectations) [bib_ref] Comment on 'developing a reporting guideline for social and psychological intervention trials, Wilson [/bib_ref]. Although masking of providers and participants is often not possible, masking outcome assessors is usually possible, even for outcomes assessed through interviews or observations. If examined, authors should report the extent to which outcome assessors remained masked to participants' intervention status. Item 11b: if relevant, description of the similarity of interventions Particularly because masking providers and participants is impossible in many social and psychological intervention trials, authors should describe any differences between interventions delivered to each group that could lead to differences in the performance and expectations of providers and participants. Important details include differences in intervention components and acceptability, co-interventions (or adjunctive interventions) that might be available to some groups and not others, and contextual differences between groups (e.g. differences in place of delivery). # Methods: analytical methods Item 12a: statistical methods used to compare group outcomes Complete statistical reporting allows the reader to understand the results and to reproduce analyses [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. For each outcome, authors should describe the methods of analysis, including transformations and adjustment for covariates, and whether the methods of analysis were chosen a priori or decided after data were collected. In the United States, trials funded by the National Institutes of Health must deposit a statistical analysis plan on www.Clinical Trials.gov with their results [bib_ref] Toward a new era of trust and transparency in clinical trials, Hudson [/bib_ref]. Authors with other funding sources should ascertain whether there are similar requirements. For cluster randomised trials, authors should state whether the unit analysed differs from the unit of assignment, and if applicable, the analytical methods used to account for differences between the unit of assignment, level of intervention, and the unit of analysis [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref]. Authors should also note any procedures and rationale for any transformations to the data. To facilitate full reproducibility, authors should report software used to run analyses and provide the exact statistical code [bib_ref] Promoting an open research culture, Nosek [/bib_ref]. Extended CONSORT-SPI item 12a: how missing data were handled, with details of any imputation method Missing data are common in trials of social and psychological interventions for many reasons, such as participant discontinuation, missed visits, and participant failure to complete all items or measures (even for participants who have not discontinued the trial). Authors should report the amount of missing data, evidence regarding the reasons for missingness, and assumptions underlying judgements about missingness (e.g. missing at random). For each outcome, authors should describe the analysis population (i.e. participants who were eligible to be included in the analysis) and the methods for handling missing data, including procedures to account for missing participants (i.e. participants who withdrew from the trial, did not complete an assessment, or otherwise did not provide data) and procedures to account for missing data items (i.e. questions that were not completed on a questionnaire) [bib_ref] Multiple outcomes and analyses in clinical trials create challenges for interpretation and..., Mayo-Wilson [/bib_ref]. Imputation methods, which aim to estimate missing data based on other data in the dataset, can influence trial results [bib_ref] Standards should be applied in the prevention and handling of missing data..., Li [/bib_ref]. When imputation is used, authors should describe the variables used for imputation, the number of imputations performed, the software procedures for executing the imputations, and the results of any sensitivity analyses conducted to test assumptions about missing data [bib_ref] Standards should be applied in the prevention and handling of missing data..., Li [/bib_ref]. For example, it is often helpful to report results without imputation to help readers evaluate the consequences of imputing data. Item 12b: methods for additional analyses, such as subgroup analyses, adjusted analyses, and process evaluations In addition to analysing impacts on primary and secondary outcomes, trials often include additional analyses, such as subgroup analyses and mediation analyses to investigate processes of change [bib_ref] Process evaluation of complex interventions: Medical Research Council guidance, Moore [/bib_ref] [bib_ref] Who benefits and how does it work? Moderators and mediators of outcome..., Gardner [/bib_ref]. All analyses should be reported at the same level of detail. Authors should indicate which subgroup analyses were specified a priori in the trial registration or protocol (Items 23 and 24), how subgroups were constructed, and distinguish confirmatory analyses from exploratory analyses. For adjusted analyses, authors should report the statistical procedures and covariates used and the rationale for these. Additionally, qualitative analyses may be used to investigate processes of change, implementation processes, contextual influences, and unanticipated outcomes [bib_ref] Process evaluation of complex interventions: Medical Research Council guidance, Moore [/bib_ref]. Authors should indicate whether such analyses were undertaken or are planned (and where they are or will be reported if so). Authors should report methods and results of qualitative analyses according to reporting standards for primary qualitative research [bib_ref] Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ, Tong [/bib_ref]. # Results: participant flow Item 13a: for each group, the numbers randomly assigned, receiving intended treatment, and analysed for the outcomes CONSORT-SPI item 13a: where possible, the number approached, screened, and eligible prior to random assignment, with reasons for non-enrolment Attrition after randomisation can affect internal validity (i.e. by introducing selection bias), and attrition before or after randomisation can affect generalisability. Authors should report available information about the total number of participants at each stage of the trial, with reasons for non-enrolment (i.e. before randomisation) or discontinuation (i.e. after randomisation). Key stages typically include: approaching participants, screening for potential eligibility, assessment to confirm eligibility, random assignment, intervention receipt, and outcome assessment. As there may be delays between each stage (e.g. between randomisation and initiation of the intervention) [bib_ref] CONSORT statement for randomized trials of nonpharmacologic treatments: a 2017 update and..., Boutron [/bib_ref] , authors should include a flow diagram to describe trial attrition in relation to each of these key stages [fig_ref] Figure 1: The CONSORT-SPI 2018 flow diagram [/fig_ref] ; Additional file 4) Item 13b: for each group, losses and exclusions after randomisation, together with reasons Authors should report participant attrition and data exclusion by the research team for each randomised group at each follow-up point [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. Authors should distinguish between the number of participants who deviate from the intervention protocol but continue to receive an intervention, discontinue an intervention but continue to provide outcome data, discontinue the trial altogether, and were excluded by the investigators. Authors should provide reasons for each loss (e.g. lost contact, died) and exclusion (e.g. excluded by the investigators because of poor adherence to intervention protocol), and indicate the number of persons who discontinued for unknown reasons. # Results: recruitment Item 14a: dates defining the periods of recruitment and follow-up The dates of a trial and its activities provide readers some information about the historical context of the trial [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. The SPIRIT 2013 Statement includes a table that authors can use to provide a complete schedule of trial activities, including recruitment practices, pre-randomisation assessments, periods of intervention delivery, a schedule of post-randomisation assessments, and when the trial was stopped [bib_ref] SPIRIT 2013 statement: defining standard protocol items for clinical trials, Chan [/bib_ref]. In the description, authors should define baseline assessment and follow-up times relative to randomisation. For example, by itself, '4-week follow-up' is unclear and could mean different things if meant after randomisation or after the end of an intervention. Item 14b: why the trial ended or was stopped Authors should state why the trial was stopped. Trials might be stopped for reasons decided a priori (e.g. sample size reached and predetermined follow-up period completed) or in response to the results. For trials stopped early in response to interim analyses (Item 7b), authors should state the reason for stopping (e.g. for safety or futility) and whether the stopping rule was decided a priori. If applicable, authors should describe other reasons for stopping, such as implementation challenges (e.g. could not recruit enough participants) or extrinsic factors (e.g. a natural disaster). Authors should indicate whether there are plans to continue collecting outcome data (e.g. long-term follow-up). baseline, including pre-intervention data on trial outcomes, and potential prognostic variables. Authors should pay particular attention to topic-specific information related to socioeconomic and other inequalities [bib_ref] Protocol for the development of a CONSORT-equity guideline to improve reporting of..., Welch [/bib_ref] [bib_ref] PRISMA-equity 2012 extension: reporting guidelines for systematic reviews with a focus on..., Welch [/bib_ref] [bib_ref] Applying an equity lens to interventions: using PROGRESS ensures consideration of socially..., O'neill [/bib_ref]. For continuous variables, authors should report the average value and its variance (e.g. mean and standard deviation). For categorical variables, authors should report the numerator and denominator for each category. Authors should not use standard errors and confidence intervals for baseline data because these are inferential (rather than descriptive): inferential statistics assess the probability that observed differences occurred by chance, and all baseline differences in randomised trials occur by chance [bib_ref] P-values in baseline tables of randomised controlled trials are inappropriate but still..., Knol [/bib_ref]. # Results: baseline data # Results: numbers analysed Item 16: for each group, number included in each analysis and whether the analysis was by original assigned groups While a flow diagram is helpful for indicating the number of participants at each trial stage, the number of participants included in each analysis often differs across outcomes and analyses [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref]. Authors should report the number of participants per intervention group for each analysis, so readers can interpret the results and perform secondary analyses of the data. For each outcome, authors should also identify the analysis population and the method used for handling missing data (Item 12a) [bib_ref] Multiple outcomes and analyses in clinical trials create challenges for interpretation and..., Mayo-Wilson [/bib_ref]. ## Results: outcomes and estimation Item 17a: for each outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) For each outcome in a trial, authors should report summary results for all analyses, including results for each trial group and the contrast between groups, the estimated magnitude of the difference (effect size), the precision or uncertainty of the estimate (e.g. 95% confidence interval or CI), and the number of people included in the analysis in each group. The p value does not describe the precision of an effect estimate, and authors should report precision even if the difference between groups is not statistically significant. For categorical outcomes, summary results for each analysis should include the number of participants with the event of interest. The effect size can be expressed as the risk ratio, odds ratio, or risk difference and its precision (e.g. 95% CI). For continuous outcomes, summary results for each analysis should include the average value and its variance (e.g. mean and standard error). The effect size is usually expressed as the mean difference and its precision (e.g. 95% CI). Summary results are often more clearly presented in a table rather than narratively in text. ## Consort-spi item 17a: indicate availability of trial data As part of the growing open-science movement, triallists are increasingly expected to maintain their datasets, linked via trial registrations and posted in trusted online repositories (see http://www.bitss.org/resource-tag/data-repository/), to facilitate reproducibility of reported analyses and future secondary data analyses. Data sharing is also associated with higher citations [bib_ref] Sharing detailed research data is associated with increased citation rate, Piwowar [/bib_ref]. Authors should indicate whether and how to obtain trial datasets, including any metadata and analytic code needed to replicate the reported analyses [bib_ref] Promoting an open research culture, Nosek [/bib_ref] [bib_ref] Data sharing statements for clinical trials: a requirement of the International Committee..., Taichman [/bib_ref]. Any legal or ethical restrictions on making the trial data available should be described [bib_ref] Data sharing statements for clinical trials: a requirement of the International Committee..., Taichman [/bib_ref]. Item 17b: for binary outcomes, presentation of both absolute and relative effect sizes is recommended By themselves, neither relative measures nor absolute measures provide comprehensive information about intervention effects. Authors should report relative effect sizes (e.g. risk ratios) to express the strength of effects and absolute effect sizes (e.g. risk differences) to indicate actual differences in events between interventions. # Results: ancillary analyses Item 18: results of any other analyses performed, including subgroup analyses, adjusted analyses, and process evaluations, distinguishing pre-specified from exploratory Authors should report the results for each additional analysis described in the methods (Item 12b), indicating the number of analyses performed for each outcome, which analyses were pre-specified, and which analyses were not pre-specified. When evaluating effects for subgroups, authors should report interaction effects or other appropriate tests for heterogeneity between groups, including the estimated difference in the intervention effect between each subgroup with confidence intervals. Comparing tests for the significance of change within subgroups is not an appropriate basis for evaluating differences between subgroups. If reporting adjusted analyses, authors should provide unadjusted results as well. Authors reporting any results from qualitative data analyses should follow reporting standards for qualitative research [bib_ref] Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ, Tong [/bib_ref] , though adequately reporting these findings will likely require more than one journal article [bib_ref] Process evaluation of complex interventions: Medical Research Council guidance, Moore [/bib_ref]. # Results: harms Item 19: all important harms or unintended effects in each group (for specific guidance, see CONSORT for Harms) [bib_ref] Better reporting of harms in randomized trials: an extension of the CONSORT..., Ioannidis [/bib_ref] Social and psychological interventions have the potential to produce unintended effects, both harmful and beneficial [bib_ref] Cures that harm: unanticipated outcomes of crime prevention programs, Mccord [/bib_ref]. These may be identified in the protocol and relate to the theory of how the interventions are hypothesised to work (Item 2b) [bib_ref] Dark logic': theorising the harmful consequences of public health interventions, Bonell [/bib_ref] , or they may be unexpected events that were not pre-specified for assessment. Harms may include indirect effects such as increased inequalities at the level of groups or places that result from the intervention [bib_ref] PRISMA-equity 2012 extension: reporting guidelines for systematic reviews with a focus on..., Welch [/bib_ref]. When reporting quantitative data on unintended effects, authors should indicate how they were defined and measured, and the frequency of each event per trial group. Authors should report all results from qualitative investigations that identify possible unintended effects because this information may help readers make informed decisions about using interventions in future research and practice. # Discussion: limitations Item 20: trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Authors should provide a balanced discussion of the strengths and limitations of the trial and its results. Authors should consider issues related to risks of bias, precision of effect estimates, the use of multiple outcomes and analyses, and whether the intervention was delivered and taken up as planned. # Discussion: generalisability Item 21: generalisability (external validity, applicability) of the trial findings Authors should address generalisability, or the extent to which the authors believe that trial results can be expected in other situations. Authors should explain how statements about generalisability relate to the trial design and execution. Key factors to consider discussing include: recruitment practices, eligibility criteria, sample characteristics, facilitators and barriers to intervention implementation, the choice of comparator, what outcomes were assessed and how, length of follow-up, and setting characteristics. # Discussion: interpretation Item 22: interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Authors should provide a brief interpretation of findings in light of the trial's objectives or hypotheses. Authors may wish to discuss plausible alternative explanations for results other than differences in effects between interventions [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref]. Authors should contextualise results and identify the additional knowledge gained by discussing how the trial adds to the results of other relevant literature [bib_ref] Trying to do more good than harm in policy and practice: the..., Chalmers [/bib_ref] , including references to previous trials and systematic reviews. If theory was used to inform intervention development or evaluation (Item 2b), authors should discuss how the results of the trial compare with previous theories about how the interventions would work [bib_ref] Realist complex intervention science: applying realist principles across all phases of the..., Fletcher [/bib_ref]. Authors should consider describing the practical significance of findings; the potential implications of findings to theory, practice and policy; and specific areas of future research to address gaps in current knowledge [bib_ref] Evaluating the quality of reporting occupational therapy randomized controlled trials by expanding..., Moberg-Mogren [/bib_ref]. Authors should avoid distorted presentation or 'spin' when discussing trial findings [bib_ref] Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for..., Boutron [/bib_ref] [bib_ref] Spin' in published biomedical literature: a methodological systematic review, Chiu [/bib_ref]. ## Important information: registration Item 23: registration number and name of trial registry Trial registration is the posting of a minimum information set in a public database, including: eligibility criteria, all outcomes, intervention protocols, and planned analyses. Trial registration aids systematic reviews and meta-analyses, and responds to decades-long calls to prevent reporting biases [bib_ref] Toward prospective registration of clinical trials, Meinert [/bib_ref] [bib_ref] Publication bias: the case for an international registry of clinical trials, Simes [/bib_ref] [bib_ref] Report from the panel on the case for registers of clinical trials..., Dickersin [/bib_ref]. Trial registration is now required for all trials published by journals that endorse the International Committee of Medical Journal Editors guidelines and for all trials funded by the National Institutes of Health in the United States as well as the Medical Research Council and National Institute for Health Research in the UK [bib_ref] Toward a new era of trust and transparency in clinical trials, Hudson [/bib_ref] [bib_ref] Clinical trial registration: a statement from the International Committee of, De Angelis [/bib_ref]. Trials should be registered prospectively, before beginning enrolment, normally in a publicly accessible website managed by a registry conforming to established standards [bib_ref] Clinical trial registration: a statement from the International Committee of, De Angelis [/bib_ref]. Authors should report the name of the trial registry, the unique identification number for the trial provided by that registry, and the stage at which the trial was registered. If authors did not register their trial, they should report this and the reason for not registering. Registries used in clinical medicine (e.g. www.Clinical-Trials.gov) are suitable for social and psychological intervention trials with health outcomes [bib_ref] Trial registration: understanding and preventing reporting bias in social work research, Harrison [/bib_ref] [bib_ref] Improving transparency and reproducibility through registration: the status of intervention trials published..., Cybulski [/bib_ref] , and several registries exist specifically for social and psychological interventions (http://www.bitss.org/resource-tag/registry/). ## Important information: protocol Item 24: where the full trial protocol can be accessed, if available Details about trial design should be described in a publicly accessible protocol (e.g. published manuscript, report in a repository) that includes a record of all amendments made after the trial began. Authors should report where the trial protocol can be accessed. Guidance on developing and reporting protocols has recently been published [bib_ref] SPIRIT 2013 statement: defining standard protocol items for clinical trials, Chan [/bib_ref]. Authors of social and psychological intervention trials who face difficulty finding a journal that publishes trial protocols could search for journals supporting the Registered Reports format (https://cos.io/rr/) or upload their trial protocols to relevant preprint servers such as PsyArXiv (https://psyarxiv.com/) and SocArXiv (https://osf.io/pre prints/socarxiv). # Important information: funding Item 25a: sources of funding and other support, role of funders Information about trial funding and support is important in helping readers to identify potential conflicts of interest. Authors should identify and describe all sources of monetary or material support for the trial, including salary support for trial investigators and resources provided or donated for any phase of the trial (e.g. space, intervention materials, assessment tools). Authors should report the name of the persons or entities supported, the name of the funder, and the award number. They should also specifically state if these sources had any role in the design, conduct, analysis, and reporting of the trial, and the nature of any involvement or influence. If funders had no involvement or influence, authors should specifically report this. ## Consort-spi item 25b: declaration of any other potential interests In addition to financial interests, it is important that authors declare any other potential interests that may be perceived to influence the design, conduct, analysis, or reporting of the trial following established criteria [bib_ref] Guidelines on authorship of medical papers, Huth [/bib_ref]. Examples include allegiance to or professional training in evaluated interventions. Authors should err on the side of caution in declaring potential interests. If authors do not have any financial, professional, personal, or other potential interests to declare, they should declare this explicitly. Important information: stakeholder involvement CONSORT-SPI new item -Item 26a: any involvement of the intervention developer in the design, conduct, analysis, or reporting of the trial Intervention developers are often authors of trial reports. Because involvement of intervention developers in trials may be associated with effect sizes [bib_ref] The impact of program developers as evaluators on criminal recidivism: results from..., Petrosino [/bib_ref] [bib_ref] No effects in independent prevention trials: can we reject the cynical view?, Eisner [/bib_ref] , authors should report whether intervention developers were involved in designing the trial, delivering the intervention, assessing the outcomes, or interpreting the data. Authors should also disclose close collaborations with the intervention developers (e.g. being a former student of the developer, serving on an advisory or consultancy board related to the intervention), and any legal or intellectual rights related to the interventions, especially if these could lead to future financial interests. CONSORT-SPI new item -Item 26b: other stakeholder involvement in trial design, conduct, or analyses Researchers are increasingly called to consult or collaborate with those who have a direct interest in the results of trials, such as providers, clients, and payers [bib_ref] A new taxonomy for stakeholder engagement in patient-centered outcomes research, Concannon [/bib_ref]. Stakeholders may be involved in designing trials (e.g. choosing outcomes) [bib_ref] Multiple outcomes and analyses in clinical trials create challenges for interpretation and..., Mayo-Wilson [/bib_ref] , delivering interventions, or interpreting trial results. Stakeholder involvement may help to better ensure the acceptability, implementability, and sustainability of interventions as they move from research to real-world settings [bib_ref] Stakeholder engagement opportunities in systematic reviews: knowledge transfer for policy and practice, Keown [/bib_ref]. When applicable, authors should describe which stakeholders were involved, how they were recruited, and how they were involved in various stages of the trial [bib_ref] A systematic review of stakeholder engagement in comparative effectiveness and patient-centered outcomes..., Concannon [/bib_ref]. Authors may find reporting standards on public involvement in research useful [bib_ref] GRIPP2 reporting checklists: tools to improve reporting of patient and public involvement..., Staniszewska [/bib_ref]. CONSORT-SPI new item -Item 26c: incentives offered as part of the trial Incentives offered to participants, providers, organisations, and others involved in a trial can influence recruitment, engagement with the interventions, and quality of intervention delivery [bib_ref] Interventions to improve recruitment and retention in clinical trials: a survey and..., Bower [/bib_ref]. Incentives include monetary compensation, gifts (e.g. meals, transportation, access to services), academic credit, and coercion (e.g. prison diversion) [bib_ref] Evidence-based behavioral medicine: what is it and how do we achieve it?, Davidson [/bib_ref]. When incentives are used, authors should make clear at what trial stage and for what purpose incentives are offered, and what these incentives entail. Authors also should state whether incentives differ by trial group, such as compensation for participants receiving the experimental rather than the comparator interventions. [fig] Figure 1: The CONSORT-SPI 2018 flow diagram [/fig] [table] Table 3: Items to report in journal or conference abstracts for social and psychological intervention trials[13] If the unit of random assignment is not the individual, refer to CONSORT for Cluster Randomised Trials and report the items included in its extension for abstracts[8] InterventionsExtent to which interventions were actually delivered by providers and taken up by participants as planned [/table] [table] Table 4: Items to report in the abstract for cluster randomised social and psychological intervention trials[8] [/table] [table] Table 5: Items to report in the main text for cluster randomised social and psychological intervention trials[8] [/table]	None	https://trialsjournal.biomedcentral.com/track/pdf/10.1186/s13063-018-2735-z	None
7d62b1581b71f60ef6bfc75dfafa268a168a1852	pubmed	Management strategies for children with COVID-19: ESPR practical recommendations	Management strategies for children with COVID-19: ESPR practical recommendations During the outbreak of the COVID-19 pandemic, guidelines have been issued by international, national and local authorities to address management and the need for preparedness. Children with COVID-19 differ from adults in that they are less often and less severely affected. Additional precautions required in the management of children address their increased radiosensitivity, need for accompanying carers, and methods for dealing with children in a mixed adult-paediatric institution. In this guidance document, our aim is to define a pragmatic strategy for imaging children with an emphasis on proven or suspected COVID-19 cases. Children suspected of COVID-19 should not be imaged routinely. Imaging should be performed only when expected to alter patient management, depending on symptoms, preexisting conditions and clinical evolution. In order to prevent disease transmission, it is important to manage the inpatient caseload effectively by triaging children and carers outside the hospital, rescheduling nonurgent elective procedures and managing symptomatic children and carers as COVID-19 positive until proven otherwise. Within the imaging department one should consider conducting portable examinations with COVID-19 machines or arranging dedicated COVID-19 paediatric imaging sessions and performing routine nasopharyngeal swab testing before imaging under general anaesthesia. Finally, regular personal hygiene, appropriate usage of personal protective equipment, awareness of which procedures are considered aerosol generating and information on how to best disinfect imaging machinery after examinations should be highlighted to all staff members. # Introduction Since the recent identification of a novel coronavirus (severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, the infection coronavirus disease 2019 ), there has been the declaration of a global pandemic, with a seemingly uncontrolled daily death toll, currently standing at more than 133,000 worldwide (as of 15 April 2020). There is an international state of fear, uncertainty and, for the most part, confusion. Confusion regarding best medical practices, confusion regarding population control and confusion regarding when and whether we will return to normality. Understanding this new disease is indeed required. The scientific literature states that the SARS-CoV-2 virus is predominantly spread through human droplet transmission (i.e. via sneezing, coughing or close contact with others <2 m away) [bib_ref] The SARS-CoV-2 outbreak: what we know, Wu [/bib_ref] , with the greatest risk during the 2-to 14-day incubation period, when many individuals may be asymptomatic [bib_ref] The SARS-CoV-2 outbreak: what we know, Wu [/bib_ref] [bib_ref] A novel coronavirus emerging in China -key questions for impact assessment, Munster [/bib_ref]. Alternatively, the virus can remain viable for several days as aerosols or on hard surfaces [bib_ref] Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1, Van Doremalen [/bib_ref] and fomite transmission is plausible if a person is in contact with an infected surface [bib_ref] Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1, Van Doremalen [/bib_ref]. Children are susceptible to COVID-19, although they appear to have a less severe course of illness than adults [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] with only 3% suffering a severe illness and almost 13% being asymptomatic. Only two paediatric deaths have been reported in the literature so far [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref] , although more cases in all paediatric age groups have been described in news reports. Whilst transplacental and intrauterine transmission are not believed to occur, perinatal infection has been described via infected mothers [bib_ref] SARS-CoV-2 infection in children: Transmission dynamics and clinical characteristics, Cao [/bib_ref] [bib_ref] An analysis of 38 pregnant women with COVID-19, their newborn infants, and..., Schwartz [/bib_ref]. The literature regarding imaging of COVID-19 in children is predominantly based on small retrospective case series and reports, without clarification of the indications for imaging. Paradoxically, many infected cases may present with normal thoracic imaging [bib_ref] Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts..., Hu [/bib_ref] whilst those who have recovered may continue to display features of characteristic disease [bib_ref] A single-center, retrospective study of COVID-19 features in children: a descriptive investigation, Ma [/bib_ref]. Given the importance of implementing measures to prevent further disease transmission and inappropriate medical treatment, our aims are to define a pragmatic strategy for imaging children in paediatric radiology departments with an emphasis on proven or suspected COVID-19 cases. We underscore some important learning points across different nations, and hope this will provide guidance and reassurance through better understanding and preparedness. ## General preparedness measures in hospitals and radiology departments General preparedness for a pandemic requires involving the whole community, not only the health care system. The aim is to reduce transmission both in public spaces and hospital settings, given that the main source of transmission is close contact between family members [bib_ref] The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak..., Guo [/bib_ref]. The National Health Commission of China reported that transmission between healthcare workers accounted for 3.8% of COVID-19 patients, lower than the respective reported incidences during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus epidemics [bib_ref] Transmission characteristics of MERS and SARS in the healthcare setting: a comparative..., Chowell [/bib_ref]. Several national authorities have therefore tried to minimize transmission through measures including countrywide curfews, closed borders, social distancing and self-quarantine. The goal of radiology preparedness is to maintain the capacity for continued operation during these extraordinary times. Solutions to reduce in-hospital transmission vary on local and national levels, and include, where feasible, a reduction in on-site staff and visitors to the hospital, maximizing the intensive care unit (ICU) capacity, managing patient flow and providing personal protective equipment measures. The hospital entrance serves as the first point of physical contact where further access can be limited, and therefore patient triage is important [bib_ref] Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts'..., Shen [/bib_ref]. Paediatric wards in many countries have been divided into COVID-19 wards and ordinary (i.e. non-COVID-19) wards. Where possible, children who are being admitted or undergoing anaesthesia are prioritised for COVID-19 testing. Entrance and exit routes for COVID-19 patients to various imaging areas should also be clearly identified. Where imaging is needed, symptomatic children are treated as possible COVID-19 cases, especially in endemic areas. For urgent requests, portable imaging examinations (e.g., portable ultrasound or radiography) are preferred to avoid any transportation of potentially infected patients within the hospital and to reduce personnel exposure. Any healthcare professional at risk of interaction with potential COVID-19 patients should utilize personal protective equipment in accordance with local and national guidance, as well as adopt any protective covering for their machine to enable more thorough cleaning afterwards. Whilst this is the ideal situation, it is unfortunate that an unprecedented surge in demand for protective gear has meant that some regions are experiencing an acute shortage of supplies; therefore, rational usage of equipment should be balanced with the need for protection. Change in policies should be explained by an infection control expert. To reduce the number of on-site staff within hospitals, those equipped with teleradiology (i.e. remote working) facilities should adopt this as much as possible. On-call rotas should be modified with backup reserve colleagues ready to take the place of those with contact and obligatory quarantine or unexpected illnesses. In many centres, all annual leave requests have been cancelled or reduced, depending on staffing levels and workload. Multidisciplinary team meetings should also be reduced to a minimum, and conducted via online communication software whenever possible. It is important to consider sensitive patient data and safety when using online meetings because some platforms have come under firm scrutiny. Finally, personal hand hygiene and social distancing inside and outside the hospital is of utmost importance. Computer workstations, mobile and hospital phones, and hand-held dictation devices should all be disinfected multiple times a day and always between different staff usages. The use of shared devices such as photocopier machines and computers should be reduced. ## Clinical presentation of covid-19 in the paediatric population Common symptoms in children with COVID-19 include fever and cough (present in half of symptomatic cases), with fever usually subsiding within 3 days [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref]. Other symptoms include fatigue, myalgia, rhinorrhoea or gastrointestinal complaints (diarrhoea) [bib_ref] Novel coronavirus: where we are and what we know, Cheng [/bib_ref]. Anecdotal evidence suggests that a loss of smell and taste occurs in a significant number of adults; however, it is uncertain if this occurs in children and it has not been recognized by the World Health Organization (WHO) as a formal symptom of COVID-19 . Maternal hypoxaemia from COVID-19 may cause intrauterine asphyxia, leading to premature delivery in 47% of cases in one study, as well as stillbirth [bib_ref] Coronavirus in pregnancy and delivery: rapid review, Mullins [/bib_ref]. In another study, this one of 33 neonates born to infected mothers, only 3/33 (9%) were infected, suffered mild tachypnoea [bib_ref] Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with..., Zeng [/bib_ref] and fully recovered within 6 days. Laboratory abnormalities vary while a consistent pattern of derangements is not found in children [bib_ref] Laboratory abnormalities in children with novel coronavirus disease 2019, Henry [/bib_ref]. Leucopenia is relatively common, being documented in approximately 30% of children [bib_ref] A case series of children with 2019 novel coronavirus infection: clinical and..., Cai [/bib_ref]. Elevated procalcitonin levels are reportedly suggestive of bacterial co-infection, and raised C-reactive protein (CRP) occurs with severe infection [bib_ref] Laboratory abnormalities in children with novel coronavirus disease 2019, Henry [/bib_ref]. Elevation of D-Dimer levels is less commonly encountered in children compared to in adults. There is little evidence of outcomes in children with coexisting health problems, although these are known to be associated with poor outcomes in children who have suffered from previous strains of coronavirus [bib_ref] Epidemiology and clinical features of human coronaviruses in the pediatric population, Varghese [/bib_ref] , and in adults with COVID-19 [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref]. The latest guidance from the Royal College of Paediatrics and Child Healthhighlights four categories of children at risk, where a lower threshold for investigation and treatment should be considered. These include: those with longterm respiratory conditions (e.g., asthma, chronic lung disease of prematurity), immunocompromised status (e.g., congenital immunodeficiency, post-transplant, immunosuppressive medication), haemodynamically significant or cyanotic heart disease and chronic kidney disease (stages 4 or 5 or on dialysis). Due to the recent outbreak of this disease, long-term follow-up data are lacking. Different guidelines appear to grade the severity of COVID-19 in children according to different criteria (Online Supplementary Material [fig_ref] Table 1: Rational use of personal protective equipment for coronavirus disease COVID-19 [/fig_ref] [bib_ref] Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts'..., Shen [/bib_ref] [bib_ref] Novel coronavirus: where we are and what we know, Cheng [/bib_ref] , and there is still a lack of information regarding how well these categories predict clinical outcomes. In a large cohort from Wuhan, China, 149/171 (87.1%) of children [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref] completely recovered, with only 3/171 (1.8%) requiring intensive care unit admission. Regarding complications in paediatric COVID-19, childhood deaths are rare [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref]. Intussusception has been reported [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref] , although whether this is specific to COVID-19 or a result of other underlying viral infection remains to be seen. Lymphadenopathy, cavitation and lung abscesses have not been reported, and pleural effusions are unusual. Coinfection with other bacterial or viral organisms is well documentedand could potentially lead to complications such as cardiac dysfunction, liver damage and renal failure [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref]. ## Triage: assessment and prioritization In general, patient assessment is recommended as per the WHO definition by inquiring about fever, symptoms of respiratory tract infection and/or close contact with someone with confirmed or suspected COVID-19. Ideally paediatric triage should be performed outside the hospital either via phone (through help desk linesor in dedicated COVID-19 areas within the emergency or outpatient departments. Admitting patients from the emergency department to the wards is based upon clinical status and preexisting conditions. Clinical pathways that aim to keep children out of the hospital as much as possible should be adopted for asymptomatic and mild cases, with strict instructions for quarantine and observation at home, with the possibility of a rapid return upon clinical deterioration. In this context, in European paediatric hospitals, triage of children is routinely based on clinical factors rather than imaging. This contrasts with recommendations from China and Iran where imaging is a routine part of the triage in the hope of identifying abnormalities when rRT-PCR (real-time reverse transcriptase polymerase chain reaction) testing is negative or unavailable [bib_ref] A single-center, retrospective study of COVID-19 features in children: a descriptive investigation, Ma [/bib_ref] [bib_ref] Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019..., Chen [/bib_ref] [bib_ref] An algorithmic approach to diagnosis and treatment of coronavirus disease 2019 (COVID-19)..., Karimi [/bib_ref]. Once the child is admitted to the hospital, clear documentation of COVID-19 status is paramount. All charts, both electronic and paper (depending on the setting), should carry a warning status about COVID-19 testing. All radiology requests should mention the infection status of the patient. When possible, patients should be scheduled appropriately to avoid overlap and contact in waiting areas, and additional time should be given to enable proper cleaning of machinery. People accompanying the child (limited to one in most centres) should also be screened for any relevant symptoms or possible contact with COVID-19 patients in the preceding 14 days, and if present, the appointment should be rescheduled or performed by personnel in the appropriate personal protective equipment (i.e. managed as if COVID-19 positive). In some European institutions, a negative PCR test is strongly recommended for any nonurgent imaging under general anaesthesia, and performed 2 days before the study. ## Indications for imaging children with covid-19 There are no internationally agreed-upon guidelines for imaging children with COVID-19. Clinical decision pathways for the diagnosis, management and treatment for COVID-19 have varied across different countries, and also across different institutions within the same country. In general, rRT-PCR of the viral RNA, performed on nasopharyngeal swab testing, remains the reference standard for diagnosis. Nevertheless, this test may suffer from limited sensitivity rates (of approximately 70%), short supply and can take time to process (1-3 days). Due to these constraints, chest CT has been used in adults as a tool for diagnosis [bib_ref] Use of chest CT in combination with negative RT-PCR assay for the..., Huang [/bib_ref] ; however, approximately 16% of children with COVID-19 exhibit no radiographic findings, and in 7% there are imaging findings of pneumonia but no symptoms [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref]. We therefore support the recommendations by the Royal College of Paediatrics and Child Healthand Italian Society of Medical and Interventional Radiology, which strongly advise that imaging should not be used routinely for the diagnosis of COVID-19 in children. Findings are typically nonspecific for SARS-CoV-2, and include patchy consolidation and ground-glass opacification, which may mimic other viral pathogens [bib_ref] Chest computed tomography in children with COVID-19 respiratory infection, Li [/bib_ref]. All imaging should be reserved for selected cases where results are anticipated to alter the child's management. Non-thoracic imaging (any modality) should be discussed on a case-by-case basis and, if not urgent, should be performed at a later stage. With this in mind, a pragmatic imaging pathway has been included for guidance. This considers the severity of symptoms according to the WHO guidelines, preexisting health conditionsand attempts to minimize imaging exposure and rRT-PCR testing for asymptomatic and milder cases, thereby preserving resources and radiologic personnel exposure [fig_ref] Figure 1: Imaging pathway for a child with suspected COVID-19 related to clinical presentation [/fig_ref]. Specific guidances for chest imaging in suspected/ confirmed COVID-19 cases are provided below. Radiography Chest radiographs can be performed as a firstline tool in symptomatic children with need for hospitalization or underlying health conditions, and to exclude other causes for respiratory complaints. Use of radiographs as a follow-up for children with a deteriorating condition to assess complications is also recommended. Lateral chest radiographs are not indicated. CT There is no routine indication for performing chest CT in children with COVID-19. A CT scan with a dose appropriate for the child should be performed only when required to answer a specific clinical query. Special consideration should be given where ICU admission or urgent intervention/surgery is required, in children with clinical deterioration despite therapy, for underlying health conditions or to exclude other causes of respiratory distress (e.g., pulmonary embolism). In many published articles, chest CT is mostly performed without This pathway is meant as a resource and was generated based on modification of available European guidelines. Each child may require individual case-bycase discussion with the radiologist. Severity scoring according to WHO guidelinesis provided in Online Supplementary Material [fig_ref] Table 1: Rational use of personal protective equipment for coronavirus disease COVID-19 [/fig_ref]. Mild symptoms are defined as those of pneumonia, without the requirement for supplementary oxygen. Relevant preexisting conditions and guidance regarding follow-up chest radiographs are taken from Royal College of Paediatrics and Child Health in the United Kingdom and British Paediatric Respiratory Society guidelines. * Only portable and by experienced operators. rRT-PCR real time reverse transcriptase polymerase chain reaction, WHO World Health Organization contrast, although the administration of intravenous iodinated contrast medium is preferred in suspected pulmonary embolism or when there is a question for mediastinal abnormality. Ultrasound There are no guidelines that advocate routine usage of lung US in children with COVID-19. Reports from Italy have advocated chest US in the ICU as a monitoring tool to detect lung collapse and consolidation to aid ventilator settings or patient positioning (from supine to prone). This practice requires experience with lung US and while it may reduce the number of repeated portable radiographs performed, introducing such a service would depend on local expertise, the availability of portable machine and staffing. US may play a role as a follow-up tool and may be requested to exclude deep venous thrombosis in selected patients due to the known thrombotic effect of COVID-19. MRI The use of MRI for the initial diagnosis of COVID-19 infection or in the further course of the disease has not been reported and is therefore not recommended. Follow-up imaging Repeat chest imaging is not required as standard routine practice, and should not be performed in children with improving clinical condition and when results are not expected to alter clinical management. ## Standardized reporting of chest ct: current role in children There are no mandatory European guidelines in place for structured CT reporting of COVID-19 in children. Nevertheless, preexisting guidelines (developed predominantly with adults in mind) could potentially provide a useful structure to collate information for future imaging research. The Radiologic Society of North America (RSNA) recently proposed a reporting language relevant to specific CT appearances [bib_ref] Radiological Society of North America Expert consensus statement on reporting chest CT..., Simpson [/bib_ref] , categorized into four classes (typical, intermediate, atypical appearances and negative for pneumonia), taking into account the potential of overlap with other diseases (Online Supplementary Material . The Dutch Society of Radiologists has proposed a reporting system entitled "CO-RADS". In this, the level of suspicion is graded from CO-RADS 1 to CO-RADS 6 (Online Supplementary Material with underlying comorbidities and differential diagnoses considered. Finally, Li et al. [bib_ref] CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19), Li [/bib_ref] have developed a CT total severity score for adults with COVID-19 , taking into account the extent of inflammatory lesions for each lobe, and scored from 0 (0%) to 4 (76-100%). The total sum of scores in all lobes provides a total severity score range of 0-20, which the authors suggest could reflect the clinical severity and therefore patient outcome. One should bear in mind that these systems have not been tested in children in whom CT findings may be absent or mild [bib_ref] SARS-CoV-2 infection in children, Lu [/bib_ref] [bib_ref] A single-center, retrospective study of COVID-19 features in children: a descriptive investigation, Ma [/bib_ref] and can overlap with other (viral) infectious diseases. Therefore, care should be taken when adopting these tools for disease probability or for clinical prognosis. ## Considerations for personal protective equipment in paediatric radiology departments Appropriate personal protective equipment prevents expected COVID-19 transmission through droplet and contact transfer, and also inhibits aerosol transmission where aerosol-generating procedures are conducted. The latter mostly include procedures carried out in the ICU, or emergency department or theatre (e.g., intubation, extubation, bronchoscopy, dental procedures, continuous positive airway pressureand are less common in radiology departments. Hence, the routine use of a particulate respirator mask (FFP) as an airborne precaution is not usually necessary in radiologyunless urgent imaging is required whilst an aerosol-generating procedure is simultaneously occurring in the vicinity (e.g., during portable studies). The Society for Interventional Radiology has produced a list of aerosol-generating procedures and propose a pathway for resource allocation. It should be borne in mind that any procedure in which the child becomes distressed is potentially an aerosol-generating procedure and different departments will have their own recommendations. In many European centres, intussusception reduction is considered an aerosol-generating procedure and is performed with water/contrast and not air, by personnel in appropriate personal protective equipment, and preferably in an operating theatre where better ventilation conditions exist. Contact and droplet precautions are generally well addressed in paediatric radiology departments while airborne precautions are harder to implement because negative-pressure rooms are not readily available. In these cases, a local exhaust ventilation device could be considered, but may be hard to obtain [bib_ref] Is your interventional radiology service ready for SARS?: The Singapore experience, Lau [/bib_ref] [bib_ref] Microbiology for radiologists: how to minimize infection transmission in the radiology department, Mirza [/bib_ref]. The continued use of positive-pressure rooms to protect the patient versus negative-pressure rooms is also controversial [bib_ref] Is your interventional radiology service ready for SARS?: The Singapore experience, Lau [/bib_ref]. Children with suspected or confirmed COVID-19 requiring imaging either as a portable study or in the radiology department (e.g., CT, MRI, fluoroscopy) should wear a surgical mask. This may prove challenging for toddlers and babies, where exceptions may often be made. In some centres, children will wear an additional protective gown and/or gloves. Non-COVID hospitalized children are not required to wear masks; however, accompanying adults in most European hospitals should be encouraged to wear a surgical mask. For radiation-based procedures, the accompanying adult is provided with a lead apron that should remain within the imaging room and be wiped down along with all other apparatus after the procedure. All other lead aprons should be stored in areas that do not face patients. For radiology personnel, protection varies depending on the procedure. [fig_ref] Table 1: Rational use of personal protective equipment for coronavirus disease COVID-19 [/fig_ref] was generated based on modified guidelines from numerous international organizations. It should be noted that within each paediatric radiology department, there are slightly modified procedures based on the local level of risk, resources and hospital-wide/nationwide guidelines. Many departments suggest that all staff in direct contact with patients wear hospital uniforms/scrubs that they change into upon arriving at work. For routine paediatric radiology daily practice, recommendations vary from surgical masks and handwashing to plastic aprons, gloves and standard surgical masks. Health care workers should wear a mask (either surgical or respirator N95, FFP2 or FFP3), gown, gloves and eye protection when working with children with suspected or confirmed COVID-19. For aerosol-generating procedures, a respirator mask and a waterproof apron should be added. In the United Kingdom, an FFP3 mask is preferred. It is recommended that all staff are fitted for all different makes of masks PPE personal protective equipment a Fluoroscopy procedures are not outlined by specific guidelines. Voiding cystourethrogram and barium enema guidelines were based on those for caregivers in contact with urine and faeces while treating COVID-19 positive patients. The suggestions for swallowing studies are based on available information from aerosol-generating procedures such as upper gastrointestinal endoscopy or dental procedures, though this remains debatable b As per national guidelines used in their institution to ensure that an acceptable seal is achieved. Lead aprons should be worn beneath personal protective equipment, which should include a full-length, longsleeve, water-resistant apron over the lead for aerosol-generating procedures, whereas standard plastic aprons are sufficient for non-aerosol-generating procedures. Both mentioned practices may vary according to local regulations and resources. For urgent fluoroscopy procedures in children with suspected COVID-19 that cannot be delayed, surgical masks, gown, gloves and eye protection should be used. For urgent upper gastrointestinal contrast studies, we suggest an FFP2/FFP3/N95 mask, gown, gloves and eye protection. Although this procedure may not generally be considered aerosol generating, it can be considered as such should suction be required. Administrative staff do not need to wear personal protective equipment, although many are choosing to wear surgical masks as a precaution. ## Donning and doffing personal protective equipment Instructional resources for putting on (donning) and taking off (doffing) personal protective equipment are provided by public health authoritiesand the Centres for Disease Control and Prevention. Some centres/ authorities have produced documents and videos explaining donning and doffing for aerosol-generatingand non-aerosol-generating procedures. In brief, for donning, these include hand hygiene, followed by gown, mask, eye protection and finally gloves. For doffing, these include removing gloves, eye protection, gown and finally the mask without touching the outside of the protective equipment. In some departments, glove removal is followed by hand hygiene, with new gloves worn before gown removal, then hand hygiene, eye protection removal and finally removing the mask. Posters or notices describing the sequences should be placed in clinical areas where donning and doffing are routinely expected to occur in appropriately labelled no-touch bins. ## Radiographer teams for working with children with covid-19 Common practice amongst radiographers in Europe include having a person or team assigned as warm/dirty/contaminated, who comes into relative close proximity with the patient, and another assigned as cold/clean to carry out portable radiography and/or to operate the CT and fluoroscopy machines. The warm/dirty/contaminated individual wears a lead apron and full personal protective equipment, and positions the patient in the CT room/fluoroscopy couch, whereas the cold/clean individual wears a surgical mask, apron and gloves (for portable imaging) or remains in the CT control room/behind the screen in the fluoroscopy room, without any additional protection. The cold/clean individual acquires the images and has no patient interaction. ## Planned elective care for children without covid-19 Clinicians in many countries have been instructed to postpone routine clinical work, including postponing radiology appointments across all modalities; in Northern Ireland for example, the deferral period has initially been defined as 2-3 months. Reducing the number of children and their carers in radiology departments will both lessen the risks of cross-infection between staff and patients (and vice versa) and protect the most vulnerable with suppressed immune systems and with complex needs. Urgent and emergent radiology exams will take place in a timely fashion as normal. Ongoing communication between radiology consultants and their clinical colleagues is imperative to ensure there is a shared definition of what constitutes a routine case; patient care pathways may need to be adjusted to incorporate a delay in screening radiology examinations, for example neonates with a suspected genetic syndrome. Some US examinations in paediatric radiology are urgent simply because of skeletal maturation over a matter of time: hip US for suspected developmental dysplasia, head US whilst the anterior fontanelle remains large enough, and spine US before the posterior vertebral elements ossify and obscure the field of view. Multidisciplinary team decisions are required to answer questions regarding how long an individual child's study can be postponed. Electronic access to patient clinical records is helpful to radiologists when vetting request forms to prioritise which studies must be performed. Over time, it will be necessary to revisit the original requests for those postponed studies as they cannot be held off indefinitely. Discussion of patient needs with our colleagues must be ongoing. Collaborative electronic communication platforms and phone calls should be utilised. ## Special considerations in mixed adult-paediatric settings Children being cared for in mixed adult-paediatric environments may be in contact with a greater number of COVID-19 patients and be imaged using the same equipment. Strict cleaning regimes should be adhered to and, where possible, dedicated paediatric lists and equipment should be employed. Local dedicated paediatric radiologists or adult radiologists familiar with paediatric imaging should continue to ensure children are imaged according to accepted protocols and guidelines. With an increasing number of infected adults requiring inpatient admission, it is likely that some hospitals will need to convert some or all of their paediatric inpatient ward and intensive care beds for adults. It would be prudent to have contingency plans to close smaller paediatric units to centre care within tertiary units. Some staff may be required to temporarily relocate or utilise picture archiving and communication system (PACS) networks to report studies from other centres in the event of staff isolation or sickness. ## Equipment management and disinfection procedures Where a suspected or confirmed COVID-19 patient requires imaging, this is preferentially performed as a portable study; if this is not possible, such as for CT or MRI, then a designated COVID-19 machine (if resources allow) should be assigned to avoid disease transmission between different machines. If there is only one CT and/or one MRI machine on site, dedicated rotations of COVID-19 positive/COVID-19 negative patients, might be required. CT/MRI Before any imaging in the department, all unnecessary equipment and toys should be removed. Where an infected child is due to attend the department, the waiting room should be emptied and any central ventilation of the room (e.g., air conditioning) should be turned off. If performing an MRI study, ventilation in the gantry should be increased to the maximum level. Where possible, imaging couches and beds should be covered with plastic drapes. After imaging examinations are performed, the room should be left for at least 20 min with the door closed to allow aerosol droplets to settle. According to American College of Radiology guidelines, depending on air exchange rates, the room could be out of service for approximately 1 h after imaging an infected patient. Disinfection procedures should be performed according to local guidelines; however, viricidal agents should be used and viruses can be inactivated using lipid solvents such as ether, 75% ethanol, chlorine-containing disinfectant, peracetic acid and chloroform. All surfaces, including doorknobs and equipment, should be cleaned. In the MRI rooms, the coils and gantry should also be wiped. Floors should be cleaned and any windows in the waiting areas should be opened to allow natural ventilation. It has been reported that COVID-19 is sensitive to ultraviolet light and heatand if a department has access to ultraviolet lamps for sterilization, this could be useful to implement in the imaging rooms. Mobile ultraviolet lamps can be used for 30-60 min at a time several times per day in between appointments when a room is empty. Ultrasound Ultrasound imaging in children with COVID-19 will be performed as a portable study when possible. Before imaging, all unnecessary accessories/probes should be removed from the machine. In some centres, keyboard and probe covers (or plastic gloves) are also applied. After the examination, the US machine should be thoroughly cleaned before leaving the isolation room and again after exiting the isolated area. Probes should be cleaned by wiping the gel from the transducer followed by disinfection [bib_ref] Infection prevention and control in ultrasound -best practice recommendations from the European..., Nyhsen [/bib_ref] , using surface disinfectant wipes according to American Institute of Ultrasound in Medicine guidelines. This should include the use of viricidal agents. The entire probe (including the cables), the US screen, keyboard, transducer gel bottle and surfaces visible to the air and within 1 m from the patient should be disinfected. Interventional radiology Any urgent interventional procedures should, depending on the age of the patient, be performed under local anaesthesia by the patient's bedside when possible. Minor interventions in older children can be performed using a local anaesthetic. If sedation is required, the procedure should take place in the operating rooms under isolation restrictions, or alternatively, if resources allow, in a designated COVID-19 interventional room. # Conclusion Measures to prevent disease transmission during the COVID-19 pandemic within paediatric radiology departments and in the course of radiologic procedures are of paramount importance. Paediatric radiology staff can make an appreciable difference by adhering to pragmatic guidelines for imaging children with suspected or confirmed COVID-19. Whilst practices are mostly homogeneous across Europe, those of individual institutions may vary depending on the local catchment population, availability and expertise of personnel, equipment and resources. We have provided advice to professionals who care for children in radiology departments, suitable for adaptation in different settings and hope that this approach will be useful in the fight against this outbreak. ## Compliance with ethical standards ## Conflicts of interest none 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/. [fig] Figure 1: Imaging pathway for a child with suspected COVID-19 related to clinical presentation. [/fig] [table] Table 1: Rational use of personal protective equipment for coronavirus disease COVID-19 [/table]	None	https://link.springer.com/content/pdf/10.1007/s00247-020-04749-3.pdf	None
b1136e28b6b0c21d1bb8cdea2e6adb500065f647	pubmed	COVID-19 epidemic: Proposed alternatives in the management of digestive cancers: A French intergroup clinical point of view (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR)	COVID-19 epidemic: Proposed alternatives in the management of digestive cancers: A French intergroup clinical point of view (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR) ## A b s t r a c t Introduction: Patients treated for malignancy are considered at risk of severe COVID-19. This exceptional pandemic has affected countries on every level, particularly health systems which are experiencing saturation. Like many countries, France is currently greatly exposed, and a complete reorganization of hospitals is ongoing. We propose here adaptations of diagnostic procedures, therapies and care strategies for patients treated for digestive cancer during the COVID-19 epidemic. Methods: French societies of gastroenterology and gastrointestinal (GI) oncology carried out this study to answer two main questions that have arisen (i) how can we limit high-risk situations for GI-cancer patients and (ii) how can we limit contact between patients and care centers to decrease patients' risk of contamination while continuing to treat their cancer. All recommendations are graded as experts' agreement according to the level of evidence found in the literature until March 2020. Results: A proposal to adapt treatment strategies was made for the main GI oncology situations. Considering the level of evidence and the heterogeneous progression of the COVID-19 epidemic, all proposals need to be considered by a multidisciplinary team and implemented with patient consent. # Introduction The current coronavirus (SARS-CoV-2) (COVID-19) epidemic is an exceptional situation. It requires us to rethink our practices in digestive oncology and raises many questions: - Should common practices be changed for the next few weeks? - What practical recommendations can be made based on the literature and the experience of Chinese teams? - Is COVID-19 infection different from other viral infections with pulmonary tropism? The scientific answer to these questions is not yet fully known. However, a study published in 2019, before the appearance of COVID-19, retrospectively evaluated 1503 cases of viral pneumonia admitted to the emergency medicine department of a Korean hospital between 2010 and 2015. Altogether, 9.4% of cases were due to a Coronavirus. Patients with cancer were not more likely than other patients to have a Coronavirus infection. The distribution of the different types of viruses was not influenced by the presence of cancer. In contrast, among patients infected with a Coronavirus, the 30-day mortality rate was significantly higher in those with cancer (24.4% versus 3.0%, p < 0.001) [bib_ref] High mortality from viral pneumonia in patients with cancer, Kim [/bib_ref]. In this study, the risk factors for death at 30 days at multivariate analysis were: age over 65 years (OR 1.661; 95% CI: 1.062-2.598, p = 0.026), viral and bacterial co-infection (OR 1.609; 95% CI: 1.045-2.478, p = 0.031), the presence of cancer (OR 2.257; 95% CI: 1.499-3.400, p = 0.001) and initial shock (OR 2.121; 95% CI: 1.028-4.373, p = 0.042). Coronavirus pulmonary infection was thus a serious event in cancer patients, with a 25% risk of death at 30 days in those with severe forms of the infection. In two large published series of 99 and 201 cases of pneumonitis with biological evidence of COVID-19, there were only two cancer patients . In the Chinese prospective database of patients with proven COVID-19 ( n = 2007) from 31 provinces, 417 were excluded due to insufficient clinical history data. Among the 1590 analyzed cases, 1% (18 patients) had a personal history of cancer. This figure was higher than the number expected in the Chinese population (0.29%) suggesting that the infection could be more common in subjects with a personal history of cancer. Results also highlighted that a severe infection was more frequent in patients with a history of cancer than in those without cancer (7/18 or 39% versus 124/1572 or 8%, p = 0.0 0 03). Moreover, in cases with surgery or chemotherapy in the preceding month, the infection was severe in 3 out of 4 cases (75%), representing a relative risk of 5.34 (95% CI 1.80-16.18, p = 0.0026) as compared to others [bib_ref] Cancer patients in SARS-CoV -2 infection: a nationwide analysis in China, Liang [/bib_ref]. However, this study had several limitations, including the size and characteristics of the study population corresponding to 18 patients classified in the cancer group but with 9 of them with a history of cancer dating back more than 4 years. However, due to the absence of other reports to date, we have to consider that severe COVID 19 leading to patients' death will be more frequent in subjects suffering from cancer. Finally, due to frequent limitations in health care resources during rapidly growing epidemics, cancer patients, especially those with metastatic diseases treated by palliative systemic treatments, may not have access to intensive care units in case of severe COVID 19 infections [bib_ref] COVID-19 pandemic: perspectives on an unfolding crisis, Spinelli [/bib_ref]. In this context, the aim is to discuss the adaptations of therapies and/or strategies for patients treated for a gastrointestinal cancer (GI). Moreover, considering the mechanisms of COVID-19 transmission, the main modifications of pathology and endoscopy procedures have been also discussed. # Methods ## Formulation of the questions The method was based on recent Chinese articles suggesting a modification of practices with the following two main objectives [bib_ref] Medical diagnosis and treatment strategies for malignant tumors of the digestive system..., Zhang [/bib_ref] [bib_ref] Treatment strategy for gastrointestinal tumor under the outbreak of novel coronavirus pneumonia..., Chen [/bib_ref]. - Limit very high-risk situations: surgery and intensive chemotherapy - Limit patients' exposure to the SARS-Cov-2 and particularly in care centers The multidisciplinary proposals are presented in the form of a table (seereporting therapeutic adaptations listed organ by organ. The proposals are guided by the two objectives above, and take into account the possibility of limited access to technical platforms. Of note, the adaptations of surgical procedures in digestive oncology have also been reviewed, discussed, detailed and published by a group of French surgeons. However, their proposals will not be detailed in the present paper [bib_ref] Strategy for the practice of digestive and oncologic surgery in COVID 19..., Tuech [/bib_ref]. Lastly, we also suggest an adaptation of surveillance in two distinct situations: during treatment and post-therapy. Data on COVID-19 are still too fragmentary to allow robust conclusions. The recommendations are therefore pragmatic with a low level of evidence and based solely on agreement or expert advice. # Methodology The current coronavirus (COVID-19) epidemic is an exceptional health situation that has prompted the French-speaking Federation of Digestive Cancerology (FFCD) to react quickly. The text is based on data from the literature and experience in China. The text was first reviewed by the members of the FFCD board during an audio conference on March 16, 2020 and was validated by members of the Steering Committee (COPIL) and the heads of the various sections of our national guidelines group (TNCD) on March 23, 2020. All scientific societies involved in digestive oncology, namely SNFGE, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR, ACHBT and also GTE-RENATEN and NETSARC for neuroendocrine tumors (NETs) and gastrointestinal stromal tumors (GISTs), contributed to the discussion. Modifications concerning hepatocellular carcinoma (HCC) and cholangio-carcinomas were discussed with experts from the AFEF (French Association for the Study of the Liver). The recommendations of expert pathologists (SFP) and experts in endoscopic procedures (SFED) were also discussed in order to select appropriate measures to implement during the epidemic. A complete version, including the indications for pathology and endoscopy procedures (SFP), has been published on our TNCD website (see online: "http://www.snfge.org/download/file/fid/3784"). Lastly, a cohort project coordinated by Professor Astrid Lièvre will be started with the network of Cooperative Groups in Oncology in France (GCO). The grading of recommendations includes 4 levels of evidence (A, B, C, agreement or expert opinion) . Grading system used for these recommendations. ## Grade Corresponding level of evidence A Strong recommendation based for example on a high-powered randomized comparative trial (s), a meta-analysis of randomized comparative trials, or an analysis of decision based on well-conducted studies. B Recommendation based on a scientific presumption from low-power randomized controlled trials, well-conducted non-randomized comparative studies or cohort studies. C Recommendation based on a low level of evidence from case-control studies, comparative studies with significant biases, retrospective studies, case series, descriptive epidemiological studies (transverse, longitudinal). ## Expert agreement or opinion Recommendation based on an expert agreement or an expert opinion in the absence of sufficient data from the literature # Results ## 1-proposals of the french pathology society (sfp) The amount of SARS-Cov-2 virus excreted in the stool may be high. The recommendations of the French Microbiology Society (SFM) concerning the management of samples specify that samples containing stools carry a high risk of contamination. Given the incubation time and the percentage of asymptomatic patients, all samples should be considered potentially infected. A recent publication has shown that fixation in formalin can inactivate the SARS-Cov-2 virus [bib_ref] Coronavirus disinfection in histopathology, Henwood [/bib_ref]. The risk of toxicity linked to formalin exposure appears to be less serious than that linked to the handling of fresh, non-fixed tissue potentially carrying SARS-Cov-2. The French Society of Pathology (SFP) published on 18/03/2020 advice for the management of sputum and bronchoalveolar lavage based on the recommendations of the SFM but without specific advice on the management of fresh digestive surgery samples and fixation in formalin. ## Recommendations - None ## Options - It seems difficult to issue specific advice for the management of fresh colectomy or small intestine resection samples, except to work with gloves, glasses and mask ( expert agreement ) - There are not enough data to decide on the management of samples for immunofluorescence ( expert agreement ) - Some centers recommend fixing endoscopic or operative digestive samples immediately in formalin , with the exception of extemporaneous examinations and suspected lymphoma, sarcoma, tuberculosis (micro-biology), pediatric tumors or special protocols (contact with the reference pathology laboratory( expert agreement ) - Proposals must be interpreted according to the intensity of the epidemic and its impact on the organization of healthcare structures. - Therapeutic adjustments must be recorded or discussed during a multidisciplinary concertation meeting (MCM), which should include a small number of participants or use videoconference systems, if feasible. - Whenever possible, the patient should be informed of the increased risk of severe COVID-19 under chemotherapy. - The benefit/risk ratio must be taken into account when prescribing chemotherapy, and especially poly-chemotherapies. - Oral treatments are to be preferred so as to limit patients' exposure in care centers, and tele-consultations should be preferred to physical consultations. The use of oral chemotherapy need to be considered case by case according to patients condition and compliance. - Whenever possible (lesions < 3 cm), particularly for HCC and liver metastases, percutaneous thermoablation is to be preferred (outpatient or 48-hour hospitalization without morbidity). ## 3-proposed adaptation of endoscopy activity (sfed recommendations) The French Society of Digestive Endoscopy (SFED) has proposed an adaptation of digestive endoscopy procedures due to the COVID-19 epidemic ( expert agreement ) The adaptation of endoscopic procedures in healthcare establishments has two objectives : 1) Strengthen and amplify all the resources of healthcare institutions in terms of anesthesia-resuscitation and medical care. 2) Facilitate the management of emergency cases of digestive disease (not linked to in order to minimize the loss of opportunity that a possible delay in diagnosis or treatment would engender. ## A /emergency situations: In the digestive tract: - Upper gastrointestinal bleeding. - Severe lower gastrointestinal bleeding. - Caustic ingestion (in accordance with recommendations). - Sigmoid volvulus. - Gastrointestinal tract obstruction requiring endoscopic stent or percutaneous endoscopic gastrostomy. ## Bilio-pancreatic tract: - Cholangitis - Acute pancreatitis - Bile duct Obstruction - Necrosectomy - Abscess drainageProposed therapeutic adjustments by organ ( * expert agreement / * * expert opinion). ## Organ oncologic situation proposals Rectum locally advanced Chemo-radiotherapy completed or in progress - Postpone surgery (delay of 11 or 7 weeks no difference (GRECCAR 6, [bib_ref] Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery..., Lefevre [/bib_ref] but more morbidity and more difficult excision) * * Beyond 12 weeks, reconsider according to hospital possibilities (availability of operating room and resuscitation unit) * Preoperative chemo radiotherapy planned - Discuss preoperative short course radiotherapy (5 × 5 Gy) without CT and delayed surgery at 12 weeks depending on the epidemic and hospital possibilities [bib_ref] Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer, Erlandsson [/bib_ref] * ## Special cases - T4 - Major response to CT-RT (GECCAR 2 criteria) - Give priority to CAP50 RT regimen and surgery at 12 weeks depending on the epidemic and hospital possibilities * - Consider organ preservation with local excision or Watch and Wait strategy ## Resectable - Postpone surgery until the end of the epidemic period ( + /-neoadjuvant CT depending on tumor characteristics (favor the regimens with capecitabine or CapOx) * * - Low morbidity surgery or thermal ablation can be considered within the usual time limits (local situations) * * ## Potentially resectable - CT with mono (favor capecitabine) * or doublet regimen (CapOx * or CapIri * * ) + /-targeted therapies, and avoid triplet regimen * The association CapOx plus anti-EGFr need to be consider with cautious [bib_ref] Addition of cetuximab to oxaliplatin-based fi rst-line combination chemotherapy for treatment of..., Maughan [/bib_ref] Non resectable - CT: mono (favor capecitabine) or doublet regimen ((CapOx * or CapIri * * ) + /targeted therapies, avoid triplet regimen * - The association CapOx plus anti-EGFr need to be consider with cautious [bib_ref] Addition of cetuximab to oxaliplatin-based fi rst-line combination chemotherapy for treatment of..., Maughan [/bib_ref]. If maintenance strategy, consider capecitabine alone + /-bevacizumab * ## Colorectal metastatic under treatment Non resectable - Consider oral treatments in stable or slowly progressive disease (capecitabine) in order to limit hospital stays [bib_ref] Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a..., Simkens [/bib_ref] , and with telemedicine or telephone follow-up * - Consider CT break of 2 months In patients with stable disease * Non operable or metastatic - Oral treatment (sorafenib / regorafenib / cabozantinib) * - Reconsider loco-regional treatments on a case-by-case basis after the epidemic * ## Squamous cell anal carcinoma Localized with indication of chemoradiotherapy - Favor the Capecitabine-Mitomycin C plus radiotherapy * regimen [bib_ref] Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option, Meulendijks [/bib_ref] Recurrence or metastatic - CapOx bi-chemotherapy or carboplatin-capecitabine (less toxic and easier to manage than 5FU-cisplatin or DCF) * * ## Neuroendocrine carcinoma ## Resectable - Do not postpone surgery or consider neoadjuvant CT or chemoradiotherapy for the rare curable forms * ## Non resectable - Do not postpone CT for the start of treatment (1st line, up to a total of 6 cycles of platinum-etoposide regimen) * - Do not use oral etoposide * - 2nd and 3rd line are to be discussed on a case-by-case basis, as well as therapeutic breaks if possible * ## Well differentiated net resectable - Postpone all surgeries if the patient is asymptomatic * ## Non resectable - Loco-regional procedures (hepatic embolization, thermo-ablation, surgical cytoreduction) are maintained on a case-by-case basis if it is necessary to control a refractory secretory syndrome. Favor teleconsultations for patients who do not need IV treatment (somatostatin analog, everolimus, sunitinib, temozolomide + /-capecitabine) * - Give priority to teleconsultation support * - Postpone assessment imaging until after the epidemic * - Postponement of surgery or heat-ablation until after the epidemic with interim treatment with TKI * B / Indications for which the procedures will not be delayed: - Diagnosis and regional involvement (endoscopy, echoendoscopy + /-fine-needle aspiration). - Positive fecal-immunochemical test (FIT test). - Iron deficiency anemia. This list is not exhaustive but any endoscopy which can be postponed for a few weeks must be discussed in the interests of the patient. ## 4-proposed adaptations for follow-up For patients undergoing systemic treatment, the monitoring of marker kinetics has shown its clinical interest in patients with increased tumor markers at baseline, particularly for colon and metastatic pancreatic cancers . In this exceptional situation of COVID-19, marker kinetics combined with remote clinical monitoring make it possible to postpone imaging examinations during the epidemic period. # Discussion Coronavirus 2019 (COVID-19) is causing an emerging viral infectious disease that is currently spreading worldwide. Although limited clinical cancer-specific data are available, patients with cancer are regarded as having a high risk of CODIV-19-related death and the question of adapting diagnostic procedures, therapies and care strategies during the epidemic period has thus arisen. Moreover, in this particular context, in which hospitals are being submerged by incoming patients requiring intensive care, it is essential to preserve a functioning healthcare system. This situation is a major issue for all patients, whether infected with COVID-19 or not. One of main questions is thus, how can we limit the risk of infection for cancer patients for a period of 2 to 3 months without excessively compromising the control of their cancer? In the current exceptional context, it is accepted in France that usual medical practices may be profoundly modified by the impact of the COVID-19 epidemic on our healthcare system. The epidemic phenomenon is known to be composed of five stages. Stage 1 is the "calm before the storm" where non-emergency care is delayed, fewer patients turn up at emergency departments, and specific departments are ready to receive patients with COVID-19. Stage 2 is the peak, varying in intensity within the same country as was the case in China and Italy. The peak can be relatively well controlled in countries that have previously experienced similar situations, such as Korea or Japan, which anticipated and attenuated the peak by adopting preventive measures such as generalized mask wearing, barrier measures in social networks, massive testing and regular disinfection of public places. In contrast, Western countries appear to be less well prepared and when the capacity of the health system is exceeded, the epidemic peak has a major impact on care for other diseases. Next comes phase 3, known as the "plateau", characterized by the continuous influx of infected patients, thereby neutralizing the healthcare system's ability to take care of other illnesses in accordance with current guidelines. The duration of phase 3 is logically linked to peak intensity as well as the availability of resources [bib_ref] COVID-19 pandemic: perspectives on an unfolding crisis, Spinelli [/bib_ref]. Phase 4 is the "the recession", the duration of which depends on the previous stages and their consequences on healthcare teams. Phase 5 is "the return back to normal situation", and includes the management of newly diagnosed patients as well as patients whose care has been postponed during the previous phases. Each phase will affect therapeutic choices at every level from the standard of care to possible adaptation of strategies or even forced postponement. The goal of the present manuscript is to suggest adaptations of diagnostic procedures, therapies and care strategies, based on expert opinion, that can be proposed in patients treated in France for GI cancer during the epidemic period. The impact of COVID-19 on the adaptations of cancer strategies proposed here is not yet known and further modifications may become necessary in the light of future publications with higher levels of evidence. # Conclusion COVID-19 is an exceptional epidemic phenomenon that affects all countries at every level: social, political, economic and healthcare. Considering the duration of COVID19 epidemic, strategies in cancer and in particular for GI tumor, will be need adapted in several patients. Taking into account that the adaptations proposed in this paper were based on a multidisciplinary overview and experts' agreement, further studies are needed to clearly evaluate the impact of these adaptations during the COVID-19 epidemic period. ## Conflict of interest The Authors have no Conflict of interest in digestive oncology topics with COVID-19. [fig] •: The postponement of the majority of complex surgeries (esophago, pancreatic or hepatic) with high morbidity must be proposed depending on the phase of the epidemic. CLINICAL TRIAL COVID-19 Cohort Project (FFCD-GCO) (Coordinator Pr. A Lièvre (Rennes)) [/fig]	None	http://www.dldjournalonline.com/article/S159086582030133X/pdf	None
7aeca758a5c055173a4f515449ce93413ac0cd4f	pubmed	Standards of Medical Care in Diabetes—2011	Standards of Medical Care in Diabetes—2011 [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref] ## I. classification and diagnosis of diabetes A. Classification of diabetes The classification of diabetes includes four clinical classes: - Type 1 diabetes (results from ␤-cell destruction, usually leading to absolute insulin deficiency) - Type 2 diabetes (results from a progressive insulin secretory defect on the background of insulin resistance) - Other specific types of diabetes due to other causes, e.g., genetic defects in ␤-cell function, genetic defects in insu-lin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drugor chemical-induced (such as in the treatment of HIV/AIDS or after organ transplantation) - Gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy that is not clearly overt diabetes) Some patients cannot be clearly classified as having type 1 or type 2 diabetes. Clinical presentation and disease progression vary considerably in both types of diabetes. Occasionally, patients who otherwise have type 2 diabetes may present with ketoacidosis. Similarly, patients with type 1 diabetes may have a late onset and slow (but relentless) progression of disease despite having features of autoimmune disease. Such difficulties in diagnosis may occur in children, adolescents, and adults. The true diagnosis may become more obvious over time. ## B. diagnosis of diabetes For decades, the diagnosis of diabetes was based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h value in the 75-g oral glucose tolerance test (OGTT). In 2009, an International Expert Committee that included representatives of the ADA, the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD) recommended the use of the A1C test to diagnose diabetes, with a threshold of Ն6.5%, and ADA adopted this criterion in 2010. The diagnostic test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. Point-of-care A1C assays are not sufficiently accurate at this time to use for diagnostic purposes. Epidemiologic datasets show a similar relationship between A1C and risk of retinopathy as has been shown for the corresponding FPG and 2-h plasma glucose thresholds. The A1C has several advantages to the FPG and OGTT, including greater convenience, since fasting is not required; evidence to suggest greater preanalytical stability; and less day-to-day perturbations during periods of stress and illness. These advantages must be balanced by greater cost, the limited availability of A1C testing in certain regions of the developing world, and the incomplete correlation between A1C and average glucose in certain individuals. In addition, A1C levels can vary with patients' ethnicity [bib_ref] Glucose-independent, black-white differences in hemoglobin A1c levels: a crosssectional analysis of 2..., Ziemer [/bib_ref] as well as with certain anemias and hemoglobinopathies. For patients with an abnormal hemoglobin but normal red cell turnover, such as sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used (an updated list is available at www.ngsp.org/interf. asp). For conditions with abnormal red cell turnover, such as pregnancy, recent blood loss or transfusion, or some anemias, the diagnosis of diabetes must employ glucose criteria exclusively. The established glucose criteria for the diagnosis of diabetes (FPG and 2-h PG) remain valid as well [fig_ref] Table 2 -: Criteria for the diagnosis of diabetes A1C Ն6 [/fig_ref]. Just as there is less than 100% concordance between the FPG and 2-h PG tests, there is not perfect concordance between A1C and either glucose-based test. Analyses of National Health and Nutrition Examination Survey (NHANES) data indicate that, assuming universal screening of the undiagnosed, the A1C cut point of Ն6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of Ն126 mg/dl (7.0 mmol/l) (7). - Evidence from a well-conducted multicenter trial - Evidence from a meta-analysis that incorporated quality ratings in the analysis Compelling nonexperimental evidence, i.e., "all or none" rule developed by Center for Evidence Based Medicine at Oxford Supportive evidence from well-conducted randomized controlled trials that are adequately powered, including: - Evidence from a well-conducted trial at one or more institutions - Evidence from a meta-analysis that incorporated quality ratings in the analysis B Supportive evidence from well-conducted cohort studies - Evidence from a well-conducted prospective cohort study or registry - Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study C Supportive evidence from poorly controlled or uncontrolled studies - Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results - Evidence from observational studies with high potential for bias (such as case series with comparison to historical controls) - Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience However, in practice, a large portion of the diabetic population remains unaware of their condition. Thus, the lower sensitivity of A1C at the designated cut point may well be offset by the test's greater practicality, and wider application of a more convenient test (A1C) may actually increase the number of diagnoses made. As with most diagnostic tests, a test result diagnostic of diabetes should be repeated to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such as a patient with a hyperglycemic crisis or classic symptoms of hyperglycemia and a random plasma glucose Ն200 mg/dl. It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, if two different tests (such as A1C and FPG) are both above the diagnostic thresholds, the diagnosis of diabetes is also confirmed. On the other hand, if two different tests are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results Ն6.5%) but not the FPG (Ͻ126 mg/dl or 7.0 mmol/l), or vice versa, that person should be considered to have diabetes. Since there is preanalytic and analytic variability of all the tests, it is also possible that when a test whose result was above the diagnostic threshold is repeated, the second value will be below the diagnostic cut point. This is least likely for A1C, somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory error, such patients are likely to have test results near the margins of the threshold for a diagnosis. The healthcare professional might opt to follow the patient closely and repeat the testing in 3-6 months. The current diagnostic criteria for diabetes are summarized in [fig_ref] Table 2 -: Criteria for the diagnosis of diabetes A1C Ն6 [/fig_ref]. C. Categories of increased risk for diabetes In 1997 and 2003, The Expert Committee on Diagnosis and Classification of Diabetes Mellitus [bib_ref] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report..., Genuth [/bib_ref] recognized an intermediate group of individuals whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered normal. These persons were defined as having impaired fasting glucose (IFG) (FPG levels 100 -125 mg/dl [5.6 -6.9 mmol/l]) or impaired glucose tolerance (IGT) h PG values in the OGTT of 140 -199 mg/dl .0 mmol/l]). It should be noted that the World Health Organization (WHO) and a number of other diabetes organizations define the cutoff for IFG at 110 mg/dl (6.1 mmol/l). Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating the relatively high risk for the future development of diabetes. IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease (CVD). IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. As is the case with the glucose measures, several prospective studies that used A1C to predict the progression to diabetes demonstrated a strong, continuous association between A1C and subsequent diabetes. In a systematic review of 44,203 individuals from 16 cohort studies with a follow-up interval averaging 5.6 years (range 2.8 -12 years), those with an A1C between 5.5 and 6.0% had a substantially increased risk of diabetes with 5-year incidences ranging from 9 -25%. An A1C range of 6.0 -6.5% had a 5-year risk of developing diabetes between 25-50% and relative risk 20 times higher compared with an A1C of 5.0% [bib_ref] A1C level and future risk of diabetes: a systematic review, Zhang [/bib_ref]. In a community-based study of black and white adults without diabetes, baseline A1C was a stronger predictor of subsequent diabetes and cardiovascular events than fasting glucose [bib_ref] Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults, Selvin [/bib_ref]. Other analyses suggest that an A1C of 5.7% is associated with diabetes risk similar to that of the high-risk participants in the Diabetes Prevention Program (DPP). Hence, it is reasonable to consider an A1C range of 5.7-6.4% as identifying individuals with high risk for future diabetes, a state that may be referred to as prediabetes. As is the case for individuals found to have IFG and IGT, individuals with an A1C of 5.7-6.4% should be informed of their increased risk for diabetes as well as CVD and counseled about effective strategies to lower their risks (see IV. PREVENTION/DELAY OF TYPE 2 DIABETES). As with glucose measurements, the continuum of risk is curvilinear-as A1C rises, the risk of diabetes rises disproportionately [bib_ref] A1C level and future risk of diabetes: a systematic review, Zhang [/bib_ref]. Accordingly, interventions should be most intensive and follow-up particularly vigilant for those with A1Cs above 6.0%, who should be considered to be at very high risk. summarizes the categories of increased risk for diabetes. ## Ii. testing for diabetes in asymptomatic patients ## Recommendations - Testing to detect type 2 diabetes and assess risk for future diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI Ն25 kg/m 2 ) and who have one or more additional risk factors for diabetes [fig_ref] Table 4 -: Criteria for testing for diabetes in asymptomatic adult individuals 1 [/fig_ref]. In those without these risk factors, testing should begin at age 45 years. (B) - If tests are normal, repeat testing carried out at least at 3-year intervals is reasonable. (E) . The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* or FPG Ն126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* or 2-h plasma glucose Ն200 mg/dl mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* or In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose Ն200 mg/dl (11.1 mmol/l) In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ## Table 3-categories of increased risk for diabetes (prediabetes) FPG 100-125 mg/dl (5.6-6.9 mmol/l): IFG or 2-h plasma glucose in the 75-g OGTT 199 mg/dl .0 mmol/l): IGT or A1C 5.7-6.4% - To test for diabetes or to assess risk of future diabetes, A1C, FPG, or 2-h 75-g OGTT is appropriate. (B) - In those identified with increased risk for future diabetes, identify and, if appropriate, treat other CVD risk factors. For many illnesses, there is a major distinction between screening and diagnostic testing. However, for diabetes, the same tests would be used for "screening" as for diagnosis. Diabetes may be identified anywhere along a spectrum of clinical scenarios ranging from a seemingly lowrisk individual who happens to have glucose testing, to a higher-risk individual whom the provider tests because of high suspicion of diabetes, to the symptomatic patient. The discussion herein is primarily framed as testing for diabetes in those without symptoms. Testing for diabetes will also detect individuals at increased future risk for diabetes, herein referred to as having prediabetes. A. Testing for type 2 diabetes and risk of future diabetes in adults Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-fourth of all people with diabetes in the U.S. may be undiagnosed. The effectiveness of early identification of prediabetes and diabetes through mass testing of asymptomatic individuals has not been proven definitively, and rigorous trials to provide such proof are unlikely to occur. However, mathematical modeling studies suggest that screening independent of risk factors beginning at age 30 or 45 years is highly cost-effective (Ͻ$11,000 per qualityadjusted life-year gained) [bib_ref] Age at initiation and frequency of screening to detect type 2 diabetes:..., Kahn [/bib_ref]. Prediabetes and diabetes meet established criteria for conditions in which early detection is appropriate. Both conditions are common and increasing in prevalence and impose significant public health burdens. There is a long presymptomatic phase before the diagnosis of type 2 diabetes is usually made. Relatively simple tests are available to detect preclinical disease. Additionally, the duration of glycemic burden is a strong predictor of adverse outcomes, and effective interventions exist to prevent progression of prediabetes to diabetes (see Recommendations for testing for diabetes in asymptomatic, undiagnosed adults are listed in [fig_ref] Table 4 -: Criteria for testing for diabetes in asymptomatic adult individuals 1 [/fig_ref]. Testing should be considered in adults of any age with BMI Ն25 kg/m 2 and one or more of the known risk factors for diabetes. Because age is a major risk factor for diabetes, testing of those without other risk factors should begin no later than age 45 years. Either A1C, FPG, or the 2-h OGTT is appropriate for testing. The 2-h OGTT identifies people with either IFG or IGT and thus more people at increased risk for the development of diabetes and CVD. It should be noted that the two tests do not necessarily detect the same individuals. The efficacy of interventions for primary prevention of type 2 diabetes [bib_ref] Diabetes Prevention Program Research Group. Reduction in the incidence of type 2..., Knowler [/bib_ref] [bib_ref] Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by..., Tuomilehto [/bib_ref] [bib_ref] Effects of diet and exercise in preventing NIDDM in people with impaired..., Pan [/bib_ref] [bib_ref] Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by..., Buchanan [/bib_ref] [bib_ref] Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial, Chiasson [/bib_ref] [bib_ref] Effect of rosiglitazone on the frequency of diabetes in patients with impaired..., Gerstein [/bib_ref] have primarily been demonstrated among individuals with IGT, not for individuals with IFG (who do not also have IGT) or for individuals with specific A1C levels. The appropriate interval between tests is not known [bib_ref] The efficacy and cost of alternative strategies for systematic screening for type..., Johnson [/bib_ref]. The rationale for the 3-year interval is that false negatives will be repeated before substantial time elapses, and there is little likelihood that an individual will develop significant complications of diabetes within 3 years of a negative test result. In the modeling study, repeat screening every 3 or 5 years was cost-effective [bib_ref] Age at initiation and frequency of screening to detect type 2 diabetes:..., Kahn [/bib_ref]. Because of the need for follow-up and discussion of abnormal results, testing should be carried out within the health care setting. Community screening outside a health care setting is not recommended because people with positive tests may not seek, or have access to, appropriate follow-up testing and care. Conversely, there may be failure to ensure appropriate repeat testing for individuals who test negative. Community screening may also be poorly targeted, i.e., it may fail to reach the groups most at risk and inappropriately test those at low risk (the worried well) or even those already diagnosed. B. Testing for type 2 diabetes in children The incidence of type 2 diabetes in adolescents has increased dramatically in the last decade, especially in minority populations [bib_ref] SEARCH for Diabetes in Youth Study Group. Testing the accelerator hypothesis: body..., Dabelea [/bib_ref] , although the disease remains rare in the general pediatric population [bib_ref] The burden of diabetes mellitus among US youth: prevalence estimates from the..., Liese [/bib_ref]. Consistent with recommendations for adults, children and youth at increased risk for the presence or the development of type 2 diabetes should be tested within the health care setting. The recommendations of the ADA Consensus Statement on Type 2 Diabetes in Children and Youth, with some modifications, are summarized in [fig_ref] Table 5 -: Testing for type 2 diabetes in asymptomatic children [/fig_ref]. C. Screening for type 1 diabetes Generally, people with type 1 diabetes present with acute symptoms of diabetes and markedly elevated blood glucose levels, and most cases are diagnosed soon after the onset of hyperglycemia. However, evidence from type 1 prevention studies suggests that measurement of islet autoantibodies identifies individuals who are at risk for developing type 1 diabetes. Such testing may be appropriate in highrisk individuals, such as those with prior transient hyperglycemia or those who have relatives with type 1 diabetes, in the context of clinical research studies (see, for example, http://www2.diabetestrialnet.org). Widespread clinical testing of asymptomatic low-risk individuals cannot currently be recommended, as it would identify very few individuals in the general population who are at risk. Individuals who screen positive should be counseled about their risk of developing diabetes. Clinical studies are being conducted to For many years, GDM was defined as any degree of glucose intolerance with onset or first recognition during pregnancy (8), whether or not the condition persisted after pregnancy, and not excluding the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but its limitations were recognized for many years. As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2 diabetes has increased [bib_ref] Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among..., Lawrence [/bib_ref]. Because of this, it is reasonable to screen women with risk factors for type 2 diabetes [fig_ref] Table 4 -: Criteria for testing for diabetes in asymptomatic adult individuals 1 [/fig_ref] for diabetes at their initial prenatal visit, using standard diagnostic criteria [fig_ref] Table 2 -: Criteria for the diagnosis of diabetes A1C Ն6 [/fig_ref]. Women with diabetes found at this visit should receive a diagnosis of overt, not gestational, diabetes. GDM carries risks for the mother and neonate. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study [bib_ref] Hyperglycemia and adverse pregnancy outcomes, Hapo Study Cooperative Research [/bib_ref] , a large-scale (ϳ25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24 -28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. After deliberations in 2008 -2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM. The group recommended that all women not known to have diabetes undergo a 75-g OGTT at 24 -28 weeks of gestation. Additionally, the group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with the mean glucose levels in the HAPO study. Current screening and diagnostic strategies, based on the IADPSG statement [bib_ref] International association of diabetes and pregnancy study groups recommendations on the diagnosis..., Metzger [/bib_ref] , are outlined in [fig_ref] Table 6 -: Screening for and diagnosis of GDM [/fig_ref]. These new criteria will significantly increase the prevalence of GDM, primarily because only one abnormal value, not two, is sufficient to make the diagnosis. The ADA recognizes the anticipated significant increase in the incidence of GDM to be diagnosed by these criteria and is sensitive to concerns about the "medicalization" of pregnancies previously categorized as normal. These diagnostic criteria changes are being made in the context of worrisome worldwide increases in obesity and diabetes rates, with the intent of optimizing gestational outcomes for women and their babies. Admittedly, there are few data from randomized clinical trials regarding therapeutic interventions in women who will now be diagnosed with GDM based on only one blood glucose value above the specified cut points (in contrast to the older criteria that stipulated at least two abnormal values.) Expected benefits to their pregnancies and offspring is inferred from intervention trials that focused on women with more mild hyperglycemia than identified using older GDM diagnostic criteria and that found modest benefits [bib_ref] Effects of medical therapies on retinopathy progression in type 2 diabetes, Landon [/bib_ref]. The frequency of their follow-up and blood glucose monitoring is not yet clear, but likely to be less intensive than women diagnosed by the older criteria. Additional well-designed clinical studies are needed to determine the optimal intensity of monitoring and treatment of women with GDM diagnosed by the new criteria (that would not have met the prior definition of GDM). It is important to note that 80 -90% of women in both of the mild GDM studies (whose glucose values overlapped with the thresholds recommended herein) could be managed with lifestyle therapy alone. Because some cases of GDM may represent preexisting undiagnosed type 2 diabetes, women with a history of GDM should be screened for diabetes 6 -12 weeks postpartum, using nonpregnant OGTT criteria. Women with a history of GDM have a greatly increased subsequent risk for diabetes (29) and should be followed up with subsequent screening for the development of diabetes or prediabetes, as outlined in II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS. [bib_ref] Diabetes Prevention Program Research Group. Reduction in the incidence of type 2..., Knowler [/bib_ref] [bib_ref] Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by..., Tuomilehto [/bib_ref] [bib_ref] Effects of diet and exercise in preventing NIDDM in people with impaired..., Pan [/bib_ref] [bib_ref] Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by..., Buchanan [/bib_ref] [bib_ref] Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial, Chiasson [/bib_ref] [bib_ref] Effect of rosiglitazone on the frequency of diabetes in patients with impaired..., Gerstein [/bib_ref]. These interventions include intensive lifestyle modification programs that have been shown to be very effective (58% reduction after 3 years) and use of the pharmacologic agents metformin, ␣-glucosidase inhibitors, orlistat, and thiazolidinediones (TZDs), each of which has been shown to decrease incident diabetes to various degrees. A summary of major diabetes prevention trials is shown in [fig_ref] Table 7 -: Therapies proven effective in diabetes prevention trials [/fig_ref]. Follow-up of all three large studies of lifestyle intervention has shown sustained reduction in the rate of conversion to type 2 diabetes, with 43% reduction at 20 years in the Da Qing study (30), 43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS) (31) and 34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS) (32). A cost-effectiveness analysis suggested that lifestyle interventions as delivered in the DPP are cost-effective (33). Group delivery of the DPP intervention in community settings has the potential to be significantly less expensive while still achieving similar weight loss (34). Based on the results of clinical trials and the known risks of progression of prediabetes to diabetes, persons with an A1C of 5.7-6.4%, IGT, or IFG should be counseled on lifestyle changes with goals similar to those of the DPP (7% weight loss and moderate physical activity of at least 150 min/week). Regarding the more difficult issue of drug therapy for diabetes prevention, a consensus panel felt that metformin should be the only drug considered (39). For other drugs, the issues of cost, side effects, and lack of persistence of effect in some studies led the panel to not recommend their use for diabetes prevention. Metformin, which was significantly less effective than lifestyle in the DPP and DPPOS, reasonably may be recommended for very-high-risk individuals (those with risk factors for diabetes and/or those with more severe or progressive hyperglycemia). Of note, in the DPP metformin was most effective compared to lifestyle in those with BMI of at least 35 kg/m 2 and was not significantly better than placebo in those over age 60 years. ## V. diabetes care A. Initial evaluation A complete medical evaluation should be performed to classify the diabetes, detect the presence of diabetes complications, review previous treatment and glycemic control in patients with established diabetes, assist in formulating a management plan, and provide a basis for continuing care. Laboratory tests appropriate to the evaluation of each patient's medical con- dition should be performed. A focus on the components of comprehensive care [fig_ref] Table 8 -: Components of the comprehensive diabetes evaluationMedical history• Age and characteristics of onset... [/fig_ref] will assist the health care team to ensure optimal management of the patient with diabetes. ## B. management People with diabetes should receive medical care from a physician-coordinated team. Such teams may include, but are not limited to, physicians, nurse practitioners, physician's assistants, nurses, dietitians, pharmacists, and mental health professionals with expertise and a special interest in diabetes. It is essential in this collaborative and integrated team approach that individuals with diabetes assume an active role in their care. The management plan should be formulated as a collaborative therapeutic alliance among the patient and family, the physician, and other members of the health care team. A variety of strategies and techniques should be used to provide adequate education and development of problem-solving skills in the various aspects of diabetes management. Implementation of the management plan requires that each aspect is understood and agreed to by the patient and the care providers and that the goals and treatment plan are reasonable. Any plan should recognize diabetes selfmanagement education (DSME) and ongoing diabetes support as an integral component of care. In developing the plan, consideration should be given to the patient's age, school or work schedule and conditions, physical activity, eating patterns, social situation and cultural factors, and presence of complications of diabetes or other medical conditions. C. Glycemic control 1. Assessment of glycemic control Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) or interstitial glucose, and A1C. The frequency and timing of SMBG should be dictated by the particular needs and goals of the patient. SMBG is especially important for patients treated with insulin to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. For most patients with type 1 diabetes and pregnant women taking insulin, SMBG is recommended three or more times daily. For these populations, significantly more frequent testing may be required to reach A1C targets safely without hypoglycemia. The optimal frequency and timing of SMBG for patients with type 2 diabetes on noninsulin therapy is unclear. A meta-analysis of SMBG in noninsulin-treated patients with type 2 diabetes concluded that some regimen of SMBG was associated with a reduction in A1C of 0.4%. However, many of the studies in this analysis also included patient education with diet and exercise counseling and, in some cases, pharmacologic intervention, making it difficult to assess the contribution of SMBG alone to improved control (40). Several recent trials have called into question the clinical utility and cost-effectiveness of routine SMBG in non-insulin-treated patients (41-43). Because the accuracy of SMBG is instrument and user dependent (44), it is important to evaluate each patient's monitoring technique, both initially and at regular intervals thereafter. In addition, optimal use of SMBG requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise, or pharmacological therapy to achieve specific glycemic goals, and these skills should be reevaluated periodically. CGM through the measurement of interstitial glucose (which correlates well with plasma glucose) is available. These sensors require calibration with SMBG, and the latter are still recommended for making acute treatment decisions. CGM devices also have alarms for hypo-and hyperglycemic excursions. Small studies in selected patients with type 1 diabetes have suggested that CGM use reduces the time spent in hypo-and hyperglycemic ranges and may modestly improve glycemic control. A larger 26-week randomized trial of 322 type 1 patients showed that adults age 25 years and older using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from ϳ7.6% to 7.1%) compared to usual intensive insulin therapy with SMBG (45). Sensor use in children, teens, and adults up to age 24 years did not result in significant A1C lowering, and there was no significant difference in hypoglycemia in any group. Importantly, the greatest predictor of A1C-lowering in this study for all agegroups was frequency of sensor use, which was lower in younger age-groups. In a smaller randomized controlled trial of 129 adults and children with baseline A1C Ͻ7.0%, outcomes combining A1C and hypoglycemia favored the group utilizing CGM, suggesting that CGM is also beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C Ͻ7.0 (46). Although CGM is an evolving technology, emerging data suggest that, in appropriately selected patients who are motivated to wear it most of the time, it may offer benefit. CGM may be particularly useful in those with hypoglycemia unawareness and/or frequent episodes of hypoglycemia, and studies in this area are ongoing. while unstable or highly intensively managed patients (e.g., pregnant type 1 women) may be tested more frequently than every 3 months. The availability of the A1C result at the time that the patient is seen (point-of-care testing) has been reported to result in increased intensification of therapy and improvement in glycemic control (49,50). The A1C test is subject to certain limitations. Conditions that affect erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient's clinical situation (44). In addition, A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability (especially type 1 patients, or type 2 patients with severe insulin deficiency), glycemic control is best judged by the combination of results of SMBG testing and the A1C. The A1C may also serve as a check on the accuracy of the patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule.contains the correlation between A1C levels and mean plasma glucose levels based on data from the international A1C-Derived Average Glucose (ADAG) trial utilizing frequent SMBG and CGM in 507 adults (83% Caucasian) with type 1, type 2, and no diabe- In the ADAG trial, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although there was a trend toward a difference between African/African American participants and Caucasian ones that might have been significant had more African/African American participants been studied. A recent study comparing A1C with CGM data in 48 type 1 diabetic children found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r ϭ 0.7) was significantly lower than in the ADAG trial (53). Whether there are significant differences in how A1C relates to average glucose in children or in African American patients is an area for further study. For the time being, the question has not led to different recommendations about testing A1C or to different interpretations of the clinical meaning of given levels of A1C in those populations. For patients in whom A1C/eAG and measured blood glucose appear discrepant, clinicians should consider the possibilities of hemoglobinopathy or altered red cell turnover, and the options of more frequent and/or different timing of SMBG or use of CGM. Other measures of chronic glycemia such as fructosamine are available, but their linkage to average glucose and their prognostic significance are not as clear as is the case for A1C. were prospective, randomized, controlled trials of intensive versus standard glycemic control in patients with relatively recently diagnosed diabetes. These trials showed definitively that improved glycemic control is associated with significantly decreased rates of microvascular (retinopathy and nephropathy) and neuropathic complications. Follow up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (57,58) and of the UKPDS cohort (59) has shown persistence of these microvascular benefits in previously intensively treated subjects, even though their glycemic control has been equivalent to that of previous standard arm subjects during follow-up. Subsequent trials in patients with more long-standing type 2 diabetes, designed primarily to look at the role of intensive glycemic control on cardiovascular outcomes also confirmed a benefit, although more modest, on onset or progression of microvascular complications. ## Glycemic goals in adults The Veterans Affairs Diabetes Trial (VADT) showed significant reductions in albuminuria with intensive (achieved median A1C 6.9%) compared to standard glycemic control, but no difference in retinopathy and neuropathy (60,61). The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study of intensive versus standard glycemic control in type 2 diabetes found a statistically significant reduction in albuminuria with an A1C target of Ͻ6.5% (achieved median A1C 6.3%) compared to standard therapy achieving a median A1C of 7.0% (62). Recent analyses from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial have shown lower rates of measures of microvascular complications in the intensive glycemic control arm compared with the standard arm (63,64). Epidemiological analyses of the DCCT and UKPDS (47,48) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair or good control. These analyses also suggest that further lowering of A1C from 7 to 6% is associated with further reduction in the risk of microvascular complications, albeit the absolute risk reductions become much smaller. Given the substantially increased risk of hypoglycemia (particularly in those with type 1 diabetes, but also in the recent type 2 trials), the concerning mortality findings in the ACCORD trial [bib_ref] Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein [/bib_ref] , and the relatively much greater effort required to achieve near-normoglycemia, the risks of lower targets may outweigh the potential benefits on microvascular complications on a population level. However, selected individual patients, especially those with little comorbidity and long life expectancy (who may reap the benefits of further lowering of glycemia below 7%) may, at patient and provider judgment, adopt glycemic targets as close to normal as possible as long as significant hypoglycemia does not become a barrier. Whereas many epidemiologic studies and meta-analyses [bib_ref] Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus, Selvin [/bib_ref] [bib_ref] Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus:..., Stettler [/bib_ref] have clearly shown a direct relationship between A1C and CVD, the potential of intensive glycemic control to reduce CVD has been less clearly defined. In the DCCT, there was a trend toward lower risk of CVD events with intensive control. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P ϭ 0.02) in CVD outcomes and a 57% reduction (P ϭ 0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm [bib_ref] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study..., Nathan [/bib_ref]. The benefit of intensive glycemic control in this type 1 cohort has recently been shown to persist for several decades [bib_ref] Modernday clinical course of type 1 diabetes mellitus after 30 years' duration:..., Nathan [/bib_ref]. The UKPDS trial of type 2 diabetes observed a 16% reduction in cardiovascular complications (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm, although this difference was not statistically significant (P ϭ 0.052), and there was no suggestion of benefit on other CVD outcomes such as stroke. However, 10 years of follow-up of the UKPDS cohort demonstrated, for participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant) (59). R e s u l t s o f t h r e e l a r g e t r i a l s (ACCORD, ADVANCE, and VADT) suggested no significant reduction in CVD outcomes with intensive glycemic control in these populations, who had more advanced diabetes than UKPDS participants. Details of these three studies are reviewed extensively in a recent ADA position statement [bib_ref] American Diabetes Association, American College of Cardiology Foundation, American Heart Association. Intensive..., Skyler [/bib_ref]. The glycemic control arm of ACCORD was halted early due to the finding of an increased rate of mortality in the intensive arm compared with the standard arm (1.41% vs. 1.14% per year; HR 1.22 [95% CI 1.01 to 1.46]); with a similar increase in cardiovascular deaths. The primary outcome of ACCORD (MI, stroke, or cardiovascular death) was lower in the intensive glycemic control group, due to a reduction in nonfatal MI, but this reduction was not statistically significant when the study was terminated [bib_ref] Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein [/bib_ref]. The potential cause of excess deaths in the intensive group of the ACCORD has been difficult to pinpoint. Exploratory analyses of the mortality findings of ACCORD (evaluating variables including weight gain, use of any specific drug or drug combination, and hypoglycemia) were reportedly unable to identify a clear explanation for the excess mortality in the intensive arm. The ACCORD investigators subsequently published additional analyses showing no increase in mortality in the intensive arm participants who achieved A1C levels Ͻ7% or in those who lowered their A1C quickly after trial enrollment. In fact, the converse was observed-those at highest risk for mortality were participants in the intensive arm with the highest A1C levels [bib_ref] Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C..., Riddle [/bib_ref]. The primary outcome of ADVANCE was a combination of microvascular events (nephropathy and retinopathy) and major adverse cardiovascular events (MI, stroke, and cardiovascular death). Intensive glycemic control significantly reduced the primary end point, although this was due to a significant reduction in the microvascular outcome, primarily development of macroalbuminuria, with no significant reduction in the macrovascular outcome. There was no difference in overall or cardiovascular mortality between the intensive compared with the standard glycemic control arms (62). The VADT randomized participants with type 2 diabetes uncontrolled on insulin or maximal dose oral agents (median entry A1C 9.4%) to a strategy of intensive glycemic control (goal A1C Ͻ6.0%) or standard glycemic control, with a planned A1C separation of at least 1.5%. The primary outcome of the VADT was a composite of CVD events. The cumulative primary outcome was nonsignificantly lower in the intensive arm (60). Unlike the UKPDS, which was carried out in patients with newly diagnosed diabetes, all three of the recent type 2 cardiovascular trials were conducted in participants with established diabetes (mean duration 8 -11 years) and either known CVD or multiple risk factors, suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The DCCT-EDIC study and the long-term follow-up of the UKPDS cohort both suggest that intensive glycemic control initiated soon after diagnosis of diabetes in patients with a lower level of CVD risk may impart long-term protection from CVD events. As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and minimal or no role when it is advanced. Consistent with this concept, data from an ancillary study of the VADT demonstrated that intensive glycemic control was quite effective in reducing CVD events in individuals with less atherosclerosis at baseline (assessed by coronary calcium) but not in persons with more extensive baseline atherosclerosis. The evidence for a cardiovascular benefit of intensive glycemic control primarily rests on long-term follow-up of study cohorts treated early in the course of type 1 and type 2 diabetes and subset analyses of ACCORD, ADVANCE, and VADT. A recent group-level metaanalysis of the latter three trials suggests that glucose lowering has a modest (9%) but statistically significant reduction in major CVD outcomes, primarily nonfatal MI, with no significant effect on mortality. A prespecified subgroup analysis suggested that major CVD outcome reduction occurred in patients without known CVD at baseline (HR 0.84 [95% CI 0.74 -0.94]) [bib_ref] Intensive glucose control and macrovascular outcomes in type 2 diabetes, Turnbull [/bib_ref]. Conversely, the mortality findings in ACCORD and subgroup analyses of VADT suggest that the potential risks of very intensive glycemic control may outweigh its benefits in some patients, such as those with very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved. Recommended glycemic goals for many nonpregnant adults are shown in [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref]. The recommendations are based on those for A1C values, with listed blood glucose levels that appear to correlate with achievement of an A1C of Ͻ7%. Less-stringent treatment goals may be appropriate for adults with limited life expectancies or advanced vascular disease. Glycemic goals for children are provided in VII.A.1.a. Glycemic control. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals. The issue of pre-versus postprandial SMBG targets is complex. Elevated postchallenge (2-h OGTT) glucose values have been associated with increased cardiovascular risk independent of FPG in some epidemiological studies. In diabetic subjects, some surrogate measures of vas-cular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia [bib_ref] Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia..., Ceriello [/bib_ref]. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution being higher at A1C levels that are closer to 7%. However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark glycemic control trials such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally, a randomized controlled trial in patients with known CVD found no CVD benefit of insulin regimens targeting postprandial glucose compared with targeting preprandial glucose [bib_ref] Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2..., Raz [/bib_ref]. A reasonable recommendation for postprandial testing and targets is that for individuals who have premeal glucose values within target but have A1C values above target, monitoring postprandial plasma glucose (PPG) 1-2 h after the start of the meal and treatment aimed at reducing PPG values to Ͻ180 mg/dl may help lower A1C. As regards goals for glycemic control for women with GDM, recommendations from the Fifth International Workshop-Conference on Gestational Diabetes [bib_ref] Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus, Metzger [/bib_ref] were to target maternal capillary glucose concentrations of: - Preprandial Յ95 mg/dl (5.3 mmol/l) and either - 1-h postmeal Յ140 mg/dl (7.8 mmol/l) or - 2-h postmeal Յ120 mg/dl (6.7 mmol/l) For women with preexisting type 1 or type 2 diabetes who become pregnant, a recent consensus statement (78) recommended the following as optimal glycemic goals, if they can be achieved without excessive hypoglycemia: - premeal, bedtime, and overnight glucose 60 -99 mg/dl (3.3-5.4 mmol/l) - peak postprandial glucose 100 -129 mg/dl (5.4 -7.1mmol/l) - A1C Ͻ6.0% D. Pharmacologic and overall approaches to treatment 1. Therapy for type 1 diabetes The DCCT clearly showed that intensive insulin therapy (three or more injections per day of insulin, or continuous subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part of improved glycemia and better outcomes (47,68). At the time of the study, therapy was carried out with short-and intermediate-acting human insulins. Despite better microvascular outcomes, intensive insulin therapy was associated with a high rate in severe hypoglycemia (62 episodes per 100 patient-years of therapy). Since the time of the DCCT, a number of rapidacting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia with equal A1C-lowering in type 1 diabetes [bib_ref] Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific..., Dewitt [/bib_ref] [bib_ref] Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with..., Rosenstock [/bib_ref]. Therefore, recommended therapy for type 1 diabetes consists of the following components: 1) use of multiple dose insulin injections (three to four injections per day of basal and prandial insulin) or CSII therapy; 2) matching of prandial insulin to carbohydrate intake, premeal blood glucose, and anticipated activity; and 3) for many patients (especially if hypoglycemia is a problem), use of insulin analogs. There are excellent reviews available that guide the initiation and management of insulin therapy to achieve desired glycemic goals [bib_ref] Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific..., Dewitt [/bib_ref] [bib_ref] Narrative review: a rational approach to starting insulin therapy, Mooradian [/bib_ref]. Because of the increased frequency of other autoimmune diseases in type 1 diabetes, screening for thyroid dysfunction, vitamin B12 deficiency, or celiac disease should be considered based on signs and symptoms. Periodic screening in absence of symptoms has been recommended, but the effectiveness and optimal frequency are unclear. ## Therapy for type 2 diabetes The ADA and the EASD published an expert consensus statement on the approach to management of hyperglycemia in individuals with type 2 diabetes (82). Highlights of this approach are: intervention at the time of diagnosis with metformin in combination with lifestyle changes (MNT and exercise) and continuing timely augmentation of therapy with additional agents (including early initiation of insulin therapy) as a means of achieving and maintaining recommended levels of glycemic control (i.e., A1C Ͻ7% for most patients). As A1C targets are not achieved, treatment intensification is based on the addition of another agent from a different class. The overall objective is to achieve and maintain glycemic control and to change interventions when therapeutic goals are not being met. The algorithm took into account the evidence for A1C-lowering of the individual interventions, their additive effects, and their expense. The precise drugs used and their exact sequence may not be as important as achieving and maintaining glycemic targets safely. Medications not included in the consensus algorithm, owing to less glucose-lowering effectiveness, limited clinical data, and/or relative expense, still may be appropriate choices in individual patients to achieve glycemic goals. Initiation of insulin at time of diagnosis is recommended for individuals presenting with weight loss or other severe hyperglycemic symptoms or signs. Postprandial glucose measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes. ## E. diabetes self-management education Recommendations - People with diabetes should receive diabetes self-management education (DSME) according to national standards when their diabetes is diagnosed and as needed thereafter. (B) - Effective self-management and quality of life are the key outcomes of DSME and should be measured and monitored as part of care. (C) - DSME should address psychosocial issues, since emotional well-being is associated with positive diabetes outcomes. (C) - Because DSME can result in costsavings and improved outcomes (B), DSME should be adequately reimbursed by third-party payors. (E) DSME is an essential element of diabetes care [bib_ref] Effectiveness of self-management training in type 2 diabetes: a systematic review of..., Norris [/bib_ref] [bib_ref] Self-management education for adults with type 2 diabetes: a metaanalysis of the..., Norris [/bib_ref] [bib_ref] Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes, Gary [/bib_ref] [bib_ref] A systematic review of psychosocial outcomes following education, self-management and psychological interventions..., Steed [/bib_ref] [bib_ref] Diabetes patient education: a meta-analysis and meta-regression, Ellis [/bib_ref] [bib_ref] Self-management education programs in chronic disease: a systematic review and methodological critique..., Warsi [/bib_ref] , and national standards for DSME [bib_ref] National standards for diabetes self-management education, Funnell [/bib_ref] are based on evidence for its benefits. Education helps people with diabetes initiate effective self-management and cope with diabetes when they are first diagnosed. Ongoing DSME and support also help people with diabetes maintain effective self-management throughout a lifetime of diabetes as they face new challenges and treatment advances become available. DSME helps patients optimize metabolic control, prevent and manage complications, and maximize quality of life in a cost-effective manner [bib_ref] Yarborough P. Diabetes self-management education core outcomes measures, Mulcahy [/bib_ref]. DSME is the ongoing process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. This process incorporates the needs, goals, and life experiences of the person with diabetes. The overall objectives of DSME are to support informed decision-making, self-care behaviors, problem-solving, and active collaboration with the health care team to improve clinical outcomes, health status, and quality of life in a cost-effective manner [bib_ref] National standards for diabetes self-management education, Funnell [/bib_ref]. Current best practice of DSME is a skills-based approach that focuses on helping those with diabetes to make informed self-management choices. DSME has changed from a didactic approach focusing on providing information to more theoretically based empowerment models that focus on helping those with diabetes make informed self-management decisions. Care of diabetes has shifted to an approach that is more patient centered and places the person with diabetes and his or her family at the center of the care model working in collaboration with health care professionals. Patientcentered care is respectful of and responsive to individual patient preferences, needs, and values and ensures that patient values guide all decision making [bib_ref] Where is the patient in diabetes performance measures? The case for including..., Glasgow [/bib_ref]. Evidence for the benefits of DSME Multiple studies have found that DSME is associated with improved diabetes knowledge and improved self-care behavior [bib_ref] Effectiveness of self-management training in type 2 diabetes: a systematic review of..., Norris [/bib_ref] , improved clinical outcomes such as lower A1C [bib_ref] Self-management education for adults with type 2 diabetes: a metaanalysis of the..., Norris [/bib_ref] [bib_ref] Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes, Gary [/bib_ref] [bib_ref] Diabetes patient education: a meta-analysis and meta-regression, Ellis [/bib_ref] [bib_ref] Self-management education programs in chronic disease: a systematic review and methodological critique..., Warsi [/bib_ref] [bib_ref] Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening..., Barker [/bib_ref] , lower self-reported weight [bib_ref] Effectiveness of self-management training in type 2 diabetes: a systematic review of..., Norris [/bib_ref] , improved quality of life [bib_ref] A systematic review of psychosocial outcomes following education, self-management and psychological interventions..., Steed [/bib_ref] [bib_ref] Meta-analysis of quality of life outcomes following diabetes self-management training, Cochran [/bib_ref] , healthy coping (94), and lower costs [bib_ref] Nutritionist visits, diabetes classes, and hospitalization rates and charges: the Urban Diabetes..., Robbins [/bib_ref]. Better outcomes were reported for DSME interventions that were longer and included follow-up support , that were culturally (100,101) and age appropriate [bib_ref] A systematic review of diabetes self-care interventions for older, African American, or..., Sarkisian [/bib_ref] [bib_ref] Meta-analysis: chronic disease self-management programs for older adults, Chodosh [/bib_ref] and tailored to individual needs and preferences, and that addressed psychosocial issues and incorporated behavioral strategies . Both individual and group approaches have been found effective [bib_ref] Assessment of group versus individual diabetes education: a randomized study, Rickheim [/bib_ref] [bib_ref] A 5-year randomized controlled study of learning, problem solving ability, and quality..., Trento [/bib_ref] [bib_ref] Williams RD: Group based training for selfmanagement strategies in people with type..., Deakin [/bib_ref]. There is growing evidence for the role of community health workers and peer [bib_ref] Diabetes control with reciprocal peer support versus nurse care management: a randomized..., Heisler [/bib_ref] [bib_ref] Different models to mobilize peer support to improve diabetes selfmanagement and clinical..., Heisler [/bib_ref] and lay leaders [bib_ref] Self-management education programmes by lay leaders for people with chronic conditions, Foster [/bib_ref] in delivering DSME and support in addition to the core team [bib_ref] Effectiveness of community health workers in the care of persons with diabetes, Norris [/bib_ref]. Diabetes education is associated with increased use of primary and preventive services and lower use of acute, inpatient hospital services [bib_ref] Nutritionist visits, diabetes classes, and hospitalization rates and charges: the Urban Diabetes..., Robbins [/bib_ref]. Patients who participate in diabetes education are more likely to follow best practice treatment recommendations, particularly among the Medicare population, and have lower Medicare and commercial claim costs [bib_ref] Assessing the value of diabetes education, Duncan [/bib_ref]. National standards for DSME National standards for DSME are designed to define quality DSME and to assist diabetes educators in a variety of settings to provide evidence-based education [bib_ref] National standards for diabetes self-management education, Funnell [/bib_ref]. The standards, most recently revised in 2007, are reviewed and updated every 5 years by a task force representing key organizations involved in the field of diabetes education and care. Reimbursement for DSME DSME, when provided by a program that meets the national standards for DSME and is recognized by the ADA or other approval bodies, is reimbursed as partof the Medicare program as overseen by the Centers for Medicare and Medicaid Services (CMS) (www. cms.hhs.gov/DiabetesSelfManagement). DSME is also covered by a growing number of other health insurance plans. MNT is an integral component of diabetes prevention, management, and selfmanagement education. In addition to its role in preventing and controlling diabetes, ADA recognizes the importance of nutrition as an essential component of an overall healthy lifestyle. A full review of the evidence regarding nutrition in preventing and controlling diabetes and its complications and additional nutritionrelated recommendations can be found in the ADA position statement, "Nutrition Recommendations and Interventions for Diabetes," published in 2007 and updated for 2008 [bib_ref] Nutrition recommendations and interventions for diabetes: a position statement of the American..., Bantle [/bib_ref]. Achieving nutrition-related goals requires a coordinated team effort that includes the active in-volvement of the person with prediabetes or diabetes. Because of the complexity of nutrition issues, it is recommended that a registered dietitian who is knowledgeable and skilled in implementing nutrition therapy into diabetes management and education be the team member who provides MNT. Clinical trials/outcome studies of MNT have reported decreases in A1C at 3-6 months ranging from 0.25% to 2.9% with higher reductions seen in type 2 diabetes of shorter duration. Multiple studies have demonstrated sustained improvements in A1C at 12 months and longer when an Registered Dietitian provided follow-up visits ranging from monthly to three sessions per year [bib_ref] Training in flexible, intensive insulin management to enable dietary freedom in people..., Dafne Study Group [/bib_ref] [bib_ref] Effectiveness of medical nutrition therapy provided by dietitians in the management of..., Franz [/bib_ref] [bib_ref] Randomized controlled community-based nutrition and exercise intervention improves glycemia and cardiovascular risk..., Goldhaber-Fiebert [/bib_ref] [bib_ref] Outcomes monitoring of health, behavior, and quality of life after nutrition intervention..., Lemon [/bib_ref] [bib_ref] Nutrition education improves metabolic outcomes among older adults with diabetes mellitus: results..., Miller [/bib_ref] [bib_ref] Effects of clinical nutrition education and educator discipline on glycemic control outcomes..., Wilson [/bib_ref] [bib_ref] Improving glycemic control in adults with diabetes mellitus: shared responsibility in primary..., Graber [/bib_ref] [bib_ref] A single nutrition counseling session with a registered dietitian improves short-term clinical..., Gaetke [/bib_ref]. Studies in nondiabetic people suggest that MNT reduces LDL cholesterol by 15-25 mg/dl up to 16% (125) and support a role for lifestyle modification in treating hypertension [bib_ref] A clinical trial of the effects of dietary patterns on blood pressure...., Van Horn [/bib_ref]. Because of the effects of obesity on insulin resistance, weight loss is an important therapeutic objective for overweight or obese individuals with prediabetes or diabetes (127). Short-term studies have demonstrated that moderate weight loss (5% of body weight) in subjects with type 2 diabetes is associated with decreased insulin resistance, improved measures of glycemia and lipemia, and reduced blood pressure (128); longer-term studies (52 weeks) showed mixed effects on A1C in adults with type 2 diabetes , and in some studies results were confounded by pharmacologic weight loss therapy. A systematic review of 80 weight loss studies of Ն1 year in duration demonstrated that moderate weight loss achieved through diet alone, diet and exercise, and meal replacements can be achieved and maintained (4.8 -8% weight loss at 12 months) [bib_ref] Weight-loss outcomes: a systematic review and metaanalysis of weight-loss clinical trials with..., Franz [/bib_ref]. The multifactorial intensive lifestyle intervention employed in the DPP, which included reduced intake of fat and calories, led to weight loss averaging 7% at 6 months and maintenance of 5% weight loss at 3 years, associated with a 58% reduction in incidence of type 2 diabetes (13). A recent randomized controlled trial looking at high-risk individuals in Spain showed the Mediterranean dietary pattern reduced the incidence of diabetes in the absence of weight loss by 52% compared to the lowfat control group [bib_ref] Reduction in the Incidence of Type 2 Diabetes with the Mediterranean Diet:..., Salas-Salvado [/bib_ref]. Look AHEAD (Action for Health in Diabetes) is a large clinical trial designed to determine whether long-term weight loss will improve glycemia and prevent cardiovascu-lar events in subjects with type 2 diabetes. One-year results of the intensive lifestyle intervention in this trial show an average 8.6% weight loss, significant reduction of A1C, and reduction in several CVD risk factors [bib_ref] Reduction in weight and cardiovascular disease risk factors in individuals with type..., Look Ahead Research Group [/bib_ref] , with benefits sustained at 4 years (135). When completed, the Look AHEAD study should provide insight into the effects of long-term weight loss on important clinical outcomes. The optimal macronutrient distribution of weight loss diets has not been established. Although low-fat diets have traditionally been promoted for weight loss, several randomized controlled trials found that subjects on low-carbohydrate diets (Ͻ130 g/day of carbohydrate) lost more weight at 6 months than subjects on low-fat diets [bib_ref] A randomized trial of a low-carbohydrate diet for obesity, Foster [/bib_ref] [bib_ref] The effects of low-carbohydrate versus conventional weight loss diets in severely obese..., Stern [/bib_ref] ; however, at 1 year, the difference in weight loss between the low-carbohydrate and low-fat diets was not significant, and weight loss was modest with both diets. A study comparing low-fat to low-carbohydrate diets, both combined with a comprehensive lifestyle program, showed the same amount of weight loss (7%) at 2 years in both groups [bib_ref] Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat..., Foster [/bib_ref]. Another study of overweight women randomized to one of four diets showed significantly more weight loss at 12 months with the Atkins lowcarbohydrate diet than with highercarbohydrate diets [bib_ref] Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in..., Gardner [/bib_ref]. Changes in serum triglyceride and HDL cholesterol were more favorable with the lowcarbohydrate diets. In one study, those subjects with type 2 diabetes demonstrated a greater decrease in A1C with a low-carbohydrate diet than with a low-fat diet [bib_ref] The effects of low-carbohydrate versus conventional weight loss diets in severely obese..., Stern [/bib_ref]. A recent meta-analysis showed that at 6 months, low-carbohydrate diets were associated with greater improvements in triglyceride and HDL cholesterol concentrations than low-fat diets; however, LDL cholesterol was significantly higher on the low-carbohydrate diets [bib_ref] Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk..., Nordmann [/bib_ref]. In a 2-year dietary intervention study, Mediterranean and low-carbohydrate diets were found to be effective and safe alternatives to a low-fat diet for weight reduction in moderately obese participants. The RDA for digestible carbohydrate is 130 g/day and is based on providing adequate glucose as the required fuel for the central nervous system without reliance on glucose production from ingested protein or fat. Although brain fuel needs can be met on lower-carbohydrate diets, long term metabolic effects of very-lowcarbohydrate diets are unclear, and such diets eliminate many foods that are im-portant sources of energy, fiber, vitamins, and minerals and are important in dietary palatability. Although numerous studies have attempted to identify the optimal mix of macronutrients for meal plans of people with diabetes, it is unlikely that one such combination of macronutrients exists. The best mix of carbohydrate, protein, and fat appears to vary depending on individual circumstances. It must be clearly recognized that regardless of the macronutrient mix, total caloric intake must be appropriate to weight management goal. Further, individualization of the macronutrient composition will depend on the metabolic status of the patient (e.g., lipid profile, renal function) and/or food preferences. Plant-based diets (vegan or vegetarian) that are well planned and nutritionally adequate have also been shown to improve metabolic control [bib_ref] A low-fat vegan diet improves glycemic control and cardiovascular risk factors in..., Barnard [/bib_ref] [bib_ref] Changes in nutrient intake and dietary quality among participants with type 2..., Turner-Mcgrievy [/bib_ref]. The primary goal with respect to dietary fat in individuals with diabetes is to limit saturated fatty acids, trans fatty acids, and cholesterol intake so as to reduce risk for CVD. Saturated and trans fatty acids are the principal dietary determinants of plasma LDL cholesterol. There is a lack of evidence on the effects of specific fatty acids on people with diabetes, so the recommended goals are consistent with those for individuals with CVD [bib_ref] A clinical trial of the effects of dietary patterns on blood pressure...., Van Horn [/bib_ref] [bib_ref] Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes..., Franz [/bib_ref]. ## Reimbursement for mnt MNT, when delivered by a registered dietitian according to nutrition practice guidelines, is reimbursed as part of the Medicare program as overseen by the Centers for Medicare and Medicaid Services (CMS) (www.cms.hhs.gov/ medicalnutritiontherapy). ## G. physical activity Recommendations - People with diabetes should be advised to perform at least 150 min/week of moderate-intensity aerobic physical activity (50 -70% of maximum heart rate). (A) - In the absence of contraindications, people with type 2 diabetes should be encouraged to perform resistance training three times per week. (A) Exercise is an important part of the diabetes management plan. Regular exercise has been shown to improve blood glucose control, reduce cardiovascular risk factors, contribute to weight loss, and improve well-being. Furthermore, regular exercise may prevent type 2 diabetes in high-risk individuals [bib_ref] Diabetes Prevention Program Research Group. Reduction in the incidence of type 2..., Knowler [/bib_ref] [bib_ref] Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by..., Tuomilehto [/bib_ref] [bib_ref] Effects of diet and exercise in preventing NIDDM in people with impaired..., Pan [/bib_ref]. Structured exercise interventions of at least 8 weeks' duration have been shown to lower A1C by an average of 0.66% in people with type 2 diabetes, even with no significant change in BMI [bib_ref] Effects of exercise on glycemic control and body mass in type 2..., Boulé [/bib_ref]. Higher levels of exercise intensity are associated with greater improvements in A1C and in fitness [bib_ref] Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in..., Boulé [/bib_ref]. A new joint position statement of the American Diabetes Association and the American College of Sports Medicine summarizes the evidence for the benefits of exercise in people with type 2 diabetes [bib_ref] Exercise and type 2 diabetes: the American College of Sports Medicine and..., Colberg [/bib_ref]. Frequency and type of exercise The U.S. Department of Health and Human Services' Physical Activity Guidelines for Americanssuggest that adults over age 18 years do 150 min/week of moderate-intensity, or 75 min/week of vigorous aerobic physical activity, or an equivalent combination of the two. In addition, the guidelines suggest that adults also do muscle-strengthening activities that involve all major muscle groups two or more days per week. The guidelines suggest that adults over age 65 years, or those with disabilities, follow the adult guidelines if possible or (if this is not possible) be as physically active as they are able. Studies included in the metaanalysis of effects of exercise interventions on glycemic control (146) had a mean number of sessions per week of 3.4, with a mean of 49 min/session. The DPP lifestyle intervention, which included 150 min/week of moderate intensity exercise, had a beneficial effect on glycemia in those with prediabetes. Therefore, it seems reasonable to recommend that people with diabetes try to follow the physical activity guidelines for the general population. Progressive resistance exercise improves insulin sensitivity in older men with type 2 diabetes to the same or even a greater extent as aerobic exercise [bib_ref] The relative benefits of endurance and strength training on the metabolic factors..., Cauza [/bib_ref]. Clinical trials have provided strong evidence for the A1C-lowering value of resistance training in older adults with type 2 diabetes [bib_ref] High-intensity resistance training improves glycemic control in older patients with type 2..., Dunstan [/bib_ref] [bib_ref] A randomized controlled trial of resistance exercise training to improve glycemic control..., Castaneda [/bib_ref] and for an additive benefit of combined aerobic and resistance exercise in adults with type 2 diabetes [bib_ref] Physical activity/ exercise and type 2 diabetes, Sigal [/bib_ref]. Evaluation of the diabetic patient before recommending an exercise program Prior guidelines suggested that before recommending a program of physical activity, the provider should assess patients with multiple cardiovascular risk factors for coronary artery disease (CAD). As discussed more fully in VI.A.5. Coronary heart disease screening and treatment, the area of screening asymptomatic diabetic patients for CAD remains unclear, and a recent ADA consensus statement on this issue concluded that routine screening is not recommended [bib_ref] Screening for coronary artery disease in patients with diabetes, Bax [/bib_ref]. Providers should use clinical judgment in this area. Certainly, high risk patients should be encouraged to start with short periods of low intensity exercise and increase the intensity and duration slowly. Providers should assess patients for conditions that might contraindicate certain types of exercise or predispose to injury, such as uncontrolled hypertension, severe autonomic neuropathy, severe peripheral neuropathy or history of foot lesions, and unstable proliferative retinopathy. The patient's age and previous physical activity level should be considered. Exercise in the presence of nonoptimal glycemic control Hyperglycemia. When people with type 1 diabetes are deprived of insulin for 12-48 h and are ketotic, exercise can worsen hyperglycemia and ketosis (155); therefore, vigorous activity should be avoided in the presence of ketosis. However, it is not necessary to postpone exercise based simply on hyperglycemia, provided the patient feels well and urine and/or blood ketones are negative. Hypoglycemia. In individuals taking insulin and/or insulin secretagogues, physical activity can cause hypoglycemia if medication dose or carbohydrate consumption is not altered. For individuals on these therapies, added carbohydrate should be ingested if pre-exercise glucose levels are Ͻ100 mg/dl (5.6 mmol/l). Hypoglycemia is rare in diabetic individuals who are not treated with insulin or insulin secretagogues, and no preventive measures for hypoglycemia are usually advised in these cases. Exercise in the presence of specific long-term complications of diabetes Retinopathy. In the presence of proliferative diabetic retinopathy (PDR) or severe nonproliferative diabetic retinopathy (NPDR), vigorous aerobic or resistance exercise may be contraindicated because of the risk of triggering vitreous hemorrhage or retinal detachment. Peripheral neuropathy. Decreased pain sensation in the extremities results in in- ## Standards of medical care creased risk of skin breakdown and infection and of Charcot joint destruction. Prior recommendations have advised non-weight-bearing exercise for patients with severe peripheral neuropathy. However, studies have shown that moderateintensity walking may not lead to increased risk of foot ulcers or reulceration in those with peripheral neuropathy [bib_ref] Daily weightbearing activity does not increase the risk of diabetic foot ulcers, Lemaster [/bib_ref]. All individuals with peripheral neuropathy should wear proper footwear and examine their feet daily to detect lesions early. Anyone with a foot injury or open sore should be restricted to non-weight-bearing activities. Autonomic neuropathy. Autonomic neuropathy can increase the risk of exerciseinduced injury or adverse event through decreased cardiac responsiveness to exercise, postural hypotension, impaired thermoregulation, impaired night vision due to impaired papillary reaction, and unpredictable carbohydrate delivery from gastroparesis predisposing to hypoglycemia. Autonomic neuropathy is also strongly associated with CVD in people with diabetes [bib_ref] Detection of Ischemia in Asymptomatic Diabetics Investigators. Detection of silent myocardial ischemia..., Wackers [/bib_ref] [bib_ref] Predictive value of cardiac autonomic neuropathy in diabetic patients with or without..., Valensi [/bib_ref]. People with diabetic autonomic neuropathy should undergo cardiac investigation before beginning physical activity more intense than that to which they are accustomed. Albuminuria and nephropathy. Physical activity can acutely increase urinary protein excretion. However, there is no evidence that vigorous exercise increases the rate of progression of diabetic kidney disease, and there is likely no need for any specific exercise restrictions for people with diabetic kidney disease. ## H. psychosocial assessment and care Recommendations - Assessment of psychological and social situation should be included as an ongoing part of the medical management of diabetes. (E) - Psychosocial screening and follow-up should include, but is not limited to, attitudes about the illness, expectations for medical management and outcomes, affect/mood, general and diabetes-related quality of life, resources (financial, social, and emotional), and psychiatric history. (E) - Screen for psychosocial problems such as depression and diabetes-related distress, anxiety, eating disorders, and cognitive impairment when selfmanagement is poor. (C) Psychological and social problems can impair the individual's [bib_ref] Anxiety and poor glycemic control: a meta-analytic review of the literature, Anderson [/bib_ref] [bib_ref] Association of diabetes-related emotional distress with diabetes treatment in primary care patients..., Delahanty [/bib_ref] [bib_ref] The prevalence of comorbid depression in adults with diabetes: a meta-analysis, Anderson [/bib_ref] or family's ability to carry out diabetes care tasks and therefore compromise health status. There are opportunities for the clinician to assess psychosocial status in a timely and efficient manner so that referral for appropriate services can be accomplished. Key opportunities for screening of psychosocial status occur at diagnosis, during regularly scheduled management visits, during hospitalizations, at discovery of complications, or when problems with glucose control, quality of life, or adherence are identified. Patients are likely to exhibit psychological vulnerability at diagnosis and when their medical status changes, e.g., the end of the honeymoon period, when the need for intensified treatment is evident, and when complications are discovered. Issues known to impact selfmanagement and health outcomes include but are not limited to: attitudes about the illness, expectations for medical management and outcomes, affect/mood, general and diabetes-related quality of life, diabetes-related distress [bib_ref] Clinical depression versus distress among patients with type 2 diabetes: not just..., Fisher [/bib_ref] , resources (financial, social, and emotional), and psychiatric history . Screening tools are available for a number of these areas [bib_ref] Behavioral and psychosocial interventions in diabetes: a conceptual review, Peyrot [/bib_ref]. Indications for referral to a mental health specialist familiar with diabetes management may include: gross noncompliance with medical regimen (by self or others) (170), depression with the possibility of self-harm, debilitating anxiety (alone or with depression), indications of an eating disorder (171), or cognitive functioning that significantly impairs judgment. It is preferable to incorporate psychological assessment and treatment into routine care rather than waiting for identification of a specific problem or deterioration in psychological status [bib_ref] Behavioral and psychosocial interventions in diabetes: a conceptual review, Peyrot [/bib_ref]. Although the clinician may not feel qualified to treat psychological problems, utilizing the patient-provider relationship as a foundation for further treatment can increase the likelihood that the patient will accept referral for other services. It is important to establish that emotional well-being is part of diabetes management. I. When treatment goals are not met For a variety of reasons, some people with diabetes and their health care providers do not achieve the desired goals of treatment [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref]. Re-thinking the treatment regimen may require assessment of barriers including income, health literacy, diabetes distress, depression, and competing demands, including those related to family responsibilities and dynamics. Other strategies may include culturally appropriate and enhanced DSME, comanagement with a diabetes team, referral to a medical social worker for assistance with insurance coverage, or change in pharmacological therapy. Initiation of or increase in SMBG, utilization of CGM, frequent contact with the patient, or referral to a mental health professional or physician with special expertise in diabetes may be useful. Providing patients with an algorithm for self-titration of insulin doses based on SMBG results may be helpful for type 2 patients who take insulin [bib_ref] Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue:..., Blonde [/bib_ref]. [bib_ref] Hypoglycemic episodes and risk of dementia in older patients with type 2..., Whitmer [/bib_ref]. Conversely, evidence from the DCCT/EDIC trial, which involved younger type 1 patients, suggested no association of frequency of severe hypoglycemia with cognitive decline [bib_ref] Long-term effect of diabetes and its treatment on cognitive function, Jacobson [/bib_ref]. Treatment of hypoglycemia (plasma glucose Ͻ70 mg/dl) requires ingestion of glucose-or carbohydratecontaining foods. The acute glycemic response correlates better with the glucose content than with the carbohydrate content of the food. Although pure glucose is the preferred treatment, any form of carbohydrate that contains glucose will raise blood glucose. Added fat may retard and then prolong the acute glycemic response. Ongoing activity of insulin or insulin secretagogues may lead to recurrence of hypoglycemia unless further food is ingested after recovery. ## J. hypoglycemia ## Recommendations Severe hypoglycemia (where the individual requires the assistance of another person and cannot be treated with oral carbohydrate due to confusion or unconsciousness) should be treated using emergency glucagon kits, which require a prescription. Those in close contact with, or having custodial care of, people with hypoglycemia-prone diabetes (family members, roommates, school personnel, child care providers, correctional institution staff, or coworkers), should be instructed in use of such kits. An individual does not need to be a health care professional to safely administer glucagon. Care should be taken to ensure that unexpired glucagon kits are available. Prevention of hypoglycemia is a critical component of diabetes management. Teaching people with diabetes to balance insulin use, carbohydrate intake, and exercise is a necessary but not always sufficient strategy. In type 1 diabetes and severely insulin-deficient type 2 diabetes, the syndrome of hypoglycemia unawareness, or hypoglycemia-associated autonomic failure, can severely compromise stringent diabetes control and quality of life. The deficient counterregulatory hormone release and autonomic responses in this syndrome are both risk factors for, and caused by, hypoglycemia. A corollary to this "vicious cycle" is that several weeks of avoidance of hypoglycemia has been demonstrated to improve counterregulation and awareness to some extent in many patients [bib_ref] Diverse causes of hypoglycemia-associated autonomic failure in diabetes, Cryer [/bib_ref]. Hence, patients with one or more episodes of severe hypoglycemia may benefit from at least shortterm relaxation of glycemic targets. ## K. intercurrent illness The stress of illness, trauma, and/or surgery frequently aggravates glycemic control and may precipitate diabetic ketoacidosis (DKA) or nonketotic hyperosmolar state, life-threatening conditions that require immediate medical care to prevent complications and death. Any condition leading to deterioration in glycemic control necessitates more frequent monitoring of blood glucose and (in ketosis-prone patients) urine or blood ketones. Marked hyperglycemia requires temporary adjustment of the treatment program and, if accompanied by ketosis, vomiting, or alteration in level of consciousness, immediate interaction with the diabetes care team. The patient treated with noninsulin therapies or MNT alone may temporarily require insulin. Adequate fluid and caloric intake must be assured. Infection or dehydration are more likely to necessitate hospitalization of the person with diabetes than the person without diabetes. The hospitalized patient should be treated by a physician with expertise in the management of diabetes. For further information on management of patients with hyperglycemia in the hospital, see VIII.A. Diabetes care in the hospital. For further information on management of DKA or nonketotic hyperosmolar state, refer to the ADA consensus statement on hyperglycemic crises [bib_ref] Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue:..., Blonde [/bib_ref]. Gastric reduction surgery, either gastric banding or procedures that involve bypassing, transposing, or resecting sections of the small intestine, when part of a comprehensive team approach, can be an effective weight loss treatment for severe obesity, and national guidelines support its consideration for people with type 2 diabetes who have BMI exceeding 35 kg/ m 2 . Bariatric surgery has been shown to lead to near-or complete normalization of glycemia in ϳ55-95% of patients with type 2 diabetes, depending on the surgical procedure. A meta-analysis of studies of bariatric surgery involving 3,188 patients with diabetes reported that 78% had remission of diabetes (normalization of blood glucose levels in the absence of medications), and that the remission rates were sustained in studies that had follow-up exceeding 2 years (177). Remission rates tend to be lower with procedures that only constrict the stomach, and higher with those that bypass portions of the small intestine. Additionally, there is a suggestion that intestinal bypass procedures may have glycemic effects that are independent of their effects on weight, perhaps involving the incretin axis. One randomized controlled trial compared adjustable gastric banding to "best available" medical and lifestyle therapy in subjects with type 2 diabetes diagn o s e d l e s s t h a n 2 y e a r s b e f o r e randomization and BMI 30 -40 kg/m 2 [bib_ref] Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized..., Dixon [/bib_ref]. In this trial, 73% of surgically treated patients achieved "remission" of their diabetes, compared with 13% of those treated medically. The latter group lost only 1.7% of body weight, suggesting that their therapy was not optimal. Overall the trial had 60 subjects, and only 13 had a BMI under 35 kg/m 2 , making it difficult to generalize these results widely to diabetic patients who are less severely obese or with longer duration of diabetes. In a more recent study involving 110 patients with type 2 diabetes and a mean BMI of 47 kg/m 2 , Roux-en-Y gastric bypass resulted in a mean loss of excess weight of 63% at 1 year and 84% at 2 years [bib_ref] Preoperative factors predicting remission of type 2 diabetes mellitus after Roux-en-Y gastric..., Hall [/bib_ref]. Bariatric surgery is costly in the short term and has some risks. Rates of morbidity and mortality directly related to the surgery have been reduced considerably in recent years, with 30-day mortality rates now 0.28%, similar to those of lapa-roscopic cholecystectomy [bib_ref] Trends in mortality in bariatric surgery: a systematic review and meta-analysis, Buchwald [/bib_ref]. Longerterm concerns include vitamin and mineral deficiencies, osteoporosis, and rare but often severe hypoglycemia from insulin hypersecretion. Cohort studies attempting to match subjects suggest that the procedure may reduce longer-term mortality rates [bib_ref] Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish..., Sjö Strö M L [/bib_ref] , and it is reasonable to postulate that there may be recouping of costs over the long run. Recent retrospective analyses and modeling studies suggest that these procedures may be cost effective, when one considers reduction in subsequent health care costs [bib_ref] Cost-effectiveness of bariatric surgery for severely obese adults with diabetes, Hoerger [/bib_ref] [bib_ref] Medication utilization and annual health care costs in patients with type 2..., Makary [/bib_ref] [bib_ref] Costefficacy of surgically induced weight loss for the management of type 2..., Keating [/bib_ref]. However, studies of the mechanisms of glycemic improvement and long-term benefits and risks of bariatric surgery in individuals with type 2 diabetes, especially those who are not severely obese, will require well-designed clinical trials, with optimal medical and lifestyle therapy of diabetes and cardiovascular risk factors as the comparator. ## M. immunization Recommendations - Annually provide an influenza vaccine to all diabetic patients at least 6 months of age. (C) - Administer pneumococcal polysaccharide vaccine to all diabetic patients Ն2 years of age. A one-time revaccination is recommended for individuals Ͼ64 years of age previously immunized when they were Ͻ65 years of age if the vaccine was administered Ͼ5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immunocompromised states, such as after transplantation. (C) Influenza and pneumonia are common, preventable infectious diseases associated with high mortality and morbidity in the elderly and in people with chronic diseases. Though there are limited studies reporting the morbidity and mortality of influenza and pneumococcal pneumonia specifically in people with diabetes, observational studies of patients with a variety of chronic illnesses, including diabetes, show that these conditions are associated with an increase in hospitalizations for influenza and its complications. People with diabetes may be at increased risk of the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, which has a mortality rate as high as 50% [bib_ref] Use of influenza and pneumococcal vaccines in people with diabetes, Smith [/bib_ref]. Safe and effective vaccines are available that can greatly reduce the risk of serious complications from these diseases [bib_ref] Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes, Colquhoun [/bib_ref] [bib_ref] Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization..., Bridges [/bib_ref]. In a case-control series, influenza vaccine was shown to reduce diabetes-related hospital admission by as much as 79% during flu epidemics [bib_ref] Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes, Colquhoun [/bib_ref]. There is sufficient evidence to support that people with diabetes have appropriate serologic and clinical responses to these vaccinations. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/). ## Vi. prevention and management of diabetes complications A. CVD CVD is the major cause of morbidity and mortality for individuals with diabetes, and the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for CVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally [bib_ref] Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific..., Buse [/bib_ref] [bib_ref] Effect of a multifactorial intervention on mortality in type 2 diabetes, Gaede [/bib_ref]. Risk for coronary heart disease (CHD) and for CVD in general can be estimated using multivariable risk factor approaches, and such a strategy may be desirable to undertake in adult patients prior to instituting preventive therapy. [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref]. Home blood pressure self-monitoring and 24-h ambulatory blood pressure monitoring may provide additional evidence of "white coat" and masked hypertension and other discrepancies between office and "true" blood pressure, and in studies in nondiabetic populations, home measurements may better correlate with CVD risk than office measurements [bib_ref] Is "isolated home" hypertension as opposed to "isolated office" hypertension a sign..., Bobrie [/bib_ref] [bib_ref] Prognostic value of ambulatory and home blood pressures compared with office blood..., Sega [/bib_ref]. However, the preponderance of the clear evidence of benefits of treatment of hypertension in people with diabetes is based on office measurements. ## Treatment goals Epidemiologic analyses show that blood pressure values Ͼ115/75 mmHg are associated with increased cardiovascular event rates and mortality in individuals with diabetes [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref] [bib_ref] Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of..., Lewington [/bib_ref] [bib_ref] Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men..., Stamler [/bib_ref]. Randomized clinical trials have demonstrated the benefit (reduction in CHD events, stroke, and nephropathy) of lowering blood pressure to Ͻ140 mmHg systolic and Ͻ80 mmHg diastolic in individuals with diabetes [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref] [bib_ref] Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension:..., Hansson [/bib_ref] [bib_ref] Association of systolic blood pressure with macrovascular and microvascular complications of type..., Adler [/bib_ref]. The ACCORD trial examined whether lowering blood pressure to a systolic Ͻ120 mmHg provides greater cardiovascular protection than a systolic blood pressure level of 130 -140 mmHg in patients with type 2 diabetes at high risk for CVD . The blood pressure achieved was 119/64 mmHg in the intensive group and 133/70 mmHg in the standard group; the difference achieved was attained with an average of 3.4 medications per participant in the intensive group and 2.1 in the standard therapy group. The primary outcome was a composite of nonfatal MI, nonfatal stroke, and CVD death; the hazard ratio for the primary end point in the intensive group was 0.88 (95% CI 0.73-1.06; P ϭ 0.20). Of the prespecified secondary end points, only stroke and nonfatal stroke were statistically significantly reduced by intensive blood pressure treatment, with a hazard ratio of 0.59 (95% CI 0.39 -0.89, P ϭ 0.01) and 0.63 (95% CI 0.41-0.96, P ϭ 0.03), respectively. If this finding is real, the number needed to treat to prevent one stroke over the course of 5 years with intensive blood pressure management is 89. In predefined subgroup analyses, there was a suggestion of heterogeneity (P ϭ 0.08) based on whether participants were randomized to standard or intensive glycemia intervention. In those randomized to standard glycemic control, the event rate for the primary end point was 1.89 per year in the intensive blood pressure arm and 2.47 in the standard blood pressure arm, while the respective rates in the intensive glycemia arm were 1.85 and 1.73. If this observation is true, it suggests that intensive management to a systolic blood pressure target of Ͻ120 mmHg may be of benefit in those who are not targeting an A1C of Ͻ6% and/or that the benefit of intensive blood pressure management is diminished by more intensive glycemia management targeting an A1C of Ͻ6%. Other recent randomized trial data include those from ADVANCE, in which treatment with an angiotensin-converting enzyme inhibitor and a thiazide-type diuretic reduced the rate of death but not the composite macrovascular outcome. However, the ADVANCE trial had no specified targets for the randomized comparison, and the mean systolic blood pressure in the intensive group (135 mmHg) was not as low as the mean systolic blood pressure in the ACCORD standard therapy group [bib_ref] Effects of a fixed combination of perindopril and indapamide on macrovascular and..., Patel [/bib_ref]. A post hoc analysis of blood pressure control in 6,400 patients with diabetes and CAD enrolled in the International Verapamil-Trandolapril (INVEST) trial demonstrated that "tight control" (Ͻ130 mmHg) was not associated with improved CV outcomes compared with "usual care" (130 -140 mmHg) [bib_ref] Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes..., Cooper-Dehoff [/bib_ref]. Only the ACCORD blood pressure trial formally has examined treatment targets Ͻ130 mmHg in diabetes. It is possible that lowering systolic blood pressure from the low-130s to less than 120 mmHg does not further reduce coronary events or death, and that most of the benefit from lowering blood pressure is achieved by targeting a goal of Ͻ140 mmHg. However, this has not been formally assessed. The absence of significant harm, the trends toward benefit in stroke, and the potential heterogeneity with respect to intensive glycemia management suggests that previously recommended targets are reasonable pending further analyses and results. Systolic blood pressure targets more or less stringent than Ͻ130 mmHg may be appropriate for individual patients, based on response to therapy, medication tolerance, and individual characteristics, keeping in mind that most analyses have suggested that outcomes are worse if the systolic blood pressure is Ͼ140 mmHg. ## Treatment strategies Although there are no well-controlled studies of diet and exercise in the treatment of hypertension in individuals with diabetes, the Dietary Approaches to Stop Hypertension (DASH) study in nondiabetic individuals has shown antihypertensive effects similar to pharmacologic monotherapy. Lifestyle therapy consists of reducing sodium intake (to Ͻ1,500 mg/day) and excess body weight; increasing consumption of fruits, vegetables (8 -10 servings/day), and low-fat dairy products (2-3 servings/day); avoiding excessive alcohol consumption (no more than 2 servings/day in men and no more than 1 serving/day in women); and increasing activity levels [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref]. These nonpharmacological strategies may also positively affect glycemia and lipid control. Their effects on cardiovascular events have not been established. An initial trial of nonpharmacologic therapy may be reasonable in diabetic individuals with mild hypertension (systolic blood pressure 130 -139 mmHg or diastolic blood pressure 80 -89 mmHg). If systolic blood pressure is Ն140 mmHg and/or diastolic is Ն90 mmHg at the time of diagnosis, pharmacologic therapy should be initiated along with nonpharmacologic therapy [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref]. Lowering of blood pressure with regimens based on a variety of antihypertensive drugs, including ACE inhibitors, ARBs, ␤-blockers, diuretics, and calcium Standards of Medical Care channel blockers, has been shown to be effective in reducing cardiovascular events. Several studies suggested that ACE inhibitors may be superior to dihydropyridine calcium channel blockers in reducing cardiovascular events [bib_ref] Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET)..., Tatti [/bib_ref] [bib_ref] The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in..., Estacio [/bib_ref] [bib_ref] Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus:..., Schrier [/bib_ref]. However, a variety of other studies have shown no specific advantage to ACE inhibitors as initial treatment of hypertension in the general hypertensive population, but rather an advantage on cardiovascular outcomes of initial therapy with low-dose thiazide diuretics [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref] [bib_ref] The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The Antihypertensive..., Officers [/bib_ref] [bib_ref] Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic..., Psaty [/bib_ref]. In people with diabetes, inhibitors of the renin-angiotensin system (RAS) may have unique advantages for initial or early therapy of hypertension. In a nonhypertension trial of high-risk individuals, including a large subset with diabetes, an ACE inhibitor reduced CVD outcomes. In patients with congestive heart failure (CHF), including diabetic subgroups, ARBs have been shown to reduce major CVD outcomes , and in type 2 patients with significant nephropathy, ARBs were superior to calcium channel blockers for reducing heart failure [bib_ref] Irbesartan Diabetic Nephropathy Trial. Collaborative Study Group. Collaborative Study Group. Cardiovascular outcomes..., Berl [/bib_ref]. Though evidence for distinct advantages of RAS inhibitors on CVD outcomes in diabetes remains conflicting [bib_ref] Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic..., Psaty [/bib_ref] , the high CVD risks associated with diabetes, and the high prevalence of undiagnosed CVD, may still favor recommendations for their use as first-line hypertension therapy in people with diabetes [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref]. Recently, the blood pressure arm of the ADVANCE trial demonstrated that routine administration of a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide significantly reduced combined microvascular and macrovascular outcomes, as well as CVD and total mortality. The improved outcomes could also have been due to lower achieved blood pressure in the perindopril-indapamide arm [bib_ref] Effects of a fixed combination of perindopril and indapamide on macrovascular and..., Patel [/bib_ref]. In addition, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed a decrease in morbidity and mortality in those receiving benazapril and amlodipine versus benazapril and hydrochlorothiazide. The compelling benefits of RAS inhibitors in diabetic patients with albuminuria or renal insufficiency provide additional rationale for use of these agents (see VI.B. Nephropathy screening and treatment). An important caveat is that most patients with hypertension require multidrug therapy to reach treatment goals, especially diabetic patients whose targets are lower. Many patients will require three or more drugs to reach target goals [bib_ref] National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection,..., Chobanian [/bib_ref]. If blood pressure is refractory to optimal doses of at least three antihypertensive agents of different classifications, one of which should be a diuretic, clinicians should consider an evaluation for secondary forms of hypertension. During pregnancy in diabetic women with chronic hypertension, target blood pressure goals of systolic blood pressure 110 -129 mmHg and diastolic blood pressure 65-79 mmHg are reasonable, as they contribute to long-term maternal health. Lower blood pressure levels may be associated with impaired fetal growth. During pregnancy, treatment with ACE inhibitors and ARBs is contraindicated, since they can cause fetal damage. Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin. Chronic diuretic use during pregnancy has been associated with restricted maternal plasma volume, which might reduce uteroplacental perfusion (213). Evidence for benefits of lipidlowering therapy Patients with type 2 diabetes have an increased prevalence of lipid abnormalities, contributing to their high risk of CVD. For the past decade or more, multiple clinical trials demonstrated significant effects of pharmacologic (primarily statin) therapy on CVD outcomes in subjects with CHD and for primary CVD prevention [bib_ref] Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective..., Baigent [/bib_ref]. Sub-analyses of diabetic subgroups of larger trials (215-219) and trials specifically in subjects with diabetes (220,221) showed significant primary and secondary prevention of CVD events Ϯ CHD deaths in diabetic populations. As shown in [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref] , and similar to findings in nondiabetic subjects, reduction in "hard" CVD outcomes (CHD death and nonfatal MI) can be more clearly seen in diabetic subjects with high baseline CVD risk (known CVD and/or very high LDL cholesterol levels), but overall the benefits of statin therapy in people with diabetes at moderate or high risk for CVD are convincing. Low levels of HDL cholesterol, often associated with elevated triglyceride lev-els, are the most prevalent pattern of dyslipidemia in persons with type 2 diabetes. However, the evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy [bib_ref] High-density lipoprotein as a therapeutic target: a systematic review, Singh [/bib_ref]. Nicotinic acid has been shown to reduce CVD outcomes [bib_ref] Fifteen year mortality in Coronary Drug Project patients: longterm benefit with niacin, Canner [/bib_ref] , although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes [bib_ref] Gemfibrozil for the secondary prevention of coronary heart disease in men with..., Rubins [/bib_ref] and in the diabetic subgroup in one of the larger trials [bib_ref] Gemfibrozil for the secondary prevention of coronary heart disease in men with..., Rubins [/bib_ref]. However, in a large trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular outcomes [bib_ref] FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in..., Keech [/bib_ref]. ## Dyslipidemia/lipid management ## Dyslipidemia treatment and target lipid levels For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to a target goal of Ͻ100 mg/dl (2.60 mmol/l). Lifestyle intervention, including MNT, increased physical activity, weight loss, and smoking cessation, may allow some patients to reach lipid goals. Nutrition intervention should be tailored according to each patient's age, type of diabetes, pharmacological treatment, lipid levels, and other medical conditions and should focus on the reduction of sat-urated fat, cholesterol, and trans unsaturated fat intake and increases in omega-3 fatty acids, viscous fiber (such as in oats, legumes, citrus), and plant stanols/ sterols. Glycemic control can also beneficially modify plasma lipid levels, particularly in patients with very high triglycerides and poor glycemic control. In those with clinical CVD or over age 40 years with other CVD risk factors, pharmacological treatment should be added to lifestyle therapy regardless of baseline lipid levels. Statins are the drugs of choice for LDL cholesterol lowering. In patients other than those described above, statin treatment should be considered if there is an inadequate LDL cholesterol response to lifestyle modifications and improved glucose control, or if the patient has increased cardiovascular risk (e.g., multiple cardiovascular risk factors or long duration of diabetes). Very little clinical trial evidence exists for type 2 diabetic patients under age 40 years or for type 1 patients of any age. In the Heart Protection Study (lower age limit 40 years), the subgroup of 600 patients with type 1 diabetes had a proportionately similar reduction in risk as patients with type 2 diabetes, although not statistically significant [bib_ref] Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol-lowering with..., Collins [/bib_ref]. Although the data are not definitive, consideration should be given to similar lipid-lowering goals in type 1 diabetic patients as in type 2 diabetic patients, particularly if they have other cardiovascular risk factors. ## Alternative ldl cholesterol goals Virtually all trials of statins and CVD outcomes tested specific doses of statins against placebo, other doses of statin, or other statins, rather than aiming for specific LDL cholesterol goals [bib_ref] Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a..., Hayward [/bib_ref]. As can be seen in [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref] , placebo-controlled trials generally achieved LDL cholesterol reductions of 30 -40% from baseline. Hence, LDL cholesterol lowering of this magnitude is an acceptable outcome for patients who cannot reach LDL cholesterol goals due to severe baseline elevations in LDL cholesterol and/or intolerance of maximal, or any, statin doses. Additionally for those with baseline LDL cholesterol minimally above 100 mg/dl, prescribing statin therapy to lower LDL cholesterol about 30 -40% from baseline is probably more effective than prescribing just enough to get LDL cholesterol slightly below 100 mg/dl. Recent clinical trials in high-risk patients, such as those with acute coronary syndromes or previous cardiovascular events , have demonstrated that more aggressive therapy with high doses of statins to achieve an LDL cholesterol of Ͻ70 mg/dl led to a significant re- duction in further events. Therefore, a reduction in LDL cholesterol to a goal of Ͻ70 mg/dl is an option in very-high-risk diabetic patients with overt CVD [bib_ref] National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, American..., Grundy [/bib_ref]. In individual patients, LDL cholesterol lowering with statins is highly variable, and this variable response is poorly understood [bib_ref] Pharmacogenetic study of statin therapy and cholesterol reduction, Chasman [/bib_ref]. Reduction of CVD events with statins correlates very closely with LDL cholesterol lowering [bib_ref] Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective..., Baigent [/bib_ref]. When maximally tolerated doses of statins fail to significantly lower LDL cholesterol (Ͻ30% reduction from patients baseline), the primary aim of combination therapy should be to achieve additional LDL cholesterol lowering. Niacin, fenofibrate, ezetimibe, and bile acid sequestrants all offer additional LDL cholesterol lowering. The evidence that combination therapy provides a significant increment in CVD risk reduction over statin therapy alone is still elusive. In 2008, a consensus panel convened by the American Diabetes Association and the American College of Cardiology recommended a greater focus on non-HDL cholesterol and apo lipoprotein B (apo B) in patients who are likely to have small LDL particles, such as people with diabetes [bib_ref] American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk:..., Brunzell [/bib_ref]. The consensus panel suggested that for statin-treated patients in whom the LDL cholesterol goal would be Ͻ70 mg/dl (non-HDL cholesterol Ͻ100 mg/ dl), apo B should be measured and treated to Ͻ80 mg/dl. For patients on statins with an LDL cholesterol goal of Ͻ100 mg/dl (non-HDL cholesterol Ͻ130 mg/dl), apo B should be measured and treated to Ͻ90 mg/dl. ## Treatment of other lipoprotein fractions or targets Severe hypertriglyceridemia may warrant immediate therapy of this abnormality with lifestyle and usually pharmacologic therapy (fibric acid derivative, niacin, or fish oil) to reduce the risk of acute pancreatitis. In the absence of severe hypertriglyceridemia, therapy targeting HDL cholesterol or triglycerides has intuitive appeal but lacks the evidence base of statin therapy. If the HDL cholesterol is Ͻ40 mg/dl and the LDL cholesterol between 100 and 129 mg/dl, gemfibrozil or niacin might be used, especially if a patient is intolerant to statins. Niacin is the most effective drug for raising HDL cholesterol. It can significantly increase blood glucose at high doses, but recent studies demonstrate that at modest doses (750 -2,000 mg/day), significant improvements in LDL cholesterol, HDL cholesterol, and triglyceride levels are accompanied by only modest changes in glucose that are generally amenable to adjustment of diabetes therapy [bib_ref] Effect of niacin on lipid and lipoprotein levels and glycemic control in..., Elam [/bib_ref] [bib_ref] Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for..., Grundy [/bib_ref]. ## Combination therapy Combination therapy, with a statin and a fibrate or statin and niacin, may be efficacious for treatment for all three lipid fractions, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis. The risk of rhabdomyolysis is higher with higher doses of statins and with renal insufficiency and seems to be lower when statins are combined with fenofibrate than gemfibrozil [bib_ref] Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2..., Jones [/bib_ref]. In the recent ACCORD study, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone, in patients with type 2 diabetes who were at high risk for CVD. However, prespecified subgroup analyses suggested heterogeneity in treatment effects according to sex, with a benefit for men and possible harm for women, and a possible benefit of combination therapy for patients with both triglyceride level Ն204 mg/dl and HDL cholesterol level Յ34 mg/dl (238). Other ongoing trials may provide much-needed evidence for the effects of combination therapy on cardiovascular outcomes. [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref] summarizes common treatment goals for A1C, blood pressure, and HDL cholesterol. ## Antiplatelet agents Recommendations - Consider aspirin therapy (75-162 mg/ day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk Ͼ10%). This includes most men Ͼ50 years of age or women Ͼ60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C) - Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk Ͻ5%, such as in men Ͻ50 and women Ͻ60 years of age with no major additional CVD risk factors), since the potential adverse effects from bleeding likely offset the potential benefits. (C) - In patients in these age-groups with ADA and the American Heart Association (AHA) have, in the past, jointly recommended that low-dose aspirin therapy be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or those with additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) [bib_ref] Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific..., Buse [/bib_ref]. These recommendations were derived from several older trials that included small numbers of patients with diabetes. Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with previous myocardial infarction or stroke (secondary prevention). Its net benefit in primary prevention among patients with no previous cardiovascular events is more controversial, both for patients with and without a history of diabetes [bib_ref] Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis..., Baigent [/bib_ref]. Two recent randomized controlled trials of aspirin specifically in patients with diabetes failed to show a significant reduction in CVD end points, raising further questions about the efficacy of aspirin for primary prevention in people with diabetes [bib_ref] Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators...., Ogawa [/bib_ref] [bib_ref] The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial..., Belch [/bib_ref]. The Anti-thrombotic Trialists' (ATT) collaborators recently published an individual patient-level meta-analysis of the six large trials of aspirin for primary prevention in the general population. These trials collectively enrolled over 95,000 participants, including almost 4,000 with diabetes. Overall, they found that aspirin reduced the risk of vascular events by 12% (RR 0.88 [95% CI 0.82-0.94]). The largest reduction was for nonfatal myocardial infarction with little effect on CHD death (RR 0.95 [95% CI 0.78 -1.15]) or total stroke. There was some evidence of a difference in aspirin effect by sex. Aspirin significantly reduced CHD events in men but not in women. Conversely, aspirin had no effect on stroke in men but significantly reduced stroke in women. Notably, sex differences in aspirin's effects have not been observed in studies of secondary prevention [bib_ref] Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis..., Baigent [/bib_ref]. In the six trials examined by the ATT collaborators, the effects of aspirin on major vascular events were similar for patients with or without diabetes: RR 0.88 (95% CI 0.67-1.15) and 0.87 (0.79 -0.96), respectively. The CI was wider for those with diabetes because of their smaller number. Based on the currently available evidence, aspirin appears to have a modest effect on ischemic vascular events with the absolute decrease in events depending on the underlying CVD risk. The main adverse effects appear to be an increased risk of gastrointestinal bleeding. The excess risk may be as high as 1-5 per 1,000 per year in real-world settings. In adults with CVD risk greater than 1% per year, the number of CVD events prevented will be similar to or greater than the number of episodes of bleeding induced, although these complications do not have equal effects on long-term health [bib_ref] Aspirin, statins, or both drugs for the primary prevention of coronary heart..., Pignone [/bib_ref]. In 2010, a position statement of the ADA, AHA, and American College of Cardiology Foundation (ACCF) updated prior joint recommendations for primary prevention [bib_ref] American College of Cardiology Foundation. Aspirin for primary prevention of cardiovascular events..., Pignone [/bib_ref]. Low dose (75-162 mg/ day) aspirin use for primary prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk (10-year risk of CVD events over 10%) and who are not at increased risk for bleeding. This generally includes most men over age 50 years and women over age 60 years who also have one or more of the following major risk factors: smoking, hypertension, dyslipi-demia, family history of premature CVD, and albuminuria. However, aspirin is no longer recommended for those at low CVD risk (women under age 60 years and men under age 50 years with no major CVD risk factors; 10-year CVD risk under 5%) as the low benefit is likely to be outweighed by the risks of significant bleeding. Clinical judgment should be used for those at intermediate risk (younger patients with one or more risk factors, or older patients with no risk factors; those with 10-year CVD risk of 5-10%) until further research is available. Use of aspirin in patients under the age of 21 years is contraindicated due to the associated risk of Reye's syndrome. Average daily dosages used in most clinical trials involving patients with diabetes ranged from 50 to 650 mg but were mostly in the range of 100 to 325 mg/day. There is little evidence to support any specific dose, but using the lowest possible dosage may help reduce side effects [bib_ref] Aspirin dose for the prevention of cardiovascular disease: a systematic review, Campbell [/bib_ref]. Although platelets from patients with diabetes have altered function, it is unclear what, if any, impact that finding has on the required dose of aspirin for cardioprotective effects in the patient with diabetes. Many alternate pathways for platelet activation exist that are independent of thromboxane A 2 and thus not sensitive to the effects of aspirin [bib_ref] Platelet activation and atherothrombosis, Davì [/bib_ref]. Therefore, while "aspirin resistance" appears higher in the diabetic patients when measured by a variety of ex vivo and in vitro methods (platelet aggrenometry, measurement of thromboxane B 2 ), these observations alone are insufficient to empirically recommend higher doses of aspirin be used in the diabetic patient at this time. Clopidogrel has been demonstrated to reduce CVD events in diabetic individuals [bib_ref] Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus, Bhatt [/bib_ref]. It is recommended as adjunctive therapy in the first year after an acute coronary syndrome or as alternative therapy in aspirin-intolerant patients. The routine and thorough assessment of tobacco use is important as a means of preventing smoking or encouraging cessation. A number of large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of brief counseling in smoking cessation, including the use of quit lines, in the reduction of tobacco use. For the patient motivated to quit, the addition of pharmacological therapy to counseling is more effective than either treatment alone. Special considerations should include assessment of level of nicotine dependence, which is associated with difficulty in quitting and relapse (247). Screening for CAD is reviewed in a recently updated consensus statement [bib_ref] Screening for coronary artery disease in patients with diabetes, Bax [/bib_ref]. To identify the presence of CAD in diabetic patients without clear or suggestive symptoms, a risk factorbased approach to the initial diagnostic evaluation and subsequent follow-up has intuitive appeal. However, recent studies concluded that using this approach fails to identify which patients with type 2 diabetes will have silent ischemia on screening tests [bib_ref] Detection of Ischemia in Asymptomatic Diabetics Investigators. Detection of silent myocardial ischemia..., Wackers [/bib_ref] [bib_ref] Detection of coronary artery disease in asymptomatic patients with type 2 diabetes..., Scognamiglio [/bib_ref]. ## Smoking cessation ## Chd screening and treatment Candidates for cardiac testing include those with 1) typical or atypical cardiac symptoms and 2) an abnormal resting ECG. The screening of asymptomatic patients remains controversial, especially as intensive medical therapy, indicated in diabetic patients at high risk for CVD, has an increasing evidence base for providing equal outcomes to invasive revascularization, including in diabetic patients [bib_ref] Optimal medical therapy with or without PCI for stable coronary disease, Boden [/bib_ref] [bib_ref] A randomized trial of therapies for type 2 diabetes and coronary artery..., Bari 2d Study [/bib_ref]. There is also some evidence that silent myocardial ischemia may reverse over time, adding to the controversy concerning aggressive screening strategies [bib_ref] Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators. Resolution of asymptomatic myocardial..., Wackers [/bib_ref]. Finally, a recent randomized observational trial demonstrated no clinical benefit to routine screening of asymptomatic patients with type 2 diabetes and normal ECGs [bib_ref] Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with..., Young [/bib_ref]. Despite abnormal myocardial perfusion imaging in more than one in five patients, cardiac outcomes were essentially equal (and very low) in screened versus unscreened patients. Accordingly, the overall effectiveness, especially the cost-effectiveness, of such an indiscriminate screening strategy is now questioned. Newer noninvasive CAD screening methods, such as computed tomography (CT) and CT angiography have gained in popularity. These tests infer the presence of coronary atherosclerosis by measuring the amount of calcium in coronary arteries and, in some circumstances, by direct visualization of luminal stenoses. Although asymptomatic diabetic patients found to have a higher coronary disease burden have more future cardiac events [bib_ref] Prognostic value of coronary computed tomographic angiography in diabetic patients without known..., Hadamitzky [/bib_ref] [bib_ref] PREDICT Study Group. Coronary calcium measurement improves prediction of cardiovascular events in..., Elkeles [/bib_ref] [bib_ref] Assessment of subclinical coronary atherosclerosis in asymptomatic patients with type 2 diabetes..., Choi [/bib_ref] , the role of these tests beyond risk stratification is not clear. Their routine use leads to radiation exposure and may result in unnecessary invasive testing such as coronary angiography and revascularization procedures. The ultimate balance of benefit, cost, and risks of such an approach in asymptomatic patients remains controversial, particularly in the modern setting of aggressive CVD risk factor control. In all patients with diabetes, cardiovascular risk factors should be assessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro-or macroalbuminuria. Abnormal risk factors should be treated as described elsewhere in these guidelines. Patients at increased CHD risk should receive aspirin and a statin and ACE inhibitor or ARB therapy if hypertensive, unless there are contraindications to a particular drug class. While clear benefit exists for ACE inhibitor and ARB therapy in patients with nephropathy or hypertension, the benefits in patients with CVD in the absence of these conditions is less clear, especially when LDL cholesterol is concomitantly controlled [bib_ref] Angiotensinconverting-enzyme inhibition in stable coronary artery disease, Braunwald [/bib_ref]. Diabetic nephropathy occurs in 20 -40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30 -299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk [bib_ref] Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease, Garg [/bib_ref] [bib_ref] Very low levels of microalbuminuria are associated with increased risk of coronary..., Klausen [/bib_ref]. Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24 h) are likely to progress to ESRD [bib_ref] Risk factors for development of incipient and overt diabetic nephropathy in patients..., Gall [/bib_ref] [bib_ref] Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A..., Ravid [/bib_ref]. However, a number of interventions have been demonstrated to re-duce the risk and slow the progression of renal disease. Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to delay the onset of microalbuminuria and the progression of micro-to macroalbuminuria in patients with type 1 [bib_ref] The effect of long-term intensified insulin treatment on the development of microvascular..., Reichard [/bib_ref] and type 2 (55,56) diabetes. The UKPDS provided strong evidence that control of blood pressure can reduce the development of nephropathy. In addition, large prospective randomized studies in patients with type 1 diabetes have demonstrated that achievement of lower levels of systolic blood pressure (Ͻ140 mmHg) resulting from treatment using ACE inhibitors provides a selective benefit over other antihypertensive drug classes in delaying the progression from micro-to macroalbuminuria and can slow the decline in GFR in patients with macroalbuminuria . In type 2 diabetes with hypertension and normoalbuminuria, RAS inhibition has been demonstrated to delay onset of microalbuminuria [bib_ref] Prevention and treatment of diabetic renal disease in type 2 diabetes: the..., Remuzzi [/bib_ref]. In addition, ACE inhibitors have been shown to reduce major CVD outcomes (i.e., myocardial infarction, stroke, death) in patients with diabetes, thus further supporting the use of these agents in patients with microalbuminuria, a CVD risk factor. ARBs do not prevent microalbuminuria in normotensive patients with type 1 or type 2 diabetes [bib_ref] Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three..., Bilous [/bib_ref] [bib_ref] Renal and retinal effects of enalapril and losartan in type 1 diabetes, Mauer [/bib_ref] ; however, ARBs have been shown to reduce the rate of progression from microto macroalbuminuria as well as ESRD in patients with type 2 diabetes . Some evidence suggests that ARBs have a smaller magnitude of rise in potassium compared with ACE inhibitors in people with nephropathy [bib_ref] A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients..., Pepine [/bib_ref] [bib_ref] ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure...., Bakris [/bib_ref]. Combinations of drugs that block the reninangiotensin-aldosterone system (e.g., an ACE inhibitor plus an ARB, a mineralocorticoid antagonist, or a direct renin inhibitor) have been shown to provide additional lowering of albuminuria [bib_ref] Randomised controlled trial of dual blockade of renin-angiotensin system in patients with..., Mogensen [/bib_ref] [bib_ref] Dual blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy: the role of..., Schjoedt [/bib_ref] [bib_ref] Beneficial impact of spironolactone in diabetic nephropathy, Schjoedt [/bib_ref] [bib_ref] AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and..., Parving [/bib_ref]. However, the long-term effects of such combinations on renal or cardiovascular outcomes have not yet been evaluated in clinical trials, and they are associated with increased risk for hyperkalemia. Other drugs, such as diuretics, calcium channel blockers, and ␤-blockers should be used as additional therapy to further lower blood pressure in patients already treated with ACE inhibitors or ARBs (212), or as alternate therapy in the rare individual unable to tolerate ACE inhibitors or ARBs. Studies in patients with varying stages of nephropathy have shown that protein restriction of dietary protein helps slow the progression of albuminuria, GFR decline, and occurrence of ESRD . Dietary protein restriction should be considered particularly in patients whose nephropathy seems to be progressing despite optimal glucose and blood pressure control and use of ACE inhibitor and/or ARBs [bib_ref] A meta-analysis of the effects of dietary protein restriction on the rate..., Kasiske [/bib_ref]. ## Assessment of albuminuria status and renal function Screening for microalbuminuria can be performed by measurement of the albumin-to-creatinine ratio in a random spot collection; 24-h or timed collections are more burdensome and add little to prediction or accuracy [bib_ref] Proteinuria and other markers of chronic kidney disease: a position statement of..., Eknoyan [/bib_ref] [bib_ref] National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease:..., Levey [/bib_ref]. Measurement of a spot urine for albumin only, whether by immunoassay or by using a dipstick test specific for microalbumin, without simultaneously measuring urine creatinine, is somewhat less expensive but susceptible to false-negative and -positive determinations as a result of variation in urine concentration due to hydration and other factors. Abnormalities of albumin excretion are defined in [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref]. Because of variability in urinary albumin excretion, two of three specimens collected within a 3-to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24 h, infection, fever, CHF, marked hyperglycemia, and marked hypertension may elevate urinary albumin excretion over baseline values. Information on presence of abnormal urine albumin excretion in addition to level of GFR may be used to stage CKD. The National Kidney Foundation classification [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref] is primarily based on GFR levels and therefore differs from other systems, in which staging is based primarily on urinary albumin excretion [bib_ref] Screening for kidney disease in adults with diabetes, Kramer [/bib_ref]. Studies have found decreased GFR in the absence of increased urine albumin excretion in a substantial percentage of adults with diabetes [bib_ref] Renal insufficiency in the absence of albuminuria and retinopathy among adults with..., Kramer [/bib_ref]. Serum creatinine should therefore be measured at least annually in all adults with diabetes, regardless of the degree of urine albumin excretion. Serum creatinine should be used to estimate GFR and to stage the level of CKD, if present. eGFR is commonly coreported by laboratories or can be estimated using formulae such as the Modification of Diet in Renal Disease (MDRD) study equation [bib_ref] A more accurate method to estimate glomerular filtration rate from serum creatinine:..., Levey [/bib_ref]. Recent reports have indicated that the MDRD is more accurate for the diagnosis and stratification of CKD in patients with diabetes than the Cockcroft-Gault formula [bib_ref] Estimation of glomerular filtration rate in diabetic subjects: Cockcroft formula or modification..., Rigalleau [/bib_ref]. GFR calculators are available at http:// www.nkdep.nih.gov. The role of continued annual quantitative assessment of albumin excretion after diagnosis of microalbuminuria and institution of ACE inhibitor or ARB therapy and blood pressure control is unclear. Continued surveillance can assess both response to therapy and progression of disease. Some suggest that reducing abnormal albuminuria (Ͼ30 mg/g) to the normal or near-normal range may improve renal and cardiovascular prognosis, but this approach has not been formally evaluated in prospective trials. Complications of kidney disease correlate with level of kidney function. When the eGFR is less than 60 ml/min/1.73 m 2 , screening for complications of CKD is indicated [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref]. Early vaccination against hepatitis B is indicated in patients likely to progress to end-stage kidney disease. Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (heavy proteinuria, active urine sediment, absence of retinopathy, rapid decline in GFR, resistant hypertension), difficult management issues, or advanced kidney disease. The threshold for referral may vary depending on the frequency with which a provider encounters diabetic patients with significant kidney disease. Consultation with a nephrologist when stage 4 CKD develops has been found to reduce cost, improve quality of care, and keep people off dialysis longer [bib_ref] Specialist evaluation in chronic kidney disease: too little, too late, Levinsky [/bib_ref]. However, nonrenal specialists should not delay educating their patients about the progressive nature of diabetic kidney disease; the renal preservation benefits of aggressive treatment of blood pressure, blood glucose, and hyperlipidemia; and the potential need for renal replacement therapy. Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to the duration of diabetes. Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20 -74 years. Glaucoma, cataracts, and other disorders of the eye occur earlier and more frequently in people with diabetes. In addition to duration of diabetes, other factors that increase the risk of, or are associated with, retinopathy include chronic hyperglycemia [bib_ref] Hyperglycemia and microvascular and macrovascular disease in diabetes, Klein [/bib_ref] , the presence of nephropathy [bib_ref] Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM, Estacio [/bib_ref] , and hypertension [bib_ref] Barbados Eye Study Group. Hyperglycemia, blood pressure, and the 9-year incidence of..., Leske [/bib_ref]. Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy (47,55, 56,64). Lowering blood pressure has been shown to decrease the progression of retinopathy. Several case series and a controlled prospective study suggest that pregnancy in type 1 diabetic patients may aggravate retinopathy [bib_ref] Diabetic retinopathy, Fong [/bib_ref] ; laser photocoagulation surgery can minimize this risk. One of the main motivations for screening for diabetic retinopathy is the established efficacy of laser photocoagulation surgery in preventing vision loss. Two large trials, the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRSshowed that panretinal photocoagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes, with greatest risk-to-benefit ratio in those with baseline disease (disc neovascularization or vitreous hemorrhage). The ETDRS (296) established the benefit of focal laser photocoagulation surgery in eyes with macular edema, particularly those with clinically significant macular edema, with reduction of doubling of the visual angle (e.g., 20/50 to 20/100) from 20% in untreated eyes to 8% in treated eyes. The ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in olderonset patients with severe NPDR or lessthan-high-risk PDR. Laser photocoagulation surgery in both trials was beneficial in reducing the risk of further vision loss, but generally not beneficial in reversing already diminished acuity. This preventive effect and the fact that patients with PDR or macular edema may be asymptomatic provide strong support for a screening program to detect diabetic retinopathy. As retinopathy is estimated to take at least 5 years to develop after the onset of hyperglycemia, patients with type 1 diabetes should have an initial dilated and comprehensive eye examination within 5 years after the onset of diabetes. Patients with type 2 diabetes, who generally have had years of undiagnosed diabetes and who have a significant risk of prevalent DR at time of diabetes diagnosis, should have an initial dilated and comprehensive eye examination soon after diagnosis. Examinations should be performed by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing the presence of diabetic retinopathy and is aware of its management. Subsequent examinations for type 1 and type 2 diabetic patients are generally repeated annually. Less-frequent exams (every 2-3 years) may be cost effective after one or more normal eye exams, while examinations will be required more frequently if retinopathy is progressing. The use of retinal photography with remote reading by experts has great potential in areas where qualified eye care professionals are not available, and may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be utilized for more complex examinations and for therapy [bib_ref] The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting..., Ahmed [/bib_ref]. In-person exams are still necessary when the photos are unacceptable and for follow-up of abnormalities detected. Photos are not a substitute for a comprehensive eye exam, which should be performed at least initially and at intervals thereafter as recommended by an eye care professional. Results of eye examinations should be documented and transmitted to the referring health care professional. For a detailed review of the evidence and further discussion of diabetic retinopathy, see the ADA's technical review and position statement on this subject [bib_ref] Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies, Ciulla [/bib_ref]. The early recognition and appropriate management of neuropathy in the pa-tient with diabetes is important for a number of reasons: 1) nondiabetic neuropathies may be present in patients with diabetes and may be treatable, 2) a number of treatment options exist for symptomatic diabetic neuropathy, 3) up to 50% of DPN may be asymptomatic and patients are at risk of insensate injury to their feet, and 4) autonomic neuropathy and particularly cardiovascular autonomic neuropathy is associated with substantial morbidity and even mortality. Specific treatment for the underlying nerve damage is currently not available, other than improved glycemic control, which may modestly slow progression (63) but not reverse neuronal loss. Effective symptomatic treatments are available for some manifestations of DPN and autonomic neuropathy. ## Diagnosis of neuropathy Distal symmetric polyneuropathy. Patients with diabetes should be screened annually for DPN using tests such as pinprick sensation, vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and assessment of ankle reflexes. Combinations of more than one test have Ͼ87% sensitivity in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers [bib_ref] Diabetic neuropathies: a statement by the American Diabetes Association, Boulton [/bib_ref]. Importantly, in patients with neuropathy, particularly when severe, causes other than diabetes should always be considered, such as neurotoxic mediations, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency (especially in those taking metformin for prolonged periods (302), renal disease, chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis [bib_ref] Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of..., Freeman [/bib_ref]. ## Diabetic autonomic neuropathy (304). The symptoms and signs of autonomic dysfunction should be elicited carefully during the history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, and, potentially, autonomic failure in response to hypoglycemia. Cardiovascular autonomic neuropathy, a CVD risk factor [bib_ref] Meta-analysis of quality of life outcomes following diabetes self-management training, Cochran [/bib_ref] , is the most studied and clinically important form of diabetic autonomic neuropathy. Cardio-vascular autonomic neuropathy may be indicated by resting tachycardia (Ͼ100 bpm) or orthostasis (a fall in systolic blood pressure Ͼ20 mmHg upon standing without an appropriate heart rate response); it is also associated with increased cardiac event rates. Gastrointestinal neuropathies (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, fecal incontinence) are common, and any section of the gastrointestinal tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control or with upper gastrointestinal symptoms without other identified cause. Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be done if symptoms are suggestive, but test results often correlate poorly with symptoms. Constipation is the most common lower-gastrointestinal symptom but can alternate with episodes of diarrhea. Diabetic autonomic neuropathy is also associated with genitourinary tract disturbances. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Symptomatic treatments DPN. The first step in management of patients with DPN should be to aim for stable and optimal glycemic control. Although controlled trial evidence is lacking, several observational studies suggest that neuropathic symptoms improve not only with optimization of control, but also with the avoidance of extreme blood glucose fluctuations. Patients with painful DPN may benefit from pharmacological treatment of their symptoms: many agents have efficacy confirmed in published randomized controlled trials, several of which are Food and Drug Administration (FDA)-approved for the management of painful DPN. ## Treatment of autonomic neuropathy Gastroparesis symptoms may improve with dietary changes and prokinetic agents such as metoclopramide or erythromycin. Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. Interventions for other manifestations of autonomic neuropathy are described in the ADA statement on neuropathy [bib_ref] Diabetic neuropathies: a statement by the American Diabetes Association, Boulton [/bib_ref]. As with DPN treatments, these interventions do not change the underlying pathology and natural history of the disease process, but may have a positive impact on the quality of life of the patient. Amputation and foot ulceration, consequences of diabetic neuropathy and/or PAD, are common and major causes of morbidity and disability in people with diabetes. Early recognition and management of risk factors can prevent or delay adverse outcomes. The risk of ulcers or amputations is increased in people who have the following risk factors: Many studies have been published proposing a range of tests that might usefully identify patients at risk of foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. An ADA task force was therefore assembled in 2008 to concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. Their recommendations are summarized below, but clinicians should refer to the task force report (305) for further details and practical descriptions of how to perform components of the comprehensive foot examination. [formula] - [/formula] At least annually, all adults with diabetes should undergo a comprehensive foot examination to identify high risk conditions. Clinicians should ask about history of previous foot ulceration or amputation, neuropathic or peripheral vascular symptoms, impaired vision, tobacco use, and foot care practices. A general inspection of skin integrity and musculoskeletal deformities should be done in a well lit room. Vascular assessment would include inspection and assessment of pedal pulses. The neurologic exam recommended is designed to identify loss of protective sensation (LOPS) rather than early neuropathy. The clinical examination to identify LOPS is simple and requires no expensive equipment. Five simple clinical tests (use of a 10-g monofilament, vibration testing using a 128-Hz tuning fork, tests of pinprick sensation, ankle reflex assessment, and testing vibration perception threshold with a biothesiometer), each with evidence from well-conducted prospective clinical cohort studies, are considered useful in the diagnosis of LOPS in the diabetic foot. The task force agrees that any of the five tests listed could be used by clinicians to identify LOPS, although ideally two of these should be regularly performed during the screening exam-normally the 10-g monofilament and one other test. One or more abnormal tests would suggest LOPS, while at least two normal tests (and no abnormal test) would rule out LOPS. The last test listed, vibration assessment using a biothesiometer or similar instrument, is widely used in the U.S.; however, identification of the patient with LOPS can easily be carried out without this or other expensive equipment. Initial screening for PAD should include a history for claudication and an assessment of the pedal pulses. A diagnostic ABI should be performed in any patient with symptoms of PAD. Due to the high estimated prevalence of PAD in patients with diabetes and the fact that many patients with PAD are asymptomatic, an ADA consensus statement on PADsuggested that a screening ABI be performed in patients over 50 years of age and be considered in patients under 50 years of age who have other PAD risk factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes Ͼ10 years). Refer patients with significant symptoms or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options. Patients with diabetes and high-risk foot conditions should be educated regarding their risk factors and appropriate management. Patients at risk should understand the implications of the LOPS, the importance of foot monitoring on a daily basis, the proper care of the foot, including nail and skin care, and the selection of appropriate footwear. Patients with LOPS should be educated on ways to substitute other sensory modalities (hand palpation, visual inspection) for surveillance of early foot problems. Patients' understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist in their care. People with neuropathy or evidence of increased plantar pressure (e.g., erythema, warmth, callus, or measured pressure) may be adequately managed with well-fitted walking shoes or athletic shoes that cushion the feet and redistribute pressure. Callus can be debrided with a scalpel by a foot care specialist or other health professional with experience and training in foot care. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extra-wide or -depth shoes. People with extreme bony deformities (e.g., Charcot foot) who cannot be accommo-dated with commercial therapeutic footwear may need custom-molded shoes. Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes. ## Vii. diabetes care in specific populations A. Children and adolescents 1. Type 1 diabetes Three-quarters of all cases of type 1 diabetes are diagnosed in individuals Ͻ18 years of age. It is appropriate to consider the unique aspects of care and management of children and adolescents with type 1 diabetes. Children with diabetes differ from adults in many respects, including changes in insulin sensitivity related to sexual maturity and physical growth, ability to provide self-care, supervision in child care and school, and unique neurological vulnerability to hypoglycemia and DKA. Attention to such issues as family dynamics, developmental stages, and physiological differences related to sexual maturity are all essential in developing and implementing an optimal diabetes regimen. Although recommendations for children and adolescents are less likely to be based on clinical trial evidence, expert opinion and a review of available and relevant experimental data are summarized in the ADA statement on care of children and adolescents with type 1 diabetes [bib_ref] Care of children and adolescents with type 1 diabetes mellitus: a statement..., Silverstein [/bib_ref]. Ideally, the care of a child or adolescent with type 1 diabetes should be provided by a multidisciplinary team of specialists trained in the care of children with pediatric diabetes. At the very least, education of the child and family should be provided by health care providers trained and experienced in childhood diabetes and sensitive to the challenges posed by diabetes in this age-group. At the time of initial diagnosis, it is essential that diabetes education be provided in a timely fashion, with the expectation that the balance between adult supervision and self-care should be defined by, and will evolve according to, physical, psychological, and emotional maturity. MNT and psychological support should be provided at diagnosis, and regularly thereafter, by individuals experienced with the nutritional and behavioral needs of the growing child and family. While current standards for diabetes management reflect the need to maintain glucose control as near to normal as safely possible, special consideration should be given to the unique risks of hypoglycemia in young children. Glycemic goals may need to be modified to take into account the fact that most children Ͻ6 or 7 years of age have a form of "hypoglycemic unawareness," including immaturity of and a relative inability to recognize and respond to hypoglycemic symptoms, placing them at greater risk for severe hypoglycemia and its sequelae. In addition, and unlike the case in adults, young children under the age of 5 years may be at risk for permanent cognitive impairment after episodes of severe hypoglycemia . Furthermore, findings from the DCCT demonstrated that nearnormalization of blood glucose levels was more difficult to achieve in adolescents than adults. Nevertheless, the increased frequency of use of basal-bolus regimens and insulin pumps in youth from infancy through adolescence has been associated with more children reaching ADA blood glucose targets [bib_ref] Insulin pump therapy in youth with type 1 diabetes: a retrospective paired..., Nimri [/bib_ref] [bib_ref] A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion..., Doyle [/bib_ref] in those families in which both parents and the child with diabetes participate jointly to perform the required diabetes-related tasks. Furthermore, recent studies documenting neurocognitive sequelae of hyperglycemia in children provide another compelling motivation for achieving glycemic targets [bib_ref] Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth..., Perantie [/bib_ref] [bib_ref] Brain metabolic alterations in patients with type 1 diabetes-hyperglycemia-induced injury, Mäkimattila [/bib_ref]. In selecting glycemic goals, the benefits on long-term health outcomes of achieving a lower A1C should be balanced against the risks of hypoglycemia and the developmental burdens of intensive regimens in children and youth. Agespecific glycemic and A1C goals are presented in [fig_ref] Table 1 -: ADA evidence grading system for clinical practice recommendations [/fig_ref]. ## Standards of medical care for albumin-to-creatinine (ACR) ratio, should be considered once the child is 10 years of age and has had diabetes for 5 years. (E) - Confirmed, persistently elevated ACR on two additional urine specimens from different days should be treated with an ACE inhibitor, titrated to normalization of albumin excretion if possible. (E) ii. Hypertension ## Recommendations - Treatment of high-normal blood pressure (systolic or diastolic blood pressure consistently above the 90th percentile for age, sex, and height) should include dietary intervention and exercise aimed at weight control and increased physical activity, if appropriate. If target blood pressure is not reached with 3-6 months of lifestyle intervention, pharmacologic treatment should be considered. (E) - Pharmacologic treatment of hypertension (systolic or diastolic blood pressure consistently above the 95th percentile for age, sex, and height or consistently greater than 130/80 mmHg, if 95% exceeds that value) should be initiated as soon as the diagnosis is confirmed. (E) - ACE inhibitors should be considered for the initial treatment of hypertension, following appropriate reproductive counseling due to its potential teratogenic effects. (E) - The goal of treatment is a blood pressure consistently Ͻ130/80 or below the 90th percentile for age, sex, and height, whichever is lower. (E) It is important that blood pressure measurements are determined correctly, using the appropriate size cuff, and with the child seated and relaxed. Hypertension should be confirmed on at least three separate days. Normal blood pressure levels for age, sex, and height and appropriate methods for determinations are available online at www.nhlbi. nih.gov/health/prof/heart/hbp/hbp_ ped.pdf. iii. Dyslipidemia ## Recommendations screening - If there is a family history of hypercholesterolemia (total cholesterol Ͼ240 mg/dl) or a cardiovascular event before age 55 years, or if family history is unknown, then a fasting lipid profile should be performed on children Ͼ2 years of age soon after diagnosis (after glucose control has been established). If family history is not of concern, then the first lipid screening should be considered at puberty (Ն10 years). All children diagnosed with diabetes at or after puberty should have a fasting lipid profile performed soon after diagnosis (after glucose control has been established). (E) - For both age-groups, if lipids are abnormal, annual monitoring is recommended. If LDL cholesterol values are within the accepted risk levels (Ͻ100 mg/dl [2.6 mmol/l]), a lipid profile should be repeated every 5 years. (E) (318) CVD. Although intervention data are lacking, the AHA categorizes children with type 1 diabetes in the highest tier for cardiovascular risk and recommends both lifestyle and pharmacologic treatment for those with elevated LDL cholesterol levels [bib_ref] Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk..., Kavey [/bib_ref] [bib_ref] Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific..., Mccrindle [/bib_ref]. Initial therapy should be with a Step 2 AHA diet, which restricts saturated fat to 7% of total calories and restricts dietary cholesterol to 200 mg/day. Data from randomized clinical trials in children as young as 7 months of age indicate that this diet is safe and does not interfere with normal growth and development [bib_ref] Serum cholesterol ester fatty acids in 7-and 13-month-old children in a prospective..., Salo [/bib_ref]. Neither long-term safety nor cardiovascular outcome efficacy of statin therapy has been established for children. However, recent studies have shown short-term safety equivalent to that seen in adults, and efficacy in lowering LDL cholesterol levels, improving endothelial function, and causing regression of carotid intimal thickening [bib_ref] Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia..., Mccrindle [/bib_ref] [bib_ref] Early statin therapy restores endothelial function in children with familial hypercholesterolemia, De Jongh [/bib_ref] [bib_ref] Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a..., Wiegman [/bib_ref]. No statin is approved for use under the age of 10 years, and statin treatment should generally not be used in children with type 1 diabetes prior to this age. ## Iv. retinopathy Recommendations - The first ophthalmologic examination should be obtained once the child is 10 years of age and has had diabetes for 3-5 years. (E) - After the initial examination, annual routine follow-up is generally recommended. Less frequent examinations may be acceptable on the advice of an eye care professional. (E) Although retinopathy most commonly occurs after the onset of puberty and after 5-10 years of diabetes duration, it has been reported in prepubertal children and with diabetes duration of only 1-2 years. Referrals should be made to eye care professionals with expertise in diabetic retinopathy, an understanding of the risk for retinopathy in the pediatric population, and experience in counseling the pediatric patient and family on the importance of early prevention/ intervention. Auto-immune thyroid disease is the most common autoimmune disorder associated with diabetes, occurring in 17-30% of patients with type 1 diabetes [bib_ref] Thyroid autoimmunity in children and adolescents with Type 1 diabetes mellitus. Diabetes, Roldán [/bib_ref]. The presence of thyroid auto-antibodies is predictive of thyroid dysfunction, generally hypothyroidism but less commonly hyperthyroidism [bib_ref] Grü ters-Kieslich A. Predictivity of thyroid autoantibodies for the development of thyroid..., Kordonouri [/bib_ref]. Subclinical hypothyroidism may be associated with increased risk of symptomatic hypoglycemia [bib_ref] The effect of subclinical hypothyroidism on metabolic control in children and adolescents..., Mohn [/bib_ref] and with reduced linear growth [bib_ref] Thyroid hormone replacement and growth of children with subclinical hypothyroidism and diabetes, Chase [/bib_ref]. Hyperthyroidism alters glucose metabolism, potentially resulting in deterioration of metabolic control. ## C. self-management No matter how sound the medical regimen, it can only be as good as the ability of the family and/or individual to implement it. Family involvement in diabetes remains an important component of optimal diabetes management throughout childhood and into adolescence. Health care providers who care for children and adolescents, therefore, must be capable of evaluating the behavioral, emotional, and psychosocial factors that interfere with implementation and then must work with the individual and family to resolve problems that occur and/or to modify goals as appropriate. d. School and day care Because a sizable portion of a child's day is spent in school, close communication with and cooperation of school or day care personnel is essential for optimal diabetes management, safety, and maximal academic opportunities. See the ADA position statement on Diabetes Care in the School and Day Care Setting (332) for further discussion. ## Standards of medical care e. Transition from pediatric to adult care As they approach the young adult years, older adolescents are at increasing physical, behavioral, and other risks [bib_ref] Clinical and psychological course of diabetes from adolescence to young adulthood: a..., Bryden [/bib_ref] [bib_ref] Burden AC, Gatling W. Psychosocial and socioeconomic risk factors for premature death..., Laing [/bib_ref]. As they leave both their home and their pediatric diabetes care providers, these older teens may become disengaged from the health care system, leading to lapses in medical care and deterioration in glycemic control [bib_ref] Problems in transition from pediatric care to adult care for individuals with..., Pacaud D [/bib_ref]. Though scientific evidence is limited to date, it is clear that early and ongoing attention be given to comprehensive and coordinated planning for seamless transition of all youth from pediatric to adult health care. The National Diabetes Education Program (NDEP) has materials available to facilitate this transition process (http:// ndep.nih.gov/transitions/). ## Type 2 diabetes The incidence of type 2 diabetes in adolescents is increasing, especially in ethnic minority populations [bib_ref] SEARCH for Diabetes in Youth Study Group. Testing the accelerator hypothesis: body..., Dabelea [/bib_ref]. Distinction between type 1 and type 2 diabetes in children can be difficult, since the prevalence of overweight in children continues to rise and since autoantigens and ketosis may be present in a substantial number of patients with features of type 2 diabetes (including obesity and acanthosis nigricans). Such a distinction at the time of diagnosis is critical since treatment regimens, educational approaches, and dietary counsel will differ markedly between the two diagnoses. Type 2 diabetes has a significant prevalence of comorbidities already present at the time of diagnosis [bib_ref] Prevalence of diabetes complications in adolescents with type 2 compared with type..., Eppens [/bib_ref]. It is recommended that blood pressure measurement, a fasting lipid profile, microalbuminuria assessment, and dilated eye examination be performed at the time of diagnosis. Thereafter, screening guidelines and treatment recommendations for hypertension, dyslipidemia, microalbuminuria, and retinopathy in youth with type 2 diabetes are similar to those for youth with type 1 diabetes. Additional problems that may need to be addressed include polycystic ovary disease and the various comorbidities associated with pediatric obesity such as sleep apnea, hepatic steatosis, orthopedic complications, and psychosocial concerns. The ADA consensus statement on this subjectprovides guidance on the prevention, screening, and treatment of type 2 diabetes and its comorbidities in young people. ## Monogenic diabetes syndromes Monogenic forms of diabetes (neonatal diabetes or maturity-onset diabetes of the young) represent a small fraction of children with diabetes (Ͻ5%), but the ready availability of commercial genetic testing is now enabling a true genetic diagnosis with increasing frequency. It is important to correctly diagnose one of the monogenic forms of diabetes, as these children may be incorrectly diagnosed with type 1 or type 2 diabetes, leading to nonoptimal treatment regimens and delays in diagnosing other family members. The diagnosis of monogenic diabetes should be considered in the following settings: diabetes diagnosed within the first 6 months of life; in children with strong family history of diabetes but without typical features of type 2 diabetes (nonobese, low-risk ethnic group); in children with mild fasting hyperglycemia (100 -150 mg/dl , especially if young and nonobese; and in children with diabetes but with negative autoantibodies without signs of obesity or insulin resistance. A recent international consensus document discusses in further detail the diagnosis and management of children with monogenic forms of diabetes [bib_ref] The diagnosis and management of monogenic diabetes in children and adolescents, Hattersley [/bib_ref]. Major congenital malformations remain the leading cause of mortality and serious morbidity in infants of mothers with type 1 and type 2 diabetes. Observational studies indicate that the risk of malformations increases continuously with increasing maternal glycemia during the first 6 -8 weeks of gestation, as defined by firsttrimester A1C concentrations. There is no threshold for A1C values below which risk disappears entirely. However, malformation rates above the 1-2% background rate of nondiabetic pregnancies appear to be limited to pregnancies in which first-trimester A1C concentrations are Ͼ1% above the normal range for a nondiabetic pregnant woman. Preconception care of diabetes appears to reduce the risk of congenital malformations. Five nonrandomized studies compared rates of major malformations in infants between women who participated in preconception diabetes care programs and women who initiated intensive diabetes management after they were already pregnant. The preconception care programs were multidisciplinary and designed to train patients in diabetes selfmanagement with diet, intensified insulin therapy, and SMBG. Goals were set to achieve normal blood glucose concentrations, and Ͼ80% of subjects achieved normal A1C concentrations before they became pregnant. In all five studies, the incidence of major congenital malformations in women who participated in preconception care (range 1.0 -1.7% of infants) was much lower than the incidence in women who did not participate (range 1.4 -10.9% of infants) [bib_ref] Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for..., Kitzmiller [/bib_ref]. One limitation of these studies is that participation in preconception care was selfselected rather than randomized. Thus, it is impossible to be certain that the lower malformation rates resulted fully from improved diabetes care. Nonetheless, the evidence supports the concept that malformations can be reduced or prevented by careful management of diabetes before pregnancy. Planned pregnancies greatly facilitate preconception diabetes care. Unfortunately, nearly two-thirds of pregnancies in women with diabetes are unplanned, leading to a persistent excess of malformations in infants of diabetic mothers. To minimize the occurrence of these devastating malformations, standard care for all women with diabetes who have child-bearing potential, beginning at the onset of puberty or at diagnosis, should include 1) education about the risk of malformations associated with unplanned pregnancies and poor metabolic control; and 2) use of effective contraception at all times, unless the patient has good metabolic control and is actively trying to conceive. Women contemplating pregnancy need to be seen frequently by a multidisciplinary team experienced in the management of diabetes before and during pregnancy. The goals of preconception care are to 1) involve and empower the patient in the management of her diabetes, 2) achieve the lowest A1C test results possible without excessive hypoglycemia, 3) assure effective contraception until stable and acceptable glycemia is achieved, and 4) identify, evaluate, and treat long-term diabetes complications such as retinopathy, nephropathy, neuropathy, hypertension, and CHD [bib_ref] Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for..., Kitzmiller [/bib_ref]. Among the drugs commonly used in the treatment of patients with diabetes, a number may be relatively or absolutely contraindicated during pregn a n c y . S t a t i n s a r e c a t e g o r y X (contraindicated for use in pregnancy) and should be discontinued before conception, as should ACE inhibitors [bib_ref] Major congenital malformations after first-trimester exposure to ACE inhibitors, Cooper [/bib_ref]. ARBs are category C (risk cannot be ruled out) in the first trimester but category D (positive evidence of risk) in later pregnancy and should generally be discontinued before pregnancy. Since many pregnancies are unplanned, health care professionals caring for any woman of childbearing potential should consider the potential risks and benefits of medications that are contraindicated in pregnancy. Women using medications such as statins or ACE inhibitors need ongoing family planning counseling. Among the oral antidiabetic agents, metformin and acarbose are classified as category B (no evidence of risk in humans) and all others as category C. Potential risks and benefits of oral antidiabetic agents in the preconception period must be carefully weighed, recognizing that data are insufficient to establish the safety of these agents in pregnancy. For further discussion of preconception care, see the ADA's consensus statement on preexisting diabetes and pregnancy [bib_ref] Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for..., Kitzmiller [/bib_ref] Diabetes is an important health condition for the aging population; at least 20% of patients over the age of 65 years have diabetes, and this number can be expected to grow rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, and coexisting illnesses such as hypertension, CHD, and stroke than those without diabetes. Older adults with diabetes are also at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, depression, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. The American Geriatric Society's guidelines for improving the care of the older person with diabetes (342) have influenced the following discussion and recommendations. The care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Some older individuals developed diabetes years earlier and may have significant complications; others who are newly diagnosed may have had years of undiagnosed diabetes with resultant complications or may have few complications from the disease. Some older adults with diabetes are frail and have other underly-ing chronic conditions, substantial diabetes-related comorbidity, or limited physical or cognitive functioning. Other older individuals with diabetes have little comorbidity and are active. Life expectancies are highly variable for this population, but often longer than clinicians realize. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals. There are few long-term studies in older adults demonstrating the benefits of intensive glycemic, blood pressure, and lipid control. Patients who can be expected to live long enough to reap the benefits of long-term intensive diabetes management and who are active, have good cognitive function, and are willing should be provided with the needed education and skills to do so and be treated using the goals for younger adults with diabetes. For patients with advanced diabetes complications, life-limiting comorbid illness, or substantial cognitive or functional impairment, it is reasonable to set less-intensive glycemic target goals. These patients are less likely to benefit from reducing the risk of microvascular complications and more likely to suffer serious adverse effects from hypoglycemia. However, patients with poorly controlled diabetes may be subject to acute complications of diabetes, including dehydrat i o n , p o o r w o u n d h e a l i n g , a n d hyperglycemic hyperosmolar coma. Glycemic goals at a minimum should avoid these consequences. Although control of hyperglycemia may be important in older individuals with diabetes, greater reductions in morbidity and mortality may result from control of other cardiovascular risk factors rather than from tight glycemic control alone. There is strong evidence from clinical trials of the value of treating hypertension in the elderly [bib_ref] Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic..., Curb [/bib_ref] [bib_ref] Treatment of hypertension in patients 80 years of age or older, Beckett [/bib_ref]. There is less evidence for lipid-lowering and aspirin therapy, although the benefits of these interventions for primary and secondary prevention are likely to apply to older adults whose life expectancies equal or exceed the time frames seen in clinical trials. Special care is required in prescribing and monitoring pharmacologic therapy in older adults. Metformin is often contraindicated because of renal insufficiency or significant heart failure. TZDs can cause fluid retention, which may exacerbate or lead to heart failure. They are contraindicated in patients with CHF (New York Heart Association class III and class IV) and if used at all should be used very cautiously in those with, or at risk for, milder degrees of CHF. Sulfonylureas, other insulin secretagogues, and insulin can cause hypoglycemia. Insulin use requires that patients or caregivers have good visual and motor skills and cognitive ability. Drugs should be started at the lowest dose and titrated up gradually until targets are reached or side effects develop. Screening for diabetes complications in older adults also should be individualized. Particular attention should be paid to complications that can develop over short periods of time and/or that would significantly impair functional status, such as visual and lower-extremity complications. ## D. cystic fibrosis-related diabetes Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in persons with CF, occurring in about 20% of adolescents and 40 -50% of adults. The additional diagnosis of diabetes in this population is associated with worse nutritional status, more-severe inflammatory lung disease, and greater mortality from respiratory failure. For reasons that are not well understood, women with CFRD are particularly vulnerable to excess morbidity and mortality. Insulin insufficiency related to partial fibrotic destruction of the islet mass is the primary defect in CFRD. Genetically determined function of the remaining ␤-cells and insulin resistance associated with infection and inflammation may also play a role. Encouraging new data suggest that early detection and aggressive insulin therapy have narrowed the gap in mortality between CF patients with and without diabetes, and have eliminated the sex difference in mortality. A consensus conference on CFRD was co-sponsored in 2009 by the American Diabetes Association, the Cystic Fibrosis Foundation, and the Pediatric Endocrine Society. Recommendations for the clinical management of CFRD can be found in an ADA position statement (344a). The management of hyperglycemia in the hospital has often been considered secondary in importance to the condition that prompted admission [bib_ref] American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and..., Clement [/bib_ref]. However, a body of literature now supports targeted glucose control in the hospital setting for potential improved clinical outcomes. Hyperglycemia in the hospital may result from stress, decompensation of type 1 or type 2 or other forms of diabetes, and/or may be iatrogenic due to withholding of anti-hyperglycemic medi-cations or administration of hyperglycem i a -p r o v o k i n g a g e n t s s u c h a s glucocorticoids or vasopressors. People with diabetes are more likely to be hospitalized and to have longer lengths of stay than those without diabetes. A recent survey estimated that 22% of all hospital inpatient days were incurred by people with diabetes and that hospital inpatient care accounted for half of the $174 billion total U.S. medical expenditures for this disease. This is due, in part, to the continued expansion of the worldwide epidemic of type 2 diabetes. While the costs of illness-related stress hyperglycemia are not known, they are likely to be significant given the poor prognosis of such patients . ## Viii. diabetes care in specific settings There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) suggested that intensive treatment of hyperglycemia improved hospital outcomes [bib_ref] American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and..., Clement [/bib_ref] [bib_ref] Intensive insulin therapy in the critically ill patients, Van Den Berghe [/bib_ref] [bib_ref] Glycometabolic state at admission: important risk marker of mortality in conventionally treated..., Malmberg [/bib_ref]. In general, these studies were heterogeneous in terms of patient population, blood glucose targets and insulin protocols, provision of nutritional support, and the proportion of patients receiving insulin, which limits the ability to make meaningful comparisons among them. Recent trials in critically ill patients have failed to show a significant improvement in mortality with intensive glycemic control [bib_ref] Benefits and risks of tight glucose control in critically ill adults: a..., Wiener [/bib_ref] [bib_ref] Intensive insulin therapy and pentastarch resuscitation in severe sepsis, Brunkhorst [/bib_ref] or have even shown increased mortality risk [bib_ref] Intensive versus conventional glucose control in critically ill patients, Nice-Sugar Study [/bib_ref]. Moreover, these recent RCTs have highlighted the risk of severe hypoglycemia resulting from such efforts [bib_ref] Benefits and risks of tight glucose control in critically ill adults: a..., Wiener [/bib_ref] [bib_ref] Intensive insulin therapy and pentastarch resuscitation in severe sepsis, Brunkhorst [/bib_ref] [bib_ref] Intensive versus conventional glucose control in critically ill patients, Nice-Sugar Study [/bib_ref] [bib_ref] Severe hypoglycemia in critically ill patients: risk factors and outcomes, Krinsley [/bib_ref] [bib_ref] Intensive insulin therapy in the medical ICU, Van Den Berghe [/bib_ref] [bib_ref] Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including..., Griesdale [/bib_ref]. The largest study to date, NICE-SUGAR, a multicenter, multinational RCT, compared the effect of intensive glycemic control (target 81-108 mg/dl, mean blood glucose attained 115 mg/dl) to standard glycemic control (target 144 -180 mg/dl, mean blood glucose attained 144 mg/dl) on outcomes among 6,104 critically ill participants, the majority of whom (Ͼ95%) required mechanical ventilation [bib_ref] Intensive versus conventional glucose control in critically ill patients, Nice-Sugar Study [/bib_ref]. Ninety-day mortality was significantly higher in the intensive versus the conventional group (78 more deaths; 27.5% vs. 24.9%, P ϭ 0.02) in both surgical and medical patients. Mortality from cardiovascular causes was more common in the intensive group (76 more deaths; 41.6% vs. 35.8%; P ϭ 0.02). Severe hypoglycemia was also more common in the intensively treated group (6.8% vs. 0.5%; P Ͻ 0.001). The precise reason for the increased mortality in the tightly con-trolled group is unknown. The results of this study lie in stark contrast to a famous 2001 single-center study that reported a 42% relative reduction in intensive-care unit (ICU) mortality in critically ill surgical patients treated to a target blood glucose of 80 -110 mg/dl [bib_ref] Intensive insulin therapy in the critically ill patients, Van Den Berghe [/bib_ref]. Importantly, the control group in NICE-SUGAR had reasonably good blood glucose management maintained at a mean glucose of 144 mg/dl, only 29 mg/dl above the intensively managed patients. Accordingly, this study's findings do not disprove the notion that glycemic control in the ICU is important. However, they do strongly suggest that it is not necessary to target blood glucose values Ͻ140 mg/dl, and that a highly stringent target of Ͻ110 mg/dl may actually be dangerous. In a recent meta-analysis of 26 trials (N ϭ 13,567), which included the NICE-SUGAR data, the pooled relative risk (RR) of death with intensive insulin therapy was 0.93 as compared with conventional therapy (95% CI 0.83-1.04) [bib_ref] Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including..., Griesdale [/bib_ref]. Approximately half of these trials reported hypoglycemia, with a pooled RR of intensive therapy of 6.0 (95% CI 4.5-8.0). The specific ICU setting influenced the findings, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63 [95% CI 0.44 -0.91]), while those in other critical care settings did not (medical ICU, RR 1.0 [95% CI 0.78 -1.28]; "mixed" ICU, RR 0.99 [95% CI 0.86 -1.12]). It was concluded that overall, intensive insulin therapy increased the risk of hypoglycemia but provided no overall benefit on mortality in the critically ill, although a possible mortality benefit to patients admitted to the surgical ICU (RR 0.63 [95% CI 0.44 -0.91]) was suggested. ## Glycemic targets in hospitalized patients Definition of glucose abnormalities in the hospital setting Hyperglycemia has been defined as any blood glucose level Ͼ140 mg/dl (7.8 mmol/l). Levels that are significantly and persistently above this may require treatment in hospitalized patients. In patients without a previous diagnosis of diabetes, elevated blood glucose may be due to "stress hyperglycemia," a condition that can be established by a review of prior records or measurement of an A1C. A1C values Ͼ6.5% suggest that diabetes preceded hospitalization [bib_ref] A new look at screening and diagnosing diabetes mellitus, Saudek [/bib_ref]. Hypoglycemia has been defined as any blood glucose level Ͻ70 mg/dl (3.9 mmol/l). This is the standard definition in outpatients and correlates with the initial threshold for the release of counterregulatory hormones. Severe hypoglycemia in hospitalized patients has been defined by many as Ͻ40 mg/dl (2.2 mmol/l), although this is lower than the ϳ50 mg/dl (2.8 mmol/l) level at which cognitive impairment begins in normal individuals [bib_ref] Hypoglycemia in diabetes, Cryer [/bib_ref]. As with hyperglycemia, hypoglycemia among inpatients is also associated with adverse short-and long-term outcomes. Early recognition and treatment of mild to moderate hypoglycemia (40 and 69 mg/dl) (2.2 and 3.8 mmol/l) can prevent deterioration to a more severe episode with potential adverse sequelae. ## Critically ill patients Based on the weight of the available evidence, for the majority of critically ill patients in the ICU setting, insulin infusion should be used to control hyperglycemia, with a starting threshold of no higher than 180 mg/dl (10.0 mmol/l). Once intravenous insulin is started, the glucose level should be maintained between 140 and 180 mg/dl (7.8 and 10.0 mmol/l). Greater benefit maybe realized at the lower end of this range. Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients. However, targets less than 110 mg/dl (6.1 mmol/l) are not recommended. Use of insulin infusion protocols with demonstrated safety and efficacy, resulting in low rates of hypoglycemia, are highly recommended. ## Noncritically ill patients With no prospective RCT data to inform specific glycemic targets in noncritically ill patients, recommendations are based on clinical experience and judgment. For the majority of noncritically ill patients treated with insulin, premeal glucose targets should generally be Ͻ140 mg/dl (7.8 mmol/l) with random blood glucose levels Ͻ180 mg/dl (10.0 mmol/l), as long as these targets can be safely achieved. To avoid hypoglycemia, consideration should be given to reassessing the insulin regimen if blood glucose levels fall below 100 mg/dl (5.6 mmol/l). Modification of the regimen is required when blood glucose values are Ͻ70 mg/dl (3.9 mmol/l), unless the event is easily explained by other factors (such as a missed meal, etc.) Occasional patients with a prior history of successful tight glycemic control in the outpatient setting who are clinically ## Standards of medical care stable may be maintained with a glucose range below the above cut points. Conversely, higher glucose ranges may be acceptable in terminally ill patients or in patients with severe comorbidities, as well as in those in patient-care settings where frequent glucose monitoring or close nursing supervision is not feasible. Clinical judgment, combined with ongoing assessment of the patient's clinical status, including changes in the trajectory of glucose measures, the severity of illness, nutritional status, or concurrent use of medications that might affect glucose levels (e.g., steroids, octreotide) must be incorporated into the day-to-day decisions regarding insulin dosing (346). ## Anti-hyperglycemic agents in hospitalized patients In the hospital setting, insulin therapy is the preferred method of glycemic control in majority of clinical situations. In the ICU, intravenous infusion is the preferred route of insulin administration. When the patient is transitioned off intravenous insulin to subcutaneous therapy, precautions should be taken to prevent hyperglycemia escape [bib_ref] Evaluation of glycemic control following discontinuation of an intensive insulin protocol, Czosnowski [/bib_ref] [bib_ref] Transition to Target: A prospective randomized trial comparing three formulae for determination..., Shomali [/bib_ref]. Outside of critical care units, scheduled subcutaneous insulin which delivers basal, nutritional, and correction (supplemental) components is preferred. Prolonged therapy with sliding scale insulin (SSI) as the sole regimen is ineffective in the majority of patients, increases risk of both hypoglycemia and hyperglycemia, and has recently been shown to be associated with adverse outcomes in general surgery patients with type 2 diabetes [bib_ref] Randomized study of basal bolus insulin therapy in the inpatient management of..., Umpierrez [/bib_ref]. SSI is potentially dangerous in type 1 diabetes. The reader is referred to several recent publications and reviews that describe currently available insulin preparations and protocols and provide guidance in use of insulin therapy in specific clinical settings including parenteral nutrition [bib_ref] Hyperglycemia during total parenteral nutrition: an important marker of poor outcome and..., Pasquel [/bib_ref] , enteral tube feedings, and with high-dose glucocorticoid therapy. There are no data on the safety and efficacy of oral agents and injectable noninsulin therapies such as GLP1 analogs and pramlintide in the hospital. They are generally considered to have a limited role in the management of hyperglycemia in conjunction with acute illness. Continuation of these agents may be appropriate in selected stable patients who are expected to consume meals at regular intervals and they may be initiated or resumed in anticipation of discharge once the patient is clinically stable. Specific caution is re-quired with metformin, due to the possibility that a contraindication may develop during the hospitalization, such as renal insufficiency, unstable hemodynamic status, or need for an imaging study that requires a radio-contrast dye. ## Preventing hypoglycemia Hypoglycemia, especially in insulintreated patients, is the leading limiting factor in the glycemic management of type 1 and type 2 diabetes. In the hospital, multiple additional risk factors for hypoglycemia are present. Patients with or without diabetes may experience hypoglycemia in the hospital in association with altered nutritional state, heart failure, renal or liver disease, malignancy, infection, or sepsis. Additional triggering events leading to iatrogenic hypoglycemia include sudden reduction of corticosteroid dose, altered ability of the patient to report symptoms, reduction of oral intake, emesis, new NPO status, inappropriate timing of short-or rapid-acting insulin in relation to meals, reduction of rate of administration of intravenous dextrose, and unexpected interruption of enteral feedings or parenteral nutrition. Despite the preventable nature of many inpatient episodes of hypoglycemia, institutions are more likely to have nursing protocols for the treatment of hypoglycemia than for its prevention. Tracking such episodes and analyzing their causes are important quality improvement activities (346). ## Diabetes care providers in the hospital Inpatient diabetes management may be effectively championed and/or provided by primary care physicians, endocrinologists, intensivists, or hospitalists. Involvement of appropriately trained specialists or specialty teams may reduce length of stay, improve glycemic control, and improve outcomes. In the care of diabetes, implementation of standardized order sets for scheduled and correctiondose insulin may reduce reliance on sliding-scale management. As hospitals move to comply with "meaningful use" regulations for electronic health records, as mandated by the Health Information Technology Act, efforts should be made to assure that all components of structured insulin order sets are incorporated into electronic insulin order sets [bib_ref] Effects of a computerized order set on the inpatient management of hyperglycemia:..., Schnipper [/bib_ref] [bib_ref] Effectiveness of a computerized insulin order template in general medical inpatients with..., Wexler [/bib_ref]. A team approach is needed to establish hospital pathways. To achieve glycemic targets associated with improved hospital outcomes, hospitals will need multidisciplinary support to develop insulin management protocols that effectively and safely enable achievement of glycemic targets (366). ## Self-management in the hospital Self-management of diabetes in the hospital may be appropriate for competent adult patients who: have a stable level of consciousness, have reasonably stable daily insulin requirements, successfully conduct self-management of diabetes at home, have physical skills needed to successfully self-administer insulin and perform SMBG, have adequate oral intake, and are proficient in carbohydrate counting, use of multiple daily insulin injections or insulin pump therapy, and sickday management. The patient and physician, in consultation with nursing staff, must agree that patient selfmanagement is appropriate under the conditions of hospitalization. Patients who use CSII pump therapy in the outpatient setting can be candidates for diabetes self-management in the hospital, provided that they have the mental and physical capacity to do so. A hospital policy and procedures delineating inpatient guidelines for CSII pump therapy are advisable. The availability of hospital personnel with expertise in CSII therapy is essential. It is important that nursing personnel document basal rates and bolus doses taken on a regular basis (at least daily). ## Dsme in the hospital Teaching diabetes self-management to patients in hospitals is a challenging task. Patients are ill, under increased stress related to their hospitalization and diagnosis, and in an environment not conducive to learning. Ideally, people with diabetes should be taught at a time and place conducive to learning-as an outpatient in a recognized program of diabetes education. For the hospitalized patient, diabetes "survival skills" education is generally a feasible approach. Patients and/or family members receive sufficient information and training to enable safe care at home. Those newly diagnosed with diabetes or who are new to insulin and/or blood glucose monitoring need to be instructed before discharge. Those patients hospitalized because of a crisis related to diabetes management or poor care at home need education to prevent subsequent episodes of hospitalization. An assessment of the need for a home health referral or referral to an outpatient diabetes education program should be part of discharge planning for all patients. ## Mnt in the hospital The goals of MNT are to optimize glycemic control, to provide adequate calories to meet metabolic demands, and to create a discharge plan for follow-up care [bib_ref] American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and..., Clement [/bib_ref] [bib_ref] McMahon MM. Diabetes nutrition recommendations for health care institutions, Schafer [/bib_ref]. ADA does not endorse any single meal plan or specified percentages of macronutrients, and the term "ADA diet" should no longer be used. Current nutrition recommendations advise individualization based on treatment goals, physiologic parameters, and medication usage. Consistent carbohydrate meal plans are preferred by many hospitals since they facilitate matching the prandial insulin dose to the amount of carbohydrate consumed [bib_ref] Menu selection, glycaemic control and satisfaction with standard and patient-controlled consistent carbohydrate..., Curll [/bib_ref]. Because of the complexity of nutrition issues in the hospital, a registered dietitian, knowledgeable and skilled in MNT, should serve as an inpatient team member. The dietitian is responsible for integrating information about the patient's clinical condition, eating, and lifestyle habits and for establishing treatment goals in order to determine a realistic plan for nutrition therapy (369,370). ## Bedside blood glucose monitoring Point-of-care (POC) blood glucose monitoring performed at the bedside is used to guide insulin dosing. In the patient who is receiving nutrition, the timing of glucose monitoring should match carbohydrate exposure. In the patient who is not receiving nutrition, glucose monitoring is performed every 4 to 6 h (371,372). More frequent blood glucose testing ranging from every 30 min to every 2 h is required for patients on intravenous insulin infusions. Safety standards should be established for blood glucose monitoring, prohibiting sharing of fingerstick lancing devices, lancets, and needles to reduce the risk of transmission of blood borne diseases. Shared lancing devices carry essentially the same risk as shared syringes and needles [bib_ref] Assisted monitoring of blood glucose: special safety needs for a new paradigm..., Klonoff [/bib_ref]. Accuracy of blood glucose measurements using POC meters has limitations that must be considered. Although the FDA allows a Ϯ20% error for blood glucose meters, questions about the appropriateness of these criteria have been raised [bib_ref] Factors driving diabetes care improvement in a large medical group: ten years..., Sperl-Hillen [/bib_ref]. Glucose measures differ significantly between plasma and whole blood, terms that are often used interchangeably and can lead to misinterpretation. Most commercially available capillary blood glucose meters introduce a correction factor of ϳ1.12 to report a "plasma adjusted" value [bib_ref] International Federation of Clinical Chemistry Scientific Division Working Group on Selective Electrodes..., D'orazio [/bib_ref]. Significant discrepancies between capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations, hypoperfusion, and the presence of interfering substances particularly maltose, as contained in immunoglobulins [bib_ref] Glucose measurement: confounding issues in setting targets for inpatient management, Dungan [/bib_ref]. Analytical variability has been described with several POC meters [bib_ref] Quality specifications for glucose meters: assessment by simulation modeling of errors in..., Boyd [/bib_ref]. Increasingly, newer generation POC blood glucose meters correct for variation in hematocrit and for interfering substances. Any glucose result that does not correlate with the patient's status should be confirmed through conventional laboratory sampling of plasma glucose. The FDA has become increasingly concerned about the use of POC blood glucose meters in the hospital and is presently reviewing matters related to their use. ## Discharge planning Transition from the acute care setting is a high-risk time for all patients, not just those with diabetes or new hyperglycemia. Although there is an extensive literature concerning safe transition within and from the hospital, little of it is specific to diabetes [bib_ref] Discharge planning from hospital to home, Shepperd [/bib_ref]. It is important to remember that diabetes discharge planning is not a separate entity, but part of an overall discharge plan. As such, discharge planning begins at admission to the hospital and is updated as projected patient needs change. Inpatients may be discharged to varied settings, including home (with or without visiting nurse services), assisted living, rehabilitation, or skilled nursing facilities. The latter two sites are generally staffed by health professionals; therefore diabetes discharge planning will be limited to communication of medication and diet orders. For the patient who is discharged to assisted living or to home, the optimal program will need to consider the type and severity of diabetes, the effects of the patient's illness on blood glucose levels, and the capacities and desires of the patient. Smooth transition to outpatient care should be ensured. The Agency for Healthcare Research and Quality recommends that at a minimum, discharge plans include: - Medication reconciliation: The patient's medications must be crosschecked to ensure that no chronic medications were stopped and to ensure the safety of new prescriptions. Whenever possible, prescriptions for new or changed medication should be filled and reviewed with the patient and family at or before discharge - Structured discharge communication: Information on medication changes, pending tests and studies, and follow-up needs must be accurately and promptly communicated to outpatient physicians, as soon as possible after discharge. Ideally the inpatient care providers or case managers/discharge planners will schedule follow-up visit(s) with the appropriate professionals, including primary care provider, endocrinologist, and diabetes educator. An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month of discharge is advised for all patients having hyperglycemia in the hospital. Clear communication with outpatient providers either directly or via hospital discharge summaries facilitates safe transitions to outpatient care. Providing information regarding the cause or the plan for determining the cause of hyperglycemia, related complications and comorbidities, and recommended treatments can assist outpatient providers as they assume ongoing care. It is important that patients be provided with appropriate durable medical equipment, medication, supplies, and prescriptions at the time of discharge in order to avoid a potentially dangerous hiatus in care. These supplies/prescriptions should include: ## Standards of medical care in the last 10 years, both in primary care settings and in endocrinology practices. Mean A1C nationally has declined from 7.82% in 1999 -2000 to 7.18% in 2004 based on National Health and Nutrition Examination Survey (NHANES) data [bib_ref] Saaddine JB. Is glycemic control improving in U.S. adults?, Hoerger [/bib_ref]. This has been accompanied by improvements in lipids and blood pressure control and led to substantial reductions in end-stage microvascular complications in those with diabetes [bib_ref] P: the business case for diabetes disease management for managed care organizations...., Beaulieu [/bib_ref]. Nevertheless, in some studies only 57.1% of adults with diagnosed diabetes achieved an A1C of Ͻ7%, only 45.5% had a blood pressure Ͻ130/80 mmHg, and just 46.5% had a total cholesterol Ͻ200 mg/dl, with only 12.2% of people with diabetes achieving all three treatment goals [bib_ref] Diabetes prevalence and therapeutic target achievement in the United States, Cheung [/bib_ref]. Moreover, there is persistent variation in quality of diabetes care across providers and across practice settings even after adjusting for patient factors that indicates the potential for substantial further improvements in diabetes care. While numerous interventions to improve adherence to the recommended standards have been implemented, a major contributor to suboptimal care is a delivery system that too often is fragmented, lacks clinical information capabilities, often duplicates services, and is poorly designed for the delivery of chronic care. The Chronic Care Model (CCM) includes six core elements for the provision of optimal care of patients with chronic disease: 1) delivery system design (moving from a reactive to a proactive care delivery system, where planned visits are coordinated through a team-based approach; 2) self-management support; 3) decision support (basing care on consistent, effective care guidelines); 4) clinical information systems (using registries that can provide patient-specific and populationbased support to the care team); 5) community resources and policies (identifying or developing resources to support healthy lifestyles); and 6) health systems (to create a quality-oriented culture). Alterations in reimbursement that reward the provision of quality care, as defined by the attainment of evidence-based quality measures, will also be required to achieve desired outcome goals. Redefinition of the roles of the clinic staff and promoting selfmanagement on the part of the patient are fundamental to the successful implementation of the CCM [bib_ref] Evidence on the Chronic Care Model in the new millennium, Coleman [/bib_ref]. Collaborative, multidisciplinary teams are best suited to provide such care for people with chronic conditions like diabetes and to facilitate patients' performance of appropriate selfmanagement. A rapidly evolving literature suggests that there are three major strategies to successfully improve the quality of diabetes care delivered by a team of providers. NDEP maintains an online resource (www.betterdiabetescare.nih.gov) to help health care professionals design and implement more effective health care delivery systems for those with diabetes. Three specific objectives, with references to literature that outlines practical strategies to achieve each, are outlined below. ## Objective 1 Provider and team behavior change: Facilitate timely and appropriate intensification of lifestyle and/or pharmaceutical therapy of patients who have not achieved beneficial levels of blood pressure, lipid, or glucose control. - Clinical information systems including registries that can prospectively identify and track those requiring assessments and/or treatment modifications by the team. - Electronic medical record-based clinical decision support at the point of care, both personalize and standardize care and can be used by multiple providers [bib_ref] Electronic medical records and diabetes care improvement: are we waiting for Godot?, O'connor [/bib_ref]. - Use of checklists and/or flow sheets that mirror guidelines. - Detailed treatment algorithms enabling multiple team members to "treat to target" and appropriately intensify therapy. - Availability of care or disease management services (384) by nurses, pharmacists, and other providers using detailed algorithms often catalyzing reduction in A1C, blood pressure, and LDL cholesterol [bib_ref] How our current medical care system fails people with diabetes: lack of..., Davidson [/bib_ref] [bib_ref] A randomized trial of the effect of community pharmacist and nurse care..., Mclean [/bib_ref]. ## Objective 2 Patient behavior change: Implement a systematic approach to support patients' behavior change efforts as needed including 1) healthy lifestyle (physical activity, healthy eating, nonuse of tobacco, weight management, effective coping, medication taking and management); 2) prevention of diabetes complications (screening for eye, foot, and renal complications; immunizations); and 3) achievement of appropriate blood pressure, lipid, and glucose goals. - Delivery of high-quality DSME, which has been shown to improve patient selfmanagement, satisfaction, and glucose control [bib_ref] Assessing the value of diabetes education, Duncan [/bib_ref] [bib_ref] Gain in patients' knowledge of diabetes management targets is associated with better..., Berikai [/bib_ref]. - Delivery of ongoing diabetes selfmanagement support (DSMS) to ensure that gains achieved during DSME are sustained . National DSME standards call for an integrated approach that includes clinical content and skills, behavioral strategies (goalsetting, problem solving), and addressing emotional concerns in each needed curriculum content area. Provision of continuing education and support (DSMS) improves maintenance of gains regardless of the educational methodology (89). - Provision of automated reminders via multiple communication channels to various subgroups of diabetic patients [bib_ref] Interventions to improve the management of diabetes in primary care, outpatient, and..., Renders [/bib_ref]. ## Objective 3 Change the system of care: Research on the comprehensive CCM suggests additional strategies to improve diabetes care, including the following: - Basing care on consistent, evidencebased care guidelines - Redefining and expanding the roles of the clinic staff (382) - Collaborative, multidisciplinary teams to provide high-quality care and support patients' appropriate selfmanagement - Audit and feedback of process and outcome data to providers to encourage population-based care improvement strategies - Care management, one of the most effective diabetes quality improvement strategies to improve glycemic control [bib_ref] Effects of quality improvement strategies for type 2 diabetes on glycemic control:..., Shojania [/bib_ref]. - Identifying and/or developing community resources and public policy that support healthy lifestyles - Alterations in reimbursement that reward the provision of appropriate and high-quality care and accommodate the need to personalize care goals, providing additional incentives to improve diabetes care The most successful practices have an institutional priority for quality of care, expanding the role of teams and staff, redesigning their delivery system, activating and educating their patients, and using electronic health record tools [bib_ref] Different paths to high-quality care: three archetypes of top-performing practice sites, Feifer [/bib_ref] [bib_ref] Improving diabetes care through a multicomponent quality improvement model in a practice-based..., Ornstein [/bib_ref]. Recent initiatives such as the Patient Centered Medical Home show promise in improving outcomes through coordinated primary care and offer new opportunities for team-based chronic disease care [bib_ref] Risk of coronary artery disease in type 2 diabetes and the delivery..., Parchman [/bib_ref]. It is clear that optimal diabetes management requires an organized, systematic approach and involvement of a coordinated team of dedicated health care professionals working in an environment where patient-centered high-quality care is a priority. [fig] •: tion is listed after each recommendation using the letters A, B, C, or E. These standards of care are revised annually by the ADA's multidisciplinary Professional Practice Committee, incorporating new evidence. Members of the Professional Practice Committee and their disclosed conflicts of interest are listed on page S97. Subsequently, as with all Position Statements, the standards of care are reviewed and approved by the Executive Committee of ADA's Board of Directors. [/fig] [table] Table 1 -: ADA evidence grading system for clinical practice recommendations [/table] [table] Table 2 -: Criteria for the diagnosis of diabetes A1C Ն6. [/table] [table] Table 4 -: Criteria for testing for diabetes in asymptomatic adult individuals 1. Testing should be considered in all adults who are overweight (BMI Ն25 kg/m 2 *) and have additional risk factors: • physical inactivity • first-degree relative with diabetes • high-risk race/ethnicity (e.g. [/table] [table] Table 6 -: Screening for and diagnosis of GDM [/table] [table] Table 5 -: Testing for type 2 diabetes in asymptomatic children [/table] [table] Table 7 -: Therapies proven effective in diabetes prevention trials [/table] [table] Table 8 -: Components of the comprehensive diabetes evaluationMedical history• Age and characteristics of onset of diabetes (e.g., DKA, asymptomatic laboratory finding) • Eating patterns, physical activity habits, nutritional status, and weight history; growth and development in children and adolescents • Diabetes education history • Review of previous treatment regimens and response to therapy (A1C records) • Current treatment of diabetes, including medications, meal plan, physical activity patterns, and results of glucose monitoring and patient's use of data • DKA frequency, severity, and cause [/table] [table] Table 10 -: Summary of glycemic recommendations for many nonpregnant adults with diabetes [/table] [table] Table 11 -: Reduction in 10-year risk of major CVD endpoints (CHD death/non-fatal MI) in major statin trials, or substudies of major trials, in diabetic subjects (n ‫؍‬ 16,032) years) and used somewhat different outcomes, but all reported rates of CVD death and nonfatal MI. In this tabulation, results of the statin on 10-year risk of major CVD endpoints (CHD death/nonfatal MI) are listed for comparison between studies. Correlation between 10-year CVD risk of the control group and the absolute risk reduction with statin therapy is highly significant (P ϭ 0.0007). Analyses provided by Craig Williams, PharmD, Oregon Health & Science University, 2007. [/table] [table] Table 12 -: Summary of recommendations for glycemic blood pressure and lipid control for most adults with diabetes [/table] [table] Table 14 -: Stages of CKD [/table] [table] Table 15 -: Management of CKD in diabetes [/table] [table] Table 16 -: Blood glucose goals should be modified in children with frequent hypoglycemia or hypoglycemia unawareness.• Postprandial blood glucose values should be measured when there is a discrepancy between pre-prandial blood glucose values and A1C levels and to help assess glycemia in those on basal/bolus regimens. [/table]	None	https://diabetesjournals.org/care/article-pdf/34/Supplement_1/S11/477902/zdc10111000s11.pdf	I. CLASSIFICATION AND DIAGNOSIS OF DIABETES, p. S12 A. Classification of diabetes B. Diagnosis of diabetes C. Categories of increased risk for diabetes (prediabetes) II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS, p. S13 A. Testing for type 2 diabetes and risk of future diabetes in adults B. Testing for type 2 diabetes in children C. Screening for type 1 diabetes III. DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS, p. S15 IV. PREVENTION/DELAY OF TYPE 2 DIABETES, p. S16 V. DIABETES CARE, p. S16 A. Initial evaluation B. Management C. Glycemic control 1. Assessment of glycemic control a. Glucose monitoring b. A1C 2. Glycemic goals in adults D. Pharmacologic and overall approaches to treatment 1. Therapy for type 1 diabetes 2. Therapy for type 2 diabetes E. Diabetes self-management education F. Medical nutrition therapy G. Physical activity H. Psychosocial assessment and care I. When treatment goals are not met J. Hypoglycemia K. Intercurrent illness L. Bariatric surgery M. Immunization VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS, p. S27 A. Cardiovascular disease 1. Hypertension/blood pressure control 2. Dyslipidemia/lipid management 3. Antiplatelet agents 4. Smoking cessation 5. Coronary heart disease screening and treatment B. Nephropathy screening and treatment C. Retinopathy screening and treatment D. Neuropathy screening and treatment E. Foot care VII. DIABETES CARE IN SPECIFIC POPULATIONS, p. S38 A. Children and adolescents 1. Type 1 diabetes Glycemic control a. Screening and management of chronic complications in children and adolescents with type 1 diabetes i. Nephropathy ii. Hypertension iii. Dyslipidemia iv. Retinopathy v. Celiac disease vi. Hypothyroidism b. Self-management c. School and day care d. Transition from pediatric to adult care 2. Type 2 diabetes 3. Monogenic diabetes syndromes B. Preconception care C. Older adults D. Cystic fibrosis–related diabetes VIII. DIABETES CARE IN SPECIFIC SETTINGS, p. S43 A. Diabetes care in the hospital 1. Glycemic targets in hospitalized patients 2. Anti-hyperglycemic agents in hospitalized patients 3. Preventing hypoglycemia 4. Diabetes care providers in the hospital 5. Self-management in the hospital 6. Diabetes self-management education in the hospital 7. Medical nutrition therapy in the hospital 8. Bedside blood glucose monitoring 9. Discharge planning IX. STRATEGIES FOR IMPROVING DIABETES CARE, p. S46
2edddbe6428c9f589152afecb3c59440545af82d	pubmed	Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines	Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines This article discusses the defi nitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are diffi cult. Variations in treatment and risk factors infl uencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria.Offprint requests to: Y. Kimura # Introduction Acute biliary infection is a systemic infectious disease which requires prompt treatment and has a signifi cant mortality rate. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] The fi rst report on acute biliary infection was Charcot's "The symptoms of hepatic fever" in 1877. [bib_ref] De la fi evre hepatique symptomatique. Comparison avec la fi evre uroseptique, Charcot [/bib_ref] This section of the Tokyo Guidelines defi nes acute cholangitis and acute cholecystitis, and describes the incidence, etiology, pathophysiology, classifi cation, and prognosis of these diseases. ## Acute cholangitis ## Defi nition Acute cholangitis is a morbid condition with acute infl ammation and infection in the bile duct. Historical aspects of terminology Hepatic fever. "Hepatic fever" was a term used for the fi rst time by [bib_ref] De la fi evre hepatique symptomatique. Comparison avec la fi evre uroseptique, Charcot [/bib_ref] in his report published in 1877. Intermittent fever accompanied by chills, right upper quadrant pain, and jaundice became known as Charcot's triad. Acute obstructive cholangitis. Acute obstructive cholangitis was defi ned by Reynolds and Dargan 3 in 1959 as a syndrome consisting of lethargy or mental confusion and shock, as well as fever, jaundice, and abdominal pain, caused by biliary obstruction. They indicated that emergent surgical biliary decompression was the only effective procedure for treating the disease. These fi ve symptoms were then called Reynolds's pentad. Longmire's classifi cation.Longmire classifi ed patients with the three characteristics of intermittent fever accompanied by chills and shivering, right upper quadrant pain, and jaundice as having acute suppurative cholangitis. Patients with lethargy or mental confusion and shock, along with the triad, were classifi ed as having acute obstructive suppurative cholangitis (AOSC). He also reported that the latter corresponded to the morbidity of acute obstructive cholangitis as defi ned by Reynolds and Dargan, [bib_ref] Acute obstructive cholangitis. A distinct syndrome, Reynolds [/bib_ref] and he classifi ed acute microbial cholangitis as follows: 1. Acute cholangitis developing from acute cholecystitis 2. Acute non-suppurative cholangitis 3. Acute suppurative cholangitis 4. Acute obstructive suppurative cholangitis 5. Acute suppurative cholangitis accompanied by hepatic abscess. ## Incidence etiology Acute cholangitis requires the presence of two factors: (1) biliary obstruction and (2) bacterial growth in bile (bile infection). Frequent causes of biliary obstruction are choledocholithiasis, benign biliary stenosis, stricture of a biliary anastomosis, and stenosis caused by malignant disease (level 4). [bib_ref] Acute cholangitis, Lipsett [/bib_ref] [bib_ref] Acute cholangitis: multivariate analysis of risk factors, Gigot [/bib_ref] Choledocholithiasis used to be the most frequent cause of the obstruction, but recently, the incidence of acute cholangitis caused by malignant disease, sclerosing cholangitis, and non-surgical instrumentation of the biliary tract has been increasing. It is reported that malignant disease accounts for about 10%-30% of cases of acute cholangitis. [fig_ref] Table 1: Etiology of acute cholangitis [/fig_ref] show some results of studies on the causes of acute cholangitis. Risk factors. The bile of healthy subjects is generally aseptic. However, bile culture is positive for microorganisms in 16% of patients undergoing a non-biliary operation, in 72% of acute cholangitis patients, in 44% of chronic cholangitis patients, and in 50% of those with biliary obstruction (level 4). [bib_ref] Bacteriological investigation of the biliary system and liver in biliary tract disease..., Edlund [/bib_ref] Bacteria in bile are identifi ed in 90% of patients with choledocholithiasis accompanied by jaundice (level 4). [bib_ref] Hazards of surgical treatment due to microorganisms in the bile, Keighley [/bib_ref] Patients with incomplete [bib_ref] Collective study results on the bacteriological examination during biliary surgery, Daida [/bib_ref] 1979 Questionnaire throughout 472 56% 5% 36% -3% Japan obstruction of the bile duct present a higher positive bile culture rate than those with complete obstruction of the bile duct. Risk factors for bactobilia include various factors, as described above. 14 Post-endoscopic retrograde cholangiopancreatography (ERCP) infectious complications. The incidence of complications after ERCP ranges from 0.8% to 12.1%, though it differs depending on the year of the report and the defi nition of complications (level 4). [bib_ref] Risk factors for complications after performance of ERCP, Vandervoort [/bib_ref] [bib_ref] Complications of endoscopic biliary sphincterotomy, Freeman [/bib_ref] [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] [bib_ref] Endoscopic sphincterotomy complications and their management: an attempt at consensus, Cotton [/bib_ref] [bib_ref] Complications of fi beroptic gastrointestinal endoscopy; 5 years' experience in a central..., Reiertsen [/bib_ref] [bib_ref] Post-ERCP pancreatitis: association with urographic visualization during ERCP, Roszler [/bib_ref] [bib_ref] Early and late complications after endoscopic sphincterotomy for biliary lithiasis with and..., Escourrou [/bib_ref] [bib_ref] Complications of endoscopic retrograde cholangiopancreatography (ERCP). A study of 10 000 cases, Bilbao [/bib_ref] Overall post-ERCP mortality is reported to be between 0.5% and 1.5% (level 4). [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] The most frequent complication is acute pancreatitis, but it is usually mild or moderate. [fig_ref] Table 3: Reports of complications caused by ERCP [/fig_ref] shows the reported incidence of various post-ERCP complications. The incidences of post-ERCP acute cholangitis and cholecystitis are, as shown in [fig_ref] Table 3: Reports of complications caused by ERCP [/fig_ref] , 0.5%-1.7% and 0.2%-0.5%, respectively. [bib_ref] Risk factors for complications after performance of ERCP, Vandervoort [/bib_ref] [bib_ref] Complications of endoscopic biliary sphincterotomy, Freeman [/bib_ref] [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit, Benchimol [/bib_ref] [bib_ref] Endoscopic sphincterotomy complications and their management: an attempt at consensus, Cotton [/bib_ref] The complications caused by ERCP performed for diagnostic and for therapeutic purposes are different. Therapeutic ERCP tends to cause all complications, including cholangitis, more frequently than diagnostic ERCP. [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] [bib_ref] Complications of fi beroptic gastrointestinal endoscopy; 5 years' experience in a central..., Reiertsen [/bib_ref] The increasing use of ERCP and the improved operators' skills and techniques in recent years have reduced the incidence of post-ERCP complications, although the incidence of acute cholecystitis has not dropped and seems unpredictable. [bib_ref] Catheteisme retrograde et sphincterotomie endoscopique. Evaluation prospective en milieu chirurgical, Lenriot [/bib_ref] Other etiologies of acute cholangitis. There are two other etiologies of acute cholangitis; Mirizzi syndrome and lemmel syndrome. Mirizzi syndrome is a morbid condition with stenosis of the common bile duct caused by mechanical pressure and/or infl ammatory changes caused by the presence of stones in the gallbladder neck and cystic ducts. [bib_ref] The Mirizzi syndrome: suggested classifi cation and surgical therapy, Mcsherry [/bib_ref] Two types have been described: type I, which is a morbid condition with the bile duct compressed from the left by the presence of stones in the gallbladder neck and cystic ducts and pericholecystic infl ammatory changes; and type II, which is a morbid condition with biliobilary fi stulation caused by pressure necrosis of the bile duct due to cholecystolithiasis. Lemmel syndrome is a series of morbid conditions in which the duodenal parapapillary diverticulum compresses or displaces the opening of the bile duct or pancreatic duct and obstructs the passage of bile in the bile duct or hepatic duct, thereby causing cholestasis, jaundice, gallstone, cholangitis, and pancreatitis. [bib_ref] Die kliniscle Bedeutung der Duodenal Divertikel, Lemmel [/bib_ref] ## Pathophysiology The onset of acute cholangitis involves two factors: (i) increased bacteria in the bile duct, and (ii) elevated intraductal pressure in the bile duct that allows translocation of bacteria or endotoxins into the vascular system (cholangio-venous refl ux). Because of its anatomical characteristics, the biliary system is likely to be affected by elevated intraductal pressure. In acute cholangitis, with the elevated intraductal biliary pressure, the bile ductules tend to become more permeable to the translocation of bacteria and toxins. This process results in serious infections that can be fatal, such as hepatic abscess and sepsis. ## Prognosis Patients who show early signs of multiple organ failure (renal failure, disseminated intravascular coagulation , alterations in the level of consciousness, and shock) as well as evidence of acute cholangitis (fever accompanied by chills and shivering, jaundice, and abdominal pain), and who do not respond to conservative treatment, should receive systemic antibiotics and undergo emergent biliary drainage. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] We have to keep in mind that unless early and appropriate biliary drainage is performed and systemic antibiotics are administered, death will occur. The reported mortality of acute cholangitis varies from 2.5% to 65% [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Clinical characteristics of impacted bile duct stone in eldely, Arima [/bib_ref] [bib_ref] Clinical evaluation of acute cholangitis -with speciaal reference to detection of prognostic..., Kunisaki [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] An analysis of infectious failures in acute cholangitis, Thompson [/bib_ref] [fig_ref] Table 4: Mortality of acute cholangitis [/fig_ref]. The mortality rate before 1980 was 50%, [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] and after 1980 it was 10%-30%. [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Clinical characteristics of impacted bile duct stone in eldely, Arima [/bib_ref] [bib_ref] Clinical evaluation of acute cholangitis -with speciaal reference to detection of prognostic..., Kunisaki [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] An analysis of infectious failures in acute cholangitis, Thompson [/bib_ref] Such differences in mortality are probably attributable to differences in early diagnosis and improved supportive treatment. The major cause of death in acute cholangitis is multiple organ failure with irreversible shock, and mortality rates have not signifi cantly improved over the years. [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency. A review of 10..., Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Ascending cholangitis: surgery versus endoscopic or percutaneous drainage, Himal [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high risk patients, Lai [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] Causes of death in patients who survive the acute stage of cholangitis include multiple organ failure, heart failure, and pneumonia. 34 ## Acute cholecystitis ## Defi nition Acute cholecystitis is an acute infl ammatory disease of the gallbladder. It is often attributable to gallstones, but many factors, such as ischemia; motility disorders; direct chemical injury; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reaction are involved. ## Incidence Acute cholecystitis cases account for 3%-10% of all patients with abdominal pain. [bib_ref] Diagnostic approaches in acute cholecystitis; a prospective study of 1333 patients with..., Eskelinen [/bib_ref] [bib_ref] Abdominal pain. An analysis of 1000 consecutive cases in a University Hospital..., Brewer [/bib_ref] [bib_ref] Acute abdominal pain in patients over 50 years of age, Telfer [/bib_ref] The percentage of acute cholecystitis cases in patients under 50 years old with abdominal pain (n = 6317) was low, at 6.3%, whereas that in patients aged 50 and over (n = 2406) was high, at 20.9% (average, 10%) [bib_ref] Acute abdominal pain in patients over 50 years of age, Telfer [/bib_ref] [fig_ref] Table 5: Acute cholecystitis in patients with abdominal pain Risk factors [/fig_ref]. ## Etiology Cholecystolithiasis accounts for 90%-95% of all causes of acute cholecystitis, while acalculous cholecystitis accounts for the remaining 5%-10% (level 4). [bib_ref] Acute calculous cholecystitis. What is new in diagnosis and therapy?, Gouma [/bib_ref] [bib_ref] Role of surgery in the management of gallstones, Mack [/bib_ref] [bib_ref] Surgery for acute and chronic cholecystitis, Hermann [/bib_ref] [bib_ref] Acute cholecystitis, Sharp [/bib_ref] [bib_ref] Acalculous disease of the gall bladder, Williamson [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Barie [/bib_ref] [bib_ref] State of the art in the diagnosis and management of acute cholecystitis, Reiss [/bib_ref] jaundice, and pancreatitis) were observed in 1%-2% of asymptomatic patients and in 1%-3% of patients with mild symptoms per year [fig_ref] Table 6: Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients [/fig_ref] , and the risk of complications increased in the fi rst several years after the discovery of gallbladder stones, but then decreased (level 2c). Every year, 6%-8% of patients whose symptoms progress from minor to serious undergo cholecystectomy, but this percentage decreases year by year. [bib_ref] Natural history of asymptomatic and symptomatic gallstones, Friedman [/bib_ref] In a follow-up of cholelithiasis patients with mild or nonspecifi c symptoms (n = 153), acute gallstone complication was observed in 15% (n = 23) and acute cholecystitis was seen in 12% (n = 18) (level 4). [bib_ref] Expectant management of patients with gallbladder stones diagnosed at planned investigation. A..., Persson [/bib_ref] According to another report, on the follow-up of the patients with asymptomatic cholelithiasis (n = 600), 16% (96) of them presented with some symptoms (average period of observation until the manifestation of symptom, 29.8 months) during the follow-up period, while 3.8% (23 patients) presented with acute cholecystitis. The rate of change from asymptomatic to symptomatic cholelithiasis is highest during the fi rst 3 years after diagnosis (15%-26%), but then declines (level 4). However, there is a report suggesting that there is no difference in the incidence of common symptoms such as heartburn and upper abdominal pain, in cholelithiasis patients between those patients with asymptomatic cholelithiasis and controls without gallstones (level 2b). [bib_ref] Correlation between gallstones and abdominal symptoms in a random population, Glambek [/bib_ref] AIDS as a risk factor. Enlarged liver and/or abnormal liver functions are observed in two/thirds of AIDS patients, some of whom have biliary tract disease. Biliary disease may occur by two mechanisms in AIDS patients: via AIDS cholangiopathy (which is more fre-quent) and via acute acalculous cholecystitis; AIDS patients with sclerosing cholangitis are also seen. AIDS cholangiopathy is often observed in middleaged male patients who have had AIDS for more than 1 year (average disease period, 15 ± 2.2 months; average age, 37 years [range, 21 to 59 years]). Ninety percent of the patients complain of upper abdominal pain and have enlarged intra-and extrahepatic bile ducts on abdominal ultrasonography. Abnormal fi ndings on abdominal ultrasonography and computed tomography are seen in 81% and 78% of patients, respectively. Biochemical tests show a marked increase in the level of alkaline phosphatase (level 4). [bib_ref] AIDS-Related biliary tract disease, Cello [/bib_ref] Acalculous cholecystitis in AIDS patients is characterized by: (1) younger age than in non-AIDS patients, (2) problems with oral ingestion (3), right upper abdominal pain, (4) a marked increase in alkaline phosphatase and a mild increase in serum bilirubin level, and (5) association with cytomegalovirus and cryptosporidium infections (level 4). [bib_ref] AIDS-Related biliary tract disease, Cello [/bib_ref] According to a review of abdominal surgery for AIDS patients, acute cholecystitis is the most frequent reason for performing open surgery in AIDS patients. [bib_ref] The incidence of intra-abdominal surgery in acquired immunodefi ciency syndrome: a statistical..., Laraja [/bib_ref] Drugs as etiologic agents. According to the review by Michielsen et al., [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] regarding the association between drugs and acute cholecystitis, 90%-95% of acute cholecystitis cases are caused by cholelithiasis, and drugs promoting the formation of stones are indirectly associated with a risk of acute cholecystitis (level 4). The etiological mechanism of drug-associated gallbladder diseases, as discussed in the review, 53 is shown in [fig_ref] Table 7: Etiological mechanisms of gallbladder diseases [/fig_ref]. It is reported that women taking oral conceptives have a higher risk of having gallbladder disease, but there also is a report which denies the association between the disease and these drugs (level 2a).Among various drugs used for the treatment of hyperlipidemia, only fi brate is shown to be associated with gallstone diseases (level 2b). [bib_ref] Clofi brate and gallstones, Cooper [/bib_ref] One report suggests that thiazides induce acute cholecystitis (level 3b), [bib_ref] Thiazides and acute cholecystitis, Rosenberg [/bib_ref] and another report denies this association (level 3b). [bib_ref] Acute cholecystitis and thiazides, Porter [/bib_ref] The administration of a large dose of ceftriaxone, a third-generation cephalosporin antimicrobial, in infants, precipitates calcium salt in bile and forms a sludge in 25%-45% of them, but these effects disappear when the medication is discontinued (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] It is reported that the longterm administration of octreotide causes cholestasis, and that administration for a year causes cholelithiasis in 50% of patients (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] Hepatic artery infusion will cause chemical cholecystitis (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] Erythromycin and ampicillin are reported to be a cause of hypersensitive cholecystitis (level 4). [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref] According to a meta-analysis of the risk of disease induced by hormone replacement therapy, the relative risks (RRs) of cholecystitis were 1.8 (95% confi dence interval [CI], 1.6-2.0) and 2.5 (95% CI, 2.0-2.9) at less than 5 years of treatment and at 5 and more years, respectively (level 1a). [bib_ref] Postmenopausal hormone replacement therapy: scientifi c review, Nelson [/bib_ref] Ascaris as an etiologic factor. The complications of ascariasis include hepatic, biliary, and pancreatic diseases. Complications in the biliary tract include: (1) cholelithiasis with the ascarid as a nidus for stone formation, (2) acalculous cholecystitis (3), acute cholangitis (4), acute pancreatitis, and (5) hepatic abscess.Biliary tract disease is caused by the obstruction of the hepatic and biliary tracts by the entry of ascarids from the duodenum through the papilla. Ascarids entering the biliary tract usually return to the duodenum in a week, but if they stay over 10 days there, they will die and form a nidus for stone formation. Ascarid-associated biliary diseases occur more frequently in women (male/female ratio, 1 : 3) and less frequently in infants. The risk of biliary complications is higher in pregnant than in non-pregnant women (level 4).In epidemic regions such as China and Southeast Asia, ascariasis is a frequent cause of cholelithiasis.Role of pregnancy. The risk of cholelithiasis in women begins to increase when adolescence begins and it declines when the menopause begins. It is also said that the use of oral conceptives is correlated with a risk of gallbladder disease. It is considered, therefore, that levels of estrogen and progesterone are involved in the formation of gallstones. [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Cholecystitis is the second most common cause of acute abdomen, following appendicitis, in pregnant women, and occurs in one of 1600 to 10 000 pregnant women (level 4). [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Cholelithiasis is the most frequent cause of cholecystitis in pregnancy and accounts for 90% or more of all causes of cholecystitis (level 4). [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] Routine ultrasonography found cholelithiasis in 3.5% of pregnant women (level 4), [bib_ref] The acute abdomen during pregnancy, Sharp [/bib_ref] but it is unknown whether pregnancy increases the risk of cholecystitis. The frequency of cholecystectomy in pregnant women is lower than that in non-pregnant women. This is not because of the lower incidence of cholecystectomy in pregnant women, but because physicians tend to refrain from performing any operation during pregnancy. Though there are few reports of patients undergoing cholecystectomy during pregnancy, there is no evidence that laparoscopic surgery increases the maternal or fetal risks (level 2c). [bib_ref] Outcome study of cholecystectomy during pregnancy, Barone [/bib_ref] Acute cholecystitis and four (or fi ve) "Fs". It has been said that the patients with cholelithiasis have factors such as "4F" and "5F" (fair, fat, female, fertile, and Antimicrobial drugs (erythromycin, ampicillin) Immunotherapy forty). Common to all individuals with these "4/5Fs" are high levels of estrogen and progesterone. According to the Framingham Study, which examined the risk factors for cholelithiasis in a 10-year follow-up study of 30-to 59-year-old subjects, the risk of cholelithiasis within 10 years was highest among the 55-to 62-year-old age group, and most of the patients were diagnosed with cholelithiasis in their fi fties and sixties. Although the incidence of cholelithiasis in female patients of all age groups is more than double that of male patients, the difference between the incidence in men and women tends to shrink with increasing age (level 1b). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] Cholelithiasis is one of the main diseases associated with obesity. The Framingham study also confi rms that cholelithiasis patients tend to be more obese than noncholelithiasis patients (level 2a). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] However, there is a report that this tendency is much more prominent in female than in male patients. [bib_ref] Age profi les of benign gallbladder disease in 2000 patients, Gutman [/bib_ref] Not only obesity but also dieting is associated with the risk of cholelithiasis. Drastic dieting increases the risk of cholelithiasis in obese people (level 2b). [bib_ref] Gallstones in obesity and weight loss, Erlinger [/bib_ref] [bib_ref] Gallstone formation during weight-reduction dieting, Liddle [/bib_ref] [bib_ref] Contributions of obesity and weight loss to gallstone disease, Everhart [/bib_ref] [bib_ref] Current status of medical and surgical therapy for obesity, Mun [/bib_ref] The incidences of both cholelithiasis and cholecystitis in obese people (age, 37-60 years; women with a body mass index [BMI] of 34 or higher and men with a BMI of 38 or more) are signifi cantly higher that those in non-obese people (cholelithiasis, 5.8% vs 1.5%; Odds ratio [OR], 4.9; women 6.4% vs 22.6%; OR, 4.7; cholecystitis, 0.8% vs 3.4%; OR, 5.2; women 4.0% vs 11.2%; OR, 3.4) (level 2b). [bib_ref] Gallstones, gallbladder disease, and pancreatitis: cross-sectional and 2-year data from the Swedish..., Torgerson [/bib_ref] The Framingham Study indicates that the number of pregnancies in those patients who had cholelithiasis at entry into a cohort or those in whom the symptoms of cholelithiasis appeared within 10 years, was signifi cantly higher than the number of pregnancies in subjects not fulfi lling these criteria (level 2b). [bib_ref] The epidemiology of gallbladder disease: observations in the Framingham Study, Friedman [/bib_ref] Though the association of "4F" and "5F" with cholelithiasis has been relatively closely examined, no study has examined the association of factors other than obesity and age with the risk of onset of acute cholecystitis. ## Pathophysiology In the majority of patients, gallstones are the cause of acute cholecystitis. The process is one of physical obstruction of the gallbladder by a gallstone, at the neck or in the cystic duct. This obstruction results in increased pressure in the gallbladder. There are two factors which determine the progression to acute cholecystitis -the degree of obstruction and the duration of the obstruction. If the obstruction is partial and of short duration the patient experiences biliary colic. If the obstruction is complete and of long duration the patient develops acute cholecystitis. If the patient does not receive early treatment, the disease becomes more serious and complications occur. Pathological classifi cation Edematous cholecystitis: fi rst stage . The gallbladder has interstitial fl uid with dilated capillaries and lymphatics. The gallbladder wall is edematous. The gallbladder tissue is intact histologically, with edema in the subserosal layer. Necrotizing cholecystitis: second stage . The gallbladder has edematous changes with areas of hemorrhage and necrosis. When the gallbladder wall is subjected to elevated internal pressure, the blood fl ow is obstructed, with histological evidence of vascular thrombosis and occlusion. There are areas of scattered necrosis, but it is superfi cial and does not involve the full thickness of the gallbladder wall. Suppurative cholecystitis: third stage (7-10 days). The gallbladder wall has white blood cells present, with areas of necrosis and suppuration. In this stage, the active repair process of infl ammation is evident. The enlarged gallbladder begins to contract and the wall is thickened due to fi brous proliferation. Intrawall abscesses are present and involve the entire thickness of the wall. Pericholecystic abscesses are present. Chronic cholecystitis. Chronic cholecystitis occurs after the repeated occurrence of mild attacks of cholecystitis, and is characterized by mucosal atrophy and fi brosis of the gallbladder wall. It can also be caused by chronic irritation by large gallstones and may often induce acute cholecystitis. Specifi c forms of acute cholecystitis. There are four specifi c forms of acute cholecystitis: (1) acalculous cholecystitis, which is acute cholecystitis without cholecystolithiasis; (2) xanthogranulomatous cholecystitis, which is characterized by the xanthogranulomatous thickening of the gallbladder wall and elevated intra-gallbladder pressure due to stones, with rupture of the the Rokitansky-Achoff sinuses. This rupture causes leakage and bile entry into the gallbladder wall. The bile is ingested by histocytes, forming granulomas consisting of foamy histocytes. Patients usually have symptoms of acute cholecystitis in the initial stage. (3) emphysematous cholecystitis, in which air appears in the gallbladder wall due to infection with gas-forming anaerobes, including Clostridium perfringens. This form is likely to progress to sepsis and gangrenous cholecystitis; it is often seen in diabetic patients. (4) Torsion of the gallbladder. [bib_ref] Congenital anomalies of the gallbladder, Gross [/bib_ref] Torsion of the gallbladder is known to occur by inherent, acquired, and other physical causes. An inherent factor is a fl oating gallbladder, which is very mobile because the gallbladder and cystic ducts are connected with the liver by a fused ligament. Acquired factors in-clude splanchnoptosis, senile humpback, scoliosis, and weight loss. Physical factors causing torsion of the gallbladder include sudden changes of intraperitoneal pressure, sudden changes of body position, a pendulum-like movement in the antefl exion position, hyperperistalsis of organs near the gallbladder, defecation, and trauma to the abdomen. ## Incidence of complications with advanced forms of acute cholecystitis The incidence of complications with advanced forms of acute cholecystitis ranges widely, from 7.2% to 26%, in reports published since 1990. [bib_ref] Gangrenous cholecystitis in the laparoscopic era, Hunt [/bib_ref] [bib_ref] Gangrenous cholecystitis: analysis of risk factors and experience with laparoscopic cholecystectomy, Merriam [/bib_ref] [bib_ref] Gangrenous cholecystitis in an urban VA hospital, Wilson [/bib_ref] [bib_ref] Factors effecting the complications in the natural history of acute cholecystitis, Bedirli [/bib_ref] [bib_ref] Surgical risks of acute cholecystitis in elderly, Tokunaga [/bib_ref] In patients with acute cholecystitis (n = 368), the incidence of morbidity was 17%, with the incidences of gangrenous, suppurative, perforating, and emphysematous cholecystitis being 7.1%, 6.3%, 3.3%, and 0.5%, respectively. 74 ## Types of complications. There are four types of complications. (1) Perforation of the gallbladder, which is caused by acute cholecystitis, injury, or tumors, and occurs most often as a result of ischemia and necrosis of the gallbladder wall. (2) Biliary peritonitis, which occurs with the entry into the peritoneal cavity of bile leaked due to various causes, including cholecystitis-induced gallbladder perforation, trauma, a catheter detached during biliary drainage, and incomplete suture after biliary operation. (3) Pericholecystic abscess, a morbid condition in which a perforation of the gallbladder wall is covered by the surrounding tissue, with the formation of an abscess around the gallbladder. (4) Biliary fi stula, which can occur between the gallbladder and the duodenum following an episode of acute cholecystitis. The fi stula is usually caused by a large gallbladder stone eroding through the wall of the gallbladder into the duodenum. If the stone is large, the patient can develop gallstone ileus, with the stone causing mechanical smallbowel obstruction at the ileocecal valve. ## Prognosis The mortality in patients with acute cholecystitis is 0-10% [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] [bib_ref] Personal experiences with 1261 cases of acute and chronic cholecystitis and cholelithiasis, Meyer [/bib_ref] [bib_ref] Acute cholecystitis, Gagic [/bib_ref] [bib_ref] Open cholecystectomy: its morbidity and mortality as a reference standard, Girard [/bib_ref] [bib_ref] Urgent and early cholecystectomy for acute gallbladder disease, Addison [/bib_ref] [bib_ref] Factors effecting the complications in the natural history of acute cholecystitis, Bedirli [/bib_ref] [bib_ref] Effects of timing of surgery, type of infl ammation, and sex on..., Gharaibeh [/bib_ref] [fig_ref] Table 8: Mortality of acute cholecystitis cholecystitis when cholecystectomy is not performed for some... [/fig_ref] , whereas the mortality in patients with postoperative cholecystitis and acalculous cholecystitis is as high as 23%-40%. [bib_ref] Acute acalculous cholecystitis: incidence, risk factors, diagnosis, and outcome, Kalliafas [/bib_ref] [bib_ref] Postoperative acute cholecystitis: a collective review of 494 cases in Japan, Inoue [/bib_ref] [bib_ref] The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year..., Savoca [/bib_ref] The mortality of elderly patients (75 years and older) tends to be higher than that of younger patients, [bib_ref] The management of acute cholecystitis in elderly patients, Hafi F [/bib_ref] [bib_ref] Surgical management of acute cholecystitis in patients 65 years of age and..., Glenn [/bib_ref] and a comorbidity such as diabetes may increase the risk of death. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] Many reports of the mortality and morbidity of acute cholecystitis are diffi cult to compare, because there are signifi cant variations in the diagnostic criteria, timing and type of operation, presence of comor bidities, and hospital support systems for critically ill patients, as well as variations in available surgical expertise. According to reports published in 1980 and before, most of the causes of death after cholecystectomy were related to postoperative infections, such as ascending cholangitis, hepatic abscess, and sepsis. [bib_ref] Personal experiences with 1261 cases of acute and chronic cholecystitis and cholelithiasis, Meyer [/bib_ref] [bib_ref] Acute cholecystitis, Gagic [/bib_ref] Since 1980, postoperative mortality from infection has decreased and the major causes of death include myocardial infarction, cardiac failure, and pulmonary infarction. [bib_ref] Open cholecystectomy: its morbidity and mortality as a reference standard, Girard [/bib_ref] [bib_ref] Urgent and early cholecystectomy for acute gallbladder disease, Addison [/bib_ref] Cholecystostomy was a common form of treatment in 1970 and before, and the most common cause of death during that period was pneumonia and sepsis. [bib_ref] Cholecystectomy in acute cholecystitis. Factors infl uencing morbidity and mortality, Gingrich [/bib_ref] Currently, the major causes of death following cholecystostomy include malignant tumor, respiratory failure, and cardiac failure. [bib_ref] Complication and late outcome following percutaneous drainage of the gallbladder in acute..., Andren-Sandberg [/bib_ref] [bib_ref] Ultrasoundguided percutaneous cholecystectomy in high-risk surgical patients, Granlund [/bib_ref] Recurrence rate of acute cholecystitis after conservative treatment Most patients with acute cholecystitis are treated with a cholecystectomy, and it is diffi cult to anticipate whether the outcome will show recurrence. Recurrences of clinical concern include the recurrence of (1) acute cholecystitis after spontaneous recovery without the undergoing of any treatment; (2) acute cholecystitis while waiting for cholecystectomy after conservative treatment with diet modifi cation and antibiotics; (3) acute There are no data on the recurrence of acute cholecystitis after resolution of the initial symptoms. The recurrence of acute cholecystitis while patients are waiting for cholecystectomy following conservative treatment ranges from 2.5% to 22%. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] [bib_ref] Acute cholecystitis treated by early and delayed surgery. A controlled clinical trial, Lahtinen [/bib_ref] In 311 patients with acute calculous cholecystitis , 25 of 39 patients who did not have a cholecystectomy during the acute stage were scheduled to undergo delayed operation after being discharged from hospital. Only 1 of the 25 patients (2.5%) developed recurrent acute cholecystitis while waiting for an operation. [bib_ref] Outcome of acute cholecystitis in patients with diabetes mellitus, Ransohoff [/bib_ref] In non-severe cases, acute cholecystitis recurred in 2% of patients within an 8-to 10-week waiting period, 6% of whom showed gallbladder perforation. [bib_ref] Acute cholecystitis treated by early and delayed surgery. A controlled clinical trial, Lahtinen [/bib_ref] Long-term recurrence is reported to be 10%-50% in 6 months to several years of observation, though there are few reports. According to a randomized controlled trial comparing non-operative treatment and cholecystectomy for patients with acute cholecystitis, excluding those with severe cases (n = 56), 11% had a history of acute cholecystitis, and 8 (24%) of 33 patients assigned to non-operative treatment underwent cholecystectomy during an observation period of 1.5-4 years. [bib_ref] Randomization to surgery or observation in patients with symptomatic gallbladder stone disease...., Sondenaa [/bib_ref] In patients with acute cholecystitis who were observed after treatment with percutaneous drainage, acute cholecystitis recurred once or more in 28 of 60 patients (47%) during an average observation period of 18 months, [bib_ref] Complication and late outcome following percutaneous drainage of the gallbladder in acute..., Andren-Sandberg [/bib_ref] and it recurred once or more in 11 of 36 (31%) patients who were observed for 37 months on average. [bib_ref] Ultrasoundguided percutaneous cholecystectomy in high-risk surgical patients, Granlund [/bib_ref] In a report of 114 patients who underwent only cholecystostomy, among 585 patients who were hospitalized because of acute cholecystitis, acute cholecystitis recurred in 5 of 23 patients observed for 6 months to 14 years and 14 of the 23 patients remained asymptomatic. [bib_ref] Radiologically guided percutaneous cholecystectomy for acute cholecystitis: long-term outcome in 50 patients, Mcloughlin [/bib_ref] [table] Table 1: Etiology of acute cholangitis [/table] [table] Table 3: Reports of complications caused by ERCP [/table] [table] Table 4: Mortality of acute cholangitis [/table] [table] Table 5: Acute cholecystitis in patients with abdominal pain Risk factors. Acute cholecystitis is the most frequent complication occurring in patients with cholelithiasis. According to the Comprehensive Survey of Living Conditions of the People on Health and Welfare conducted by the Medical Statistics Bureau of the Japanese Ministry of Health and Welfare, the number of those with acute cholecystitis has increased, from 3.9 million in 1979 to over 10 million in 1993 (Public Welfare Index in Japan; 1933; level 4). According to the review by Friedman, 48 of the natural history of cholelithiasis, serious symptoms or complications (acute cholecystitis, acute cholangitis, clinical [/table] [table] Table 6: Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients [/table] [table] Table 7: Etiological mechanisms of gallbladder diseases [/table] [table] Table 8: Mortality of acute cholecystitis cholecystitis when cholecystectomy is not performed for some reason, such as surgical risk or the patient's decision (with or without biliary drainage); and (4) cholangitis after cholecystectomy. [/table] [bib_ref] Drug-induced gallbladder disease. Incidence, aetiology and management, Michielsen [/bib_ref]	None	https://link.springer.com/content/pdf/10.1007%2Fs00534-006-1152-y.pdf	None
1fa9210cd5679198a38bc51ba8c0e00761fa343d	pubmed	Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop	Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop Background: Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists.Methods: A geographically diverse panel of experts was convened for the purpose of deriving an evidenceinformed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm.Results: A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy. Conclusions: Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes. # Background Envenomation by pit vipers (family Viperidae, subfamily Crotalinae, genera Crotalus, Agkistrodon, and Sistrurus) is a dynamic and potentially serious medical condition. Approximately 9,000 patients are treated for snakebite and 5 die in the United States (US) each year [bib_ref] Animal-related fatalities in the United States -an update, Langley [/bib_ref]. The use of antivenom is increasing over time. Forty-four percent of patients whose cases were reported to US poison centers in 2007 were treated with antivenom, a significant increase from 30% in 2000 [bib_ref] Use of antivenom for snakebites reported to United States poison centers, Spiller [/bib_ref]. The proportion of patients receiving antivenom varies more than 5-fold between states. Poison center data suggest a case-fatality rate among rattlesnake victims of approximately 1 death per 736 patients [bib_ref] Epidemiology of severe and fatal rattlesnake bites published in the American Association..., Walter [/bib_ref]. The clinical manifestations of crotaline envenomation vary considerably based on a complex interplay between the victim and the venom exposure. Some critical manifestations, such as airway involvement and anaphylaxis to venom, are so uncommon that few clinicians gain experience managing these findings. To our knowledge, all extant treatment algorithms were created by a single author or by a small group of authors with similar experience [bib_ref] Crotalidae polyvalent immune Fab for the treatment of pediatric crotaline envenomation, Goto [/bib_ref] [bib_ref] Pediatric snakebites: lessons learned from 114 cases, Campbell [/bib_ref] [bib_ref] Bites of venomous snakes, Gold [/bib_ref]. Many algorithms are specific for the treatment of subpopulations of crotaline victims, such as children or those envenomated in regions where copperhead snakes predominate. Few authors describe their methods for algorithm development, and many algorithms do not fully describe post-stabilization care. Significant variations in practice exist; two studies demonstrate that the proportion of snakebite victims who undergo fasciotomy is five times greater in an institution where snakebite victims are managed primarily by surgeons, compared to an institution where snakebite victims are admitted and managed primarily by medical toxicologists [bib_ref] A large single-center experience with treatment of patients with crotalid envenomations: outcomes..., Corneille [/bib_ref] [bib_ref] Epidemiology and hospital course of rattlesnake envenomations cared for at a tertiary..., Tanen [/bib_ref]. Antivenom is expensive (current wholesale cost greatly exceeds US$1,000/vial) and associated with immunologic risk, and it is imperative for the physician to use this resource wisely. The objective of this project was to produce an evidence-informed unified treatment algorithm for pit viper snakebite management in the US, with the goal of reducing unnecessary variations in practice and improving outcomes for snake envenomation victims. # Methods Because only one randomized clinical trial involving the treatment of crotaline snakebite with antivenom has ever been published, a formal meta-analysis could not be used for rule development [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. A standardized evidence-based rule development process, such as that proposed by the GRADE working group, cannot be used to develop an algorithm because the clinical questions cannot be defined in advance. Therefore, using a trained external facilitator, we used structured methods to achieve an evidence-informed consensus among a diverse group of experts. Two authors (EJL, RCD) recruited panel members based on their published envenomations research and clinical experience. In order to ensure a diversity of experience, panel members were chosen from across the regions of the US where crotaline envenomations are common, with no more than one panel member chosen from the same geographic area. A group size of nine experts was chosen to permit the required diversity of experience while keeping the consensus-building process manageable. One of the original panel members (SCC) had to withdraw from the process; he was replaced on the panel by a colleague from the same institution, but remained involved in the project as a non-voting participant and contributor. The nine panel members have extensive clinical experience managing crotaline snakebite in a variety of clinical settings , and have published 57 peer-reviewed articles on the subject. One additional author (EJL) participated in the panel meeting but did not vote. The consensus process was managed by a professional facilitator (David Kovick, JD, Consensus Building Institute, Cambridge, MA). Competing interests of all participants were disclosed prior to decision-making. One author (EJL) created an initial "straw man" draft algorithm, which was distributed to all panelists. The draft algorithm identified key decision points in the treatment process, posed questions about best treatment practices, and served as a starting point for discussion. Initial modifications to the "straw man" were processed using a modified Delphi methodology, through which panelists provided substantive feedback through the facilitator. The revised algorithm was presented to the panel in a 90-minute webinar, where facilitated discussion was used to identify initial areas of consensus and prioritize issues requiring further discussion. A second round of modified Delphi revisions was then completed. Final algorithm development took place during a 1.5-day inperson meeting held in Denver, Colorado, in May, 2010, which was governed by a structured consensus-building process. In resolving points of divergence among panel members, the panel relied upon published data (where available), supported by the collective experience of panel members. Consensus was defined as unanimous agreement of all panel members. After minor text revisions, the final algorithm was sent to panelists electronically for a conclusive vote. In order to provide the panel members with a complete literature base, research staff performed a structured literature search to identify articles relevant to the treatment of crotaline snakebite in the United States, using the search strategy in [fig_ref] Table 2: Search Strategy [/fig_ref]. Two researchers reviewed the titles and abstracts of all articles to identify those which might contain original data about (a) the management of crotaline snakebite with the current (ovine Fab) antivenom or (b) the management of crotaline snakebite without antivenom. In the event of disagreement, the article was pulled and reviewed. Full text copies of the 42 articles containing original data relevant to the key questions identified in preliminary panel deliberations were obtained and provided for panel members' use during deliberations. Recurrence of one or more venom effects (local pain and swelling and/or hematologic abnormalities such as coagulopathy and thrombocytopenia) following successful initial treatment with antivenom is a known problem in the management of venomous snakebite. Early issue identification revealed that prevention and treatment of these recurrence phenomena was a topic with some disagreement. Four data sources were utilized to inform the panel discussion of this issue. Statisticians reanalyzed raw data from databases created in the premarketing studies of the current antivenom to extract specific information about recurrence phenomena [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref] [bib_ref] Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid..., Dart [/bib_ref]. The same statistical team reanalyzed raw data from databases created in a phase IV post-marketing study of Fab antivenom to extract specific information about recurrence phenomena. The research team reviewed the results of the literature search to identify and summarize all articles containing data about recurrence phenomena. These three data sources were prepared into resource documents for the panel members. During the in-person meeting, two authors provided formal presentations. One panelist (AMR) analyzed and presented case-level data about recurrence phenomena observed at her center, while a second participant (EJL) presented a structured review of the literature related to recurrence phenomena. In addition, three panelists provided informal presentations. One panelist (SAS) presented an analysis of the prognostic significance of fibrin split products in the identification of patients at risk for late hematologic effects, while two other panelists (SPB and WB) presented data about recurrence phenomena at their centers. ## Role of the funding source This was an investigator-initiated project conceived, designed, and executed by two authors (EJL and RCD) # Results ## Final unified treatment algorithm The unified treatment algorithm is shown in [fig_ref] Figure 1: Unified Treatment Algorithm for the Management of Pit Viper Snakebite in the... [/fig_ref]. At the time this algorithm was developed, the only antivenom commercially available for the treatment of pit viper envenomation in the US is Crotalidae Polyvalent Immune Fab (ovine) (CroFab ® , Protherics, Nashville, TN). All treatment recommendations and dosing apply to this antivenom. This algorithm does not consider treatment with whole IgG antivenom (Antivenin (Crotalidae) Polyvalent, equine origin (Wyeth-Ayerst, Marietta, Pennsylvania, USA)), because production of that antivenom has been discontinued and all extant lots have expired. This antivenom also does not consider treatment with other antivenom products under development. Because the panel members are all hospitalbased physicians, the panel did not evaluate field first aid or other prehospital therapy. In order to create an algorithm that was simple enough to be used effectively, the panel decided not to include specific recommendations for the management of certain rare manifestations of crotaline snakebite. These included snakebites to the head and neck, snakebites causing rhabdomyolysis, and apparent anaphylactic or anaphylactoid reactions to venom. In addition the panel recognized that no treatment algorithm could ## Emergency department and hospital management of pit viper snakebite ## Includes: rattlesnakes, copperheads, and cottonmouths (water moccasins) ## Assess patient Mark leading edge of swelling and tenderness every 15-30 minutes Immobilize and elevate extremity Treat pain (IV opioids preferred) Obtain initial lab studies (protime, Hgb, platelets, fibrinogen) Update tetanus Contact poison control center (1-800-222-1222) ## Check for signs of envenomation Swelling, tenderness, redness, ecchymosis, or blebs at the bite site, or Elevated protime; decreased fibrinogen or platelets, or Systemic signs, such as hypotension, bleeding beyond the puncture site, refractory vomiting, diarrhea, angioedema, neurotoxicity ## Apparent dry bite / no bite Do not administer antivenom Observe patient 8 hours Repeat labs prior to discharge If patient develops signs of envenomation, return to box 2 ## Check for indications for antivenom Swelling that is more than minimal and that is progressing, or Elevated protime; decreased fibrinogen or platelets, or Any systemic signs ## Apparent minor envenomation Do not administer antivenom Observe patient 12-24 hours Repeat labs at 4-6 hours and prior to discharge If patient develops progression of any signs of envenomation, return to box 3 ## Determine if initial control of envenomation has been achieved Swelling and tenderness not progressing Protime, fibrinogen, and platelets normal or clearly improving Clinically stable (not hypotensive, etc.) Neurotoxicity resolved or clearly improving ## Administer antivenom Establish IV access and give IV fluids Pediatric antivenom dose = adult dose Mix 4-6 vials of crotaline Fab antivenom (CroFab ® ) in 250 ml NS and infuse IV over 1 hour For patients in shock or with serious active bleeding Increase initial dose of antivenom to 8-12 vials Call physician expert (see box 12) Initiate first dose of antivenom in ED or ICU For suspected adverse reaction: hold infusion, treat accordingly, and call physician-expert Re-examine patient for treatment response within 1 hour of completion of antivenom infusion ## Repeat antivenom until initial control is achieved. If initial control is not achieved after 2 doses of antivenom, call physician expert (see box [bib_ref] Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid..., Dart [/bib_ref] ## Monitor patient Perform serial examinations Maintenance antivenom therapy may be indicated Read Box 13 (Maintenance Antivenom Therapy) Observe patient 18-24 hours after initial control for progression of any venom effect Follow-up labs 6-12 hours after initial control and prior to discharge ## When to call a physician-expert Direct consultation with a physician-expert is recommended in certain high-risk clinical situations: ## Life-threatening envenomation Shock Serious active bleeding Facial or airway swelling ## Hard to control envenomation Envenomation that requires more than 2 doses of antivenom for initial control ## Recurrence or delayed-onset of venom effects Worsening swelling or abnormal labs (protime, fibrinogen, platelets, or hemoglobin) on follow-up visits ## Allergic reactions to antivenom ## If transfusion is considered Uncommon clinical situations Bites to the head and neck Rhabdomyolysis Suspected compartment syndrome Venom-induced hives and angioedema ## Complicated wound issues If no local expert is available, a physician-expert can be reached through a certified poison center or the antivenom manufacturer's line ## Treatments to avoid in pit viper snakebite Cutting and/or suctioning of the wound Ice NSAIDs Prophylactic antibiotics Prophylactic fasciotomy Routine use of blood products Shock therapy (electricity) Steroids (except for allergic phenomena) Tourniquets ## Maintenance antivenom therapy Maintenance therapy is additional antivenom given after initial control to prevent recurrence of limb swelling Maintenance therapy is 2 vials of antivenom Q6H x 3 (given 6, 12, and 18 hours after initial control) Maintenance therapy may not be indicated in certain situations, such as Minor envenomations Facilities where close observation by a physicianexpert is available. Follow local protocol or contact a poison center or physician-expert for advice. provide ideal advice for all situations or serve as a substitute for clinical judgment. Legitimate variations in practice will always exist, and care may appropriately vary based on several factors, including patient presentation, available treatment resources, patient comorbidities, and patient preference. The panel explicitly determined that the consensus treatment algorithm is not a standard of care. ## Post-discharge planning Patient assessment and initial management (box 1) The initial approach to management of a patient with suspected pit viper snake envenomation begins with history, physical examination, and measurement of vital signs. Palpation of the envenomated area and marking the leading edge of swelling and tenderness every 15 -30 minutes is a useful way to determine whether local tissue effects have stabilized or are progressing [bib_ref] Bites of venomous snakes, Gold [/bib_ref]. Although not evidence based, the panel recommends immobilization and elevation of the envenomated extremity to reduce swelling. In order to avoid obstructing lymphatic outflow, speed resolution of swelling, and possibly reduce the risk of blister formation in flexor creases, major joints such as the elbow should be maintained in relative extension (≤ 45 degrees of flexion). Opioids are preferred over non-steroidal anti-inflammatory drugs (NSAIDs) because of the theoretical risk of bleeding associated with NSAID use in patients who may develop coagulopathy or thrombocytopenia due to envenomation. Although Clostridium tetani infection has not been reported following crotaline snakebite, it has occurred following envenomation by other vipers [bib_ref] Tetanus after white-lipped green pit viper (Trimeresurus albolabris) bite, Suankratay [/bib_ref] [bib_ref] Tetanus complicating snakebite in northern Nigeria; clinical presentation and public health implications, Habib [/bib_ref]. Standard recommendations for tetanus booster immunization (DTaP, Tdap, or Td as appropriate for the patient's age) should be followed . Notification of a certified poison center is recommended for all cases of snake envenomation, for two reasons. First, poison center personnel can identify situations where use of this algorithm may be inappropriate, and can provide treatment recommendations based on local snake species and medical treatment resources. Second, certified poison centers provide deidentified data to the National Poison Data System, which is used by public health professionals and policymakers. In the US, access to a certified poison center can be made through a single, toll-free number: 1-800-222-1222. ## Signs of crotaline envenomation (box 2) Approximately 80% of pit viper bites result in the injection of venom [bib_ref] The legitimacy of rattlesnake bites in central Arizona, Curry [/bib_ref]. Pit viper venom is a complex mixture of proteins and other macromolecules, with more than 50 identified components. The clinical effects produced by envenomation can be broadly classified into three groups. Local tissue effects include soft tissue necrosis and chemically mediated inflammation. A number of venom components, including myotoxic phospholipases A2 such as crotoxin, venom metalloproteinases that activate tumor necrosis factor-alpha (TNF-α), myotoxin a, hyaluronidase, phosphomonoesterase, phosphodiesterase, arginine ester hydrolase, and histamine-and bradykinin-like factors, cause direct tissue injury and produce a broad cytokine response in the victim [bib_ref] Bites of venomous snakes, Gold [/bib_ref] [bib_ref] Snake venom metalloproteinases: Their role in the pathogenesis of local tissue damage, Gutierrez [/bib_ref] [bib_ref] Processing of pro-tumour necrosis factor-α by venom metalloproteinases: a hypothesis towards explaining..., Moura-Da-Silva [/bib_ref] [bib_ref] Human cytokine response to Texas crotaline envenomation before and after antivenom administration, Crocker [/bib_ref]. Clinically, these effects are evident as pain, redness, swelling, tenderness, and myonecrosis that begin adjacent to the bite site and spread with movement of the venom through the lymphatic system. More than 90% of envenomated pit viper victims develop local tissue effects [bib_ref] Bites of venomous snakes, Gold [/bib_ref]. Hematologic venom effects include fibrinogen degradation and platelet aggregation and destruction [bib_ref] Hemostatic aspects of envenomation by North American snakes, Kitchens [/bib_ref] [bib_ref] Action of snake venom components on the haemostatic system, Hutton [/bib_ref]. On a laboratory basis, these are manifest by decreased fibrinogen levels, elevated prothrombin time, and thrombocytopenia. Detection of fibrin split products may be an early sign of a hematologic venom effect, and is a sensitive predictor of subsequent coagulopathy. In prospective studies, the presence of fibrin split products within the first 12 hours of treatment predicted subsequent hypofibrinogenemia with 87% sensitivity and 69% specificity [bib_ref] Dart RC: Recurrent and persistent coagulopathy following pit viper envenomation, Boyer [/bib_ref]. In some patients, elevated fibrin split products were the only early signs of developing hypofibrinogenemia. Clinically, oozing of blood from the bite site and ecchymosis of the surrounding tissue are common. Systemic bleeding may manifest as nuisance bleeding, such as gingival bleeding or haemolacria, or more serious bleeding, such as significant epistaxis, gastrointestinal bleeding, or intracranial hemorrhage. Even among the population with severe defibrination or thrombocytopenia, most patients do not develop medically significant bleeding [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref]. However, severe and fatal bleeding complications have been reported [bib_ref] Fatality in a case of envenomation by Crotalus adamanteus initially successfully treated..., Kitchens [/bib_ref] [bib_ref] Recurrent coagulopathy with delayed significant bleeding after crotaline envenomation, O'brien [/bib_ref] [bib_ref] Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation, Camilleri [/bib_ref] [bib_ref] Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune..., Ruha [/bib_ref]. Systemic venom effects include hypotension from direct cardiovascular toxicity, third-spacing and vasodilatation, nausea and vomiting, angioedema, and neurotoxicity. Many pit vipers envenomations can cause patients to experience a metallic taste and localized neuromuscular effects (fasciculation and myokymia). Severe systemic neurotoxicity induced by Mojave toxin A, including cranial neuropathy and flaccid paralysis, are frequent manifestations from Mojave rattlesnake (Crotalus scutulatus) and Southern Pacific rattlesnake (C. helleri) envenomation, but have been rarely reported following envenomation by other US rattlesnake species [bib_ref] Neurotoxicity associated with suspected southern Pacific rattlesnake (Crotalus viridis helleri) envenomation, Bush [/bib_ref] [bib_ref] Rattlesnake envenomation with neurotoxicity refractory to treatment with crotaline Fab antivenom, Richardson [/bib_ref] [bib_ref] Successful treatment of crotalid-induced neurotoxicity with new polyspecific crotalid Fab antivenom, Clark [/bib_ref]. Even within the same species, significant regional variations exist in neurotoxic venom components [bib_ref] Geographical variation in Crotalus scutulatus scutulatus (Mojave rattlesnake) venom properties, Glenn [/bib_ref]. In practice, the treating physician can assess for all of these venom effects with a focused history and physical examination and review of basic laboratory studies. Serial measurements of prothrombin time, hemoglobin, and platelet counts are recommended for all pit viper victims. Fibrinogen is a more sensitive measure of venom-induced defibrination than prothrombin time, and should be followed, if obtainable. Although onetime measurement of fibrin split products in the first 12 hours post-bite is useful for early detection of incipient hematologic venom effects, no proven role in therapy has been established for serial fibrin split product measurements, and an elevated FSP alone is not an indication for antivenom treatment [bib_ref] Dart RC: Recurrent and persistent coagulopathy following pit viper envenomation, Boyer [/bib_ref]. Most treatment resources include a grading scale for crotaline envenomation. The reliability and validity of these scales have not been established. Furthermore, because snake envenomation is a dynamic disease state, grading assigned at a single point in time may be a poor representation of overall severity. The panel members unanimously concluded that these scales are of little value outside of a research context, and therefore did not include a grading scale in these recommendations. Instead, the panel recommends serial examination of the patient for specific venom effects, with treatment based on the evolution of medically significant venom effects over time. ## Indications for antivenom (box 3) Administration of antivenom, in adequate doses, effectively halts the spread of local tissue effects, reduces hematologic venom effects, and reduces systemic effects resulting from crotaline envenomation [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref] [bib_ref] Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid..., Dart [/bib_ref] [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref] [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref]. Treatment with antivenom is indicated for any patient with progressive local tissue effects, hematologic venom effects, and systemic signs attributable to venom. The panel recommends withholding antivenom from patients with limb envenomations who have localized pain and swelling as the only manifestation of envenomation, provided that these local tissue effects are not progressing. For extremity envenomations, some panelists use a threshold of swelling that has crossed a major joint [wrist, elbow, ankle, or knee] and is progressing for this purpose, while other panelists treat minor hand envenomations more aggressively. Unfortunately, it is not known whether early administration of antivenom in a patient with apparently minor envenomation improves long-term limb functional outcomes. Regardless of the threshold chosen, patients with apparently minor envenomations require close observation, and should be given antivenom promptly if venom effects are progressing. Because hematologic venom effects can progress over time, all patients seen early after envenomation with significantly abnormal prothrombin time, fibrinogen, and/ or platelet count caused by envenomation should receive antivenom. Patients with hypotension, systemic bleeding, or other systemic venom effects should receive antivenom emergently. Any degree of true neurotoxicity, including localized fasciculations or myokymia, is an indication for antivenom administration. Some patients may present with symptoms attributable to anxiety; in the absence of signs of progressive envenomation, these patients can be reassured and observed. ## Antivenom administration (box 4) Antivenom dosing is titrated to clinical response. The targeted clinical response is often termed, "initial control of the envenomation syndrome," and consists of arrest of the progression of local tissue venom effects, a clear trend toward improvement in any hematologic venom effects, and resolution of all systemic venom effects (excluding fasciculations or myokymia, which may be refractory to antivenom [bib_ref] Bites of venomous snakes, Gold [/bib_ref] [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. An initial dose of 4 to 6 vials was chosen for the premarketing trials because of equivalent binding capacity to then-standard doses of equine antivenom and was shown to be effective in two premarketing studies [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref] [bib_ref] Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid..., Dart [/bib_ref]. Subsequent experience has shown that most victims of rattlesnake envenomation achieve initial control with one or two such doses, while most copperhead snake victims can be successfully treated with a single 4-vial dose [bib_ref] Crotalidae polyvalent immune Fab (ovine) antivenom is efficacious for envenomations by Southern..., Bush [/bib_ref] [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref]. Very few patients continue to experience progressive venom effects after 18 vials of antivenom [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref] [bib_ref] Factors associated with difficulty achieving initial control with Crotalidae Polyvalent Immune Fab..., Yin [/bib_ref]. However, with the exception of a single case report, patients who did not achieve initial control after 20 vials of antivenom do not respond to subsequent doses [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Recurrent coagulopathy with delayed significant bleeding after crotaline envenomation, O'brien [/bib_ref] [bib_ref] Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation, Camilleri [/bib_ref] [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref]. Panel members noted that inexperienced health care providers sometimes use large doses of antivenom in an attempt to treat clinical effects that did not respond to therapy, but could be safely observed. The reason for limiting initial dosing to 4 to 6 vials is primarily cost, but also the theoretical increased risk of serum sickness with larger protein loads. Initial control doses of less than 4 vials have not been well studied. Antivenom should be administered via intravenous infusion. In animal studies, the combination of subcutaneous and intravenous administration of antivenom was no better than intravenous administration alone [bib_ref] Subcutaneous crotaline Fab antivenom for the treatment of rattlesnake envenomation in a..., Offerman [/bib_ref]. Skin testing is not necessary or recommended prior to administration of the current antivenom [bib_ref] Bites of venomous snakes, Gold [/bib_ref]. In addition to cleavage and removal of the immunogenic Fc portion of the immunoglobulin molecule, the currently available antivenom undergoes column affinity purification. Symptoms of acute anaphylactoid reactions, such as pruritus, urticaria, or wheezing occur in approximately 6% of patients [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref] [bib_ref] Acute hypersensitivity reactions associated with administration of Crotalidae polyvalent immune Fab antivenom, Cannon [/bib_ref]. Most cases are mild and do not preclude continued administration of antivenom. However, severe acute allergic reactions, including reactions involving airway compromise, have been described [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref] [bib_ref] Immediate hypersensitivity reaction associated with the rapid infusion of Crotalidae polyvalent immune..., Holstege [/bib_ref]. As a result, the panel recommends that the first dose of antivenom be administered in a clinical setting, such as an emergency department or intensive care unit, where the medications, equipment, and skilled personnel required to manage an airway emergency are immediately available. If there is no acute reaction to initial dosing, subsequent doses of antivenom can be administered in a less monitored setting, such as a hospital ward. Management of allergic effects is discussed below. The panel recommended increasing the initial dose of antivenom to 8 to 12 vials in patients who present with immediately life-threatening venom effects, such as shock or serious active bleeding. In a large Phase IV study of severely envenomated pit viper victims (approximately 13% of the patients who were treated with antivenom), 69% of patients required more than one dose of antivenom to achieve initial control [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref]. The median dose of antivenom used to achieve initial control in this population was 9 vials (interquartile range: 6 to 15 vials). Additionally, bites by large rattlesnakes are associated with more severe envenomation that requires administration of higher doses of antivenom [bib_ref] Large snake size suggests increased snakebite severity in patients bitten by rattlesnakes..., Janes [/bib_ref]. In the presence of immediately life-threatening venom effects, the panel believed that the benefit of more rapid control of hypotension and bleeding expected with an aggressive dosing strategy exceeded the benefit that could be gained by administration of a more typical 4 to 6 vial antivenom dose in patients. Although this practice is common among the panel members, it has not been empirically studied. The panel recommends routine administration of intravenous crystalloid solution to any pit viper victim who requires antivenom. Venom causes vasodilatation and capillary leakage, leading to relative volume depletion, and antivenom infusion can cause histamine release. Although the standard dilution of antivenom is one dose (4 -6 vials) in 250 ml normal saline, some panelists choose large volumes of dilution (1000 ml) in patients for whom there is no contraindication. In general, each dose of antivenom is infused over one hour. Faster infusion may be preferred for critically ill patients who are in shock or actively hemorrhaging. Some panelists start antivenom administration at a slow initial rate (e.g. 25 ml/hr for 10 minutes), followed by an increased infusion rate (balance of dose administered over 50 minutes) if no acute hypersensitivity reaction is observed, while others prefer a single infusion rate strategy to reduce medical errors. In the absence of data, the panel did not make an infusion rate recommendation. Although routine pre-treatment with antihistamines is not generally recommended, some panelists do so as a matter of clinical routine. No evidence bears on this practice. Because antivenom is intended to neutralize the dose of injected venom, the pediatric dose of antivenom is the same as the adult dose. Although this hypothesis has not been critically tested, it is consistent with observation in pediatric case series [bib_ref] Crotaline Fab antivenom for the treatment of children with rattlesnake envenomation, Offerman [/bib_ref] [bib_ref] Antivenom therapy for snakebites in children: is there evidence?, Schmidt [/bib_ref]. ## Assessment for initial control of the envenomation syndrome (boxes 5 and 11) Approximately half of antivenom-treated patients require more than one dose of antivenom to achieve initial control [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. Therefore, the treating physician should examine the patient and repeat indicated laboratory studies soon after antivenom is administered to evaluate for treatment response. Because fibrinogen and platelet levels change rapidly after antivenom administration, coagulation studies and platelet counts should be rechecked within one hour of antivenom dosing. If initial control of the envenomation syndrome is achieved, the patient can be observed, either as an inpatient or in a clinical observation unit, to make certain that this clinical response is maintained. If the first dose of antivenom does not succeed in producing initial control, the initial dose should be repeated. Failure to achieve initial control after two doses of antivenom is uncommon. In a large retrospective study, only 17% of rattlesnake victims and 2% of Agkistrodon (copperhead and water moccasin) victims required more than 12 vials of antivenom to achieve initial control, and the presence of thrombocytopenia and neurologic venom effects prior to antivenom therapy were independently associated with the difficulty achieving initial control [bib_ref] Factors associated with difficulty achieving initial control with Crotalidae Polyvalent Immune Fab..., Yin [/bib_ref]. Consultation with a physician, clinical toxicologist, or other expert who has specific training and expertise in the management of venomous snakebite is recommended in this and other high-risk clinical situations. Information about how to reach such an expert can be found on the algorithm (box 12), or below. ## Post-stabilization monitoring and administration of maintenance therapy (boxes 6 and 13) Snake envenomation is a dynamic clinical process. Although clinical improvement virtually always follows administration of adequate antivenom doses, recurrence or delayed-onset of one or more venom effects occurs in approximately half of patients treated with Fab antivenom [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. Serial physician examinations and laboratory studies are necessary to detect recurrent or delayed-onset venom effects. When it occurs, local tissue recurrence typically develops within 6 to 36 hours of initial control. Recurrent local tissue effects are clinically evident to the patient and generally respond well to re-treatment with antivenom. The onset of recurrent or delayed-onset hematologic venom effects is much more variable, with most cases occurring 2 -7 days after initial control and some cases up to 10 days after initial control [bib_ref] Dart RC: Recurrent and persistent coagulopathy following pit viper envenomation, Boyer [/bib_ref] [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref]. When antivenom is administered to treat recurrent coagulopathy or thrombocytopenia, the treatment response is generally attenuated compared with the response to initial antivenom therapy [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation, Camilleri [/bib_ref] [bib_ref] Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune..., Ruha [/bib_ref] [bib_ref] Biphasic rattlesnake venominduced thrombocytopenia, Offerman [/bib_ref] [bib_ref] Relationship of venom effects to venom antigen and antivenom serum concentrations in..., Seifert [/bib_ref]. Hematologic venom effects are most often clinically occult; few patients experience medically significant bleeding even in the setting of profound defibrination or thrombocytopenia [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref]. The ideal duration of hospitalization and frequency of follow-up observations and laboratory studies is unknown. After the first 24 hours, the marginal benefit of continued hospitalization appears to be small, and follow-up monitoring in the outpatient setting is appropriate for most patients. The panel recommends that patients be observed in the hospital for 18 -24 hours following initial control of the envenomation syndrome, with serial examinations performed approximately every 6 -8 hours during this interval. The panel recommends that most patients have laboratory studies (protime, hemoglobin, platelet count, and fibrinogen level) measured twice prior to discharge: once 6 -12 hours after initial control, which appears to be the time at which the risk of recurrent hematologic venom effects is greatest, and again prior to discharge [bib_ref] Dart RC: Recurrent and persistent coagulopathy following pit viper envenomation, Boyer [/bib_ref]. Unfavourable trends in protime, fibrinogen, or platelet counts should prompt additional testing. Because only 5 -10% of copperhead envenomation victims develop hematologic venom effects at any time, it is reasonable to forego one set of follow-up lab tests in those copperhead victims who have never manifest coagulopathy, thrombocytopenia, or systemic bleeding [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref]. In the current FDA-approved prescribing information, the manufacturer of antivenom recommends administration of additional 2-vial doses of antivenom given 6, 12, and 18 hours after initial control is achieved. In a randomized clinical trial, this practice reduced the proportion of patients with recurrent local tissue effects from 8/16 (50%) to 0/15 (0%) [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. However, cases of recurrent local tissue effects developing in maintenancetreated patients have been reported [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Crotalidae polyvalent immune Fab (ovine) antivenom is efficacious for envenomations by Southern..., Bush [/bib_ref] [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref] [bib_ref] Crotaline Fab antivenom for the treatment of children with rattlesnake envenomation, Offerman [/bib_ref]. The cost-effectiveness of maintenance therapy is unclear; in a randomized clinical trial, patients randomized to receive maintenance therapy and patients randomized to receive additional antivenom administered as needed to treat recurrent swelling received the same median number of antivenom vials [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. The extent to which maintenance therapy reduces the risk of recurrent and delayedonset hemorrhagic venom effects is not precisely known. Results of the antivenom phase III premarketing trial appeared to show a reduction in the incidence rate of recurrent hematologic venom effects in patients who received maintenance therapy. In that trial, recurrent thrombocytopenia was noted in 2/14 (14%) patients who received maintenance antivenom therapy, compared with 9/16 (56%) patients who did not receive maintenance therapy. In the same study, recurrent hypofibrinogenemia was noted in 2/14 (14%) of patients receiving maintenance therapy and 7/16 (44%) of those who did not receive maintenance. Small sample size and the large proportion of patients in the no-maintenance group who received rescue therapy due to recurrent local tissue effects makes any estimate of the effect of maintenance antivenom therapy difficult to interpret. Furthermore, the baseline risk of hematologic venom effects varies approximately 10-fold based on the envenomating species and the initial severity of the envenomation, with rattlesnake victims and patients with high initial clinical severity apparently at the greatest risk [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref] [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref]. In a recent case series from central Arizona, 32% of patients developed new or recurrent hematologic abnormalities after initial control [bib_ref] Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune..., Ruha [/bib_ref]. Finally, the panelists noted that the safety of a "watchful waiting" strategy is wholly dependent on the quality and frequency of follow-up observations, which may vary depending on local hospital resources and staffing patterns. In light of the above information, the practice of administering maintenance antivenom therapy is controversial. Historically, some centers recommend maintenance therapy universally, while others do so in the minority of cases [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Crotalidae polyvalent immune Fab (ovine) antivenom is efficacious for envenomations by Southern..., Bush [/bib_ref] [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref]. Given the wide variation in clinical practice patterns the panelists concluded that a "one size fits all" or simplified decision rule was inappropriate for the question of whether to administer maintenance therapy. The panel recommended consultation with a regional poison center or local snakebite treatment expert to assist in the determination of whether to give maintenance antivenom therapy. ## Management of patients with apparent dry bites or minor envenomations (boxes 9 and 10) Approximately 20 -25% of crotaline snakebites are "dry"; no venom effects develop [bib_ref] The legitimacy of rattlesnake bites in central Arizona, Curry [/bib_ref]. Although the majority of patients with apparent dry bites have not been envenomated, some patients who initially present with a wound but no other signs of envenomation (i.e. no swelling, ecchymosis, vesicle formation, or hematologic or systemic venom effects) develop signs of envenomation after a latent period of minutes to hours [bib_ref] Reliability of clinical presentation for predicting significant pit viper envenomation, Hurlbut [/bib_ref]. In addition, some patients present with apparent minor venom effects (ecchymosis, swelling, and/or vesicles limited to the immediate area of the bite site without systemic venom effects). All panel members reported having treated patients who presented in this manner and subsequently developed significant progressive signs of envenomation. To our knowledge, there are no data to describe the typical time course or define a "safe" period of observation after which the risk of delayedonset venom effects is minimal, although the best available evidence suggests that 6 hours is not long enough in many cases [bib_ref] Reliability of clinical presentation for predicting significant pit viper envenomation, Hurlbut [/bib_ref]. Cost-benefit implications are largely unknown. The panel members recommended that, in general, patients with apparent non-envenomation be observed in a health care facility for at least 8 hours, with repeat platelet count, prothrombin time, fibrinogen, and hemoglobin measurement prior to discharge. Anecdotal evidence suggests some patients, such as children and those with lower extremity envenomations, may develop significant tissue effects more than 8 hours after an apparent dry bite, and therefore may require longer observation. Patients with apparently minor envenomation and no evidence of progression should be observed longer, in the range of 12 -24 hours. These observation periods might be appropriately shortened or prolonged based on a number of factors, including the age and general health of the patient, bite location, envenomating species, social support available to the patient, patient preference, and ability of the treating facility to provide efficient and cost-effective observation services. Patients who have had no further progression of venom effects during an appropriate period of observation may be discharged when certain criteria are met. As with any patient going home from the hospital, the patient must be able to perform activities of daily living unassisted or with the assistance available in the home, have adequate pain control on oral medications, and have no other outstanding medical issues requiring hospital care. In addition, the patient should not have any unfavorable trends in protime, fibrinogen levels, or platelet counts, since deterioration in one or more of these parameters may be an early sign of recurrent or delayed-onset hematologic venom effects. Following discharge, patients should be instructed to maintain limb elevation as much as possible to speed resolution of swelling. Progressive swelling that does not improve with elevation or signs of abnormal bleeding, such as gingival bleeding, easy bruising, or melena, may be the hallmark of recurrent hematologic venom effects, and should lead to prompt re-evaluation. Serum sickness, a type III hypersensitivity reaction caused by administration of exogenous proteins, is a known complication of antivenom therapy. In prospective studies, approximately 5 -10% of patients treated with ovine Fab antivenom develop signs of serum sickness, such as fever, rash, myalgias, and arthralgias [bib_ref] Acute hypersensitivity reactions associated with administration of Crotalidae polyvalent immune Fab antivenom, Cannon [/bib_ref]. Serum sickness following Fab antivenom administration is generally mild and responds well to treatment with oral antihistamines and corticosteroids. At the time of discharge, patients should be instructed about the symptoms of serum sickness and given directions regarding follow-up care should serum sickness develop. Few data exist to inform the number and timing of follow-up visits. In general, the panel felt that mandatory follow-up visits were not needed for patients who had minimal envenomation and did not require antivenom administration. Similarly, because the risk of late hematologic venom effects is small, routine follow-up of patients with uncomplicated copperhead snake envenomations who did not develop hematologic venom effects during hospitalization is unlikely to provide clinical benefit to a patient. On the other hand, patients with rattlesnake envenomations and those who demonstrated hematologic venom effects during the acute phase of therapy are at high risk for late hematologic venom effects that most often occur 2 -7 days after antivenom therapy [bib_ref] Dart RC: Recurrent and persistent coagulopathy following pit viper envenomation, Boyer [/bib_ref] [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Fatality in a case of envenomation by Crotalus adamanteus initially successfully treated..., Kitchens [/bib_ref] [bib_ref] Recurrent coagulopathy with delayed significant bleeding after crotaline envenomation, O'brien [/bib_ref] [bib_ref] Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation, Camilleri [/bib_ref] [bib_ref] Two cases of rattlesnake envenomation with delayed coagulopathy, Miller [/bib_ref] [bib_ref] Southern Pacific rattlesnake bite: a unique clinical challenge, Wasserberger [/bib_ref]. Follow-up visits with laboratory testing are therefore recommended 2 -3 days and 5 -7 days after discharge, with additional visits as needed based on signs, symptoms, and laboratory trends. ## High risk situations requiring expert consultation (box 12) Of the crotaline victims treated with antivenom, approximately 13% develop severe envenomation [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref]. Clinicians who practice outside of referral centers that see a large volume of snakebite patients rarely have the opportunity to develop a large base of experience treating critically envenomated patients. For this reason, the panel identified certain high-risk clinical situations in which consultation with a physician who has specific training and expertise in the management of crotaline snakebite is strongly encouraged. In institutions where bedside consultation is available, bedside consultation should be sought. In the remainder of institutions, telephone consultation, facilitated by a regional poison center, is recommended. Even if local practice calls for transfer of patients from the presenting facility to a tertiary care center, early consultation with a physicianexpert (or, alternatively, a pharmacologist or clinical toxicologist with specific training and expertise in snakebite management) is recommended to ensure that early interventions are ideal and all appropriate preparations are made at the receiving facility. ## Patients with life-threatening envenomation Frank hypotension, active hemorrhage, and airway edema are uncommon but life-threatening manifestations of crotaline snakebite [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref]. Evidence supports a benefit from antivenom therapy in the former two situations, while the use of antivenom combined with active airway management is recommended for the latter situation based on case reports [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Crotaline Fab antivenom appears to be effective in cases of severe North..., Lavonas [/bib_ref] [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref] [bib_ref] Airway obstruction following canebrake rattlesnake envenomation, Kerns [/bib_ref]. For the reasons previously described, the panel recommended a larger initial dose of antivenom for patients with shock or active hemorrhage due to snakebite. Only 1% of snake envenomations involve the head or neck, but the experience of panel members suggests a high risk of subsequent loss of airway. This situation is considered analogous to thermal airway burns, in which early endotracheal intubation may prevent the need for surgical airway placement and its attendant complications. ## Difficult to control envenomations Even in a severely envenomated cohort, initial control of the envenomation syndrome can be achieved with one or two doses of antivenom in most patients [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref]. Case reports of refractory neurotoxicity and hematologic toxicity exist, but the available evidence do not define a point at which further administration of antivenom is likely to be futile [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Rattlesnake envenomation with neurotoxicity refractory to treatment with crotaline Fab antivenom, Richardson [/bib_ref] [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref] [bib_ref] Biphasic rattlesnake venominduced thrombocytopenia, Offerman [/bib_ref]. In addition to assisting with cost-benefit estimation, a physician-expert may be able to identify secondary complications (e.g. rhabdomyolysis from persistent myokymia) that require additional interventions. Consultation with a physicianexpert is recommended in cases where initial control of the envenomation syndrome has not been achieved following two doses of antivenom. ## Recurrent or delayed-onset of venom effects As described above, the management of recurrent or delayed-onset hematologic venom effects is controversial. Most patients tolerate hematologic venom effects well, but several serious cases and one fatality have been described [bib_ref] Fatality in a case of envenomation by Crotalus adamanteus initially successfully treated..., Kitchens [/bib_ref]. Compared to the initial treatment response, the response to repeat antivenom dosing is often attenuated and may be transient [bib_ref] Initial postmarketing experience with Crotalidae polyvalent immune Fab for treatment of rattlesnake..., Ruha [/bib_ref] [bib_ref] Biphasic rattlesnake venominduced thrombocytopenia, Offerman [/bib_ref] [bib_ref] Relationship of venom effects to venom antigen and antivenom serum concentrations in..., Seifert [/bib_ref]. While guidelines exist, there is no settled clinical decision rule for which patients require retreatment, and estimates of which patients are at highest risk are largely derived from experience with other diseases [bib_ref] Recurrence phenomena after immunoglobulin therapy for snake envenomations: Part 2. Guidelines for..., Boyer [/bib_ref]. Although the risk to the patient of additional antivenom dosing appears to be minimal, cost-benefit considerations are significant, particularly when re-hospitalization is required. For these reasons, the panel recommends direct consultation with a physician-expert to assist in management of these patients. ## Allergic reactions to antivenom Signs of immediate hypersensitivity to antivenom are observed in 5 -6% of patients treated with ovine Fab antivenom [bib_ref] Short-term outcomes following Fab antivenom therapy for severe crotaline snakebite, Lavonas [/bib_ref] [bib_ref] Acute hypersensitivity reactions associated with administration of Crotalidae polyvalent immune Fab antivenom, Cannon [/bib_ref]. Although most of these reactions are relatively minor and do not preclude antivenom therapy, some are severe. As described above, the initial management of a hypersensitivity reaction is straightforward: halt the antivenom infusion and administer antihistamines, corticosteroids, and fluids as needed until signs of hypersensitivity have resolved. Epinephrine may be required for severe reactions. At this point, the decision to resume or discontinue antivenom therapy involves a complex balancing of risk and benefit that the panel could not reduce to an algorithm. Because few clinicians have the opportunity to gain experience with this uncommon clinical scenario, consultation with an expert clinician is recommended. ## Hematologic venom effects when transfusion is considered Thrombin-like enzymes in crotaline venom incompletely cleave fibrinogen, leading to the formation of an unstable fibrin clot that is not cross-linked [bib_ref] Hemostatic aspects of envenomation by North American snakes, Kitchens [/bib_ref] [bib_ref] Recombinant factor VIIa for treatment of gastrointestinal hemorrhage following rattlesnake envenomation, Ruha [/bib_ref]. The mechanism that underlies venom-induced thrombocytopenia is less well-understood; venom-induced injury to platelet cell membranes and endothelial activation caused by microvascular damage have been proposed [bib_ref] Action of snake venom components on the haemostatic system, Hutton [/bib_ref] [bib_ref] Recombinant factor VIIa for treatment of gastrointestinal hemorrhage following rattlesnake envenomation, Ruha [/bib_ref] [bib_ref] Hemorrhage induced by snake venom metalloproteinases: Biochemical and biophysical mechanisms involved in..., Gutierrez [/bib_ref]. Transfusion alone can produce transient improvement in coagulation parameters and platelet counts, but rarely has a sustained effect unless adequate doses of antivenom have also been administered. Aggressive antivenom administration should always precede fresh frozen plasma, cryoprecipitate, or platelet transfusion if antivenom is available. Transfusion is indicated for cases in which medically significant bleeding is occurring. Whether administration of additional antivenom and transfusion are appropriate for patients who are not actively bleeding but who have profound coagulopathy, profound thrombocytopenia, or multicomponent hematological venom effects (both thrombocytopenia and defibrinogenation) remains unclear [bib_ref] Rational use of Crotalidae polyvalent immune Fab (ovine) in the management of..., Yip [/bib_ref]. Although most patients tolerate hematological venom effects without incident, severe or fatal bleeding events have occurred [bib_ref] Fatality in a case of envenomation by Crotalus adamanteus initially successfully treated..., Kitchens [/bib_ref] [bib_ref] Recurrent coagulopathy with delayed significant bleeding after crotaline envenomation, O'brien [/bib_ref] [bib_ref] Conservative management of delayed, multicomponent coagulopathy following rattlesnake envenomation, Camilleri [/bib_ref] [bib_ref] Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune..., Ruha [/bib_ref]. Transfusion also has associated cost and risks. Consultation prior to transfusion is recommended, when possible, to maximize the utility of transfusion and reduce unnecessary use of blood products. ## Rhabdomyolysis Although crotaline venom is directly myotoxic, clinically severe rhabdomyolysis is uncommon in the United States [bib_ref] Severe myonecrosis in a fatal case of envenomation by the canebrake rattlesnake..., Kitchens [/bib_ref]. Although routine creatine kinase measurement is not recommended, specific patients, such as those with severe local tissue injury and/or prolonged systemic neurotoxicity can develop rhabdomyolysis. Consultation with a physician-expert is recommended in these cases. ## Suspected compartment syndrome Crotaline snakebite can produce pain, swelling, induration, paresthesias, color changes (e.g. bluish discoloration from bruising), difficult-to-palpate pulses, and tenderness in the envenomated extremity, mimicking the initial signs of compartment syndrome. However, true compartment syndrome is much less common, and a prospective observational study in humans showed that most rattlesnake victims have greater blood flow in the envenomated than in the non-envenomated limb [bib_ref] Noninvasive vascular studies in management of rattlesnake envenomations to extremities, Curry [/bib_ref]. Animal research and human experience demonstrate that antivenom administration reduces compartment pressures, and surgical groups who used to perform fasciotomy frequently now acknowledge that antivenom administration often precludes the need for fasciotomy [bib_ref] A large single-center experience with treatment of patients with crotalid envenomations: outcomes..., Corneille [/bib_ref] [bib_ref] Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment..., Lavonas [/bib_ref] [bib_ref] Fasciotomy worsens the amount of myonecrosis in a porcine model of crotaline..., Tanen [/bib_ref] [bib_ref] Rattlesnake bites in children: Antivenin treatment and surgical indications, Shaw [/bib_ref]. In one large case series of patients treated in a tertiary referral center, only 8/236 (3.4%) of patients received a fasciotomy or digital dermotomy [bib_ref] Epidemiology and hospital course of rattlesnake envenomations cared for at a tertiary..., Tanen [/bib_ref]. Measurement of compartment pressure prior to consideration of fasciotomy is recommended. Compartment pressure measurement may not be feasible in cases of digital envenomation. Consultation with a physician-expert is recommended whenever compartment syndrome is suspected and prior to any fasciotomy or digit dermotomy. ## Venom-induced hives and angioedema Anaphylactic and anaphylactoid reactions to venom are uncommon manifestations of snakebite which can range in severity from urticarial rash to multisystem organ failure and angioedema causing airway loss [bib_ref] Rapid-onset shock and/or anaphylactoid reactions from rattlesnake bites in central Arizona, Curry [/bib_ref]. At least 2 deaths have been reported [bib_ref] Annual report of the American Association of Poison Control Centers Toxic Exposure..., Litovitz [/bib_ref] [bib_ref] Annual report of the American Association of Poison Control Centers' National Poisoning..., Lai [/bib_ref]. Although standard therapy includes antihistamines, steroids, epinephrine, and antivenom, the ideal management of this condition is unknown. Because these patients are often critically ill and require aggressive, multimodal therapy, panel members recommended expert consultation. ## Complicated wound issues Crotaline envenomation causes local tissue necrosis by a variety of mechanisms, some of which are not reversible with antivenom therapy [bib_ref] In vivo ability of antimyotoxin a serum plus polyvalent (Crotalidae) antivenom to..., Ownby [/bib_ref]. Although venominduced inflammation often mimics infection, true bacterial cellulitis is uncommon, affecting approximately 3% of snakebite patients [bib_ref] The incidence of wound infection following crotalid envenomation, Clark [/bib_ref]. Rarely, severe infections have been reported [bib_ref] Necrotizing fasciitis of the upper extremity resulting from a water moccasin bite, Angel [/bib_ref]. Confusion about whether an envenomated extremity is inflamed or infected may lead to unnecessary medical care, including intravenous antibiotics and prolonged hospitalization [bib_ref] Copperhead snakebites: clinical severity of local effects, Scharman [/bib_ref]. Decisions about debridement and tissue grafting may also be complex. Consultation with an expert who has experience managing envenomated wounds may improve these decisions. ## Treatments to avoid in pit viper snakebite (box 15) The panel recommends against several therapies that are commonly utilized to treat crotaline envenomation, but which are ineffective, unnecessary, or harmful. Wound incision and suction does not remove meaningful amounts of venom and can worsen local tissue injury [bib_ref] Suction for venomous snakebite: a study of "mock venom" extraction in a..., Alberts [/bib_ref] [bib_ref] Effects of a negative pressure venom extraction device (Extractor) on local tissue..., Bush [/bib_ref]. Although little evidence exists to condemn the topical application of ice, this measure appears to be ineffective [bib_ref] Local heat and cold application after eastern cottonmouth moccasin (Agkistrodon piscivorus) envenomation..., Cohen [/bib_ref]. More aggressive forms of cryotherapy, such as ice water immersion, have been associated with severe iatrogenic tissue injury [bib_ref] What are we doing? An evaluation of cryotherapy for envenomation, Frank [/bib_ref]. Although this issue has not been subjected to study, panel members recommended avoiding the use of non-steroidal anti-inflammatory drugs (NSAIDs) because of the theoretical harm associated with the platelet dysfunction caused by NSAIDs in a potentially thrombocytopenic patient. Prophylactic antibiotics, prophylactic fasciotomy, and the routine use of blood products should be avoided for the reasons discussed above. Application of electrical current from a spark plug or hand-held "stun gun" has been recommended for therapy based on anecdotal experience from a missionary physician in Ecuador [bib_ref] High voltage shock treatment for snake bite, Guderian [/bib_ref]. Subsequent animal research and human experience have shown this practice to be ineffective and associated with significant tissue injury [bib_ref] Failure of electric shock treatment for rattlesnake envenomation, Dart [/bib_ref] [bib_ref] Electric shocks are ineffective in the treatment of lethal effects of rattlesnake..., Johnson [/bib_ref] [bib_ref] Electric shock does not save snakebitten rats, Howe [/bib_ref] [bib_ref] Use of stun guns for venomous bites and stings: a review, Welch [/bib_ref] [bib_ref] Electric shock: a potentially hazardous approach to treating venomous snakebite, Gold [/bib_ref]. There is a paucity of data about the role of corticosteroids in crotaline snakebite. Based on unpublished experience and controlled trial data from the United States showing that corticosteroids do not improve outcome in old world viper (family Viperidae, subfamily Viperidae) envenomation, administration of corticosteroids is reserved for treatment of hypersensitivity phenomena [bib_ref] Specific antivenin and prednisone in viperbite poisoning: controlled trial, Reid [/bib_ref] [bib_ref] The management of snake bite, Reid [/bib_ref]. Although data from envenomations by snakes native to the United States are lacking, arterial tourniquet application is ineffective and sometimes associated with apparent harm when used to treat South American crotaline snakes [bib_ref] Tourniquet ineffectiveness to reduce the severity of envenoming after Crotalus durissus snake..., Amaral [/bib_ref]. Although pressure immobilization has a confirmed role in the management of highly neurotoxic elapid snake envenomations, its role in crotaline envenomation is unclear. In porcine models of severe western diamondback rattlesnake envenomation, pressure immobilization prolonged survival, with varying effects on local tissue injury [bib_ref] Pressure immobilization delays mortality and increases intracompartmental pressure after artificial intramuscular rattlesnake..., Bush [/bib_ref] [bib_ref] Pilot studies of pressureimmobilization bandages for rattlesnake envenomations, Meggs [/bib_ref]. Similarly, lymphatic constricting bands reduce the absorption of venom into the systemic circulation in animal models, but whether this strategy is more likely to improve or worsen overall outcomes is unknown [bib_ref] Effects of constriction bands on rattlesnake venom absorption: A pharmacokinetic study, Burgess [/bib_ref]. Neither pressure immobilization nor use of lymphatic constricting bands is recommended. # Discussion Management of a simple case of crotaline snakebite involves many clinical decisions. Clinical trials in this area are challenging to conduct. To our knowledge, only five clinical trials of crotaline snakebite have been performed. One of these was randomized [bib_ref] A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for..., Dart [/bib_ref]. A second randomized trial was attempted, but terminated early due to low enrollment . A third identified trial was non-randomized [bib_ref] Affinity-purified, mixed monospecific crotalid antivenom ovine Fab for the treatment of crotalid..., Dart [/bib_ref]. Finally, two trials were identified involving an antivenom product that is not currently licensed in the US. One of these trials has been completed, but results have only been published in preliminary form . The other is ongoing. In situations where high quality evidence does not exist, clinical recommendations can be primarily influenced by factors other than the results of clinical trials. These factors include uncertainty in the estimates of likely benefit, risk, inconvenience, and cost of therapy, and varying values of clinicians and patients [bib_ref] Rating quality of evidence and strength of recommendations: Going from evidence to..., Guyatt [/bib_ref]. Available techniques for evidence-based decision-making do not provide tools for dealing with regional variations in disease characteristics, differences in treatment resources available at different centers, or situations in which the amount of unpublished experience equals or exceeds the amount of data in the peer-reviewed literature. By definition, evidence-based hypothesis testing cannot begin until each specific clinical question is defined; this creates a circular problem when creating complex, highlybranched treatment algorithms. For these reasons, we believed that an evidence-informed structured consensus process would produce a final result that was more useful to clinicians and patients than a formal evidence-based medicine approach. Notwithstanding these limitations, it is possible to describe these treatment recommendations in GRADE terms [bib_ref] Rating quality of evidence and strength of recommendations: Going from evidence to..., Guyatt [/bib_ref]. The decision to give antivenom to patients with limb-threatening envenomation or severe systemic effects is a strong recommendation based on moderate quality evidence; despite the lack of placebocontrolled trials, concordant results of a large number of observational studies and animal experiments make it clear that the benefits of therapy outweigh the associated risks and burdens. All other recommendations are weak recommendations based on very low quality evidence. This process, and its output, have limitations. Although we took care to minimize the introduction of commercial bias through conflict-of-interest disclosure, exclusion of the project sponsor from the decision-making process, diversity of panel membership, use of a trained facilitator, and structured decision-making methods, we cannot exclude the possibility that prior relationships between project participants and the manufacturer of antivenom may have influenced the opinions and practice patterns of panel members. These concerns may be mitigated somewhat by the observation that, although the treatment algorithm contained here is more comprehensive than recently published treatment guidance from unrelated authors, the indications for antivenom are essentially similar [bib_ref] A large single-center experience with treatment of patients with crotalid envenomations: outcomes..., Corneille [/bib_ref] [bib_ref] Evidence-based, multidisciplinary approach to the development of a Crotalidae polyvalent antivenin (CroFab)..., Weant [/bib_ref] [bib_ref] Chicago: American College of Surgeons Committee on Trauma, Cribari [/bib_ref]. Rather than rely solely on expert opinion, we utilized several strategies to inform the decision-making process. We performed a comprehensive literature review and made all publications containing original data available at the time of panel deliberations. In addition, we utilized our gap analysis to identify data needs and develop information targeted to those needs. To this end, we performed focused analysis of line-level data collected in the phase II and III clinical trials, a phase IV database created by the antivenom manufacturer, and a separate prospectively-collected database from a high-volume snakebite treatment center. Whenever the above methods did not produce clear data to inform a treatment decision, we explicitly acknowledged this limitation in the manuscript. # Conclusions Venomous snakebite is a complex and dynamic clinical entity that is characterized by a wide variation in clinical effects and response to therapy. Using a structured, evidence-informed decision-making process, we provide treatment guidelines that may reduce unnecessary variation in care and improve clinical outcomes. and RCD were voting members of the expert consensus panel, which was chaired by a professional facilitator. SCC provided input during algorithm development and participated in the expert consensus panel as a nonvoting member. EJL created the manuscript draft. All authors read, revised and contributed to the final manuscript. EJL takes responsibility for the work as a whole. Competing interests SPB is an employee of Faculty Medical Group of Loma Linda University School of Medicine, which has received research funding from Protherics. SPB derives no personal financial benefit from this relationship. EJL and RCD are employees of the Denver Health and Hospital Authority, which has received research funding from Protherics. None of these authors derive personal financial benefit from this relationship. WB, VB, JNB, WPK, WHR, AMR, SAS, and DAT declare that they have no competing interests. The views expressed by VB and DAT in this article are those of the authors, and do not reflect the official policy or position of the US Air Force, the US Navy, the US Department of Defense, or the US government. [fig] Figure 1: Unified Treatment Algorithm for the Management of Pit Viper Snakebite in the United States. [/fig] [fig] Figure 2: Patients who develop no venom effects during the observation period should be discharged with instructions to return promptly if signs of envenomation develop or progress. Discharge criteria and post-discharge management (boxes 7, 8, and 14) [/fig] [table] Table 2: Search Strategy [/table]	None	https://bmcemergmed.biomedcentral.com/counter/pdf/10.1186/1471-227X-11-2	None
9b429b085e92df94ffd0d4be6d6c3f2abee85546	pubmed	Management of patients infected with airborne-spread diseases: An algorithm for infection control professionals	Management of patients infected with airborne-spread diseases: An algorithm for infection control professionals Background: Many US hospitals lack the capacity to house safely a surge of potentially infectious patients, increasing the risk of secondary transmission. Respiratory protection and negative-pressure rooms are needed to prevent transmission of airbornespread diseases, but US hospitals lack available and/or properly functioning negative-pressure rooms. Creating new rooms or retrofitting existing facilities is time-consuming and expensive. Methods: Safe methods of managing patients with airborne-spread diseases and establishing temporary negative-pressure and/or protective environments were determined by a literature review. Relevant data were analyzed and synthesized to generate a response algorithm. Results: Ideal patient management and placement guidelines, including instructions for choosing respiratory protection and creating temporary negative-pressure or other protective environments, were delineated. Findings were summarized in a treatment algorithm. Conclusion: The threat of bioterrorism and emerging infections increases health care's need for negative-pressure and/or protective environments. The algorithm outlines appropriate response steps to decrease transmission risk until an ideal protective environment can be utilized. Using this algorithm will prepare infection control professionals to respond more effectively during a surge of potentially infectious patients following a bioterrorism attack or emerging infectious disease outbreak. (Am J Infect Control 2005;33:571-9.) Terrorist attacks using biologic agents pose a substantial threat to the safety, health, and security of US citizens. As the 2001 anthrax attacks illustrated, only a small amount of agent is required to have a tremendous impact in terms of morbidity, costs, and mental health effects. [bib_ref] The role of an advanced practice public health nurse in bioterrorism preparedness, Mondy [/bib_ref] These consequences would likely have been exponentially greater if the terrorists had utilized an agent that causes a communicable disease because this could have resulted in the rapid spread of secondary infections. [bib_ref] The role of an advanced practice public health nurse in bioterrorism preparedness, Mondy [/bib_ref] According to the Centers for Disease Control and Prevention (CDC), terrorists are likely to choose an agent that would result in the greatest terror or mass casualties.In this regard, infectious agents that are spread via airborne droplet nuclei, such as smallpox, have the potential for a massive public health impact.Any infectious disease spread by droplet nuclei, such as smallpox, Mycobacterium tuberculosis (TB), and Severe Acute Respiratory Syndrome (SARS), poses a threat to the health of other patients, staff, and visitors in the hospital setting. There is no single way to protect susceptible persons from transmission; it is recommended that a combination of methods be used. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] For hospitalized patients, airborne precautions are used to decrease health care-associated spread of airborne-spread diseases. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] This category of isolation precautions consists of protective measures designed to remove as many of the droplet nuclei from the air as possible and eliminate the risk of inhalation by susceptible people. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Airborne precautions consist of engineering controls, such as the use of a negativepressure environment, and the use of personal protective equipment in the form of respirators. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] One major challenge to airborne precautions adherence is the well-documented lack of negativepressure rooms available in hospitals. [bib_ref] Evaluation of rooms with negative-pressure ventilation used for respiratory isolation in seven..., Fraser [/bib_ref] [bib_ref] Improved tuberculosis infection control practices in Maryland acute care hospitals, Fuss [/bib_ref] [bib_ref] The challenge of hospital infection control during a response to bioterrorist attacks, Grow [/bib_ref] [bib_ref] APIC and CDC survey of Mycobacterium tuberculosis isolation and control practices in..., Kellerman [/bib_ref] In addition, research conducted in the early 1990s indicates that many rooms designed to be negative pressure do not consistently function as required. [bib_ref] Evaluation of rooms with negative-pressure ventilation used for respiratory isolation in seven..., Fraser [/bib_ref] [bib_ref] A ventilation-filtration unit for respiratory isolation, Marier [/bib_ref] In a more recent study conducted in 10 St. Louis hospitals, this finding was reaffirmed: only 51% of the negativepressure rooms tested functioned properly. [bib_ref] Follow-up evaluation of respiratory isolation rooms in 10 Midwestern hospitals, Dahl [/bib_ref] Even the monitoring systems installed to verify continuously that negative pressure was maintained were found to be faulty. When smoke testing was conducted to verify negative-pressure functioning in rooms with a continuous monitoring system, only 50% were found to actually be negative pressure. [bib_ref] Negative-pressure monitoring of tuberculosis isolation rooms within New York State hospitals, Pavelchak [/bib_ref] Nonfunctioning negative-pressure rooms are believed to contribute to health care-associated outbreaks of TB [bib_ref] Evaluation of rooms with negative-pressure ventilation used for respiratory isolation in seven..., Fraser [/bib_ref] and could therefore be an exposure risk for other infectious agents, such as smallpox and SARS. Despite the lack of properly functioning negativepressure rooms, the need for health care facility negative-pressure rooms continues to increase. This was illustrated by the recent outbreak of SARS in Toronto, Canada. As the number of SARS cases increased, the need for negative-pressure facilities increased at an almost parallel rate. [bib_ref] Responding to the severe acute respiratory syndrome (SARS) outbreak: lessons learned in..., Farquharson [/bib_ref] In response, Mount Sinai Hospital in Toronto was forced to expand its number of negative-pressure beds 7-fold, and future expansions are under consideration. [bib_ref] Responding to the severe acute respiratory syndrome (SARS) outbreak: lessons learned in..., Farquharson [/bib_ref] It has been estimated that Canada's 3 to 4 month outbreak of SARS cost $1.5 to $2 billion. 14 US hospitals can learn from Toronto's SARS experience and examine the potential consequences of a bioterrorism attack using smallpox or an outbreak of SARS in which many additional negative-pressure rooms or protected environments may be required to help contain disease spread. This includes anticipating the growing need for additional negative-pressure rooms or alternative protective environments. Long-term solutions include the construction of new negative-pressure rooms or units, purchasing portable isolation units that can be quickly assembled, maintaining or repairing current rooms, or retrofitting existing rooms. [bib_ref] Controlling the exotic diseases: 1. Isolation facilities, Clayton [/bib_ref] [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] Unfortunately, these options are extremely costly and require extensive time and planning. [bib_ref] Controlling the exotic diseases: 1. Isolation facilities, Clayton [/bib_ref] [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] In the interim, decisions must be made concerning how and where to house safely the potentially infectious patients. Previous publications have outlined appropriate planning and response steps for bioterrorism and emerging infections. [bib_ref] The challenge of hospital infection control during a response to bioterrorist attacks, Grow [/bib_ref] [bib_ref] Responding to the severe acute respiratory syndrome (SARS) outbreak: lessons learned in..., Farquharson [/bib_ref] [bib_ref] Controlling the exotic diseases: 1. Isolation facilities, Clayton [/bib_ref] However, these publications either assume that negative-pressure rooms are available and functioning or that patients will be transported immediately to appropriate facilities. They do not identify alternative options for responding in suboptimal situations, such as when a negative-pressure environment is not available. Although alternative arrangements for a negative-pressure environment are not completely protective, they do offer some degree of protection and help reduce disease transmission risk. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] In addition, a clear algorithm is needed to outline the order of response steps that should be implemented to maximize existing protective environments until ideal isolation can be established. Purpose statement: This article's purpose is to provide infection control professionals (ICP), health care epidemiologists, or hospital disaster planners an algorithm for patient management following a bioterrorism attack or naturally occurring infectious disease outbreak that is airborne spread, such as smallpox, SARS, and TB. This algorithm will guide users on proper patient management and placement to decrease secondary exposure risk. It should be noted that this algorithm is designed for patient management during small airborne infectious disease outbreaks following a bioterrorism attack or emergence of a new pathogen involving a slow trickle of patients, such as the early onset of SARS in Canada.If a large-scale bioterrorism attack that results in hundreds or thousands of victims occurred, different response strategies would be required, such as the creation of very large negative-pressure areas or physically isolated areas for contagious patients. Examples of such systems have been delineated in the literature. [bib_ref] Use of a portable forced air system to convert existing hospital space..., Rosenbaum [/bib_ref] The algorithm and guidelines in this article should be used as part of a facility's disaster planning efforts because many of the recommendations require advanced planning to implement. ICPs and hospital epidemiologists play a critical role in hospital disaster planning, but a multidisciplinary approach should be utilized. Decisions regarding placement for potentially infectious patients should be coordinated among the ICP, hospital epidemiologist, administration, facilities engineering professionals, and others. # Methods A literature review was conducted using the following key terms in Medline, PubMed, and CINAHL databases: negative pressure, ventilation, filtration, respiratory isolation, and airborne isolation. In addition, the snowballing technique (identifying relevant references from the reference list of other publications) and expert consultation were utilized. Only English language research articles in peer-reviewed journals, national organization publications, and book chapters that discuss methods of and provide empirical evidence related to airborne isolation and/or establishing negative air pressure for rooms/areas were utilized. Editorials, articles published in nonpeer reviewed journals or those that address negative pressure unrelated to room air balance, and non-English language articles were excluded. Abstracts and titles were screened, and only those that met the aforementioned criteria were considered. From a total of 86 titles and abstracts, only 13 met the criteria. Searching the reference lists of these and consulting environmental health experts resulted in an additional 11 relevant publications, for a total of 24 articles. Data from the 24 relevant articles were extracted; specifically, details of patients/samples, intervention, study type, study quality, and results were recorded in a spreadsheet. Studies were grouped by topic and quality of evidence, with randomized controlled trials assumed to provide the best evidence. Nonrandomized and other study designs were considered to provide less reliable evidence. Next, components were compiled into a visual step-by-step process. After the initial analysis was completed, the findings were discussed with content experts, and minor adjustments were made when applicable. # Results Based on information identified in the literature review, a response algorithm for airborne infection isolation patient management and placement was developed (see [fig_ref] Fig 1: Patient management and placement for airborne precautions respiratory protection, [/fig_ref]. This algorithm can be used by all health care facilities that need to manage safely and isolate patients with diseases or conditions that can be transmitted via airborne droplet nuclei. For entities that do not have adequate numbers of properly functioning negative-pressure rooms, this algorithm provides guidance for temporary solutions regarding room selection and creation of safer environments for staff, patients, and visitors. Droplet nuclei are small airborne particles (#5 m in size) that are expelled when infected patients sneeze or cough. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] Eventually, these particles will settle to the ground, but they can remain suspended in the air for hours unless they are removed by ventilation or filtration. [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] As long as droplet nuclei are airborne, they remain a risk to nearby susceptible people, who can inhale the particles and become infected. Airborne precautions encompass a category of measures needed to prevent the spread of organisms that can be transmitted by airborne droplet nuclei. 4,5 See [fig_ref] Table 1: Disease/condition requiring airborne isolation precautions 4Chickenpox [/fig_ref] for a list of diseases and conditions that require airborne precautions and how long they are needed. The first group of infection control measures related to airborne precautions involves engineering controls to redirect, remove, or filter infectious particles from the air. This is accomplished by the use of ventilation and filtration or a combination of these measures. [bib_ref] A ventilation-filtration unit for respiratory isolation, Marier [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] The second group of airborne precautions infection control measures involves protection of susceptible persons. Precautions include wearing appropriate [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] having immune staff care for infected patients when applicable (eg, staff immunized against the patient's disease), limiting patient transport, and restricting the number of staff going into airborne isolation rooms. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Protective measures for airborne precautions, such as appropriate respiratory protection, have been well delineated in the literature. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Use of a portable forced air system to convert existing hospital space..., Rosenbaum [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] The algorithm in [fig_ref] Fig 1: Patient management and placement for airborne precautions respiratory protection, [/fig_ref] response steps needed to address both groups of airborne precautions infection control measures: decreasing the bioburden of infectious particles in the air and reducing the risk to susceptible people. The results from the literature review are summarized in the order depicted on the response algorithm, starting with the most protective measures and working toward the least. The algorithm and the results section delineate the appropriate order in which the steps should be instituted to provide the best protection by reducing the risk of secondary spread. ## Choosing respiratory protection As soon as a patient is suspected of having an airborne-spread disease, protective measures must be implemented. Respiratory protection is the first protective measure. Health care workers should wear an N-95 mask or powered air purifying respirator (PAPR) when in the patient's room. A surgical mask should be placed on patients who are to be transported. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Room placement Ideally, infected patients are placed in an airborne infectious isolation room (AIIR) that meets specific engineering controls that limit or prevent the spread of infectious particles to people outside the room. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] AIIRs decrease the health care-associated transmission risk by redirecting contaminated air in the patient's room to the outside environment and/or filtering it before recirculation. This protects susceptible staff, patients, and visitors outside the AIIR against exposure to the infectious aerosols. However, staff and visitors who enter AIIRs must wear N-95 respirators or PAPRs to protect themselves from inhaling aerosolized infectious particles. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Requirements for AIIRs include the following: (1) negative air pressure (in which the air flows from the adjacent corridor into the patient's isolation room), (2) a minimum of 6 to12 air changes per hour, (3) room air exhausted directly to the outside or filtered through a high-efficiency particulate air (HEPA) filter before recirculation, and (4) keeping the door to the room closed except when entering/leaving the room. [bib_ref] A ventilation-filtration unit for respiratory isolation, Marier [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Whenever possible, an isolation room with an anteroom is preferable because it will further decrease the risk of droplet nuclei escaping from the infected patient's room. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] It does not matter whether the anteroom is positive or negative pressure in relation to the corridor, but it must be positive pressure in relation to the isolation room to be effective. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] If a negative-pressure room is available, its functioning should be verified, and the patient should be transported to the room as soon as possible. [bib_ref] Evaluation of rooms with negative-pressure ventilation used for respiratory isolation in seven..., Fraser [/bib_ref] [bib_ref] Negative-pressure monitoring of tuberculosis isolation rooms within New York State hospitals, Pavelchak [/bib_ref] An isolation gown or linen sheet should be placed on the patient before transfer from the room, making sure to cover as much as the patient as possible. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Covering the patient before transport reduces the risk of cross contamination from the patient. In addition, a surgical mask should be placed on the patient before transport. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] If a traditional AIIR is not available, the use of a Discontinue precautions only after patient is on effective therapy, is clinically improving, and has 3 consecutive negative sputum smears collected on different days or TB is ruled out. Viral hemorrhagic fever Maintain precautions for duration of illness. Airborne precautions for VHFs are not reflected in HICPAC's isolation guidelines, but more recent research indicates the need to implement these precautions when feasible. In mass casualty events in which negative pressure is not available, strict adherence to isolation precautions outlined by the JAMA consensus article will help reduce the risk of transmission. [bib_ref] Hemorrhagic fever viruses as biological weapons: medical and public health management, Borio [/bib_ref] negative-pressure enclosure, such as a tent or booth, is the next best option. [bib_ref] Use of a portable forced air system to convert existing hospital space..., Rosenbaum [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Many portable tent or booth setups are commercially available, but they are cost prohibitive for many hospitals. [bib_ref] Controlling the exotic diseases: 1. Isolation facilities, Clayton [/bib_ref] [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] A less expensive alternative has been delineated in the literature but requires preplanning. [bib_ref] Use of a portable forced air system to convert existing hospital space..., Rosenbaum [/bib_ref] What should be done if there are no available negative-pressure rooms or enclosures and your facility does not have prearranged plans for rapid creation of such? When feasible, the patient should be transferred to a facility with a functioning negative-pressure room as soon as possible, [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] but, in the interim, response steps must be implemented to protect hospital staff, patients, and visitors. If traditional negative-pressure rooms or enclosures are not available, appropriate patient placement for airborne precautions must be a multidisciplinary decision among the ICP, health care epidemiologist, facilities engineering, environmental health and safety, administration, medical staff, and others. ## Temporary negative pressure As an interim measure, temporary negative pressure can be obtained by 1 of 4 methods. provides detailed instructions on how to achieve temporary negative pressure with interventions ordered by preference. All methods of establishing temporary negative pressure should be utilized as interim protective measures only. Patients should be transported to a room with verified negative-pressure functionality as soon as possible to provide the best protection against infection transmission. Bleeding air from the room through fixed or portable room air recirculation systems or using a centrifugal blower to exhaust air directly to the outside from the patient's room are the best options for achieving temporary negative pressure (See for more information). [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Room air recirculation units are more effective than exhausting air outside using a centrifugal blower and are, therefore, preferable. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] If room air recirculation units are not available and a centrifugal blower will be used to create negative pressure, the unit must be set up to exhaust air out through a window. [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] As with standard negative-pressure rooms, the door to the room must be kept closed. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] As an alternative to a centrifugal blower, some air cleaners can also be utilized, but they must be designed specifically for this purpose. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Traditional floor or window fans can also be used to create temporary negative pressure, although this should only be done as a last resort because it is the least effective option and can actually contribute to transmission if set up incorrectly (See and [fig_ref] Fig 2: Appropriate placement of floor and/or window fans to facilitate removal of contaminated... [/fig_ref]. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] Used alone to create wind in a room, fans only serve to recirculate airborne infectious particles; this could actually increase rather than decrease the risk of transmission. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] However, fans are effective at redirecting infectious particles and thus decreasing the room's bioburden if they are positioned correctly. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] [fig_ref] Fig 2: Appropriate placement of floor and/or window fans to facilitate removal of contaminated... [/fig_ref] provides a visual depiction of appropriate fan setup and some necessary instructions. Because fresh air generally comes from outdoors and is directed in through open windows or doors (something that is not feasible in most hospitals), the use of a floor or window fan to help increase circulation or redirect infectious particles from the contaminated room may not be a viable option. Consult facilities engineering and/or environmental health and safety when considering establishing temporary negative pressure through any method of exhausting room air. Although this is an easy task to accomplish, the remainder of the facility can suffer from an air pressure imbalance if steps are not taken to replace the loss of air in the room. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] In addition, the room from which to exhaust contaminated air should be chosen carefully; if contaminated air is exhausted near intake vents, open windows, or nearby susceptible people, infection transmission can occur. [bib_ref] A ventilation-filtration unit for respiratory isolation, Marier [/bib_ref] The room chosen should meet the following criteria: (1) have a window that is $25 feet away from air intakes or other open windows and (2) be more than 100 yards from another occupied building or high-risk area.If any temporary method of obtaining negative pressure is utilized, it must be discontinued as soon as possible because it does not provide the correct mix of fresh air for comfort and poses a risk to those near the exhaust site. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Various organizations and regulatory agencies, including the American Institute of Architects and the American Society of Heating, Refrigerating, and Air-Conditioning Engineers, provide guidelines . Methods of establishing temporary negative pressure Methods to obtain temporary negative pressure (in order of preference): (1) Bleed air* from the room through a fixed room air recirculation system (2) Bleed air* from the room through a portable room air recirculation system (3) Use a centrifugal blower to exhaust air outside from the patient's room (the unit must be set up to exhaust air out through a window y ) (4) Use a specifically designed air cleaner to exhaust air outside from the patient's room (the unit must be set up to exhaust air out through a window y ) (5) Use floor and/or window fans to exhaust air outside the patient's room z *Remove appropriate amount of air volume to achieve negative pressure (to remove more air than flows into the room). and recommendations regarding safe exhaust of potentially contaminated air. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] These guidelines should be consulted prior to instituting temporary negative-pressure systems. Setting up temporary negative-pressure rooms/areas requires preplanning and a multidisciplinary approach. This must be included in hospital disaster planning efforts. If negative pressure is not available and cannot be temporarily achieved, other interim measures need to be implemented to prevent the transmission of airborne-spread diseases. The heating, ventilation, and air conditioning (HVAC) systems of the patient's room and facility need to be evaluated to determine proper patient placement and filtration intervention needs. Ventilation systems that recirculate air pose a hazard if contaminated air exhausted from the room of infected patients is not filtered prior to discharging it into the general ventilation system and recirculating it to clean areas. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Contaminated air must either be discharged to the outside away from air intakes or filtered prior to recirculation. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Filtration options consist of induct or portable filtration systems/units. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] In-duct HEPA filter systems are more effective at removing infectious particles than portable filtration units and are, therefore, the preferred method of recirculating contaminated air. [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] [bib_ref] An industrial hygiene approach to tuberculosis control, Conroy [/bib_ref] Although the efficacy of HEPA-filtration removal of some organisms believed to be spread by droplet nuclei, such as smallpox and SARS, has never been evaluated, research indicates that HEPA filters effectively remove other particles that are the same size as droplet nuclei, such as Aspergillus spores. [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] Therefore, HEPA filters would most likely be effective at removing droplet nuclei and other particles in the 1 to 5 m size range. In the absence of negative-pressure rooms or in-duct HEPA filters, 2 interventions will help decrease the transmission risk of infections spread via droplet nuclei: (1) physical isolation of the patient and (2) use of portable HEPA-filtration units. [bib_ref] APIC and CDC survey of Mycobacterium tuberculosis isolation and control practices in..., Kellerman [/bib_ref] [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities, Centers For [/bib_ref] The first intervention, physical isolation, should be implemented regardless of whether portable filtration units are available. Physical isolation consists of placing potentially infectious individuals in a room as far away from others as possible and keeping the door to the room closed as much as possible. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] For patients with smallpox, physical isolation was historically accomplished through home isolation or the creation of smallpox wards or facilities. [bib_ref] Smallpox as a biological weapon: medical and public health management. Working Group..., Henderson [/bib_ref] More recently, home quarantine (for contacts of SARS) and development of physically isolated wards (for patients with SARS) were again utilized to help prevent the spread of disease.In addition to physical isolation, engineering controls will decrease the air's bioburden that will in turn help prevent transmission. [bib_ref] An industrial hygiene approach to tuberculosis control, Conroy [/bib_ref] The first engineering control is to shut down the HVAC system in the patient's room when possible. However, this should only be done if it will not affect the HVAC system to the rest of the hospital.The final engineering control involves the use of portable HEPA-filtration units. Portable HEPA units work in 2 ways: (1) they filter airborne contaminants from room air, and (2) they help increase the number of air changes per hour, which further improves the number of airborne contaminants removed from the room. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] Although they are not 100% effective at removing infectious particles from the air, portable HEPA-filtration units provide more protection than the regular HVAC system alone, which only reduces particle concentrations by 34%. [bib_ref] Effect of ventilation and filtration on submicrometer particles in an indoor environment, Jamriska [/bib_ref] HEPA filtration units remove $99.97% of 0.3 m size and 100% of larger size particles (such as droplet nuclei) from the air but require time to filter an entire room's air volume. [bib_ref] Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control, Miller-Leiden [/bib_ref] [bib_ref] An industrial hygiene approach to tuberculosis control, Conroy [/bib_ref] [bib_ref] An evaluation of portable high-efficiency particulate air filtration for expedient patient isolation..., Mead [/bib_ref] A HEPA-filtration unit can clear 90% of particles in a 760 cubic foot room within 5 minutes compared with $120 minutes needed in a room without a HEPAfiltration unit, but clearance times also depend on the room's airflow rate. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] Portable filtration units do not eliminate secondary transmission risk to staff, visitors, or other patients either in or outside the room. However, portable HEPA units do decrease the droplet nuclei bioburden in the air, which reduces the risk of secondary transmission. [bib_ref] An industrial hygiene approach to tuberculosis control, Conroy [/bib_ref] Although not completely protective, this is far superior to using only the facility's standard HVAC system. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] [bib_ref] An industrial hygiene approach to tuberculosis control, Conroy [/bib_ref] [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] A second fan must be utilized to help draw contaminated air from the room at the same rate at which the fan at the door is drawing air into the room. [bib_ref] Portable HEPA filtration for TB isolation in hospitals and clinics, Tepper [/bib_ref] The fan in the window must be facing the outside of the building to direct air outward, and the window must be open. If the room's windows do not open, this fan system must not be utilized; the wind created by such a set-up may actually lead to an increased risk of transmission. [bib_ref] Reducing the spread of tuberculosis in your workplace, Hodge [/bib_ref] Many manufacturers recommend that portable HEPA-filtration units be placed in the center of the room, but this is not feasible in hospital settings. In addition, a 1995 study by Rutala et al illustrated that this is also not necessary. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] Rutala et al found that the filtration units were effective regardless of placement in the room. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] The overall portable filtration unit effectiveness depended on the air's bioburden of infectious particles, the facility's HVAC system, and the individual room's airflow rate and size. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] Therefore, portable filtration units should be placed as close to the patient as possible, without interfering with staff work flow or medical equipment in the room. [bib_ref] An evaluation of portable high-efficiency particulate air filtration for expedient patient isolation..., Mead [/bib_ref] In addition, health care providers should not stand between the patient and the portable HEPA unit's air intake because this can increase their exposure risk. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] [bib_ref] An evaluation of portable high-efficiency particulate air filtration for expedient patient isolation..., Mead [/bib_ref] Disadvantages to the use of portable filtration units include physical obstruction, air drafts, and noise. [bib_ref] Efficacy of portable filtration units in reducing aerosolized particles in the size..., Rutala [/bib_ref] In addition, the associated costs of purchasing and running one or more of these units may make them cost prohibitive for many hospitals. Prices range from $1000 to $2200 per unit and another $100 per year for filter replacements, and there is an uncalculated associated cost for electricity to power the machine(s). [bib_ref] An evaluation of portable high-efficiency particulate air filtration for expedient patient isolation..., Mead [/bib_ref] [bib_ref] Performance and costs of particle air filtration technologies, Fisk [/bib_ref] [bib_ref] Costs associated with tuberculosis control programs at hospitals caring for children, Kellerman [/bib_ref] Although $1000 per machine is a relatively inexpensive investment for disaster preparedness, the actual cost to a hospital would be exponentially higher in a mass casualty incident, such as a large smallpox or SARS outbreak, when hundreds of such machines might be needed. ## Other patient management issues After the patient has been transported to another room, whether internally or externally, the room in which the patient was originally housed may require decontamination before the next patient can be safely admitted. Some diseases, such as SARS and smallpox, can be spread by hand-to-mouth transfer of infectious particles because of direct contact with patient secretions or contaminated materials (ie., contact) and airborne droplet nuclei; these patients require both airborne and contact precautions. One component of contact precautions is thorough environmental decontamination to prevent transmission. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Therefore, all horizontal surfaces and inanimate objects in the contaminated vacated room must be decontaminated before the next patient is admitted.Hospital decontamination protocols should be followed. This will not apply to all patients. Decontamination is only needed for the rooms of patients on contact precautions in addition to airborne precautions. [bib_ref] Guidelines for isolation precautions in hospitals, Garner [/bib_ref] Once the patient is housed in the safest environment possible, the ICP or hospital epidemiologist must be notified (unless they had been consulted during patient placement). In addition, other groups or departments identified by hospital infection control policies should also be notified at this time. Hospital reporting and notification policies and procedures should always be followed. If the patient is suspected of having a reportable, communicable disease as defined by the facility's state department of health, this incident should be reported to the local health department. [bib_ref] Case definitions for public health surveillance, Wharton [/bib_ref] Hospital policy and state health department reporting regulations should always be followed. [bib_ref] Case definitions for public health surveillance, Wharton [/bib_ref] It is imperative that early, accurate, and complete reporting be made to the local health department. Efforts to include this critical aspect of public health must begin with early collaboration. While awaiting diagnosis confirmation, it is prudent to begin a list of potentially exposed individuals. This will aid in the health department's epidemiologic investigation if a communicable disease, such as TB, SARS, or smallpox, is confirmed. Utilize CDC definitions of a ''contact'' to determine the list of potentially exposed individuals. [bib_ref] Case definitions for public health surveillance, Wharton [/bib_ref] The definition of a ''contact'' should be based on the specific suspected diagnosis because the definition can differ between infectious diseases. 32 # Discussion Preventing the transmission of airborne-spread diseases remains a challenge for hospitals. A combination of protective measures aimed at decreasing the air's bioburden of infectious particles and reducing the risk to susceptible people must be employed. Engineering controls, such as the use of properly functioning negative-pressure rooms or enclosures, and infection control measures, such as respirator use, play a significant role in decreasing the spread of airbornespread diseases. Unfortunately, many hospitals do not have adequate negative-pressure rooms available, and some of these rooms' airflow systems do not function properly. As the need for airborne precautions increases because of the risks of SARS, smallpox, and other bioterrorist or emerging infectious conditions, hospitals must develop plans to accommodate safely the potential surges of these patients. Adequate numbers of properly functioning negative-pressure rooms or areas are the ideal to which all health care facilities must aspire. Hospital disaster planners must address ways to accommodate not only surge capacity for mass casualties but also, and more specifically, a surge of potentially airborne infectious patients. This includes development of a plan to mobilize negative-pressure beds or areas rapidly should such a need arise. This must be a priority for US hospitals. However, accommodations for new negative-pressure rooms or enclosures are costly; sources for such endeavors are outside this article's scope but must be addressed. In the interim, alternative options are needed until new negative-pressure facilities can be created, repaired, or retrofitted or until a potentially infectious patient can be transferred to a facility with properly functioning negative pressure. The algorithm depicted in [fig_ref] Fig 1: Patient management and placement for airborne precautions respiratory protection, [/fig_ref]. Use of this algorithm should help prepare ICPs and hospital epidemiologists to respond better to a bioterrorism attack or airbornespread infectious disease outbreak by providing guidelines for proper patient management and placement. This article's algorithm is designed for patient management during the early onset of a bioterrorism attack or emerging infectious disease outbreak. It will be most helpful as a planning tool for ICPs and hospitals and as a response algorithm during a slow surge of potentially infectious patients. Under other scenarios, such as a large-scale bioterrorism attack that results in hundreds or thousands of victims, the usefulness of these recommendations may be limited. Hospitals must plan for both small and large infectious disease outbreak scenarios. This algorithm is one option for addressing these needs but is not the solution for all US hospital negative-pressure surge capacity issues. Future initiatives need to evaluate the current numbers of negative-pressure rooms available in US hospitals, the total available occupancy, and the percentage of those that meet the functional standard. In addition, cost-effective approaches to development of large negative-pressure areas that can be mobilized rapidly after a bioterrorism attack or infectious disease outbreak must be identified. Furthermore, the best locations within or around the facility for the placement of isolation rooms/areas need to be determined. Hospital disaster plans must address these issues. [fig] Fig 1: Patient management and placement for airborne precautions respiratory protection, [/fig] [fig] Fig 2: Appropriate placement of floor and/or window fans to facilitate removal of contaminated air. For visual clarity, the door appears open in the picture but should always remain closed, except when staff need to enter or exit the room. A floor or table fan should be placed near the doorway pointing toward the window fan. Never point a fan toward the patient's door because this can facilitate the spread of infectious particles into the corridor. [/fig] [table] Table 1: Disease/condition requiring airborne isolation precautions 4Chickenpox (Varicella)Maintain precautions until all lesions are crusted. For exposed susceptible individuals, begin precautions 10 days after exposure and continue until 21 days after last exposure (up to 28 days if VZIG given). [/table]	None	http://www.ajicjournal.org/article/S019665530500581X/pdf	None
90baf6658515074723eff9918fed0499b175a7d8	pubmed	Consensus guidelines for managing the airway in patients with COVID‐19	Consensus guidelines for managing the airway in patients with COVID‐19 # Introduction This consensus statement has been brought together at short notice to advise on airway management for patients with coronavirus disease 2019 . It applies to all those who manage the airway ('airway managers'). It draws on several sources including relevant literature but more immediately from information from clinicians practicing in China, Italy and airway experts in the UK. It is probably incomplete but aims to provide an overview of principles. It The one-page summary [fig_ref] Figure 1: One-page summary for emergency tracheal intubation of the coronavirus disease 2019 patient [/fig_ref] may be useful as a stand-alone resource, and the principles of safe, accurate and swift management must always be considered [fig_ref] Figure 2: Principles of coronavirus disease 2019 airway management [/fig_ref]. The full paper is likely to be of greater value as a reference when planning local services. The advice is based on available evidence and consensus at the time of writing, in what is a fast-moving arena. Some references refer to English or UK governmental sites for up-to-date advice. Those practicing in other countries should be aware that advice in their country may differ and is regularly updated, so they should also refer to their own national guidance. ## Covid-19: the need for airway interventions and risks to airway managers Severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2), which causes COVID-19, is a single-stranded ribonucleic acid -encapsulated corona virus and is highly contagious. Transmission is thought to be predominantly by droplet spread (i.e. relatively large particles that settle from the air), and direct contact with the patient or contaminated surfaces (fomites), rather than airborne spread, in which smaller particles remain in the air longer [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] [bib_ref] Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1, Van Doremalen [/bib_ref]. Procedures during initial airway management and in the intensive care unit (ICU) may generate aerosols which will increase risk of transmission [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref]. Healthcare workers (HCW) treating patients with COVID-19 are at increased risk of contracting the illness [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref] [bib_ref] Clinical characteristics of Coronavirus disease 2019 in China, Guan [/bib_ref]. The predominant COVID-19 illness is a viral pneumonia. Airway interventions are mainly required for tracheal intubation and establishing controlled ventilation. However, as the epidemic increases, there will be many patients in the community with COVID-19 who are asymptomatic or have mild disease. These patients may present for emergency surgery for unrelated conditions. ## Staff safety The highest viral load of SARS-CoV-2 appears in the sputum and upper airway secretions [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref]. Tracheal intubation is a potentially high-risk procedure for the airway manager, particularly as it risks exposure to a high viral load and if transmission occurs to HCWs, this may be associated with more severe illness [bib_ref] Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. For this reason, airway managers should take appropriate precautions. This is clearly an area of great importance [bib_ref] Staff safety during emergency airway management for COVID-19 in Hong Kong, Cheung [/bib_ref]. Whereas this article focuses predominantly on management of the airway, staff protection is too important not to include. We discuss in brief: aerosol-generating procedures and personal protective equipment are only one part of a system to reduce viral exposure. There is extensive advice which is updated regularly on infection prevention and control related to COVID-19. and tracheal suction without a 'closed in-line system.' ## Aerosol-generating procedures Transmission of infection is also likely to be possible from faeces and blood although detection of virus in the blood is relatively infrequent [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref]. ## High-flow and low-flow nasal oxygen There is much debate about the degree to which high-flow nasal oxygen is aerosol-generating and the associated risk of pathogen transmission. Older machines may expose staff to greater risk. The risk of bacterial transmission has been assessed as low [bib_ref] Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial..., Leung [/bib_ref] , but the risk of viral spread has not been studied. There are other reasons not to use high-flow nasal oxygen in a situation of mass illness and mass mechanical ventilation. First, it may simply delay tracheal intubation in those for whom treatment escalation is appropriate [bib_ref] High-flow nasal oxygen therapy in intensive care and anaesthesia, Renda [/bib_ref]. Second, the very high oxygen usage risks depleting oxygen stores, which is a risk as a hospital's oxygen usage may increase many-fold during an epidemic. For all these reasons, high-flow nasal oxygen is not currently recommended for these patients around the time of tracheal intubation. Low-flow nasal oxygen (i.e. < 5 l.min À1 via normal nasal cannula) may provide some oxygenation during apnoea and might therefore delay or reduce the extent of hypoxaemia during tracheal intubation. There is no evidence we are aware of regarding its ability to generate viral aerosols, but on balance of likelihood, considering the evidence with high-flow nasal oxygen, this appears unlikely. It is neither recommended nor recommended against during emergency tracheal intubation of patients who are likely to have a short safe apnoea time. In patients who are not hypoxaemic, without risk factors for a short safe apnoea time, and who are predicted to be easy to intubate, it is not recommended. Systems to prevent contamination of healthcare workers, including personal protective equipment Personal protective equipment (PPE) forms only one part of a system to prevent contamination and infection of HCWs during patient care. In addition to PPE, procedures such as decontamination of surfaces and equipment, minimising unnecessary patient and surface contact and careful waste management are essential for risk reduction. The virus can remain viable in the air for a prolonged period and on nonabsorbent surfaces for many hours or even days [bib_ref] Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1, Van Doremalen [/bib_ref]. The importance of cleaning, equipment decontamination and correct use of PPE use cannot be overstated. In the SARS epidemic, which was also caused by a corona virus, HCW were at very high risk for infection, but reliable use of PPE significantly reduced this risk [bib_ref] SARS safety and science, Nicolle [/bib_ref] [bib_ref] SARS among critical care nurses, Loeb [/bib_ref].. It has been suggested that double-gloving for tracheal intubation might provide extra protection and minimise spread by fomite contamination of equipment and surrounds [bib_ref] Effect of single-versus double gloving on virus transfer to health care workers'..., Casanova [/bib_ref]. Fogging of googles and/or eyewear when using PPE is a practical problem for tracheal intubation in up to 80% of cases (personal communication Huafeng Wei, USA); anti-fog measures and iodophor or liquid soap may improve this. Training and practising PPE use before patient management is essential for staff and patient safety. Ideally, patients are managed in single, negative pressure rooms with good rates of air exchange (> 12 exchanges per hour) to minimise risk of airborne exposure [bib_ref] Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus..., Wax [/bib_ref]. In reality, many ICU side rooms do not meet this standard and, when critical care is expanded to areas outside of ICU, airway management may take place in rooms with positive pressure (e.g. operating theatres) or those with reduced air exchanges. Most operating theatres are positive pressure with high rates of air exchange. These factors may have implications for transmission risk, retention of aerosols and therefore what constitutes appropriate PPE [bib_ref] Role of air distribution in SARS transmission during the largest nosocomial outbreak..., Li [/bib_ref]. Guidance on PPE requirements after tracheal intubation is beyond the scope of this document. ## Tracheal intubation of the critically ill This is a high-risk procedure with physiological difficulty: around 10% of patients in this setting develop severe hypoxaemia (S p O 2 < 80%) and approximately 2% experience cardiac arrest [bib_ref] Airway challenges in critical care, Nolan [/bib_ref] [bib_ref] Guidelines for the management of tracheal intubation in critically ill adults, Higgs [/bib_ref]. These figures are likely to be higher for patients with severe COVID-19 and drive some of the principles below. The first-pass success rate of tracheal intubation in the critically ill is often < 80% with up to 20% of tracheal intubations taking > two attempts [bib_ref] Airway challenges in critical care, Nolan [/bib_ref]. Officer has written to all UK doctors to explain regulatory support for this. At its extreme peak, care may also be delivered by retired staff and medical students. Due to the high consequence nature of airway management in these patients, both for the patient and staff, it is recommended that these staff do not routinely take part in airway management of COVID-19 patients. In some circumstances, the development of a specific tracheal intubation team may be an appropriate solution where case load is sufficient. ## The most appropriate airway manager We recommend that the 'most appropriate' clinician manages the airway. This is to enable successful airway management that is safe, accurate and swift. Deciding who is the most appropriate airway manager requires consideration of factors such as the available clinicians' airway experience and expertise, whether they fall into any of the groups of clinicians who would be wise to avoid tracheal intubation, the predicted difficulty of airway management, its urgency and whether a tracheal intubation team is available. On occasion, this may necessitate senior anaesthetists managing airways in lieu of junior anaesthetists or intensivists who do not have an anaesthesia background. However, it is unlikely and unnecessary that tracheal intubation will be the exclusive preserve of one specialty. Judgement will be required. ## Staff who should avoid involvement in airway management This is a problematic area and there is no national guidance. In some locations, healthcare providers are excluding staff who are themselves considered high risk. Current evidence would include in this group: older staff (the mortality curve rises significantly > 60 years of age); cardiac disease; chronic respiratory disease; diabetes; recent cancer; and perhaps hypertension [bib_ref] Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref] [bib_ref] Clinical characteristics of Coronavirus disease 2019 in China, Guan [/bib_ref]. Whereas no clear evidence exists, it is logical to also not include staff who are immunosuppressed or pregnant from airway management of COVID-19 patients. ## Simulation Due to the uncertainties inherent in the new processes to be adopted, we recommend regular and full in-situ simulation of planned processes, to facilitate familiarity and identification of otherwise unidentified problems, before these processes are used in urgent and emergent patient care situations. ## Single vs. reusable equipment Where practical, single-use equipment should be used. However, where single-use equipment is not of the same quality as re-usable equipment this creates a conflict. It is also possible that supplies of single-use equipment may run short. The balance of risk to patients and staff (frontline and those involved in transport and decontamination of equipment) should be considered if a decision is made to use reusable airway equipment. We recommend use of the equipment most likely to be successful, while balancing the above factors. Reusable equipment will need appropriate decontamination. It is important to precisely follow manufacturer's instructions for decontamination of reusable equipment. ## When to intubate the critically ill covid-19 patient This document does not consider when patients' tracheas should be intubated. However, in order to avoid aerosolgenerating procedures, it is likely that patients' tracheas may be intubated earlier in the course of their illness than in other settings. ## Fundamentals of airway management for a patient with suspected or confirmed covid-19 Airway management for patients who are suspected or confirmed to have COVID-19 follows similar principles in both emergency and non-emergency settings [fig_ref] Figure 1: One-page summary for emergency tracheal intubation of the coronavirus disease 2019 patient [/fig_ref]. 12 Use a tracheal intubation checklist [fig_ref] Figure 7: Emergency tracheal intubation checklist in a patient with coronavirus disease 2019 [/fig_ref] and also see Supporting Information, Appendix S2). This is designed to aid preparedness and should be checked before entering the patient's room as part of preparation. 13 Use a cognitive aid if difficulty arises [fig_ref] Figure 8: Cognitive aids for use when managing unexpected difficulty when intubating a patient... [/fig_ref] Anaesthetic and airway technique for emergency tracheal intubation 1 A rapid sequence induction (RSI) approach is likely to be adopted. Use of cricoid force is controversial [bib_ref] The cricoid debate -balancing risks and benefits, Cook [/bib_ref] , so use it where a trained assistant can apply it but promptly remove it if it contributes to tracheal intubation difficulty. 2 Meticulous pre-oxygenation should be with a wellfitting mask for 3-5 min. A closed circuit is optimal (e.g. anaesthetic circle breathing circuit) and a rebreathing circuit (e.g. Mapleson's C ('Waters') circuit is preferable to a bag-mask which expels viruscontaining exhaled gas into the room. ## 20-30 cmh 2 o immediately after tracheal intubation. 15 Secure the tracheal tube as normal. 16 Start mechanical ventilation only after cuff inflation. Ensure there is no leak. 17 Confirm tracheal intubation with continuous waveform capnography. 18 Confirming correct depth of insertion may be difficult. a Auscultation of the chest is difficult when wearing airborne precaution PPE and is likely to risk contamination of the stethoscope and staff, so is not recommended. b Watching for equal bilateral chest wall expansion with ventilation is recommended. b Declare difficulty or failure to the team at each stage. c Mask ventilation may be deferred initially and a secondgeneration SGA used as an alternative between attempts at laryngoscopy. This may reduce aerosol generation due to improved airway seal d If an emergency FONA is required, the simplified DAS 2018 guidance should be followed [fig_ref] Figure 8: Cognitive aids for use when managing unexpected difficulty when intubating a patient... [/fig_ref] ## Predicted difficult airway The choice of airway technique in a predicted difficult airway will be specific to the patient's needs and is therefore beyond the scope of this guideline. Many techniques for managing the difficult airway will include potentially aerosol-generating proceduressee above. While there are reports from other countries of use of awake tracheal intubation note: a Topicalisation of the airway will need to be considered carefully to minimise aerosol-generating procedures and coughing. a Undertake appropriate physiotherapy and tracheal and oral suction as normal before extubation. b Prepare and check all necessary equipment for mask or low flow (< 5 l.min À1 ) nasal cannula oxygen delivery before extubation. c After extubation, ensure the patient immediately wears a facemask as well as their oxygen mask or nasal cannulae where this is practical. d During anaesthesia, drugs to minimise coughing at emergence include dexmedetomidine, lidocaine and opioids [bib_ref] Medications to reduce emergence coughing after general anaesthesia with tracheal intubation: a..., Tung [/bib_ref]. The value of these is unproven in critical care and needs to be balanced against adverse impact on respiratory drive, neuromuscular function and blood pressure. For these reasons, routine use is currently unlikely. e While an SGA may be considered as a bridge to extubation to minimise coughing this involves a second procedure and the possibility of airway difficulty after SGA placement so is unlikely to be a first-line procedure [bib_ref] The laryngeal mask airway as an adjunct to extubation on the intensive..., Glaisyer [/bib_ref] [bib_ref] Use of the ProSeal LMA in the ICU to facilitate weaning from..., Laver [/bib_ref]. f Likewise, the use of an airway exchange catheter is relatively contra-indicated in a patient with COVID-19 due to potential coughing etc. ## Airway management during cardiac arrest The UK Resuscitation Council has published statements on the management of cardiac arrest in patients with COVID-19. Airway procedures undertaken during management of cardiac arrest are likely to expose the rescuer to a risk of viral transmission. "The minimum PPE requirements to assess a patient, start chest compressions and establish monitoring of the cardiac arrest rhythm are an FFP3 facemask, eye protection, plastic apron, and gloves.". Avoid listening or feeling for breathing by placing your ear and cheek close to the patient's mouth. In the presence of a trained airway manager early tracheal intubation with a cuffed tracheal tube should be the aim. Before this, insertion of an SGA may enable ventilation of the lungs with less aerosol generation than facemask ventilation. In the absence of a trained airway manager, rescuers should use those airway techniques they are trained in. Insertion of an SGA should take priority over facemask ventilation to minimise aerosol generation. An SGA with a high seal pressure should be used in preference to one with a low seal. This will usually be a second-generation SGA where available. ## Airway management for anaesthesia While it is beyond the scope of this document to define which patients need precautions, it is worth noting that patients may be asymptomatic with COVID-19 but infective [bib_ref] Presumed asymptomatic carrier transmission of COVID-19, Bai [/bib_ref] [bib_ref] Transmission of 2019-nCoV infection from an asymptomatic contact in Germany, Rothe [/bib_ref] [bib_ref] Serial interval of novel coronavirus (2019-nCoV) infections, Nishiura [/bib_ref] , though symptomatic patients are more likely to pose a risk of transmission. During an epidemic, there should be a very low threshold for considering a patient at risk of being infective and it may become necessary to treat all airway interventions as high risk. Decisions around airway management should be undertaken using the fundamental principles described above. Airway management should be safe, accurate and swift. There is likely to be a lower threshold for use of an SGA over facemask ventilation and also a lower threshold for tracheal intubation. If using an SGA, spontaneous ventilation may be preferred to controlled ventilation, to avoid airway leak. Drug choices may differ from when intubating a patient with critical illness and, in particular if the patient is not systemically unwell, ketamine may not be chosen as the induction agent. Note that tracheal intubation is associated with more coughing at extubation than when an SGA is used. opioids (e.g. fentanyl, remifentanil) before extubation. # Conclusions The management of patients with known or suspected COVID-19 requires specific considerations to safety for staff and patients. Accuracy is critical, and clinicians should avoid unreliable, unfamiliar or repeated techniques during airway management, thus enabling it to be safe, accurate and swift. Swift care means that it is timely, without rush and similarly without delay. We have highlighted principles that may achieve these goals, but the details of these principles may be subject to change as new evidence emerges. [fig] Figure 1: One-page summary for emergency tracheal intubation of the coronavirus disease 2019 patient. [/fig] [fig] Figure 2: Principles of coronavirus disease 2019 airway management. [/fig] [fig] a: Institutionl preprtion (equipment for routine mngement nd for mnging difficulty; dequte numbers of ppropritely trined stff; vilbility of trchel intubtion checklists; PPE etc.) should be in plce well before irwy mngement occurs. If this does not lredy exist, it is strongly recommended it is put in plce urgently. Resources from this guideline my form prt of tht preprtion.b Tem nd individul preprtion require knowledge of the institutionl preprtion, the skills required, how to use PPE correctly nd ssessment of the ptient's irwy to predict difficulty nd prepre the irwy strtegy(Fig. 3). It is ccepted tht MACOCHA (Mlmptti, obstructive sleep pnoe, c-spine movement, mouth opening, com, hypoxemi, nonnesthetist intubtor[25]) is not widely used but it is vlidted nd recommended. [/fig] [fig] 23: Create a COVID-19 tracheal intubation trolley or pack. Critically ill patients may need to be intubated in a location other than ICU. On ICU, tracheal intubation will likely take place in single rooms. Prepare a tracheal intubation trolley or pack that can be taken to the patient and decontaminated after use. Have a strategy. The airway strategy (the primary plan and the rescue plans, and when they are transitioned to) should be in place and the airway team briefed before any part of airway management takes place. 4 Involve the smallest number of staff necessary.This is not an argument for solo operators but staff who have no direct role in the airway procedure should not unnecessarily be in the room where airway management is taking pace. Three individuals are likely required: an intubator; an assistant; and a third person to give drugs and watch monitors. A runner should be watching from outside and be able to summon help rapidly if needed(Fig. 4).5 Wear appropriate, checked PPE (see above). Even in an emergency and including cardiac arrest, PPE should be in worn and checked before all airway management and staff should not expose themselves to risk in any circumstance. 6 Avoid aerosol-generating procedures wherever possible. If a suitable alternative is available, use it. If aerosol generation takes place, the room is considered contaminated, airborne precaution PPE should be used and the room should be deep cleaned after 20 min [24].7 Focus on promptness and reliability. The aim is to achieve airway management successfully at the first attempt. Do not rush but make each attempt the best it can be. Multiple attempts are likely to increase risk to multiple staff and to patients. [/fig] [fig] 8Figure 3: Use techniques that are known to work reliably across a range of patients, including when difficulty is encountered. The actual technique may differ according to local practices and equipment. Where training and availability is in place this is likely to include: a Use of a kit dump mat (Fig. 5); b Videolaryngoscopy for tracheal intubation; c A 2-person 2-handed mask ventilation with a VE-grip (Fig. 6); d A second-generation supraglottic airway device (SGA)for airway rescue (e.g. i-gel, Ambu Aura Gain, LMA ProSeal, LMA Protector) MACOCHA score and prediction of difficult intubation. Adapted from[23]. [/fig] [fig] Figure 4, Figure 5: Personnel plan for tracheal intubation of a patient with coronavirus disease 2019. Adapted from[20]. Exemplar of kit dump mat. The emergency front-of-neck airway kit may be excluded from the airway kit dump due to the risk of contamination and could be placed outside of the room with immediate access if required.well, a sticker with the individual's name can be placed on the top of the visor to aid communication with other staff. [/fig] [fig] 3: Place a heat and moisture exchange (HME) filter between the catheter mount and the circuit. Noninvasive ventilation should be avoided. High-flow nasal oxygen is not recommended.4 Patient positioning, including ramping in the obese and reverse Trendelenburg positioning, should be adopted to maximise safe apnoea time. [/fig] [fig] 12: Intubate with a tracheal tube size 7.0-8.0 mm internal diameter (ID) in women or 8.0-9.0 mm ID in mens, in line with local practice. Use a tracheal tube with a subglottic suction port where possible.13 At tracheal intubation, place the tracheal tube without losing sight of it on the screen and pass the cuff 1-2 cm below the cords, to avoid bronchial intubation. [/fig] [fig] Figure 6: (a). Two-handed two-person bag-mask technique with the VE hand position; the second person squeezes the bag. (b). The C hand position, which should be avoided. Reproduced with permission of Dr A. Matioc. [/fig] [fig] Figure 7: Emergency tracheal intubation checklist in a patient with coronavirus disease 2019. Adapted from[20] with permission. [/fig] [fig] Figure 8: Cognitive aids for use when managing unexpected difficulty when intubating a patient with coronavirus disease 2019. (a) Unexpected difficult tracheal intubation. (b) Cannot intubate, cannot oxygenate. Adapted from [20] with permission. (c) Vortex approach cognitive aid. From [27] with permission. [/fig] [fig] c: Lung ultrasound or hest x-ray may be needed if there is doubt about bilateral lung ventilation. 19 One orret position is established reord depth of traheal tube insertion prominently.20 Pass a nasogastri tube after traheal intubation is omplete and ventilation established to minimise the need for later interventions.21 If the patient has not yet been onfirmed as COVID-19 positive ollet a deep traheal sample using losed sution for COVID-19 testing. Some upper airway samples are false negatives. 22 A visual reord of traheal intubation should be prominently visible on the patient's room (see also Supporting Information, Appendix S3). [/fig] [table] 10: Do not use techniques you have not used before or are not trained in. Again, for the reasons stated above, this is not a time to test new techniques. 11 Ensure all necessary airway kit is present in the room before tracheal intubation takes place. This includes the airway trolley and a cognitive aid consistent with the rescue strategy. [/table] [table] 14: Use clear language and closed loop communication. It may be hard to communicate when wearing PPE and staff may be working outside normal areas of practice. Give simple instructions. Speak clearly and loudly, without shouting. When receiving instructions repeat what you have understood to the person speaking. If team members do not know each other [/table] [table] 11: Laryngoscopy should be undertaken with the device most likely to achieve prompt first-pass tracheal intubation in all circumstances in that operator's handsin most fully trained airway mangers this is likely to be a videolaryngoscope. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/anae.15054	Severe acute respiratory syndrome‐corona virus‐2, which causes coronavirus disease 2019 (COVID‐19), is highly contagious. Airway management of patients with COVID‐19 is high risk to staff and patients. We aimed to develop principles for airway management of patients with COVID‐19 to encourage safe, accurate and swift performance. This consensus statement has been brought together at short notice to advise on airway management for patients with COVID‐19, drawing on published literature and immediately available information from clinicians and experts. Recommendations on the prevention of contamination of healthcare workers, the choice of staff involved in airway management, the training required and the selection of equipment are discussed. The fundamental principles of airway management in these settings are described for: emergency tracheal intubation; predicted or unexpected difficult tracheal intubation; cardiac arrest; anaesthetic care; and tracheal extubation. We provide figures to support clinicians in safe airway management of patients with COVID‐19. The advice in this document is designed to be adapted in line with local workplace policies.
0aefe7a647b4e7c1105df628d2cbca69712a64f5	pubmed	Endocrine surgery during and after the COVID-19 epidemic: Expert guidelines from AFCE	Endocrine surgery during and after the COVID-19 epidemic: Expert guidelines from AFCE The COVID-19 pandemic commands a major reorganisation of the entire French healthcare system. In France, general rules have been issued nationally and implemented by each healthcare centre, both public and private, throughout France. Guidelines drafted by an expert group led by the French-speaking Association of Endocrine Surgery (AFCE) propose specific surgical management principles for thyroid, parathyroid, endocrine pancreas and adrenal surgery during and after the COVID-19 epidemic. # Introduction The ongoing COVID-19 pandemic commands a major reorganisation of the entire French healthcare system [bib_ref] Technical Advisory Group for Infectious H. COVID-19: what is next for public..., Heymann [/bib_ref]. To respond to the present and expected influx of patients needhttps://doi.org/10.1016/j.jviscsurg.2020.04.018 1878-7886/© 2020 Elsevier Masson SAS. All rights reserved. ing a period of intensive care [bib_ref] High prevalence of obesity in severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) requiring..., Simonnet [/bib_ref] , the short-term priority has been directing available material and human resources toward sectors dispensing care for COVID-19 patients [bib_ref] Critical care utilisation for the COVID-19 outbreak in Lombardy, Italy: early experience..., Grasselli [/bib_ref] [bib_ref] Blueprint for restructuring a department of surgery in concert with the health..., Zarzaur [/bib_ref]. This policy has entailed the almost complete descheduling of non-urgent surgery [bib_ref] COVID-19: all non-urgent elective surgery is suspended for at least three months..., Iacobucci [/bib_ref]. More than a month now after the start of the epidemic, there is a pressing need to manage other health disorders not linked to COVID-19, but for which deferral of surgery until after the epidemic is over, could worsen prognosis or be life-threatening. It is also important to be thinking now about the conditions under which surgery can be resumed at a normal pace after the epidemic. General rules have been put out nationally and implemented by each healthcare centre, both public and private, throughout France. Specific guidelines have been proposed for visceral surgery [bib_ref] Strategy for the practice of digestive and oncological surgery during the COVID-19..., Tuech [/bib_ref]. Likewise, to meet their need for specific guidelines, the French-speaking Association of Endocrine Surgery (AFCE) brought together a group of experts to propose principles for the surgical management of thyroid, parathyroid, endocrine pancreas and adrenal pathologies during the COVID-19 epidemic and afterwards, for when surgical activity will be able to return gradually to its normal pattern. These guidelines were drafted in the light of the existing literature. They will be updated as knowledge advances. ## General principles for scheduling surgery during and after the covid-19 epidemic Four scheduling levels were defined to help prioritise patients (these levels may change according to how the epidemic setting evolves) [fig_ref] Figure 1: General principles for scheduling endocrine surgery during and after the COVID-19 epidemic [/fig_ref] : - urgent surgery that must be carried out as soon as possible because even a short deferral would be life-threatening; - semi-urgent surgery that can be deferred for a few weeks but not beyond 3 months without threat to life or adverse effects on cancer or functional prognosis; - high-priority elective surgery that can wait for several months but must be given scheduling priority as soon as the epidemic is over; - distant elective surgery that can be deferred until well after the epidemic is over, even more than 6 months, without compromising the indication. For urgent surgery, the ratio of the benefits expected from surgery to the risks incurred by scheduling it dur-ing the epidemic must always be evaluated according to how both the national and local contexts are evolving, in particular the resources available: operating room, consumables and hospital capacities, particularly if intensive care may be needed. When surgery is prescribed in the epidemic setting, short hospital stays or outpatient care is recommended [bib_ref] At last a step forward toward ambulatory care for endocrine surgery in..., Brunaud [/bib_ref] , provided this does not increase the risk of rehospitalisation. To limit operating time and the risk of postoperative complications, the surgery should also be performed by one or more experienced surgeons. Even if no symptoms of COVID-19 are apparent, the risk of infection should be assessed beforehand as it may be associated with unfavourable prognosis [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref]. Any surgery on a patient infected or suspected of being infected must be performed according to the rules laid down by the hospital's hygiene teams and infectiologists. ## Thyroid and parathyroid surgery thyroid cancers Differentiated thyroid cancers most often have an excellent prognosis [bib_ref] Thyroid cancer, Cabanillas [/bib_ref] , and there is no high level of proof supporting an optimal surgery deferral time [fig_ref] Figure 2: Principles for scheduling thyroid cancers during and after the COVID-19 epidemic [/fig_ref]. During the epidemic, any thyroid tumour suspected of malignancy (Bethesda 5 or 6) must be discussed at a multidisciplinary team (MDT) meeting. When there are clinical or paraclinical signs pointing to an aggressive form of cancer (recurrent nerve palsy, local invasion with esophageal, vascular or tracheal involvement, massive lymph nodes infiltration [bib_ref] American Thyroid Association management guidelines for adult patients with thyroid nodules and..., Haugen [/bib_ref] , surgery must be programmed as semi-urgent. If anaplastic, poor differentiated thyroid carcinoma or lymphoma is suspected, a surgical biopsy must be performed before any surgery is undertaken. If either of these diagnoses is confirmed, an appropriate treatment with corticoids and/or chemotherapy must be proposed as first line therapy [bib_ref] Effect of primary treatment on survival in anaplastic thyroid carcinoma, Besic [/bib_ref]. If there is no loco-regional aggressiveness, deferral of surgery for differentiated carcinoma will depend on lymph node and tumour size. A tumour size greater than or equal to 2 cm and/or associated with lymph nodes can be deferred without risk until the epidemic is over but must then be given priority and scheduled within the following 3 months. Tumours smaller than 2 cm in size, with no ganglion metastases, can be deferred until well after the end of the epidemic. Although the prognosis of medullary thyroid carcinoma (MTC) is slightly less favourable than that of follicular differentiated thyroid cancer [bib_ref] Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma, Jr [/bib_ref] , the care deferral guidelines given above still hold. ## Benign thyroid disorders Most thyroidectomies for benign lesions can be deferred without risk [fig_ref] Figure 3: Principles for scheduling surgery for benign thyroid disorders during and after the... [/fig_ref]. However, specific situations can require semi-urgent scheduling, e.g. thyrotoxicosis (Graves's disease, toxic nodules, toxic goiters, iatrogenic hyperthyroidism) resistant to or poorly controlled by synthetic anti-thyroid (SAT) agents [bib_ref] The Graves' disease, consensus of the French Society of Endocrinology, Bartes [/bib_ref]. In this situation, lithium, potassium perchlorate, and if this fails, plasmapheresis may be useful to normalise levels of triiodothyronine (T3) and control those of thyroxine (T4) at the time of surgery. Non-suspect goiters responsible for severe compressive symptoms (inspiratory dyspnea due to tracheal compres- sion, dysphagia due to esophageal compression, superior vena cava syndrome due to deep vein compression) must also be scheduled for semi-urgent surgery before the epidemic ends. ## Hyperparathyroidism Surgical treatment of primary hyperparathyroidism (HPT) is generally not urgent [fig_ref] Figure 4: Principles for scheduling parathyroid surgery during and after the COVID-19 epidemic [/fig_ref] [bib_ref] A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery, Silverberg [/bib_ref]. In the COVID-19 epidemic setting, its scheduling depends on the presence or absence of severe hypercalcemia, defined by a very high level of blood calcium > 3.5 mmol/L (140 mg/L) [bib_ref] Parathyroidectomy for hypercalcemic crisis: 40 years' experience and long-term outcomes, Cannon [/bib_ref] , and/or the presence of clinical complications-acute pancreatitis secondary to HPT, brown tumour, calciphylaxis, fracture osteopenia, heart rhythm disorders (QT shortening on ECG, bradycardia with risk of asystole) with cardiac insufficiency [bib_ref] Parathyroidectomy for hypercalcemic crisis: 40 years' experience and long-term outcomes, Cannon [/bib_ref] [bib_ref] Calciphylaxis due to hyperparathyroidism, Roy [/bib_ref] [bib_ref] The association of primary hyperparathyroidism with pancreatitis, Bai [/bib_ref]. In all cases, hypocalcemic treatment must first be given. In the epidemic setting, the use of cinacalcet is recommended [bib_ref] Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism, Peacock [/bib_ref]. In cases of severe hypercalcemia, surgery must be scheduled as semi-urgent, without waiting for the epidemic to end, or as urgent when it escapes control by the medical treatment. If there is no severe hypercalcemia, surgery can be deferred without risk until the epidemic is over. These guidelines are valid for cases of genetically determined primary HPT. For tertiary HPT, the blood calcium threshold defining severe hypercalcemia must be lowered to 2.8 mmol/L to protect renal grafts (nephrocalcinosis, acute tubular necrosis, lithiasis) and bone and vascular impact [bib_ref] Tertiary hyperparathyroidism: is less than a subtotal resection ever appropriate? A study..., Pitt [/bib_ref] [bib_ref] Characteristics of persistent hyperparathyroidism after renal transplantation, Yamamoto [/bib_ref]. For secondary HPT, surgical treatment is not recommended during the epidemic because of the higher risk of COVID-19 infection in dialysed patients [bib_ref] Minimising the risk of COVID-19 among patients on dialysis, Ikizler [/bib_ref]. When indicated, surgery must be scheduled as a priority in the three months following the epidemic in cases of disabling bone pain, brown tumour or temporary contraindication for renal transplant [bib_ref] Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder..., Ketteler [/bib_ref]. ## Technical aspects of neck surgery Uni-or bilateral cervicotomy is the approach recommended for the surgical treatment of thyroid or parathyroid pathologies in the epidemic setting, so as to limit operating time and complication risk [bib_ref] Is it possible to limit the risks of thyroid surgery, Daher [/bib_ref]. Surgery requiring a thoracic or mediastinal approach and/or postoperative intensive care [bib_ref] Morbidity of total thyroidectomy for substernal goiter: a series of 70 patients, Tabchouri [/bib_ref] must be deferred whenever possible until after the epidemic is over. Endoscopic surgical approaches, with or without robotic assistance, are not recommended [bib_ref] Extracervical approaches to thyroid surgery: evolution and review, Sephton [/bib_ref]. If there is no dysphonia, laryngoscopy before or after surgery is not recommended [bib_ref] COVID-19 pandemic: effects and evidence-based recommendations for otolaryngology and head and neck..., Kowalski [/bib_ref] because of the high risk of airborne SARS-CoV-2 transmission during such examination [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref]. Neuromonitoring of the inferior laryngeal nerve is recommended: - to make sure the neuromuscular apparatus of the larynx is functioning before and after surgery [bib_ref] Does intraoperative neuromonitoring of recurrent nerves have an impact on the postoperative..., Mirallie [/bib_ref] ; - to reduce the risk of bilateral recurrent nerve palsy that can require intensive care and interruption of surgery if the signal is lost during the dissection of the first side [bib_ref] International neural monitoring study group guideline 2018 part I: staging bilateral thyroid..., Schneider [/bib_ref]. Peroperative PTH assay is possible but must not increase time spent in the operating room. The usual guidelines for the prevention and/or management of postoperative hypocalcemia remain unchanged during the epidemic [bib_ref] Randomised controlled trial of alfacalcidol supplementation for the reduction of hypocalcemia after..., Genser [/bib_ref]. ## Neuroendocrine tumours of the pancreas In the epidemic setting, the indication for the surgical treatment of a neuroendocrine tumour of the pancreas must be discussed in an MDT meeting to assess the balance between the risks of surgery and its oncological and/or secretory benefits [fig_ref] Figure 5: Principles for scheduling surgery for neuroendocrine tumours of the pancreas during and... [/fig_ref] [bib_ref] ENETS consensus guidelines update for gastroduodenal neuroendocrine neoplasms, Delle Fave [/bib_ref]. The management of Grade 3 carcinomas (poorly differentiated) has already been the subject of guidelines as part of the French National Digestive Oncology Thesaurus, and the COVID-19 epidemic does not change the usual guidelines favouring chemotherapy or neoadjuvant radio-chemotherapy [bib_ref] ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumours and neuroendocrine carcinomas, Garcia-Carbonero [/bib_ref]. A pancreatectomy may be indicated when a curative resection can be considered after clinical and morphological reassessment [bib_ref] Pancreatic neuroendocrine tumours: the impact of surgical resection on survival, Hill [/bib_ref] , in which case surgery is scheduled as semi-urgent before the epidemic has ended. Patients with a well-differentiated neuroendocrine tumour of the pancreas (Grades G1, G2 or G3), that is nonsecretory, can be deferred until well after the epidemic is over. If there is an associated secretory syndrome, a medical treatment should first be given [bib_ref] ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms:..., Jensen [/bib_ref]. If this treatment fails to control the secretory syndrome satisfactorily, pancreatectomy must be scheduled as semi-urgent before the end of the epidemic. If the medical treatment is effective, surgery can be deferred until well after the epidemic has ended. When technically possible, laparoscopy is recommended for left pancreatectomies and enucleations to minimise postoperative impact on respiratory function and hospital length of stay [bib_ref] Strategy for the practice of digestive and oncological surgery during the COVID-19..., Tuech [/bib_ref] [bib_ref] The association of primary hyperparathyroidism with pancreatitis, Bai [/bib_ref]. ## Adrenal lesions In the epidemic setting, the indication for the surgical treatment of an adrenal lesion must be discussed at an MDT meeting to assess the balance of risk and its oncological and/or secretory benefits [fig_ref] Figure 6: Principles for scheduling surgery for adrenal tumours during and after the COVID-19... [/fig_ref]. Lesions suspected to be malignant (adrenal cortical carcinoma, metastases) must undergo surgery when they are considered resectable [bib_ref] European Society of Endocrine Surgeons (ESES) and European Network for the Study..., Gaujoux [/bib_ref] [bib_ref] Adrenocortical carcinoma: impact of surgical treatment, Mirallie [/bib_ref]. In cases of secretory syndrome, prior management by a medical treatment is recommended (metyrapone, ketoconazole). Surgery must be scheduled as semi-urgent, before the end of the epidemic, in an expert centre [bib_ref] Adrenalectomy Risk Score: an original preoperative surgical scoring system to reduce mortality..., Caiazzo [/bib_ref]. Chromaffin lesions (pheochromocytoma and/or paraganglioma) must first receive an appropriate anti-hypertension treatment (alpha-blocking agents, beta-blocking agents, calcium inhibitors), and be monitored by an experienced care team [bib_ref] Pheochromocytoma and paraganglioma, Neumann [/bib_ref]. If this treatment controls the secretory syndrome, close monitoring can be continued until the adrenalectomy, which will be scheduled as a priority when the epidemic ends. If this treatment fails to control the secretory syndrome satisfactorily, surgery can be scheduled as semi-urgent, before the epidemic ends, in an experienced centre. For other secretory adrenal lesions (in particular, hypercorticism and hyperaldosteronism), an appropriate medical treatment (steroidogenesis inhibitors, anti-aldosterone) must first be implemented. If the secretory syndrome is not controlled or if impact is marked, adrenalectomy can be scheduled as semi-urgent during the epidemic. In other cases, adrenalectomy can be scheduled well after the epidemic has ended. During the epidemic, laparoscopy remains the preferred approach for adrenalectomy. Conversely, for suspect lesions and/or those larger than 10 cm, laparotomy is recommended [bib_ref] Long-term survival after adrenalectomy for stage I/II adrenocortical carcinoma (ACC): a retrospective..., Donatini [/bib_ref]. ## Postoperative follow-up in the epidemic setting Postoperative follow-up consultations must be maintained during the epidemic. Tele-consultation is recommended to ensure continuity of care while limiting the risks of coronavirus propagation in healthcare centres. For a consultation in which a diagnosis of cancer or a therapeutic strategy is to be announced, some form of video exchange is recommended. Whenever possible, blood tests and imaging must be performed outside hospitals. In a situation where medical drugs of major therapeutic importance may be in short supply, patients, who are dependent on a hormone substitution treatment, should be reminded never to interrupt their treatment longer than 24 h for corticoids [bib_ref] Adrenal insufficiency, Arlt [/bib_ref] , longer than 48 h for calcium [bib_ref] Heath 3rd H. Hypocalcemic emergencies, Reber [/bib_ref] , and longer than one week for thyroid hormones [bib_ref] Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a..., Clyde [/bib_ref]. # Disclosure of interest The authors declare that they have no competing interest. [fig] Figure 1: General principles for scheduling endocrine surgery during and after the COVID-19 epidemic. [/fig] [fig] Figure 2: Principles for scheduling thyroid cancers during and after the COVID-19 epidemic. * Loco-regional aggressiveness defined as the presence of recurrent nerve paralysis, local invasion with esophageal, vascular or tracheal involvement, or massive ganglion infiltration. (Anapl = anaplastic, Lymph: lymphoma; MDT: multidisciplinary team). [/fig] [fig] Figure 3: Principles for scheduling surgery for benign thyroid disorders during and after the COVID-19 epidemic. * Synthetic anti-thyroid agents, lithium, potassium perchlorate, plasmapheresis. (Med TTT = medical treatment). [/fig] [fig] Figure 4: Principles for scheduling parathyroid surgery during and after the COVID-19 epidemic. Blood calcium > 3.5 mmol/L and/or presence of clinical complications (acute pancreatitis secondary to HPT, brown tumour, calciphylaxis fracture osteopenia, cardiac rhythm disorder with heart failure). * Hydration, calcimimetic (Med TTT = medical treatment). [/fig] [fig] Figure 5: Principles for scheduling surgery for neuroendocrine tumours of the pancreas during and after the COVID-19 epidemic. * Diazoxide, proton pump inhibitor, somatostatin analogues, (TTT med: medical treatment; MDT: multidisciplinary team). [/fig] [fig] Figure 6: Principles for scheduling surgery for adrenal tumours during and after the COVID-19 epidemic. * Steroidogenesis inhibitors (metyrapone, ketoconazole), anti-hypertensive agents (alpha-blocking drugs, beta-blocking drugs, calcium inhibitors), anti-aldosterone diuretics, (Med TTT:medical treatment, pheochr: pheochromocytoma; MDT: multidisciplinary team). [/fig]	None	None	None
7d310db6a25b3ac97aba9393a4b421f865689ef0	pubmed	Executive summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: second edition by the Japanese Society of Pain Clinicians	Executive summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: second edition by the Japanese Society of Pain Clinicians Neuropathic pain has a substantial effect on quality of life (QOL). The Japanese Society of Pain Clinicians (JSPC) has developed clinical guidelines of pharmacotherapy for neuropathic pain. These guidelines offer clarity on recommendations based on both the most recent scientific evidence and expert opinions. Understanding the concept, disease entity, and burden of neuropathic pain, as well as its screening and diagnosis are important steps before starting pharmacotherapy. As well as other guidelines, the guidelines propose several lines of pharmacotherapies in a step-wise manner. To name a few different points, our guidelines propose an extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus, which has been found to be effective for post-herpetic neuralgia in Japan, as one of the second-line drugs. When prescribing opioid analgesics, proposed as the third-line drugs, for neuropathic pain, the guidelines recommend physicians continue evaluations on either abuse or addiction. The guidelines do not recommend concomitant use of nonsteroidal anti-inflammatory drugs and acetaminophen because of lack of clinical evidence of their efficacy. If patients do not respond well to pharmacotherapy, which is prescribed in a step-wise manner, other treatment strategies should be considered to improve patients' activities of daily living and QOL. # Introduction Neuropathic pain has a substantial effect on quality of life (QOL) and is associated with a high economic burden for both individuals and society. It arises from a heterogeneous group disorders that affect the peripheral and central somatosensory nervous systems. It is now regarded as a distinct clinical entity despite a large variety of causes. People with neuropathic pain may experience altered pain sensation, areas of numbness or burning, and continuous or intermittent evoked or spontaneous pain. Thus, neuropathic pain is an unpleasant sensory and emotional experience. Professional organizations, including the Japanese Society of Pain Clinicians (JSPC), and nations have developed guidelines of pharmacotherapy for neuropathic pain. Existing guidelines share some common elements, including dosing thresholds, necessity of titration, and risk mitigation strategies. However, there is considerable variability in the specific recommendations (e.g., range of dosing thresholds), audience (e.g., primary care clinicians versus specialists), use of evidence (e.g., systematic review, grading of evidence and recommendations, and role of expert opinion) and rigor of methods for addressing conflicts of interest. Most guidelines do not reflect the insurance system and approved medications in respective countries. In 2011, the JSPC published the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain, first edition, based on evidence from scientific studies available at that time. According to the most recent scientific evidence, clinical guidelines should be updated after every 5 years. Therefore, the JSPC renewed the guidelines and published its second edition in 2016. These guidelines offered clarity on recommendations based on the most recent scientific evidence in addition to existing evidence and expert opinions. The diversity of scientific viewpoints about neuropathic pain and its pharmacological treatment strategies is still not enough. Therefore, the JSPC based the recommendations after consideration of the clinical evidence, contextual evidence (including benefits and harms, values and preferences, and resource allocation), and expert opinions. The JSPC hopes that not only Japanese, but also international intended end-users are aware of the existence of the guidelines and put them into practice. After publication, dissemination of the key messages of the guidelines is of paramount importance. Publication of executive summaries as a quick reference guide and the production in a format like as a downloadable version, which can be globally read and understood as a stand-alone document, are helpful. To accomplish this, the present article summarizes the recommendations and rationales of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain, second edition, published in 2016 [fig_ref] Table 1: Clinical questions in the clinical guidelines for pharmacotherapy of neuropathic pain by... [/fig_ref]. Interested readers would be referred to the full-length version of the guidelines to completely understand the proper context of the recommendations. The guidelines are structured by three large categories (i.e., overview of neuropathic pain; diagnosis and treatment of neuropathic pain; and disease with present neuropathic pain) and 37 sub-entries. For these, 58 clinical questions (CQs) are set (details in [fig_ref] Table 1: Clinical questions in the clinical guidelines for pharmacotherapy of neuropathic pain by... [/fig_ref]. In this executive summary, we described headings of the sub-entries and CQs which indicate numbers in the guidelines [fig_ref] Table 1: Clinical questions in the clinical guidelines for pharmacotherapy of neuropathic pain by... [/fig_ref]. ## Task force The JSPC committee nominated the task force members from a pool of specialists with adequate clinical experience to cover multidisciplinary areas, and the JSPC Board gave the final approval. The task force comprised a total 30 physicians: 3 academic consultants, 1 external expert, 7 core working members, 8 working members, and 11 collaborators ("Appendix"). ## Drafting recommendations A draft of clinical questions (CQs) was created by the core members. Each member in charge of the CQs drafted the recommendations and general background descriptions. Then, respective members reviewed, modified, and rewrote each statement on a reciprocal basis. In some fields, only outdated articles such as for tricyclic antidepressant were available for references. The entire articles, including the latest ones, were reviewed regardless of the published year. The reference articles included those searched under Pub-Med, Japan Medical Abstract Society (excluding the minutes) and Cochrane Collaboration. Finally, the external expert reviewed the statements in these guidelines, and the final version was established. The document created by each author was reviewed and revised twice in a cross-checking manner and then finally reviewed and revised again by the entire committee members. ## Evidence and recommendation levels The task force decided to use the evidence and recommendation levels [fig_ref] Table 2: Level of evidence and strength of recommendation Level of evidence Level A [/fig_ref] , based on the recommendations of the Japanese Medical Information Network Distribution Service (MINDS) for developing clinical practice guidelines, which was published in 2014 by the Japan Council for Quality Health Care. Evaluations were made on all crucial outcomes, including hazard, of all important articles. The levels were first suggested by the authors and cross checked twice by the core members and then determined by the entire guidelines committee. Finally, the committee discussed the entire evidence to decide whether it can be recommended. The final levels of recommendations for each of the CQs were thus determined. Overview of the understanding neuropathic pain CQ1: How do we define and understand neuropathic pain in clinical medicine? CQ2: How do we understand the pathology of neuropathic pain? CQ6: What is the chronic pain syndrome in neuropathic pain patients? Neuropathic pain is defined as "pain caused by a lesion or disease of the somatosensory nervous system" [bib_ref] A new definition of neuropathic pain, Jensen [/bib_ref]. Neuropathic pain should not indicate a single disease, but rather should be recognized as a pathological condition present in many patients complaining of pain. Neuropathic pain emerges when there is a lesion or disease in any of the nociceptive pathways from the peripheral nerves to the cerebrum. The pathological mechanisms include abnormal sensitivity of the somatosensory nervous system and functional impairment in the descending pain modulatory system. It is noteworthy that clinical criteria, which are based on overall findings of patients with neuropathic pain, are necessary in the diagnosis of neuropathic pain because it is often impossible to demonstrate consistent data from diagnostic tests for neuropathic pain. In "Guidelines for Pharmacological Treatment of Neuropathic Pain" published by the JSPC in 2011, the term "damage" had been used to describe a "lesion." As this term "lesion" includes a condition that does not involve an irreversible anatomical change such as compression, it was changed to "lesion" according to the "Taxonomy for Pain Clinics" issued by the JSPC (2011). In addition to these biological factors, it should be mentioned that pain is usually affected by bio-psycho-social factors. Hence, we need clinical criteria that not only evaluate the pathological condition of the somatosensory nervous system, but also predict the presence or absence of psychosocial factors. In fact, neuropathic pain is accompanied by various comorbidities such as sleep disorder, lack of energy, depression, anxiety, dry mouth, and loss of appetite [bib_ref] Peripheral neuropathic pain: a multidimensional burden for patients, Meyer-Rosberg [/bib_ref]. Although it has not been clearly understood how these comorbidities are associated with pain, the psychosocial factors for these conditions are consistent with those of a vicious cycle known as the fear-avoidance model, in addition to sleep disorder. These conditions have not yet been defined, but are referred to as the "chronic pain syndrome" [bib_ref] The fear-avoidance model of musculoskeletal pain: Current state of scientific evidence, Leeuw [/bib_ref] , which is a consequence of complex interactions of bio-psycho-social factors. Therefore, we should evaluate their impact on patients' QOL, and then determine the management plan. ## Diseases which present neuropathic pain ## Cq3: what diseases are associated with neuropathic pain? CQ4: What is the neuropathic and nociceptive pain classification and its clinical significance? [bib_ref] A randomized placebo controlled trial of duloxetine for central pain in multiple..., Brown [/bib_ref]. Post-operative neuropathic pain (e.g., painful scar) and iatrogenic neuropathy (e.g., post-thoracotomy neuropathic pain, post-mastectomy neuropathic pain) CQ51: Does perioperative drug administration reduce post-operative neuropathic pain? 1B CQ52: Are there any drugs that are useful for complete chronic post-thoracotomy pain? 1A CQ53:Are there any drugs that are useful for complete chronic post-mastectomy pain? 1B CQ54: What drug is useful for pain after inguinal hernia repair? 2B 37. Cervical and lumbar radiculopathy CQ55: Are antidepressants useful for cervical and lumbar radiculopathy? 2B CQ56: Are calcium channel alpha-2-delta ligands effective for lumbar radiculopathy? 1C CQ57: Are opioids effective for cervical and lumbar radiculopathy? 2D CQ58: Are there any drugs other than antidepressants, calcium channel alpha-2-delta ligands, and opioids that are effective for cervical and lumbar radiculopathy? 2D Recommended treatment is certainly of benefit to patients with neuropathic pain, and the benefit exceeds the harm or burden. In the statement, the term "should" is used 2 (weak): Recommended treatment might be of benefit to patients with neuropathic pain or the benefit may or may not exceed the harm or burden from the recommended treatment. In the statement, the term "might" is use 1 3 ## Cq5: is acute pain that is associated with peripheral nerve inflammation regarded as neuropathic pain? Nutritional, metabolic, traumatic, ischemic, toxic, genetic, infectious, compression/entrapment, immune, neoplastic, or neurodegenerative disorders can cause neuropathic pain. [fig_ref] Table 3: Diseases that can cause neuropathic pain Iatrogenic neuropathy Post-thoracotomy pain syndromePost-traumatic sequelae/post-operative... [/fig_ref] lists some diseases that can be associated with neuropathic pain. These are just examples, and there are more diseases that are not listed in this table [bib_ref] Progress and future prospects for neuropathic pain treatment in Japan. A proposal..., Hanaoka [/bib_ref]. Pain is defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" [bib_ref] The fear-avoidance model of musculoskeletal pain: Current state of scientific evidence, Leeuw [/bib_ref]. The types of pain developed by bodily causes are classified into nociceptive pain and neuropathic pain. Nociceptive pain is defined as "pain that arises from actual or threatened damage to non-neural tissues and is due to the activation of nociceptors". It will be helpful to classify and evaluate nociceptive pain and neuropathic pain when we plan to treat pain due to these causes. However, pathological conditions of nociceptive pain and neuropathic pain often overlap clinically, and such a state is called the mixed pain condition. To control the mixed pain condition, pharmacotherapies for each pathologic condition would be necessary for appropriate pain control. There is a controversy regarding whether acute peripheral nerve inflammation should be included in the neuropathic pain category. The most representative diseases that develop acute pain in association with direct inflammation on the peripheral nerve include shingles in the acute phase and radiculopathy due to intervertebral disc displacement. Although nociceptive pain and neuropathic pain may be present at the same time during a transition phase from acute to chronic pain in association with peripheral nerve inflammation, it is currently difficult to figure out how much of the acute pain induced by shingles or intervertebral disc displacement is neuropathic pain. Therefore, in these guidelines, we would not include the acute pain associated with terminal nerve inflammation in the neuropathic pain category. In surveys conducted in Japan that focused on chronic pain, an individual with chronic pain was defined as a person who had experienced pain with a severity of 4 or above on an 11-point numeric rating scale (NRS: 0 = no pain; 10 = worst pain imaginable) for at least twice a week for 3-6 months. As a result, the prevalence was found to be 15.2% for chronic pain in the musculoskeletal system and 26.4% for chronic pain among varied etiologies [bib_ref] Investigation of chronic musculoskeletal pain (3rd report): With special reference to the..., Nakamura [/bib_ref] [bib_ref] A large-scale survey on chronic pain and neuropathic pain in Japan, Ogawa [/bib_ref]. Of these, the prevalence of those who were likely to have neuropathic pain according to the PainDETECT Japanese version [bib_ref] Validity and reliability of the Japanese version of the PainDETECT questionnaire: a..., Matsubayashi [/bib_ref] and the "Neuropathic Pain Screening Questionnaire (Japanese version)" was 6.5 and 6.4%, respectively. ## Epidemiology of neuropathic pain Considering the relationship between neuropathic pain and the specific disease, cancer pain was systematically reviewed [bib_ref] Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review, Benneti [/bib_ref]. Among patients with cancer pain, 59.4% had nociceptive pain, 19.0% had only neuropathic pain, 20.1% had a mixture of nociceptive pain and neuropathic pain, and 1.5% had pain of unknown origin or other types of pain. In the European Association for Palliative Care, a study was conducted using the PainDETECT in 670 patients with pain out of 1051 cancer patients; according to the results, 79.7% patients had nociceptive pain, 16.9% had neuropathic pain, and 3.4% had pain of unknown origin. Compared to the patients with nociceptive pain, those with neuropathic pain required stronger opioid analgesics and adjuvant analgesics, and their performance state remained worse [bib_ref] Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative..., Rayment [/bib_ref]. ## Cq11: what are the clinical characteristics of neuropathic pain? Neuropathic pain is distinctive pain that is different from nociceptive pain. It is characterized by spontaneous pain (continuous or intermittent) or pain induced by stimulation (allodynia, hypersensitivity) at the site supplied by the affected nerve, which is complicated by various sensory abnormalities caused by the disturbance of a nerve. The characteristic features of neuropathic pain are in the descriptions of the screening tools developed in the EU, US, and Japan [fig_ref] Table 4: Comparisons among various screening tools [/fig_ref]. The differences in the features of pain characteristic to each disease are presented in [fig_ref] Table 5: Differences in features between neuropathic pain and nociceptive [/fig_ref] [ [bib_ref] From discovery to clinical trials: treatment strategies for central neuropathic pain after..., Hulsebosch [/bib_ref] [bib_ref] Contemporary assessment and management of neuropathic pain, Irving [/bib_ref] [bib_ref] Pathophysiology of pain: from theory to clinical evidence, Jensen [/bib_ref] [bib_ref] Management of herpes zoster (shingles) and postherpetic neuralgia, Johnson [/bib_ref]. Positive and negative findings in the somatosensory system of neuropathic pain and nociceptive pain can be useful when making a diagnosis [fig_ref] Table 5: Differences in features between neuropathic pain and nociceptive [/fig_ref] [bib_ref] Pathophysiology of pain: from theory to clinical evidence, Jensen [/bib_ref]. Based on these characteristics of neuropathic pain, multiple screening tools have been developed to easily evaluate the possibility that a patient has neuropathic pain in routine medical practice. There are tools known as the Japanese neuropathic pain screening questionnaire [bib_ref] Development of the neuropathic pain screening questionnaire for Japanese patients with chronic..., Ogawa [/bib_ref] , PainDETECT Japanese version [bib_ref] Validity and reliability of the Japanese version of the PainDETECT questionnaire: a..., Matsubayashi [/bib_ref] , and Leeds assessment of neuropathic symptoms and signs (LANSS) Japanese version [bib_ref] Development of the Japanese version of the Leeds Assessment of the Neuropathic..., Isomura [/bib_ref] developed in Japan. All of these are just screening tools for neuropathic pain in general clinical settings, and these demonstrate high sensitivity but moderate specificity. There is a systematic review that compared and evaluated the quality (e.g., validity, reliability) of each screening tool [bib_ref] Neuropathic pain screening questionnaires have limited measurement properties: a systematic review, Mathieson [/bib_ref]. All tools were supported at the low evidence level; hence, "use of a screening tool should not replace a detailed clinical evaluation" as stated in the guidelines above. Therefore, it is recommended to use a screening tool available, but we should not use the result of the screening tool as a diagnosis of neuropathic pain by itself. To diagnose neuropathic pain, the International Association for the Study of Pain (IASP) developed the flowchart-form diagnostic algorithm (grading system) [bib_ref] Neuropathic pain: redefinition and a grading system for clinical and research purposes, Treede [/bib_ref]. The details of this algorithm are described elsewhere. Briefly, first identify the present illness and the past medical history that suggest neuropathic pain. Then, perform a sensory-disturbance evaluation in a neurological examination and a test that confirms the diagnosis of neurological lesion or a disease. It is desirable to establish a diagnosis following an algorithm by the IASP neuropathic pain specific interest group. ## Treatment strategy for neuropathic pain ## Cq12: what is the impact of neuropathic pain on qol? CQ13: What is the summary of the management plan for neuropathic pain? ## Cq14: how do we establish the treatment goal for neuropathic pain? The severity of neuropathic pain is relatively higher than that of other pain conditions, and neuropathic pain affects greatly patients' health-related QOL. Further, patients with neuropathic pain were more likely to have prolonged disease duration and more medical expenses [bib_ref] Neuropathic pain: Quality-of-life impact, costs and cost effectiveness of therapy, O'connor [/bib_ref]. It was found that the higher the pain severity, the lower the QOL of patients [bib_ref] The specific disease burden of neuropathic pain: results of a French nationwide..., Attal [/bib_ref] [bib_ref] Prevalence of chronic pain with neuropathic pain characteristics in the general population, Bouhassira [/bib_ref]. The treatment goal should be planned based on both the severity of pain and their impaired activities of daily living (ADL) and QOL. In a clinical study of chronic pain, it is recommended to evaluate the following six items: intensity of pain, physical functions, mental functions, level of patients' satisfaction, signs of adverse reactions, and adherence to the treatments [bib_ref] Initiative on methods, measurement and pain assessment in clinical trials. Interpreting the..., Dworkin [/bib_ref] [bib_ref] Core outcome domains for chronic pain clinical trials: IMMPACT recommendations, Turk [/bib_ref]. It is considered crucial to evaluate these factors comprehensively in clinical practice. The basic treatment strategy is a pharmacotherapy that can relieve the pain. However, if the patients do not respond well to pharmacotherapy, which is prescribed in a stepwise manner, or when their adherence to pharmacotherapy is not adequate, neuromodulatory treatments or other interventional treatments are considered. Further, to improve the patients' ADL and QOL, functional exercises such as rehabilitations are provided to patients so that they will be able to recover their self-efficacy. Thus, it is very important to provide interor multi-disciplinary treatments for neuropathic pain by combining various treatment approaches according to their bio-psycho-social factors. ## Pharmacotherapy for neuropathic pain ## Cq15:what are indexes of the effects of pharmacotherapy for neuropathic pain and the levels of recommendation for the respective drugs? Pathological conditions and diseases associated with neuropathic pain vary greatly; it is extremely difficult to conduct a clinical study for each one of the conditions and diseases. Therefore, in these guidelines, we aim to present recommendations for neuropathic pain and selected drugs. Some of the drugs listed in these guidelines are not covered by the health insurance when used for neuropathic pain diseases in Japan. Such drugs should be used only after fully informing patients. Different from other published recommendations [e.g., 27], the guidelines presented an algorithm of pharmacotherapies, which is structured by the first to third-line drugs, instead of presenting an evidence list. Drugs that would have a potential to demonstrate analgesic effects on multiple diseases associated with neuropathic pain and have been approved in Japan as analgesics were selected as the first-line drugs. Out of all analgesics approved in Japan, tricyclic antidepressant (amitriptyline), pregabalin, and duloxetine are recommended as the first-line drugs. For the second-line drugs, we selected analgesic drugs that are effective for only 1 type of disease associated with neuropathic pain . Opioid analgesics are shown to be effective for multiple diseases associated with neuropathic pain. However, we consider them as the third-line drugs because there have been safety concerns for their long-term use. Of all opioid analgesics, only tramadol has been classified as a secondline drug as its improvement effect on QOL is relatively high and its risk for developing addiction is low. It is desirable to receive a collaborative consultation from a pain management specialist when considering a long-term administration of opioid analgesics including tramadol. In the original first edition of the guidelines, mexiletine hydrochloride was recommended as the second-line drug because it has been approved for painful diabetic neuropathy. However, because of low efficacy and high incidence of adverse effects, we did not recommend it in the second edition of the guidelines [bib_ref] Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis, Finnerup [/bib_ref] [bib_ref] Efficacy of oral mexiletine for neuropathic pain with allodynia: a double-blind, placebo-controlled,..., Wallace [/bib_ref]. Topical therapies with lidocaine have been reported effective [bib_ref] 5% lidocaine plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an..., Baron [/bib_ref] [bib_ref] Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or a combination of both?:..., Rehm [/bib_ref] , and recommended in overseas guidelines, while this is not approved in Japan. Therefore, we did not demonstrate topical lidocaine in the algorithm. ## First-line drugs ## Pregabalin Pregabalin inhibits the release of excitatory neurotransmitters by combining with alpha-2-delta subunits of voltagedependent calcium channels in the central nervous system. Similarly, gabapentin and gabapentin enacarbil work by combining with alpha-2-delta subunits of voltage-dependent Neuropathic pain pharmacotherapy algorithm in the Japanese Society of Pain Clinicians calcium channels. Pregabalin is the only analgesic drug approved for both peripheral and central neuropathic pain in Japan. Neither gabapentin nor gabapentin enacarbil is approved for pain conditions. Pregabalin has greater analgesic potential compared to placebo for both Japanese and other patients with varied peripheral and central neuropathic pain diseases (e.g., post-herpetic neuralgia [bib_ref] Efficacy and safety of pregabalin for post-herpetic neuralgia: A multicenter collaborative randomized..., Ogawa [/bib_ref] , painful diabetic polyneuropathy [bib_ref] Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic..., Satoh [/bib_ref] , and post-spinal cord injury pain [bib_ref] A randomized trial of pregabalin in patients with neuropathic pain due to..., Cardenas [/bib_ref]. Pregabalin also improves sleep disturbance, depression, and anxiety associated with neuropathic pain. These favorable effects can be clearly observed not only with respect to pain but also patients' QOL. The use of gabapentin, as well as pregabalin, for neuropathic pain is supported by evidence from studies worldwide. Gabapentin enacarbil has good evidence for neuropathic pain. However, these studies have not been confirmed for Japanese neuropathic pain patients yet. ## Serotonin-noradrenaline reuptake inhibitors (snri) The analgesic effect of serotonin-noradrenaline reuptake inhibitors (SNRIs) is considered to be mediated by activation of the descending pain inhibitory system. The analgesic potential of duloxetine, an SNRI, has been demonstrated in a clinical study on pain and numbness associated with diabetic neuropathy. Its safety has been confirmed in a 52-week study [bib_ref] Superiority of duloxetine to placebo in improving diabetic neuropathic pain: Results of..., Yasuda [/bib_ref]. Further, it was shown that duloxetine improved central neuropathic pain compared to placebo in patients with multiple sclerosiss [bib_ref] A randomized placebo controlled trial of duloxetine for central pain in multiple..., Brown [/bib_ref]. Duloxetine is approved in Japan for not only painful diabetic polyneuropathy and other chronic pain condition (i.e., osteoarthritis, chronic low back pain, and fibromyalgia), but also major depression. The clinical studies of duloxetine for painful diabetic polyneuropathy, osteoarthritis, and chronic low back pain did not include patients with depressive disorders in Japan. Thus, its analgesic property is independent of its anti-depressant mechanism. In addition, its analgesic effects on cancer chemotherapy-induced neuropathy [bib_ref] Alliance for clinical trials in oncology. Effect of duloxetine on pain, function..., Smith [/bib_ref] and low back pain associated with radiculopathy [bib_ref] Efficacy of duloxetine in chronic low back pain with a neuropathic pain..., Schukro [/bib_ref] have been also observed. On the basis of these evidences, duloxetine was upgraded as one of the firs-line drugs in the second edition of the guidelines from the second-line drug in the original first edition. Duloxetine improves not only pain, but also QOL in patients with peripheral neuropathy. In addition to duloxetine, two other SNRIs, venlafaxine and milnacipran, are available but both are not approved for any neuropathic pain diseases in Japan. ## Tricyclic antidepressants (tcas) TCAs are significantly effective for a variety of peripheral and central neuropathic pain compared to placebo. It has been found that the analgesic mechanisms of TCAs are different from those of other anti-depressants. Among TCAs, only amitriptyline is approved for peripheral neuropathic pain in Japan. It has been reported that there is no difference in analgesic effects between the tertiary amine TCAs (amitriptyline and imipramine), which show well-balanced serotonin-noradrenaline reuptake inhibition, and the secondary amine TCA (nortriptyline), which shows relatively selective noradrenaline reuptake inhibition [bib_ref] Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial, Watson [/bib_ref] [bib_ref] Nortriptyline for neuropathic pain in adults, Derry [/bib_ref]. Hence, the secondary amine TCA (nortriptyline) is considered more favorable than the tertiary amine TCAs (amitriptyline and imipramine) for being superior in tolerability, but equivalent in analgesic effects. As a majority of clinical studies using TCAs had been conducted before 2000, their effects on QOL are still unknown due to lack of appropriate evaluations. ## Second-line drugs ## Extract from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus (erv) In clinical studies conducted only in Japan, the extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus (ERV) has been found to be effective, particularly for post-herpetic neuralgia, and has been approved for it [bib_ref] Effects of neurotropin tablets on postherpetic neuralgia: A placebo-controlled multicenter double blind..., Yamamura [/bib_ref]. It is thought that the extract from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus activates the descending pain inhibitory system, which produces the analgesic effect. In addition to the analgesic effects, this drug does not induce serious adverse reactions and its tolerability is very high. It has been used for more than 20 years in clinical practice in Japan and has been highly safe. Although sleep disorder associated with pain improved, efficacy for other aspects of QOL has not yet been evaluated. ## Opioid analgesic [weak]: tramadol Tramadol acts as both a mu-opioid receptor agonist and SNRI. It is categorized as an opioid analgesic [weak], which is not designated as a restricted opioid for medical use. The analgesic effects of tramadol have been demonstrated for painful diabetic polyneuropathy [bib_ref] Doubleblind randomized trial of tramadol for the treatment of the pain of..., Harati [/bib_ref] [bib_ref] Tramadol relieves pain and allodynia in polyneuropathy: a randomized, double-blind, controlled trial, Sindrup [/bib_ref] , postherpetic neuralgia [bib_ref] Tramadol in post-herpetic neuralgia: A randomized, double-blind, placebo-controlled trial, Boureau [/bib_ref] , and cancer-related neuropathic pain [bib_ref] Tramadol in the treatment of neuropathic cancer pain: a double-blind, placebo-controlled study, Arbaiza [/bib_ref]. Improvement in QOL has been also confirmed. Although development of addiction is very unlikely, caution is required for long-term use. It is best to use this drug for a short-term treatment [bib_ref] Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis, Finnerup [/bib_ref]. Adverse effects (e.g., constipation, sleepiness, vomiting) induced by tramadol are generally milder than those of other opioid analgesics. With both analgesic effects and QOL improvement, tramadol is given priority over other opioid analgesics. In the second edition of the guidelines, it is recommended as a second-line drug due to low safety concerns associated with long-term use [bib_ref] Rates of abuse of tramadol remain unchanged with the introduction of new..., Cicero [/bib_ref]. ## Third-line drugs ## Opioid analgesics Opioid analgesics are effective for a variety of diseases associated with peripheral and central neuropathic pain, including painful diabetic polyneuropathy and post-herpetic neuralgia [bib_ref] Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis, Finnerup [/bib_ref]. There is abundant evidence for the analgesic efficacy of morphine and oxycodone. Transdermal fentanyl (both 1-and 3-day patches) has been approved for moderate-severe cancer pain when switching from other opioid analgesics. Buprenorphine hydrochloride is a partial agonist for mu-opioid receptors, showing equivalent efficacy. Incidence of adverse effects (e.g., nausea, constipation, sleepiness) induced by opioid analgesics is relatively high, and these could persist for a long time throughout the treatment period [bib_ref] Chronic non-cancer pain and the long term utility of opioids, Watson [/bib_ref]. Moreover, there is no systematic investigation made on the long-term safety of these opioid analgesics. Opioid analgesics might not be safer than other drugs due to adverse effects, such as development of hypogonadism or addiction, though the incidence is low. We consider them as the third-line drugs because opioid analgesics have safety concerns for long-term use. Hence, it is desirable to receive a collaborative consultation from a pain management specialist when using opioid analgesics [moderate and strong] listed in this chapter. When prescribing opioids for chronic pain conditions including neuropathic pain, we always need to continue evaluations on either abuse or addiction. The recommended maintenance dose of an opioid analgesic is 15-120 mg/day when converted to oral morphine hydrochloride. The JSPC has been continuously considering the risk-benefit of pharmacotherapy for neuropathic pain from a long-term perspective. We are now debating the necessity of lowering the upper limit of maintenance doses (e.g., 60 mg/ day) of opioid analgesics following a US report [bib_ref] Opioid prescriptions for chronic pain and overdose: a cohort study, Dunn [/bib_ref]. ## Cq16: what is the level of recommendation of nsaids and acetaminophen for neuropathic pain? There is no high-quality study that has demonstrated the efficacy of both NSAIDs, including selective cyclooxygenase (COX)-2 inhibitors, and acetaminophen for neuropathic pain. Concomitant use of NSAIDs in addition to pharmacotherapy can be effective in the treatment of a mixed pain condition where neuropathic pain is complicated by nociceptive inflammatory pain [bib_ref] Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain, Romano [/bib_ref]. It is not recommended for mixed pain condition as there is hardly any anti-inflammatory effects with acetaminophen. # Discussion Clinical guidelines represent one strategy for improving prescribing practices and health outcomes. Efforts are required to disseminate the guideline and achieve widespread adoption and implementation of the recommendations in clinical settings. These guidelines provide recommendations that are based on the best available evidence that was interpreted and informed by expert opinion. Some of the clinical or scientific evidence for the recommendations are still low in quality. For future guideline development worldwide, more investigations are necessary to fill in critical evidence gaps. The evidence review for these guidelines clearly illustrate that there is much to be learn about the effectiveness, safety, and economic efficiency of long-term and combined pharmacotherapies. The JSPC will revisit these guidelines as new evidence becomes available to determine when evidence gaps have been sufficiently closed to warrant an update of the clinical guidelines. These guidelines are intended to improve communication among clinicians working in varied clinical settings and patients about concept of neuropathic pain, its specific disease burden, the goals of treatment, and the risks and benefits of pharmacotherapies. These are also intended to improve the safety and effectiveness of pain treatment. The JSPC is committed to evaluating the guidelines to identify the impact of the recommendations on clinician and patient outcomes, both intended and unintended, and revising the recommendations in the future when warranted. [table] Table 2: Level of evidence and strength of recommendation Level of evidence Level A (strong) Evidence from the results of studies is established. The results will not change even if further studies are conducted Level B (moderate) Some clinical investigations moderately support the results but evidence is not enough and confirmed. Further studies might change the results Level C (low) Although some clinical investigations suggest the results, the results are still controversial. Further studies would be required and these might change the results Level D (very low) There is insufficient evidence for the results. Further studies should be conducted to consider the validity of the results Strength of recommendation 1 (strong): [/table] [table] Table 3: Diseases that can cause neuropathic pain Iatrogenic neuropathy Post-thoracotomy pain syndromePost-traumatic sequelae/post-operative sequelae (e.g., persistent post-operative wound pain) Post-ischemic myelopathy [/table] [table] Table 4: Comparisons among various screening tools [/table] [table] Table 5: Differences in features between neuropathic pain and nociceptive (inflammatory) pain [/table]	None	https://link.springer.com/content/pdf/10.1007/s00540-018-2501-0.pdf	None
e9456da140e3615973e247390b9de62dfec7a89a	pubmed	Ocular oncology practice guidelines during COVID-19 pandemic-An expert consensus	Ocular oncology practice guidelines during COVID-19 pandemic-An expert consensus The outbreak of rapidly spreading COVID-19 pandemic in December 2019 has witnessed a major transformation in the health care system worldwide. This has led to the re-organization of the specialty services for the effective utilization of available resources and ensuring the safety of patients and healthcare workers. Suspension of oncology services will have major implications on cancer care due to delayed diagnosis and treatment leading to irreversible adverse consequences. Therefore various oncology organizations have called for a continuation of cancer care during this crisis with diligence. The COVID-19 pandemic has forced the clinicians to transform the components of care from screening to outpatient care and primary management. The purpose of this article is to establish guidelines and recommendations for ocular oncology in the management of ocular tumors set by a multidisciplinary team of experts including ocular, medical and radiation oncologists, and pathologists. As the pandemic is evolving fast, it will require constant updates and reformation of health strategies and guidelines for safe and quality health care. Ocular oncology is a branch that deals with tumors of the eye including eyelid, ocular surface, intraocular structures, and orbit. It has always remained as a specialty with a limited number of trained ocular oncologists and ancillary staff in India and worldwide, as compared to other ophthalmology subspecialties. Ocular oncology functions as a multidisciplinary team and requires a coordinated approach for an optimal outcome. The primary goal in the management of ocular malignancies is life salvage, followed by eye and vision salvage. We relentlessly aim at reducing the mortality and morbidity in ocular oncology practice by time-bound and protocol-based management, which makes it a challenging and engaging specialty. The impact on the outcome can be adverse if the management is neglected or delayed in cancer patients.There is a growing concern that coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can impact the management of cancer patients by overwhelming the medical care systems and overshadowing the rest of the clinical care. There is an international consensus that any patient with a potentially malignant tumor diagnosed during the COVID-19 pandemic should undergo a thorough clinical assessment, appropriate investigations, and possibly a biopsy to confirm the diagnosis and protocol-based management as appropriate. Ocular oncology is not an exception. Thereby, ocular oncology service continues to function irrespective of the situation, war, or wrath. We recognize the careful balance between prioritized patient care and the risk of inadvertent exposure of healthcare workers and patients to In this report, we aim to propose the basic guidelines and strategies for the continuation of ocular oncology services during the COVID-19 pandemic. These guidelines remain dynamic and may evolve as the nature of disease transmission changes in the future. Individual decisions may have regional influence depending on the COVID-19 burden, medical, logistical, and organizational considerations. # Methods In May 2020 all the authors including a multidisciplinary team of ocular oncologists, medical oncologists, pediatric oncologists, radiation oncologists, and pathologists coordinated and communicated through email to put forward the disease-specific guidelines in ocular oncology. The guidelines are based on the collective opinion of the experts in the specialty. Some of the authors (FPM, SGH) were also part of the practice guidelines survey conducted by the ocular oncology group for the American Academy of Ophthalmology that has been published.Guidelines for Ocular Oncology during COVID-19/SARS-CoV-2 Pandemic I. Basic screening and triage of patients This includes the universal guidelines and triage of patients depending on the symptoms and travel history.Triage of patients at four different levels (Quad-triage) is recommended that includes online registration, teleconsultation with specialist/trainee, onsite physical screening, and clinical evaluation by decision-making specialist []. Online appointments and registration can avoid onsite crowding. COVID-19 questionnaires to identify laboratory-confirmed, and suspect case as outlined and defined by the Ministry of Health and Family Welfare (MoHFW) is taken.If it is a COVID-19 suspect or laboratory-confirmed case, the patient gets directly referred for investigation, and further management at the government designated COVID-19 care center. If associated with emergency symptoms such as intractable eye pain, vomiting, headache, visual loss, and signs associated with increased intraocular pressure and/or suspected malignancy, the patient is given appointment and examination planned in the pre-designated area by the decision-making specialist with full personal protection equipment (PPE) and offered symptomatic primary treatment before referring to the COVID-19 center. If the symptoms are mild and tolerable, the ocular examination is delayed until the patient is tested negative and complete recovery from COVID-19. Second level triage by teleconsultation with specialists/ fellows before clinic visits are encouraged for detailed history and documentation that can reduce the consultation duration in the clinic with the specialist. Teleophthalmology with video consultation in the diagnosis of ocular tumors has major pitfalls especially in new intraocular and orbital cases that may require detailed evaluation. However, eyelid and conjunctival lesions are less challenging.Follow-up cases are scheduled according to the stability of the disease. Onsite triage is done during the scheduled clinic visit according to the published guidelines with thermal screening and questionnaires.Patients on chemotherapy are isolated from the rest of the patients in the waiting area considering the risk of acquiring infection due to immunosuppression. Clinical triage is recommended wherein a decision-making specialist attends to the patients to differentiate benign from malignant tumors, vision-threatening tumors, and plan management accordingly. Follow-up cases are scheduled according to the stability of the disease.ophthalmologists.The healthcare workers are the most valuable resource of the country worldwide. While we are in the process of resuming the clinical and surgical practices, the protection of healthcare workers is of paramount importance.Adherence to handwashing, antiseptic foaming, and appropriate patient protection with masks to cover their mouth and nose before entering the clinic must be strictly enforced. The healthcare worker protective measures with PPE depends on the risk of exposure to disease transmission, and regional disease burden. It should be used appropriately and not wastefully. The new guidelines for the rationale use of PPE for non-COVID-19 hospitals were recently released by MoHFW.Personal protection equipment (PPE) can be - Full PPE: long-sleeved whole body covering impermeable garment (hazardous material suit), shoe cover, N95/3-ply impermeable mask, goggles, full-face shield or visor, headgear/hood, and double gloves. The plastic apron should be worn over permeable garments - Essential PPE: full-face shield or visor, goggles, N95/3-ply impermeable mask, gloves, and +/-surgeon's gown. ## Ii. healthcare worker safety Donning and doffing of PPE should be followed as per the standard guidelines. Teleconsultation before the clinical visit for details regarding the disease as mentioned in the triage system can minimize the time spent in the outpatient clinic []. Previous medical documents preferably should be submitted online by the patient before the clinical visit, so that the patient details are reviewed by the specialist in advance.No attendants are to be allowed, except in the case of children and senior citizens where only one attendant should be allowed during a consultation. Avoid conversation with the patient while examination. The slit-lamp examination should be performed as mandated with protection. Indirect ophthalmoscopy is performed with a mounted face shield. If at all scleral depression is required, a cotton-tipped applicator is preferred over a scleral depressor. In the case of infants and children, when examined under restraint are likely to increase the aerosol levels due to crying; examiner and assistant should be extremely cautious. Gloves to be discarded/disinfected after every patient. Counseling to be performed in the clinic immediately following the examination, maintaining a safe distance of 1-2 m. Patients and/or families should be given an option of counseling over a video conference for a detailed explanation, and decision making. ## Iii. surgical safety measures It is the aerosol generating procedures (AGPs) that carries a high risk of virus transmission. These include intubation, extubation, manual ventilation, open suctioning of the respiratory tract, high flow nasal oxygen, administration of humified oxygen, surgeries involving high-speed drilling, and mucosal exposure.Local anesthesia (LA) is preferred over general anesthesia (GA). Surgical procedures under GA should have an interval of 20-30 min between cases for aerosol clearance. Electrosurgery with diathermy cauterization plays a major role in oncosurgeries for hemostasis, but there is evidence that it can lead to particle aerosolization.Their use should be Contd... minimized, and bipolar cautery should be used at the lowest power setting instead of the monopolar device whenever possible to minimize plumes and thus aerosol production.It is preferable to use a high vacuum and high flow suction devices whenever available. This may allow the rapid suction of potentially dangerous aerosols. Hypotensive anesthesia should be preferred for reducing intraoperative bleeding. The endoscopic surgical approach for orbitotomy and high-speed drilling must be avoided. If the oncosurgery involves sinus exposure as in exenteration or orbitotomy, it is preferable for the surgeons and assistants to use full PPE.Patients presenting with cough and or fever on the day of surgery or EUA must be postponed and systematic screening for COVID-19 should be considered. In case a healthcare worker has been infected, two PCR-negative swabs are required for rejoining the work. ## Iv. disease-specific guidelines in ocular oncology ## Retinoblastoma Retinoblastoma is considered a priority where new and active cases are attended to and treated as usual.It is challenging as it involves examination under anesthesia (EUA) for new patients and follow-up cases. Unlike adult ocular tumors EUA is performed in all case scenarios for grouping and staging before commencing the treatment in children. It is preferable to perform bone marrow biopsy and or cerebrospinal fluid cytology during the initial EUA for suspected malignancy in children to avoid repeated anesthesia if facilities are available. EUA carries a moderate risk of disease transmission. During EUA, the anesthetist and assistant are expected to be in full PPE with proper precaution during intubation and extubation. The examiner and assistant must stay outside the operation theatre during the same. Considering the need for fundus evaluation and visualization without compromising on personal protection, the examiner is expected to be protected with a 3-ply mask/N95 mask, protective glasses, gloves, and a gown. Instillation of 5% Povidone-iodine in the conjunctival cul-de-sac 5 min before examination is known to have a virucidal effect.Indirect ophthalmoscope and lens should be disinfected after every examination as per the standard guidelines by the vitreoretinal society.Regarding the primary management protocols and indications, it remains unchanged be it systemic intravenous chemotherapy, interventional intra-arterial chemotherapy, or enucleation.During treatment, ideally every child undergoes EUA before the chemotherapy cycles every 3-4 week. After the initial EUA, during chemotherapy cycles, in order to reduce the repeated risk of aerosol transmission and infection, subsequent EUAs and focal therapy may be performed after 2-3 cycles or alternative cycles unless the clinical situation demands more frequent intervention. Focal therapy including laser, cryotherapy, local injections may be planned as appropriate []. Transfer of care to local pediatric/medical oncologists may be considered to avoid the risk of COVID-19 transmission during travel. Considering the risk of community-acquired infection in children undergoing chemotherapy, the private transport vehicle is preferable to commute to and fro from the hospital. Local support groups and NGO may be approached for aid and assistance. In patients who are under remission for < 6 months, follow-up EUA's should not be delayed for > 4-6 weeks. For those who have been deemed stable for more than a year after the last treatment for disease activity, EUA may be deferred by 3 months. Retinoblastoma screening in children with family history including sibling screening should not be delayed due to the known risk that can have adverse consequences. Screening of the fellow eye in unilateral retinoblastoma can be postponed depending on the risks involved (germline/familial and age of the child). However, older children can be seen in the clinic and fundus findings documented with ultra-widefield fundus imaging (Octopus/ Clarus) if available. Radiological imaging is performed in all new cases with bilateral and unilateral retinoblastoma as a part of evaluation and staging. Scheduled radiological surveillance may be deferred for 3 months. ## Uveal melanoma All newly diagnosed cases are treated as appropriately without delay due to its deadly nature.However, a delay of 2-3 weeks may not affect the outcome. Detailed evaluation including indirect ophthalmoscopy and documentation followed by ultrasonography are to be performed following established guidelines. Systemic screening with laboratory investigations and radiological evaluation for staging must be done. Management options and indication of brachytherapy versus enucleation remain unchanged.The surgical procedure is done under general anesthesia following all the COVID-19 safety recommendations. Long-term follow-up patients post-brachytherapy > 1 year, and post-enucleation > 3 months can be deferred by 3 months. Teleophthalmology with a coordinated approach with ocular oncologist/retina specialists locally and transfer of care for follow-up should be considered. Intravitreal anti-VEGF/steroid injections post-radiation for retinopathy and maculopathy can be delayed by 1-2 months. ## Vitreoretinal lymphoma Primary vitreoretinal lymphoma that has a central nervous sytem (CNS) involvement is often initially diagnosed by an ophthalmologist. Initial evaluation includes serological tests to rule out inflammatory mimics and systemic evaluation. The disease being lethal will mandate immediate attention and treatment.In the presence of a CNS involvement with radiological evidence, a diagnostic lumbar puncture can help avoid vitrectomy.Therefore, radiological assessment is done before surgical intervention in suspected vitreoretinal lymphoma. Currently accepted management modalities involve stereotactic radiotherapy or intravitreal injections. Intravitreal injections will require frequent hospital visits and risky for the patient especially if they are on concurrent chemotherapy and immunocompromised. Stereotactic radiotherapy as a primary management modality can avoid such associated risks []. ## Benign intraocular tumors The most common benign intraocular tumor is circumscribed choroidal hemangioma. Vascular tumors of retina and choroid can cause significant visual compromise due to exudation and sub-foveal fluid accumulation.This may require early intervention. They are often diagnosed clinically, and ancillary procedures such as fundus fluorescein angiography (FFA) and indocyanine green angiography (ICG) aid in the diagnosis. It is preferable to avoid angiographic procedures unless absolutely indicated. In the presence of progressive visual loss, treatment cannot be delayed. Laser therapy may be performed as per the existing protocols. Photodynamic therapy (PDT) must be deferred for the meanwhile considering the associated medical risks. This can be substituted with anti-VEGF injections in the interim period [].5. Orbital tumors Malignant orbital tumors that have aggressive lethal behavior that may lead to death or visual compromise and permanent disability require immediate attention. These include rhabdomyosarcoma, primary neuroectodermal tumors (PNET), sarcoma, and optic nerve glioma in children.Similarly, lacrimal gland adenoid cystic carcinoma, adenocarcinoma, orbital metastasis, lymphoma, and other high-grade malignancy mandates urgent attention in adults.Orbitotomy and biopsy be it incision or excision should not be delayed. Orbital exenteration if indicated may involve exposure of sinus mucosa that is known to carry a high risk for disease transmission. Care must be taken not to breach the bony orbital wall especially the thin medial wall to enter the ethmoid sinus. In cases with expected sinus mucosal exposure due to local invasion into the paranasal sinus and/or lacrimal apparatus, surgeons are advised to wear a full PPE as discussed earlier. Management is according to the standard protocols be it systemic chemotherapy or radiotherapy. Benign tumors except those that can cause a potential threat to vision and permanent disability can be delayed until after the peak of the pandemic are seen []. ## Eyelid tumors Malignant eyelid tumors, especially the lethal ones including sebaceous gland carcinoma, malignant melanoma, and Merkle cell carcinoma require timely attention and cure. Delay in the management of basal cell carcinoma and squamous cell carcinoma can lead to progression of growth, often leading to invasion and difficulty in complete excision. Primary management is surgical excision with frozen section margin clearance followed by reconstruction.Fresh tissues for the frozen section has to be handled with utmost precaution while transporting to the pathologist. Staff responsible should be wearing PPE including, masks, protective glasses, and gloves. The pathologist should be informed in advance regarding the procedure and time of tissue retrieval so that the laboratory is prepared. Chemoradiation in indicated cases is not delayed. Benign tumors of the eyelid can be observed, and surgery delayed. Postoperative follow-up duration of malignant tumors will remain the same as per the protocol. Teleophthalmology could be utilized for routine follow-ups [].7. Conjunctival tumors Ocular surface tumors that are potentially benign can be observed and management delayed. Malignant tumors of conjunctiva often do not exhibit rapid progression. The gold standard in the management of conjunctival tumors including conjunctival melanoma and ocular surface squamous neoplasia (OSSN) is surgical excision. Although Cosmetic concern of patient Patient counselling regarding risks vs benefits AS-OCT -Anterior segment optical coherence tomography; UBM -Ultrasound biomicroscopy topical therapy in OSSN is an established primary modality, in the current situation to avoid/minimize regular hospital and pharmacy visits, primary surgical excision under local anesthesia may be preferred.The decision to choose surgery versus topical treatment may be guided by local logistics. In a diagnosed COVID-19 patient, topical therapy is preferred over surgical excision. Drugs can be dispensed for 1 month and review planned after patient testing negative for COVID-19. Teleophthalmology and telementoring in conjunctival tumors is an option for diagnosis and management in collaboration with the primary ophthalmologist as it is not difficult to get high-quality ocular surface images. Plaque brachytherapy if indicated as an adjuvant procedure is to be performed 4 weeks post-surgical excision that may aid in buying time, or even delayed to a maximum of 6 weeks []. V. Ocular pathology guidelines COVID-19 pandemic poses risk to ocular pathologists and technicians and other personnel involved in the storage and transportation of specimens, as it can be a source of disease transmission.The protocols if followed strictly will help minimize the associated risks.1. General measures and laboratory procedures All the specimens should be considered potentially contaminated. Utmost precautions, immediate clean-up of spillage, and general cleanliness should be the rule. Work should be confined to a limited area. Personnel handling tissues should wear gloves, N95 masks, face masks with shields (or protective glasses), aprons or fluid-impervious gowns. Areas, where tissues are handled, must be used by authorized personnel only. ## Tissue handling/transportation (routine hpe tissue) All specimens are to be placed in well-constructed containers with a secure lid to avoid leaking during transportation. Care should be taken to avoid contamination of the outside of the container while collection. The specimen should be kept moist in proper fixative. Tissues to be kept in fixative for 24-48 h depending on the size. ## Frozen section/intra-operative cytology tissue The risk of disease transmission is high during the frozen section with fresh unfixed tissues. Frozen section for ocular pathology specimens that are of the highest risk is conjunctiva, nasolacrimal specimens, nasal, and sinus biopsies. There should be communication between the clinicians and pathologists to identify COVID-19 suspect/laboratory confirmed cases prior to the frozen section procedure. On case-to-case basis the value of frozen section should be evaluated by the clinicians and pathologists. It is advisable to defer the procedure if the report will not contribute to a high-value intraoperative intervention, and alter patient outcome. Recommended PPE is to be worn while handling tissues. While performing frozen sections confine contamination to a smaller area. Do not contaminate reusable items like mounting media containers. Precautions should be taken so that aerosols are not created in the cryostat. The frozen section slides should be immersed in alcohol immediately. Following this, the staining solution must be discarded into appropriate disinfectant (e.g., 10% bleach/sodium hypochlorite). While disinfecting the cryostat it is mandatory to wear protective personnel equipment. Defrost and decontaminate with appropriate, hospital-approved disinfectant (1% Sodium hypochlorite solution). The blades must be removed, and discarded in a 1% sodium hypochlorite solution. The entire cryostat must be wiped from inside with a 1% sodium hypochlorite solution. Immediate transfer of tissue to 10% neutral buffered formalin is advised as soon as the frozen section procedure is complete. The work area should be cleaned with a % hypochlorite solution wearing a fresh pair of gloves. ## Tissue disposal, cleaning, and disinfection All tissues should be labeled "Hazardous Infectious Waste" double-lined with red bag and sent to off-site for incineration. Work surfaces and instruments should be cleaned and disinfected with 1% sodium hypochlorite. Needles, blades, glass slides, unbroken glassware, and sharp plastic items are to be disposed of in puncture-proof containers with 1% sodium hypochlorite. ## Digital pathology Telepathology/digital pathology has allowed us to capture high-resolution images of biopsy specimens and has enabled us to continue operations during the COVID-19 pandemic. These digital images can be shared and viewed anywhere. The images are sent through a microscope with a camera. The slides moved around by a biotechnician and images are beamed live through team viewer. Also, the digital scanner captures images from different areas of the slides and sends it to the reporting ocular pathologist. The digital scanner requires someone to load the images and this can sometimes be a limitation. ## Vi. medical/pediatric oncology guidelines The rapidly spreading COVID-19 poses a greater challenge in patients with cancer undergoing treatment especially considering their immune status. Basic guidelines of handwashing and use of personal protection equipment by patients and staff are professionally monitored on entering and leaving the hospital premises. Patients undergoing treatment must be under strict physical isolation with home confinement during cycles and single room admission in hospitals. For the patients to survive cancer and this pandemic, it is important to support the families to access the care for treatment and, ensure the availability of trained oncology teams. The initial reports from Wuhan were alarming but also depends on regional cancer epidemiology, heterogeneity of cancer types, stage of presentation, and age of the patient.The guidelines are set for continuing multidisciplinary care during SARS-CoV-2/COVID-19 pandemic around the index cancers that is more common. The WHO Global Initiative for Childhood Cancer (GICC) has identified 6 common pediatric cancers as index cancers that have a good prognosis, and curative using established standard of care and regimens.This fortunately also includes retinoblastoma. There should not be any delay in the diagnosis and timely management of cancer patients during any infectious disease pandemic with the available resources. Any patient newly diagnosed with cancer should be thoroughly investigated without delay for accurate diagnosis, staging, and risk stratification for planning the treatment during and beyond the pandemic. The indications of ancillary diagnostic procedures like bone marrow biopsy and lumbar puncture for staging remains the same. Systemic chemotherapy is commenced as indicated with the standard protocols. The primary or secondary growth factor can be considered to abbreviate periods of neutropenia and hospitalization. Despite the known risk of COVID-19 infection in cancer patients due to the immunocompromised status, there is still no evidence or published guidelines for prophylactic therapy with antivirals. In the presence of concurrent COVID-19 infection in a patient, the safest approach will be to commence disease-oriented therapy after recovery from the viral infection.Telemedicine in oncology can aid in remote (local) chemotherapy supervision, review of laboratory reports, symptomatic management, and follow-up of inactive/stable cases. Tumor board meetings can be conducted through teleconferencing. ## Vii. radiation oncology guidelines The indications of radiotherapy and the practical guidelines during COVID-19 have been discussed by the experts.Conventional stereotactic radiotherapy includes 25 fractions extending over 4-5 weeks. Due to COVID-19 situation, there is a push towards hypofractionated protocols across the globe by various international societies like American Society of Therapeutic Radiation Oncology, European Society of Therapeutic Radiation Oncology), European Society of Medical Oncology, and the stereotactic radiosurgery/ radiotherapy societies.This minimizes the number of visits to the hospital and thereby minimizes the exposure to COVID-19 atmosphere as it is much faster than conventional stereotactic radiotherapy. Hypofractionated radiosurgery has been tried earlier for large meningiomas.Frameless hypofractionated image-guided volumetric modulated arc (stereotactic radiotherapy) to a dose of 25 Gy in 5 fractions over 1 week can be considered in orbital tumors/intraocular tumors requiring radiotherapy. # Conclusion In conclusion, the management of ocular malignancy should not be delayed or deferred as compared to benign tumors. It is worrying for cancer patients to contract COVID-19 infection. All the more worrying is patients becoming indirect victims of the pandemic due to late diagnosis and treatment and progression of disease leading to poor prognosis. As we are witnessing the evolution of the COVID-19, it is convincing to believe that the virus is here to stay. Therefore, a careful coexistence, and understanding of the overall impact of the pandemic to health and healthcare is essential. ## Financial support and sponsorship Nil. ## Conflicts of interest There are no conflicts of interest.	None	None	The outbreak of rapidly spreading COVID-19 pandemic in December 2019 has witnessed a major transformation in the health care system worldwide. This has led to the re-organization of the specialty services for the effective utilization of available resources and ensuring the safety of patients and healthcare workers. Suspension of oncology services will have major implications on cancer care due to delayed diagnosis and treatment leading to irreversible adverse consequences. Therefore various oncology organizations have called for a continuation of cancer care during this crisis with diligence. The COVID-19 pandemic has forced the clinicians to transform the components of care from screening to outpatient care and primary management. The purpose of this article is to establish guidelines and recommendations for ocular oncology in the management of ocular tumors set by a multidisciplinary team of experts including ocular, medical and radiation oncologists, and pathologists. As the pandemic is evolving fast, it will require constant updates and reformation of health strategies and guidelines for safe and quality health care.
db59e1b1e06aef201a8d0217f3e8373c518a2e86	pubmed	KASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease	KASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] ## List of key questions The committee identified the following key questions to be covered in these guidelines. Current evidence and recommendations are provided for each key question. 1. What is the burden of ALD in Korea? 2. How should moderate drinking, heavy drinking, binge drinking, hazardous drinking, harmful drinking, and alcohol use disorder be defined? 3. What diseases are included in the spectrum of ALD? 4. What is the natural history of ALD? 5. How do the quantity of alcohol consumed, drinking habit, and type of alcohol affect the development of ALD? 6. How do sex, ethnicity, and obesity affect ALD? 7. What is the relationship between viral hepatitis and ALD? 8. What are the characteristics of the pathophysiology of ALD? 9. What are the criteria for the clinical diagnosis of ALD? [bib_ref] Psychometric properties of the alcohol use disorders identification test: a Korean version, Kim [/bib_ref]. Is a liver biopsy necessary for the diagnosis of ALD? 11. What is the prognosis for alcoholic hepatitis? 12. What are useful prognostic factors for alcoholic hepatitis? 13. How is therapy for alcohol withdrawal syndrome (AWS) implemented? 14. What methods are available to promote alcohol abstinence? [bib_ref] Association between alcohol consumption and metabolic syndrome among Korean adults: nondrinker versus..., Park [/bib_ref]. Is enteral or parenteral nutritional support helpful for patients with ALD? [bib_ref] Prevalence of alcoholic liver disease among Korean adults: results from the fourth..., Park [/bib_ref]. What treatments increase the survival rate in alcoholic hepatitis? 17. Which patients should be given steroids or pentoxifylline treatment? 18. How should treatment outcomes for alcoholic hepatitis be evaluated? [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref]. What should be done for patients with alcoholic hepatitis who are nonresponsive to medical treatment? 20. What are the indications for liver transplantation in patients with ALD? 21. What pharmacologic agents are being tried for treatment of ALD? 22. What policies are needed to decrease harmful use of alcohol in Korea? ## Epidemiology Alcohol consumption ranks third among the risk factors for disease and disability throughout the world, and causes 2.5 million deaths annually, constituting 4% of all deaths worldwide. [bib_ref] Alcohol and public health, Room [/bib_ref] ALD, including liver cirrhosis and hepatocellular carcinoma (HCC), is responsible for approximately 25% of deaths due to alcohol consumption,which demonstrates the importance of ALD in the gen-eral population. The number of alcohol-related deaths is directly proportional to the per-capita alcohol consumption. [bib_ref] Are the recent trends in liver cirrhosis mortality affected by the changes..., Corrao [/bib_ref] [bib_ref] Large decreases in alcohol-related problems following a slight reduction in alcohol consumption..., Smart [/bib_ref] According to a European study, every 1 L increase in per-capita alcohol consumption increases the incidence of liver cirrhosis by 14% in men and 8% in women. [bib_ref] Per capita alcohol consumption and liver cirrhosis mortality in 14 European countries, Ramstedt [/bib_ref] The Korean culture is lenient toward drinking and the inebriated state. Alcohol is considered a social lubricant, and drinking is thought to be an important component in business and various other social interactions. Alcohol consumption has increased over the past 40 years in Korea concomitantly with the country's rapid socioeconomic development. The per-capita alcohol consumption in Korea increased from 7 L in the 1980s to , and is now considered to be among the highest in the world [fig_ref] Figure 1: Adult alcohol consumption per capita in 2005 [/fig_ref].Economic loss due to alcohol has increased in line with the increase in alcohol consumption, from 2.6% of the gross domestic product (GDP) in 2000 to 2.9% of the GDP in 2004. [bib_ref] Socioeconomic costs of alcohol drinking in Korea, Chung [/bib_ref] [bib_ref] Socioeconomic costs of alcohol drinking in Korea, Lee [/bib_ref] The large absolute increase in alcohol consumption has led to a rapid increase in alcohol-related diseases and accidents. [bib_ref] Korean status of alcoholics and alcoholrelated health problems, Park [/bib_ref] According to recent data from the Korea National Health and Nutrition Examination Survey (KNHANES), the prevalence of alcohol use disorder, identified as a score of 12 or higher on the Korean version of the Alcohol Use Disorders Identification Test (AUDIT, AU-DIT-K), increased from 21.3% in 2005 to [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref].1% in 2009, which ## Hazardous drinking and alcohol use disorder Excessive drinking is associated with an increased risk of disease, the most prominent of which is ALD. [bib_ref] Alcohol-related morbidity and mortality, Rehm [/bib_ref] [bib_ref] Meta-analysis of alcohol intake in relation to risk of liver cirrhosis, Corrao [/bib_ref] [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref] Therefore, it is of critical importance that hazardous drinkers are identified and treated in order to prevent or slow the progression of ALD. Hazardous drinkers are generally identified based on criteria developed by the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the World Health Organization (WHO), in which moderate drinking, heavy drinking, binge drinking, hazardous drinking (NIAAA: at-risk drinking), and harmful drinking are defined based on both the amount of alcohol consumed and drink-ing habit [fig_ref] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking,... [/fig_ref]. [bib_ref] Assessing alcohol problems : a guide for clinicians and researchers. NIAAA treatment..., Allen [/bib_ref] Although most patients with alcohol use disorder are hazardous drinkers, hazardous drinking is generally defined as the stage before alcohol use disorder, and is therefore only used when alcohol use disorder is not present. Alcohol use disorder is diagnosed with a focus on psychological, social, and physical problems, and disability caused by alcohol consumption in the past 12 months, rather than on the amount of alcohol consumed or the drinking habit. Criteria from the WHO and the American Psychiatric Association (APA) are generally used. The APA's Diagnostic and Statistical Manuals of Mental Disorders, 4th Edition (DSM-IV) divides alcohol use disorder into two categories: alcohol abuse and alcohol dependence.Alcohol abuse, which generally refers to the stage prior to alcohol dependence, is defined as persistent drinking despite recurrent social, interpersonal, and legal problems as a result of the alcohol use, and it is known that around 10% of alcohol abusers progress to alcohol dependence. [bib_ref] Prospective evaluation of the four DSM-IV criteria for alcohol abuse in a..., Schuckit [/bib_ref] Alcohol dependence is a condition that results from the prolonged and (usually) high consumption of alcohol that has resulted in physiological dependence on this consumption. This dependence produces significant problems in the person's life. Due to the ambiguity in the definition of alcohol abuse, the WHO's International Classification of Diseases, 10th Revision (ICD 10) does not classify it,and alcohol use disorder is defined in the recently revised DSM-V as mild, moderate, or severe based on the severity rather than alcohol abuse versus dependence (Appendix 1). [bib_ref] The conceptual development of DSM-V, Regier [/bib_ref] [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref] Screening test for alcohol use disorder Given that a significant portion of patients who visit primary care facilities are hazardous drinkers, the risk for many diseases due to alcohol consumption may be decreased with proper recognition and interventions that lead to abstinence or decreased drinking. [bib_ref] Provider training for patient-centered alcohol counseling in a primary care setting, Ockene [/bib_ref] [bib_ref] Strategies to increase alcohol screening in health care settings, Fleming [/bib_ref] [bib_ref] Hazardous and harmful alcohol consumption in primary care, Reid [/bib_ref] [bib_ref] Screening for alcohol problems in primary care: a systematic review, Fiellin [/bib_ref] The best screening test for hazardous drinkers is a questionnaire, since this has been shown to have a higher sensitivity than blood-based tests. [bib_ref] Comparison of the CAGE questionnaire versus some biochemical markers in the diagnosis..., Girela [/bib_ref] While many questionnaires are available, the ones most frequently used are the CAGE (Cut down, Annoyed, Guilty, Eyeopener) questionnaire and the AUDIT questionnaire. The CAGE questionnaire is simple, being based on four yes/no questions, and while easily adoptable it has low sensitivity for hazardous drinking, the stage before alcohol use disorder (Appendix 2). [bib_ref] Hazardous and harmful alcohol consumption in primary care, Reid [/bib_ref] [bib_ref] The CAGE questionnaire: validation of a new alcoholism screening instrument, Mayfield [/bib_ref] [bib_ref] The CAGE questionnaire for alcohol misuse: a review of reliability and validity..., Dhalla [/bib_ref] [bib_ref] The value of the CAGE in screening for alcohol abuse and alcohol..., Aertgeerts [/bib_ref] [bib_ref] Joint use of clinical parameters, biological markers and CAGE questionnaire for the..., Bataille [/bib_ref] [bib_ref] Screening for problem drinking : Comparison of CAGE and AUDIT, Bradley [/bib_ref] AUDIT is a ten-item questionnaire developed by the WHO and is appropriate for most primary care settings (Appendix 3). [bib_ref] Screening for problem drinking : Comparison of CAGE and AUDIT, Bradley [/bib_ref] such as the quantity consumed and the drinking habit, the next three items gauge alcohol dependence, and the last four items measure the level of harmful drinking such as the psychological and social impacts. AUDIT is the most appropriate test for identifying both alcohol use disorder and hazardous drinking, 37-39 with AUDIT-K being used for a Korean cohort (Appendix 4). [bib_ref] Screening criteria of alcoholism by alcohol use disorders identification test (AUDIT) in..., Kim [/bib_ref] The disadvantages of AUDIT include the larger number of questions and the longer time required to grade each question. Therefore, a shorter version has been developed, called AUDIT-Consumption (AUDIT-C), which employs only the first three questions regarding alcohol consumption. This has the advantage of a shorter testing time while maintaining a relatively high sensitivity and specificity. [bib_ref] The AU-DIT alcohol consumption questions (AUDIT-C): an effective brief screening test for..., Bush [/bib_ref] [bib_ref] Audit-3 and audit-4: effectiveness of two short forms of the alcohol use..., Gual [/bib_ref] Given the limited amount of time available for outpatients in Korea, the third question of AUDIT (AUDIT-3) alone can also be used to reduce the response time, since in this version of AUDIT the third question of AUDIT regarding binge drinking is asked first, and if the answer is negative for the past 1 year, screening is ended early due to the low likelihood of that patient being a hazardous drinker; while for a positive answer, additional AUDIT questions are asked to complete the screening test. 41 ## [recommendations] 2. If a patient appears to be at risk of alcohol-related medical problems, a structured questionnaire, such as AUDIT, should be administered to obtain more qualitative information about a patient's alcohol consumption and problems. (A1) 3. AUDIT-K is recommended as a screening test for outpatients with alcohol use disorder; alternatively, AUDIT-C or AU-DIT-3 may be used for convenient testing. (B1) # Future research 1. There is a need to assess the prevalence of ALD in patients with alcohol use disorder. ## Natural history of alcoholic liver dis-ease ALD encompasses a broad spectrum of diseases including fatty liver, hepatitis, liver cirrhosis, and HCC. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Multiple stages of liver injury may coexist in a given individual. [bib_ref] Morphology of alcoholic liver disease, Lefkowitch [/bib_ref] [bib_ref] Alcoholic liver disease. An update, Mendez-Sanchez [/bib_ref] [bib_ref] Alcoholic liver disease, O'shea [/bib_ref] In ALD, the occurrence and severity of liver fibrosis is important in the progression of the disease to liver cirrhosis [fig_ref] Figure 2: Natural history, spectrum, and pathophysiology of alcoholic liver disease [/fig_ref]. A Korean study tracking 727 patients with ALD for an average period of 480 days found that the overall death rate was 14.6%, with the main causes of death being variceal bleeding (31.1%), liver failure (24.5%), and hepatorenal syndrome/sepsis (11.3%).However, the natural history of ALD remains unclear. Regardless of the spectrum of ALD, abstaining from alcohol prevents progression of the disease, improves the survival rate, and decreases the need for liver transplantation. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Moreover, liver fibrosis and liver cirrhosis may occur in 5-15% of abstaining patients, and so abstinence per se does not guarantee a disappearance of ALD. [bib_ref] Fatty liver: a study of 270 patients with biopsy proven fatty liver..., Leevy [/bib_ref] [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcoholic steatohepatitis, Stickel [/bib_ref] Alcoholic fatty liver Alcoholic fatty liver, also known as alcoholic steatosis, is the ini-tial presentation of liver injury due to chronic alcohol consumption. Fatty liver is the most common disease associated with alcohol use, and is seen in 80-90% of heavy drinkers. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] While full recovery is possible with abstinence at this stage, one study found that continued alcohol use (≥400 g/week) increased the risk of progression to cirrhosis in 30% of cases, and to fibrosis or cirrhosis in 37%. [bib_ref] Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver, Teli [/bib_ref] However, significant liver injury may still occur in individuals who drink less. Once alcoholic fatty liver develops, it is not clear whether it will remain a fatty liver or progress to a more severe liver disease. Comorbidities due to environmental and genetic factors, viral hepatitis, obesity, and HIV infection may convert alcoholic fatty liver into steatohepatitis. ## Alcoholic hepatitis Alcoholic hepatitis (also known as alcoholic steatohepatitis), which is usually accompanied by fatty liver disease includes a broad spectrum of pathological processes. Symptomatic patients present with advanced liver disease, with concomitant cirrhosis in more than 50% of them. [bib_ref] Prognosis of alcoholic cirrhosis in the presence and absence of alcoholic hepatitis, Orrego [/bib_ref] The prognosis is even worse with severe alcoholic hepatitis, with a 1-month mortality of 40%. [bib_ref] Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial, Carithers [/bib_ref] Drink excessively, may induce recurrent episodes of alcoholic hepatitis in patients with ALD, and if this is severe or associated with liver cirrhosis, complications occur due to liver failure and portal hypertension, leading to a high short-term mortality. In addition, longterm follow-up of these patients has shown that they rarely improve, instead usually remaining with alcoholic hepatitis or progressing to liver cirrhosis. [bib_ref] Natural history of alcoholic hepatitis. IV. Glycosaminoglycuronans and collagen in the hepatic..., Galambos [/bib_ref] Liver fibrosis is common in alcoholic hepatitis and is accelerated in the presence of chronic alcoholic hepatitis. [bib_ref] Alcoholic hepatitis, Lucey [/bib_ref] Even in patients with fatty liver or steatohepatitis but without liver fibrosis, 38-56% will eventually progress to liver cirrhosis with continued alcohol consumption. [bib_ref] Nonalcoholic steatohepatitis--a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and..., Cortez-Pinto [/bib_ref] [bib_ref] Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of..., Pares [/bib_ref] [bib_ref] Incidence and mortality of alcoholic hepatitis in Denmark 1999-2008: a nationwide population..., Sandahl [/bib_ref] Alcoholic liver cirrhosis Long-term excessive drinking results in a 15-30% lifetime risk of alcoholic liver cirrhosis. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] [bib_ref] Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver, Teli [/bib_ref] [bib_ref] Prognosis and life expectancy in chronic liver disease, Propst [/bib_ref] At the time of diagnosis of alcoholic liver cirrhosis it is accompanied by no complications in 24% of patients, ascites alone in 55%, variceal bleeding alone in 6%, combined ascites and variceal bleeding in 4%, and hepatic encephalopathy in 11%. [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] In a patient initially presenting without complications, ascites (12%), variceal bleeding (6%), and hepatic encephalopathy (4%) may appear as a first complication within 1 year of diagnosis. [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] The rate of decompensation within 1 year of a diagnosis is 37.6% with alcoholic liver cirrhosis, compared to 25.2% in non-alcoholic liver cirrhosis. [bib_ref] The rate of decompensation and clinical progression of disease in people with..., Fleming [/bib_ref] As in other diseases, alcoholic liver cirrhosis may lead to decompensated liver cirrhosis and is associated with a risk of developing HCC. [bib_ref] A 20-year prospective study of cirrhosis, Saunders [/bib_ref] The incidence of HCC is 7.2-16.0% in alcoholic liver cirrhosis, with a 1% annual risk in patients with decompensated alcoholic liver cirrhosis. 61,66-69 Viral hepatitis plays a significant role in the development of HCC in chronic drinkers. [bib_ref] National survey of hepatocellular carcinoma in heavy drinkers in Japan, Horie [/bib_ref] The overall risk of death in patients with alcoholic liver cirrhosis is 5-30 times higher in alcoholics than in the general population. [bib_ref] All-cause mortality in people with cirrhosis compared with the general population: a..., Fleming [/bib_ref] For advanced alcoholic liver cirrhosis the median survival time is 1-2 years and the 5-year survival rate is 23-50%, which is worse than that for non-alcoholic liver cirrhosis. [bib_ref] Alcoholic liver disease, Bruha [/bib_ref] In compensated alcoholic liver cirrhosis, the 5-year survival rate approaches 90% with abstinence but decreases to less than 70% with continued drinking. [bib_ref] Alcoholic liver disease: natural history, Diehl [/bib_ref] In decompensated alcoholic liver cirrhosis the 5-year survival rate is 60% with abstinence and 30% with continued drinking. [bib_ref] Liver disease in alcohol abusers: clinical perspective, Diehl [/bib_ref] The median survival time for decompensated alcoholic liver cirrhosis is 61 months, [bib_ref] Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165..., Alvarez [/bib_ref] and 80% of patients who continue drinking even in the presence of ascites will die within 7 months. [bib_ref] Continued heavy drinking and survival in alcoholic cirrhotics, Borowsky [/bib_ref] The 1-year mortality rate is 17% among patients with liver cirrhosis but without any complications, while this increases to 20-64% if complications develop, in which case the 5-year mortality rate approaches 58-85%. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] Future research There is a need to elucidate the natural history of ALD. ## Risk factors for alcoholic liver disease ## Quantity of alcohol consumed A standard drink is sometimes used as a unit measure to estimate the quantity of alcohol consumed, and it varies markedly between countries; in Korea it corresponds to 12 g of pure alcohol. The risk of ALD substantially increases in both sexes when alcohol consumption exceeds 30 g/day. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] An increased risk of liver injury with alcohol consumption exceeding 30 g/day was found in the large-scale Dionysos cohort study performed in northern Italy. [bib_ref] Prevalence of chronic liver disease in the general population of northern Italy:..., Bellentani [/bib_ref] [bib_ref] Alcohol and cirrhosis: dose--response or threshold effect?, Kamper-Jorgensen [/bib_ref] There are also other reports of a proportional relationship between the quantity of alcohol consumed and the risk of ALD. The minimum amount of alcohol required for liver cirrhosis is 20-40 g/ day in men and 10-20 g/day in women, and most retrospective studies also show that the risk of liver injury is increased when alcohol consumption exceeds 40-80 g/day. [bib_ref] Alcohol consumption and the risk of alcohol related cirrhosis in women, Norton [/bib_ref] [bib_ref] Ascitic cirrhosis in relation to alcohol consumption, Pequignot [/bib_ref] [bib_ref] Greater risk of ascitic cirrhosis in females in relation to alcohol consumption, Tuyns [/bib_ref] [bib_ref] Alcohol consumption and the risk of cirrhosis, Batey [/bib_ref] [bib_ref] Determinants of alcohol use and abuse: Impact of quantity and frequency patterns..., Zakhari [/bib_ref] [bib_ref] Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy, Amini [/bib_ref] Many prospective studies have found a proportional relationship between the quantity of alcohol consumed and the presence of alcoholic liver injury. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcohol and mortality, Klatsky [/bib_ref] [bib_ref] A prospective study of alcoholic liver disease and mortality, Bouchier [/bib_ref] According to the USA guidelines for non-alcoholic fatty liver disease, significant alcohol consumption has been defined in the past 2 years as exceeding 21 standard drinks per week in men and 14 standard drinks per week in women. [bib_ref] Endpoints and clinical trial design for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by..., Chalasani [/bib_ref] In conclusion, there is a quantity dependent relationship between the amount of alcohol consumed and the risk of ALD. Although most prospective and retrospective studies demonstrate that the prevalence of liver injury increases in proportion to the daily alcohol intake, this relationship does not always hold, suggesting that other factors, such as genetic predisposition, can also be involved. [bib_ref] Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for..., Hrubec [/bib_ref] [bib_ref] Epidemiology of alcoholic liver disease, Grant [/bib_ref] Drinking habit ALD is seen more frequently in daily drinkers than in intermittent drinkers. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcohol and cirrhosis: dose--response or threshold effect?, Kamper-Jorgensen [/bib_ref] [bib_ref] Epidemiology of alcoholic cirrhosis, Wilkinson [/bib_ref] Binge drinking, a form of drinking habit that has recently surfaced as a social problem in many countries, is defined as consuming more than five drinks for men and four drinks for women over a time period of 2 hours [fig_ref] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking,... [/fig_ref]. [bib_ref] Determinants of alcohol use and abuse: Impact of quantity and frequency patterns..., Zakhari [/bib_ref] This consumption of a large amount of alcohol over a short period of time is associated with the development of ALD. [bib_ref] Diet and stroke, Renaud [/bib_ref] [bib_ref] Effect of binge drinking on the liver: an alarming public health issue?, Mathurin [/bib_ref] The risk of ALD is also increased with habits such as drinking without meals, drinking at multiple locations at a time, mixing drinks, and initiating alcohol drinking at a younger age. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] [bib_ref] Drinking patterns, dependency and life-time drinking history in alcoholrelated liver disease, Hatton [/bib_ref] ## Types of alcohol While few studies have investigated the association between type of alcohol and liver injury, the available data suggest that liver injury is associated more strongly with the total quantity of alcohol consumed than with the type of alcohol. A notable finding is that small amounts of wine reportedly decrease mortality rates associated with both cardiovascular and non-cardiovascular disease, including liver disease. [bib_ref] Mortality associated with moderate intakes of wine, beer, or spirits, Gronbaek [/bib_ref] [bib_ref] Type of alcohol consumed and mortality from all causes, coronary heart disease,..., Gronbaek [/bib_ref] However, there is still controversy regarding the association between the type of alcohol consumed and the risk of liver injury, especially for liver cirrhosis. ## Sex The frequency of liver injury is higher among women than men, even when the same quantity of alcohol is consumed. Many studies have found that the incidence of alcoholic liver injury is higher in women than in men with a daily alcohol consumption of 30-80 g. [bib_ref] Alcohol and mortality, Klatsky [/bib_ref] [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] High blood alcohol levels in women. The role of decreased gastric alcohol..., Frezza [/bib_ref] Liver injury occurs more easily in women, including over shorter time periods or involving smaller quantities of alcohol. [bib_ref] Sex-related differences among 100 patients with alcoholic liver disease, Morgan [/bib_ref] [bib_ref] Changing pattern of alcoholic liver disease in Great Britain: relation to sex..., Krasner [/bib_ref] The relatively safe level of alcohol consumption in women has been reported as less than 10-20 g. [bib_ref] Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of..., Pares [/bib_ref] [bib_ref] Greater risk of ascitic cirrhosis in females in relation to alcohol consumption, Tuyns [/bib_ref] [bib_ref] A prospective study of alcoholic liver disease and mortality, Bouchier [/bib_ref] [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] Morbidity in alcoholics. Evidence for accelerated development of physical disease in women, Ashley [/bib_ref] In a large prospective study, the risk of developing ALD with a weekly alcohol consumption of 336-492 g differed significantly between men (7.0) and women (17.0). [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] The risk of liver cirrhosis was dramatically increased in women with a daily alcohol intake exceeding 40 g. [bib_ref] Alcohol consumption and the risk of alcohol related cirrhosis in women, Norton [/bib_ref] [bib_ref] Sex-related differences among 100 patients with alcoholic liver disease, Morgan [/bib_ref] [bib_ref] Morbidity in alcoholics. Evidence for accelerated development of physical disease in women, Ashley [/bib_ref] The blood alcohol concentration is higher in women than in men after consuming the same amount of alcohol, resulting in a higher risk of ALD. [bib_ref] Ethanol elimination in males and females: relationship to menstrual cycle and body..., Marshall [/bib_ref] Women exhibit a decreased level of alcohol dehydrogenase (ADH) in the stomach, resulting in a slower first step of alcohol metabolism, increased bioavailability of alco-hol, and increased risk of liver injury. [bib_ref] High blood alcohol levels in women. The role of decreased gastric alcohol..., Frezza [/bib_ref] In addition, factors such as a lower body distribution of alcohol due to a higher body fat content and an estrogen-induced increase in oxidative stress and inflammation contribute to the increased risk of ALD in women. [bib_ref] Gender differences in pharmacokinetics of alcohol, Baraona [/bib_ref] ## Ethnicity There may be an association between ethnicity and the risk of alcoholic liver injury. [bib_ref] Racial and ethnic differences in alcohol-associated aspartate aminotransferase and gamma-glutamyltransferase elevation, Stewart [/bib_ref] The frequency of alcoholic liver cirrhosis is higher in African-American and Latin-American men than in white men, and the death rate for this condition is the highest among Latin-American men. [bib_ref] The critical dimension of ethnicity in liver cirrhosis mortality statistics, Stinson [/bib_ref] These differences seem to be independent of the quantity of alcohol consumed. 106 ## Malnutrition Protein-calorie malnutrition is a common clinical manifestation of ALD.The degree of malnutrition is known to be strongly correlated with the development of complications such as ascites, hepatic encephalopathy, and hepatorenal syndrome, and a gradual increase in mortality.ALD is accompanied by deficiencies in micronutrients such as folate, thiamine, pyridoxine, vitamin A, vitamin E, zinc, and magnesium, and such deficiencies in folate, vitamin E, and zinc may accelerate liver disease. [bib_ref] Nutrition and alcoholic liver disease, Halsted [/bib_ref] [bib_ref] Alcoholic liver disease and malnutrition, Mcclain [/bib_ref] Obesity Obesity increases the severity of alcohol-induced liver injury. [bib_ref] Obesity and alcoholic liver disease, Diehl [/bib_ref] The relationship between obesity and alcohol consumption differs between men and women. [bib_ref] Beer consumption and the 'beer belly': scientific basis or common belief?, Schutze [/bib_ref] [bib_ref] The association of lifetime alcohol use with measures of abdominal and general..., Bergmann [/bib_ref] In obese persons, excessive drinking leads to increased risks of liver disease, [bib_ref] Co-occurrence of obesity and patterns of alcohol use associated with elevated serum..., Tsai [/bib_ref] [bib_ref] A cohort study of the effect of alcohol consumption and obesity on..., Shen [/bib_ref] liver cirrhosis, and mortality. [bib_ref] Body mass index and risk of liver cirrhosis in middle aged UK..., Liu [/bib_ref] [bib_ref] Effect of body mass index and alcohol consumption on liver disease: analysis..., Hart [/bib_ref] [bib_ref] Risk factors for alcoholic liver disease in China, Lu [/bib_ref] High body mass index and fasting glucose are independent risk factors for the progression of liver fibrosis even after correcting for the amount of alcohol consumed and the duration of alcohol abuse, [bib_ref] Risk factors of fibrosis in alcohol-induced liver disease, Raynard [/bib_ref] which is thought to be due to insulin resistance and hyperinsulinemia. [bib_ref] Alcohol and liver fibrosis, Cubero [/bib_ref] Therefore, obesity is an important risk factor for liver cirrhosis in the presence of excessive drinking. [bib_ref] Risk factors of fibrosis in alcohol-induced liver disease, Raynard [/bib_ref] [bib_ref] Excess weight risk factor for alcoholic liver disease, Naveau [/bib_ref] ## Genetic factors Concomitant alcoholic liver cirrhosis is seen three times as frequently in monozygotic twins than in dizygotic twins, suggesting a genetic susceptibility in ALD. [bib_ref] Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for..., Hrubec [/bib_ref] Several family studies have also suggested an association between alcohol dependence and genetic factors. [bib_ref] Alcohol problems in adoptees raised apart from alcoholic biological parents, Goodwin [/bib_ref] Genetic polymorphisms in enzymes involved in alcohol metabolism, such as ADH2, ADH3, and aldehyde dehyrogenase 2 (ALDH2), are related to alcohol dependence and ALD. [bib_ref] Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic..., Zintzaras [/bib_ref] The ALDH22 allele produces an ALDH2 variant with greatly reduced enzymatic activity and delayed aldehyde metabolism, and a lower risk of developing alcohol addiction; a meta-analysis of data related to Asian populations found that the presence of the ALDH22 allele was associated with a lower frequency of alcohol dependence and ALD. [bib_ref] Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (2) allele..., Li [/bib_ref] The frequency of the ALDH22 allele was significantly lower among Korean patients with alcoholic liver cirrhosis than among those without it. [bib_ref] Genetic polymorphisms of alcohol-metabolizing enzymes and cytokines in patients with alcohol induced..., Kim [/bib_ref] [bib_ref] Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in..., Lee [/bib_ref] Mutation of the gene encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been suggested as a genetic risk factor for ALD, with a higher frequency of PNPLA3 rs738409 GG found in a highrisk group for progression to ALD. [bib_ref] Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing..., Sookoian [/bib_ref] Two recent meta-analyses have provided evidence of an association between genetic polymorphisms in the gene encoding interleukin (IL)-10 and alcoholism, [bib_ref] Interleukin-10 gene polymorphism is associated with alcoholism but not with alcoholic liver..., Marcos [/bib_ref] and an increased risk of ALD among alcoholics with allelic variants of the gene encoding glutathione-S -transferase. [bib_ref] Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease, Marcos [/bib_ref] However, these candidate genes have not been confirmed in Korean studies. Studies of ALD have thus far been limited to identifying specific genetic mutations, indicating a need for genome-wide association analyses. ## Viral factors The prevalence of hepatitis C virus (HCV) is higher among alcoholics than non-alcoholics, and the combination of HCV and alcohol has a synergistic effect on liver injury. [bib_ref] Hepatitis C virus and alcohol, Siu [/bib_ref] Possible underlying mechanisms for this include immune suppression, stimulation of viral replication, increased oxidative stress, and hepatocyte cytoxicity. Alcohol intake by patients with HCV infection increases the risk of liver cirrhosis and HCC, [bib_ref] The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in..., Harris [/bib_ref] and reduces their responses to interferon treatment. [bib_ref] Alcohol use and treatment of hepatitis C virus: results of a national..., Anand [/bib_ref] Unlike for HCV, data is limited regarding the association between hepatitis B virus (HBV) and progression of liver disease due to alcohol consumption. Nevertheless, alcohol consumption does have an adverse effect on hepatitis patients. [bib_ref] Southern Europe as an example of interaction between various environmental factors: a..., Donato [/bib_ref] Specifically, alcohol directly affects host-cell metabolism and gene expression, which acts to increase the expression and replication of viral genes. [bib_ref] Ethanol and hepatocellular injury, French [/bib_ref] Therefore, patients with HBV should avoid consuming alcohol. 97 ## Smoking Smoking is a risk factor for ALD, causes oxidative stress, and accelerates fibrosis in patients with ALD.Abstaining from smoking is therefore recommended in patients with ALD. ## Coffee Many studies have found that the risk of ALD reduces as coffee consumption increases, and that coffee may suppress the development of ALD. [bib_ref] Cof fee and liver diseases, Muriel [/bib_ref] [bib_ref] Coffee, cirrhosis, and transaminase enzymes, Klatsky [/bib_ref] [bib_ref] Coffee, caffeine, and the risk of liver cirrhosis, Corrao [/bib_ref] [bib_ref] Does coffee protect against liver cirrhosis?, Gallus [/bib_ref] A marked decrease in mortality due to liver disease was found among those who drink three or more cups of coffee per day compared to those who drink two or fewer cups per day. [bib_ref] Coffee intake and mortality from liver cirrhosis, Tverdal [/bib_ref] The consumption of caffeinated drinks other than coffee is not associated with a decreased incidence of liver cirrhosis, which suggests that substances other than caffein in coffee have an important role in ALD. 140 ## [recommendations] ## Excessive drinking, defined as an average alcohol consumption exceeding 40 g/day in men and 20 g/day in women, increases the risk of alcoholic liver injury and should be avoided. (a1) 5. daily or binge drinking increases the risk of ald and should be avoided. (a1) 6. Alcohol abstinence is necessary for patients with chronic viral hepatitis. (B1) 7. Obesity and smoking increase ALD, and so weight control and smoking cessation are recommended. (B1) # Future research 1. There is a need to characterize cases of ALD that are accompanied by other liver diseases such as viral hepatitis. 2. There is a need to assess the interactions between the risk factors for ALD. 3. There is a need for genome-wide association studies involving patients with ALD. ## Pathophysiology of alcoholic liver dis-ease The pathophysiology of ALD varies according to the stage of the disease and the presence of genetic and non-genetic factors affect the onset and clinical progression of ALD.models, and because these experiments only cause moderate degrees of liver disease, fibrosis, and injury, the mechanism underlying the pathophysiology of ALD in humans has not yet been fully elucidated. 144 ## Alcoholic fatty liver (steatosis) Steatosis is the initial reaction to alcohol abuse and is characterized by the adiposis of hepatocytes. Alcoholic fatty liver occurs through many complex mechanisms, via the following four steps. [bib_ref] Alcoholic liver disease: pathogenesis and new therapeutic targets, Gao [/bib_ref] First, alcohol oxidation leads to increases in the synthesis of nicotinamide adenine dinucleotide (NADH), triglycerides, and fatty acids, and to the suppression of mitochondrial β-oxidation. [bib_ref] Alcohol and lipids, Baraona [/bib_ref] Second, there is an increase in the influx of free fatty acids from the adipose tissue and chylomicrons from the visceral mucosa into the liver. [bib_ref] Alcohol and lipids, Baraona [/bib_ref] Third, ethanol mediates the suppression of adenosinemonophosphate-activated protein kinase (AMPK) activation, resulting in an increase in lipid biosynthesis, suppression of peroxisome proliferator-activated receptor α (PPARα), and decrease in lipolysis due to the activation of sterol regulatory element binding protein 1c (SREBP1c). [bib_ref] Role of adiponectin in the protective action of dietary saturated fat against..., You [/bib_ref] [bib_ref] Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in..., Ji [/bib_ref] [bib_ref] Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage, Nakajima [/bib_ref] Fourth, there is acetaldehyde-induced mitochondria and microtubule damage, resulting in decreased NADH oxidation and accumulation of very-low-density lipoprotein (VLDL). 145 ## Alcoholic steatohepatitis Steatohepatitis is defined as a condition with fatty liver, inflammatory cell infiltration comprising mainly polymorphonuclear leukocytes, and hepatocyte injury. In ALD, although alcoholic steatohepatitis is a necessary step in the progression to liver fibrosis and cirrhosis, liver fibrosis is not included in the definition of steatohepatitis. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Currently, there is no consensus on the pathologic classification of steatohepatitis, and the severity of this condition is determined by environmental factors such as the quantity of alcohol consumed, lifestyle, and dietary habits. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Various factors affect the onset of alcoholic steatohepatitis. First, the toxic effect of acetaldehyde and the production of oxygen free radicals affect the development of this condition. Ethanol is metabolized into acetaldehyde by ADH within the cytosol, P450 within the microsomes, and catalase within the peroxisomes. Ethanol metabolism results in the production of oxygen free radicals, peroxidation of lipids, and a decrease in mitochondrial glutathione and S-adenosyl-L-methionine (SAMe) levels, and these metabolites sensitize the hepatocyte to injury. Acetaldehyde is then metabo-lized by mitochondrial ADH into acetate, which combines with protein and DNA to alter their function, ultimately affecting protein synthesis. [bib_ref] Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption, Niemela [/bib_ref] [bib_ref] Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde, Theruvathu [/bib_ref] These products then act as auto-antigens to activate the immune system, increasing the lymphocyte count and causing liver injury. Furthermore, acetaldehyde causes oxidative stress and apoptosis through mitochondrial damage and impairment of glutathione function. [bib_ref] Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and..., Seitz [/bib_ref] Second, there are pro-inflammatory cytokines. Alcohol metabolites and oxygen free radicals stimulate the signal-transduction pathways related to nuclear factor-κB (NFκB), signal transducer and activator of transcription-Janus kinase (STAT-JAK), and c-Jun N-terminal kinase (JNK), which induce the production of inflammation mediators such as tumor necrosis factor-α (TNF-α), IL-17, CXC chemokines, and osteopontin. [bib_ref] Intrahepatic gene expression in human alcoholic hepatitis, Seth [/bib_ref] Alcohol abuse disrupts the normal intestinal microbiota and increases the permeability of the endotoxins produced by intestinal bacteria, increasing serum lipopolysaccharide levels, [bib_ref] endotoxin-neutralizing-capacity, sCD14, sI-CAM-1, and cytokines in patients with various degrees of alcoholic..., Urbaschek [/bib_ref] and causing an inflammatory reaction in Kupffer cells via the CD14/toll-like receptor 4 (TLR 4) pathway. [bib_ref] Alcoholic liver injury involves activation of Kupffer cells by endotoxin, Thurman [/bib_ref] This inflammatory environment in ALD causes the infiltration of polymorphonuclear leukocytes, production of oxygen free radicals, and hepatocyte injury. ## Fibrosis in alcoholic liver disease Liver fibrosis is a recovery response seen in every form of chronic liver injury, and is characterized by the excessive accumulation of extracellular matrix proteins such as collagen. [bib_ref] Liver fibrosis, Bataller [/bib_ref] [bib_ref] Mechanisms of hepatic fibrogenesis, Friedman [/bib_ref] Fibrosis can occur in alcoholic steatohepatitis, and occurs mainly where ADH is located, typically in pericentral and perisinusoidal regions. [bib_ref] Liver fibrosis, Bataller [/bib_ref] In the progression stage, collagen bands become apparent and bridging fibrosis develops. This stage precedes liver cirrhosis and the formation of regeneration nodules. The cytological and molecular biological mechanism of fibrosis in ALD is currently not well understood. [bib_ref] Alcohol and liver fibrosis, Cubero [/bib_ref] Metabolites of alcohol such as acetaldehyde directly activate hepatic stellate cells (HSCs), the main producers of collagen in the injured liver, and play a major role in the production of portal fibroblasts and bone-marrow-derived myofibroblasts. [bib_ref] Liver fibrosis, Bataller [/bib_ref] [bib_ref] Mechanisms of hepatic fibrogenesis, Friedman [/bib_ref] HSCs are also activated by injured hepatocytes, activated Kupffer cells, and infiltration of polymorphonuclear leukocytes. These cells secrete growth factors such as transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF), cytokines such as leptin, angiotensin II, IL-8, and TNF-α, soluble mediators such as nitric oxide, and oxygen free radicals. Importantly, oxygen free radicals stimulate the signaling pathway within HSCs, which includes extracellular signal-regulated kinase, phosphoinositide 3 kinase (PI3K)/Akt, and JNK. [bib_ref] Cytokines and renin-angiotensin system signaling in hepatic fibrosis, Moreno [/bib_ref] These oxygen free radicals also enhance the activity of tissue inhibitor of metalloproteinase 1, reducing the activity of metalloproteinases and stimulating the accumulation of extracellular matrix proteins such as collagen. # Future research 1. There is a need to study how genetic differences influence the progression of liver fibrosis. ## Clinical diagnosis of alcoholic liver disease For the diagnosis of ALD, the presence of heavy drinking, which is a prerequisite, must be confirmed through history and questionnaires and may be supplemented by blood tests. Identifying liver disease might require methods such as a physical examination, blood tests, and radiologic studies, and a liver biopsy may also be performed under certain circumstances. ## History taking The type of alcoholic beverage, quantity of alcohol consumed, weekly drinking frequency, and duration of drinking are all important data to obtain during history-taking. Since patients frequently deny or underreport the amount of drinking, it is helpful to obtain the drinking history through questionnaires or from family members. Although currently there is no consensus on the minimum amount of alcohol required for ALD, a cutoff that is often applied is an average alcohol intake exceeding 40 g/day in men and 20 g/ day in women. [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] Detecting symptoms of alcohol abuse in primary care settings, Mcquade [/bib_ref] [bib_ref] Biological correlates and detection of alcohol abuse and alcoholism, Eckardt [/bib_ref] [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] The average daily alcohol intake is calculated using the following equation: [amount consumed (mL)×alcohol by volume (%)×specific gravity of alcohol (0.785)×number of drinking days per week]÷7. For example, if a person drinks one Soju bottle (360 mL, 19% alcohol by volume) three times a week, then the amount consumed would be (360 mL×19%×0.785)÷100 =53.7 g, and the average daily alcohol intake would be (53.7 g×3) ÷7=23 g. The alcohol contents of various forms of alcoholic beverage are listed in [fig_ref] Table 3: Alcohol contents of different types of alcoholic beverage The Korean Association for... [/fig_ref]. A standard drink in Korea contains 12 g of alcohol (as defined by the Ministry of Health and Welfare), and so is approximately equal to 1.5 nips of Soju (90 mL), 1 can of beer (355 mL), 1 bowl of Makgeolli (230 mL), 1 glass of wine (120 mL), or 1 nip of whisky (40 mL). ## Symptoms and signs The effects of ALD can range from being asymptomatic to liver failure and death. While symptoms and signs such as epigastric discomfort, fever, fatigue, anorexia, malaise, weight loss, tender hepatomegaly, jaundice, spider angiomata, cachexia, gynecogenic changes, and right upper-quadrant abdominal bruit may occur, they are nonspecific. [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] [bib_ref] The importance of a coexistent hepatic rub and bruit. A clue to..., Sherman [/bib_ref] [bib_ref] Enlarged, tortuous arteries and hepatic bruit, Goldstein [/bib_ref] In severe alcoholic hepatitis or liver cirrhosis, symptoms and signs such as ascites, lower extremity edema, hepatic encephalopathy, and esophageal variceal bleeding may be seen. [bib_ref] Alcoholic hepatitis, Mendenhall [/bib_ref] Damage to organs other than the liver may manifest as gastritis, peptic ulcer, pancreatitis, neuropathy, myopathy, Dupuytren's contracture, cardiomyopathy, arrhythmia, anemia, parotid gland hypertrophy, lacrimal gland hypertrophy, altered mental status due to delirium tremens, and sleep disorders. [bib_ref] Relationship between ethanol-related diseases and nutritional status in chronically alcoholic men, Estruch [/bib_ref] [bib_ref] The risk of alcohol, Anderson [/bib_ref] [bib_ref] Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to..., Lazarevic [/bib_ref] [bib_ref] H pylori infection and other risk factors associated with peptic ulcers in..., Salih [/bib_ref] [bib_ref] Alcohol drinking and risk of hospitalization for heart failure with and without..., Klatsky [/bib_ref] [bib_ref] Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis, Preedy [/bib_ref] ## Blood tests Blood tests for detecting a history of chronic alcohol consumption include serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltranspeptidase (GGT), mean corpuscular volume (MCV), and carbohydrate deficient transferrin (CDT). [bib_ref] Screening for excessive alcohol drinking. Comparative value of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and..., Yersin [/bib_ref] [bib_ref] Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl..., Reynaud [/bib_ref] [bib_ref] CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative..., Conigrave [/bib_ref] Combining the results of several of these tests is superior to using any single test. [bib_ref] Combinations of carbohydrate-deficient transferrin, mean corpuscular erythrocyte volume, gamma-glutamyltransferase, homocysteine and folate..., Rinck [/bib_ref] In ALD, AST elevation is more prominent than that of ALT, but the levels of AST and ALT usually do not exceed 300 IU/L. Alcoholic hepatitis may be suspected when the AST/ALT ratio exceeds 2, 174,175 and has a very high probability when it exceeds 3. [bib_ref] High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy..., Nyblom [/bib_ref] Because GGT is elevated by alcohol consumption in about 75% of habitual drinkers, it is useful to determine whether a patient with ALD has indeed abstained from drinking. [bib_ref] Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase, Seitz [/bib_ref] However, care must be exercised since GGT may also be elevated due to non-alcoholic liver disease, obesity, diabetes, smoking, or drug use. [bib_ref] Additive effects of moderate drinking and obesity on serum gammaglutamyl transferase activity, Puukka [/bib_ref] [bib_ref] Alcohol biomarkers in applied settings: recent advances and future research opportunities, Litten [/bib_ref] In general, GGT levels recover slowly following abstinence from alcohol. MCV may also be elevated by heavy drinking, and is occasionally observed when the daily alcohol consumption exceeds 60 g. [bib_ref] Macrocytosis of chronic alcoholism, Wu [/bib_ref] [bib_ref] Biochemical and haematological markers of alcohol intake, Whitehead [/bib_ref] While MCV elevation alone has a low sensitivity, this is increased when accompanied by GGT elevation or when the levels decrease following treatment; [bib_ref] Biochemical detection and monitoring of alcohol abuse and abstinence, Sharpe [/bib_ref] MCV returns to normal after several months of abstinence. [bib_ref] Macrocytosis in alcohol-related liver disease: its value for screening, Morgan [/bib_ref] While CDT is known as a useful biochemical marker for heavy drinking, [bib_ref] Screening for excessive alcohol drinking. Comparative value of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and..., Yersin [/bib_ref] [bib_ref] Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl..., Reynaud [/bib_ref] [bib_ref] Carbohydrate-deficient transferrin as a marker of chronic alcohol abuse: a critical review..., Arndt [/bib_ref] [bib_ref] Carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse: a critical review..., Bortolotti [/bib_ref] it is not a popular measure due to its high specificity but low sensitivity. [bib_ref] Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review, Salaspuro [/bib_ref] Other findings seen with progression of liver disease include a decrease in serum albumin, increase in bilirubin, prolonged prothrombin time, and decrease in platelet count. ## Radiologic tests Radiologic tests can be used to identify steatosis, evaluate the progression of liver disease and the presence of complications, and rule out diseases such as biliary tract disease and liver tumors. [bib_ref] Prognostic indicators in compensated cirrhosis, Zoli [/bib_ref] However, radiologic tests alone cannot be used for the definitive diagnosis of alcohol as the cause of liver disease. Ultrasonography is useful for identifying steatosis, and findings such as liver morphology and splenomegaly can be used to evaluate the progression of liver disease. [bib_ref] A position statement on NAFLD/NASH based on the EASL 2009 special conference, Ratziu [/bib_ref] Although abdominal computed tomography (CT) scans and magnetic resonance imaging (MRI) are more accurate than ultrasonography for evaluating steatosis, there currently are no standardized test protocols and these methods are costly. [bib_ref] Noninvasive quantitation of human liver steatosis using magnetic resonance and bioassay methods, Assignies [/bib_ref] [bib_ref] Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic..., Mancini [/bib_ref] Liver elastography may be used to indirectly evaluate the degree of fibrosis in ALD. This test is based on the correlation between liver stiffness due to fibrosis and liver elasticity, and employs ultrasonography or MRI. [bib_ref] Ultrasound-based Liver Elastography: Recent Advances, Lee [/bib_ref] [bib_ref] Clinical applications of transient elastography, Jung [/bib_ref] [bib_ref] Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of..., Wang [/bib_ref] While these tests have the advantage of being noninvasive, they are also non-standardized and care must be exercised when interpreting the results since the presence of steatosis and severe inflammation may interfere with correct interpretations. ## Histologic diagnosis ## Histologic findings A liver biopsy is the standard test for making a definitive diagnosis of ALD and evaluating the inflammatory activity and fibrosis stage. Common histologic findings in ALD include steatosis, hepatocyte injury, lobular inflammation, Mallory-Denk bodies, megamitochondria, ductular proliferation, ductular bilirubinostasis, intraparenchymal cholestasis, fibrosis, and liver cirrhosis. [bib_ref] Morphology of alcoholic liver disease, Lefkowitch [/bib_ref] [bib_ref] Histologic spectrum of alcoholic liver disease, Macsween [/bib_ref] Although histologic findings are sometimes used to classify ALD into simple steatosis or fatty liver, steatohepatitis, hepatic fibrosis, or liver cirrhosis, it is possible for these conditions to coexist in a patient, and currently there is no definitive classification scheme for these findings. Alcoholic fatty liver is the most common finding in ALD, wherein hepatocytes exhibit typical macrovesicular steatosis characteristics such as cell expansion due to large fat droplets, and displacement of the nucleus toward the cell membrane. [bib_ref] Pathology of alcoholic liver disease. VA Cooperative Study Group 119, French [/bib_ref] These changes first appear in the central zone of the lobule and progress over time to eventually encompass the entire lobule. [bib_ref] Pathology of alcoholic liver disease. VA Cooperative Study Group 119, French [/bib_ref] The ballooning degeneration of hepatocytes is occasionally accompanied by apoptotic bodies. Mallory-Denk bodies, the eosinophilic and crescentic aggregation of intermediate filaments and other proteins around the nucleus, may also be seen. Specific histologic characteristics of alcoholic steatohepatitis include steatosis, ballooning degeneration of hepatocytes, and lobular infiltration by inflammatory cells, especially by polymorphonuclear neutrophils.Megamitochondria and Mallory-Denk bodies, although not specific for ALD, are nonetheless suggestive of active drinking. Periportal ductular proliferation, ductular bilirubinostasis, and intraparenchymal cholestasis may also be observed. Fibrous tissue may begin to accumulate around the terminal hepatic vein in the lobular central zone, and then progress to perisinusoidal and pericellular areas, resulting in the characteristic "chicken-wire fibrosis." Sclerosing hyaline necrosis refers to hepatocyte necrosis in zone 3 accompanied by perivenular and perisinusoidal fibrosis. The occurrence of terminal hepatic vein occlusion and sinusoid narrowing will increase the portal pressure and thicken the fibrous septum, ultimately resulting in the micronodular form of liver cirrhosis. [bib_ref] Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological..., Mathurin [/bib_ref] Clinical application of liver biopsy A liver biopsy is performed percutaneously with sonographic guidance or via the jugular vein; the latter approach is used when a percutaneous liver biopsy is contraindicated due to severe coagulopathy or moderate-to-severe ascites. [bib_ref] Transjugular liver biopsy--indications, adequacy, quality of specimens, and complications--a systematic review, Kalambokis [/bib_ref] A liver biopsy carries the risk of complications such as intraperitoneal hemorrhage and abdominal pain, and may be fatal in rare instances. Furthermore, the accuracy of a liver biopsy is limited by factors such as sampling error and interobserver variation. A liver biopsy, while not necessary for diagnosis or treatment, is useful for establishing an ALD diagnosis and for assessing the severity of disease to predict the prognosis in all patients with suspected ALD. [bib_ref] Appropriateness of liver biopsy, Poynard [/bib_ref] [bib_ref] Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with..., Naveau [/bib_ref] Around 20% of alcohol abusers with abnormal liver function tests were found to have etiologies other than alcohol, and only 70% of patients with suspected severe alcoholic hepatitis were definitively diagnosed with alcoholic hepatitis using a liver biopsy. [bib_ref] Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy..., Levin [/bib_ref] In patients with severe alcoholic hepatitis, the existence of severe inflammation was a useful marker for whether treatment with steroids would be effective. [bib_ref] Survival and prognostic factors in patients with severe alcoholic hepatitis treated with..., Mathurin [/bib_ref] In patients with a diagnosis of alcoholic steatohepatitis without sepsis, severe intraparenchymal cholestasis, along with Maddrey's discriminant function (DF) score, was an independent predictor for short-term mortality. [bib_ref] Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis, Spahr [/bib_ref] Also, in patients with acute exacerbation of alcoholic liver cirrhosis, early liver biopsy was useful for confirming the diagnosis of alcoholic hepatitis as well as estimating the prognosis. [bib_ref] The role of liver biopsy in the diagnosis and prognosis of patients..., Mookerjee [/bib_ref] A liver biopsy is rarely performed for the diagnosis and treatment of ALD in Korea. However, for patients with severe alcoholic hepatitis who may need specific medical treatment such as corticosteroids, a liver biopsy may be considered for a definitive diagnosis and for determining the prognosis. ## Classification and clinical features of alcoholic liver disease The diagnosis of ALD may be made in patients with a daily alcohol consumption exceeding 40 g in men and 20 g in women, with clinical, laboratory, radiological, or histological evidence of liver disease, and in whom other etiologies for liver injury can be excluded. Although excluding other etiologies of liver disease such as viral hepatitis, non-alcoholic fatty liver disease, and drug-induced liver injury is helpful for diagnosing ALD, because it is possible that more than one etiology is present, it is important to identify which is the main lesion. ALD is categorized based on the underlying pathology into alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver cirrhosis [fig_ref] Table 4: Clinical features of alcoholic liver disease PMNL, polymorphonuclear leukocyte [/fig_ref].While exclusive forms do exist, overlapping clinical features are seen in most cases. Alcoholic fatty liver is usually asymptomatic. In blood tests, AST, ALT, or bilirubin levels may be normal or mildly elevated. [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] While these values typically return to normal following several weeks of alcohol abstinence, [bib_ref] Histologic spectrum of alcoholic liver disease, Macsween [/bib_ref] in some cases the disease may progress to liver fibrosis or cirrhosis. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] Alcoholic hepatitis presents with various clinical features. In mild cases it is difficult to distinguish alcoholic hepatitis from alcoholic fatty liver, while in severe cases alcoholic hepatitis carries a high risk of death due to liver failure. Liver fibrosis may lead to portal hypertension, making it difficult to distinguish it from liver cirrhosis. [bib_ref] Alcoholic hepatitis, Mendenhall [/bib_ref] Blood tests may reveal anemia, leukocytosis, and thrombocytopenia, and the AST/ALT ratio typically exceeds 2. [bib_ref] The SGOT/SGPT ratio--an indicator of alcoholic liver disease, Cohen [/bib_ref] [bib_ref] High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy..., Nyblom [/bib_ref] [bib_ref] Serum activity of mitochondrial aspartate aminotransferase: a sensitive marker of alcoholism with..., Nalpas [/bib_ref] While these clinical features usually resolve following abstinence, they may last more than 6 months in severe alcoholic hepatitis. Alcoholic liver cirrhosis and liver cirrhosis due to other etiologies share similar clinical features. [bib_ref] A systematic review of the diagnostic accuracy of physical examination for the..., De Bruyn [/bib_ref] While it is not uncommon to be asymptomatic, anorexia and malnutrition due to habitual drinking can result in weight loss and skeletal muscle atrophy. Progression of liver cirrhosis may cause spider angioma, gynecomastia, and jaundice, and portal hypertension may result in variceal bleeding, ascites, and hepatic encephalopathy. Even in alcoholic liver cirrhosis, alcohol abstinence and proper nutrition can result in improved clinical features. 48 ## [recommendations] 8. Thorough history-taking for details such as the amount, frequency, duration, and type of drinking is necessary to make a diagnosis of ALD. (A1) 9. With adequate history of excessive drinking and clinical evidence for liver disease, the diagnosis of ALD can be made. In patients with severe alcoholic hepatitis requiring corticosteroid treatment, a liver biopsy should be considered for both a definitive diagnosis and estimation of prognosis. (B1) # Future research 1. There is a need to evaluate the usefulness of a liver biopsy in ALD. 2. There is a need for standardized histological criteria for the classification and evaluation of the severity of ALD. 3. There is a need to develop noninvasive diagnostic methods for ALD. ## Prognosis evaluation for alcoholic liver disease Evaluation of the prognosis for ALD focuses mainly on alcoholic hepatitis. Severe alcoholic hepatitis is traditionally defined as having a DF score of ≥32 or as having the evidence of hepatic encephalopathy. Severe alcoholic hepatitis has a poor prognosis without treatment, with a 28-day mortality rate of 30-50%. [bib_ref] Survival and prognostic factors in patients with severe alcoholic hepatitis treated with..., Mathurin [/bib_ref] In patients with alcoholic hepatitis of all severities, early prognosis stratification and treatment decisions are important for improving the prognosis. Various prognostic models in patients with alcoholic hepatitis have been developed over the past decades, such as the DF score, Model for End-Stage Liver Disease (MELD) score, Glasgow Alcoholic Hepatitis Score (GAHS), and the ABIC (Age, Bilirubin, International Normalized Ratio, Creatinine) score [fig_ref] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/fig_ref]. The DF score was first introduced in 1978 in a clinical trial assessing the treatment response to corticosteroids in patients with alcoholic hepatitis, and was modified slightly in 1989. The modified DF (mDF) score has been widely used for stratifying the severity of alcoholic hepatitis in practice. [bib_ref] Corticosteroid therapy of alcoholic hepatitis, Maddrey [/bib_ref] Patients with alcoholic hepatitis and an mDF score of <32 had a survival rate of 90%, while those with an mDF score of ≥32 had a survival of rate of 50-65%. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] The MELD score was initially developed to estimate the prognosis in patients who had undergone the transjugular intrahepatic portosystemic shunt (TIPS) procedure, and was later adopted as a model for selecting candidates for liver transplantation.Several studies have investigated the utility of the MELD score for assessing the prognosis of patients with ALD, albeit with different cutoff values. [bib_ref] MELD accurately predicts mortality in patients with alcoholic hepatitis, Dunn [/bib_ref] [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] [bib_ref] Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis..., Sheth [/bib_ref] [bib_ref] Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis, Vaa [/bib_ref] One study proposed that a MELD score of 21 provided high sensitivity and specificity in detecting patients with a poor prognosis. The MELD score was found to be a more useful predictor of prognosis in patients with accompanying ascites or hepatic encephalopathy. [bib_ref] MELD accurately predicts mortality in patients with alcoholic hepatitis, Dunn [/bib_ref] [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] The GAHS was developed to overcome the limitations of other models in assessing the prognosis of patients with alcoholic hepatitis, such as the low specificity of the mDF score and the unclear cutoff value for the MELD score. [bib_ref] Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and..., Forrest [/bib_ref] In patients with an mDF score of ≥32, those with a GAHS of <9 gained no survival benefit with steroid treatment, while those with a GAHS of ≥9 had a poor prognosis without steroid treatment. Therefore, the GAHS may be useful for identifying a subgroup of patients who may derive benefit from corticosteroids among patients with an mDF score of ≥32. [bib_ref] The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids, Forrest [/bib_ref] The ABIC model was constructed using four components: age, serum bilirubin, prothrombin time, and serum creatinine. Using cutoff values of 6.71 and 9.0, the ABIC model divided patients with alcoholic hepatitis into those with a low, intermediate, and high risk of death at 90 days, which was also useful in predicting mortality at 1 year. [bib_ref] A new scoring system for prognostic stratification of patients with alcoholic hepatitis, Dominguez [/bib_ref] Patients with an intermediate risk of death may benefit from corticosteroid or pentoxifylline therapy. [bib_ref] A new scoring system for prognostic stratification of patients with alcoholic hepatitis, Dominguez [/bib_ref] One study found the hepatic venous pressure gradient (HVPG) to be higher in patients who died due to alcoholic hepatitis than in those who survived, while another study found no association between HVPG and the short-or long-term prognosis of patients with alcoholic hepatitis. [bib_ref] Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients..., Rincon [/bib_ref] [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] Further research on this subject is needed. Some studies have found that the prognosis in patients with alcoholic hepatitis can be estimated more accurately from the Child-Turcotte-Pugh (CTP) score and the mDF score than from the MELD score, [bib_ref] Comparison of model for end-stage liver disease score with discriminant function and..., Jeong [/bib_ref] but most studies show that the mDF and MELD scores are more predictive than the CTP score. Hence, the CTP score is not usually used for estimating prognosis in alcoholic hepatitis. [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] [bib_ref] Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score..., Ali [/bib_ref] Korean studies have found the mDF score to be an independent prognostic factor for alcoholic hepatitis, with the MELD score yielding comparable results.Based on recent studies, the mDF, MELD, ABIC scores, and GAHS appear to be better prognostic models than the CTP score. All of the models were found to be good predictors of short-term mortality but poor predictors of long-term mortality. [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] Based on these studies, the mDF and MELD scores are useful for predicting short-term mortality and guiding treatment decisions in patients with severe alcoholic hepatitis. The GAHS and the ABIC score also show potential as prognostic models for alcoholic hepatitis. [bib_ref] Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score..., Ali [/bib_ref] [bib_ref] Treatment of severe forms of alcoholic hepatitis: Where are we going?, Mathurin [/bib_ref] With respect to predicting survival in patients treated with corticosteroids, early change in bilirubin level (ECBL; defined as a change in bilirubin levels after 1 week of treatment) and the Lille model based on ECBL are notable and are described in the following section. [bib_ref] Bilirubin response to corticosteroids in severe alcoholic hepatitis, Morris [/bib_ref] [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] [Recommendation] [bib_ref] Psychometric properties of the alcohol use disorders identification test: a Korean version, Kim [/bib_ref]. The mDF score and the MELD score are useful for determining the prognosis and guiding treatment in patients with alcoholic hepatitis. (A1) # Future research 1. There is a need for clinical models that predict poor prognosis among patients with an mDF score of <32. ## Treatment for alcoholic liver disease The treatment for ALD varies depending on the stage of the disease. For alcoholic fatty liver, abstinence or controlled drinking is the most important treatment. The various treatment approaches for alcoholic hepatitis are described in separate section. For alcoholic liver cirrhosis, treatment involves abstinence and following the KASL Clinical Practice Guidelines for Liver Cirrhosis. ## Therapy for alcohol withdrawal syndrome AWS refers to the group of symptoms and signs that occur 6-24 hours following the abrupt cessation of alcohol consumption among those who habitually drink excessively. Symptoms and signs include those of autonomic nervous system activation such as tachycardia, sweating, and hand tremor, gastrointestinal symptoms such as nausea and vomiting, and if severe, deficits in cognitive function such as hallucinations, seizures, and withdrawal delirium that may lead to death. Alcohol withdrawal seizure is a rebound phenomenon that can occur following the abrupt cessation of alcohol consumption that is due to a lowered seizure threshold. Because there is no need for anticonvulsants in patients with alcohol withdrawal seizure, it is necessary to distinguish it from genuine seizure. Delirium tremens is a serious complication of AWS, typical symptoms of which include altered mental status, disorientation to person, place, or time, and intra-and inter-daily variations of symptoms. [bib_ref] Management of alcohol withdrawal delirium. An evidence-based practice guideline, Mayo-Smith [/bib_ref] The symptoms are typically worst at 3-5 days following the abrupt cessation of alcohol consumption. Signs of autonomic nervous system activation such as high fever, tachycardia, hypertension, and sweating, as well as comorbidities such as dehydration, electrolyte imbalance, renal failure, head trauma, infection, gastrointestinal bleeding, pancreatitis, and liver failure should be carefully and strictly evaluated, and frequent monitoring of vital signs is necessary. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] The Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is known to be helpful for evaluating the severity of AWS, treatment planning, and facilitating objective communication between healthcare providers. However, high scores may be seen in psychiatric conditions that are similar to AWS, such as anxiolytic withdrawal, anxiety disorder, and physical conditions such as sepsis, hepatic encephalopathy, and severe pain. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] For this reason, the CIWA protocol is not recommended for a diagnosis of AWS. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] A comparison of inpatient versus outpatient treatment revealed that outpatient treatment was more cost-effective, but there was no difference in the alcohol abstinence rate at 6 months. [bib_ref] Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with..., Hayashida [/bib_ref] If there are serious complications of AWS such as delirium, seizures, or physical and/or psychological comorbidities, admission and inpatient treatment is recommended, with treatment goals of symptomatic relief without complications and maintenance of abstinence as a long-term treatment. Therefore, psychiatric consultation is recommended for the evaluation and acute management of AWS and long-term abstinence planning. For pharmacological treatment, long-acting benzodiazepines (e.g., chlordiazepoxide and diazepam) are recommended for the prevention of seizures, with effects such as anxiety relief, sedation, and somnolence via activation of gamma-aminobutyric acid (GABA). [bib_ref] Pharmacotherapies for alcohol abuse. Withdrawal and treatment, Saitz [/bib_ref] Lorazepam, which is an intermediate-acting benzodiazepine, is recommended for patients with severe AWS, advanced age, recent head trauma, liver failure, respiratory failure, other serious medical comorbidities, or obesity. Lorazepam is started at a dosage of 6-12 mg/day and tapered off following resolution of the withdrawal symptoms [fig_ref] Table 6: Treatment of alcohol withdrawal syndrome [/fig_ref]. [bib_ref] Alcohol abuse and depence, O'coner [/bib_ref] Diminished cognitive function due to thiamine deficiency is common in patients with alcohol use disorder; thiamine should thus be given to all patients with AWS (100-300 mg/day) and maintained for 2-3 months following resolution of their withdrawal symptoms. 233 ## [recommendations] 11. For AWS, psychiatric consultation is recommended for the evaluation, treatment, and long-term planning of alcohol abstinence. (A1) [bib_ref] Burden of liver disease in the United States: summary of a workshop, Kim [/bib_ref] ## Alcohol abstinence Alcohol abstinence is the most important treatment for patients with ALD, [bib_ref] Continued heavy drinking and survival in alcoholic cirrhotics, Borowsky [/bib_ref] [bib_ref] Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis...., Pessione [/bib_ref] since it improves their survival and prognosis and prevents the progression to liver cirrhosis through histologic improvements and a reduction in portal pressure. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] [bib_ref] Effects of ethanol consumption on hepatic hemodynamics in patients with alcoholic cirrhosis, Luca [/bib_ref] [bib_ref] The prognosis and outcome of alcoholic liver disease, Morgan [/bib_ref] Many treatment methods are currently being used to help maintain abstinence. 237 ## Pharmacologic treatment While many drugs have been used to promote alcohol abstinence among patients with alcohol use disorder, the use of these agents is limited to those with liver-function abnormalities (liverfunction tests: >3×normal increase in bilirubin) or renal failure. There are few studies that target ALD patients with the exception of baclofen. More studies are required to obtain evidence of their efficacy and safety in patients with ALD. Baclofen is a GABAB receptor agonist that is used as a muscle relaxant. [bib_ref] Antispasticity drugs: mechanisms of action, Davidoff [/bib_ref] A study involving patients with liver cirrhosis found that a 12-week course of baclofen effectively maintained abstinence by reducing the craving for alcohol. [bib_ref] Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent..., Addolorato [/bib_ref] Further studies should investigate the use of baclofen for abstinence in patients with ALD. [bib_ref] Baclofen for alcohol withdrawal, Liu [/bib_ref] [bib_ref] Baclofen effect related to liver damage, Heydtmann [/bib_ref] Acamprosate reduces the withdrawal effects of and the craving for alcohol. The desired concentration for acamprosate is reached within 1-2 weeks of initiating treatment and it is effective at maintaining abstinence in alcohol-dependent patients following withdrawal. [bib_ref] The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals:..., Mann [/bib_ref] [bib_ref] Acamprosate for alcohol dependence: a sexspecific meta-analysis based on individual patient data, Mason [/bib_ref] Treatment is initiated 3-7 days following the last episode of alcohol consumption and started after withdrawal symptoms have resolved. With respect to dosage, 1,998 mg/day is given to patients with a body weight of ≥60 kg and decreased by a one-third for those with a body weight of <60 kg, for a total treatment period of 3-6 months. [bib_ref] Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol..., Bouza [/bib_ref] [bib_ref] Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a..., Anton [/bib_ref] [bib_ref] Combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE Study): examination..., Donovan [/bib_ref] Naltrexone decreases the concentration of dopamine in the brain and dampens activation of the reward pathway by alcohol, thereby decreasing excessive drinking and recurrence rates and increasing abstinence duration in patients with alcohol dependence. [bib_ref] Opioid antagonists for alcohol dependence, Rosner [/bib_ref] [bib_ref] Opioid antagonists for pharmacological treatment of alcohol dependence-a critical review, Soyka [/bib_ref] With respect to dosage, 25 mg is given during the first 1-3 days and increased to 50 mg thereafter, with a typical total treatment period of 3-6 months, but this can also last for up to 12 months.Because there is risk of toxic liver injury, naltrexone is not recommended in patients with ALD. Disulfiram is an inhibitor of ALDH that causes a buildup of acetaldehyde in the body following alcohol consumption. [bib_ref] Disulfiram: an old therapeutic with new applications, Barth [/bib_ref] Since the buildup of acetaldehyde results in unpleasant symptoms such as flushing, dizziness, nausea, vomiting, arrhythmia, dyspnea, and headache, it is known as an aversive therapy and is currently not commonly used. ## Psychosocial treatment The goal of psychosocial treatment is to allow the patient to understand and obtain insight into his or her pathological pattern of drinking. Active psychological support should be provided with focus on the environment, reasons, and expected consequences of drinking, and should be accompanied by family and group therapy as well. [bib_ref] Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol..., Miller [/bib_ref] [bib_ref] Behavioral therapies for drug abuse, Carroll [/bib_ref] The aim of individual psychotherapy for a patient with alcohol dependence is to establish a therapeutic plan by careful psychiatric evaluation and select treatment modalities such as individual interview, psychoeducation, group therapy, and cognitive behavioral therapy. The treatment principles of alcohol dependence involve (1) allowing the patient to accept his or her lack of control over alcohol, (2) providing education regarding alcohol dependence, and (3) helping the patient to achieve control over him-or herself in order to maintain abstinence. This sort of treatment should not end as part of inpatient treatment, but instead should be continued after discharge to prevent recurrence. It is therefore important that patients with alcohol dependence actively get involved in group therapy such as Alcoholics Anonymous. This group meets on a nationwide basis and makes it possible to reduce the craving for alcohol and maintain healthy abstinence through peer support. Social support from family and friends is also necessary for successful therapy. Alcohol dependence is a dysfunctional family disorder, in that in many cases it is not only the patient who needs treatment but also family members who are subject to abuse from the patient. Both the patient and his or her family may benefit from active involvement in family education and therapy. Community alcohol counseling centers provide regular abstinence meetings, family meetings, and psychoeducation; coordination with these facilities may prove very helpful. Other methods of psychosocial treatment include motivational enhancement, 12-step facilitation therapy, cognitive behavioral therapy, social skills training, and coping skills training. Behavioral therapy involves training the patient to use methods other than alcohol to alleviate anxiety, and includes interventions such as relaxation therapy and assertive training. Psychiatric consultation is recommended for psychosocial treatment. Brief interventions are effective methods that involve providing pertinent evaluation, information, and advice to reduce risky drinking behavior and risk of ALD. [bib_ref] Brief interventions for alcohol problems: a review, Bien [/bib_ref] Commonly used brief interventions include motivational interviewing and counseling over a short time span. A brief intervention is delivered in a structured fashion, among which the FRAMES (Feedback, Responsibility, Ad-vice, Menu, Empathy, Self-efficacy) model is representative. The FRAMES method involves feedback about the dangers of continued drinking, emphasizes the drinker's responsibility in assuming the choices and consequences of drinking, advises abstinence, provides a menu of alternatives, empathizes with the drinker's perspective, and encourages self-motivation for abstinence. [bib_ref] A randomized controlled trial of Moderation-Oriented Cue Exposure, Heather [/bib_ref] [bib_ref] The efficacy of motivational interviewing as a brief intervention for excessive drinking:..., Vasilaki [/bib_ref] Brief interventions have been reported to lower morbidity and mortality related to drinking, and to be an effective non-pharmacologic approach for abstinence. [bib_ref] The efficacy of motivational interviewing as a brief intervention for excessive drinking:..., Vasilaki [/bib_ref] [bib_ref] The effectiveness of brief alcohol interventions in primary care settings: a systematic..., Kaner [/bib_ref] Brief interventions may be implemented in various healthcare settings, such as the inpatient or outpatient setting, private clinic, or public healthcare settings such as community counseling centers, or even healthcare services in the workplace and universities. It is a cost-effective method at a primary medical institution and is effective in patients with mild ALD. [bib_ref] Brief interventions for alcohol problems: a review, Bien [/bib_ref] [bib_ref] Can methodological features account for patient-treatment matching findings in the alcohol field?, Moyer [/bib_ref] [Recommendations] ## In patients with ald, alcohol abstinence is the most important treatment. (a1) 15. In patients with ALD, pharmacologic and psychosocial treatment can be implemented to achieve alcohol abstinence. (B2) [bib_ref] Prevalence of alcoholic liver disease among Korean adults: results from the fourth..., Park [/bib_ref]. In patients with ALD, baclofen and acamprosate can be used to achieve alcohol abstinence. (B2) 17. In hazardous drinkers and patients with alcohol use disorder, brief interventions should be implemented to encourage abstinence or controlled drinking. (A1) # Future research 1. There is a need to evaluate the efficacy of combined therapy of baclofen and psychosocial therapy for alcohol abstinence in ALD. 2. There is a need to identify effective brief intervention methods. 3. There is a need to evaluate the efficacy and safety of naltrexone and acamprosate in ALD. 4. There is a need to evaluate new pharmacologic treatments for abstinence in ALD. ## Nutritional therapy Many patients with ALD are malnourished, and the complications of ALD are significantly associated with the nutritional status.nutritional support in ALD patients. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] [bib_ref] Nutritional support in patients with chronic liver disease, Henkel [/bib_ref] While active nutritional support is known to improve biochemical markers and the nutritional status of ALD patients, it is not clear whether it also improves their survival rate. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] [bib_ref] Nutritional support for liver disease, Koretz [/bib_ref] Patients with severe alcoholic hepatitis who received parenteral nutrition had higher early mortality rates but lower late mortality rates than those receiving steroid treatment, with the net result being no difference in their overall mortality rates. [bib_ref] Short-and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral..., Cabre [/bib_ref] Long-term supplementation with branched-chain amino acids is known to improve nitrogen balance and yield improvements in hepatic encephalopathy and liver function tests. [bib_ref] Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized..., Marchesini [/bib_ref] Branched-chain amino acid supplementation at 34 g/day reduces the number of hospitalizations due to the complications of alcoholic liver cirrhosis such as infection, gastrointestinal bleeding, ascites, and hepatic encephalopathy. [bib_ref] Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis, Hirsch [/bib_ref] Depending on the state of the patient, protein and calorific intakes of 1.2-1.5 g/kg/day protein and 35-40 kcal/ kg/day, respectively, are recommended. [bib_ref] ESPEN Guidelines on Enteral Nutrition: Liver disease, Plauth [/bib_ref] If three meals per day does not provide an adequate nutritional intake, a greater number of smaller meals is recommended. [bib_ref] Liver cirrhosis: rationale and modalities for nutritional support--the European Society of Parenteral..., Lochs [/bib_ref] [bib_ref] Effect of a late evening meal on nitrogen balance in patients with..., Swart [/bib_ref] [bib_ref] Nocturnal oral glucose supplementation. The effects on protein metabolism in cirrhotic patients..., Zillikens [/bib_ref] If the patient is actively ill or in a critical state, higher protein (1.5 g/kg/day) and calorific (40 kcal/kg/day) intakes should be considered in conjunction with medical treatment. While long term oral or parenteral nutrition is thought to be helpful for patients with alcoholic liver cirrhosis, definite conclusions cannot be drawn at present due to limitations in previous studies such as small sample size or insufficient treatment periods. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] Sufficient nutritional support can reduce the complications of ALD without imposing any additional risk.Currently there are no clear guidelines regarding the supplementation of vitamins or minerals in patients with ALD. However, it is recommended that patients with nutritional deficiency should be given adequate amounts of vitamin A, thiamine, vitamin B12, folic acid, pyridoxine, vitamin D, and zinc along with nutritional therapy. [bib_ref] Nutrition in alcoholic liver disease, Dicecco [/bib_ref] [Recommendations] [bib_ref] Meta-analysis of alcohol intake in relation to risk of liver cirrhosis, Corrao [/bib_ref]. Active and sufficient nutritional support should be provided to patients with ALD. If three meals per day do not provide adequate nutrition, additional meals in the early morning and late at night can help restore nutritional balance. (B1) [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref]. Vitamin and mineral supplementation should be provided along with nutritional therapy to patients with ALD. (B1) ## Treatment of alcoholic hepatitis ## Alcohol abstinence Alcohol abstinence is the most important treatment for alcoholic hepatitis, [bib_ref] Alcoholic hepatitis, Lucey [/bib_ref] and should be administered as described above. ## Nutritional therapy Most patients with severe alcoholic hepatitis are malnourished. Although several studies have shown that enteral nutrition improves the survival rate irrespective of steroid treatment, it is still not clear whether nutritional therapy is effective in treating severe alcoholic hepatitis. [bib_ref] Short-and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral..., Cabre [/bib_ref] [bib_ref] Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic..., Alvarez [/bib_ref] Steroids Corticosteroids (prednisolone 40 mg/day for 28 days) are the most commonly recommended treatment for severe alcoholic hepatitis. They are thought to act by reducing the transcription of proinflammatory cytokines such as TNF-α. In patients with histologically confirmed severe alcoholic hepatitis, serum levels of TNF-α and intercellular adhesion molecule-1 (ICAM-1) were shown to decrease with steroid treatment, and the degree of change in the soluble form of ICAM-1 was found to be correlated with the degree of histological improvement. [bib_ref] Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular..., Spahr [/bib_ref] Indications for treatment with steroids are the presence of severe alcoholic hepatitis with a poor prognosis. Various prognosis prediction models such as mDF, MELD, and GAHS can be used to determine which patients should take steroids. Scores of mDF score ≥32, MELD >21, or GAHS ≥9, or hepatic encephalopathy are commonly used indications. Steroids are usually contraindicated in those with gastrointestinal bleeding, renal failure, pancreatitis, or uncontrolled infection. Steroid treatment for alcoholic hepatitis has been investigated in many randomized controlled trials, and conflicting results were obtained in early clinical studies and meta-analyses. [bib_ref] Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial, Carithers [/bib_ref] [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] [bib_ref] Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables, Christensen [/bib_ref] [bib_ref] A randomized trial of prednisolone in patients with severe alcoholic hepatitis, Ramond [/bib_ref] [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual..., Mathurin [/bib_ref] [bib_ref] Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with..., Rambaldi [/bib_ref] While a Cochrane review of 15 studies found no survival benefit from steroids, 278 a subgroup analysis involving only "low-bias risk" studies revealed a survival benefit from steroids in patients with an mDF score of ≥32 or with hepatic encephalopathy. [bib_ref] Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with..., Rambaldi [/bib_ref] An analysis involving pooled data found that the 28-day survival rate was higher in the steroid group (84.6%) than in the placebo group (65.1%; P =0.001). [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual..., Mathurin [/bib_ref] That finding was recently confirmed in a study using data from the five recent randomized controlled trials [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] Therefore, steroids should be useful in patients with an mDF score of ≥32. ECBL and the Lille model were recently introduced to predict prognosis based on the response to steroid treatment [fig_ref] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/fig_ref]. ECBL is defined when the bilirubin level at 7 days of treatment is lower than that on the first day of treatment. One study found that the 6-month survival rate was 82% in severe alcoholic hepatitis patients with confirmed ECBL but only 23% in those without ECBL.The Lille model is an improved model that includes ECBL as well as several additional variables. The probability of death is scored from 0 to 1 in the Lille model, and the 6-month survival rate was 25% in those patients with a score of >0.45, which is significantly lower than that of 85% for those with a Lille score of <0.45. [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] In a more recent study, patients were subdivided according to the percentile distribution of the Lille scores (≤35th, 35th-70th, and ≥70th percentiles), and classified as complete responders (≤0.16), partial responders (0.16-0.56), and null responders (≥0.56); the 28-day survival rate differed significantly between these groups, at 91.1%, 79.4%, and 53.3%, respectively. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] Given that infection occurs more frequently in patients who do not re-spond to steroid treatment than in those who do respond, it would be reasonable to discontinue steroids if the patient is thought to be a null responder based on ECBL or the Lille model. [bib_ref] Infection in patients with severe alcoholic hepatitis treated with steroids: early response..., Louvet [/bib_ref] The survival rate in these patients may be significantly higher after liver transplantation than when continuing with medical treatment only. [bib_ref] Early liver transplantation for severe alcoholic hepatitis, Mathurin [/bib_ref] However, a social consensus is needed on this issue. In conclusion, treatment with steroids is effective in patients with mDF scores of ≥32. However, if ECBL is not observed or the Lille score is ≥0.56, steroids should be discontinued and other rescue therapies such as liver transplantation should be considered [fig_ref] Figure 3: Treatment algorithm for severe alcoholic hepatitis [/fig_ref]. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] Pentoxifylline Pentoxifylline, given at a dose of 400 mg three times daily for 28 days, may be tried as an alternative to steroids for treating severe alcoholic hepatitis. [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] Pentoxifylline is a selective phosphodiesterase inhibitor that increases intracellular cAMP levels, which in turn decrease the expression of cytokines such as TNF-α, IL-8, and macrophage inflammatory protein-1a.Pentoxifylline may be used in patients with infection or renal failure. A study involving 101 patients with severe alcoholic hepatitis found that the 28-day mortality rate was significantly lower in the pentoxifylline group (24.5%) than in the placebo group (46.1%). [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] Given that the percentage of deaths due to hepatorenal syndrome was 50% (6 of 12 patients) in the pentoxifylline group and 92% (22 of 24 patients) in the placebo group, it appears that the increase in survival rate may be due to a decrease in the incidence of hepatorenal syndrome. [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] A randomized comparative study of pentoxifylline and steroids found that the death rate was lower in the pentoxifylline group. [bib_ref] Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial, De [/bib_ref] However, that study involved only a small group of patients, and the survival rate in the steroid group was far lower than that reported previously, thereby questioning the validity and acceptability of the conclusion. Another randomized controlled trial comparing the efficacies of pentoxifylline and corticosteroids in treating severe alcoholic hepatitis was recently performed in Korea. The 1-month survival rate of patients receiving pentoxifylline was 74.5%, compared to 87.0% in those receiving prednisolone. Although the trial was intended to assess the non-inferiority of pentoxifylline compared to corticosteroids, the observed efficacy of pentoxifylline was not statistically equivalent to that of corticosteroids, supporting corticosteroids as a preferred option for severe alcoholic hepatitis.It is currently unclear whether combination therapy of steroids and pentoxifylline is superior to monotherapy with either agent. A recent study found no survival benefit at 4 weeks or 6 months with combination therapy of steroids and pentoxifylline. [bib_ref] Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival..., Sidhu [/bib_ref] Therefore, combination therapy is not recommended at present. The efficacy of early switching to pentoxifylline in steroid nonresponders has been investigated by either switching patients without ECBL to pentoxifylline or continuing them on steroids; 286 the 2-month survival rates did not differ between the two groups, at 35.5% and 31.0%, respectively. Pentoxifylline is therefore not recommended as a rescue therapy since steroid non-responders do not seem to obtain any benefit from an early switch to this drug. In spite of these limitations, pentoxifylline is considered an effective alternative agent to steroids in the treatment of severe alcoholic hepatitis and improves survival rate. 287 ## Anti-tnf-α agents Several anti-TNF-α agents have been tested as treatments for alcoholic hepatitis under the assumption that clinical improvement may be seen by blocking TNF-α, a major cytokine involved in alco-holic hepatitis. A pilot study demonstrated the efficacy of combination therapy of infliximab and steroids. [bib_ref] Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a..., Spahr [/bib_ref] However, the mortality rate was found to be higher with combination therapy in a follow-up study, and therefore infliximab is currently not recommended for the treatment of severe alcoholic hepatitis. [bib_ref] A double-blind randomized controlled trial of infliximab associated with prednisolone in acute..., Naveau [/bib_ref] Treatment with etanercept was also associated with a higher 6-month mortality rate, mainly due to higher rates of serious infections compared to the placebo group. [bib_ref] A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of..., Boetticher [/bib_ref] Therefore, anti-TNF-α agents are currently not recommended for the treatment of alcoholic hepatitis. ## Antioxidants N -acetylcysteine has not yet been found to be effective as a treatment for alcoholic hepatitis. [bib_ref] Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute..., Moreno [/bib_ref] A recent trial of combination therapy with N -acetylcysteine and steroids found an increase in the short-term survival rate but no improvement in the long-term survival rate. [bib_ref] Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis, Nguyen-Khac [/bib_ref] Specifically, the 1-month mortality rate was lower in the combination therapy group (8%) than in the steroid-only group (24%), but the 3-month and 6-month survival rates did not differ significantly between the two groups. Interestingly, the number of deaths due to hepatorenal syndrome was lower in the combination therapy group (9%) than in the steroid-only group (22%). [bib_ref] Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis, Nguyen-Khac [/bib_ref] Further research is needed to evaluate the efficacy of Nacetylcysteine. # Future research 1. There is a need for new drugs that may be combined with steroids or pentoxifylline to increase the therapeutic efficacy in the treatment of severe alcoholic hepatitis. 2. There is a need to identify clinical factors that respond to ste- ## Liver transplantation ALD is one of the most common indications for liver transplantation in North America and Europe. [bib_ref] Liver transplantation for alcoholic liver disease in Europe: a study from the..., Burra [/bib_ref] [bib_ref] An analysis of the OPTN/UNOS Liver Transplant Registry, Waki [/bib_ref] There is a tendency to avoid liver transplantation in chronic drinkers due to concerns about their continued drinking damaging the transplanted liver. The survival rate of livers transplanted due to ALD is similar to [bib_ref] Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival,..., Mackie [/bib_ref] [bib_ref] Histological features after liver transplantation in alcoholic cirrhotics, Burra [/bib_ref] [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] or higher than 293 that of liver transplantation due to other causes. Indications for transplantation in ALD are identical to those in other end-stage liver diseases. It is also known that the presence of ALD has no impact on the survival rate following liver transplantation in those with end-stage liver disease. [bib_ref] Effect of alcoholic liver disease and hepatitis C infection on waiting list..., Lucey [/bib_ref] The increase in survival rate following liver transplantation is limited to CTP class C patients with decompensated liver cirrhosis. [bib_ref] Immediate listing for liver transplantation versus standard care for Child-Pugh stage B..., Vanlemmens [/bib_ref] The 1-year and 5-year survival rates were found to be increased in CTP class C patients after liver transplantation than in the control group, but no such statistically significant increase in survival rate was seen in CTP class A or B patients.Six months of alcohol abstinence may result in improvement of liver disease and avoid unnecessary liver transplantation; therefore, an abstinence period of 6 months prior to liver transplantation is thought to be necessary. [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] Minimal criteria for placement of adults on the liver transplant waiting list:..., Lucey [/bib_ref] [bib_ref] Liver transplantation for alcoholic liver disease: a survey of transplantation programs in..., Everhart [/bib_ref] [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation..., Perney [/bib_ref] [bib_ref] A simple score for predicting alcohol relapse after liver transplantation: results from..., De Gottardi [/bib_ref] However, many recent studies have questioned whether 6 months of abstinence is a reliable predictor for resumption of drinking following transplantation, and have found poor predictability. [bib_ref] Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection..., Mccallum [/bib_ref] [bib_ref] Predictors of relapse to harmful alcohol after orthotopic liver transplantation, Kelly [/bib_ref] Recidivism following liver transplantation is common, with estimated rates of 10-52%. [bib_ref] Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival,..., Mackie [/bib_ref] [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation..., Perney [/bib_ref] [bib_ref] A simple score for predicting alcohol relapse after liver transplantation: results from..., De Gottardi [/bib_ref] [bib_ref] Predictors of relapse to harmful alcohol after orthotopic liver transplantation, Kelly [/bib_ref] [bib_ref] Liver transplantation for alcohol-related cirrhosis: a single centre long-term clinical and histological..., Schmeding [/bib_ref] [bib_ref] Analysis of factors that predict alcohol relapse following liver transplantation, Jauhar [/bib_ref] [bib_ref] Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic..., Dimartini [/bib_ref] [bib_ref] Long-term follow-up of patients with alcoholic liver disease after liver transplantation in..., Bjornsson [/bib_ref] [bib_ref] Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the..., Faure [/bib_ref] [bib_ref] Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?, Pageaux [/bib_ref] [bib_ref] Long term follow-up and outcome of liver transplantation for alcoholic liver disease:..., Biselli [/bib_ref] Alcohol consumption following liver transplantation causes histologic damage in the liver, including liver fibrosis. [bib_ref] Histological features after liver transplantation in alcoholic cirrhotics, Burra [/bib_ref] [bib_ref] Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?, Pageaux [/bib_ref] [bib_ref] Patterns of alcohol consumption after liver transplantation, Tang [/bib_ref] Heavy drinking following liver transplantation adversely affects the survival rate regardless of the reason for liver transplantation. [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Liver transplantation for alcohol-related cirrhosis: a single centre long-term clinical and histological..., Schmeding [/bib_ref] [bib_ref] Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the..., Faure [/bib_ref] Various physical and psychological factors should be carefully evaluated prior to liver transplantation and such factors should also be followed up and monitored following liver transplantation. [bib_ref] Liver transplantation for alcoholic liver disease, Zetterman [/bib_ref] For liver transplantation performed in a patient with alcoholic hepatitis alone or alcoholic hepatitis superimposed on alcoholic cirrhosis, the survival rates of the transplanted liver and the patient did not differ significantly from those for patients with alcoholic cirrhosis alone. [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] The impact of acute alcoholic hepatitis in the explanted recipient liver on..., Wells [/bib_ref] [bib_ref] Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis:..., Singal [/bib_ref] Most European and North American liver transplantation centers do not consider patients with severe alcoholic hepatitis as candidates for liver transplantation, based on them not fulfilling the criterion of alcoholic abstinence for 6 months prior to liver transplantation. [bib_ref] Alcoholic liver disease, O'shea [/bib_ref] [bib_ref] Minimal criteria for placement of adults on the liver transplant waiting list:..., Lucey [/bib_ref] However, a prospective, multicenter study found an increase in survival rate with liver transplantation in patients with severe alcoholic hepatitis who are not responsive to medical treatment. [bib_ref] Early liver transplantation for severe alcoholic hepatitis, Mathurin [/bib_ref] Therefore, liver transplantation may be considered in patients whose severe alcoholic hepatitis has not responded to medical treatment. However, improvement in long term survival must be verified in future studies. Similar to those who have received liver transplantation for other causes, patients who have received liver transplantation due to ALD exhibit a high incidence of de novo cancer in other areas of the body. [bib_ref] Liver transplantation for alcoholic liver disease in Europe: a study from the..., Burra [/bib_ref] [bib_ref] Immediate listing for liver transplantation versus standard care for Child-Pugh stage B..., Vanlemmens [/bib_ref] [bib_ref] Alcohol abuse and de novo tumors in liver transplantation, Zanus [/bib_ref] [bib_ref] Increased cancer risk after liver transplantation: a population-based study, Haagsma [/bib_ref] [bib_ref] De novo malignancies after liver transplantation: incidence comparison with the Korean cancer..., Park [/bib_ref] Such de novo cancers are associated with an increased mortality following transplantation. It is thought that the immunosuppressive drugs that are used post-transplantation are related to the onset of new cancers. It is also known that liver transplantation due to ALD, compared to other causes, is associated with a strikingly high rate of cardiovascular complications. 293 ## [recommendations] 24. Liver transplantation should be considered in patients with decompensated liver cirrhosis. (A1) [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref]. Early liver transplantation may be considered in patients with severe alcoholic hepatitis who do not respond to medical treatment. (A2) # Future research 1. There is a need to determine the appropriate timeline for liver transplantation with regard to abstinence from alcohol in patients with ALD. ## Miscellaneous therapies ## Propylthiouracil Histologic findings of central hypoxia due to thyroid hormone can occur in ALD, raising the question of whether propylthiouracil (PTU) would be effective in reducing pericentral hypoxia and cellular damage by suppressing metabolic activation due to ethanol. Some studies have found that PTU improves the mortality rate by suppressing hypermetabolic activation. [bib_ref] Commentary on the hypermetabolic state and the role of oxygen in alcohol-induced..., Mezey [/bib_ref] [bib_ref] Long-term treatment of alcoholic liver disease with propylthiouracil, Orrego [/bib_ref] However, a Cochrane meta-analysis of 6 studies involving 710 ALD patients that compared PTU versus placebo found no clear improvement in liver histology or in the liver-related or overall mortality rate. [bib_ref] Propylthiouracil for alcoholic liver disease, Rambaldi [/bib_ref] ## Colchicine Colchicine affects liver fibrosis by suppressing collagen production, activating collagenase activity, and suppressing collagen transcellular trafficking. It has also been found to contribute to the production of cytokines that stimulate fibroblast proliferation. As such, colchicine has been investigated as a treatment agent for ALD. Clinical studies involving patients with alcoholic liver cirrhosis found that colchicine exhibited anti-inflammatory and anti-fibrotic effects, [bib_ref] Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient..., Morgan [/bib_ref] [bib_ref] Treatment of cirrhosis with colchicine. A double-blind randomized trial, Kershenobich [/bib_ref] and had a positive effect on survival. [bib_ref] Colchicine in the treatment of cirrhosis of the liver, Kershenobich [/bib_ref] However, subsequent controlled trials produced conflicting results, and a meta-analysis of 15 randomized trials involving 1,714 patients with ALD found no clear association between colchicine and liver function or histologic improvement, or liver-related or overall mortality. [bib_ref] Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis, Rambaldi [/bib_ref] Therefore, considering its side effects, colchicine is not recommended for treatment of ALD. ## Polyunsaturated lecithin Polyunsaturated lecithin (PUL) is a cell membrane component found in soybean extract. While its mechanism of action is unclear, it is thought to act by modulating collagenase activity. [bib_ref] Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in..., Li [/bib_ref] A study involving baboons with alcoholic liver damage found that PUL caused histologic improvement in the liver and decreased the activation of hepatic stellate cells. [bib_ref] Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon, Lieber [/bib_ref] However, there was no clear association between polyenylphosphatidylcholine and progression of liver fibrosis in a follow-up randomized controlled study. [bib_ref] Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease, Lieber [/bib_ref] Since PUL is a component of normal cells with a favorable side effect profile, this agent should be investigated further. ## S-adenosyl-l-methionine SAMe is a methyl-group donor that is involved in the biosynthesis of glutathione, a major intracellular antioxidant. A clinical study found that SAMe improved survival in both CTP class A and B patients compared to the placebo group. Although some studies have found that SAMe has treatment value in ALD, a meta-analysis found SAMe to exert no statistically significant effects on overall mortality, 334,335 liver-related mortality, complications, or liver transplantation results. [bib_ref] S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial, Mato [/bib_ref] Metadoxine Metadoxine antioxidant therapy has been approved for the treatment of ALD in several countries. A large randomized controlled trial involving 136 patients with fatty liver that compared a 3-month course of metadoxine (1,500 mg/day) with placebo found meaningful improvements in liver function in both groups but with a faster recovery course in the metadoxine group. [bib_ref] Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized..., Caballeria [/bib_ref] The persistence of fatty liver as visualized by ultrasonography was significantly decreased in the metadoxine group relative to the placebo group (28% vs. 70%). These positive effects were more noticeable in patients who had abstained from alcohol than in those who had continued to drink. However, the clinical implications remain unclear, and metadoxine is therefore not recommended for the treatment of ALD. Further research is needed to investigate the effects of metadoxine. ## Angiotensin ii receptor blocker One randomized controlled trial has found that combination therapy with the angiotensin II receptor antagonist candesartan and ursodeoxycholic acid effects a greater histologic improvement than monotherapy with ursodeoxycholic acid. 339 ## Anti-cytokine agents Anti-cytokine treatment has been proposed based on the effect of cytokines on liver fibrosis and cirrhosis. [bib_ref] Cytokine gene expression in cirrhotic and non-cirrhotic human liver, Llorent [/bib_ref] Although there are reports of anti-inflammatory effects of thalidomide, misoprostol, adiponectin, and probiotic agents, more evidence is needed before these agents should be used as treatments for ALD. [bib_ref] Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty..., Li [/bib_ref] [bib_ref] Adiponectin, a new member of the family of soluble defense collagens, negatively..., Yokota [/bib_ref] Silymarin Silymarin, a milk thistle extract with activating and anti-oxidative properties, has been evaluated in many studies as a potential treatment agent for ALD. [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases, Rambaldi [/bib_ref] [bib_ref] Randomized controlled trial of silymarin treatment in patients with cirrhosis of the..., Ferenci [/bib_ref] Although one study found that silymarin contributes to improved survival, this result has not been confirmed for ALD patients in meta-analyses such as the Cochrane review. [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases, Rambaldi [/bib_ref] [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C liver diseases--a systematic..., Rambaldi [/bib_ref] Future research There are isolated reports that PTU, colchicine, PUL, SAMe, metadoxine, and silymarin affect the prognosis of ALD patients, but these have not been confirmed. There is a need to investigate new pharmacologic agents. ## Strategies for the reduction and pre-vention of harmful use of alcohol Chronic, excessive alcohol consumption and binge drinking are risk factors for various physical and psychological diseases; there should thus be consistent and nationwide efforts to address this issue. Strategies for decreasing the harmful use of alcohol should be implemented through various public, private, and government organizations.In 2010 the WHO implemented the "Global Strategy to Reduce Harmful Use of Alcohol" campaign and proposed areas for national action. [bib_ref] The WHO global strategy to reduce the harmful use of alcohol, Chick [/bib_ref] However, the lenient culture toward drinking, cheap pricing of distilled beverages, and easy accessibility to alcohol in Korea have all contributed to the physical, psychological, social, and economical damage caused by alcohol use. [bib_ref] Socioeconomic costs if alcohol drinking in Korea, Chung [/bib_ref] Strategies to reduce the harmful use of alcohol include reducing its accessibility by limiting sales or increasing prices, restricting alcohol-related advertising, promoting preventive education and public campaigns, and implementing early identification and intervention programs. Verified strategies such as increasing prices and limiting accessibility are currently not in place in Korea, and the adolescent-related policies that are present are not strictly enforced. Furthermore, preventive education and public campaigns are grossly insufficient due to issues such as budgetary constraints, and early identification and intervention programs for hazardous or harmful drinking are not being implemented appropriately at present. There is a need for a change in the public perception toward harmful use of alcohol and specific and realistic strategies for alcohol control such as enforcing the legal drinking age, restricting alcohol-related advertisements, modifying liquor taxes, setting minimum prices for alcohol, limiting public drinking, and starting early intervention and mandatory treatment programs for intoxicated individuals.[Recommendation] [bib_ref] Provider training for patient-centered alcohol counseling in a primary care setting, Ockene [/bib_ref]. There is a need to increase public attention towards the harmful use of alcohol, and specific strategies such as limiting the accessibility of alcohol, price controls, and banning alcohol-related advertisements should be implemented. (A1) [fig] Figure 1: Adult alcohol consumption per capita in 2005 (World Health Organization Global Status Report on Alcohol and Health, 2011). [/fig] [fig] Figure 2: Natural history, spectrum, and pathophysiology of alcoholic liver disease. [/fig] [fig] Figure 3: Treatment algorithm for severe alcoholic hepatitis. http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/fig] [fig] [: Recommendations] 20. Alcohol abstinence is the single most important treatment for improving survival in alcoholic hepatitis. (A1) 21. Treatment with steroids is needed for patients with severe alcoholic hepatitis who have an mDF score of ≥32. (A1) 22. During steroid treatment it is important to identify patients with a high mortality risk based on ECBL or the Lille score, where rescue therapy such as liver transplantation may be considered. (B1) 23. Pentoxifylline is an alternative treatment agent to steroids that can improve the survival rate in patients with severe alcoholic hepatitis. (B1) [/fig] [table] Table 1: The grading of recommendations, assessment, development, and evaluation (GRADE) system [/table] [table] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking, harmful drinking, alcohol abuse, and alcohol dependence 20-22 http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table] [table] Table 3: Alcohol contents of different types of alcoholic beverage The Korean Association for the Study of the Liver (KASL) KASL clinical practice guidelines: management of alcoholic liver disease http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table] [table] Table 4: Clinical features of alcoholic liver disease PMNL, polymorphonuclear leukocyte; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time. *Usually <300 IU/L. † Ultrasonography, computed tomography, and magnetic resonance imaging. http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table] [table] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/table] [table] Table 6: Treatment of alcohol withdrawal syndrome (AWS)227,228,[230][231][232] Indications for admission Significant AWS, high levels of recent drinking, history of withdrawal seizures or delirium tremens, co-occurrence of a serious medical or psychiatric illness, or failure of outpatient treatment Dosage and routes given for a standard fixed-dose regimen, which includes dose tapers over time. ‡ Alternative to benzodiazepine that is effective in seizure prevention. § To be used carefully as adjunctive therapy only in cases of agitation or psychotic symptoms such as hallucinations that are not controlled by benzodiazepine. [/table] [table] , 326: http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table]	None	http://www.who.int/substance_abuse/publications/global_alcohol_report/msbgsruprofiles.pdf	In Korea, alcoholic liver disease (ALD) is the second most common cause of chronic liver disease after viral liver disease, and the rate of alcohol-related deaths is high, at 9.6 deaths per 100,000 persons per year. Nevertheless, the Korean culture is lenient toward drinking and the inebriated state, which is due to alcohol being considered an important social lubricant for both business and private gatherings. ALD tends to be thought of as a personal problem, and as such its importance is underestimated. Furthermore, academic interest in ADL is dwindling since the advent of antiviral therapy. However, given the keen worldwide interest and research into ALD, there remains a need for clinical practice guidelines that are tailored to the Korean healthcare system for the management of this disease. This need prompted the Korean Association for the Study of the Liver (KASL) to develop the “KASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease”, based on a systematic approach to reflect evidence-based medicine and expert opinion in internal medicine and psychiatry, with the aim of setting clinical practice guidelines for the management of ALD and improving public health in Korea.
49d4d271602e4caa08a354ebdb2c6cbf82e0f5bf	pubmed	British Society of Gastroenterology position statement on serrated polyps in the colon and rectum	British Society of Gastroenterology position statement on serrated polyps in the colon and rectum Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations-serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and reevaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement).SUMMARY OF RECOMMENDATIONSEvidence that serrated lesions (SLs) have premalignant potential Statement 1 Some SSLs have molecular, genetic and pathological features consistent with being precursor lesions to CpG island methylator phenotype (CIMP)+ colorectal cancers (CRCs), which represent 15%-30% of all CRCs (moderate quality evidence, 100% agreement).Pathology and nomenclature of SLsStatement 2We suggest adopting the terms hyperplastic polyp (HP), SSL, SSL with dysplasia, traditional serrated adenoma (TSA) or mixed polyp to describe SLs in the colorectum, using the WHO criteria to define SSL (weak recommendation, low quality evidence, 82% agreement).Detection and resection of SLsStatement 3We suggest a minimum withdrawal time of 6 min to enhance SL detection. Chromoendoscopy can also enhance SL detection (weak recommendation, low quality evidence, 100% agreement).Statement 4We recommend that colonoscopy is the best current test for SL detection, with other modalities performing less well (faecal occult blood test (FOBT)/faecal immunochemical test (FIT)±stool DNA, CT colonography (CTC), flexible sigmoidoscopy, capsule colonoscopy) (strong recommendation, moderate quality evidence, 100% agreement).Statement 5We suggest that endoscopic resection of proximal SSLs, particularly those ≥10 mm in size, should be undertaken by operators who demonstrate achievement of outcomes for incomplete resection rates, serrated polyp detection rates and expertise in assessment of these at colonoscopy (see BSG-Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline on large non-pedunculated colorectal polyps (LNPCPs) 2015 and statements 13 and 14) (weak recommendation, low quality evidence, 91% agreement).Surveillance strategies after detection of SLsStatement 6We suggest that given the elevated CRC risk in patients who meet the WHO criteria for serrated polyposis syndrome (SPS), and that effective surveillance appears to reduce CRC risk, these patients should be offered one to two yearly colonoscopic surveillance (weak recommendation, low quality evidence, 90% agreement). ABSTRACT Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations-serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and reevaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement). ## Summary of recommendations Evidence that serrated lesions (SLs) have premalignant potential Statement 1 Some SSLs have molecular, genetic and pathological features consistent with being precursor lesions to CpG island methylator phenotype (CIMP)+ colorectal cancers (CRCs), which represent 15%-30% of all CRCs (moderate quality evidence, 100% agreement). ## Pathology and nomenclature of sls # Statement 2 We suggest adopting the terms hyperplastic polyp (HP), SSL, SSL with dysplasia, traditional serrated adenoma (TSA) or mixed polyp to describe SLs in the colorectum, using the WHO criteria to define SSL (weak recommendation, low quality evidence, 82% agreement). ## Detection and resection of sls # Statement 3 We suggest a minimum withdrawal time of 6 min to enhance SL detection. Chromoendoscopy can also enhance SL detection (weak recommendation, low quality evidence, 100% agreement). We recommend that colonoscopy is the best current test for SL detection, with other modalities performing less well (faecal occult blood test (FOBT)/faecal immunochemical test (FIT)±stool DNA, CT colonography (CTC), flexible sigmoidoscopy, capsule colonoscopy) (strong recommendation, moderate quality evidence, 100% agreement). # Statement 5 We suggest that endoscopic resection of proximal SSLs, particularly those ≥10 mm in size, should be undertaken by operators who demonstrate achievement of outcomes for incomplete resection rates, serrated polyp detection rates and expertise in assessment of these at colonoscopy (see BSG-Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline on large non-pedunculated colorectal polyps (LNPCPs) 2015 and statements 13 and 14) (weak recommendation, low quality evidence, 91% agreement). ## Surveillance strategies after detection of sls # Statement 6 We suggest that given the elevated CRC risk in patients who meet the WHO criteria for serrated polyposis syndrome (SPS), and that effective surveillance appears to reduce CRC risk, these patients should be offered one to two yearly colonoscopic surveillance (weak recommendation, low quality evidence, 90% agreement). # Statement 7 We suggest that after piecemeal endoscopic mucosal resection (EMR) of a SL ≥20 mm that an examination of the resection site be performed within 2-6 months postresection (weak recommendation, low quality evidence, 100% agreement). We suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with SSLs that appear associated with a higher risk of future neoplasia or CRC (SSLs ≥10 mm or SLs harbouring dysplasia including TSAs) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement). We suggest that at present for HPs or SSLs <10 mm in size without dysplasia, there is no clear indication for colonoscopic surveillance unless sufficient in size, location and number to meet the criteria for SPS (weak recommendation, very low quality evidence, 90% agreement). ## Special situations: sps # Statement 10 We suggest that upper GI surveillance for polyposis or extraluminal surveillance for non-GI cancers is not necessary in patients with SPS where other genetic causes have been excluded (weak recommendation, very low quality evidence, 100% agreement). # Statement 11 We suggest that all patients with SPS should be referred to clinical genetics services or a polyposis registry, where local resources allow (weak recommendation, very low quality evidence, 100% agreement). # Statement 12 We suggest that surgery should be considered in patients with SPS who have lesions that are not amenable to colonoscopic resection because of their size, site or number (weak recommendation, very low quality evidence, 100% agreeent). We suggest that surgery should aim to remove all lesions that are not amenable to endoscopic resection, and could take the form of: segmental colectomy, total colectomy with ileorectal anastomosis or proctocolectomy (with or without ileoanal pouch formation) depending on the lesion burden and distribution (weak recommendation, very low quality evidence, 100% agreement). ## Education, audit and benchmarks and research questions # Statement 13 We recommend that clinicians involved in the care of patients with serrated polyps, especially endoscopists and pathologists, acquire the knowledge and skills to recognise and differentiate the various types of SLs (strong recommendation, moderate quality evidence, 100% agreement). # Statement 14 We suggest that benchmarking SL detection rates is challenging and affected by case mix, patient ethnicity, histopathological diagnosis and the inclusion of distal SLs; however, endoscopists who wish to assess their proximal serrated polyp detection rate might aim for a detection rate >5% (weak recommendation, low quality evidence, 88% agreement). # Statement 15 We suggest that the current evidence base for clinical decision making for patients with SLs is poor. Clinicians are strongly advised to support prospective studies that will bolster this evidence and avoid empirical management decisions, to allow formal guidelines to be developed (weak recommendation, low quality evidence, 100% agreement). # Background and methodology This British Society of Gastroenterology (BSG) position statement is the output of a working group convened by the vice presidents for the BSG (Endoscopy section) to provide clinical guidance on the management of patients diagnosed with hyperplastic and serrated polyps. Topics for the review were developed by the multidisciplinary working group including basic scientists (SJL, IT), clinical geneticists (IT), pathologists (ACB, NAS), gastroenterologists ( JEE, SD, SNK, PSP, MDR, CJR), colorectal surgeons (SKC) and epidemiologists (WSA). These topics include major clinical issues encountered by clinicians caring for patients with hyperplastic and serrated polyps, as well as audit and benchmarks, education and questions for further research. As the evidence base was not felt to be sufficient for a formal BSG guideline, a position statement was developed, which offers clinical guidance and points the likely direction of thinking of the society, with the position statement being replaced by a formal guideline in due course. An initial teleconference was used to outline key clinical questions for the group to consider. For each identified question, a member of the working group performed a comprehensive keyword literature search, reviewed and analysed the quality of the evidence and summarised the key points. Where appropriate evidence existed, a 'position statement' was drawn up according to the GRADE recommendations (strong or weak/conditional recommendations; high, moderate, low or very low quality evidence). [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] Following each round of electronic voting, statements were adopted using a modified Delphi process when ≥80% of the working group agreed with them. If after two rounds there was continuing disagreement, if 50% of the group agreed and <20% disagreed, statements were accepted. 2 Initial searches were completed in June 2015; during the Delphi process for non-agreed statements that required subsequent rounds, further searches for key papers that might further guide the working group were permitted due to initially poor but rapidly developing evidence base, final search June 2016. The position statement has been reviewed and agreed by the BSG Endoscopy Section Committee and BSG Clinical Standards and Services Committee. This is not a BSG clinical guideline due to the methodology used; however, it does represent the view of the multidisciplinary expert working group panel, which represent BSG # Introduction The adenoma-carcinoma sequence describes the sequential accumulation of a series of genetic mutations leading to advanced adenomas and then invasive cancer. Over the last 30 years, this model has been used as an essential framework to understand the pathogenesis of CRC. More recently, painstaking molecular and phenotypic characterisation of CRC has demonstrated significant pathogenic heterogeneity and the taxonomic subdivision of CRC now necessarily encompasses the tumour precursor lesion and molecular pathogenesis, alongside lesion distribution and morphological phenotype (figure 1). Importantly, these alternative pathways to the conventional adenoma-carcinoma model appear to account for 15%-30% of CRC cases and are significantly over-represented in interval cancers (figure 1). [bib_ref] Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification,..., East [/bib_ref] [bib_ref] Role of the serrated pathway in colorectal cancer pathogenesis, Leggett [/bib_ref] [bib_ref] Serrated neoplasia-role in colorectal carcinogenesis and clinical implications, Ijspeert [/bib_ref] Hyperplastic (serrated) polyps had previously been considered benign and lacking in premalignant potential; 8 however, multiple lines of evidence suggested that some subtypes of HP were precursor lesions for cancers of nonadenomatous origin, as part of the 'serrated pathway' to CRC. Evidence that SLs have premalignant potential Molecular, genetic, pathological and epidemiological ## Cpg island methylator phenotype Methylation is the addition of a methyl group (CH 3 ) to the cytosine nucleotide in a CpG dinucleotide context. Methylation of gene promoters is a physiological mechanism to regulate gene expression without altering the DNA sequence and is thus termed an 'epigenetic' change. When aberrant DNA methylation results in the transcriptional silencing of important tumour suppressor genes, neoplastic growth can be promoted. This aberrant methylation has been called the CIMP and is thought to be important in the serrated pathway. CIMP status can be detected by screening a panel of genes that are known to be particularly susceptible to promoter methylation. 10 CIMP+ tumours probably account for a third of all CRCs, although the prevalence varies considerably depending on the marker panel used, the population being studied and the colonic regional distribution. [bib_ref] The CpG island methylator phenotype in colorectal cancer: progress and problems, Hughes [/bib_ref] The serrated neoplasia pathway SLs of the colorectum are characterised histologically by a sawtoothed appearance of the crypt epithelium. Formerly, all lesions exhibiting this characteristic morphology were called HPs and were thought to have no malignant potential; 8 however, more recently SLs have been characterised by their morphological and molecular profiles into different subsets, which vary in their risk of malignant transformation. ## Sessile serrated lesions The use of CIMP marker panels provided molecular tools to investigate the precursor lesions of CIMP+ tumours. Many benign sessile serrated polyps (SSPs) are BRAF mutant and are CIMP+, [bib_ref] BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas, Chan [/bib_ref] [bib_ref] Frequent CpG island methylation in serrated adenomas of the colorectum, Park [/bib_ref] [bib_ref] Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas, Goldstein [/bib_ref] [bib_ref] Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status..., O'brien [/bib_ref] and analysis of SSLs with an adjacent region of cancer show shared immunohistochemical and molecular features between the benign and malignant foci. [bib_ref] Sessile serrated adenomas with low-and high-grade dysplasia and early carcinomas: an immunohistochemical..., Sheridan [/bib_ref] [bib_ref] A serrated colorectal cancer pathway predominates over the classic WNT pathway in..., Boparai [/bib_ref] [bib_ref] Colonic intra-epithelial carcinoma occurring in a hyperplastic polyp via a serrated adenoma, Tanaka [/bib_ref] Furthermore, case reports describe the development of cancer within serrated polyps that were left in situ and followed-up endoscopically. This evidence has led to the establishment of a proposed serrated neoplasia pathway, where HPs initiated by BRAF or less commonly KRAS, mutation proceed to SSLs with the accumulation of epigenetic gene silencing, although it may be that SSLs arise de novo. Inactivation of tumour suppressor genes causes the development of cellular atypia (SSL with dysplasia) with eventual progression to cancer. There is a progressive increase of BRAF mutant CIMP+ tumours from the rectum to the caecum [bib_ref] Assessment of colorectal cancer molecular features along bowel subsites challenges the conception..., Yamauchi [/bib_ref] and the reason behind this proximal predilection is unknown. Considering the spectrum of colorectal cancer (CRC)-conventional adenomas progress by the sequential accumulation of genetic mutations and chromosomal instability causing microsatellite stable (MSS) tumours. Microsatellite instability (MSI) is the result of defective DNA repair through inactivation of mismatch repair genes and is epitomised by the germline mutation of Mis-Match Repair (MMR) genes seen in Lynch syndrome (hereditary non-polyposis coli). The sessile serrated neoplasia pathway is often initiated by genetic mutation of BRAF or KRAS genes but then progresses by methylation of tumour suppressing genes (CpG island methylator phenotype (CIMP)). Both MSS and unstable tumours can result depending on the genes epigenetically silenced as the lesions progress. Comparatively, little is known about the traditional serrated pathway, but evidence is accumulating that this is a distinct molecular subtype. [bib_ref] The serrated pathway to colorectal carcinoma: current concepts and challenges, Bettington [/bib_ref] FAP, familial adenomatous polyposis. ## Traditional serrated adenomas The pathogenesis of these sporadic lesions is less clear. The serrated phenotype differs from that seen in HP and SSPs, resulting from surface indentations associated with the characteristic ectopic crypt foci that develop orthogonally to the crypt axis. [bib_ref] Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA), Torlakovic [/bib_ref] Molecular features are not as clearly defined as SSLs, but includes KRAS or BRAF mutations along with variable levels of CIMP positivity. Recently, high levels of GREM1 expression in the epithelium of these lesions have been reported, with the suggestion that they are the sporadic corollary of polyps in hereditary mixed polyposis syndrome. [bib_ref] Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem..., Davis [/bib_ref] Unlike some SSLs, these tumours do not appear to progress through mismatch repair gene methylation and microsatellite instability (MSI). The over-representation of MSI [bib_ref] Microsatellite instability in interval colon cancers, Sawhney [/bib_ref] and CIMP+ 29 tumours in interval cancers (tumours identified in between endoscopic screening examinations) has led to the suggestion that sessile serrated adenomas (SSA) can progress very rapidly. This may be partly true for SLs that develop a mutator phenotype with the loss of MLH-1 function but the over-representation in interval tumours is just as likely to be due to the well-described difficulty in endoscopic detection of these lesions. Statement 1 Some SSLs have molecular, genetic and pathological features consistent with being precursor lesions to CIMP+ CRCs, which represent 15%-30% of all CRCs (moderate quality evidence, 100% agreement). ## Nomenclature and pathological features of sls The nomenclature of SLs is complex as there are differences of opinion between the UK, European and the US pathologists regarding the optimal terminology and the pathological features required to make a diagnosis of an SL (box 1). We recommend usage of the WHO criteria to diagnose SSL. This means that three crypts-or two adjacent crypts-showing at least one of the features listed in box 1 are required to be present for a diagnosis of SSL. There is no strict 'ranking order' of these features in terms of their importance for the diagnosis and there is also no minimum number of these features that need to be present (apart from the minimum number of characteristic crypts). In this position statement we have elected to use terminology developed by Bateman and Shepherd, which is approved by the Pathology sections of the BSG and NHS Bowel Cancer Screening Programme. In the USA, the term SSA was originally coined, which encompassed the morphology of these lesions and implied their premalignant nature; however, such lesions do not generally contain 'true' cytological dysplasia. [bib_ref] Serrated adenomatous polyposis in humans, Torlakovic [/bib_ref] WHO proposed the term sessile serrated adenoma/polyp (SSA/P); 31 however, again this suggests cytological atypia and many lesions would not meet the pathological definition of being polypoid. Therefore, the UK terminology recommends the term SSL with or without dysplasia. This accounts for the pathology and morphology seen and critically distinguishes lesions, which harbour cytological dysplasia that are thought to be higher risk and on an accelerated pathway to carcinogenesis. The recommended terms for the UK pathological classification of serrated polyps are listed in box 2. The 'mixed polyp' category was retained for unusual cases, for example, those showing mixed features of SSL and TSA, or polyps thought to represent true 'collision tumours' comprising an adenoma and an HP; however, most polyps showing features of SSL together with one or more areas of dysplasia are likely to represent SSLs in which dysplasia has arisen, rather than 'collision tumours'. There are problems of interobserver variability with the pathological reporting of SLs that may in part stem from variations in terminology and diagnostic criteria mainly between HPs an SSLs; however, this is likely to improve with uniformity of terminology and experience, with one study showing use of a reference article may improve reproducibility. [bib_ref] A multinational, internet-based assessment of observer variability in the diagnosis of serrated..., Glatz [/bib_ref] TSA show classical cytological dysplasia and distinctive features (eosinophilic cytoplasm, ectopic crypts, pencillate nuclei), and are managed more like classical adenomas. Readers are directed to the guidance document for a more detailed discussion of the pathological issues (http://jcp.bmj. com/content/68/8/585.full.pdf+html). [bib_ref] UK guidance for the pathological reporting of serrated lesions of the colorectum, Bateman [/bib_ref] # Statement 2 We suggest adopting the terms HP, SSL, SSL with dysplasia, TSA or mixed polyp to describe SLs in the colorectum, using the WHO criteria to define SSL (weak recommendation, low quality evidence, 82% agreement). ## Box 1 key histological features of sessile serrated lesions (ssls) ▸ Irregular distribution of crypts ▸ Dilatation of crypt bases ▸ Serration present at crypt bases ▸ Branched crypts ▸ Horizontal extension of crypt bases* ▸ Dysmaturation of crypts † ▸ Herniation of crypts through muscularis mucosa ▸ WHO criteria-at least three crypts or at least two adjacent crypts must show one or more of these features to enable a diagnosis of SSLs 31 ▸ American Gastroenterology Association criteria-one crypt showing the characteristic features is sufficient for the diagnosis of SSLs 26 Involved crypts often have an 'L' or inverted 'T' shape. †Dysmaturation is disordered cellular maturation within crypts and is evidenced by subtle nuclear enlargement, crowding, pseudostratification and mitotic activity together with the presence of a disorganised mixture of non-mucus containing epithelial cells and mature goblet cells within the deep aspects of crypts. In this context, assessment of proliferation index, for example, using MIB-1 may provide supporting evidence for a diagnosis of SSLs by highlighting epithelial cell proliferation within the superficial half of crypts. However, such immunohistochemistry, while sometimes helpful, does not reveal features that are alone diagnostic of SSLs. ## Box 2 recommended terminology for (non-invasive) serrated lesions of the colon and rectum ▸ Hyperplastic polyp ▸ Sessile serrated lesion (SSL) ▸ SSL with dysplasia ▸ Traditional serrated adenoma ▸ Mixed polyp ## Detection and resection of sls detection at colonoscopy prevalence The prevalence of SLs, and especially SSLs is difficult to determine accurately. The results from the published literature are highly variable, due to inconsistent diagnostic criteria, inappropriate histological classification of different subtypes, variation in polyp detection rates among endoscopists, use of different endoscopic enhancing modalities and population selection criteria. A number of studies have demonstrated that review of polyps previously labelled as hyperplastic results in significant numbers being reclassified as serrated adenomas. Furthermore, there is substantial interobserver variation even among GI pathologists in diagnosing SSLs. [bib_ref] Reinterpretation of histology of proximal colon polyps called hyperplastic in 2001, Khalid [/bib_ref] Despite these caveats, there is evidence suggesting that SSL detection is improving, [bib_ref] Variation in the detection of serrated polyps in an average risk colorectal..., Hetzel [/bib_ref] presumably as a result of either increased recognition by endoscopists and/or pathologists [fig_ref] Table 1: Summary of colonoscopic studies evaluating prevalence and detection rates for serrated lesions [/fig_ref]. The prevalence of SLs based on autopsy studies has been reported as between 13% and 35%, [bib_ref] Predictors of presence, multiplicity, size and dysplasia of colorectal adenomas. A necropsy..., Jass [/bib_ref] [bib_ref] The prevalence of polyps of the large intestine in Oslo: an autopsy..., Vatn [/bib_ref] [bib_ref] Polyps of the large intestine in Aarhus, Denmark. An autopsy study, Johannsen [/bib_ref] [bib_ref] Polyps and cancer of the large bowel: a necropsy study in Liverpool, Williams [/bib_ref] with these lesions accounting for 27%-51% of all colorectal polyps. More recent pathology series have demonstrated that the most common SL encountered is the HP, accounting for 24%-42% of all resected colorectal polyps and 83%-96% of all SLs; SSLs represent 2%-4% of all polyps and 3%-11% of SLs. TSAs are much less common, generally accounting for <1% of all polyps and 1%-7% of SLs. [bib_ref] Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected..., Carr [/bib_ref] [bib_ref] Demographic and pathological characteristics of serrated polyps of colorectum, Higuchi [/bib_ref] [bib_ref] Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients, Lash [/bib_ref] The distribution of SLs varies with the type: HPs and TSAs are usually found in the left colon, while SSLs occur more often in the proximal colon. [bib_ref] Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected..., Carr [/bib_ref] [bib_ref] Demographic and pathological characteristics of serrated polyps of colorectum, Higuchi [/bib_ref] [bib_ref] Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients, Lash [/bib_ref] [bib_ref] High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study..., Spring [/bib_ref] The published literature on colonoscopic detection of SLs is summarised in table 1. The studies have mostly been retrospective and have varied in the patient population, details of the colonoscopy procedure and reporting of the results. Excluding those studies that have investigated patients with MutYH-associated polyposis (MAP) or SPS, the majority of the evidence relates to average-risk screening patients. Overall, SLs account for 11%-53% of all polyps detected at colonoscopy in screening populations, SSLs for 1%-13% [bib_ref] Variation in the detection of serrated polyps in an average risk colorectal..., Hetzel [/bib_ref] and TSAs for 0.1%-1.9%. [bib_ref] Prevalence of different subtypes of serrated polyps and risk of synchronous advanced..., Buda [/bib_ref] [bib_ref] Prevalence of serrated polyps and association with synchronous advanced neoplasia in screening..., Hazewinkel [/bib_ref] Spring et al reported SL prevalence results for an unselected population (ie, symptomatic as well as screening patients), with SLs overall accounting for 40% of all polyps, SSLs for 9% and TSAs for <1%. Many patients will have more than one serrated polyp present; Álavrez et al reported that the mean number of serrated polyps detected was 2, with a range of 1-25. ## Endoscopic appearance of sls Endoscopically, HPs tend to be diminutive (<5 mm), pale, sessile [bib_ref] Polyps and cancer of the large bowel: a necropsy study in Liverpool, Williams [/bib_ref] and have a type II asteroid, stellate or papillary Kudo pit pattern when examined with chromoendoscopy or narrowband imaging. [bib_ref] Comparative study of conventional colonoscopy, chromoendoscopy, and narrow-band imaging systems in differential..., Su [/bib_ref] The endoscopic features of SSLs include sessile or flat morphology with proximal SSLs more likely to be flat than distal lesions, 61 a resemblance to prominent folds, [bib_ref] A morphologic analysis of sessile serrated polyps observed during routine colonoscopy (with..., Tadepalli [/bib_ref] pale colour, [bib_ref] Clinicopathologic and endoscopic features of colorectal serrated adenoma: differences between polypoid and..., Oka [/bib_ref] indistinct borders 62 and mucus capping. [bib_ref] A morphologic analysis of sessile serrated polyps observed during routine colonoscopy (with..., Tadepalli [/bib_ref] In 52% of SSLs, a rim of bubbles or debris is present that can help delineate the lesions and serve as an identification aid. [bib_ref] A morphologic analysis of sessile serrated polyps observed during routine colonoscopy (with..., Tadepalli [/bib_ref] Additional features on narrow band imaging (NBI) include a cloud-like surface, an irregular shape and dark spots inside the crypts. [bib_ref] Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution..., Hazewinkel [/bib_ref] SSLs typically have a type II-O or open Kudo pit pattern on a magnified view; several studies have reported this pit pattern has good sensitivity (84%-97%) and specificity (66%-86%) for identifying SSLs. [bib_ref] Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution..., Hazewinkel [/bib_ref] [bib_ref] A novel pit pattern identifies the precursor of colorectal cancer derived from..., Kimura [/bib_ref] [bib_ref] Evaluation of magnifying colonoscopy in the diagnosis of serrated polyps, Ishigooka [/bib_ref] TSAs tend to be protuberant and/or pedunculated, with a type IV ( pinecone-like or fern-like) pit pattern. [bib_ref] Prevalence of different subtypes of serrated polyps and risk of synchronous advanced..., Buda [/bib_ref] [bib_ref] Traditional serrated adenoma of the colorectum: clinicopathologic implications and endoscopic findings of..., Kim [/bib_ref] In a prospective study, Rondagh et al 66 demonstrated the proximal serrated polyps (PSPs) were more likely to be sessile and less likely to be diminutive compared with distally located lesions. ## Colonoscopy for sl detection There have been few studies which have focussed directly on colonoscopic detection of SLs. Most data are drawn from studies where SLs were detected incidentally and adenomas were the primary end point, and many predate accurate pathological distinction of SLs. Hence, data are not as robust as for adenoma detection rates (ADRs). Furthermore, there is no clear correlation between SL detection rates and interval cancer, unlike that seen for ADRs. Interval cancers are over-represented in the serrated pathway and higher 'polyp' detection rates have been shown to be protective for right-sided CRCs. [bib_ref] Analysis of administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal..., Baxter [/bib_ref] It is possible therefore that improvements in SL detection rates might have a greater impact on interval cancer rates than improvements in ADR, although ADR and SL detection show some correlation (see benchmarks). Summary data on interventions which may or may not improve SL detection are presented in table 2. ## Withdrawal time In a Dutch screening cohort, longer withdrawal time had an OR of 1.12 for detection of SLs. [bib_ref] Differences in proximal serrated polyp detection among endoscopists are associated with variability..., De Wijkerslooth [/bib_ref] Analysis of data from the New Hampshire colonoscopy registry reported an incidence rate ratio of 1.77 for each minute beyond 6 min withdrawal time to a maximum at 9 min. [bib_ref] Serrated and adenomatous polyp detection increases with longer withdrawal time: results from..., Butterly [/bib_ref] In both cases, similar improvements were seen for ADRs. ## Chromoendoscopy Chromoendoscopy consistently improves adenomatous as well as non-adenomatous polyps detection rates, with the vast majority of the latter being SLs. A summary of four studies performed between 2002 and 2006, reported an increase in hyperplastic or non-adenomatous polyp detection from 23% to 45% overall, and from 9% to 16% in the proximal colon. [bib_ref] Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification,..., East [/bib_ref] More recent studies have confirmed this result and effect size in multicentre studies from Germany (46.2% vs 29.5% SLs, rectum excluded) [bib_ref] Pancolonic chromoendoscopy with indigo carmine versus standard colonoscopy for detection of neoplastic..., Pohl [/bib_ref] and the USA (high-definition colonoscopes; mean non-neoplastic lesions per patient 1.8 vs 1.0). [bib_ref] High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening, Kahi [/bib_ref] All studies used indigocarmine dye as a surface contrast agent. The use of chromoendoscopy to increase yield of serrated polyps in the right colon is currently being trialled in an FOBT-positive screening population in Wales (Contrast Enhanced Colonoscopy (CONSCOP) study; ClinicalTrials.gov identifier: NCT01972451). ## High definition In a small single-centre cohort study, detection rates for proximal HPs and for large (≥10 mm) HPs were not different. [bib_ref] A comparative study of standard vs. high definition colonoscopy for adenoma and..., East [/bib_ref] In a Dutch screening cohort, use of high-definition colonoscopes did not improve PSP detection, multivariate ORs 1.07. [bib_ref] Differences in proximal serrated polyp detection among endoscopists are associated with variability..., De Wijkerslooth [/bib_ref] High-definition compared with standard-definition colonoscopy provided only a marginal incremental yield in polyp detection rates of 3.8% (95% CI 1% to 6.7%) in a meta-analysis suggesting that any benefit seen may be small. [bib_ref] High definition colonoscopy vs. standard video endoscopy for the detection of colonic..., Subramanian [/bib_ref] ## Proximal colon retroflexion Proximal colon retroflexion showed a modest increase in proximal SL detection, although this gain might have been achieved with a repeated examination in the forward view. [bib_ref] Right-sided adenoma detection with retroflexion versus forward-view colonoscopy, Chandran [/bib_ref] Narrowed spectrum endoscopy NBI showed improved detection in a single-centre, singleoperator study for detection of SLs in the setting of SPS; [bib_ref] Increased polyp detection using narrow band imaging compared with high resolution endoscopy..., Boparai [/bib_ref] however, a multicentre study from the same group did not confirm this. [bib_ref] Narrow-band imaging for the detection of polyps in patients with serrated polyposis..., Hazewinkel [/bib_ref] Four different meta-analyses of NBI versus white light, including more than 3000 patients, failed to show improvements in adenoma or polyp detection rates, suggesting a benefit for serrated polyps is unlikely. [bib_ref] Electronic imaging to enhance lesion detection at colonoscopy, Ket [/bib_ref] Similarly, there is no clear detection benefit for either flexible spectral imaging colour enhancement (Fujinon) [bib_ref] Live image processing does not increase adenoma detection rate during colonoscopy: a..., Aminalai [/bib_ref] [bib_ref] Comparison of detection and miss rates of narrow band imaging, flexible spectral..., Chung [/bib_ref] [bib_ref] Computed virtual chromoendoscopy versus standard colonoscopy with targeted indigocarmine chromoscopy: a randomised..., Pohl [/bib_ref] or iSCAN (Pentax) with tone enhancement. [bib_ref] High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition..., Hoffman [/bib_ref] [bib_ref] Prospective, randomized, back-to-back trial evaluating the usefulness of i-SCAN in screening colonoscopy, Hong [/bib_ref] [bib_ref] High-definition colonoscopy with i-Scan: better diagnosis for small polyps and flat adenomas, Testoni [/bib_ref] Recent data from the new generation of brighter NBI systems (Excera III, Olympus) in a large study looking specifically at SLs detection rates in the proximal colon did not show an overall benefit in the number of proximal SLs detected, but did show a significant benefit for larger SLs. [bib_ref] Narrow-band imaging versus white light for the detection of proximal colon serrated..., Rex [/bib_ref] Underwater endoscopy has been proposed to improve ADRs. Data for SL are limited but in one study combining two randomised controlled trials there was no overall benefit in proximal SL detection rate of 6% vs 12%. [bib_ref] The water method significantly enhances detection of diminutive lesions (adenoma and hyperplastic..., Leung [/bib_ref] Antispasmodics Hyoscine butylbromide (Buscopan) increased polyp detection in the right colon, 0.43 vs 0.31, p=0.01 in one randomised controlled trial; 92 however, a meta-analysis that included this study found no increase in polyp detection rate overall (OR 1.09, 95% CI 0.91 to 1.31). [bib_ref] The impact of hyoscine-N-butylbromide on adenoma detection during colonoscopy: meta-analysis of randomized,..., Rondonotti [/bib_ref] ## Bowel preparation Few studies have had detection of SLs as a primary outcome. In a Dutch screening study, quality of bowel preparation was not associated with lower proximal SL detection rates, multivariate OR 0.98 (95% CI 0.92 to 1.05). [bib_ref] Differences in proximal serrated polyp detection among endoscopists are associated with variability..., De Wijkerslooth [/bib_ref] In a US registry-based study, serrated polyp detection rates were similar for optimal (excellent or good) versus fair bowel preparation, with an OR of 0.75 (95% CI 0.31 to 1.80) for poor prep versus optimal prep for PSP detection. [bib_ref] Impact of fair bowel preparation quality on adenoma and serrated polyp detection:..., Anderson [/bib_ref] This effect may result from a thicker mucus cap on SLs with lower preparation quality assisting detection. ## Wide angle and enhanced mucosal views In a tandem study, the Third Eye Retroscope detected 77 vs 58 non-adenomatous polyps, but in the right colon this was only 19 vs 22 non-adenomatous polyps, so better detection of clinically relevant SLs was not demonstrated. [bib_ref] Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the..., Leufkens [/bib_ref] Other novel devices to reveal more mucosa have been recently reported such as G-Eye, Full Spectrum Endoscopy and Third Eye Panoramic Device; however, no current studies report data that allow assessment of proximal SL detection rates. Data for SLs are not yet reported for SL detection rates for other devices, which may improve mucosal visualisation, for example, Endocuff, Endorings. # Statement 3 We suggest a minimum withdrawal time of 6 min to enhance SL detection. Chromoendoscopy can also enhance SL detection (weak recommendation, low quality evidence, 100% agreement). ## Detection by other modalities Although colonoscopic detection of SLs may not be perfect, at present there is not enough evidence to suggest that colonoscopy can be replaced by alternative technologies. CTC has difficulty detecting flat and sessile lesions. The limited published data on the detection of lesions other than conventional adenomas by CTC suggest that this technique lacks adequate sensitivity. [bib_ref] Sensitivity of CT colonography for nonpolypoid colorectal lesions interpreted by human readers..., Park [/bib_ref] However, one recent study of flat colonic lesions has suggested that serrated and HPs are more likely to coat with oral contrast than adenomatous polyps, and this may represent a way forward in CTC identification of SLs. [bib_ref] Contrast coating for the surface of flat polyps at CT colonography: a..., Kim [/bib_ref] ## Stool markers The potential role of FIT in detecting SLs has been evaluated in a recent study by Heigh et al; however, the results were poor at both 50 and 100 ng/mL cut-off values. This is probably because SLs are less likely to bleed than conventional adenomas. [bib_ref] Histopathological assessment of bleeding from polyps of the colon and rectum, Waldock [/bib_ref] Stool DNA tests may offer the ability to detect SLs noninvasively. In a prospective study of 456 screening/surveillance patients, Heigh et al 96 demonstrated that mBMP3 proved highly discriminant for detection of SSLs >1 cm in size. Lidgard et al 97 evaluated the clinical performance of an automated stool DNA assay in a blinded, case-control study. Stool samples were analysed from 459 screening/surveillance patients and from 544 symptomatic patients, including 30 patients with SSAs. The stool DNA assay measured β-actin (a marker of total human DNA), mutant KRAS, aberrantly methylated BMP3 and NDRG4 and faecal haemoglobin. Its sensitivity for SSA >1 cm was 60%. In a recent large study in an average-risk cohort by Imperiale et al 98 using FIT versus FIT plus multitarget stool DNA testing, FIT plus DNA significantly outperformed FIT alone for the detection of serrated polyps 1 cm or more in size, 42.4% vs 5.1%, respectively, p<0.001. Colon capsule data are limited, especially for reporting of serrated polyps; however, in the largest study reported the serrated polyp detection rate by capsule colonoscopy was up to a third less than by colonoscopy. [bib_ref] Accuracy of capsule colonoscopy in detecting colorectal polyps in a screening population, Rex [/bib_ref] # Statement 4 We recommend that colonoscopy is the best current test for SL detection, with other modalities performing less well (FOBT/FIT ±stool DNA, CTC, flexible sigmoidoscopy, capsule colonoscopy) (strong recommendation, moderate quality evidence, 100% agreement). ## Resection There has been concern in the gastroenterological community that the risk of trying to resect SLs might potentially outweigh the reduction on CRC risk, especially for larger lesions in the High definition [bib_ref] Differences in proximal serrated polyp detection among endoscopists are associated with variability..., De Wijkerslooth [/bib_ref] Narrowed spectrum endoscopy (NBI, FICE, iSCAN) 71 Chromoendoscopy 5 Right colon retroflexion 74 ## Antispasmodics 75 Good vs adequate bowel preparation Wide angle and enhanced mucosal views [bib_ref] Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the..., Leufkens [/bib_ref] [bib_ref] Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy..., Gralnek [/bib_ref] [bib_ref] Safety and efficacy of a novel balloon colonoscope: a prospective cohort study, Gralnek [/bib_ref] FICE, flexible spectral imaging colour enhancement; NBI, narrow band imaging. right colon, 100 mainly on the basis of data from a large German study of postpolypectomy complications pre-2005. [bib_ref] The Munich Polypectomy Study (MUPS): prospective analysis of complications and risk factors..., Heldwein [/bib_ref] For smaller SLs <10 mm in size standard polypectomy techniques can be applied, although the flat morphology of the lesions can make them difficult to grip. Use of a stiff snare and submucosal lifting may help in these situations. For lesions in the proximal colon cold snaring is preferred. We suggest that resection of large proximal SSPs is optimally dealt with by individuals and centres with expertise in recognition, detailed assessment and therapy of these lesions. This recommendation is based on the higher risk of incomplete resection and complications associated with removal of large sessile polyps in the right colon and some evidence of a favourable effect of a threshold volume for better outcomes. [bib_ref] Risk factors for adverse events related to polypectomy in the English Bowel..., Rutter [/bib_ref] [bib_ref] Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study, Pohl [/bib_ref] [bib_ref] British Society of Gastroenterology/ Association of Coloproctologists of Great Britain and Ireland..., Rutter [/bib_ref] These data, combined with variability in SL detection and assessment (see statements , and data on comparing the similar outcomes on safety of endoscopic resection in adenomas and SSLs, [bib_ref] Endoscopic mucosal resection for large serrated lesions in comparison with adenomas: a..., Pellise [/bib_ref] suggest a significant role for operator variability and outcomes in the management of these lesions. Therefore, for larger lesions ≥10 mm endoscopists should meet the competencies and standards set out in the BSG 2015 guidelines on management of large non-polypoid colorectal polyps. [bib_ref] British Society of Gastroenterology/ Association of Coloproctologists of Great Britain and Ireland..., Rutter [/bib_ref] Specific variations in technique such as underwater EMR, 106 use of suction to create pseudopolyps 107 and use of specific snares have been proposed as being of help but cannot be recommended at present as being significantly better than standard EMR technique to remove these lesions. [bib_ref] Outcomes of EMR of defiant colorectal lesions directed to an endoscopy referral..., Buchner [/bib_ref] There is some evidence to suggest that use of a microprocessor controlled diathermy unit, care with use of excessive diathermy and achieving complete endoscopic resection in the first attempt may help to reduce the incidence of complications and recurrence of these lesions. # Statement 5 We suggest that endoscopic resection of proximal SSLs, particularly those ≥10 mm in size, should be undertaken by operators who demonstrate achievement of outcomes for incomplete resection rates, serrated polyp detection rates and expertise in assessment of these at colonoscopy (see BSG-ACPGBI guideline on LNPCPs 2015, and statements 13 and 14) (weak recommendation, low quality evidence, 91% agreement). ## Surveillance strategies after detection of sls Data to guide surveillance strategy after detection of SLs are limited with essentially no high-quality prospective data available or likely to be available in the next few years. ## High-risk situations SPS (see the 'Serrated polyposis syndrome' section) appears to lead to a substantial future risk of CRC that can be reduced, at least over 5 years, by intensive colonoscopic surveillance. The US multisociety taskforce guidelines have suggested surveillance at one yearly intervals may be appropriate, [bib_ref] Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by..., Lieberman [/bib_ref] although data on the effectiveness of yearly surveillance and possibly lower risks estimates of future cancer during surveillance were not available to these guidelines groups (see the 'Serrated polyps in colitis' section). Risk estimates do not seem to exceed those for Lynch syndrome and molecular mechanisms to CRC such as loss of DNA mismatch repair may be shared. Therefore, once all larger polyp have been removed, with only polyps 5 mm or less remaining, surveillance can be initiated every 1-2 years (see [fig_ref] Figure 2: Serrated surveillance flow chart [/fig_ref] , with the later interval appropriate for those not developing further polyps rapidly once the colon has been cleared, see Hassan et al 112 for suggested algorithm flow chart. Patients who are first-degree relatives of patients with SPS with at last one PSP (WHO criteria 2), but not meeting the WHO criteria 1 or 3 (see box 3) may be at lower risk. [bib_ref] Serrated polyposis: prospective study of first-degree relatives, Oquiñena [/bib_ref] # Statement 6 We suggest that given the elevated CRC risk in patients who meet the WHO criteria for SPS, and that effective surveillance appears to reduce CRC risk, these patients should be offered one to two yearly colonoscopic surveillance (weak recommendation, low quality evidence, 90% agreement). There are data from clinical studies in adenomatous polyps that piecemeal resection increases the risk of lesion recurrence, [bib_ref] Incidence and predictors of "late" recurrences after endoscopic piecemeal resection of large..., Khashab [/bib_ref] with epidemiological data pointing to a risk of interval cancer from partly resected SLs. The CARE study suggested that rates of residual lesion are much higher for SLs than for adenomas. [bib_ref] Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study, Pohl [/bib_ref] Therefore, it is logical that the same guidance after piecemeal resection of adenomas should apply to piecemeal resection of serrated polyps, that is, a site check at 2-6 months for lesions 20 mm or greater in size. This is consistent with the BSG 2015 guideline on management of large LNPCPs. [bib_ref] British Society of Gastroenterology/ Association of Coloproctologists of Great Britain and Ireland..., Rutter [/bib_ref] This guideline also suggests that where possible polyps <20 mm in size be resected en bloc; however, this may be a particular challenge for SL in the right colon. Therefore, if SLs between 10 and 20 mm are resected piecemeal it may be left to the endoscopist discretion as to whether a site check is required at 2-6 months or whether standard surveillance intervals can be applied (see statement 8), depending on patient factors and assessment of likelihood of complete excision. Recent data from a large series in Australia suggest that the recurrence rate for SSPs ≥20 mm resected with piecemeal EMR is lower than for adenomas but still significant, 7% vs 20% at 12 months. [bib_ref] Endoscopic mucosal resection for large serrated lesions in comparison with adenomas: a..., Pellise [/bib_ref] # Statement 7 We suggest that after piecemeal EMR of a SL ≥20 mm that an examination of the resection site be performed within 2-6 months postresection (weak recommendation, low quality evidence, 100% agreement). ## Moderate risk situations The presence of sporadic SSA/Ps may represent an mucosal field defect with detection of one SSA/P making detection of synchronous SSA/P 115-117 as well as metachronous SSA/P during Box 3 WHO definition of serrated polyposis syndrome 2010 31 1. At least five serrated polyps proximal to the sigmoid colon, two of which are >10 mm in diameter 2. Any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis 3. More than 20 serrated polyps of any size distributed throughout the colon *Serrated lesion refers to any combination of hyperplastic polyps and sessile serrated polyps. surveillance more likely. There is evidence they are also associated with neoplasia. Patients with baseline advanced adenomas and proximal SSA/P were more likely to have advanced neoplasia detected at follow-up, however, this was not the case for baseline tubular adenomas. [bib_ref] Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are..., Schreiner [/bib_ref] In addition, a retrospective study found that 15% of patients with SSA/P at baseline endoscopy had advanced neoplasia over an 8.3-year follow-up. [bib_ref] Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased..., Lu [/bib_ref] ## Higher risk lesions There is evidence that larger SSA/Ps (≥ 10 mm) are predictive of advanced neoplasia 51 52 120-124 with a number of studies demonstrating that this association is synchronous. Furthermore, increasing size of SSA/P has been associated with dysplasia and found to be predictive of CRC. [bib_ref] The presence of large serrated polyps increases risk for colorectal cancer, Hiraoka [/bib_ref] SSA/P prevalence as well as the presence of dysplasia is associated with increasing age, but the risk and rate of progression of SSA/P to dysplasia and cancer has not been clearly delineated. However, a mean progression interval of 15 years from SSA/P without cytological dysplasia to cancer has been suggested. [bib_ref] Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients, Lash [/bib_ref] There is discrepancy in the reported risk of metachronous CRC in the setting of SSA/P. Some studies have found that there is no evidence of increased risk of metachronous CRC. [bib_ref] Relationship of colonoscopy-detected serrated polyps with synchronous advanced neoplasia in average-risk individuals, Álvarez [/bib_ref] However, a recent study found an HR for CRC of 2.5 (95% CI 0.8 to 7.8) in individuals with large serrated polyps, equivalent to that of advanced adenomas. [bib_ref] Long-term risk of colorectal cancer in individuals with serrated polyps, Holme [/bib_ref] Other studies also support SSA/P as an independent risk factor for CRC, with incidence significantly higher in patients with SSA than control patients with hyperplastic and adenomatous polyps. [bib_ref] Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased..., Lu [/bib_ref] A large Danish population-based study has recently suggested that SSA/Ps are risk equivalent to adenomas in terms of future long-term CRC risk, with SSPs with dysplasia and TSAs being particularly high risk 128 (see [fig_ref] Figure 2: Serrated surveillance flow chart [/fig_ref]. The US Multi-Society Task Force on CRC guidelines from 2012 and the European Society of GI Endoscopy polyp surveillance guidelines from 2013 both recommend a surveillance examination at 3 years for patients with a single SSP ≥10 mm in size. # Statement 8 We suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with SSLs that appear associated with a higher risk of future neoplasia or CRC (SSLs ≥10 mm or SLs harbouring dysplasia including TSAs) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement). ## Lower risk lesions Diminutive HPs in the rectosigmoid are not thought to be risk markers for future CRC risk. Whether one or two proximal small or diminutive HPs or SSLs are risk markers for future CRC is unclear, with studies reporting risk showing most risk is associated with larger lesions (see High risk lesions). Pathological distinction of HPs and SSLs also becomes more challenging as lesion size decreases. Similar to data for adenomas, the number of SSA/P has also been implicated in a retrospective study where three or more serrated polyps were an independent predictor of synchronous advanced neoplasia. [bib_ref] Association between serrated polyps and the risk of synchronous advanced colorectal neoplasia..., Ng [/bib_ref] Overall, data are limited to support any significant excess risk of small SSA/P. Multiple serrated polyps <10 mm in size, especially in a young patient, might represent an incomplete phenotypic expression of SPS and therefore surveillance in this setting needs to be individualised to the size, location and pathology of the lesions in an individual patient (see [fig_ref] Figure 2: Serrated surveillance flow chart [/fig_ref]. # Statement 9 We suggest that at present for HPs or SSLs <10 mm in size without dysplasia there is no clear indication for colonoscopic surveillance unless sufficient in size, location and number to meet the criteria for SPS (weak recommendation, very low quality evidence, 90% agreement). ## Other considerations There are no data on longitudinal risk after polypectomy, however, one study has demonstrated 47% of large SSA/P that underwent polypectomy were incompletely removed. [bib_ref] Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study, Pohl [/bib_ref] There are multiple case reports describing carcinomas arising from SSA/P, and interval cancers are more likely to be derived from the serrated pathway. [bib_ref] Long-term colorectal-cancer incidence and mortality after lower endoscopy, Nishihara [/bib_ref] However, in a study where 23 large serrated polyps were left in situ for a median of 11.0 years, none of these developed malignant tumour. [bib_ref] Long-term risk of colorectal cancer in individuals with serrated polyps, Holme [/bib_ref] ## Special situations: sps and serrated polyps in colitis serrated polyposis syndrome Serrated polyps can be multiple and if present in sufficient numbers and size can meet the criteria for SPS ( previously called HP syndrome; WHO definition, box 3). Estimates of the prevalence of SPS in the population have traditionally been very low, with figures of 1:100 000 quoted; however, in screening populations the prevalence may be higher. In FOBT-based screening, the prevalence of SPS may exceed 1:300, although the rate in colonoscopy-based programmes is approximately 1:2000, making this an important syndrome for screening colonoscopists to recognise in these programmes [fig_ref] Table 3: Serrated polyposis syndrome prevalence in population-based screening by modality [/fig_ref]. [bib_ref] High prevalence of hyperplastic polyposis syndrome (serrated polyposis) in the NHS Bowel..., Biswas [/bib_ref] [bib_ref] High colonoscopic prevalence of proximal colon serrated polyps in average-risk men and..., Kahi [/bib_ref] [bib_ref] Hyperplastic polyposis: prevalence and cancer risk, Lockett [/bib_ref] [bib_ref] High prevalence of serrated polyposis syndrome in FIT-based colorectal cancer screening programmes, Moreira [/bib_ref] [bib_ref] Hyperplastic polyposis syndrome in asymptomatic patients: the result from the colorectal-cancer screening..., Orlowska [/bib_ref] SPS was originally described to avoid misclassification as familial adenomatous polyposis (FAP), and was not thought to confer any increased risk of CRC; 139 however, this was challenged in 1996 where a case series of CRC associated with SPS was described. [bib_ref] Serrated adenomatous polyposis in humans, Torlakovic [/bib_ref] Subsequent larger recent series from the Netherlands and the USA have confirmed an increased risk of CRC during colonoscopic surveillance of 7% at 5 years and two cancers in 44 patients over 2 years, although these estimates may be inflated by ascertainment bias, and a recent large international multicentre series reported a lower rate of 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). [bib_ref] Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome:..., Ijspeert [/bib_ref] A multicentre Spanish series also reported a lower than previously reported risk, 1.9% CRC risk at 5 years. [bib_ref] Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large..., Carballal [/bib_ref] In a series from the same group in the Netherlands and from an international cohort the risk of CRC in first-degree relative was five times that of the general population. [bib_ref] Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis..., Boparai [/bib_ref] In common with other colonic polyposis, there has been consideration of whether extracolonic GI polyposis (upper GI tract of small bowel) exists, with none reported, 141 or whether there might be an association with extracolonic cancers. No report confirms an association with extracolonic carcinoma; however, one report indicated an association with pancreatic carcinoma in first-degree relatives of patients with SPS, which has not been supported in another case series. # Statement 10 We suggest that upper GI surveillance for polyposis or extraluminal surveillance for non-GI cancers is not necessary in patients with SPS where other genetic causes have been excluded (weak recommendation, very low quality evidence, 100% agreement). Given the multiple polyps, high risk of CRC, evidence of familial clustering, associated family history of CRC in 50% of cases and increased risk of CRC in first-degree relatives, there has been a concerted effort to find a genetic cause for SPS. Genes (and associated syndromes) associated with an SPS phenotype include: MUTYH (MAP); BMPR1A ( juvenile polyposis syndrome); 147 SMAD4 ( juvenile polyposis syndrome); PTEN (Cowden syndrome 150 ); GREM1 (hereditary mixed polyposis syndrome 151 ); RNF43 (multiple serrated polyps 152 ). However, no genetic mutation is identified for the majority of cases. In a series of 65 individuals fulfilling the WHO criterion 1 or 3, systematically investigated for mutations in these genes, no significant abnormalities were found. [bib_ref] Germline mutations in the polyposis-associated genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1..., Clendenning [/bib_ref] Thus, while determining whether an individual fulfils the WHO definition of SPS is relatively straightforward; the phenotypic overlap with other syndromes is an important potential pitfall. We therefore recommend that all patients with a clinical diagnosis of SPS are referred to a clinical genetics unit or dedicated polyposis registry to ensure that an alternative diagnosis is not missed. In addition, centralisation of individuals and families into such units allows appropriate recall for surveillance, identification of relatives who should also have surveillance and facilitates research into SPS and its underlying genetics. # Statement 11 We suggest that all patients with SPS should be referred to clinical genetics services or a polyposis registry, where local resources allow (weak recommendation, very low quality evidence, 100% agreement). On the same basis as other polyposis syndrome, for example, attenuated FAP, endoscopic management may be appropriate if the size, location and number of polyps are manageable, the patient is willing and the appropriate endoscopic skill set is available (usually tertiary centres). A recent series for Amsterdam suggests that once the colon is cleared relatively few patients (3/41) need surgery during 5 years of intensive surveillance with no cancer developing 154 (for position statement see the 'Surveillance strategies after detection of SLs' section). Statement (repeated from surveillance section) [bib_ref] Role of the serrated pathway in colorectal cancer pathogenesis, Leggett [/bib_ref] We suggest that given the elevated CRC risk in patients who meet the WHO criteria for SPS, and that effective surveillance appears to reduce CRC risk, these patients should be offered one to two yearly colonoscopic surveillance (weak recommendation, low quality evidence, 90% agreement). However, in the same series 26 of 78 inception patients came to surgery for cancer at presentation, extensive polyposis or high risk or unresectable polyps. [bib_ref] Incidence of colonic neoplasia in patients with serrated polyposis syndrome who undergo..., Hazewinkel [/bib_ref] As with other polyposis syndromes therefore, surgical resection should be seriously considered when colonoscopic removal of polyps is not feasible, in order to reduce cancer risk. [bib_ref] Endoscopic and surgical management of serrated colonic polyps, Leonard [/bib_ref] These surgical principles apply when cancer is detected in the context of SPS. # Statement 12 We suggest that surgery should be considered in patients with SPS who have lesions that are not amenable to colonoscopic resection because of their size, site or number (weak recommendation, very low quality evidence, 100% agreement). We suggest that surgery should aim to remove all lesions that are not amenable to endoscopic resection, and could take the form of: segmental colectomy, total colectomy with ileorectal anastomosis or proctocolectomy (with or without ileoanal pouch formation) depending on the lesion burden and distribution (weak recommendation, very low quality evidence, 100% agreement). ## Serrated polyps in colitis Patients with longstanding extensive colitis have an increased risk of developing CRC. Although many colitis-associated cancers may develop from sporadic adenomas (the adenomacarcinoma sequence), it is recognised that a proportion of cancers in patients with colitis arise from an inflammationcancer pathway involving a different frequency, sequence and timing of molecular events (eg, earlier loss of Adenomatous Polyposis Coli (APC) function and later p53 mutation) compared with sporadic, non-IBD-related carcinogenesis. Very little consideration has been given to the possibility of a serrated dysplasia pathway for inflammation-driven carcinogenesis in colitis. ## Incidence Serrated polyps do occur in IBD; however, the incidence of SLs in patients with colitis is unknown. Historical studies may be unreliable, due to under-reporting of a lesion that was previously believed to be of no clinical significance and the lesions may be even more difficult to identify in inflamed mucosa. Several studies have reviewed pathology specimens to determine the incidence of serrated histology in colitis-associated neoplasia. Bossard et al 156 reported that serrated preneoplastic lesions accounted for 6.9% (2/29) of all preneoplastic lesions in inflamed IBD mucosa, a lower proportion than that seen in patients without IBD, although this may be due to sample size. Rubio compared the histological phenotypes of neoplasia in 96 colectomy specimens in patients with colitic cancer. [bib_ref] Serrated neoplasias and de novo carcinomas in ulcerative colitis: a histological study..., Rubio [/bib_ref] In colitis, a dysplastic serrated pattern occurred in 12% of the neoplasia in circumscribed Dysplasia Associated Lesion or Mass (DALM)-type lesions and in 29% of the adenomatous (Adenoma Like Mass (ALM)) lesions with well-defined borders surrounded by non-dysplastic colorectal mucosa; however, the invading cancer phenotype was serrated in only in 4% of the colitic cancers . In an earlier study by Rubio et al, 158 the histological phenotype of dysplasia adjacent to CRCs was assessed in 50 IBD and 50 non-IBD colectomy specimens. Serrated neoplasia accounted for 28.9% (11 out of 38) of the non-invasive dysplastic lesions abutting IBD carcinomas but only 3.4% (1 out of 29) of control specimens. Aust et al 159 demonstrated activating BRAF mutations typical of SSPs were identified in 9% (3 out of 33) of colitis-associated cancers, consistent with the hypothesis that some colitis-associated cancers may arise through the serrated pathway. ## Different pathways to neoplasia As described above, it is clear that some cancers in colitis have associated serrated histopathology; what is unknown is whether this serrated pathway is promoted by colitic inflammation or coincidental to it. Several studies paint a rather mixed picture. Odze et al 160 found no significant difference in the prevalence of KRAS mutations, loss of heterozygosity of APC, 3p, p53 or p16, between chronic UC-associated HPs (not SSPs per se), sporadic HPs and inflamed colitic mucosa. Srivastava et al [bib_ref] Hyperplastic/serrated polyposis in inflammatory bowel disease: a case series of a previously..., Srivastava [/bib_ref] reported three patients with longstanding IBD who developed numerous hyperplastic/serrated colonic polyps similar to those described in the SPS. Two patients had CRC. KRAS mutation was detected in 45% (5/11) polyps and the mucinous adenocarcinoma, more than expected for the standard serrated pathway. Moreover, BRAF mutations were not identified in any of the serrated polyps tested, raising the possibility of a separate IBD-serrated pathway. Bossard et al 156 retrospectively reviewed neoplastic lesions from 36 patients with IBD. These included one HP and one TSA, both of which exhibited the V600E BRAF mutation without MSI or MMR deficiency. The TSA was close to a mucinous adenocarcinoma, which exhibited the BRAF mutation and MSI with loss of hMLH1. This is consistent with the sequence of molecular events described in the serrated pathway. KRAS mutations are uncommon in the serrated pathway, but are observed preferentially in sporadic colorectal carcinogenesis. KRAS activating mutations occur very early in IBD-related carcinogenesis, as evidenced by KRAS mutations being detected in control inflammatory non-dysplastic mucosa. [bib_ref] Involvement of the serrated neoplasia pathway in inflammatory bowel disease-related colorectal oncogenesis, Bossard [/bib_ref] This suggests that the serrated pathway is distinct from the inflammationcancer pathway and that thus far there is no clear evidence to suggest that SLs seen in colitis are more common that might be seen sporadically. Therefore, there may be no specific colitis-associated SL, in contrast to the accepted concept of colitis-associated dysplasia/cancer. The strength of the data available means no statement on SLs in colitis was felt to be appropriate at this time. ## Education, audit and benchmarks and research questions pathological and endoscopic images of sls Video demonstration of technique for en bloc hot snare EMR of a 12 mm right-sided SSL: https://www.youtube.com/watch? v=Z_GKfMmRve0. # Statement 13 We recommend that clinicians involved in the care of patients with serrated polyps, especially endoscopists and pathologists, acquire the knowledge and skills to recognise and differentiate the various types of SLs (strong recommendation, moderate quality evidence, 100% agreement). Given the accepted importance of the serrated pathway in clinical practise for gastroenterologists, surgeons and pathologists, we would recommend that knowledge in these areas be incorporated into the new national gastroenterology curriculum for higher training (figures 3A-D and 4A-D). ## Audit and benchmarks The ADR is now an accepted quality marker for colonoscopy, for both general (BSG Quality and Safety indicators) and for screening colonoscopy. [bib_ref] Quality indicators for colonoscopy, Rex [/bib_ref] There is some evidence that the ADR correlates with SSL-DR 41 and proximal SL-DR The overall detection rates for SLs (ie, percentage of colonoscopes with ≥1 such lesion) have been reported as 4%-35% in average-risk screening populations, 13%-21% in unselected populations (ie, symptomatic as well as screening patients) and 10% in surveillance patients [fig_ref] Table 1: Summary of colonoscopic studies evaluating prevalence and detection rates for serrated lesions [/fig_ref]. [bib_ref] Differences in detection rates of adenomas and serrated polyps in screening versus..., Anderson [/bib_ref] A number of studies have also shown that the DR for proximal SLs is 3%-13% in screening populations. [bib_ref] Endoscopic detection of proximal serrated lesions and pathologic identification of sessile serrated..., Payne [/bib_ref] Focussing on SSLs, the DR has been reported as 0.6%-11% in screening populations, and 5% in an unselected population [fig_ref] Table 1: Summary of colonoscopic studies evaluating prevalence and detection rates for serrated lesions [/fig_ref]. [bib_ref] Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians, Kumbhari [/bib_ref] Detection rates for TSAs in screening populations has been have been shown to be <1%. Three studies have reported DRs of 1%-11% for all serrated adenomas in screening populations. [bib_ref] Relationship of colonoscopy-detected serrated polyps with synchronous advanced neoplasia in average-risk individuals, Álvarez [/bib_ref] Other studies have investigated DRs for 'significant SLs' such as large SPs (DR 1.8%-2.3% in average-risk screening populations, and dysplastic/large proximal non-dysplastic SLs in an unselected population (DR 2.5% 125 ). Any attempt to set a benchmark for SL-DR needs to take into account that there is considerable variability in the detection rates for individual endoscopists. Results from a single-centre study of 7192 patients undergoing screening colonoscopes by 13 different endoscopists revealed that SSL detection per 100 colonoscopes ranged from 0 in the lowest detector to 2.2 in the highest detector. [bib_ref] Variation in the detection of serrated polyps in an average risk colorectal..., Hetzel [/bib_ref] The detection rate of PSLs ranged from 1% to 18% among 15 different endoscopists at the two US centres in a study of 6681 patients undergoing average-risk screening. [bib_ref] High colonoscopic prevalence of proximal colon serrated polyps in average-risk men and..., Kahi [/bib_ref] The results of these two retrospective studies are supported by a prospective study from the Netherlands of 1426 people undergoing colonoscopic screening; the PSP-DR ranged from 6% to 22% among five different endoscopists. [bib_ref] Differences in proximal serrated polyp detection among endoscopists are associated with variability..., De Wijkerslooth [/bib_ref] While endoscopic skills are undoubtedly important, the detection rates for SLs are also influenced by the quality of pathology reporting. Payne et al have recently reported a multicentre US and German study; detection rates for SLs (defined as SSA/P, SSA with dysplasia or HPs >1 cm in the proximal colon) ranged from 0% to 13.1% among the 32 centres, with four centres reporting no PSLs at all over the 2-year period of the study. Guidance for the pathological diagnosis of SLs has recently been published in the UK 37 and this will be reinforced within the updated Reporting Lesions in the NHS Bowel Cancer Screening Programme document that is due to be published in 2017. We envisage that these publications will help to reduce interobserver variability between pathologists during the assessment of SLs. A high-quality histology report for a SL should include the lesion type (according to the classification system in box 2), size, presence and grade of any dysplasia; and proximity to the diathermy/ stalk margin if this is practically possible. The detection rate may also be influenced by ethnicity as demonstrated in a single-centre, and single endoscopist, study from Australia, which revealed that the SSL-DR was significantly higher in Caucasians when compared with Chinese (7.0% vs 2.0%). [bib_ref] Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians, Kumbhari [/bib_ref] This was also seen in a necropsy study from New Zealand. [bib_ref] Predictors of presence, multiplicity, size and dysplasia of colorectal adenomas. A necropsy..., Jass [/bib_ref] With the caveats mentioned above, it is clear that SLs can be detected at colonoscopy and in view of the importance of the SL pathway in the development of right-sided CRC, setting a quality standard for their detection would be an important step towards reducing the risk of proximal CRC. Kahi et al [bib_ref] High colonoscopic prevalence of proximal colon serrated polyps in average-risk men and..., Kahi [/bib_ref] have attempted to set such a benchmark for proximal SLs; based on a retrospective analysis of two colonoscopy databases, the maximum detection rate was approximately 20% in screening populations. In view of the correlation between the PSL-DR and the ADR, the authors used linear regression to model the relationship between adenoma detection and PSP detection for each endoscopist and to derive PSP detection rates corresponding to ADRs of 25% in men and 15% in women. [bib_ref] Quality in the technical performance of colonoscopy and the continuous quality improvement..., Rex [/bib_ref] The PSL-DR was demonstrated to be 5% for both men and women. Recent Dutch data suggest that the PSP detection rate is strongly correlated with the clinically relevant serrated polyp detection rate (R=0.94), but less so for ADR (R=0.54), supporting PSP detection rate as a benchmark. [bib_ref] The proximal serrated polyp detection rate is an easy-to-measure proxy for the..., Ijspeert [/bib_ref] # Statement 14 We suggest that benchmarking SL detection rates is challenging and affected by case mix, patient ethnicity, histopathological diagnosis and the inclusion of distal SLs; however, endoscopists who wish to assess their PSP detection rate might aim for a detection rate >5% (weak recommendation, low quality evidence, 88% agreement). ## Research questions ▸ What molecular markers predict the future malignant potential of SSPs. ▸ How can we increase accuracy and decrease interobserver variability between pathologists assessing SSPs? ▸ Which technologies and techniques will increase the detection of SLs at colonoscopy? ▸ Will intensive detection, removal and surveillance of proximal SSPs result in significant reduction in mortality from colorectal cancer and all-cause mortality. ▸ What would be the appropriate surveillance interval for proximal SSPs with and without coexisting colorectal cancer and coexisting adenomas. ▸ Is surveillance for SLs cost-effective? ▸ What chemopreventive measures would reduce the development and growth of SLs and associated cancers? ▸ What biomarkers can select patients at high risk of SLs? ▸ How can we integrate SSP into current paradigms for 'optical biopsy' at colonoscopy? ▸ How can training in recognition and resection of SLs be optimised? # Statement 15 We suggest that the current evidence base for clinical decision making for patients with SLs is poor. Clinicians are strongly advised to support prospective studies that will bolster this evidence and avoid empirical management decisions, to allow formal guidelines to be developed (weak recommendation, low quality evidence, 100% agreement). [fig] Figure 2: Serrated surveillance flow chart. [/fig] [fig] Figure 3: colon. Note the adherent mucus cap which aids detection. (B) The same lesion after washing and application of indigocarmine dye-spray to clarify lesion boarders and extent. (C) Lesion lifted with dilute methylene blue in lifting solution providing contrasting background to aid precise resection. (D) Postpolypectomy defect after cold snare piecemeal endoscopic mucosal resection. [/fig] [fig] Figure 4: A) A microvesicular hyperplastic polyp showing serration within the upper half of the lesion and with none of the characteristic features of a sessile serrated lesion (SSL) (magnification ×100). (B) An SSL showing pronounced serration at the crypt base and horizontal spreading of a crypt, forming a typical 'L' or 'boot' shape (magnification ×200). (C) An SSL showing a sharp distinction between areas showing no dysplasia and low-grade dysplasia (magnification ×100). (D) A traditional serrated adenoma (TSA) showing a pronounced villous growth pattern, pencillate nuclei, eosinophilic cytoplasm and ectopic crypt foci (magnification ×200). (Reproduced from Bateman and Shepherd, 37 with permission from BMJ Publishing Group.) [/fig] [table] Table 1: Summary of colonoscopic studies evaluating prevalence and detection rates for serrated lesions [/table] [table] Table 2: Interventions at colonoscopy which may improve serrated lesion detection rates (adapted from East et al68 ) [/table] [table] Table 3: Serrated polyposis syndrome prevalence in population-based screening by modality (adapted from East et al 68 ) [/table]	None	https://gut.bmj.com/content/gutjnl/66/7/1181.full.pdf	Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations—serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and re-evaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement).

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