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Guideline sources The following summarized guidelines for the evaluation and management of follicular lymphoma (FL) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2021), the British Society for Haematology (BSH 2020), the Italian Group for Bone Marrow Transplantation (GITMO/SIES/SIE 2013), and the Spanish Society of Hematology and Hemotherapy (SEHH 2011). 1 2 3 4 Calculator Calculator Calculat Eastern Cooperative Oncology G Follicular Lymphoma Internation Karnof Guidelines 1. Classification and risk stratification Staging: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 1/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, use the Ann Arbor classification system for the initial staging of FL. E As per SIE 2013 guidelines, use the Ann Arbor system for staging FL. E Prognostic scores: As per ESMO 2021 guidelines, consider using the Follicular Lymphoma International Prognostic Index 1/2 and PRIMA prognostic index risk factors for prognostic purposes. E As per SIE 2013 guidelines, assess the Follicular Lymphoma International Prognostic Index prognostic score in all patients with FL. E 2. Diagnostic investigations Imaging for staging: As per ESMO 2021 guidelines: Obtain CT of the neck, chest, and abdomen in the initial evaluation of patients with FL. E Obtain positron emission tomography-CT for routine staging B and to confirm localized stage I/II disease before involved-site radiotherapy. E As per BSH 2020 guidelines, obtain FDG-positron emission tomography/CT before initiating treatment in patients with newly diagnosed FL. Consider obtaining contrast-enhanced CT. E As per SIE 2013 guidelines: Obtain CT of the neck, chest, abdomen, and pelvis in the initial evaluation and staging of patients with FL. Obtain positron emission tomography for staging of patients with a limited- stage disease on CT and possibly being candidates for radiotherapy only. Recognize that FL is a FDG-avid disease and positron emission tomography allows the identification of a higher number of nodal and extranodal areas compared with CT. E Consider obtaining pre-treatment positron emission tomography to allow an optimal assessment of response in patients requiring chemotherapy if an early-stage disease (stage II) and therapy fitness make the probability of complete remission high. E Laboratory evaluation: As per ESMO 2021 guidelines, obtain CBC, routine blood chemistry (including immunoglobulin levels, LDH, -2-microglobulin, and uric acid), and screening tests for human immunodeficiency virus, HBV, and HCV in patients with FL. E As per BSH 2020 guidelines, obtain the following baseline laboratory tests before initiating immunochemotherapy in patients with FL: CBC flow cytometry on blood (or bone marrow aspirate) if peripheral blood lymphocytosis or abnormal lymphocytes are seen on blood film urea, creatinine, and electrolytes LFTs including albumin calcium, phosphate uric acid LDH https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 2/8 6/29/23, 4:07 AM Follicular lymphoma Pathway -2 microglobulin hepatitis B (surface antigen and core antibody), hepatitis C and human immunodeficiency virus. E As per SIE 2013 guidelines, obtain CBC and routine blood chemistry, including LDH, -2 microglobulin, and uric acid in patients with FL. E Show 2 more Cardiac evaluation: as per BSH 2020 guidelines, consider obtaining an ECG and echocardiography before initiating anthracycline-containing chemotherapy in patients aged > 70 years and/or with a history of cardiac disease including ischemic heart disease, hypertension, or diabetes. E 3. Diagnostic procedures Biopsy and histopathology: As per ESMO 2021 guidelines, perform surgical specimen/excisional lymph node biopsy for the diagnosis of FL. Consider performing core biopsies if lymph nodes are not easily accessible. E Show 2 more As per BSH 2020 guidelines, perform bone marrow aspiration and trephine biopsy for staging in patients with newly diagnosed FL. Consider reviewing this after discussion with the patient if it will not alter therapy. Take into consideration the impact of this decision on prognostic score calculations and access to clinical trials. E As per SIE 2013 guidelines, perform a bone marrow biopsy in the initial evaluation and staging of patients with FL. E Show 2 more 4. Medical management General principles: treat FL grade IIIb as an aggressive lymphoma, whereas grades 1, 2, and 3A as an indolent disease. E Management of localized disease, watchful waiting: As per ESMO 2021 guidelines: Consider offering a watch-and-wait strategy or rituximab monotherapy in selected patients with localized (stage I-II) FL. C Offer observation in patients with duodenal-type FL only as long as asymptomatic. B As per BSH 2020 guidelines, consider offering observation without involved-site radiotherapy in patients with limited stage FL undergone localized excision and where there may be concerns by the clinician or patient about radiotherapy to a particular site. E As per GITMO/SIES/SIE 2013 guidelines, do not offer watchful waiting in patients with stage I-II disease, with the exception of patients with a short life expectancy due to severe comorbidity or with contraindications to therapy. D Management of localized disease, involved-site radiotherapy: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 3/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, offer involved-site radiotherapy with a dose of 24-30 Gy as the preferred approach in patients with localized FL, B and consider combining with single- agent rituximab. B As per BSH 2020 guidelines, offer involved-site radiotherapy with a dose of 24 Gy in 12 daily fractions in patients with limited stage FL that can be encompassed within a radiotherapy field. E As per GITMO/SIES/SIE 2013 guidelines, offer external involved-field radiotherapy at the dose of 24 Gy in patients with stage I-II disease, low tumor burden, and with documented contiguity of involved lymph nodes treatable in the same radiotherapy field. B Management of localized disease, systemic therapy: As per ESMO 2021 guidelines, offer systemic therapy (as indicated in patients with advanced stages) in patients with stage I-II FL with a high tumor burden, adverse clinical prognostic features, or if involved-site radiotherapy is not feasible. B As per GITMO/SIES/SIE 2013 guidelines, offer chemoimmunotherapy in patients with stage II disease when there is a high tumor burden or a high-risk scoring system. B Management of advanced disease, general principles: As per BSH 2020 guidelines: Consider offering enrolment in a clinical trial, if available. E Assess the GELF criteria in all patients with advanced stage FL to assess the requirement of treatment. E As per GITMO/SIES/SIE 2013 guidelines, consider initiating treatment in patients with stage II-IV disease in case of any of the following: systemic symptoms high tumor burden (> 3 lymph nodes measuring > 3 cm or a single lymph node > 7 cm) extranodal disease cytopenia due to marrow involvement spleen involvement ( 16 cm by CT) leukemic phase serous effusion symptomatic or life-endangering organ involvement rapid lymphoma progression consistently increased LDH levels. E Management of advanced disease, watchful waiting: As per ESMO 2021 guidelines, offer a watch-and-wait strategy as a standard approach in patients with asymptomatic advanced (stage III-IV) FL. A As per BSH 2020 guidelines, consider offering observation alone or rituximab monotherapy in patients with asymptomatic, advanced-stage FL. E As per GITMO/SIES/SIE 2013 guidelines, offer watchful waiting as the standard of care in patients with asymptomatic, stage II-IV, non-bulky disease. B Management of advanced disease, induction of remission: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 4/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, initiate therapy only upon the development of symptoms, including B symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion, or rapid lymphoma progression. A Show 4 more As per BSH 2020 guidelines: Consider offering induction rituximab monotherapy in patients with asymptomatic, advanced-stage FL. E Offer rituximab or obinutuzumab with chemotherapy in patients requiring treatment. Decide on the chemotherapy options with which the antibody should be paired (such as bendamustine, chlorambucil, CHOP, CVP) depending on patient factors and clinician choice. E As per GITMO/SIES/SIE 2013 guidelines, offer front-line chemoimmunotherapy in patients with stage III-IV disease. B Show 3 more Management of advanced disease, maintenance of remission: As per ESMO 2021 guidelines: Offer rituximab maintenance every 2 months for 2 years after immunochemotherapy. B Consider offering radioimmunotherapy consolidation after chemotherapy as an alternative. B Do not offer myeloablative consolidation followed by ASCT after chemotherapy as first-line therapy in responding patients. D As per BSH 2020 guidelines: Consider offering rituximab or obinutuzumab (whichever antibody was used in induction) maintenance for a period of 2 years in patients responding to therapy (partial or complete response) after discussing the risks and benefits with the patient. E Do not offer high-dose therapy with ASCT as first-line therapy in patients with FL. D As per GITMO/SIES/SIE 2013 guidelines, offer maintenance therapy with rituximab in patients reaching at least a partial response at the end of first-line therapy. A 5. Preventative measures Antibiotic prophylaxis: administer adequate prophylaxis (antibiotics and/or IgG) in patients with symptomatic recurrent infections based on prior treatment (such as with fludarabine or bendamustine). E Routine immunizations: consider offering annual seasonal influenza vaccination in patients with FL. E 6. Follow-up and surveillance Serial clinical assessment: As per ESMO 2021 guidelines: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 5/8 6/29/23, 4:07 AM Follicular lymphoma Pathway Obtain clinical monitoring every 6 months for 2 years after local radiotherapy, and once a year subsequently if clinically indicated. E Obtain clinical monitoring every 3-6 months for 2 years after (during continuous) systemic treatment, and every 6-12 months subsequently. B As per BSH 2020 guidelines, obtain regular clinical assessments modified according to the disease behavior. E Serial laboratory assessment: As per ESMO 2021 guidelines: Obtain CBC and routine chemistry including IgG levels every 6 months for 2 years, thereafter only as needed for evaluation of suspicious symptoms. E Obtain evaluation of thyroid function at 1, 2, and 5 years after neck irradiation. E As per BSH 2020 guidelines: Consider obtaining CBC, urea, creatinine, and LFTs at each clinical visit. Do not measure LDH levels routinely. E Obtain annual thyroid function testing in patients undergone neck irradiation. E As per SIE 2013 guidelines, do not obtain routine assessments of molecular response. D Serial imaging assessment: As per ESMO 2021 guidelines: Obtain minimal adequate radiological or other examinations every 6 months for 2 years, and optionally annually up to 5 years. B Avoid obtaining regular CT outside of clinical trials, and do not obtain positron emission tomography-CT for surveillance. D As per BSH 2020 guidelines, obtain post-treatment cross-sectional imaging only in case of suspicion of relapse requiring treatment (such as clinically significant lymphadenopathy not attributable to another cause, or B symptoms). E As per SIE 2013 guidelines: Insufficient evidence to recommend interim positron emission tomography for guiding treatment decisions. I Do not obtain routine positron emission tomography for follow-up. D Assessment of minimal residual disease: consider obtaining minimal residual disease screening in a clinical trial setting but not for guiding therapeutic strategies in clinical practice. E Management of relapse, biopsy: As per ESMO 2021 guidelines, perform a new confirmatory biopsy in patients with suspected disease relapse or progression. E As per BSH 2020 guidelines, perform biopsy, wherever practicable, to assess for high-grade transformation in patients with suspected relapsed FL. E Management of relapse (watchful waiting): consider offering observation alone in asymptomatic patients with relapsed disease lacking standard indications for therapy. E Management of relapse, radiotherapy: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 6/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, consider offering low-dose involved-site radiotherapy (2 2 Gy) for the management of patients with localized symptomatic disease. E As per BSH 2020 guidelines, consider offering low-dose radiotherapy for symptom control in patients with relapse. E Management of relapse, systemic therapy: As per ESMO 2021 guidelines, offer a non-cross-resistant regimen in early systemic relapses (< 12-24 months). E Show 8 more As per BSH 2020 guidelines, consider offering enrolment in a clinical trial, especially in patients with early progression following primary therapy. E Show 7 more As per GITMO/SIES/SIE 2013 guidelines, add rituximab to chemotherapy as reinduction if there is no evidence of resistance to rituximab in fit patients relapsing after first-line chemoimmunotherapy and requiring treatment. B Show 2 more Management of relapse, stem cell transplantation: As per ESMO 2021 guidelines, consider offering allo-SCT in selected younger patients with later relapses with a high-risk profile or relapse after ASCT. C As per BSH 2020 guidelines, consider offering early referral for transplantation in fit patients with shorter durations of response following first-line therapy. E Show 7 more As per GITMO/SIES/SIE 2013 guidelines, offer ASCT is recommended in young (< 65 years old) fit patients relapsing within 12 months from the end of front-line chemoimmunotherapy and achieving a response to chemoimmunotherapy reduction. E Show 2 more Clinical findings Symptoms Past medical history Fatigue Gastrointestinal bleeding Fever Abdominal exam Night sweats Weight loss Ascites Hepatomegaly Head and neck exam Palpable abdominal mass Neck mass Splenomegaly Lymphatic exam Lab findings Axillary lymphadenopathy serum LDH Cervical lymphadenopathy Imaging findings Femoral lymphadenopathy Inguinal lymphadenopathy Epidural mass https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 7/8 6/29/23, 4:07 AM Follicular lymphoma Pathway Lymphadenopathy Hilar lymphadenopathy Mediastinal lymphadenopathy Hematological findings Pleural effusion Spinal cord compression Anemia blood leukocyte count blood platelet count Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. References 1. M Dreyling, M Ghielmini, S Rule et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Mar;32 3 298 308. Open 2. Armando L pez-Guillermo, Dolores Caballero, Miguel Canales et al. Clinical practice guidelines for first-line/after-relapse treatment of patients with follicular lymphoma. Leuk Lymphoma. 2011 Dec;52 Suppl 3 1 14. Open 3. Christopher McNamara, Silvia Montoto, Toby A Eyre et al. The investigation and management of follicular lymphoma. Br J Haematol. 2020 Nov;191 3 363 381. Open 4. Pier Luigi Zinzani, Monia Marchetti, Atto Billio et al. SIE, SIES, GITMO revised guidelines for the management of follicular lymphoma. Am J Hematol. 2013 Mar;88 3 185 92. Open 5. Qiushi Chen, Turgay Ayer, Loretta J Nastoupil et al. Initial management strategies for follicular lymphoma. Int J Hematol Oncol. 2012 Oct; 1 1 35 45. Open 6. M Hutchings, M Ladetto, C Buske et al. ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients. Ann Oncol. 2018 Aug 1;29 8 1687 1700. Open 7. Abraham S Kanate, Ambuj Kumar, Peter Dreger et al. Maintenance Therapies for Hodgkin and Non- Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol. 2019 May 1;5 5 715 722. Open 8. Steven H Kroft, Cordelia E Sever, Adam Bagg et al. Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists. Arch Pathol Lab Med. 2021 Mar 1;145 3 269 290. Open 9. C Buske, M Hutchings, M Ladetto et al. ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018 Mar 1;29 3 544 562. Open 10. Philippe Solal-C ligny, Pascal Roy, Philippe Colombat et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1;104 5 1258 65. Open https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 8/8

Guideline sources The following summarized guidelines for the evaluation and management of food allergy are prepared by our editorial team based on guidelines from the European Academy of Allergy and Clinical Immunology (EAACI 2014). 1 2 2 2 3 4 Definition Food allergy is an adverse food-stimulated immune response initiated on exposure to a given food. 2 Epidemiology Food allergy is mostly caused by IgE-mediated antibodies (type 1 or early; 48%) and IgE- independent immune response including type IV (18%), type III (10%), and type II (6%) to specific foods (milk, eggs, wheat, fish, soy, peanuts, fish, shellfish, cherries, peaches, plums, apricots, nuts, and seeds) influenced by genetic and environmental (improved hygiene, lifestyle, diet and nutrition) factors. 2 Pathophysiology The prevalence of IgE-mediated food allergy in the United States is estimated at 10,000 in 100,000 adults. 3 Disease course https://web.pathway.md/diseases/recx9BemsByRO8E4B 1/6 6/29/23, 4:07 AM Food allergy Pathway Clinical manifestations of an immediate reaction include anaphylactic shock, urticaria, and angioedema. Late reaction food reaction symptoms include fatigue, irritability, depression, hyperactivity, insomnia, headache, poor concentration, paleness, itching limbs, involuntary bedwetting, asthma, colds, indigestion, colic, diarrhea, bloating, and skin lesions. The disease impairs quality of life necessitating lifelong prevention of the specific food. 2 Prognosis and risk of recurrence The mortality risk associated with fatal anaphylaxis is < 1%. 4 Guidelines 1. Diagnostic investigations Clinical history: obtain a detailed clinical history to evaluate patients with suspected food allergy, eliciting allergens, timing and chronicity, symptoms, severity and signs, reproducibility, known risk factors, family history, and coexisting medical problems, including other allergic diseases. B Evaluation for cofactors: assess the potential role of cofactors such as exercise, NSAIDs, omeprazole, or alcohol intake. B Specific allergy testing: Direct specific allergy testing according to clinical history, as IgE sensitization does not always predict clinically relevant food allergy. B Consider either skin prick testing or specific serum IgE testing to assess for specific allergens, depending on local availability as well as potential contraindications to skin prick testing. C Serum total IgE testing: consider obtaining serum total IgE in patients with severe eczema, a very high total IgE level suggests that positive specific IgE results should be interpreted with care, as they may represent asymptomatic sensitization. C Component-resolved diagnostic tests: consider component-resolved diagnostic tests in patients in whom skin prick test and specific serum IgE tests are inconclusive. C Oral food challenge: Perform an oral food challenge if clinical history with skin prick test and/or serum IgE results is not highly predictive. B Perform oral food challenges in a specialist setting, with emergency support immediately available. B Unconventional tests: avoid the use of unconventional tests as an alternative or complementary diagnostic tool in the workup of suspected food allergy. D 2. Medical management General principles: Identify patients at risk of severe reactions in a prompt manner. B https://web.pathway.md/diseases/recx9BemsByRO8E4B 2/6 6/29/23, 4:07 AM Food allergy Pathway Assess patients who have received adrenaline in the emergency department. B Symptomatic therapy: consider antihistamines for children and adults with acute non-life- threatening symptoms from food allergy. C Show 2 more Adrenaline autoinjector: Provide a prescription for an adrenaline autoinjector to patients with any of the following: previous anaphylaxis to any food food allergy associated with persistent or severe asthma exercise-induced food-dependent anaphylaxis. B Self-administered corticosteroids: consider providing a prescription for patient-held corticosteroids, to be administered in the case of an allergic reaction in order to prevent late- phase respiratory symptoms. C Specific immunotherapy: avoid routine clinical use of food allergen-specific immunotherapy for primary food allergy, because it is associated with risk of adverse reactions, including anaphylaxis. D Anti-IgE therapy: avoid the use of anti-IgE alone or in combination with specific immunotherapy for the treatment of food allergy. D 3. Nonpharmacologic interventions Elimination diets: Advise avoidance of dietary triggers as the key treatment in the management of food allergy. B Continue elimination diets until provocation tests are performed in patients in whom the elimination diet leads to a significant relief of symptoms. B Probiotics: avoid prescribing probiotic supplements for the management of food allergy. D 4. Specific circumstances Patients with coexisting asthma: include short-acting -agonists in the management plan for all patients with coexisting asthma, to be initiated for bronchospasm after adrenaline has been given. B Patients with cow's milk allergy: advise the consumption of extensively hydrolyzed cow's milk formulas in patients with cow's milk allergy, especially in infants and young children. Consider advising amino acid formulas, especially for the subgroup of patients with more severe symptoms. A Pediatric patients: avoid prescribing soy formulas before 6 months of age and at any age in the presence of gastrointestinal symptoms. From 6 to 12 months, consider it on a case-by- case basis. D 5. Patient education https://web.pathway.md/diseases/recx9BemsByRO8E4B 3/6 6/29/23, 4:07 AM Food allergy Pathway General counseling: educate patients and caregivers regarding which foods should be avoided, give practical advice on avoidance measures, and provide teaching on how to recognize and treat allergic reactions. B 6. Follow-up and surveillance Assessment of treatment response: perform oral food challenges at regular intervals in order to assess achievement of tolerance. B Indications for dietitian referral: refer patients on long-term elimination diets to a dietitian for appropriate counseling. B Indications for specialist referral: refer patients with eosinophilic esophagitis to an allergist/immunologist for diagnostic evaluation. B Clinical findings Symptoms Past medical history Abdominal pain Allergic reactions Chronic diarrhea Anaphylaxis Dizziness Asthma Dysphagia Atopic dermatitis Itching in the mouth Atopy Itchy nose, mouth, eyes, throat, skin Integument exam Nausea Angioedema Raised, itchy red rash Sneezing Swelling Vomiting Respiratory exam Dyspnea Wheezing References 1. Muraro A, Werfel T, Hoffmann-Sommergruber K et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014 Aug;69 8 1008 25. Open 2. Wioletta Agnieszka Zukiewicz-Sobczak, Paula Wr blewska, Piotr Adamczuk et al. Causes, symptoms and prevention of food allergy. Postepy Dermatol Alergol. 2013 Apr;30 2 113 6. Open 3. Christopher M Warren, Jialing Jiang, Ruchi S Gupta. Epidemiology and Burden of Food Allergy. Curr Allergy Asthma Rep. 2020 Feb 14;20 2 6. Open https://web.pathway.md/diseases/recx9BemsByRO8E4B 4/6 6/29/23, 4:07 AM Food allergy Pathway 4. Paul J Turner, Elina Jerschow, Thisanayagam Umasunthar et al. Fatal Anaphylaxis: Mortality Rate and Risk Factors. J Allergy Clin Immunol Pract. Sep-Oct 2017;5 5 1169 1178. Open 5. Muraro A, Halken S, Arshad SH et al. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy. 2014 May;69 5 590 601. Open 6. Pajno GB, Fernandez-Rivas M, Arasi S et al. EAACI Guidelines on allergen immunotherapy: IgE- mediated food allergy. Allergy. 2018 Apr;73 4 799 815. Open 7. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2014. Open 8. Gideon Lack. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012 May;129 5 1187 97. Open 9. Ruchi S Gupta, Christopher M Warren, Bridget M Smith et al. Prevalence and Severity of Food Allergies Among US Adults. JAMA Netw Open. 2019 Jan 4;2 1):e185630. Open 10. Jessica Savage, Christina B Johns. Food allergy: epidemiology and natural history. Immunol Allergy Clin North Am. 2015 Feb;35 1 45 59. Open 11. Ruchi S Gupta, Christopher M Warren, Bridget M Smith et al. The Public Health Impact of Parent- Reported Childhood Food Allergies in the United States. Pediatrics. 2018 Dec;142 6):e20181235. Open 12. Sheriene Moussa Afify, Isabella Pali-Sch ll. Adverse reactions to food: the female dominance A secondary publication and update. World Allergy Organ J. 2017 Dec 27;10 1 43. Open 13. Elissa M Abrams, Scott H Sicherer. Diagnosis and management of food allergy. CMAJ. 2016 Oct 18;188 15 1087 1093. Open 14. American Academy of Allergy, Asthma & Immunology. Choosing Wisely AAAAI recommendations. Choosing Wisely. 2012. Open 15. Jihyun Kim, Eunyoung Chang, Youngshin Han et al. The incidence and risk factors of immediate type food allergy during the first year of life in Korean infants: a birth cohort study. Pediatr Allergy Immunol. 2011 Nov;22 7 715 9. Open 16. David M Fleischer, Edmond S Chan, Carina Venter et al. A Consensus Approach to the Primary Prevention of Food Allergy Through Nutrition: Guidance from the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and the Canadian Society for Allergy and Clinical Immunology. J Allergy Clin Immunol Pract. 2021 Jan;9 1 22 43.e4. Open 17. Cristina A Carter, Michael Pistiner, Julie Wang et al. Food Allergy in Restaurants Work Group Report. J Allergy Clin Immunol Pract. 2020 Jan;8 1 70 74. Open 18. Hugh A Sampson, Seema Aceves, S Allan Bock et al. Food allergy: a practice parameter update- 2014. J Allergy Clin Immunol. 2014 Nov;134 5 1016 25.e43. Open 19. Margitta Worm, Imke Reese, Barbara Ballmer-Weber et al. Guidelines on the management of IgE- mediated food allergies: S2k-Guidelines of the German Society for Allergology and Clinical Immunology DGAKI in collaboration with the German Medical Association of Allergologists AeDA , the German Professional Association of Pediatricians BVKJ , the German Allergy and Asthma Association DAAB , German Dermatological Society DDG , the German Society for Nutrition DGE , the German Society for Gastroenterology, Digestive and Metabolic Diseases DGVS , the German Society for Oto-Rhino- Laryngology, Head and Neck Surgery, the German Society for Pediatric and Adolescent Medicine DGKJ , the German Society for Pediatric Allergology and Environmental Medicine GPA , the German Society for Pneumology DGP , the German Society for Pediatric Gastroenterology and Nutrition https://web.pathway.md/diseases/recx9BemsByRO8E4B 5/6 6/29/23, 4:07 AM Food allergy Pathway GPGE , German Contact Allergy Group DKG , the Austrian Society for Allergology and Immunology GAI , German Professional Association of Nutritional Sciences VDOE and the Association of the Scientific Medical Societies Germany AWMF . Allergo J Int. 2015;24 256 293. Open https://web.pathway.md/diseases/recx9BemsByRO8E4B 6/6

Guideline sources The following summarized guidelines for the evaluation and management of foodborne illness are prepared by our editorial team based on guidelines from the American Association of Family Physicians (AAFP 2015). 1 Guidelines 1. Diagnostic investigations Stool culture: obtain stool cultures as a diagnostic standard for patients with bacterial foodborne illness. However, culture results are positive in < 40% of cases. B 2. Medical management Ondansetron: administer a single dose of ondansetron in pediatric patients with clinically significant gastroenteritis-related vomiting. A Oral rehydration therapy: initiate oral rehydration therapy for the prevention and treatment of dehydration in patients of all ages. A Empiric antibiotics: consider empiric antibiotic therapy in cases of suspected foodborne illness if the patient is febrile and has signs of invasive disease, if symptoms have persisted for > 1 week or are severe, or if hospitalization may be required. C References https://web.pathway.md/diseases/recobywkhiqSBls3T 1/2 6/29/23, 4:07 AM Foodborne illness Pathway 1. Timothy L Switaj, Kelly J Winter, Scott R Christensen. Diagnosis and Management of Foodborne Illness. Am Fam Physician. 2015 Sep 1;92 5 358 65. Open https://web.pathway.md/diseases/recobywkhiqSBls3T 2/2

Guideline sources The following summarized guidelines for the evaluation and management of fournier's gangrene are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022), the World Society of Emergency Surgery (WSES/AAST 2021), the Surgical Infection Society Europe (SIS-E/WSES 2018), the Eastern Association for the Surgery of Trauma (EAST 2018), and the Infectious Diseases Society of America (IDSA 2014). 1 2 3 4 5 Calculator Laboratory Risk Indicator for Ne Guidelines 1. Classification and risk stratification Risk stratification: consider using Laboratory Risk Indicator for Necrotising Fasciitis score for an early diagnosis and Fournier's Gangrene Severity Index for prognosis and risk stratification https://web.pathway.md/diseases/rect5iux52FsxdhU2 1/5 6/29/23, 4:07 AM Fournier's gangrene Pathway of patients with suspected Fournier's gangrene. C 2. Diagnostic investigations Clinical examination: consider eliciting a focused medical history and performing a physical examination, including DRE, in patients with suspected Fournier's gangrene. C Laboratory tests: Consider obtaining the following laboratory tests to assess the status of patients with suspected Fournier's gangrene and signs of systemic infection or sepsis: CBC inflammatory markers (such as, CRP, procalcitonin) serum creatinine electrolytes blood gas analysis. C Show 2 more Computed tomography: Consider obtaining CT in stable patients with suspected Fournier's gangrene. C Do not obtain CT in patients with Fournier's gangrene and hemodynamic instability persisting after proper resuscitation. D 3. Medical management Hemodynamic support: initiate prompt appropriate hemodynamic support in patients with Fournier's gangrene. B Antibiotic therapy: As per EAU 2022 guidelines, initiate broad-spectrum antibiotics in patients with Fournier's gangrene at presentation, with subsequent refinement according to culture and clinical response. A As per AAST 2021 guidelines, initiate empiric antimicrobial therapy as soon as the diagnosis of Fournier's gangrene is suspected. B Show 2 more As per WSES 2018 guidelines, initiate prompt appropriate antibiotic therapy in patients with Fournier's gangrene. B As per IDSA 2014 guidelines: Initiate broad-spectrum empiric antibiotic therapy (such as vancomycin or linezolid plus piperacillin-tazobactam or a carbapenem, or plus ceftriaxone and metronidazole) in patients with suspected or documented necrotizing fasciitis, including coverage for aerobes, anaerobes, group A streptococci, and MRSA. B Administer penicillin plus clindamycin in patients with documented group A streptococcal necrotizing fasciitis. B https://web.pathway.md/diseases/rect5iux52FsxdhU2 2/5 6/29/23, 4:07 AM Fournier's gangrene Pathway Adjunctive treatment: do not use adjunctive treatments (such as hyperbaric oxygen therapy, negative-pressure therapy, or honey-soaked dressings) in patients with Fournier's gangrene except in the context of clinical trials. D 4. Surgical interventions Surgical management (general principles): Consider planning surgical management of early and delayed surgical sequelae in patients with Fournier's gangrene with a multidisciplinary and skilled team. C Consider using a multidisciplinary and tailored approach based upon the extent of perineal involvement, the degree of fecal contamination, and the possible presence of sphincter or urethral damage. C Surgical management, timing: As per AAST/WSES 2021 guidelines: Perform surgical intervention in patients with Fournier's gangrene as soon as possible. B Do not delay surgical intervention because of the imaging. D As per EAST 2018 guidelines, perform early initial debridement within 12 hours of diagnosis in patients with necrotizing soft tissue infection. B As per SIS-E/WSES 2018 guidelines, perform early and extensive initial surgical debridement to improve survival in patients with Fournier's gangrene. B Surgical management, technique: As per AAST/WSES 2021 guidelines: Consider removing all necrotic tissue. C Consider performing orchiectomy or other genital surgery only if strictly necessary and possibly based on a urologic consultation. C As per SIS-E/WSES 2018 guidelines, consider performing fecal diversion, either by colostomy or fecal tube system with or without negative pressure therapy, in cases of Fournier's gangrene with fecal contamination. C Surgical management, revision: As per EAU 2022 guidelines, perform repeated surgical debridement within 24 hours of presentation. A As per AAST/WSES 2021 guidelines: Consider planning repeat surgical revisions (exploration and debridement) according to patient conditions. C Consider performing seriated surgical revisions until the patient is free of necrotic tissue. C 5. Specific circumstances Patients with urosepsis: use the qSOFA score to identify patients with potential sepsis. A Show 5 more https://web.pathway.md/diseases/rect5iux52FsxdhU2 3/5 6/29/23, 4:07 AM Fournier's gangrene Pathway 6. Follow-up and surveillance Indications for surgical consultation: obtain prompt surgical consultation for patients with aggressive infections associated with signs of systemic toxicity or suspicion of necrotizing fasciitis or gas gangrene. B Clinical findings Symptoms Past medical history Fever Immunocompromising condition Sepsis Vital signs Neurological exam Hypotension Signs of shock Altered mental status Tachycardia Lab findings Integument exam ESR Gangrene blood glucose Hemorrhagic bullae serum CRP Skin blisters serum creatinine Skin crepitus serum sodium Skin erythema Skin induration Skin tenderness Skin ulceration Tissue necrosis Hematological findings WBC count Studies 2017 INSTINCT In ICU patients with necrotizing soft tissue infection, intravenous polyspecific IgG was not superior to placebo with respect to physical component summary score at 6 m. Martin B Madsen et al. Intensive Care Med. 2017 Nov. References 1. Antonio Tarasconi, Gennaro Perrone, Justin Davies et al. Anorectal emergencies: WSES AAST guidelines. World J Emerg Surg. 2021 Sep 16;16 1 48. Open 2. Sartelli M, Guirao X, Hardcastle TC et al. 2018 WSES/SIS E consensus conference: recommendations for the management of skin and soft-tissue infections. World J Emerg Surg. 2018 Dec 14;13 58. Open https://web.pathway.md/diseases/rect5iux52FsxdhU2 4/5 6/29/23, 4:07 AM Fournier's gangrene Pathway 3. G. Bonkat, R. Bartoletti, F. Bruy re et al. EAU Guidelines on Urological Infections. EAU. 2022. Open 4. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59 2):e10 52. Open 5. Rondi B Gelbard, Paula Ferrada, D Dante Yeh et al. Optimal timing of initial debridement for necrotizing soft tissue infection: A Practice Management Guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2018 Jul;85 1 208 214. Open https://web.pathway.md/diseases/rect5iux52FsxdhU2 5/5

Guideline sources The following summarized guidelines for the evaluation and management of frostbite are prepared by our editorial team based on guidelines from the Wilderness Medical Society (WMS 2019; 2012) and the American College of Chest Physicians (ACCP 2014). 1 2 3 Guidelines 1. Diagnostic investigations Diagnostic imaging: As per WMS 2019 guidelines: Obtain noninvasive imaging with technetium pyrophosphate or MRA, if available, at an early stage in patients with delayed presentation of frostbite (4-24 hours from the time of the frostbite thawing) to assess tissue viability and guide timing and extent of amputation. B Consider obtaining angiography, technetium-99 bone scan and/or MRI, in conjunction with clinical findings, to assist in determining surgical margins. B As per ACCP 2014 guidelines: https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 1/8 6/29/23, 4:07 AM Frostbite Pathway Obtain angiography and/or technecium-99 triple-phase bone scan in patients with deep injuries to assist in directing therapy and for prognostic purposes. B Obtain repeated angiography every 12-24 hours to evaluate the response to therapy. B 2. Respiratory support Suplemental oxygen: Do not administer routine supplemental oxygen in non-hypoxic patients. D Consider administering supplemental oxygen in the field delivered by face mask or nasal cannula in patients with hypoxia (oxygen saturation < 88%) or at high altitude (> 4,000 m). C Hyperbaric oxygen therapy: As per WMS 2019 guidelines, insufficient evidence to recommend hyperbaric oxygen therapy for the treatment of patients with frostbite. I As per ACCP 2014 guidelines, insufficient evidence to recommend the routine use of hyperbaric oxygen therapy for the treatment of patients with frostbite. I 3. Medical management Setting of care: As per WMS 2019 guidelines, decide on hospital admission and discharge on an individual basis, including factors such as severity of the injury, coexisting injuries, comorbidities, and need for hospital-based interventions (tPA, vasodilators, surgery) or supportive therapy, as well as ease of access to appropriate community medical and nursing support. B Show 3 more As per ACCP 2014 guidelines, obtain full reassessment of patients on arrival to a hospital setting. Assess and manage underlying unstable comorbidities, trauma or hypothermia before initiating treatment for frostbitten extremities. B Hydration: As per WMS 2019 guidelines, administer fluids both in hospital and field clinic to prevent clinical dehydration. B Show 4 more As per ACCP 2014 guidelines: Administer oral or IV rehydration depending on the severity and ability of the patient to tolerate oral fluids. B Administer warmed IV fluids in patients with hypothermia, as dehydration may be compounded by cold diuresis due to suppression of ADH. B Analgesics: As per WMS 2019 guidelines, administer ibuprofen in the field at a dose of 12 mg/kg/day divided BID to a maximum of 2,400 mg/day divided QID. B Show 2 more https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 2/8 6/29/23, 4:07 AM Frostbite Pathway As per ACCP 2014 guidelines, consider administering aspirin 75 mg for its rheologic effect. C Show 3 more Thrombolytic therapy: As per WMS 2019 guidelines, obtain a risk(cid:0)/benefit analysis when considering thrombolytic therapy. Consider administering thrombolytic therapy only in patients with deep injuries with potential for significant morbidity (such as extending into the proximal interphalangeal joints of digits). Show 4 more As per ACCP 2014 guidelines: Recognize that recombinant tPA is contraindicated in trauma and its efficacy is reduced if used beyond 24 hours. B Discontinue recombinant tPA when perfusion is restored to distal vessels or at 48 hours if no improvement is observed. B Heparin: Insufficient evidence to support the use of LMWH or UFH for initial management of patients with frostbite in the field or hospital/field clinic. I Consider administering heparin 500 units/hours as adjunctive therapy in tPA protocols. B Low molecular weight dextran: consider administering warmed IV low molecular weight dextran both in the field and hospital/field clinic to decrease blood viscosity by preventing RBC aggregation and formation of microthrombi. C Show 2 more Vasodilators: As per WMS 2019 guidelines, consider administering IV iloprost as first-line therapy in patients with grade 3-4 frostbite within < 72 hours after injury, if tPA is contraindicated, and in austere environments where tPA infusion is considered risky or evacuation to a treatment facility will be delayed. B Show 3 more As per ACCP 2014 guidelines, consider administering iloprost if there is a history of trauma or if the exposure occurred over 24 hours ago. B Antibiotics: As per WMS 2019 guidelines, administer systemic antibiotics, either oral or parenteral, in the hospital/field clinic in patients with significant trauma, other potential infectious sources, or signs and symptoms of cellulitis or sepsis. B As per ACCP 2014 guidelines: Consider administering prophylactic antibiotics in patients with severe injuries (grades 3-4), particularly if associated with significant edema or malnutrition (homeless, chronic alcohol abuse or return from extreme altitude). B Administer systemic antibiotics in patients with proven infection, trauma and cellulitis. B Management of hypothermia: As per WMS 2019 guidelines, treat moderate and severe hypothermia before initiating treatment for frostbite injury, both in the field and hospital/field clinic. Consider treating mild https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 3/8 6/29/23, 4:07 AM Frostbite Pathway hypothermia concurrently with the frostbite injury, both in the field and hospital/field clinic. B As per ACCP 2014 guidelines, treat moderate or severe hypothermia to > 35 C before initiating frostbite warming. B Management of corneal frostbite: offer artificial tears, topical antibiotics, topical NSAIDs, and cycloplegics in patients with corneal frostbite. B 4. Nonpharmacologic interventions Protection: As per WMS 2019 guidelines, protect the frozen tissue from further damage if a body part is frozen in the field. Remove jewelry or other constrictive extraneous material from the body part. Do not rub or apply ice or snow to the affected area. Show 7 more As per ACCP 2014 guidelines, move patients with frostbite out of the wind, provide shelter and give warm fluids. B Show 4 more Passive thawing: As per WMS 2019 guidelines, allow frozen tissue to thaw if environmental and situational conditions allow for spontaneous or slow thawing. B Show 4 more As per ACCP 2014 guidelines, recognize that the decision to thaw the frostbitten tissue in the field commits to a course of action, including pain control, maintaining warm water baths at a constant temperature, protecting tissue from further injury during rewarming and eventual transport. Consider letting patients to walk on a frozen limb to safety rather than risk refreezing in extreme circumstances. B Active rewarming: As per WMS 2019 guidelines, initiate field rewarming as follows only if the frozen part can be kept thawed and warm until the patient arrives at definitive care: perform field rewarming by warm water bath immersion if the proper resources are available and definitive care is > 2 hours distant; avoid using other heat sources (such as fire, space heater, oven, heated rocks) because of the risk of thermal burn injury heat the water to 37-39 C (98.6-102.2 F), using a thermometer to maintain this range; determine a safe water temperature by placing a caregiver's uninjured hand in the water for at least 30 seconds to confirm that the water temperature is tolerable and will not cause burn injury, if a thermometer is not available consider circulating water around the frozen tissue to help maintain correct temperature warm the water continuously and carefully to the target temperature, as the water may cool quickly after the rewarming process is started avoid pressing skin press against the bottom or sides of the pot if the frozen part is being rewarmed in a pot complete rewarming when the involved part takes on a red or purple appearance and becomes soft and pliable to the touch, a process usually accomplished in approximately 30 minutes, but varying depending on the extent and depth of injury https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 4/8 6/29/23, 4:07 AM Frostbite Pathway allow the affected tissues to air dry or gently dry with a blotting technique (not rubbing) to minimize further damage. B Show 4 more As per ACCP 2014 guidelines, initiate field rewarming only if there is no further risk of refreezing. Recognize that tissue that thaws then refreezes results in more extensive injury. B Show 3 more Aloe vera: As per WMS 2019 guidelines: Consider applying topical aloe vera to thawed tissue in the field before application of dressings. C Apply topical aloe vera cream or gel to the thawed tissue in the hospital/field clinic before applying dressings. Reapply topical aloe vera cream or gel at each dressing change, or every 6 hours. B As per ACCP 2014 guidelines, apply topical aloe vera cream or gel (a potent antiprostaglandin agent) to thawed tissue before applying dressings. B Hydrotherapy: insufficient evidence to recommend specific temperature, timing, or duration of hydrotherapy for the treatment of patients with forstbite after thawing. I 5. Surgical interventions Dressing: As per WMS 2019 guidelines, insufficient evidence to support applying a dressing to a frostbitten part intended to remain frozen until rewarming can safely be achieved. I Show 2 more As per ACCP 2014 guidelines: Obtain detailed assessment of severe injuries. Consider appraising and debriding blisters under general anesthesia. B Splint, elevate and wrap the affected part in a loose, protective dressing with padding between affected digits. B Debridement: As per WMS 2019 guidelines: Do not perform routine debridement of blisters in the field. Perform aspiration of blisters and apply dry gauze dressing in the field to minimize infection risk if a clear, fluid-filled blister is tense and at high risk for rupture during evacuation. Do not aspirate or debride hemorrhagic bullae in the field. D Consider debriding or aspirating clear, cloudy, or tense blisters in the hospital/field clinic at the discretion of the treating provider, with consideration of patient circumstances. C As per ACCP 2014 guidelines, do not perform debridement in patients with deep injuries until imaging is performed. D Fasciotomy: https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 5/8 6/29/23, 4:07 AM Frostbite Pathway As per WMS 2019 guidelines, perform prompt surgical decompression for limb salvage in patients elevated compartment pressures. B As per ACCP 2014 guidelines, perform post-thaw fasciotomy if reperfusion is compromised by compartment syndrome. B Sympathectomy: As per WMS 2019 guidelines, insufficient evidence to recommend surgical sympathectomy for the treatment of patients with frostbite. I As per ACCP 2014 guidelines, consider performing sympathectomy with a great caution for the management of long-term sequelae of frostbite, such as pain (often due to vasospasm), paresthesias and hyperhidrosis, recognizing that it is irreversible and the availability of alternative IV vasodilators. Amputation: As per WMS 2019 guidelines: Perform expeditious amputation if the patient develops signs and symptoms of sepsis attributed to infected frostbitten tissue. Delay amputation if otherwise until definitive demarcation occurs, a process that may take weeks to months. B Assess the need for and the timing of any amputations by a surgeon with experience evaluating and treating frostbite. Consider obtaining a telemedicine or electronic consultation with a surgical frostbite expert to guide local surgeons with amputation when no local expert is available. B As per ACCP 2014 guidelines, avoid performing immediate amputation unless there is wet gangrene, liquefaction, overwhelming infection or spreading sepsis, recognizing that premature amputation increases morbidity and is likely to lead to poor subsequent function. D 6. Preventative measures Protection from cold: Advise the following measures to minimize the exposure of tissue to cold to prevent frostbite: avoiding environmental conditions predisposing to frostbite, specifically < -15 C or 5 F, even with low wind speeds protecting skin from moisture, wind, and cold avoiding perspiration or wet extremities increasing insulation and skin protection (such as adding clothing layers, changing from gloves to mitts) ensuring beneficial behavioral responses to changing environmental conditions (such as not being under the influence of illicit drugs, alcohol, or extreme hypoxemia) using chemical hand and foot warmers and electric foot warmers to maintain peripheral warmth (warmers should be close to body temperature before being activated and must not be placed directly against skin or constrict flow if used within a boot) regularly checking oneself and the group for extremity numbness or pain and warming the digits and/or extremities as soon as possible if there is concern that frostbite may be developing https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 6/8 6/29/23, 4:07 AM Frostbite Pathway recognizing frostnip or superficial frostbite before it becomes more serious minimizing duration of cold exposure. B Show 2 more Maintaining peripheral perfusion: Advise the following preventative measures to ensure local tissue perfusion: maintaining adequate core temperature and body hydration minimizing the effects of known diseases and medications, and substances (including awareness and symptoms of alcohol and drug use) that might decrease perfusion covering all skin and the scalp to insulate from the cold minimizing blood flow restriction, such as occurs with constrictive clothing, footwear, or immobility ensuring adequate nutrition using supplemental oxygen in severely hypoxic conditions (such as > 7,500 m). B Advise exercising to increase the core and peripheral temperatures to prevent frostbite. B Tetanus prophylaxis: As per WMS 2019 guidelines, administer tetanus prophylaxis according to standard guidelines. B As per ACCP 2014 guidelines, follow standard guidelines to determine the need for the tetanus toxoid administration, as frostbite injuries are not inherently tetanus-prone wounds. B 7. Follow-up and surveillance Recovery: Offer appropriate footwear and orthotics to provide optimal function in patients with insensate affected limb. B Offer early multidisciplinary rehabilitation produces for better long-term functional results. B Clinical findings Symptoms Past medical history Clumsiness AUD Edema Integument exam Numbness Pain Bruises Paresthesia Cyanosis Digital necrosis Social history Gangrene Illicit drug use Pallor Skin blisters Skin erythema https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 7/8 6/29/23, 4:07 AM Frostbite Pathway References 1. Scott E McIntosh, Luanne Freer, Colin K Grissom et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2019 Update. Wilderness Environ Med. 2019 Dec;30 4S S19 S32. Open 2. Charles Handford, Pauline Buxton, Katie Russell et al. Frostbite: a practical approach to hospital management. Extrem Physiol Med. 2014; 3 7. Open 3. Brandy Drake, Ryan Paterson, Geoffrey Tabin et al. Wilderness Medical Society practice guidelines for treatment of eye injuries and illnesses in the wilderness. Wilderness Environ Med. 2012 Dec;23 4 325 36. Open 4. Scott E McIntosh, Matthew Hamonko, Luanne Freer et al. Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite. Wilderness Environ Med. 2011 Jun;22 2 156 66. Open https://web.pathway.md/diseases/recMAJ6C5n4kFGgpd 8/8

Guideline sources The following summarized guidelines for the evaluation and management of functional dyspepsia are prepared by our editorial team based on guidelines from the British Society of Gastroenterology (BSG 2022), the American College of Gastroenterology (ACG/CAG 2017), and the Maastricht V/Florence Consensus Report (Maastricht V/Florence 2017). 1 2 3 Guidelines 1. Screening and diagnosis Differential diagnosis: exclude H. pylori gastritis before making a reliable diagnosis of functional dyspepsia. A Diagnosis: Recognize that most patients with dyspepsia will have functional dyspepsia as the underlying cause of their symptoms after investigation. B Diagnose functional dyspepsia in the presence of bothersome epigastric pain or burning, early satiation and/or postprandial fullness of > 8 weeks duration in the absence of upper gastrointestinal alarm symptoms or signs. B 2. Diagnostic investigations https://web.pathway.md/diseases/recZHCBG24opDw9BU 1/4 6/29/23, 4:08 AM Functional dyspepsia Pathway Testing for Helicobacter pylori: obtain noninvasive testing for H. pylori ('test and treat') in all patients with dyspepsia in the absence of alarm features. A Laboratory tests: Obtain a CBC in 55 years old patients with dyspepsia. B Obtain celiac serology in all patients with functional dyspepsia and overlapping IBS-type symptoms. B Diagnostic imaging: consider obtaining urgent abdominal CT to exclude pancreatic cancer in 60 years old patients with abdominal pain and weight loss. B Motility testing: Do not obtain routine motility studies in patients with functional dyspepsia. D Consider obtaining motility studies in selected patients with functional dyspepsia with a strong suspicion of gastroparesis. C Gastric emptying testing: do not obtain routine gastric emptying testing in patients with typical symptoms of functional dyspepsia. D pH monitoring: do not obtain routine 24-hour pH monitoring in patients with typical symptoms of functional dyspepsia. D 3. Diagnostic procedures Upper gastrointestinal endoscopy: Perform urgent endoscopy only in the following patients if no other upper gastrointestinal alarm symptoms or signs are reported: age 55 years, dyspepsia and weight loss age > 40 years, coming from an area at an increased risk of gastric cancer or having a family history of gastroesophageal cancer. B Consider performing non-urgent endoscopy in 55 years old patients with treatment- resistant dyspepsia or dyspepsia with either a raised platelet count or nausea or vomiting. C 4. Medical management Setting of care: Manage patients with functional dyspepsia referred to secondary care ideally in a specialist clinic with access to an interested clinician, dietetic and lifestyle support with access to efficacious drugs and gut-brain behavioral therapies. B Refer patients with functional dyspepsia to gastroenterology in secondary care in the following situations: diagnostic doubt severe symptoms symptoms refractory to first-line treatments individual patient requesting a specialist opinion. B Helicobacter pylori eradication: https://web.pathway.md/diseases/recZHCBG24opDw9BU 2/4 6/29/23, 4:08 AM Functional dyspepsia Pathway As per BSG 2022 guidelines: Initiate eradication therapy for the treatment of H. pylori-positive patients with functional dyspepsia. A Confirm successful eradication of H. pylori after 'test and treat' only in patients with an increased risk of gastric cancer. B As per ACG 2017 guidelines, initiate treatment for H. pylori infection in H. pylori-positive patients with functional dyspepsia. A Acid suppression therapy: As per BSG 2022 guidelines, offer empirical acid suppression therapy with PPIs at the lowest dose A or histamine-2-receptor antagonists in patients without H. pylori infection. B As per ACG 2017 guidelines, offer empirical PPIs in H. pylori-negative patients with functional dyspepsia or in patients remaining symptomatic despite eradication of the infection. B Prokinetics: As per BSG 2022 guidelines, consider offering certain prokinetics, such as tegaserod, B acotiamide, itopride, and mosapride, for the treatment of patients with functional dyspepsia. C As per ACG 2017 guidelines, offer prokinetics in patients with functional dyspepsia not responding to PPIs, H. pylori eradication therapy or TCAs. B Tricyclic antidepressants: As per BSG 2022 guidelines, consider offering TCAs as gut-brain neuromodulators as second-line therapy in patients with functional dyspepsia providing a careful explanation as to the rationale for their use and counseling patients about their side effect profile. Initiate TCAs at a low dose (such as 10 mg amitriptyline once daily) and titrate slowly to a maximum of 30-50 mg once daily. B As per ACG 2017 guidelines, offer TCAs in patients with functional dyspepsia not responding to PPIs or H. pylori eradication therapy (if appropriate). B Other antidepressants: insufficient evidence to support the use of SSRIs I or SNRIs as gut- brain neuromodulators as second-line therapy for global symptoms in patients with functional dyspepsia. I Show 2 more Antipsychotics: consider offering antipsychotics, such as sulpiride 100 mg QID or levosulpiride 25 mg TID, as second-line therapy in patients with functional dyspepsia providing a careful explanation as to the rationale for their use and counseling patients on their side effect profile. C Anticonvulsants: consider offering pregabalin 75 mg once daily as second-line therapy in patients with functional dyspepsia only in specialist settings. C 5. Nonpharmacologic interventions Dietary modifications: insufficient evidence to recommend dietary therapies, including a diet low in FODMAP, in patients with functional dyspepsia. I https://web.pathway.md/diseases/recZHCBG24opDw9BU 3/4 6/29/23, 4:08 AM Functional dyspepsia Pathway Physical activity: advise practicing regular aerobic exercise in all patients with functional dyspepsia. B Psychological interventions: As per BSG 2022 guidelines, consider offering the following interventions for global symptoms in patients with functional dyspepsia: interpersonal psychodynamic-informed psychotherapy cognitive-behavioral therapy and metacognitive therapy stress management approaches hypnotherapy. C As per ACG 2017 guidelines, consider offering psychological therapies in patients with functional dyspepsia not responding to drug therapy. C Alternative and complementary medicine: do not use complementary or alternative medicines in patients with functional dyspepsia. D 6. Patient education General counseling: Establish an effective and empathic doctor-patient relationship and a shared understanding as the cornerstone of the management of functional dyspepsia, which may also reduce healthcare utilization and improve quality of life. B Educate patients with functional dyspepsia about the diagnosis, its underlying pathophysiology, and the natural history of the condition including common symptom triggers. Introduce functional dyspepsia as a disorder of gut-brain interaction together with a simple account of the gut-brain axis and how this is impacted by diet, stress, cognitive, behavioral and emotional responses to symptoms and post-infective changes. B 7. Follow-up and surveillance Management of severe or refractory disease: involve a multidisciplinary support team in the management of patients with severe or refractory functional dyspepsia. B Show 3 more References 1. Christopher J Black, Peter A Paine, Anurag Agrawal et al. British Society of Gastroenterology guidelines on the management of functional dyspepsia. Gut. 2022 Sep;71 9 1697 1723. Open 2. Paul Moayyedi, Brian E Lacy, Christopher N Andrews et al. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol. 2017 Jul;112 7 988 1013. Open 3. P Malfertheiner, F Megraud, C A O'Morain et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut. 2017 Jan;66 1 6 30. Open https://web.pathway.md/diseases/recZHCBG24opDw9BU 4/4

Guideline sources The following summarized guidelines for the evaluation and management of gallbladder cancer are prepared by our editorial team based on guidelines from the Enhanced Recovery After Surgery Society (ERASS 2023), the European Society of Medical Oncology (ESMO 2023; 2016), the Society for Immunotherapy of Cancer (SITC 2023), the European Association for the Study of the Liver (EASL 2022), the American Society for Gastrointestinal Endoscopy (ASGE 2021), the American Society of Clinical Oncology (ASCO 2019), and the American College of Radiology (ACR 2019). 1 2 4 5 6 7 8 9 10 Guidelines 1. Screening and diagnosis Indications for screening: https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 1/7 6/24/23, 2:54 AM Gallbladder cancer Pathway As per EASL 2022 guidelines, consider obtaining screening for gallbladder cancer with ultrasound and/or MRI/MRCP at least annually in patients with large-duct PSC, regardless of disease stage. C As per ESMO 2016 guidelines, consider obtaining screening for biliary cancer only in at-risk patients, such as patients with PSC. E 2. Classification and risk stratification Staging: As per ESMO 2023 guidelines, classify biliary tract cancer according to the International Classification of Diseases-11 criteria. B Show 3 more As per ESMO 2016 guidelines: Consider obtaining EUS, with or without nodal biopsy, to clarify N-stage and to acquire information regarding vessel involvement. E Consider performing staging laparoscopy on an individual basis to exclude the presence of peritoneal metastases, if it will influence the decision to proceed with major resection. E Prognosis: recognize that elevated CA19-9 is associated with poorer prognosis. B 3. Diagnostic investigations Diagnostic imaging: As per ESMO 2023 guidelines, obtain radiological imaging before ERCP or percutaneous transhepatic cholangiography in patients with jaundice. B As per ESMO 2016 guidelines, consider obtaining abdominal ultrasound for initial evaluation (identification of biliary obstruction). E Show 2 more 4. Diagnostic procedures Biopsy and histopathology: As per ESMO 2023 guidelines, perform a core biopsy for diagnostic pathology and molecular profiling before any nonsurgical treatment. B Show 2 more As per ESMO 2016 guidelines: Follow standardized reporting tools (minimum dataset) for pathology examination and reporting of surgically-resected specimens. E Report the size and number of tumors, grade, the presence of satellite nodules, and vascular and/or perineural invasion to guide decisions regarding adjuvant therapy. B https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 2/7 6/24/23, 2:54 AM Gallbladder cancer Pathway 5. Medical management General principles: Provide patients with biliary tract cancer with a designated point of contact within the multidisciplinary team for advice and support (such as a nurse specialist). E Ensure full access to palliative care and symptom management (including pain control) for patients with biliary tract cancer. E Adjuvant chemotherapy: As per ESMO 2023 guidelines, consider offering adjuvant chemotherapy with capecitabine in patients with gallbladder cancer following resection. B As per ASCO 2019 guidelines: Offer adjuvant capecitabine chemotherapy for 6 months in patients with resected biliary tract cancer. B Consider offering chemoradiotherapy in patients with gallbladder cancer with a microscopically positive surgical margin resection (R1). C Definitive systemic therapy (first-line therapy): offer cisplatin plus gemcitabine as first-line therapy in patients with a performance status of 0-1. A Show 3 more Landmark trials: TOPAZ-1 In patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease, durvalumab was superior to placebo with respect to overall survival. Do-Youn Oh et al. NEJM Evid. 2022. Definitive systemic therapy, second- and later-line therapy: As per ESMO 2023 guidelines, offer 5-fluorouracil, leucovorin, and oxaliplatin as second-line therapy after cisplatin plus gemcitabine. A Show 7 more As per SITC 2023 guidelines, offer pembrolizumab monotherapy in patients with previously treated, advanced high MSI/MMR-deficient biliary tract cancer. Offer dostarlimab monotherapy for MMR-deficient tumors only. B Show 3 more 6. Therapeutic procedures Radiotherapy: consider offering radiotherapy after completion of adjuvant capecitabine in selected patients (R1 resection of gallbladder carcinoma). C Biliary stenting: https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 3/7 6/24/23, 2:54 AM Gallbladder cancer Pathway As per ESMO 2023 guidelines, perform biliary drainage and subsequent treatment in patients with biliary obstruction. Perform percutaneous transhepatic drainage when endoscopic access is not possible. B Prefer a metal stent in patients with a life expectancy of > 3 months. B Show 2 more As per ASGE 2021 guidelines, consider performing either endoscopic or percutaneous transhepatic biliary drainage in patients with unresectable malignant hilar obstruction undergoing palliative drainage. Make the final decision based on patient preferences, disease characteristics, and local expertise. C Show 3 more As per ACR 2019 guidelines: Place a percutaneous internal/external biliary catheter as an initial therapeutic procedure in patients with malignant hilar obstruction. B Place an endoscopic internal biliary catheter with a removable plastic stent as an initial therapeutic procedure in patients with dilated bile ducts and coagulopathy (INR > 2.0 or platelet count < 60, 000) or moderate-to-massive ascites. B 7. Perioperative care Preoperative care (counseling): Provide preoperative information and counseling regarding the upcoming liver surgery. Consider using brochures and multimedia support to improve verbal counseling. B Advise preoperative smoking cessation at least 4 weeks before hepatectomy. Advise alcohol cessation in heavy drinkers (> 24 g/day for females or > 36 g/day for males) 4-8 weeks before surgery. A Preoperative care (nutrition): obtain a nutritional assessment before liver surgery. Administer enteral supplementation at least 7-14 days before surgery to optimize nutritional status in malnourished patients (weight loss > 10% or > 5% over 3 months and reduced BMI or a low fat- free mass index). A Show 2 more Preoperative care (rehabilitation): offer prehabilitation in high-risk patients (elderly, malnourished or overweight patients, smokers, or patients with psychological disorders) before liver surgery. Initiate prehabilitation 4-6 weeks before the operation depending upon the urgency of surgery. Insufficient evidence to recommend the content (physical exercises, dietary interventions, or anxiety reduction exercises) and duration of the prehabilitation program for liver surgery. B Preoperative care (biliary drainage): perform biliary drainage in the cholestatic liver (> 50 mmol/L). Avoid performing surgery until the bilirubin level drops < 50 mmol/L. B Preoperative care (antibiotic prophylaxis): administer antibiotic prophylaxis (such as cefazolin) within 60 minutes before surgical incision with no extension into the postoperative period. https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 4/7 6/24/23, 2:54 AM Gallbladder cancer Pathway Consider administering a targeted antibiotic preemptive regimen based on preoperative bile culture in case of complex liver surgery with biliary reconstruction. B Preoperative care (corticosteroids): administer a preoperative dose of corticosteroids (methylprednisolone 500 mg). Insufficient evidence for its use in diabetic patients undergoing liver surgery. B Preoperative care (preanesthetic medication): avoid administering long-acting anxiolytic drugs, particularly in the elderly. D Show 3 more Intraoperative care (anesthesia and analgesia): Administer multimodal analgesia, including the potential use of intrathecal opioids, both for open A and laparoscopic surgery. B Recognize that thoracic epidural analgesia can provide excellent analgesia for open liver surgery but has significant disadvantages. Do not use regional anesthesia techniques in laparoscopic surgery as multimodal analgesia combined with judicious IV opioids provide functional analgesia. Perform continuous local anesthetic wound infiltration to provide lower complication rates and overall equivalent analgesia to thoracic epidural analgesia. Perform local anesthetic transversus abdominis plane blockade as a supplement to standard analgesia to improve pain control and reduce opioid usage. A Intraoperative care (temperature management): maintain perioperative normothermia with multimodal temperature management (including circulating water garments or forced warm air) during open and minimally invasive liver surgery. B Intraoperative care (fluid management): Maintain low central venous pressure (< 5 cmH O) with close monitoring during hepatic transection. A Prefer balanced crystalloids over 0.9% saline or colloids for fluid maintenance. Provide goal- directed fluid therapy to optimize cardiac output and end-organ perfusion, recognizing that this may be particularly beneficial after the intraoperative liver resection during a low central venous pressure state to restore tissue perfusion, with patients having comorbidities and reduced cardiac function benefiting the most. A Postoperative care (thromboprophylaxis): administer routine postoperative LMWH or UFH to reduce the risk of thromboembolic events unless exceptional circumstances make this unsafe. Use intermittent pneumatic compression devices to reduce this risk further. B Postoperative care (early mobilization): initiate early mobilization (out of bed) after liver surgery from the operative day until hospital discharge. Insufficient evidence regarding the optimal duration of mobilization. B Postoperative care (nutrition): implement early oral intake with a normal diet after hepatectomy. Assess the individualized needs for artificial nutrition in malnourished patients, patients with complications causing several days of fasting, and patients with liver cirrhosis. Prefer enteral administration for artificial nutrition. A Show 2 more https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 5/7 6/24/23, 2:54 AM Gallbladder cancer Pathway Postoperative care (antiemetics): use a multimodal approach to postoperative nausea and vomiting. Administer postoperative nausea and vomiting prophylaxis with at least 2 antiemetic drugs, such as dexamethasone and ondansetron. A Postoperative care (laxatives): insufficient evidence to support the routine use of postoperative laxatives, gum chewing, herbal medicine, or decoction to stimulate bowel movement after liver surgery. I 8. Surgical interventions Surgical resection (indications): perform radical surgery (including lymphadenectomy) as the only curative-intent treatment for biliary tract cancers. Decide on the exact nature and extent of surgery depending on tumor subtype and location agreed at a specialist hepatobiliary multidisciplinary tumor board meeting. B Show 3 more Surgical resection (technical considerations): perform liver resection laparoscopically, in trained teams and when clinically appropriate, to reduce the postoperative length of stay and complication rates. B Show 3 more 9. Specific circumstances Patients with gastric outlet obstruction: consider placing self-expandable metallic stents or performing surgical gastrojejunostomy in patients with incurable malignant gastric outlet obstruction undergoing palliative intervention. Decide between these approaches based on patient characteristics and preferences, multidisciplinary input, and local expertise. C Show 2 more 10. Follow-up and surveillance Assessment of treatment response: Consider obtaining CA 19-9 for the assessment of treatment response. C Re-assess patients by a multidisciplinary team to discuss surgery in case of response following locoregional or systemic treatment of locally advanced tumors. B Follow-up: follow up patients developing treatment-related complications and cancer recurrence. Consider obtaining surveillance with 3-6 monthly visits during the first 2 years and 6-12-monthly visits for up to 5 years or as clinically indicated. Consider obtaining clinical assessment, laboratory tests, tumor markers, and chest and abdominopelvic CT. B Show 4 more Rehabilitation: consider offering rehabilitation to counteract impairments related to cancer and its treatments to maximize the quality of life in survivorship. B https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 6/7 6/24/23, 2:54 AM Gallbladder cancer Pathway References 1. Ga tan-Romain Joliat, Kosuke Kobayashi, Kiyoshi Hasegawa et al. Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery ERAS Society Recommendations 2022. World J Surg. 2023 Jan;47 1 11 34. Open 2. Bashar J Qumseya, Laith H Jamil, Badih Joseph Elmunzer et al. ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction. Gastrointest Endosc. 2021 Aug;94 2 222 234.e22. Open 3. Jean-Marc Dumonceau, Andrea Tringali, Ioannis S Papanikolaou et al. Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy ESGE Clinical Guideline Updated October 2017. Endoscopy. 2018 Sep;50 9 910 930. Open 4. J W Valle, I Borbath, S A Khan et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v28-v37. Open 5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on Sclerosing Cholangitis. J Hepatol. 2022 May 31;S0168 8278 22 00326 9. Open 6. A Vogel, J Bridgewater, J Edeline et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Feb;34 2 127 140. Open 7. Rachna T Shroff, Erin B Kennedy, Melinda Bachini et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J Clin Oncol. 2019 Apr 20;37 12 1015 1027. Open 8. Expert Panel on Interventional Radiology:, Alexandra H Fairchild, Eric J Hohenwalter et al. ACR Appropriateness Criteria Radiologic Management of Biliary Obstruction. J Am Coll Radiol. 2019 May;16 5S S196 S213. Open 9. Ronan J Kelly, Katherine Bever, Joseph Chao et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer. 2023 Jun;11 6):e006658. Open 10. ASGE Standards of Practice Committee, Terry L Jue, Andrew C Storm et al. ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction. Gastrointest Endosc. 2021 Feb;93 2 309 322.e4. Open https://web.pathway.md/diseases/rec7AzQA8CnJmT9L8 7/7

Guideline sources The following summarized guidelines for the evaluation and management of gallbladder polyps are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2022), the European Society of Gastrointestinal Endoscopy (ESGE/EFISDS/EAES/ESGAR 2022), the European Association for the Study of the Liver (EASL 2022; 2016), the British Society of Gastroenterology (BSG 2019), the American College of Gastroenterology (ACG 2015), and the American Society for Gastrointestinal Endoscopy (ASGE 2013). 1 2 3 4 5 6 7 Calculator CholeS score for duration of lap Guidelines 1. Classification and risk stratification https://web.pathway.md/diseases/rec6gB551elGYX49Q 1/4 6/24/23, 2:54 AM Gallbladder polyps Pathway Risk of malignancy: consider obtaining multidisciplinary discussion to assess the perceived individual risk of malignancy in patients with polypoid lesions of the gallbladder measuring 10 mm. B 2. Diagnostic investigations Diagnostic imaging: Obtain abdominal ultrasound for primary evaluation of polypoid lesions of the gallbladder. B Consider obtaining alternative imaging modalities (such as contrast-enhanced and EUS) to aid decision-making in difficult cases in centers with appropriate expertise and resources. B 3. Surgical interventions Indications for cholecystectomy, polyps >= 10 mm: As per ESGE/EFISDS/EAES/ESGAR 2022 guidelines, perform cholecystectomy in surgically fit patients with polypoid lesions of the gallbladder measuring 10 mm. B As per EASL 2016 guidelines, perform cholecystectomy in patients with gallbladder polyps 10 mm, without or with gallstones, regardless of symptoms. B As per ASGE 2013 guidelines, consider performing cholecystectomy in asymptomatic patients with gallbladder polyps > 10 mm. C Indications for cholecystectomy, polyps 6-9 mm: As per ESGE/EFISDS/EAES/ESGAR 2022 guidelines, perform cholecystectomy in surgically fit patients with 6-9 mm polypoid lesions of the gallbladder and 1 of the following risk factors for malignancy: age > 60 years history of PSC asian ethnicity sessile polypoid lesion (including focal gallbladder wall thickening > 4 mm). B As per EASL 2016 guidelines, consider performing cholecystectomy in patients with asymptomatic gallbladder stones and gallbladder polyps 6-10 mm. C Indications for cholecystectomy (polyps <= 5 mm): do not perform cholecystectomy in patients with asymptomatic gallbladder stones and gallbladder polyps 5 mm. D Indications for cholecystectomy, symptomatic polyps: As per ESGE/EFISDS/EAES/ESGAR 2022 guidelines, consider performing cholecystectomy in surgically fit patients with polypoid lesions of the gallbladder with symptoms potentially attributable to the gallbladder and no demonstrated alternative cause explaining symptoms. Counsel patients about the benefit of cholecystectomy versus the risk of persistent symptoms. B https://web.pathway.md/diseases/rec6gB551elGYX49Q 2/4 6/24/23, 2:54 AM Gallbladder polyps Pathway As per ASGE 2013 guidelines, perform cholecystectomy in symptomatic patients with gallbladder polyps. B Indications for cholecystectomy, growing polyps: As per ESGE/EFISDS/EAES/ESGAR 2022 guidelines, perform cholecystectomy in patients with a polypoid lesion of the gallbladder reaching 10 mm in size during follow-up. Take into consideration the current size of the polypoid lesion along with patient risk factors if the polypoid lesion grows by 2 mm within the 2-year follow-up period. Consider obtaining a multidisciplinary discussion to decide on the continuation of monitoring versus cholecystectomy. B As per EASL 2016 guidelines, consider performing cholecystectomy in patients with growing polyps. C 4. Specific circumstances Patients with primary sclerosing cholangitis, monitoring: As per AASLD 2022 guidelines, consider obtaining ultrasound surveillance every 6 months in patients with PSC and gallbladder polyps 8 mm. E As per BSG 2019 guidelines, consider obtaining an annual ultrasound of the gallbladder in patients with PSC. Direct management by a specialist hepatopancreaticobiliary multidisciplinary team if polyps are identified. C Patients with primary sclerosing cholangitis, cholecystectomy: As per AASLD 2022 guidelines, consider performing cholecystectomy in patients with advanced PSC with gallbladder polyps > 8 mm, preferably at an experienced center. E As per EASL 2022 guidelines, perform cholecystectomy in patients with PSC with gallbladder polyps 8 mm in size and smaller polyps growing in size due to the high risk of malignancy or dysplasia. B As per EASL 2016 guidelines, consider performing cholecystectomy in asymptomatic patients with PSC and gallbladder polyps, irrespective of size. C As per ACG 2015 guidelines, perform cholecystectomy in patients with PSC and gallbladder polyps > 8 mm to prevent the development of gallbladder adenocarcinoma. B As per ASGE 2013 guidelines, perform cholecystectomy in patients with PSC in the presence of any gallbladder polyps. B 5. Follow-up and surveillance Serial imaging assessment: As per ESGAR 2022 guidelines, do not obtain follow-up in patients with a gallbladder polypoid lesion of 5 mm and no risk factors for malignancy. D Show 2 more https://web.pathway.md/diseases/rec6gB551elGYX49Q 3/4 6/24/23, 2:54 AM Gallbladder polyps Pathway As per ASGE 2013 guidelines, consider obtaining serial abdominal ultrasound every 12 months in asymptomatic patients with gallbladder polyps 6-10 mm and no other risk factors for gallbladder cancer. C References 1. Christopher L Bowlus, Lionel Arriv , Annika Bergquist et al. AASLD Practice Guidance on Primary Sclerosing Cholangitis and Cholangiocarcinoma. Hepatology. 2022 Sep 9. Open 2. EASL. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016 Jul;65 1 146 181. Open 3. Chapman MH, Thorburn D, Hirschfield GM et al. British Society of Gastroenterology and UK PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019 Aug;68 8 1356 1378. Open 4. Anderson MA, Appalaneni V, Ben-Menachem T et al. The role of endoscopy in the evaluation and treatment of patients with biliary neoplasia. Gastrointest Endosc. 2013 Feb;77 2 167 74. Open 5. Kieran G Foley, Max J Lahaye, Ruedi F Thoeni et al. Management and follow-up of gallbladder polyps: updated joint guidelines between the ESGAR, EAES, EFISDS and ESGE. Eur Radiol. 2022 May;32 5 3358 3368. Open 6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on Sclerosing Cholangitis. J Hepatol. 2022 May 31;S0168 8278 22 00326 9. Open 7. Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110 5 646 59. Open https://web.pathway.md/diseases/rec6gB551elGYX49Q 4/4

Guideline sources The following summarized guidelines for the evaluation and management of gallstone disease are prepared by our editorial team based on guidelines from the Danish Surgical Society (DSS 2022), the American Society of Anesthesiologists (ASA/ACE/OS/AACE/ASMBS/OMA 2020), the World Society of Emergency Surgery (WSES 2020), the American College of Radiology (ACR 2019), the North American Neuroendocrine Tumor Society (NANETS 2017), the Japanese Society of Gastroenterology (JSG/JBA/JGES 2017), the European Association for the Study of the Liver (EASL 2016), the American Society for Gastrointestinal Endoscopy (ASGE 2015; 2010), the American Association of Family Physicians (AAFP 2014), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES 2010). 1 2 3 4 5 6 7 8 9 10 11 Calculator Calculator CholeS score for duration of lap Diagnostic criteria for acute chol https://web.pathway.md/diseases/recS6g9oRq28F02Qm 1/7 6/24/23, 2:54 AM Gallstone disease Pathway Guidelines 1. Diagnostic investigations History and physical examination: elicit medical history and perform a physical examination to identify characteristic findings of gallbladder stones (episodic attacks of severe pain in the right upper abdominal quadrant or epigastrium for at least 15-30 minutes with radiation to the right back or shoulder and a positive reaction to analgesics). B Diagnostic imaging: As per WSES 2020 guidelines, obtain abdominal ultrasound as the preferred initial imaging technique for gallstone disease due to its cost-effectiveness, wide availability, reduced invasiveness, and good accuracy. A As per ACR 2019 guidelines: Obtain abdominal ultrasound as initial evaluation in patients with RUQ pain with suspected biliary disease. B Obtain abdominal MRI (with or without IV contrast) with MRCP or contrast-enhanced abdominal CT in patients with RUQ pain with suspected biliary disease in the setting of negative or equivocal ultrasound and in the absence of fever or leukocytosis. B As per EASL 2016 guidelines: Obtain abdominal ultrasound in patients with a recent history of biliary pain. A Consider obtaining EUS or MRI in case of strong clinical suspicion of gallbladder stones and negative abdominal ultrasound. C As per AAFP 2014 guidelines, obtain abdominal ultrasound as initial imaging in patients with suspected gallstones or complications of gallstones. B As per ASGE 2010 guidelines, proceed to cholecystectomy without additional biliary evaluation in patients with symptomatic cholelithiasis being surgical candidates and having a low probability of choledocholithiasis. B Laboratory tests: Do not obtain routine laboratory tests in addition to abdominal ultrasound to confirm the presence of gallstones. D Consider obtaining liver biochemical tests in individually selected cases. C 2. Medical management Expectant management: As per DSS 2022 guidelines, consider offering observation as an alternative to laparoscopic cholecystectomy in patients with uncomplicated gallstone disease. C As per JSG 2017 guidelines: https://web.pathway.md/diseases/recS6g9oRq28F02Qm 2/7 6/24/23, 2:54 AM Gallstone disease Pathway Do not offer treatment in asymptomatic patients with fully evaluable gallbladder walls. D Obtain annual follow-up, including physical examination, abdominal ultrasound, and other modalities as appropriate, in patients with gallstones because of the risk for hepatic dysfunction or gallbladder cancer. B As per EASL 2016 guidelines, do not offer routine treatment in patients with asymptomatic gallbladder stones. D As per AAFP 2014 guidelines, offer expectant management in patients with incidentally detected, asymptomatic gallstones. B Bile acid litholysis: As per JSG 2017 guidelines: Offer oral dissolution therapy in patients with gallstone disease refusing surgery. B Offer oral dissolution therapy with bile acid formulations in patients with radiolucent cholesterol gallstones with normal gallbladder function. B As per EASL 2016 guidelines, do not offer litholysis using bile acids alone or in combination with extracorporeal shock wave lithotripsy in patients with gallbladder stones. D Management of pain: administer NSAIDs (such as diclofenac, indomethacin) for the treatment of biliary colic. B 3. Therapeutic procedures Extracorporeal shock wave lithotripsy: As per JSG 2017 guidelines: Offer extracorporeal shock wave lithotripsy in patients with gallstone disease refusing surgery. B Offer extracorporeal shock wave lithotripsy in patients with non-calcified cholesterol gallstones with normal gallbladder function. B As per EASL 2016 guidelines, do not offer extracorporeal shock wave lithotripsy in patients with gallbladder stones. D 4. Perioperative care Perioperative antibiotic prophylaxis: As per EASL 2016 guidelines, do not administer routine antibiotic prophylaxis before elective laparoscopic cholecystectomy. D As per AAFP 2014 guidelines, do not administer antibiotic prophylaxis in low-risk patients undergoing elective laparoscopic cholecystectomy. D 5. Surgical interventions https://web.pathway.md/diseases/recS6g9oRq28F02Qm 3/7 6/24/23, 2:54 AM Gallstone disease Pathway Cholecystectomy, indications: As per JBA/JGES/JSG 2017 guidelines, perform cholecystectomy in patients with cholecystolithiasis presenting with any symptoms. B As per EASL 2016 guidelines, perform cholecystectomy as the preferred option for the treatment of patients with symptomatic gallbladder stones. B Show 5 more As per SAGES 2010 guidelines, perform laparoscopic cholecystectomy in patients with symptomatic cholelithiasis. B Cholecystectomy (timing): Perform cholecystectomy as early as possible in patients with uncomplicated biliary colic. B Perform early laparoscopic cholecystectomy, within 72 hours after preoperative ERCP for choledocholithiasis, in patients with simultaneous gallbladder and bile duct stones. B Cholecystectomy, choice of approach: As per JBA/JGES/JSG 2017 guidelines, perform laparoscopic cholecystectomy as the first- choice surgical procedure in institutions with adequate experience. A Show 2 more As per EASL 2016 guidelines, perform laparoscopic cholecystectomy as the standard method of cholecystectomy in patients with symptomatic gallbladder stones. A Show 4 more As per AAFP 2014 guidelines, perform laparoscopic cholecystectomy as the standard treatment in patients with gallstone disease. A Cholecystectomy (technical considerations): recognize that day-surgery may be as safe as overnight stay laparoscopic cholecystectomy in patients without systemic disease. B Show 2 more Cholecystectomy (management of postoperative leaks): perform ERCP as first-line therapy for postoperative biliary leaks. A 6. Specific circumstances Elderly patients: Perform cholecystectomy in the elderly and in patients with high anesthetic risk with gallstone complications (such as acute cholecystitis, gallstone pancreatitis, or obstructive jaundice) as soon as the general status allows surgery. B Do not withhold laparoscopic cholecystectomy solely based on the chronological age. D Pregnant patients: As per EASL 2016 guidelines, perform laparoscopic cholecystectomy during pregnancy in case of urgent indication, regardless of trimester. B Show 2 more https://web.pathway.md/diseases/recS6g9oRq28F02Qm 4/7 6/24/23, 2:54 AM Gallstone disease Pathway As per AAFP 2014 guidelines, perform laparoscopic cholecystectomy when indicated, during any trimester of pregnancy. A Patients undergoing bariatric surgery: As per AACE 2020 guidelines: Initiate oral UDCA to reduce the risk of cholelithiasis due to rapid weight loss in patients undergoing sleeve gastrectomy, Roux-en-Y gastric bypass, or biliopancreatic diversion with duodenal switch (500 mg once daily for sleeve gastrectomy and 300 mg BID for Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch). A Consider performing prophylactic cholecystectomy to avoid choledocholithiasis in asymptomatic patients with known gallstones and a history of Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch, since traditional ERCP can no longer be performed in these patients. C As per EASL 2016 guidelines, consider offering UDCA to prevent cholesterol gallstone formation in patients on long-term therapy with somatostatin or analogs. C Show 2 more 7. Preventative measures Primary prevention (lifestyle interventions): consider advising healthy lifestyle and food, regular physical activity, and maintenance of ideal body weight to prevent the formation of cholesterol gallbladder stones and symptomatic gallstones. C Primary prevention, pharmacological interventions: As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines, initiate oral UDCA to reduce the risk of cholelithiasis due to rapid weight loss in patients undergoing sleeve gastrectomy, Roux-en-Y gastric bypass, or biliopancreatic diversion with duodenal switch (500 mg once daily for sleeve gastrectomy and 300 mg BID for Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch). A As per EASL 2016 guidelines, do not offer pharmacological prevention of gallstones in the general population. D Show 4 more Prophylactic cholecytectomy: As per NANETS 2017 guidelines, perform prophylactic cholecystectomy at the time of index surgery in patients with gastrointestinal NETs if there is a high likelihood that long-term therapy with somatostatin analogs will be required (such as in patients with liver metastases, peritoneal disease, or significant nodal involvement). Do not perform prophylactic cholecystectomy in asymptomatic patients receiving somatostatin analogs after primary tumor removal without cholecystectomy. Consider delaying cholecystectomy until a future abdominal procedure is planned (such as hepatic cytoreduction), or until symptoms of biliary colic or complications from embolization develop. E https://web.pathway.md/diseases/recS6g9oRq28F02Qm 5/7 6/24/23, 2:54 AM Gallstone disease Pathway As per EASL 2016 guidelines, do not perform routine prophylactic cholecystectomy in patients undergoing bariatric surgery. D 8. Follow-up and surveillance Discharge from hospital: consider discharging patients undergoing uncomplicated laparoscopic cholecystectomy on the day of surgery. Ensure adequate control of postoperative pain, nausea, and vomiting for successful same-day discharge. C Management of postoperative bile duct injury: obtain urgent investigation including laboratory tests (WBC, bilirubin, LFTs) and imaging (abdominal ultrasound, contrast-enhanced CT, MRCP) to detect bile leak and/or intra-abdominal fluid in patients suspected bile duct injury after surgery, while keeping the patient in hospital under close observation. B Show 2 more Management of persistent symptoms: Consider obtaining EUS or MRCP in the diagnostic evaluation of patients with biliary symptoms after cholecystectomy. C Do not perform endoscopic sphincterotomy in patients with abdominal pain after cholecystectomy without significant abnormalities on imaging or laboratory studies. D References 1. EASL. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016 Jul;65 1 146 181. Open 2. James R Howe, Kenneth Cardona, Douglas L Fraker et al. The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017 Jul;46 6 715 731. Open 3. ASGE Standards of Practice Committee, Krishnavel V Chathadi, Vinay Chandrasekhara et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015 Apr;81 4 795 803. Open 4. ASGE Standards of Practice Committee, John T Maple, Tamir Ben-Menachem et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc. 2010 Jan;71 1 1 9. Open 5. D Wayne Overby, Keith N Apelgren, William Richardson et al. SAGES guidelines for the clinical application of laparoscopic biliary tract surgery. Surg Endosc. 2010 Oct;24 10 2368 86. Open 6. Expert Panel on Gastrointestinal Imaging:, Christine M Peterson, Michelle M McNamara et al. ACR Appropriateness Criteria Right Upper Quadrant Pain. J Am Coll Radiol. 2019 May;16 5S S235 S243. Open 7. Susumu Tazuma, Michiaki Unno, Yoshinori Igarashi et al. Evidence-based clinical practice guidelines for cholelithiasis 2016. J Gastroenterol. 2017 Mar;52 3 276 300. Open 8. Jeffrey I Mechanick, Caroline Apovian, Stacy Brethauer et al. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures https://web.pathway.md/diseases/recS6g9oRq28F02Qm 6/7 6/24/23, 2:54 AM Gallstone disease Pathway 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity Silver Spring). 2020 Apr;28 4 O1 O58. Open 9. Michele Pisano, Niccol Allievi, Kurinchi Gurusamy et al. 2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis. World J Emerg Surg. 2020; 15 61. Open 10. Sherly Abraham, Haidy G Rivero, Irina V Erlikh et al. Surgical and nonsurgical management of gallstones. Am Fam Physician. 2014 May 15;89 10 795 802. Open 11. Daniel M nsted Shabanzadeh, Dorthe Wiinholdt Christensen, Caroline Ewertsen et al. National clinical practice guidelines for the treatment of symptomatic gallstone disease: 2021 recommendations from the Danish Surgical Society. Scand J Surg. 2022 Aug 24;14574969221111027. Open 12. Hina Arif-Tiwari, MDa, Kristin K. Porter et al. ACR Appropriateness Criteria Abnormal Liver Function Tests. ACR. 2023. Open https://web.pathway.md/diseases/recS6g9oRq28F02Qm 7/7

Guideline sources The following summarized guidelines for the evaluation and management of gastric artery aneurysm are prepared by our editorial team based on guidelines from the Society for Vascular Surgery (SVS 2020). 1 Guidelines 1. Diagnostic investigations Diagnostic imaging: obtain CT angiography as the diagnostic tool of choice in patients with suspected gastric or gastroepiploic artery aneurysms. B Show 2 more Screening for other aneurysms: Consider obtaining abdominal axial imaging to screen for concomitant abdominal aneurysms. C Consider obtaining one-time screening CT angiography (or MRA) of the head, neck, and chest in patients with segmental arterial mediolysis. C 2. Therapeutic procedures Indications for repair: treat all gastric artery and gastroepiploic artery aneurysms of any size. B https://web.pathway.md/diseases/recyMknspseTSg3FI 1/2 6/24/23, 2:54 AM Gastric artery aneurysm Pathway Choice of repair: perform endovascular embolization as first-line treatment of gastric artery and gastroepiploic artery aneurysms. B 3. Follow-up and surveillance Surveillance imaging: Consider obtaining interval surveillance (every 12- 24 months) with axial imaging (CT angiography or MRA) in patients with segmental medial arteriolysis in light of reported cases of rapid arterial transformation. C Consider obtaining post-embolization surveillance every 1-2 years with axial imaging to assess for vascular remodeling and evidence of aneurysm reperfusion. C References 1. Rabih A Chaer, Christopher J Abularrage, Dawn M Coleman et al. The Society for Vascular Surgery clinical practice guidelines on the management of visceral aneurysms. J Vasc Surg. 2020 Jul;72 1S 3S 39S. Open https://web.pathway.md/diseases/recyMknspseTSg3FI 2/2

Guideline sources The following summarized guidelines for the evaluation and management of gastric cancer are prepared by our editorial team based on guidelines from the Society for Immunotherapy of Cancer (SITC 2023), the American College of Gastroenterology (ACG 2023; 2017; 2015), the American Society of Clinical Oncology (ASCO 2023), the European Society of Medical Oncology (ESMO 2022), the British Society of Gastroenterology (BSG 2022; 2019), the European Reference Network on Genetic Tumour Risk Syndromes (GENTURIS/EURACAN/ESMO 2022), the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS 2021), the European Society of Gastrointestinal Endoscopy (ESGE 2021; 2017), the American Society for Gastrointestinal Endoscopy (ASGE 2021; 2017; 2015), the American Gastroenterological Association (AGA 2020), the European Society of Gastrointestinal Endoscopy (ESGE/ESP/SPED/EHMSG 2019), the European Reference Network on Rare Adult Solid Cancers (EURACAN/ESMO 2018), the British Sarcoma Group (BSG 2017), and the American Society for Clinical Pathology (ASCP/CAP/ASCO 2017). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 1/13 6/24/23, 2:55 AM Gastric cancer Pathway Guidelines 1. Screening and diagnosis Indications for screening (asymptomatic patients): obtain population-based endoscopic screening in asymptomatic persons only in regions with a very high incidence of gastric cancer. B Indications for screening, familial cancer syndromes: As per ESMO 2022 guidelines, refer patients with suspected familial cancer syndrome to a geneticist for assessment. B As per ACG 2015 guidelines, consider screening for gastric cancer in patients at risk for or affected with Lynch syndrome by baseline upper gastrointestinal endoscopy with gastric biopsy at age 30-35 years. Consider obtaining ongoing surveillance every 3-5 years if there is a family history of gastric or duodenal cancer. C 2. Classification and risk stratification Staging: perform a physical examination, obtain CBC with differential, liver and renal function tests, contrast-enhanced CT of the chest, abdomen pelvis, and perform upper gastrointestinal endoscopy for initial staging and risk assessment. B Show 2 more 3. Diagnostic investigations Testing for Helicobacter pylori infection: test for H. pylori infection in all patients with low-grade gastric MALT lymphoma, or a history of endoscopic resection of early gastric cancer. B Show 2 more 4. Diagnostic procedures Upper gastrointestinal endoscopy: Perform urgent endoscopy only in the following patients if no other upper gastrointestinal alarm symptoms or signs are reported: age 55 years, dyspepsia and weight loss age > 40 years, coming from an area at an increased risk of gastric cancer or having a family history of gastroesophageal cancer. B Biopsy: As per ESGE 2021 guidelines, take at least 6 biopsies in patients with suspected advanced gastric cancer. B Show 3 more https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 2/13 6/24/23, 2:55 AM Gastric cancer Pathway As per ESGE 2017 guidelines, consider performing EUS-guided sampling aiming at a core biopsy after the failure of standard biopsy techniques in patients with diffuse gastric wall thickening. Consider using newly developed biopsy techniques under optical endoscopic guidance as an alternative. C Show 3 more Histopathology: Make the diagnosis from multiple (5-8) endoscopic biopsies to guarantee an adequate representation of the tumor. B Report the histological diagnosis according to the WHO criteria. B Ancillary testing: As per SITC 2023 guidelines, obtain tumor testing for PD-L1 expression B and high MSI/MMR deficiency status in all patients with esophagogastric cancer. B Use the CPS to quantify PD-L1 expression in patients with esophagogastric adenocarcinoma. B Consider obtaining MSI status testing by next-generation sequencing. Consider obtaining MMR status testing by immunohistochemistry. Show 3 more As per ESMO 2022 guidelines, assess HER2 expression by immunohistochemistry and/or amplification by in situ hybridization, PD-L1 by immunohistochemistry according to CPS, A and MSI-high/MMR deficiency B as validated predictive biomarkers for drug therapy. A As per CAP 2017 guidelines: Obtain HER2 testing on tumor tissue in patients with advanced gastric adenocarcinoma being potential candidates for HER2-targeted therapy. A Obtain HER2 testing on tumor tissue of the biopsy or resection specimens (primary or metastasis), if such specimens are available and adequate, or on FNA specimens (cell blocks) as an acceptable alternative, preferably before initiating trastuzumab therapy. B Diagnostic laparoscopy and peritoneal lavage: perform diagnostic laparoscopy and peritoneal washings for cytology in patients with resectable gastric cancer being also candidates for perioperative chemotherapy. B Recognize that patients with positive lavage cytology are uncertain candidates for curatively-intended surgical resection. 5. Medical management General principles: ensure multidisciplinary treatment planning before any treatment decision. B Management of locoregional disease (perioperative chemotherapy): offer perioperative (pre- and postoperative) chemotherapy in patients with stage IB resectable gastric cancer. A Show 3 more Management of locoregional disease (adjuvant chemoradiotherapy): offer adjuvant chemotherapy in patients with stage IB gastric cancer undergone surgery without administration of preoperative chemotherapy. A Show 5 more https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 3/13 6/24/23, 2:55 AM Gastric cancer Pathway Management of advanced/metastatic disease (first-line chemotherapy): offer first-line chemotherapy with a platinum and a fluoropyrimidine, and prefer oxaliplatin, especially for older patients. A Show 2 more Management of advanced/metastatic disease, targeted therapy and immunotherapy: As per ASCO 2023 guidelines, offer nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy as first-line therapy in HER2-negative patients with gastric adenocarcinoma and PD-L1 CPS 5. B Show 3 more As per SITC 2023 guidelines, do not offer single-agent immune checkpoint inhibitor therapy in patients with untreated, advanced, microsatellite stable/MMR-proficient esophagogastric cancer. Consider offering single-agent anti-PD-1 therapy as an option in patients with untreated, advanced, high MSI/MMR-deficient esophagogastric cancer ineligible for chemotherapy. D Show 2 more As per ESMO 2022 guidelines, offer trastuzumab-chemotherapy in patients with HER2-positive tumors. A Show 7 more As per ASCO/ASCP/CAP 2017 guidelines, offer combination chemotherapy and HER2-targeted therapy as initial treatment in appropriate patients with HER2-positive advanced gastric adenocarcinoma. B Management of advanced/metastatic disease (liver metastasis): Offer systemic adjuvant therapy in patients with liver metastases from gastric cancer. B Offer adjuvant imatinib after hepatectomy in patients with liver metastases from gastrointestinal stromal tumors. B Palliative care: offer early palliative care referral and nutritional support to patients with gastric cancer. A 6. Nonpharmacologic interventions Nutritional support: offer dietary support with attention to vitamin and mineral deficiencies in patients with gastric cancer. B 7. Therapeutic procedures Endoscopic gastroduodenal stenting: consider placing self-expandable metallic stents or performing surgical gastrojejunostomy in patients with incurable malignant gastric outlet obstruction undergoing palliative intervention. Decide between these approaches based on patient characteristics and preferences, multidisciplinary input, and local expertise. C Show 2 more https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 4/13 6/24/23, 2:55 AM Gastric cancer Pathway 8. Perioperative care Patients with hereditary diffuse gastric cancer: Include the following in the management of patients with hereditary diffuse gastric cancer: prophylactic gastrectomy after age 20 years (> 80% risk by age 80) breast cancer surveillance in females beginning at age 35 years with annual mammography and breast MRI and clinical breast examination every 6 months colonoscopy beginning at age 40 years in families including colon cancer. B 9. Surgical interventions Surgical resection (locoregional disease): consider performing endoscopic or surgical resection alone in selected patients with very early tumors (stage IA). C Show 2 more Surgical resection, advanced/metastatic disease: As per ESMO 2022 guidelines: Do not offer gastrectomy in patients with metastatic gastric cancer unless required for palliation of symptoms. D Do not offer resection of metastases in general, but consider offering individually in highly selected patients with oligometastatic disease responsive to chemotherapy. D As per JSHBPS 2021 guidelines: Do not perform hepatectomy in patients with liver metastases from gastric cancer. D Perform hepatectomy with curative intent in patients with liver metastases from G1/G2 gastroenteropancreatic NETs. B Palliative gastrojejunostomy: Consider performing surgical gastrojejunostomy or placing self-expandable metallic stents in patients with incurable malignant gastric outlet obstruction undergoing palliative intervention. Decide between these approaches based on patient characteristics and preferences, multidisciplinary input, and local expertise. C Consider preferring surgical gastrojejunostomy in patients with a life expectancy of > 6 months and good performance status. 10. Specific circumstances Patients with precancerous gastric lesions (etiology): Recognize that: patients with chronic atrophic gastritis or intestinal metaplasia are at risk for gastric adenocarcinoma A patients with advanced stages of gastritis, that is, atrophy and/or intestinal metaplasia affecting both antral and corpus mucosa, are at higher risk for gastric adenocarcinoma B https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 5/13 6/24/23, 2:55 AM Gastric cancer Pathway histologically confirmed intestinal metaplasia is the most reliable marker of atrophy in gastric mucosa. A Recognize that the management of patients with chronic atrophic gastritis or intestinal metaplasia intends to prevent high-grade dysplasia and invasive carcinoma. B Patients with precancerous gastric lesions, upper GI endoscopy: As per BSG 2019 guidelines, perform a full systematic endoscopy (examination time of a minimum of 7 minutes) of the stomach with clear photographic documentation of gastric regions and pathology in patients at higher risk for gastric adenocarcinoma, including atrophic gastritis and gastric intestinal metaplasia. B Show 10 more As per SPED/ESP/EHMSG/ESGE 2019 guidelines, perform endoscopy in patients with advanced stages of atrophic gastritis, particularly if H. pylori serology is negative. B Show 3 more As per ASGE 2017 guidelines, consider regarding a firm, round subepithelial lesion with central umbilication along the greater curve of the antrum of the stomach as diagnostic for a pancreatic rest. C Patients with precancerous gastric lesions, endoscopic ultrasound: As per ACG 2023 guidelines, consider performing EUS for the diagnosis of nonlipomatous subepithelial lesions. C Show 2 more As per ASGE 2017 guidelines: Consider performing EUS to further characterize indeterminate subepithelial lesions. C Do not perform further EUS for a pancreatic rest. D As per ASGE 2015 guidelines, perform EUS with or without FNA in the evaluation of gastric submucosal lesions. A Patients with precancerous gastric lesions, biopsy: As per ACG 2023 guidelines, avoid performing bite-on-bite biopsies in the evaluation of subepithelial lesions before an EUS. D Show 2 more As per BSG 2019 guidelines, perform biopsy to confirm the diagnosis in patients with image- enhanced features of chronic atrophic gastritis. Direct biopsies at mucosal sites within Sydney protocol areas where enhanced imaging discloses gastric intestinal metaplasia. Collect biopsy samples in separate containers and label them as either 'directed' or 'random' to corroborate the endoscopic staging assessment. B Show 3 more As per SPED/ESP/EHMSG/ESGE 2019 guidelines, perform gastric biopsies both for H. pylori infection diagnosis and identification of advanced stages of atrophic gastritis during the first diagnostic upper gastrointestinal endoscopy, to adequately stage gastric precancerous conditions. B Show 2 more https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 6/13 6/24/23, 2:55 AM Gastric cancer Pathway As per ASGE 2017 guidelines, consider performing FNA or fine needle biopsy of lesions arising from the muscularis propria for histologic evaluation. C As per ASGE 2015 guidelines, perform biopsy or resection of solitary gastric polyps when possible. A Show 4 more Patients with precancerous gastric lesions (serum pepsinogen levels): assess serum pepsinogen I level and serum pepsinogen I/II ratio to identify patients with advanced stages of atrophic gastritis, and perform endoscopy in these patients, particularly if H. pylori serology is negative. B Patients with precancerous gastric lesions, H. pylori eradication: As per AGA 2020 guidelines, test for and eradicate H. pylori infection in patients with gastric intestinal metaplasia. B As per BSG 2019 guidelines: Initiate H. pylori eradication therapy to reduce the risk of gastric adenocarcinoma development in patients with atrophic gastritis. A Consider initiating H. pylori eradication therapy to reduce the risk of developing gastric adenocarcinoma in patients with H. pylori-associated gastric intestinal metaplasia or dysplasia. B As per SPED/ESP/EHMSG/ESGE 2019 guidelines, initiate H. pylori eradication therapy for the management of non-atrophic chronic gastritis, regression of atrophic gastritis, and to reduce the risk of gastric cancer in patients with non-atrophic and atrophic gastritis. A Show 2 more Patients with precancerous gastric lesions, NSAIDs: As per BSG 2019 guidelines, do not use NSAIDs or COX-2 inhibitors to reduce the risk of progression of premalignant lesions of the stomach. D As per SPED/ESP/EHMSG/ESGE 2019 guidelines: Do not use COX-1 or COX-2 inhibitors to slow the progression of gastric precancerous conditions. D Consider offering daily low-dose aspirin for the prevention of various cancers, including gastric cancer, in selected patients. C Patients with precancerous gastric lesions (antioxidants): do not use antioxidants to reduce the prevalence of premalignant gastric lesions. D Patients with precancerous gastric lesions, endoscopic resection: As per ACG 2023 guidelines, consider performing endoscopic mucosal resection or endoscopic submucosal dissection for the resection of type 1 gastric NETs. C Show 2 more As per BSG 2019 guidelines, perform en bloc resection of all gastric dysplasia and early gastric adenocarcinoma. Recognize that an endoscopic mucosal resection technique can achieve en https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 7/13 6/24/23, 2:55 AM Gastric cancer Pathway bloc excision for lesions 10 mm in size, but only an endoscopic submucosal dissection technique can ensure en bloc excision for lesions > 10 mm in size. A Show 3 more As per ASGE 2015 guidelines: Perform endoscopic resection and surveillance endoscopy in patients with confirmed gastric intestinal metaplasia with high-grade dysplasia when feasible. B Consider performing polypectomy of fundic gland polyps 1 cm, hyperplastic polyps 0.5 cm, and adenomatous polyps of any size when possible. C Patients with precancerous gastric lesions, surgical resection: As per ACG 2023 guidelines: Consider performing either submucosal tunneling endoscopic resection or surgical resection, when resection is necessary, for the management of subepithelial lesions originating from the muscularis propria layer of the esophagus and GEJ. C Insufficient evidence to recommend surveillance versus resection of gastric gastrointestinal stromal tumors < 2 cm in size. Consider resecting gastric gastrointestinal stromal tumors > 2 cm and all non-gastric gastrointestinal stromal tumors owing to their malignant potential. I As per ASGE 2017 guidelines: Perform surgery for gastric gastrointestinal stromal tumors > 2 cm in size or with high-risk features. B Consider removing lesions with malignant potential requiring treatment, either endoscopically or surgically, based on the type of lesion, size, location, patient preference, and available expertise. C Patients with precancerous gastric lesions, endoscopic surveillance: As per AGA 2020 guidelines: Avoid obtaining routine endoscopic surveillance in patients with gastric intestinal metaplasia. D Avoid performing a routine short-interval repeat endoscopy for risk stratification of patients with gastric intestinal metaplasia. D As per BSG 2019 guidelines, obtain endoscopic surveillance every 3 years in patients with extensive atrophic gastritis or gastric intestinal metaplasia, defined as affecting the antrum and body. B Show 4 more As per SPED/ESP/EHMSG/ESGE 2019 guidelines, perform immediate high-quality endoscopic reassessment with chromoendoscopy (virtual or dye-based) in patients with dysplasia in the absence of an endoscopically defined lesion. Perform biopsies for the staging of gastritis (if not previously done) and endoscopic surveillance within 6 months (if high-grade dysplasia) to 12 months (if low-grade dysplasia), if no lesion is detected in this high-quality endoscopy. B Show 6 more As per ASGE 2017 guidelines, consider obtaining surveillance with EUS for gastric gastrointestinal stromal tumors < 2 cm in size. C https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 8/13 6/24/23, 2:55 AM Gastric cancer Pathway Show 2 more As per ASGE 2015 guidelines, consider performing endoscopy within 6 months of the diagnosis of pernicious anemia or the development of upper gastrointestinal symptoms in patients with pernicious anemia. C Show 3 more Patients with gastrointestinal stromal tumor (diagnosis): Make the diagnosis of gastrointestinal stromal tumor by a pathologist experienced in the disease. E Confirm the diagnosis before initiating neoadjuvant therapy with imatinib, since there is a wide differential. E Patients with gastrointestinal stromal tumor, endoscopic ultrasound: As per EURACAN/ESMO 2018 guidelines, obtain EUS and then follow-up in patients with gastric nodules < 2 cm. B As per BSG 2017 guidelines, obtain EUS in patients with lesions > 2 cm in diameter. E Patients with gastrointestinal stromal tumor, biopsy: As per GENTURIS/EURACAN/ESMO 2022 guidelines, perform resection if diagnosis of a gastrointestinal stromal tumor is made on biopsy unless major morbidity is expected. B As per EURACAN/ESMO 2018 guidelines, perform biopsy/excision in patients with tumors 2 cm. B As per BSG 2017 guidelines: Perform needle biopsy in patients with lesions > 2 cm in diameter, particularly if the lesion is in the stomach. E Consider performing percutaneous core needle biopsy if the tumor is inaccessible to EUS- guided biopsy. E Patients with gastrointestinal stromal tumor, mutational analysis: As per EURACAN/ESMO 2018 guidelines, obtain mutational analysis in the diagnostic work-up of patients with gastrointestinal stromal tumors (with the possible exclusion of < 2 cm non-rectal gastrointestinal stromal tumors). B As per BSG 2017 guidelines: Obtain mutational analysis and immunohistochemistry by an accredited laboratory for the diagnosis of gastrointestinal stromal tumors. E Obtain mutational analysis before neoadjuvant therapy since some gastrointestinal stromal tumors are insensitive to imatinib, such as patients with D842V mutation in exon 18 of PDGFRA. E Patients with gastrointestinal stromal tumor, chemotherapy, local/locoregional disease: As per GENTURIS/EURACAN/ESMO 2022 guidelines, consider offering neoadjuvant avapritinib in patients with PDGFRA-D842V mutation. B Show 2 more https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 9/13 6/24/23, 2:55 AM Gastric cancer Pathway As per EURACAN/ESMO 2018 guidelines, offer neoadjuvant therapy with imatinib if R0 surgery with no expected major sequelae is not feasible. B Show 4 more As per BSG 2017 guidelines: Consider offering preoperative imatinib in patients with large gastric or rectal primaries where immediate resection is likely to be morbid, such as total gastrectomy or abdomino-perineal resection. E Offer adjuvant imatinib for 3 years in patients at high risk of recurrence or distant relapse, provided the tumor is not likely to be resistant to therapy (PDGFRA exon 18 mutation D842V). E Patients with gastrointestinal stromal tumor, chemotherapy, advanced/metastatic disease: As per GENTURIS/EURACAN/ESMO 2022 guidelines, offer imatinib 400 mg/day as first-line therapy in patients with locally advanced, inoperable, and metastatic disease, except for gastrointestinal stromal tumors without KIT/PDGFRA mutations or with a PDGFRA exon 18 D842V mutation. A Show 7 more As per EURACAN/ESMO 2018 guidelines, offer imatinib in patients with locally advanced inoperable and metastatic disease. A Show 7 more As per BSG 2017 guidelines, offer imatinib 400 mg/day in patients with unresectable or metastatic disease. Consider offering a larger dose of imatinib in patients with exon 9 mutation in KIT. E Show 2 more Patients with gastrointestinal stromal tumor (radiotherapy): consider offering radiotherapy as a palliative resource in selected patients with gastrointestinal stromal tumor. C Patients with gastrointestinal stromal tumor, surgical excision, local/locoregional disease: As per GENTURIS/EURACAN/ESMO 2022 guidelines, perform complete surgical excision of the lesion with no dissection of clinically negative lymph nodes in patients with localized gastrointestinal stromal tumor. B Show 2 more As per EURACAN/ESMO 2018 guidelines, perform complete surgical excision of the lesion, with no dissection of clinically negative lymph nodes, for the treatment of patients with localized gastrointestinal stromal tumor. B Show 2 more As per ASGE 2017 guidelines, perform surgery in patients with gastric gastrointestinal stromal tumors > 2 cm in size and in patients with high-risk features. B Patients with gastrointestinal stromal tumor, surgical excision, advanced/metastatic disease: As per EURACAN/ESMO 2018 guidelines: Individualize surgery of residual metastatic disease after making the decision with the patient in the case of uncertainty. B https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 10/13 6/24/23, 2:55 AM Gastric cancer Pathway Consider performing surgical excision of progressing disease in individual patients with limited progression, while continuing imatinib. C As per BSG 2017 guidelines, consider performing surgery or other local measures, such as radiofrequency ablation, in patients with isolated progression. E Patients with gastrointestinal stromal tumor, surveillance imaging: As per GENTURIS/EURACAN/ESMO 2022 guidelines, obtain active surveillance in patients with gastrointestinal stromal tumor, if a biopsy is not feasible. B As per ASGE 2017 guidelines, consider obtaining surveillance EUS in patients with gastrointestinal stromal tumors < 2 cm in size. C As per BSG 2017 guidelines, obtain cross-sectional follow-up imaging in patients with a high- risk disease on adjuvant therapy at intervals of every 3-6 months during 3 years of treatment, 3 monthly for 2 years following cessation of treatment, and thereafter every 6 months for 3 years and annually for 5 years. E Show 2 more As per ASGE 2015 guidelines, consider obtaining annual EUS in patients with gastrointestinal stromal tumors < 2 cm to determine the progression of size or change in echo features, if surgical resection is not performed. C 11. Follow-up and surveillance Follow-up: obtain regular follow-up for investigation and treatment of symptoms, psychological support, and early detection of recurrence. B Show 3 more References 1. Banks M, Graham D, Jansen M et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019 Sep;68 9 1545 1575. Open 2. F Lordick, F Carneiro, S Cascinu et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Oct;33 10 1005 1020. Open 3. Sapna Syngal, Randall E Brand, James M Church et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110 2 223 62; quiz 263. Open 4. Pedro Pimentel-Nunes, Diogo Lib nio, Ricardo Marcos-Pinto et al. Management of epithelial precancerous conditions and lesions in the stomach MAPS II European Society of Gastrointestinal Endoscopy ESGE , European Helicobacter and Microbiota Study Group EHMSG , European Society of Pathology ESP , and Sociedade Portuguesa de Endoscopia Digestiva SPED guideline update 2019. Endoscopy. 2019 Apr;51 4 365 388. Open 5. Casali PG, Abecassis N, Aro HT et al. Gastrointestinal stromal tumours: ESMO EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Suppl 4):iv68-iv78. Open https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 11/13 6/24/23, 2:55 AM Gastric cancer Pathway 6. Ian Judson, Ramesh Bulusu, Beatrice Seddon et al. UK clinical practice guidelines for the management of gastrointestinal stromal tumours GIST . Clin Sarcoma Res. 2017 Apr 21;7 6. Open 7. Ronan J Kelly, Katherine Bever, Joseph Chao et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer. 2023 Jun;11 6):e006658. Open 8. Angela N Bartley, Mary Kay Washington, Carol Colasacco et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017 Feb;35 4 446 464. Open 9. Christopher J Black, Peter A Paine, Anurag Agrawal et al. British Society of Gastroenterology guidelines on the management of functional dyspepsia. Gut. 2022 Sep;71 9 1697 1723. Open 10. Brian C Jacobson, Amit Bhatt, Katarina B Greer et al. ACG Clinical Guideline: Diagnosis and Management of Gastrointestinal Subepithelial Lesions. Am J Gastroenterol. 2023 Jan 1;118 1 46 58. Open 11. Standards of Practice Committee, Ashley L Faulx, Shivangi Kothari et al. The role of endoscopy in subepithelial lesions of the GI tract. Gastrointest Endosc. 2017 Jun;85 6 1117 1132. Open 12. ASGE Standards of Practice Committee, John A Evans, Vinay Chandrasekhara et al. The role of endoscopy in the management of premalignant and malignant conditions of the stomach. Gastrointest Endosc. 2015 Jul;82 1 1 8. Open 13. Masakazu Yamamoto, Masahiro Yoshida, Junji Furuse et al. Clinical practice guidelines for the management of liver metastases from extrahepatic primary cancers 2021. J Hepatobiliary Pancreat Sci. 2021 Jan;28 1 1 25. Open 14. P G Casali, J Y Blay, N Abecassis et al. Gastrointestinal stromal tumours: ESMO EURACAN GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2022 Jan;33 1 20 33. Open 15. Roos E Pouw, Maximilien Barret, Katharina Biermann et al. Endoscopic tissue sampling Part 1 Upper gastrointestinal and hepatopancreatobiliary tracts. European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2021 Nov;53 11 1174 1188. Open 16. Samir Gupta, Dan Li, Hashem B El Serag et al. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology. 2020 Feb;158 3 693 702. Open 17. Chey WD, Leontiadis GI, Howden CW et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017 Feb;112 2 212 239. Open 18. Manish A Shah, Erin B Kennedy, Ashley E Alarcon-Rozas et al. Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline. J Clin Oncol. 2023 Jan 5;JCO2202331. Open 19. ASGE Standards of Practice Committee, Terry L Jue, Andrew C Storm et al. ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction. Gastrointest Endosc. 2021 Feb;93 2 309 322.e4. Open 20. Jean-Marc Dumonceau, Pierre H Deprez, Christian Jenssen et al. Indications, results, and clinical impact of endoscopic ultrasound EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy ESGE Clinical Guideline Updated January 2017. Endoscopy. 2017 Jul;49 7 695 714. Open https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 12/13 6/24/23, 2:55 AM Gastric cancer Pathway 21. ASGE Standards of Practice Committee, Early DS, Acosta RD et al. Adverse events associated with EUS and EUS with FNA. Gastrointest Endosc. 2013 Jun;77 6 839 43. Open 22. Muhammad Miftahussurur, Yoshio Yamaoka, David Y Graham. Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev Mol Med. 2017 Mar 21;19:e4. Open 23. E C Smyth, M Verheij, W Allum et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v38-v49. Open 24. N Stjepanovic, L Moreira, F Carneiro et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Oct 1;30 10 1558 1571. Open 25. Kaveh Sharzehi, Amrita Sethi, Thomas Savides. AGA Clinical Practice Update on Management of Subepithelial Lesions Encountered During Routine Endoscopy: Expert Review. Clin Gastroenterol Hepatol. 2022 Nov;20 11 2435 2443.e4. Open https://web.pathway.md/diseases/recTVyH1TVJCJ34JE 13/13

Guideline sources The following summarized guidelines for the evaluation and management of gastric outlet obstruction are prepared by our editorial team based on guidelines from the American Society for Gastrointestinal Endoscopy (ASGE 2021; 2010) and the American Gastroenterological Association (AGA 2021). 1 2 3 Guidelines 1. Diagnostic investigations Diagnostic endoscopy: perform endoscopy for the evaluation of gastric outlet obstruction in patients with peptic ulcer disease. A 2. Therapeutic procedures General principles: decide on specific interventions in patients with alimentary tract obstruction in a multidisciplinary setting including oncologists, surgeons and endoscopists and take into account the characteristics of the obstruction, patient's expectations, prognosis, expected subsequent therapies and functional status. B Endoscopic balloon dilation: consider performing endoscopic balloon dilation for gastric outlet obstruction in patients with peptic ulcer disease. C Endoscopic gastroduodenal stenting: https://web.pathway.md/diseases/recuWSpTkKFdgzFsd 1/2 6/24/23, 2:54 AM Gastric outlet obstruction Pathway p g g As per AGA 2021 guidelines: Consider placing an enteral stent in patients with gastric outlet obstruction not being candidates for gastrojejunostomy (surgical or EUS-guided). C Do not place enteral stents in patients with multiple luminal obstructions or severely impaired gastric motility because of the limited benefit in these scenarios. Consider placing venting gastrostomy in these patients. D As per ASGE 2021 guidelines, consider placing self-expandable metallic stents or performing surgical gastrojejunostomy in patients with incurable malignant gastric outlet obstruction undergoing palliative intervention. Decide between these approaches based on patient characteristics and preferences, multidisciplinary input, and local expertise. C Show 3 more 3. Surgical interventions Gastrojejunostomy: As per AGA 2021 guidelines, consider performing surgical gastrojejunostomy in patients with gastric outlet obstruction with a life expectancy > 2 months, having good functional status and being surgically fit. C Show 2 more As per ASGE 2021 guidelines, consider performing surgical gastrojejunostomy or placing self- expandable metallic stents in patients with incurable malignant gastric outlet obstruction undergoing palliative intervention. Decide between these approaches based on patient characteristics and preferences, multidisciplinary input, and local expertise. C Show 2 more References 1. ASGE Standards of Practice Committee, Terry L Jue, Andrew C Storm et al. ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction. Gastrointest Endosc. 2021 Feb;93 2 309 322.e4. Open 2. Osman Ahmed, Jeffrey H Lee, Christopher C Thompson et al. AGA Clinical Practice Update on the Optimal Management of the Malignant Alimentary Tract Obstruction: Expert Review. Clin Gastroenterol Hepatol. 2021 Sep;19 9 1780 1788. Open 3. ASGE Standards of Practice Committee, Subhas Banerjee, Brooks D Cash et al. The role of endoscopy in the management of patients with peptic ulcer disease. Gastrointest Endosc. 2010 Apr;71 4 663 8. Open https://web.pathway.md/diseases/recuWSpTkKFdgzFsd 2/2

Guideline sources The following summarized guidelines for the evaluation and management of gastroesophageal reflux disease are prepared by our editorial team based on guidelines from the American Gastroenterological Association (AGA 2023; 2012), the United European Gastroenterology (UEG/EAES 2022), the American College of Gastroenterology (ACG 2021; 2013), the European Society of Gastrointestinal Endoscopy (ESGE 2020), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN/NASPGHAN 2018), the American Academy of Pediatrics (AAP 2018), and the American College of Endocrinology (ACE/AACE 2016). 1 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Definition GERD is a disorder characterized by symptoms or signs caused by regurgitation of gastric contents into the esophagus, larynx, oral cavity, or lungs. 12 Epidemiology https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 1/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway Epidemiology GERD is due to transient lower esophageal sphincter relaxations, reduced lower esophageal sphincter pressure, hiatal hernias, impaired esophageal clearance, and delayed gastric emptying. 14 Pathophysiology The estimated prevalence of GERD symptoms in the United States ranges from 6% to 30%, with a weekly prevalence of symptoms approaching 20%. 13 Disease course Reflux of gastric contents leads to damage of the esophagus, heartburn, bronchoconstriction, esophagitis, strictures, Barrett's esophagus, and esophageal cancer. 15 Prognosis and risk of recurrence Barrett's esophagus occurs in about 10% of patients with chronic GERD. 16 Calculator Los Angeles classification of es Guidelines 1. Screening and diagnosis Diagnostic criteria: establish a presumptive diagnosis of GERD in the setting of typical symptoms of heartburn and regurgitation. B Differential diagnosis: Obtain diagnostic evaluation before institution of therapy in patients with non-cardiac chest pain suspected due to GERD. B Exclude a cardiac cause in patients with chest pain before the commencement of a gastrointestinal evaluation. B 2. Classification and risk stratification Endosopic classification: Categorize the endoscopic appearance of erosive esophagitis according to the Los Angeles classification system. B https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 2/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway Obtain further testing in patients with Los Angeles Grade A esophagitis to confirm the presence of GERD. B 3. Diagnostic investigations Barium esophagram: do not obtain barium swallow solely as a diagnostic test for GERD. D Ambulatory esophageal reflux monitoring: obtain reflux monitoring off therapy to establish the diagnosis in patients with suspected but not clear GERD, if endoscopy shows no objective evidence of GERD. B Show 2 more Esophageal manometry: do not obtain high-resolution manometry solely as a diagnostic test for GERD. D Screening for Helicobacter pylori infection: do not screen patients with GERD for H. pylori infection. Do not administer eradication therapy routinely as part of antireflux therapy. D Evaluation for gastroparesis: consider evaluating for the presence of gastroparesis in patients with GERD refractory to acid-suppressive treatment. C 4. Diagnostic procedures Upper gastrointestinal endoscopy: perform upper gastrointestinal endoscopy as the first test for evaluation of patients presenting with dysphagia or other alarm symptoms (weight loss and gastrointestinal bleeding) and of patients with multiple risk factors for Barrett's esophagus. B Show 2 more 5. Medical management Initial therapy: administer an 8-week trial of empiric PPIs once daily before a meal in patients with classic GERD symptoms of heartburn and regurgitation without alarm symptoms. B Show 4 more Maintenance therapy: As per ACG 2021 guidelines: Administer PPIs at the lowest dose that effectively controls GERD symptoms and maintains healing of reflux esophagitis in patients with GERD requiring maintenance therapy with PPIs. B Initiate maintenance therapy indefinitely or perform antireflux surgery in patients with Los Angeles grade C or D esophagitis. B As per ACG 2012 guidelines, titrate long-term acid suppression therapy with PPIs or H2RAs to the lowest effective dose needed to achieve therapeutic goals for pharmacological treatment of patients with GERD. B https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 3/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway Management of PPI side effects: consider switching PPIs in the setting of side effects. C Show 3 more Non-acid suppressive therapies: Do not use the following agents in patients with GERD: histamine-2-receptor antagonists for healing erosive esophagitis D baclofen in the absence of objective evidence of GERD D prokinetic agents of any kind unless there is objective evidence of gastroparesis D sucralfate, except during pregnancy. D Do not add medical therapies routinely in patients not responding to PPIs. D 6. Nonpharmacologic interventions Dietary modifications: Consider advising patients to avoid: meals within 2-3 hours of bedtime "trigger foods" for symptom control. C Weight loss: As per ACG 2021 guidelines, offer weight loss for improvement of GERD symptoms in patients with overweight or obesity. B As per AACE 2016 guidelines: Offer weight loss with the goal of losing 10% of body weight in patients with overweight or obesity and gastroesophageal reflux. A Prescribe PPIs during weight loss interventions in patients with overweight or obesity and persistent gastroesophageal reflux symptoms. A Smoking cessation: consider advising patients to avoid tobacco products/smoking. C Sleep-related interventions: consider advising elevating head of bed for nighttime symptom control. C 7. Therapeutic procedures Transoral incisionless fundoplication: As per ACG 2021 guidelines: Consider performing transoral incisionless fundoplication in patients with troublesome regurgitation or heartburn not wishing to undergo antireflux surgery and not having a severe esophagitis (Los Angeles grade C or D) or hiatal hernias > 2 cm. C Consider performing transoral incisionless fundoplication in patients with regurgitation as their primary PPI-refractory symptom and in patients with abnormal gastroesophageal reflux documented by objective testing. C https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 4/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway As per ESGE 2020 guidelines, do not perform transoral incisionless fundoplication as an alternative to PPI therapy or antireflux surgery for the treatment of GERD. Consider offering transoral incisionless fundoplication in patients with mild GERD not willing to take PPIs or undergo antireflux surgery. D Medigus ultrasonic surgical endostapler: do not perform Medigus ultrasonic surgical endostapler for the treatment of patients with GERD. Perform Medigus ultrasonic surgical endostapler in clinical trials only. D Stretta radiofrequency ablation: consider offering Stretta radiofrequency ablation of the lower esophageal sphincter to relieve symptoms only in selective patients in the absence of erosive esophagitis and a hiatal hernia. C Magnetic sphincter augmentation: consider offering magnetic sphincter augmentation as an alternative to laparoscopic fundoplication in patients with regurgitation failed medical management. B 8. Perioperative care Preoperative evaluation: Obtain careful evaluation to ensure that GERD is present and causes the symptoms, to exclude achalasia (which can be associated with symptoms such as heartburn and regurgitation that can be confused with GERD) and conditions that might be contraindications to invasive treatment, such as absent contractility, before performing invasive therapy for GERD. B Obtain high-resolution manometry before antireflux surgery or endoscopic therapy to rule out achalasia and absent contractility. Obtain provocative testing to identify contractile reserve (such as multiple rapid swallows) in patients with ineffective esophageal motility. B 9. Surgical interventions Indications for antireflux surgery: As per ACG 2021 guidelines, offer antireflux surgery by an experienced surgeon as an option for long-term treatment in patients with objective evidence of GERD, especially in patients with: severe reflux esophagitis (Los Angeles grade C or D) large hiatal hernias persistent, troublesome GERD symptoms. B As per ESGE 2020 guidelines, do not perform antireflux mucosectomy for the treatment of patients with GERD. D Technical considerations for antireflux surgery: consider performing posterior partial fundoplication over total posterior or anterior 90 degrees fundoplication in adult patients with GERD. Consider performing anterior > 90 degrees fundoplication as an alternative. C Bariatric surgery: https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 5/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway As per ACG 2021 guidelines, consider offering Roux-en-Y gastric bypass as an option for the treatment of GERD in patients with obesity eligible for bariatric surgery and willing to accept its risks and requirements for lifestyle alterations. C As per AACE 2016 guidelines: Consider offering Roux-en-Y gastric bypass as the bariatric surgery procedure of choice in patients with obesity and moderate-to-severe gastroesophageal reflux symptoms. C Do not use intragastric balloons for weight loss in patients with established gastroesophageal reflux. D 10. Specific circumstances Pregnant patients: recognize that PPIs are safe in pregnant patients, if clinically indicated. B Pediatric patients (diagnostic imaging): Consider obtaining a barium swallow or ultrasound to exclude anatomical abnormalities but not for the diagnosis of GERD in infant and pediatric patients. C Avoid obtaining scintigraphy for the diagnosis of GERD in infant and pediatric patients. D Pediatric patients (upper GI endoscopy): Avoid performing upper gastrointestinal endoscopy for the diagnosis of GERD in infant and pediatric patients. D Consider performing upper gastrointestinal endoscopy with biopsies to assess complications of GERD in patients with a suspected underlying mucosal disease or before escalating treatment. B Pediatric patients (manometry): Avoid obtaining manometry for the diagnosis of GERD in infant and pediatric patients. D Consider obtaining manometry in patients with a suspected motility disorder. B Pediatric patients (pH monitoring): Consider obtaining pH-multichannel intraluminal impedance testing only for the following purposes: correlate persistent troublesome symptoms with acid and non-acid gastroesophageal reflux events B clarify the role of acid and non-acid reflux in the etiology of esophagitis and other signs and symptoms suggestive of GERD C determine the efficacy of acid suppression therapy C differentiate non-erosive reflux disease, hypersensitive esophagus, and functional heartburn in patients with normal endoscopy. C Consider obtaining pH-metry only for the following purposes, if pH-multichannel intraluminal impedance testing is not available: correlate persistent troublesome symptoms with acid gastroesophageal reflux events https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 6/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway clarify the role of acid reflux in the etiology of esophagitis and other signs and symptoms suggestive of GERD determine the efficacy of acid suppression therapy. B Pediatric patients (biomarkers): Do not use salivary pepsin for the diagnosis of GERD in infant and pediatric patients. D Avoid using currently available extraesophageal biomarkers for the diagnosis of GERD in infant and pediatric patients. D Pediatric patients (trial of transpyloric/jejunal feeding): avoid offering a trial of transpyloric/jejunal feeding for the diagnosis of GERD in infant and pediatric patients. D Pediatric patients (trial of PPIs): Consider offering a 4-8 week trial of PPIs for typical symptoms (heartburn, retrosternal or epigastric pain) as a diagnostic test for GERD in pediatric patients. C Avoid offering a trial of PPIs as a diagnostic test for GERD in infant patients and in patients presenting with extraesophageal symptoms. D Pediatric patients (dietary modifications): consider administering thickened feed for the treatment of visible regurgitation/vomiting in infant patients with GERD. C Show 2 more Pediatric patients (transpyloric/jejunal feeding): consider administering transpyloric/jejunal feeding as an alternative to fundoplication for the treatment of infant and pediatric patients with GERD refractory to optimal treatment. C Pediatric patients (positioning therapy): Consider advising head elevation or left lateral positioning for GERD symptoms in pediatric patients. C Do not offer positional therapy (head elevation, lateral and prone positioning) for the treatment of GERD symptoms in sleeping infants. D Pediatric patients (acid suppression therapy): initiate PPIs as first-line therapy for reflux-related erosive esophagitis in infant and pediatric patients with GERD. A Consider initiating H2RAs if PPIs are not available or contraindicated. B Show 4 more Pediatric patients (prokinetics): Consider administering baclofen before surgery in pediatric patients if other pharmacological treatments have failed. C Avoid using domperidone and metoclopramide in the treatment of GERD in infant and pediatric patients. Avoid using other prokinetics (erythromycin, bethanechol) as first-line therapy in infant and pediatric patients with GERD. D Pediatric patients (probiotics): avoid using prebiotics or probiotics for the treatment of GERD. D Pediatric patients (alternative and complementary medicine): Avoid offering massage therapy for the treatment of GERD in infant patients. D https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 7/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway Avoid offering herbal medications for the treatment of GERD. D Pediatric patients (parental/patient counseling): Provide patient/parental education and support as part of the treatment of GERD. A Consider informing caregivers and patients that excessive body weight is associated with an increased prevalence of GERD. C Pediatric patients (assessment of treatment response): Assess treatment efficacy and exclude alternative causes of symptoms in infant and pediatric patients not responding to 4-8 weeks of optimal medical therapy for GERD. A Obtain a regular assessment of the ongoing need for long-term acid suppression therapy in infant and pediatric patients with GERD. A Pediatric patients (indications for referral): Refer infant and pediatric patients with GERD to a pediatric gastroenterologist in the following situations: presence of alarm signs or symptoms suggesting an underlying gastrointestinal disease patients are refractory to optimal treatment patients cannot be permanently weaned from pharmacological treatment within 6-12 months (consider obtaining additional evaluation after 4-8 weeks of optimal GERD therapy if clinically indicated). A Pediatric patients (indications for antireflux surgery): Consider performing antireflux surgery, including fundoplication, in infant and pediatric patients with GERD with any of the following: life-threatening complications (such as cardiorespiratory failure) of GERD after failure of optimal medical treatment symptoms refractory to optimal therapy, after appropriate evaluation excluding other underlying diseases chronic conditions (neurologically impaired, cystic fibrosis) with a significant risk of GERD- related complications the need for chronic pharmacotherapy to control signs and/or symptoms of GERD. C Pediatric patients (alternatives to fundoplication): do not perform total esophagogastric disconnection as first-line surgical treatment in infant and pediatric patients with GERD refractory to optimal treatment. D Consider performing total esophagogastric disconnection as a rescue procedure in neurologically impaired pediatric patients with a failed fundoplication. D Show 2 more Preterm infants: Recognize that: gastroesophageal reflux is almost universal in preterm infants gastroesophageal reflux is a physiologic process secondary to frequent transient lower esophageal sphincter relaxation, relatively large-volume liquid diet, and age-specific body positioning gastroesophageal reflux is a normal developmental phenomenon resolving with maturation pathologic gastroesophageal reflux occurs when reflux of acidic gastric contents causes injury to the lower esophageal mucosa https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 8/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway most gastroesophageal reflux episodes in preterm infants are only weakly acidic because of their lower gastric acidity and frequent milk feedings, making esophageal injury unlikely to occur signs commonly ascribed to gastroesophageal reflux in preterm infants include feeding intolerance or aversion, poor weight gain, frequent regurgitation, apnea, desaturation, bradycardia, and behavioral signs, including irritability and perceived postprandial discomfort the temporal association of perceived signs of gastroesophageal reflux with either acidic or nonacidic reflux episodes as measured by multichannel intraesophageal impedance and pH is not supported, and the signs will usually improve with time without treatment data regarding the possible association between worsening lung disease attributable to gastroesophageal reflux and microaspiration in mechanically ventilated preterm infants are sparse there is marked variability in the diagnosis and treatment of gastroesophageal reflux in preterm infants among neonatal ICUs, perhaps because the diagnosis is usually made by clinical assessment of signs and symptoms and/or a trial of nonpharmacologic or pharmacologic treatment rather than definitive tests. (Expert Opinion). E Show 2 more Patients with peptic strictures: Administer continuous PPI therapy following peptic stricture dilation, in order to improve dysphagia and reduce the need for repeated dilations. B Consider performing intralesional injection of corticosteroids in refractory, complex strictures due to GERD. C Patients with extraesophageal symptoms, evaluation: As per AGA 2023 guidelines, assess for extraesophageal manifestations of GERD, including laryngitis, chronic cough, asthma, and dental erosions, in patients with GERD to determine whether GERD may be a contributing factor to these conditions. B Show 7 more As per ACG 2021 guidelines, obtain evaluation for non-GERD causes in patients with possible extraesophageal manifestations before ascribing symptoms to GERD. B Show 7 more Patients with extraesophageal symptoms, management: As per AGA 2023 guidelines, consider offering an initial single-dose PPI trial titrating up to BID in patients with typical GERD symptoms and potential extraesophageal manifestations. C Show 2 more As per ACG 2021 guidelines: Consider offering a trial of PPIs BID for 8-12 weeks before obtaining additional testing in patients with both extraesophageal and typical GERD symptoms. C Perform surgical or endoscopic antireflux procedures in patients treated for extraesophageal reflux disease only if objective evidence of reflux is present. B 11. Follow-up and surveillance https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 9/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway Monitoring for Barrett's esophagus: Perform repeat endoscopy in patients with severe erosive reflux disease after a course of antisecretory therapy, in order to exclude underlying Barrett's esophagus. B Consider screening for Barrett's esophagus in patients with GERD being at high risk based on epidemiologic profile. C Management of refractory disease: optimize PPI therapy as the first step in the management of patients with refractory GERD. B Show 7 more References 1. Philip O Katz, Kerry B Dunbar, Felice H Schnoll-Sussman et al. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol. 2021 Nov 22. Open 2. Stephan C Bischoff, Johann Ockenga, Ahad Eshraghian et al. Practical guideline on obesity care in patients with gastrointestinal and liver diseases Joint ESPEN/UEG guideline. Clin Nutr. 2023 Apr 10;42 6 987 1024. Open 3. Rachel Rosen, Yvan Vandenplas, Maartje Singendonk et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Mar;66 3 516 554. Open 4. W Timothy Garvey, Jeffrey I Mechanick, Elise M Brett et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3 1 203. Open 5. Bas L A M Weusten, Maximilien Barret, Albert J Bredenoord et al. Endoscopic management of gastrointestinal motility disorders - part 2 European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2020 Jul;52 7 600 614. Open 6. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108 3 308 28. Open 7. Eichenwald EC. Diagnosis and Management of Gastroesophageal Reflux in Preterm Infants. Pediatrics. 2018 Jul;142 1 . pii: e20181061. Open 8. American Gastroenterological Association. Choosing Wisely: Recommendations of the American Gastroenterological Association. Choosing Wisely. 2012 Apr. Open 9. Joan W Chen, Marcelo F Vela, Kathryn A Peterson et al. AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review. Clin Gastroenterol Hepatol. 2023 Apr 13;S1542 3565 23 00143 X. Open 10. Camilleri M, Parkman HP, Shafi MA et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013 Jan;108 1 18 37. Open 11. Sheraz Markar, Alexandros Andreou, Luigi Bonavina et al. UEG and EAES rapid guideline: Update systematic review, network meta-analysis, CINeMA and GRADE assessment, and evidence-informed https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 10/11 6/24/23, 2:55 AM Gastroesophageal reflux disease Pathway European recommendations on surgical management of GERD. United European Gastroenterol J. 2022 Oct;1 16. Open 12. Sandhu DS, Fass R. Current Trends in the Management of Gastroesophageal Reflux Disease. Gut Liver. 2018 Jan 15;12 1 7 16. Open 13. Richter JE, Rubenstein JH. Presentation and Epidemiology of Gastroesophageal Reflux Disease. Gastroenterology. 2018 Jan;154 2 267 276. Open 14. Clarrett DM, Hachem C. Gastroesophageal Reflux Disease GERD . Mo Med. 2018 May-Jun;115 3 214 218. Open 15. Tack J, Pandolfino JE. Pathophysiology of Gastroesophageal Reflux Disease. Gastroenterology. 2018 Jan;154 2 277 288. Open 16. Harnik IG. In the Clinic. Gastroesophageal Reflux Disease. Ann Intern Med. 2015 Jul 7;163 1 ITC1. Open 17. Society of Hospital Medicine. Choosing Wisely SHM recommendations. Choosing Wisely. 2013. Open 18. American Gastroenterological Association. Choosing Wisely AGA recommendations. Choosing Wisely. 2012. Open 19. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2014. Open 20. Laura E Targownik, Deborah A Fisher, Sameer D Saini. AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology. 2022 Feb 16;S0016 5085 21 04083 X. Open 21. Barbara Farrell, Kevin Pottie, Wade Thompson et al. Deprescribing proton pump inhibitors: Evidence- based clinical practice guideline. Can Fam Physician. 2017 May;63 5 354 364. Open 22. St phane Groulx, Heather Limburg, Marion Doull et al. Guideline on screening for esophageal adenocarcinoma in patients with chronic gastroesophageal reflux disease. CMAJ. 2020 Jul 6;192 27 E768 E777. Open 23. SHP. Choosing Wisely SHP recommendations. SHP. 2013. Open https://web.pathway.md/diseases/recx1QuF4NuiAPSjI 11/11

Guideline sources The following summarized guidelines for the evaluation and management of gastroesophageal varices (GEV) are prepared by our editorial team based on guidelines from the European Society of Gastrointestinal Endoscopy (ESGE 2022), the European Association for the Study of the Liver (EASL 2018), the American Association for the Study of Liver Diseases (AASLD 2017), the American College of Gastroenterology (ACG 2016), the British Society of Gastroenterology (BSG 2015), the American Society for Gastrointestinal Endoscopy (ASGE 2014), and the American College of Gastroenterology (ACG/AASLD 2007). 1 2 3 4 5 6 7 8 8 8 9 10 Definition GEV are abnormally dilated submucosal distal veins developing at sites near the formation of gastroesophageal collateral circulation. 8 Epidemiology GEV are most frequently caused by portal hypertension (a result of cirrhosis due to alcoholic liver disease, NASH, and hepatitis C infection). 8 Pathophysiology https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 1/6 6/24/23, 3:16 AM Gastroesophageal varices Pathway The rate of hospitalization due to esophageal varices in the United States is estimated at 1181 per 100,000 population/year. 9 Disease course GEV correlate with the severity of liver disease and are present with other symptoms of chronic liver disease including spider nevi, jaundice, palmar erythema, splenomegaly, ascites, encephalopathy, and caput medusae. The disease increases the risk of variceal bleeding and rebleeding and is associated with increased morbidity and mortality. 10 Prognosis and risk of recurrence The six-week mortality rate of patients with index esophageal variceal bleeding is approximately 20%. 8 Guidelines 1. Screening and diagnosis Indications for screening: As per EASL 2018 guidelines, obtain screening upper gastrointestinal endoscopy for GEV, if not previously diagnosed and treated, in patients with decompensated cirrhosis. B Show 2 more As per BSG 2015 guidelines, obtain performing endoscopy in all patients with cirrhosis at the time of diagnosis. A As per ASGE 2014 guidelines, obtain screening endoscopy in all patients with a diagnosis of cirrhosis, to assess for esophageal and gastric varices. A Show 3 more As per ACG 2007 guidelines, perform screening upper gastrointestinal endoscopy when a diagnosis of cirrhosis is made in order to assess for the presence of esophageal and/or gastric varices. B 2. Classification and risk stratification Endoscopic classification: Classify esophageal varices as small or large (> 5 mm) on upper gastrointestinal endoscopy, with the latter classification encompassing medium and large-sized varices when 3 grades (small, medium, large) are used. B Report the presence or absence of red signs on varices. B 3. Medical management https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 2/6 6/24/23, 3:16 AM Gastroesophageal varices Pathway Primary prevention of variceal hemorrhage: As per ESGE 2022 guidelines: Initiate nonselective -blockers (preferably carvedilol), if not contraindicated, to prevent the development of variceal bleeding in patients with compensated advanced chronic liver disease and clinically significant portal hypertension (hepatic venous pressure gradient > 10 mmHg and/or liver stiffness by transient elastography > 25 kPa). B Perform endoscopic band ligation as the endoscopic prophylactic treatment of choice in patients unable to receive nonselective -blocker therapy with high-risk esophageal varices on screening upper gastrointestinal endoscopy. Repeat endoscopic band ligation every 2-4 weeks until variceal eradication is achieved. Obtain surveillance upper gastrointestinal endoscopy every 3-6 months in the first year following eradication. B As per EASL 2018 guidelines, initiate primary prophylaxis upon detection of high-risk varices - small varices with red signs, medium or large varices irrespective of Child-Pugh classification, or small varices in Child-Pugh C patients - in patients with decompensated cirrhosis A , ascites, or an acute intercurrent condition. B Show 7 more As per AASLD 2017 guidelines, initiate nonselective -blockers for the prevention of first variceal hemorrhage in patients with small varices at high risk of bleeding (red wale sign or red spot). E Show 5 more As per BSG 2015 guidelines, initiate primary prophylaxis in patients with grade I varices and red signs or grade 2-3 varices, irrespective of the severity of the liver disease. A Show 6 more As per ASGE 2014 guidelines, perform endoscopic variceal ligation in patients with large esophageal varices unable to tolerate or having contraindications to nonselective -blockers. B Show 3 more Secondary prevention of variceal hemorrhage: As per ESGE 2022 guidelines: Perform follow-up endoscopic band ligations at 1- to 4-weekly intervals to eradicate esophageal varices (secondary prophylaxis) in patients undergone endoscopic band ligation for acute esophageal variceal hemorrhage. B Initiate nonselective -blockers (propranolol or carvedilol) in combination with endoscopic therapy for secondary prophylaxis in esophageal variceal hemorrhage in patients with advanced chronic liver disease. A As per AASLD 2017 guidelines, initiate nonselective -blockers combined with endoscopic variceal ligation as first-line therapy for the prevention of rebleeding in patients with a history of variceal hemorrhage. E Show 3 more As per BSG 2015 guidelines, initiate nonselective -blockers (propranolol or nadolol) and variceal band ligation combination therapy for secondary prophylaxis in patients with variceal hemorrhage. A https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 3/6 6/24/23, 3:16 AM Gastroesophageal varices Pathway Show 9 more As per ASGE 2014 guidelines: Repeat endoscopy with endoscopic variceal ligation after treatment of the acute episode of variceal hemorrhage until varices have been eradicated. B Consider repeating endoscopy at 1- to 8-week intervals for endoscopic variceal ligation for secondary prophylaxis. C Management of beta-blockers: Avoid high doses of nonselective -blockers in patients with refractory ascites and SBP (e.g. > 160 mg/day of propranolol or > 80 mg/day of nadolol), given that they might be associated with worse outcomes. D Decrease or temporarily hold nonselective -blockers in patients with refractory ascites and severe circulatory dysfunction (systolic BP < 90 mmHg, serum sodium < 130 meq/L) or hepatorenal syndrome. Consider re-introduction if clinical status improves. E 4. Specific circumstances Pregnant patients: Obtain screening upper endoscopy for esophageal varices in the second trimester in pregnant patients with suspected portal hypertension. B Initiate treatment with -blockers and/or offer band ligation in pregnant patients with large esophageal varices. B 5. Preventative measures Primary prevention: As per AASLD 2017 guidelines, insufficient evidence to support the use of nonselective - blockers for the prevention of varices formation. I As per ACG 2007 guidelines, do not use nonselective -blockers to prevent the development of varices in patients with cirrhosis. D 6. Follow-up and surveillance Surveillance endoscopy: As per BSG 2015 guidelines, consider repeating endoscopy at 2-3-year intervals if no varices are found at the time of the first endoscopy. C Show 2 more As per ACG 2007 guidelines: Repeat upper gastrointestinal endoscopy in 3 years in patients with compensated cirrhosis and no varices on the initial endoscopy. A https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 4/6 6/24/23, 3:16 AM Gastroesophageal varices Pathway Obtain upper gastrointestinal endoscopy in patients with hepatic decompensation, and yearly thereafter. A References 1. Garcia-Tsao G, Abraldes JG, Berzigotti A et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017 Jan;65 1 310 335. Open 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 3. Dhiraj Tripathi, Adrian J Stanley, Peter C Hayes et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015 Nov;64 11 1680 704. Open 4. Ian M Gralnek, Marine Camus Duboc, Juan Carlos Garcia-Pagan et al. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2022 Sep 29. Open 5. Garcia-Tsao G, Sanyal AJ, Grace ND et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007 Sep;46 3 922 38. Open 6. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 7. Joo Ha Hwang, Amandeep K Shergill, Ruben D Acosta et al. The role of endoscopy in the management of variceal hemorrhage. Gastrointest Endosc. 2014 Aug;80 2 221 7. Open 8. Umesha Boregowda, Chandraprakash Umapathy, Nasir Halim et al. Update on the management of gastrointestinal varices. 2019 Jan 21;10 1 1 21.2019 Jan 21;10 1 1 21. Open 9. Shantanu Solanki, Khwaja Fahad Haq, Raja Chandra Chakinala et al. Inpatient burden of esophageal varices in the United States: analysis of trends in demographics, cost of care, and outcomes. Ann Transl Med. 2019 Sep;7 18 480. Open 10. Said A Al-Busafi, Julia McNabb-Baltar, Amanda Farag et al. Clinical manifestations of portal hypertension. Int J Hepatol. 2012;2012 203794. Open 11. de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015 Sep;63 3 743 52. Open 12. Umesha Boregowda, Chandraprakash Umapathy, Nasir Halim et al. Update on the management of gastrointestinal varices. World J Gastrointest Pharmacol Ther. 2019 Jan 21;10 1 1 21. Open 13. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 14. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 15. Zachary Henry, Kalpesh Patel, Heather Patton et al. AGA Clinical Practice Update on Management of Bleeding Gastric Varices: Expert Review. Clin Gastroenterol Hepatol. 2021 Jun;19 6 1098 1107.e1. Open https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 5/6 6/24/23, 3:16 AM Gastroesophageal varices Pathway https://web.pathway.md/diseases/rec9MnwsHIoir9ytM 6/6

Guideline sources The following summarized guidelines for the evaluation and management of gastrointestinal stromal tumors (GIST) are prepared by our editorial team based on guidelines from the Spanish Group for Research on Sarcomas (GEIS/SEOM 2023), the European Reference Network on Genetic Tumour Risk Syndromes (GENTURIS/EURACAN/ESMO 2022), the British Sarcoma Group (BSG 2017), and the American Society for Gastrointestinal Endoscopy (ASGE 2017; 2015). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Diagnosis: Make the diagnosis of gastrointestinal stromal tumor by a pathologist experienced in the disease. E Confirm the diagnosis before initiating neoadjuvant therapy with imatinib, since there is a wide differential. E 2. Diagnostic investigations https://web.pathway.md/diseases/reccYKyQAenMjDTV9 1/5 6/24/23, 3:16 AM Gastrointestinal stromal tumors Pathway Imaging for staging: obtain contrast-enhanced abdominopelvic CT with image acquisitions of the arterial and portal phases for evaluating tumor extension. B Circulating tumor DNA: insufficient evidence to recommend assessing circulating tumor DNA for clinical purposes. I 3. Diagnostic procedures Endoscopic ultrasound: as per BSG 2017 guidelines, obtain EUS in patients with lesions > 2 cm in diameter. E Core-needle biopsy: Perform a core needle biopsy for the initial diagnosis of GIST. B Do not perform a biopsy in patients with imatinib-resistant GIST with the sole purpose of determining the KIT/PDGFRA genotype. D Excisional biopsy: As per GENTURIS 2022 guidelines, perform resection if diagnosis of a gastrointestinal stromal tumor is made on biopsy unless major morbidity is expected. B As per BSG 2017 guidelines: Perform needle biopsy in patients with lesions > 2 cm in diameter, particularly if the lesion is in the stomach. E Consider performing percutaneous core needle biopsy if the tumor is inaccessible to EUS- guided biopsy. E Mutational analysis: As per SEOM 2023 guidelines, obtain mutational analysis in all patients with GIST requiring medical treatment. B As per BSG 2017 guidelines: Obtain mutational analysis and immunohistochemistry by an accredited laboratory for the diagnosis of GIST. E Obtain mutational analysis before neoadjuvant therapy since some GIST are insensitive to imatinib, such as patients with D842V mutation in exon 18 of PDGFRA. E 4. Medical management General principles: manage patients with gastrointestinal stromal tumor by an experienced multidisciplinary team. E Management of local/locoregional disease, neoadjuvant therapy: As per GEIS/SEOM 2023 guidelines, consider offering neoadjuvant imatinib in certain patients with high volume, requiring function-sparing surgery, or at risk of bleeding. C https://web.pathway.md/diseases/reccYKyQAenMjDTV9 2/5 6/24/23, 3:16 AM Gastrointestinal stromal tumors Pathway As per GENTURIS/EURACAN/ESMO 2022 guidelines, consider offering neoadjuvant avapritinib in patients with PDGFRA-D842V mutation. B As per BSG 2017 guidelines, consider offering preoperative imatinib in patients with large gastric or rectal primaries where immediate resection is likely to be morbid, such as total gastrectomy or abdominoperineal resection. E Management of local/locoregional disease, surgical excision: As per GENTURIS/EURACAN/ESMO 2022 guidelines, perform complete surgical excision of the lesion with no dissection of clinically negative lymph nodes in patients with localized gastrointestinal stromal tumor. B Show 2 more As per ASGE 2017 guidelines, perform surgery in patients with gastric and colorectal GIST > 2 cm in size and in patients with high-risk features. B Management of local/locoregional disease, adjuvant therapy: As per GEIS/SEOM 2023 guidelines, use the NIH-modified risk criteria to determine the risk of relapse for the indication of adjuvant imatinib. A Show 4 more As per GENTURIS/EURACAN/ESMO 2022 guidelines: Offer adjuvant therapy with imatinib 400 mg/day for 3 years in patients with a significant risk of relapse. A Consider offering adjuvant imatinib at a higher dose of 800 mg/day for 3 years in patients with KIT exon 9 mutation. C As per BSG 2017 guidelines, offer adjuvant imatinib for 3 years in patients at high risk of recurrence or distant relapse, provided the tumor is not likely to be resistant to therapy (PDGFRA exon 18 mutation D842V). E Management of advanced/metastatic disease, systemic therapy, first line: As per GEIS/SEOM 2023 guidelines, offer imatinib 400 mg/day as first-line therapy in patients with metastatic GIST. A Show 3 more As per GENTURIS/EURACAN/ESMO 2022 guidelines, offer imatinib 400 mg/day as first-line therapy in patients with locally advanced, inoperable, and metastatic disease, except for GIST without KIT/PDGFRA mutations or with a PDGFRA exon 18 D842V mutation. A Show 4 more As per BSG 2017 guidelines, offer imatinib 400 mg/day in patients with unresectable or metastatic disease. Consider offering a larger dose of imatinib in patients with exon 9 mutation in KIT. E Management of advanced/metastatic disease, systemic therapy, second line: As per GEIS/SEOM 2023 guidelines, offer sunitinib 50 mg/day 4 weeks on, 2 weeks off as second-line therapy in patients with GIST. A Consider offering a continuous dose of sunitinib 37.5 mg once daily for better tolerance. B https://web.pathway.md/diseases/reccYKyQAenMjDTV9 3/5 6/24/23, 3:16 AM Gastrointestinal stromal tumors Pathway As per GENTURIS/EURACAN/ESMO 2022 guidelines, offer sunitinib 50 mg/day 4 weeks on/2 weeks off or, as an alternative schedule, 37.5 mg once daily as second-line therapy in case of confirmed progression or rare intolerance on imatinib. A As per BSG 2017 guidelines, offer sunitinib 50 mg/day for 4 weeks every 6 weeks, or 37.5 mg/day continuously as second-line therapy in patients with advanced/metastatic disease. E Management of advanced/metastatic disease, systemic therapy, third and fourth lines: As per GEIS/SEOM 2023 guidelines, offer regorafenib 160 mg/day 3 weeks on, 1 week off as third-line therapy, and ripretinib 150 mg/day as fourth-line therapy in patients with GIST. A As per GENTURIS/EURACAN/ESMO 2022 guidelines: Offer regorafenib 160 mg/day for 3 out of every 4 weeks as third-line therapy in patients progressing on or failing to respond to imatinib and sunitinib. A Offer ripretinib 150 mg/day as fourth-line therapy in patients progressing on or intolerant to imatinib, sunitinib, and regorafenib. A As per BSG 2017 guidelines, offer regorafenib as third-line therapy in patients with advanced/metastatic disease. E Management of advanced/metastatic disease, surgical excision: As per GEIS/SEOM 2023 guidelines, consider performing surgery in metastatic disease on an individual basis within a multidisciplinary tumor board. C As per BSG 2017 guidelines, consider performing surgery or other local measures, such as radiofrequency ablation, in patients with isolated progression. E Management of advanced/metastatic disease (radiotherapy): consider offering radiotherapy as a palliative resource in selected patients with gastrointestinal stromal tumor. C 5. Follow-up and surveillance Surveillance imaging: As per ESMO 2022 guidelines, obtain active surveillance in patients with gastrointestinal stromal tumor, if a biopsy is not feasible. B As per ASGE 2017 guidelines, consider obtaining surveillance EUS in patients with GIST < 2 cm in size. C As per BSG 2017 guidelines, obtain cross-sectional follow-up imaging in patients with a high- risk disease on adjuvant therapy at intervals of every 3-6 months during 3 years of treatment, 3 monthly for 2 years following cessation of treatment, and thereafter every 6 months for 3 years and annually for 5 years. E Show 2 more As per ASGE 2015 guidelines, consider obtaining annual EUS in patients with GIST < 2 cm to determine the progression of size or change in echo features, if surgical resection is not performed. C https://web.pathway.md/diseases/reccYKyQAenMjDTV9 4/5 6/24/23, 3:16 AM Gastrointestinal stromal tumors Pathway References 1. P G Casali, J Y Blay, N Abecassis et al. Gastrointestinal stromal tumours: ESMO EURACAN GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2022 Jan;33 1 20 33. Open 2. C sar Serrano, Rosa lvarez, Juan Antonio Carrasco et al. SEOM GEIS clinical guideline for gastrointestinal stromal tumors 2022 . Clin Transl Oncol. 2023 May 2. Online ahead of print. Open 3. Ian Judson, Ramesh Bulusu, Beatrice Seddon et al. UK clinical practice guidelines for the management of gastrointestinal stromal tumours GIST . Clin Sarcoma Res. 2017 Apr 21;7 6. Open 4. ASGE Standards of Practice Committee, John A Evans, Vinay Chandrasekhara et al. The role of endoscopy in the management of premalignant and malignant conditions of the stomach. Gastrointest Endosc. 2015 Jul;82 1 1 8. Open 5. Standards of Practice Committee, Ashley L Faulx, Shivangi Kothari et al. The role of endoscopy in subepithelial lesions of the GI tract. Gastrointest Endosc. 2017 Jun;85 6 1117 1132. Open 6. Casali PG, Abecassis N, Aro HT et al. Gastrointestinal stromal tumours: ESMO EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Suppl 4):iv68-iv78. Open https://web.pathway.md/diseases/reccYKyQAenMjDTV9 5/5

Guideline sources The following summarized guidelines for the evaluation and management of gastroparesis (GP) are prepared by our editorial team based on guidelines from the American College of Gastroenterology (ACG 2022; 2013), the American Gastroenterological Association (AGA 2022), the European Society for Neurogastroenterology and Motility (ESNM/UEG 2021), and the European Society of Gastrointestinal Endoscopy (ESGE 2020). 1 2 3 4 5 6 6 6 6 6 Definition GP is a syndrome characterized by delayed gastric emptying and symptoms thereof in the absence of gastric outlet obstruction. 6 Epidemiology GP is most frequently caused by diabetes mellitus neuropathy and idiopathic causes. Other causes include iatrogenic vagotomy (surgery for peptic ulcer disease, fundoplication), post-infection, CNS diseases (stroke, other causes of autonomic neuropathy, Parkinson's disease, spinal cord injury), paraneoplastic syndrome, polymyositis, scleroderma, drugs (opiates, anticholinergic drugs), https://web.pathway.md/diseases/recclytopqFECMeFt 1/7 6/24/23, 3:16 AM Gastroparesis Pathway metabolic disorders (hypothyroidism, hyperparathyroidism, Addison's disease), lung transplantation, anorexia nervosa, and pregnancy. 6 Pathophysiology The incidence of GP in the United States women and men is estimated at 9.8 per 100,000 person- years and 2.4 per 100,000 person-years, respectively. 6 Disease course Clinical manifestations include nausea, vomiting, upper abdominal pain or discomfort, early satiety, postprandial fullness, bloating, heartburn, and dysphagia. Severe disease is related to depression, anxiety, increased hospitalizations, medication, or tube feeding decreasing quality of life. 6 Prognosis and risk of recurrence GP independently is not associated with increased mortality. 6 Guidelines 1. Screening and diagnosis Clinical presentation: Recognize that: GP refers to a symptom or set of symptoms associated with delayed gastric emptying A and severely disturbed gastric motor function in the absence of mechanical obstruction B nausea and vomiting are cardinal symptoms of GP B dyspeptic symptoms, such as postprandial fullness, early satiation, epigastric pain, as well as bloating in the upper abdomen and belching are often present in GP B symptoms in GP overlap mainly with postprandial distress syndrome and less with epigastric pain syndrome symptoms of functional dyspepsia B GP is associated with a significant decrease in quality of life A GP is associated with psychosocial comorbidities, such as anxiety and depression. A Diagnosis: diagnose GP based on the combination of symptoms of GP, absence of gastric outlet obstruction or ulceration, and delay in gastric emptying. A Differential diagnosis: As per AGA 2022 guidelines, review symptoms and perform a physical examination to exclude disorders possibly mimicking medically refractory GP. B As per UEG 2021 guidelines: Exclude eating disorders in case of weight loss. B Consider obtaining imaging to exclude small bowel obstruction. C As per ACG 2013 guidelines, consider evaluating for the presence of GP in patients with GERD refractory to acid-suppressive treatment. C https://web.pathway.md/diseases/recclytopqFECMeFt 2/7 6/24/23, 3:16 AM Gastroparesis Pathway Show 3 more 2. Classification and risk stratification Risk factors: Recognize that the following conditions are associated with an increased risk for the development of GP: diabetes A partial gastric resection/vagotomy, bariatric surgery, and antireflux surgery B certain neurological disorders, such as Parkinson's disease, multiple sclerosis, and amyloid neuropathy B certain connective tissue diseases B certain drugs, such as opioids. A Recognize that the prognosis of GP depends on the cause. B Severity assessment: classify patients with GP into mild, moderate, or severe based on symptoms and the results of a properly performed gastric emptying study. B 3. Diagnostic investigations Pre-test preparation: Discontinue medications affecting gastric emptying at least 48 hours before diagnostic testing, or > 48 hours before testing depending on the pharmacokinetics of the medication. A Measure blood glucose level in patients with diabetes before gastric emptying testing, and treat hyperglycemia with a test started after blood glucose is < 275 mg/dL. B Gastric emptying studies, modalities: As per ACG 2022 guidelines, obtain scintigraphic gastric emptying as the first-line test for the evaluation of GP in patients with upper gastrointestinal symptoms. B Show 3 more As per ESNM/UEG 2021 guidelines: Obtain gastric emptying testing to establish a diagnosis of GP. A Obtain scintigraphic gastric emptying or breath test assessment as a valid test for diagnosing GP. A Gastric emptying studies, methodology: As per ACG 2022 guidelines, ensure appraising the emptying of a solid meal over 3 hours during scintigraphic gastric emptying. B As per AGA 2022 guidelines, verify the appropriate methodology of the gastric emptying study to ensure an accurate diagnosis of delayed gastric emptying. B Functional lumen imaging probe: consider obtaining endoluminal functional lumen imaging probe evaluation for characterizing pyloric function and predicting treatment outcomes after https://web.pathway.md/diseases/recclytopqFECMeFt 3/7 6/24/23, 3:16 AM Gastroparesis Pathway peroral pyloromyotomy in patients with GP. C Evaluation for underlying cause: screen patients with GP for the presence of diabetes mellitus, thyroid dysfunction, neurological disease, prior gastric or bariatric surgery, and autoimmune disorders. A Show 3 more 4. Diagnostic procedures Upper gastrointestinal endoscopy: perform upper gastrointestinal endoscopy to establish a diagnosis of GP. A 5. Medical management General principles: As per ACG 2022 guidelines, consider offering pharmacotherapy to improve gastric emptying and GP symptoms in patients with idiopathic and diabetic GP, taking into account the benefits and risks of treatment. C As per AGA 2022 guidelines: Identify the predominant symptom and initiate treatment based on that symptom. B Recognize the multiple treatment options available for the management of nausea and vomiting. B Cessation of precipitating medications: Discontinue narcotics and other medications delaying gastric emptying to establish the diagnosis with a gastric emptying test. A Consider discontinuing pramlintide and GLP-1 agonists before initiation of therapy for GP in patients taking these medications, as they have been associated with delayed gastric emptying. C Glycemic control: consider ensuring optimal glucose control to reduce the future risk of aggravation of GP in patients with diabetic GP. C Prokinetics and antiemetics: As per ACG 2022 guidelines, consider offering metoclopramide for the management of refractory symptoms in patients with GP. C Show 3 more As per UEG 2021 guidelines, offer dopamine-2 antagonists and 5-HT4 agonists for the management of patients with GP. B Neuromodulators: As per ACG 2022 guidelines, do not use central neuromodulators for the treatment of patients with GP. D https://web.pathway.md/diseases/recclytopqFECMeFt 4/7 6/24/23, 3:16 AM Gastroparesis Pathway As per AGA 2022 guidelines, consider offering neuromodulators for the treatment of GP- associated abdominal pain. Do not use opioids. C Ghrelin agonists: do not use ghrelin agonists for the treatment of patients with GP. D Haloperidol: do not use haloperidol for the treatment of patients with GP. D 6. Nonpharmacologic interventions Dietary therapy: As per ACG 2022 guidelines, offer a small particle size diet as dietary management of GP to increase likelihood of symptom relief and enhance gastric emptying. B As per UEG 2021 guidelines: Implement dietary adjustments for managing patients with GP. B Provide nutritional support in the form of enteral or parenteral nutrition in case of severe weight loss or intractable vomiting. B As per ACG 2013 guidelines, refer patients to a dietitian for counseling regarding consumption of frequent small volume nutrient meals low in fat and soluble fiber. B Show 5 more Acupuncture: consider offering acupuncture, alone or acupuncture in combination with prokinetic drugs, for symptom control in patients with diabetic GP. Do not offer acupuncture for other etiologies of GP. C Herbal products: do not use herbal therapies, such as Rikkunshito or STW5 for the treatment of patients with GP. D 7. Therapeutic procedures Indications for endoscopic pylorus-directed therapies: consider offering endoscopic pylorus- directed therapies only in patients with symptoms suggestive of GP in combination with objective proof of delayed gastric emptying using a validated test, and only when medical therapy has failed. B Intrapyloric injection of botulinum toxin: As per ACG 2022 guidelines, do not administer intrapyloric injection of botulinum toxin in patients with GP. D As per ESGE 2020 guidelines: Do not use botulinum toxin injections for the treatment of unselected patients with GP. D Do not use botulinum toxin injection as the screening test to select patients for endoscopic pyloromyotomy or other pylorus-directed therapies. D Endoscopic pyloric dilation: avoid performing balloon dilation for the treatment of unselected patients with GP. D https://web.pathway.md/diseases/recclytopqFECMeFt 5/7 6/24/23, 3:16 AM Gastroparesis Pathway Endoscopic transpyloric stenting: do not perform transpyloric stenting for the treatment of patients with GP. D Gastric electrical stimulation: As per ACG 2022 guidelines, consider offering gastric electrical stimulation for symptom control in patients with GP. C As per AGA 2022 guidelines, consider offering gastric electrical stimulation in patients with GP and refractory/intractable nausea and vomiting failed standard therapy and not taking opioids. C 8. Perioperative care Perioperative antibiotic prophylaxis: administer prophylactic antibiotics during gastric POEM. Adapt the choice and duration of antibiotics according to national or local protocols. B 9. Surgical interventions Gastric peroral endoscopic myotomy: As per ACG 2022 guidelines, consider performing pyloromyotomy for symptom control in patients with GP with symptoms refractory to medical therapy. C As per AGA 2022 guidelines, consider performing gastric POEM in selected patients with refractory GP with severe delay in gastric emptying, using a thoughtful team approach involving motility specialists and advanced endoscopists at a center of excellence. C As per ESGE 2020 guidelines, consider performing gastric POEM only in carefully selected patients. Perform gastric POEM only in expert centers, preferably in the context of a clinical trial. B Show 3 more References 1. Jolien Schol, Lucas Wauters, Ram Dickman et al. United European Gastroenterology UEG and European Society for Neurogastroenterology and Motility ESNM consensus on gastroparesis. United European Gastroenterol J. 2021 Apr;9 3 287 306. Open 2. Camilleri M, Parkman HP, Shafi MA et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013 Jan;108 1 18 37. Open 3. Michael Camilleri, Braden Kuo, Linda Nguyen et al. ACG Clinical Guideline: Gastroparesis. Am J Gastroenterol. 2022 Aug 1;117 8 1197 1220. Open 4. Brian E Lacy, Jan Tack, C Prakash Gyawali. AGA Clinical Practice Update on Management of Medically Refractory Gastroparesis: Expert Review. Clin Gastroenterol Hepatol. 2022 Mar;20 3 491 500. Open https://web.pathway.md/diseases/recclytopqFECMeFt 6/7 6/24/23, 3:16 AM Gastroparesis Pathway 5. Bas L A M Weusten, Maximilien Barret, Albert J Bredenoord et al. Endoscopic management of gastrointestinal motility disorders - part 1 European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2020 Jun;52 6 498 515. Open 6. Adil E Bharucha. Epidemiology and natural history of gastroparesis. 2015 Mar;44 1 9 19.2015 Mar;44 1 9 19. Open 7. Adil E Bharucha. Epidemiology and natural history of gastroparesis. Gastroenterol Clin North Am. 2015 Mar;44 1 9 19. Open https://web.pathway.md/diseases/recclytopqFECMeFt 7/7

Guideline sources The following summarized guidelines for the evaluation and management of gender dysphoria are prepared by our editorial team based on guidelines from the American College of Obstetricians and Gynecologists (ACOG 2021), the Endocrine Society (ES 2017), and the American Psychiatric Association (APA 2015). 1 2 3 Guidelines 1. Screening and diagnosis Gender identity: Recognize that: gender is a nonbinary construct that allows for a range of gender identities and that a person's gender identity may not align with the sex assigned at birth gender identity and sexual orientation are distinct but interrelated constructs stigma, prejudice, discrimination, and violence affect the health and well-being of transgender and gender-nonconforming people gender-questioning/transgender and gender-nonconforming children and adolescents have different developmental needs and not all youth will persist in a transgender and gender- nonconforming identity into adulthood transgender and gender-nonconforming people are more likely to experience positive life outcomes when they receive social support or trans-affirmative care. E https://web.pathway.md/diseases/recaYQMG48XRcfBeX 1/4 6/24/23, 3:16 AM Gender dysphoria Pathway Diagnosis: Ensure that only trained mental health professionals meeting the following criteria diagnose gender dysphoria/gender incongruence in adults: competence in using the DSM and/or the International Classification of Diseases for diagnostic purposes ability to diagnose gender dysphoria/gender incongruence and make a distinction between gender dysphoria/gender incongruence and conditions having similar features (such as body dysmorphic disorder) training in diagnosing psychiatric conditions ability to undertake or refer for appropriate treatment ability to psychosocially assess the person's understanding, mental health, and social conditions that can impact gender-affirming hormone therapy practice of regularly attending relevant professional meetings. E Ensure that only trained mental health professionals meeting the following criteria diagnose gender dysphoria/gender incongruence in children and adolescents: training in child and adolescent developmental psychology and psychopathology competence in using the DSM and/or the International Classification of Diseases for diagnostic purposes ability to make a distinction between gender dysphoria/gender incongruence and conditions having similar features (such as body dysmorphic disorder) training in diagnosing psychiatric conditions ability to undertake or refer for appropriate treatment ability to psychosocially assess the person's understanding and social conditions that can impact gender-affirming hormone therapy practice of regularly attending relevant professional meetings knowledge of the criteria for puberty blocking and gender-affirming hormone treatment in adolescents. E 2. Medical management Management of prepubertal children: make decisions regarding the social transition of prepubertal youths with gender dysphoria/gender incongruence with the assistance of a mental health professional or another experienced professional. E Show 2 more Management of adolescents: initiate treatment to suppress pubertal development in adolescents meeting diagnostic criteria for gender dysphoria/gender incongruence, fulfilling criteria for treatment, and requesting treatment. B Show 5 more Management of adults (evaluation): confirm the diagnostic criteria of gender dysphoria/gender incongruence and the criteria for the endocrine phase of gender transition before initiating https://web.pathway.md/diseases/recaYQMG48XRcfBeX 2/4 6/24/23, 3:16 AM Gender dysphoria Pathway treatment. B Show 2 more Management of adults, counseling: As per ACOG 2021 guidelines: Discuss fertility and parenting desires early in the process of transition before the initiation of hormone therapy or gender affirmation surgery. E Recognize that gender-affirming hormone therapy is not effective contraception. Counsel sexually active individuals with retained gonads not wishing to become pregnant or cause pregnancy in others about the possibility of pregnancy if thet have a sexual activity involving sperm and oocytes. E As per ES 2017 guidelines, consider educating transgender individuals undergoing treatment about the onset and course of physical changes induced by sex hormone treatment. C Management of adults, surgery: As per ACOG 2021 guidelines, perform hysterectomy with or without bilateral salpingo- oophorectomy in patients with gender dysphoria desiring this procedure. E As per ES 2017 guidelines, consider determining the necessity of including a total hysterectomy and oophorectomy as part of gender-affirming surgery. E Show 6 more 3. Follow-up and surveillance Serial clinical and laboratory assessment: consider obtaining regular clinical evaluation for physical changes and potential adverse changes in response to sex steroid hormones and laboratory monitoring of sex steroid hormone levels every 3 months during the first year of hormone therapy in transgender males and females and then once or twice yearly. C Show 2 more Surveillance for osteoporosis: obtain bone mineral density measurements when risk factors for osteoporosis exist, specifically in persons discontinuing sex hormone therapy after gonadectomy. B Surveillance for malignancy: As per ACOG 2021 guidelines, screen any anatomical structure warranting screening, regardless of gender identity, to guide preventive medical care. E As per ES 2017 guidelines: Consider following breast-screening guidelines recommended for non-transgender females for transgender females with no known increased risk of breast cancer. C Consider obtaining individualized screening according to personal risk for prostatic disease and prostate cancer in transgender females treated with estrogens. C 4. Quality improvement https://web.pathway.md/diseases/recaYQMG48XRcfBeX 3/4 6/24/23, 3:16 AM Gender dysphoria Pathway Health equity and accessibility: Ensure that obstetric-gynecology offices are inclusive and invite all persons needing obstetric or gynecologic care. Ensure that obstetrician-gynecologists educate themselves and their medical teams about appropriate language and the health needs of transgender patients. E Recognize that most medications used for gender transition are common and can be safely prescribed by a wide variety of healthcare professionals with appropriate training and education, including, but not limited to, obstetrician-gynecologists, family or internal medicine physicians, endocrinologists, advanced practice clinicians, and psychiatrists. E References 1. Wylie C Hembree, Peggy T Cohen-Kettenis, Louis Gooren et al. Endocrine Treatment of Gender- Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017 Nov 1;102 11 3869 3903. Open 2. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice, American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women. Health Care for Transgender and Gender Diverse Individuals: ACOG Committee Opinion, Number 823. Obstet Gynecol. 2021 Mar 1;137 3):e75-e88. Open 3. American Psychological Association. Guidelines for psychological practice with transgender and gender nonconforming people. Am Psychol. 2015 Dec;70 9 832 64. Open https://web.pathway.md/diseases/recaYQMG48XRcfBeX 4/4

Guideline sources The following summarized guidelines for the evaluation and management of generalized anxiety disorder are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2023), the U.S. Preventive Services Task Force (USPSTF 2022), the Women's Preventive Services Initiative (WPSI 2020), the Anxiety Disorders Association of Canada (ADAC 2014), the British Association for Psychopharmacology (BAP 2014), and the National Institute for Health and Care Excellence (NICE 2011). 1 2 3 4 5 6 7 7 8 9 10 Definition GAD is a chronic disorder characterized by excessive anxiety and worry about a number of events or activities (e.g., work, home, and social) symptoms, and tension, which an individual finds difficult to control. 7 Epidemiology GAD is mostly caused by genetic (altered DNA methylation and single nucleotide polymorphism) and environmental factors (stress, trauma, etc.). 7 Pathophysiology https://web.pathway.md/diseases/recULNMK8C8cNBOuE 1/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway Pathophysiology The lifetime prevalence of DSM-5 GAD in the United States is estimated at 7800 cases per 100,000 individuals. 8 Disease course Clinical manifestations include restless feeling, fatigue, difficulty concentrating, irritability, muscle tension, sleep disturbance, arguments with relatives or friends, difficulty/inability to complete tasks, restriction of usual activities, with associated autonomic, cardiovascular, respiratory, gastrointestinal, and urinary symptoms decreasing the overall health of the individual. GAD is associated with various comorbidities including depression, dysthymia, bipolar I and II, panic disorder with/without agoraphobia, social phobia, specific phobia, substance use disorder, and personality disorders (avoidant, dependent, obsessive-compulsive, paranoid, schizoid, and antisocial). 9 Prognosis and risk of recurrence Anxiety disorders are associated with an increased risk of death with a natural mortality rate ratio of 1.39 (95% CI 1.28-1.51) and an unnatural mortality rate ratio of 2.46 (95% CI 2.20-2.73). 10 Calculator Calculator Generalized anxiety disorder-7 s Hamilton anxiety scale HAM A Guidelines 1. Screening and diagnosis Diagnosis: consider a diagnosis of GAD in patients presenting with anxiety or substantial worry and in patients who attend primary care frequently who have a chronic physical health problem or do not have a physical health problem but are seeking reassurance about somatic symptoms or are repeatedly worrying about a wide range of different issues. E Indications for screening (women): obtain screening for anxiety in adolescent and adult females aged 13 years, including pregnant and postpartum females. E Indications for screening (children): Obtain screening for anxiety in children and adolescents aged 8-18 years. B Insufficient evidence to assess the balance of benefits and harms of screening for anxiety in children aged 7 years. I Indications for screening (general population): do not obtain routine screening for the presence of anxiety symptoms in all patients. D https://web.pathway.md/diseases/recULNMK8C8cNBOuE 2/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway 2. Diagnostic investigations Assessment: conduct a comprehensive assessment in patients with GAD that considers the degree of distress and functional impairment; the effect of any comorbid mental health disorder, substance misuse, or medical condition; and past response to treatment. E 3. Medical management General principles: offer drug treatment to patients with GAD as a choice of second-line therapy. A Show 3 more Antidepressants: As per ADAC 2014 guidelines, evidence from randomized control trials supports the use of SSRIs (including escitalopram and sertraline), as well as the use of SNRIs (duloxetine and venlafaxine XR) for the treatment of GAD. A As per NICE 2011 guidelines, offer a SSRI to patients with GAD if they choose drug treatment. Consider sertraline first because it is the most cost-effective drug. Offer an alternative SSRI if sertraline is ineffective. A As per NICE 2011 guidelines, offer a serotonin noradrenaline reuptake inhibitor to patients with GAD if sertraline is ineffective. A Anticonvulsants: As per ADAC 2014 guidelines, in patients with GAD, randomized control trials indicate that the anticonvulsant pregabalin was more effective than placebo and as effective as benzodiazepines. A As per NICE 2011 guidelines, consider pregabalin in patients with GAD if they cannot tolerate SSRIs or serotonin noradrenaline reuptake inhibitors. B Antipsychotics: do not offer an antipsychotic for the treatment of patients with GAD in primary care as the evidence for clinical efficacy is poor, while the risk of serious side effects are well- known. D Benzodiazepines: As per ADAC 2014 guidelines: Alprazolam, bromazepam, diazepam, and lorazepam have demonstrated effectiveness to manage GAD. A Do not offer a benzodiazepine for the treatment of patients with GAD in primary or secondary care except as a short-term measure during crises. Buspirone: several randomized control trials show that buspirone was more potent than placebo and as effective as benzodiazepines. A Trazodone: in a randomized control trial, trazodone was as effective as diazepam. B Herbal preparations: https://web.pathway.md/diseases/recULNMK8C8cNBOuE 3/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway Lavender oil has revealed success comparable to lorazepam to treat GAD. A Galphimia glauca extract has revealed success comparable to lorazepam to treat GAD. B 4. Nonpharmacologic interventions Transcranial magnetic stimulation: in a small open trial, repetitive transcranial magnetic stimulation was effective as monotherapy or as an adjunct to SSRIs for the treatment of GAD. B Exercise training: A randomized control trial of adjunctive resistance training or aerobic exercise demonstrated significant symptomatic improvements compared to a wait-list condition. B Acupuncture: insufficient evidence to determine efficacy of acupuncture in GAD or anxiety neurosis. I Meditation and yoga: adjunctive meditation and yoga-based treatments may be beneficial in patients with GAD, as suggested by open-label studies. B Updated evidence: TAME In adults with a diagnosed anxiety disorder, mindfulness-based stress reduction was noninferior to escitalopram with respect to anxiety levels reduction as assessed with clinical global impression of severity scale. Elizabeth A Hoge et al. JAMA Psychiatry. 2022 Nov 9. Bright light therapy: in a randomized control trial, there were no significant improvements with initiating bright light therapy compared with placebo. B Active monitoring: monitor the symptoms and functioning of patients with GAD. Active monitoring may improve less severe presentations and avoid the need for further interventions. E Over-the-counter preparations: insufficient evidence to recommend over the counter preparations to patients with GAD. Discuss the use of over the counter preparations, explain the potential for interactions with other medications (for example, St John's wort with oral contraception). I First-line therapy: Offer one or more of the following first-line, low-intensity interventions to patients with GAD guided by the patient's preference, if symptoms have not improved after education and active monitoring: individual non-facilitated self-help (usually involving minimal contact with a healthcare professional) individual guided self-help (supported by a trained practitioner, who facilitates the program and reviews progress and outcome) https://web.pathway.md/diseases/recULNMK8C8cNBOuE 4/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway participation in psychoeducational groups (conducted by trained practitioners and based on the principles of CBT; groups with a ratio of one therapist to about 12 participants). B Include printed or electronic materials of a readability level suitable for the individual based on the treatment principles of CBT in the individual non-facilitated and guided self-help. B Second-line therapy: Offer a choice of the following to patients with GAD if functional impairment is marked or symptoms have not improved after low intensity interventions: an individual, high-intensity psychological intervention - CBT or applied relaxation, in which patients learn to apply relaxation skills in anxiety provoking situations B drug treatment. A Show 2 more 5. Specific circumstances Patients with comorbid mental health conditions: Treat the primary disorder first in patients with a comorbid depressive or other anxiety disorder - that is, the first is the one that is more severe and treatment of which is more likely to improve overall functioning. E Treat the substance misuse first in patients with harmful and dependent substance misuse, as it may lead to substantial improvement in the symptoms of GAD. E Patients with cancer (evaluation): obtain regular screening and assessment for anxiety in all patients with cancer in all phases of illness. B Show 3 more Patients with cancer (management): offer a combination of psychotherapeutic and psychopharmacological modalities for the treatment of anxiety in patients with cancer. A Show 4 more 6. Patient education Patient education: educate patients with known and suspected presentations of GAD about their disorder and the treatment options. Education may improve less severe presentations and avoid the need for further interventions. E 7. Follow-up and surveillance Follow-up: offer drug treatment to patients with GAD if the condition has not responded to a full course of a high-intensity psychological treatment. E Show 4 more Likelihood Ratios https://web.pathway.md/diseases/recULNMK8C8cNBOuE 5/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway Pertinent positives The following findings increase the probability of generalized anxiety disorder in adults. -1 Finding LR+ Value Positive GAD-7 score 5.1 (4.3-6.0) Positive BAI-PC score 4.6 (2.3-8.9) Positive ADS-GA score 3.2 (1.3-8.0) Positive SDDS-PC score 2.6 (1.6-4.1) Show 2 more Pertinent negatives The following findings decrease the probability of generalized anxiety disorder in adults. -1 Finding LR- Value Negative PRIME-MD score 0.12 (0.05-0.29) Negative GAD-7 score 0.13 (0.07-0.26) Negative GAD-Q-IV score 0.18 (0.1-0.5) Negative BAI-PC score 0.19 (0.05-0.68) Show 1 more References 1. L Grassi, R Caruso, M B Riba et al. Anxiety and depression in adult cancer patients: ESMO Clinical Practice Guideline. ESMO Open. 2023 Apr;8 2 101155. Epub 2023 Mar 14. Open 2. Tim Kendall, director, visiting professor et al. Management of generalised anxiety disorder in adults: summary of NICE guidance. BMJ. 2011; 342 c7460. Open 3. Katzman MA, Bleau P, Blier P et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14 Suppl 1 S1. Open 4. David S Baldwin, Ian M Anderson, David J Nutt et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014 May;28 5 403 39. Open 5. US Preventive Services Task Force, Carol M Mangione, Michael J Barry et al. Screening for Anxiety in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. 2022 Oct 11;328 14 1438 1444. Open 6. Kimberly D Gregory, David Chelmow, Heidi D Nelson et al. Screening for Anxiety in Adolescent and Adult Women: A Recommendation From the Women's Preventive Services Initiative. Ann Intern Med. 2020 Jul 7;173 1 48 56. Open 7. Michelle A Patriquin, Sanjay J Mathew. The Neurobiological Mechanisms of Generalized Anxiety Disorder and Chronic Stress. Chronic Stress Thousand Oaks). Jan-Dec 2017;1 2470547017703993. Open https://web.pathway.md/diseases/recULNMK8C8cNBOuE 6/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway 8. Ayelet Meron Ruscio, Lauren S Hallion, Carmen C W Lim et al. Cross-sectional Comparison of the Epidemiology of DSM 5 Generalized Anxiety Disorder Across the Globe. 2017 May 1;74 5 465 475.2017 May 1;74 5 465 475. Open 9. Analuc a A Alegr a, Deborah S Hasin, Edward V Nunes et al. Comorbidity of generalized anxiety disorder and substance use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2010 Sep;71 9 1187 95; quiz 1252 3. Open 10. Sandra M Meier, Manuel Mattheisen, Ole Mors et al. Increased mortality among people with anxiety disorders: total population study. Br J Psychiatry. 2016 Sep;209 3 216 21. Open 11. Gautam S, Jain A, Gautam M et al. Clinical Practice Guidelines for the Management of Generalised Anxiety Disorder GAD and Panic Disorder PD . Indian J Psychiatry. 2017 Jan;59 Suppl 1 S67 S73. Open 12. Hicks JK, Bishop JR, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium CPIC Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug;98 2 127 34. Open 13. Risa B Weisberg. Overview of generalized anxiety disorder: epidemiology, presentation, and course. J Clin Psychiatry. 2009;70 Suppl 2 4 9. Open 14. Oriana Vesga-L pez, Franklin R Schneier, Samuel Wang et al. Gender differences in Generalized Anxiety Disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions NESARC . J Clin Psychiatry. 2008 Oct;69 10 1606 16. Open 15. Gemma Taylor, Ann McNeill, Alan Girling et al. Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ. 2014 Feb 13;348:g1151. Open 16. Patricia Moreno-Peral, Sonia Conejo-Cer n, Emma Motrico et al. Risk factors for the onset of panic and generalised anxiety disorders in the general adult population: a systematic review of cohort studies. J Affect Disord. 2014 Oct;168 337 48. Open 17. Borwin Bandelow, Reinhard Boerner J, Siegfried Kasper et al. The diagnosis and treatment of generalized anxiety disorder. Dtsch Arztebl Int. 2013 Apr;110 17 300 9; quiz 310. Open 18. Borwin Bandelow, Sophie Michaelis, Dirk Wedekind. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017 Jun;19 2 93 107. Open 19. Allison Bickett and Hazel Tapp. Anxiety and diabetes: Innovative approaches to management in primary care. Exp Biol Med Maywood). 2016 Sep; 241 15 1724 1731. Open 20. Eva-Maria Siegmann, Helge H O M ller, Caroline Luecke et al. Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 1;75 6 577 584. Open 21. E Sherwood Brown, Patricia A. Chandler. Mood and Cognitive Changes During Systemic Corticosteroid Therapy. Prim Care Companion J Clin Psychiatry. 2001 Feb;3 1 17 21. Open 22. Daniel David, Ioana Cristea, Stefan G Hofmann. Why Cognitive Behavioral Therapy Is the Current Gold Standard of Psychotherapy. Front Psychiatry. 2018 Jan 29;9 4. Open 23. Robert H Howland. Buspirone: Back to the Future. J Psychosoc Nurs Ment Health Serv. 2015 Nov;53 11 21 4. Open https://web.pathway.md/diseases/recULNMK8C8cNBOuE 7/8 6/24/23, 3:16 AM Generalized anxiety disorder Pathway 24. Jeffrey R Strawn, Laura Geracioti, Neil Rajdev et al. Pharmacotherapy for Generalized Anxiety Disorder in Adults and Pediatric Patients: An Evidence-Based Treatment Review. Expert Opin Pharmacother. 2018 Jul;19 10 1057 1070. Open 25. Ayelet Meron Ruscio, Lauren S Hallion, Carmen C W Lim et al. Cross-sectional Comparison of the Epidemiology of DSM 5 Generalized Anxiety Disorder Across the Globe. JAMA Psychiatry. 2017 May 1;74 5 465 475. Open 26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision DSM 5 TR ). APA. 2022. Open 27. Alan D Bell, Caroline MacCallum, Shari Margolese et al. Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions. Cannabis Cannabinoid Res. 2023 Mar 27. Open 28. Barbara L Andersen, Christina Lacchetti, Kimlin Ashing et al. Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update. J Clin Oncol. 2023 Apr 19;JCO2300293. Open 29. Corina Benjet, Nur Hani Zainal, Yesica Albor et al. A Precision Treatment Model for Internet-Delivered Cognitive Behavioral Therapy for Anxiety and Depression Among University Students: A Secondary Analysis of a Randomized Clinical Trial. JAMA Psychiatry. 2023 Jun 7;e231675. Online ahead of print. Open https://web.pathway.md/diseases/recULNMK8C8cNBOuE 8/8

Guideline sources The following summarized guidelines for the evaluation and management of genital herpes are prepared by our editorial team based on guidelines from the U.S. Preventive Services Task Force (USPSTF 2023; 2014), the Infectious Diseases Society of America (IDSA/CDC/NIH/HIVMA 2023; 2018), the Center for Disease Control (CDC 2021), the French National College of Gynecologists and Obstetricians (CNGOF 2018), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2017), and the World Health Organization (WHO 2016). 1 2 3 4 5 6 7 8 9 10 10 11 12 13 Definition Genital herpes is a sexually transmitted viral infection characterized by primary and recurrent genital inflammation and lesions. 10 Epidemiology Genital herpes is mostly caused by HSV-2 and HSV-1 transmitted through sexual contact. 10 Pathophysiology The incidence of genital herpes in North America is estimated to range from 5000 to 24000 per 100,000 people per year. 11 https://web.pathway.md/diseases/recglkWFSOh6s6aIz 1/8 6/24/23, 3:19 AM Genital herpes Pathway Disease course Clinical manifestations include lesions of mucous membrane presenting as bilateral clusters of macules, papules, followed by vesicles, pustules, and ulcers on the external genitalia with symptoms of pain, itching, burning, dysuria, lymphadenopathy, fever, cervicitis (women), and proctitis (homosexual men). Complications in women include aseptic meningitis and urinary retention. Recurrent episodes may show prodromal symptoms of paresthesia and pains in the area of lumbosacral dermatomes. Asymptomatic genital shedding without any clinical symptoms is quite frequent. The disease increases psychological stress with frequent recurrences. 12 Prognosis and risk of recurrence Untreated pregnancy-related genital herpes is associated with a mortality of 0.062 per 1,000 births in neonates. 13 Guidelines 1. Screening and diagnosis Indications for screening: do not obtain routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant persons. D 2. Diagnostic investigations Laboratory testing: obtain laboratory testing to confirm the diagnosis of genital herpes. B 3. Medical management Management of first episode: As per CDC 2021 guidelines: Administer any of the following antiviral regimens for 7-10 days in patients with a first clinical episode of genital herpes: Situation Guidance 400 mg PO TID Acyclovir 250 mg PO TID Famciclovir 1,000 mg PO BID. E Valacyclovir Consider extending treatment if healing is incomplete after 10 days of therapy. E https://web.pathway.md/diseases/recglkWFSOh6s6aIz 2/8 6/24/23, 3:19 AM Genital herpes Pathway As per SOGC 2017 guidelines, administer antiviral therapy with valacyclovir in patients with proven genital herpes. B As per WHO 2016 guidelines, consider administering antiviral therapy with a standard dose of aciclovir C in adult and adolescent patients with a first clinical episode of genital HSV infection. B Management of recurrent episode: As per CDC 2021 guidelines, administer any of the following regimens for episodic therapy in patients with recurrent HSV-2 genital herpes: Situation Guidance 800 mg PO BID for 5 days Acyclovir 800 mg PO TID for 2 days 1,000 mg PO BID for 1 day Famciclovir 500 mg PO once, followed by 250 mg BID for 2 days 125 mg PO BID for 5 days 500 mg PO BID for 3 days Valacyclovir 1,000 mg PO once daily for 5 days. E As per WHO 2016 guidelines, consider administering antiviral therapy with acyclovir in adult and adolescent patients with a recurrent episode of genital HSV infection. C 4. Specific circumstances Pregnant patients, evaluation: As per CNGOF 2018 guidelines: Do not obtain virologic confirmation for genital herpes lesions during pregnancy in patients with a history of genital herpes. D Obtain virological confirmation with PCR and assess for the specific IgG type in pregnant patients with genital lesions with no previous history of genital herpes. E As per SOGC 2017 guidelines, assess for the history of genital herpes early in pregnancy. B Show 2 more Pregnant patients, suppressive therapy: As per CDC 2021 guidelines, initiate suppression therapy with acyclovir (400 mg PO TID) or valacyclovir (500 mg PO BID) at 36 weeks of gestation in pregnant patients with recurrent genital herpes. E As per CNGOF 2018 guidelines: https://web.pathway.md/diseases/recglkWFSOh6s6aIz 3/8 6/24/23, 3:19 AM Genital herpes Pathway Initiate antiviral prophylaxis from 36 weeks of gestation until delivery in patients with either a first or recurrent episode of genital herpes during pregnancy. B Do not initiate routine prophylaxis in patients with a history of genital herpes but no recurrence during pregnancy. D As per SOGC 2017 guidelines, initiate suppression therapy with acyclovir or valacyclovir at 36 weeks of gestation to decrease the risk of clinical lesions and viral shedding at the time of delivery and decrease the need for C-section in pregnant patients with known recurrent genital HSV infection. A Pregnant patients (antiviral therapy): administer antiviral therapy with aciclovir (200 mg 5 times daily) or valaciclovir (1,000 mg BID for the first episode, 500 mg BID for a recurrent episode) for 5- 10 days in patients with a first or recurrent episode of genital herpes during pregnancy. B Pregnant patients, considerations for delivery: As per CNGOF 2018 guidelines: Offer Cesarean delivery in patients with a suspected or confirmed first episode of genital herpes at the onset of labor, (Grade B) < 6 weeks before delivery, or in the event of premature rupture of membranes at term. E Consider offering Cesarean delivery in patients with a recurrence of genital herpes at the onset of labor when the membranes are intact. Consider offering vaginal delivery in cases of prolonged rupture of membranes. E As per SOGC 2017 guidelines: Offer Cesarean delivery at delivery in pregnant patients with recurrent HSV in the presence of prodromal symptoms or a lesion suggestive of HSV. B Counsel pregnant patients with primary genital herpes in the third trimester of pregnancy about the high risk of transmitting HSV to their neonates. Offer Cesarean delivery to decrease this risk. B Patients with HIV (primary prevention): encourage using latex condoms to to prevent transmission of HSV-2 and other sexually transmitted pathogens. B Show 5 more Patients with HIV, suppressive therapy: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, initiate suppressive therapy with acyclovir (400 mg PO BID), valacyclovir (500 mg PO BID), or famciclovir (500 mg PO BID) to prevent recurrences of HSV lesions in human immunodeficiency virus-positive patients with severe or frequent HSV recurrences or wishing to minimize the frequency of recurrences, including pregnant patients. A Show 2 more As per CDC 2021 guidelines, initiate daily suppressive therapy with any of the following antiviral regimens in human immunodeficiency virus-positive patients with genital herpes: Situation Guidance 400-800 mg PO BID or TID Acyclovir https://web.pathway.md/diseases/recglkWFSOh6s6aIz 4/8 6/24/23, 3:19 AM Genital herpes Pathway 500 mg PO BID Famciclovir 500 mg PO BID. E Valacyclovir Patients with HIV, antiviral therapy: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, administer acyclovir (400 mg PO TID), valacyclovir (1,000 mg PO BID), or famciclovir (500 mg PO BID) for 7-10 days for the first episode and 5-10 days for a recurrent episode of genital herpes in human immunodeficiency virus-positive patients. A Show 3 more As per CDC 2021 guidelines, administer any of the following antiviral regimens for 5-10 days as episodic therapy in human immunodeficiency virus-positive patients with recurrent genital herpes: Situation Guidance 400 mg PO TID Acyclovir 500 mg PO BID Famciclovir 1,000 mg PO BID. E Valacyclovir Patients with HIV (pregnant patients): administer acyclovir as the antiviral drug of choice during pregnancy, particularly during the second and third trimesters. B Show 4 more Patients with HIV (pediatric patients): advise adolescent and young adult patients with human immunodeficiency virus infection to use condoms to prevent HSV infection and other sexually transmitted diseases. B Show 3 more Neonate patients: Obtain various samples (blood and CSF) for HSV PCR to confirm the diagnosis in neonates with suspected neonatal herpes. E Administer IV acyclovir 20 mg/kg TID A in neonates with suspected neonatal herpes before the PCR results are available. Decide on the duration of the treatment depending on the clinical form. E 5. Patient education General counseling: As per SOGC 2017 guidelines, counsel on condom use and safe sex in patients with proven genital herpes. B https://web.pathway.md/diseases/recglkWFSOh6s6aIz 5/8 6/24/23, 3:19 AM Genital herpes Pathway As per USPSTF 2014 guidelines, provide intensive behavioral counseling to all sexually active adolescents and adults at increased risk for STIs. B 6. Preventative measures Condom use: advise using condoms to reduce the risk of genital herpes transmission. B Suppressive therapy: As per CDC 2021 guidelines, initiate suppressive therapy with any of the following regimens in patients with recurrent HSV-2 genital herpes: Situation Guidance 400 mg PO BID Acyclovir 500-1,000 mg PO once daily Valacyclovir 250 mg PO BID. E Famciclovir As per SOGC 2017 guidelines: Consider initiating suppressive therapy in patients with 6 recurrences per year, < 6 recurrences per year but with significant complications, significantly affected quality of life, or social and sexual dysfunction. C Consider initiating suppressive therapy to reduce the risk of transmission to a sexual partner or fetus/neonate. C As per WHO 2016 guidelines, consider initiating suppressive therapy with aciclovir C in adolescent and adult patients with recurrent episodes of severe, or distress-causing genital HSV infection. Reassess the need for continued therapy after 1 year C References 1. Panel on Opportunistic Infections in Children with and Exposed to HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children with and Exposed to HIV Herpes Simplex Virus. Department of Health and Human Services. 2018. Open 2. No authors listed. WHO Guidelines for the Treatment of Genital Herpes Simplex Virus. Geneva: World Health Organization; 2016. Open 3. US Preventive Services Task Force, Carol M Mangione, Michael J Barry et al. Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2023 Feb 14;329 6 502 507. Open 4. Kimberly A Workowski, Laura H Bachmann, Philip A Chan et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021 Jul 23;70 4 1 187. Open https://web.pathway.md/diseases/recglkWFSOh6s6aIz 6/8 6/24/23, 3:19 AM Genital herpes Pathway 5. Marie-Victoire S nat, Olivia Anselem, Olivier Picone et al. Prevention and management of genital herpes simplex infection during pregnancy and delivery: Guidelines from the French College of Gynaecologists and Obstetricians CNGOF . Eur J Obstet Gynecol Reprod Biol. 2018 May;224 93 101. Open 6. Deborah Money, Marc Steben. No. 207 Genital Herpes: Gynaecological Aspects. J Obstet Gynaecol Can. 2017 Jul;39 7):e105-e111. Open 7. LeFevre ML, U.S. Preventive Services Task Force. Behavioral counseling interventions to prevent sexually transmitted infections: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Dec 16;161 12 894 901. Open 8. Deborah M Money, Marc Steben. No. 208 Guidelines for the Management of Herpes Simplex Virus in Pregnancy. J Obstet Gynaecol Can. 2017 Aug;39 8):e199-e205. Open 9. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 10. Dinesh Jaishankar, Deepak Shukla. Genital Herpes: Insights into Sexually Transmitted Infectious Disease. Microb Cell. 2016 Jun 27;3 9 438 450. Open 11. Jean-Elie Malkin. Epidemiology of genital herpes simplex virus infection in developed countries. Herpes. 2004 Apr;11 Suppl 1 2A 23A. Open 12. Andreas Sauerbrei. Optimal management of genital herpes: current perspectives. 2016 Jun 13;9 129 41.2016 Jun 13;9 129 41. Open 13. Katharine J Looker, Amalia S Magaret, Margaret T May et al. First estimates of the global and regional incidence of neonatal herpes infection. 2017 Mar;5 3):e300-e309.2017 Mar;5 3):e300-e309. Open 14. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC et al. Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Dec 20;316 23 2525 2530. Open 15. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC et al. Screening USPSTF for Gynecologic Conditions With Pelvic Examination US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317 9 947 953. Open 16. American Association of Family Physicians. Choosing Wisely AAFP recommendations. Choosing Wisely. 2018. Open 17. Katharine J Looker, Amalia S Magaret, Margaret T May et al. First estimates of the global and regional incidence of neonatal herpes infection. Lancet Glob Health. 2017 Mar;5 3):e300-e309. Open 18. Andreas Sauerbrei. Optimal management of genital herpes: current perspectives. Infect Drug Resist. 2016 Jun 13;9 129 41. Open 19. Charlotte James, Manale Harfouche, Nicky J Welton et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020 May 1;98 5 315 329. Open 20. Ian H Spicknall, Elaine W Flagg, Elizabeth A Torrone. Estimates of the Prevalence and Incidence of Genital Herpes, United States, 2018. Sex Transm Dis. 2021 Jan 23. Open 21. Mary Jo Groves. Genital Herpes: A Review. Am Fam Physician. 2016 Jun 1;93 11 928 34. Open 22. Zane A Brown, Carolyn Gardella, Anna Wald et al. Genital herpes complicating pregnancy. Obstet Gynecol. 2005 Oct;106 4 845 56. Open https://web.pathway.md/diseases/recglkWFSOh6s6aIz 7/8 6/24/23, 3:19 AM Genital herpes Pathway 23. A Sauerbrei. Herpes Genitalis: Diagnosis, Treatment and Prevention. Geburtshilfe Frauenheilkd. 2016 Dec;76 12 1310 1317. Open 24. Sarah A E Logan, Eithne MacMahon. Viral meningitis. BMJ. 2008 Jan 5;336 7634 36 40. Open https://web.pathway.md/diseases/recglkWFSOh6s6aIz 8/8

Guideline sources The following summarized guidelines for the management of gestational transient thyrotoxicosis are prepared by our editorial team based on guidelines from the American Thyroid Association (ATA 2017). 1 2 2 2 3 3 Definition Gestational transient thyrotoxicosis refers to non-autoimmune hyperthyroidism in pregnant women, and is associated with hyperemesis gravidarum. 2 Epidemiology Gestational transient thyrotoxicosis is caused by alterations in thyroid function associated with pregnancy, such as elevation of thyroxine binding globulin, increased iodine clearance in kidneys, and stimulation of the thyroid gland by hCG. 2 Pathophysiology In Europe, the prevalence of gestational transient thyrotoxicosis at 8-14 weeks of pregnancy is estimated at 2-3%. In Asian women, the prevalence is higher and estimated at 11%. 3 Disease course Gestational transient thyrotoxicosis presents with signs and symptoms of hyperthyroidism and elevation of thyroid hormone in women with negative thyroid-receptor antibodies and no history of hyperthyroidism. 2 Prognosis and risk of recurrence https://web.pathway.md/diseases/recDnposPumjheM3P 1/2 6/24/23, 3:20 AM Gestational transient thyrotoxicosis Pathway Overt hyperthyroidism during pregnancy can lead to poor maternal and fetal outcomes. Maternal complications of pregnancy associated with hyperthyroidism include pre-term delivery, miscarriage, hypertension, and HF. The fetal and neonatal complications of maternal hyperthyroidism include goiter formation and hyperthyroidism, which can lead to intrauterine growth restriction and failure to thrive in the neonate. 3 Guidelines 1. Medical management Supportive care: provide supportive therapy, management of dehydration, and hospitalization if needed in women with abnormal maternal thyroid tests attributable to gestational transient thyrotoxicosis. B Antithyroid drugs: avoid using antithyroid drugs for the treatment of gestational transient thyrotoxicosis. D Beta-blockers: consider using -blockers if required for symptomatic relief in women with gestational transient thyrotoxicosis. B References 1. Erik K Alexander, Elizabeth N Pearce, Gregory A Brent et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27 3 315 389. Open 2. M Taha Albaar, John M F Adam. Gestational transient thyrotoxicosis. 2009 Apr;41 2 99 104.2009 Apr;41 2 99 104. Open 3. Artak Labadzhyan, Gregory A Brent, Jerome M Hershman et al. Thyrotoxicosis of Pregnancy. 2014 Dec 1;1 4 140 144.2014 Dec 1;1 4 140 144. Open https://web.pathway.md/diseases/recDnposPumjheM3P 2/2

Guideline sources The following summarized guidelines for the evaluation and management of gestational trophoblastic disease (GTD) are prepared by our editorial team based on guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG 2021), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2021), the American College of Radiology (ACR 2019), the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG 2017), and the European Society of Medical Oncology (ESMO 2013). 1 2 3 4 5 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s https://web.pathway.md/diseases/recvnulMd4asYAt0n 1/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway Guidelines 1. Screening and diagnosis Clinical presentation: Recognize the clinical presentation of molar pregnancy: Situation Guidance Irregular vaginal bleeding Most commonly Positive pregnancy test Supporting ultrasound evidence B Hyperemesis Less common Excessive uterine enlargement Hyperthyroidism Early-onset preeclampsia Abdominal distension due to theca lutein cysts E Dyspnea and hemoptysis due to pulmonary metastasis Very rare New-onset seizures or paralysis due to brain metastasis. B Recognize that any patient developing persistent vaginal bleeding after a pregnancy is at risk of having GTD. B 2. Classification and risk stratification Prognosis: As per SOGC 2021 guidelines: Recognize that: the outlook for patients treated for gestational trophoblastic neoplasia is generally excellent with an overall cure rate close to 100% further pregnancies are achieved in approximately 80% of patients following treatment for gestational trophoblastic neoplasia with either methotrexate alone or multi-agent chemotherapy there is an increased risk of premature menopause in patients treated with combination agent chemotherapy. B https://web.pathway.md/diseases/recvnulMd4asYAt0n 2/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway Warn patients, especially if approaching the age of 40 years, of the potential negative impact of combination agent chemotherapy on fertility, particularly with high-dose chemotherapy. B As per ESMO 2013 guidelines: Use the FIGO scoring system to determine the risk of gestational trophoblastic neoplasia becoming resistant to single-agent chemotherapy, recognizing that it is of no value in placental site trophoblastic tumor/epithelioid trophoblastic tumor. B Recognize that residual lung or uterine masses following chemotherapy for low- or high-risk diseases are not predictive of recurrence. B 3. Diagnostic investigations Pregnancy testing: As per RCOG 2021 guidelines: Advise patients to do a urinary pregnancy test 3 weeks after a miscarriage or medical abortion. E Obtain urine hCG in all patients with persistent or irregular vaginal bleeding lasting > 8 weeks after pregnancy. E As per RANZCOG 2017 guidelines, obtain pregnancy testing in all cases of persistent or irregular vaginal bleeding after a pregnancy event. E Serum hCG levels: obtain serum hCG levels in female patients of reproductive age presenting with abnormal uterine bleeding, bleeding > 6 weeks following pregnancy, or evidence of metastatic disease to promptly diagnose and manage GTD. B Show 3 more Diagnostic imaging: As per SOGC 2021 guidelines: Obtain CXR during initial workup for post-molar gestational trophoblastic neoplasia to look for lung metastases, and pelvic ultrasound to assess extent of disease in the pelvis. B Obtain the following during initial workup for suspected choriocarcinoma, gestational trophoblastic neoplasia after a non-molar pregnancy, and/or post-molar gestational trophoblastic neoplasia with lung metastases on CXR: pelvic ultrasound chest and abdomen CT (with arterial phase through the liver) brain MRI. B As per ACR 2019 guidelines, obtain transabdominal and/or transvaginal ultrasound and Doppler ultrasound for suspected or initial diagnosis of GTD as well as for local staging and risk assessment of suspected or established gestational trophoblastic neoplasia. B Show 4 more 4. Diagnostic procedures https://web.pathway.md/diseases/recvnulMd4asYAt0n 3/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway Histopathology: As per RCOG 2021 guidelines, perform histological examination for definitive diagnosis of molar pregnancy. B Show 5 more As per SOGC 2021 guidelines: Perform histological examination of any products of conception appearing abnormal at the time of dilatation and curettage to rule out GTD. B Differentiate complete hydatidiform mole, partial hydatidiform mole, and malignant trophoblastic disease by a gynecologic pathologist for tailored follow-up and management of gestational trophoblastic neoplasia. B As per RANZCOG 2017 guidelines, avoid performing a biopsy in patients with vaginal gestational trophoblastic neoplasia located in the fornices or suburethrally because of their highly vascular nature. D Show 2 more Prenatal karyotyping: consider performing prenatal invasive fetal karyotyping if it is unclear if the pregnancy is a complete mole with a coexisting normal twin or a possible singleton partial molar pregnancy, or in patients with an abnormal placenta, such as suspected mesenchymal hyperplasia of the placenta. C 5. Medical management Setting of care: As per RCOG 2021 guidelines, consider referring all patients with persistently elevated human chorionic gonadotrophin either after an ectopic pregnancy has been excluded, or after two consecutive treatments with methotrexate for a pregnancy of unknown location to a GTD center. E Show 5 more As per SOGC 2021 guidelines: Manage patients with GTD in specialized centers and record their data in centralized (regional and/or national) registries, if possible. A Refer patients with gestational trophoblastic neoplasia to a specialist in gynecologic oncology for staging, risk scoring, and treatment. A Chemotherapy: As per RCOG 2021 guidelines: Consider offering single-agent or multi-agent chemotherapy in patients with gestational trophoblastic neoplasia. C Offer treatment based on the International Federation of Gynecology and Obstetrics 2000 scoring system for gestational trophoblastic neoplasia following assessment at the treatment center. B https://web.pathway.md/diseases/recvnulMd4asYAt0n 4/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway As per SOGC 2021 guidelines, consider offering prophylactic chemotherapy only in high-risk patients unlikely to return for regular follow-up. C Show 3 more As per ESMO 2013 guidelines, consider offering either single-agent methotrexate (with or without folinic acid) or actinomycin D in patients with a FIGO score of 0-6. B Show 6 more Anti-D immunoglobulin: As per RCOG 2021 guidelines, administer anti-D prophylaxis following removal of a molar pregnancy. E As per SOGC 2021 guidelines, administer anti-D immune globulin after uterine evacuation to prevent alloimmunization in all Rh-negative patients. A As per ESMO 2013 guidelines, administer anti-D prophylaxis following suction dilation and curettage of partial hydatidiform mole. B 6. Surgical interventions Uterine curettage and hysterectomy, indications: As per RCOG 2021 guidelines, consider performing suction curettage as the method of choice for removal of complete molar pregnancies. E Show 2 more As per SOGC 2021 guidelines: Perform surgical evacuation by suction dilatation and curettage or hysterectomy followed by hCG surveillance for the treatment of patients with hydatidiform mole. B Offer performing either suction evacuation of the uterus or hysterectomy as the initial management of patients with suspected hydatidiform mole. B Consider performing hysterectomy in selected patients with low-risk gestational trophoblastic neoplasia. B As per ESMO 2013 guidelines, perform suction dilation and curettage in patients with singleton molar pregnancies. B Show 3 more Uterine curettage and hysterectomy, technical considerations: As per RCOG 2021 guidelines, consider using ultrasound guidance during removal and curettage to minimize the chance of perforation and to ensure that as much tissue as possible is removed. E Show 4 more As per RANZCOG 2017 guidelines, perform suction evacuation as the preferred initial management regardless of uterine size. E Repeated surgery: As per RCOG 2021 guidelines: https://web.pathway.md/diseases/recvnulMd4asYAt0n 5/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway Perform urgent surgery in patients experiencing heavy or persistent vaginal bleeding causing acute hemodynamic compromise, particularly in the presence of retained pregnancy tissue on ultrasound. E Counsel with the relevant GTD referral center before performing surgery for the second time in the same pregnancy, outside the context of acute compromise. B As per RANZCOG 2017 guidelines: Consider performing a second evacuation in selected cases because of problematic bleeding. Consider performing hysteroscopy in order to locate persistent focus during the second evacuation. E Do not perform repeat evacuation if -hCG > 5,000 or in the presence of metastases. D As per ESMO 2013 guidelines, perform second dilation and curettage for recurrence in patients with singleton molar pregnancy only after discussion with a GTD reference center, as it usually does not prevent the subsequent need for chemotherapy. B 7. Specific circumstances Patients with ectopic pregnancy: Manage patients with ectopic pregnancy suspected to be molar in nature as any other case of ectopic pregnancy. E Send a tissue specimen to a center with appropriate expertise for pathological review, if there is a local tissue diagnosis of ectopic molar pregnancy. E 8. Patient education General counseling: As per RCOG 2021 guidelines: Counsel patients with a twin pregnancy where there is one viable fetus and the other pregnancy is molar about the potential increased risk of perinatal morbidity and the outcome for gestational trophoblastic neoplasia. B Warn patients, especially if approaching the age of 40 years, of the potential negative impact of combination agent chemotherapy on fertility, particularly with high-dose chemotherapy. B As per SOGC 2021 guidelines: Refer patients with recurrent GTD for genetic counseling and testing, as this is a rare scenario that may be associated with a familial gene mutation. B Refer patients with recurrent GTD for genetic counseling and testing as this is a rare scenario that may be associated with a familial gene mutation. B 9. Follow-up and surveillance Serial hCG monitoring: https://web.pathway.md/diseases/recvnulMd4asYAt0n 6/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway As per RCOG 2021 guidelines, follow-up patients with complete molar pregnancy for 6 months from the date of uterine removal, if hCG has reverted to normal within 56 days of the pregnancy. B Show 3 more As per SOGC 2021 guidelines, obtain serial hCG monitoring during post-molar follow-up. A Show 3 more Serial hCG monitoring (RAZNCOG): Obtain weekly quantitative -hCG levels monitoring post-evacuation until three consecutive normal levels are seen. Do not obtain further testing for partial moles. Continue monthly monitoring until cleared for complete moles. E Diagnose persistent GTD in case of a rise of > 10% over 2 weeks (3 weekly -hCG levels) or a fall of < 10% over 3 weeks (4 weekly -hCG levels). Obtain a metastatic screening and assess the WHO risk score in such cases. E Contraception: As per RCOG 2021 guidelines, advise patients not to conceive until their follow-up is complete. B Show 2 more As per SOGC 2021 guidelines: Recognize that hormonal contraception can be safely prescribed and intrauterine contraceptive devices can be inserted after normalization of hCG levels. B Administer reliable contraception throughout the entire duration of follow-up in patients undergoing follow-up after molar pregnancy. B As per RANZCOG 2017 guidelines, delay the insertion of an intrauterine device for at least 6 weeks after the evacuation of the uterus and hCG normalization to minimize the risk of perforation of the uterus. E Post-treatment hormone therapy: consider using exogenous estrogens, other fertility drugs and HRT once hCG levels have returned to normal. E Subsequent pregnancy: As per RCOG 2021 guidelines: Do not obtain post-pregnancy hCG in pregnant patients following a previous molar pregnancy not required treatment for gestational trophoblastic neoplasia. D Do not perform histological examination of the placental tissue from any normal pregnancy, after a molar pregnancy. D As per SOGC 2021 guidelines: Obtain early ultrasound, close examination of the placenta and histologic examination of any nonviable pregnancy during follow-up of subsequent pregnancy in patients with previous gestational trophoblastic neoplasia or recurrent molar pregnancy. A Refer patients becoming pregnant during follow-up for GTD or gestational trophoblastic neoplasia to gynecologic oncology and maternal-fetal medicine for assessment and https://web.pathway.md/diseases/recvnulMd4asYAt0n 7/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway management. B Subsequent pregnancy (RAZNCOG): advise avoiding pregnancy during follow-up. Consider prescribing oral contraceptives. E Clinical findings Symptoms Past medical history Abdominal pain Nephrotic syndrome Amenorrhea Abdominal exam Back pain Bloating Bilateral ovarian enlargement Chest pain Integument exam Cough Dizziness Jaundice Galactorrhea Virilization Headache Hemoptysis Hematological findings Hyperemesis Polycythemia Loss of appetite Seizure Shortness of breath Vaginal bleeding Vaginal discharge Vomiting Weight loss Neurological exam ICP Gynecologic exam Uterine enlargement Lab findings hCG serum free T3 serum free T4 serum TSH Imaging findings Molar pregnancy https://web.pathway.md/diseases/recvnulMd4asYAt0n 8/9 7/1/23, 12:02 AM Gestational trophoblastic disease Pathway Likelihood Ratios Pertinent positives The following findings increase the probability of gestational trophoblastic disease in adults. 5 Finding LR+ Value Presence of molar pregnancy 1.7 Pertinent negatives The following findings decrease the probability of gestational trophoblastic disease in adults. 5 Finding LR- Value Absence of molar pregnancy 0.8 References 1. No authors listed. Management of Gestational Trophoblastic Disease: Green-top Guideline No. 38 June 2020. BJOG. 2021 Feb;128 3):e1-e27. Open 2. M J Seckl, N J Sebire, R A Fisher et al. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi39 50. Open 3. Lua Eiriksson, Erin Dean, Alexandra Sebastianelli et al. Guideline No. 408 Management of Gestational Trophoblastic Diseases. J Obstet Gynaecol Can. 2021 Jan;43 1 91 105.e1. Open 4. Paul Duggan, Yee Leung, Deborah Neesham et al. Management of gestational trophoblastic disease. RANZCOG. 2017 Mar. Open 5. Expert Panel on Women s Imaging Panel, Kika M Dudiak, Katherine E Maturen et al. ACR Appropriateness Criteria Gestational Trophoblastic Disease. J Am Coll Radiol. 2019 Nov;16 11S S348 S363. Open 6. Fowler DJ, Lindsay I, Seckl MJ et al. Routine pre-evacuation ultrasound diagnosis of hydatidiform mole: experience of more than 1000 cases from a regional referral center. Ultrasound Obstet Gynecol. 2006 Jan;27 1 56 60. Open https://web.pathway.md/diseases/recvnulMd4asYAt0n 9/9

Guideline sources The following summarized guidelines for the evaluation and management of giant cell arteritis (GCA) are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ACC 2022), the Vasculitis Foundation (VF/ACR 2021), the American Heart Association (AHA/ASA 2021), the British Society for Rheumatology (BSR 2020), the European League Against Rheumatism (EULAR 2020; 2018), the Swedish Society of Rheumatology (SSR 2019), the French Study Group for Large Vessel Vasculitis (GEFA 2016), the British Society for Rheumatology (BSR/BHPR 2010), and the Society for Cardiovascular Angiography and Interventions (SCAI/STS/SVM/AATS/SCA/AHA/ACR/ACC/ASA/SIR 2010). 1 2 3 4 5 6 7 8 9 10 11 12 13 13 14 Definition GCA is an inflammatory vasculitis affecting medium and large-sized arteries, with a predilection for the temporal arteries. 11 https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 1/11 7/1/23, 12:02 AM Giant cell arteritis Pathway Epidemiology In patients with GCA, the interaction of genetic and epigenetic factors causes pathologic activation of vascular dendritic cells, CD4 T cells, and macrophages, leading to granulomatous inflammation of the adventitia and hyperplasia of the intima. These vascular changes cause ischemic complications in tissues fed by medium and large-sized vessels. 13 Pathophysiology In the United States, the incidence of GCA is estimated at 18.9 cases per 100,000 person-years, while the prevalence is estimated at 228 persons per 100,000 population. 12 Disease course Ophthalmoplegia, vertebrobasilar insufficiency, central vision loss, stroke, and aortic aneurysm and rupture may occur as direct complications of vascular involvement. 13 Prognosis and risk of recurrence Permanent vision loss occurs in approximately 15-20% of patients of GCA. 14 Guidelines 1. Screening and diagnosis Diagnosis: As per EULAR 2018 guidelines: Consider establishing the diagnosis of GCA without obtaining additional tests (biopsy or further imaging) in patients with high clinical suspicion and a positive imaging. C Recognize that the diagnosis of GCA is unlikely in patients with a low clinical probability and a negative imaging. Make additional efforts towards a diagnosis in all other cases. B As per BSR 2010 guidelines: Suspect large-vessel GCA in patients with prominent systemic symptoms, limb claudication or persistently high inflammatory markers despite adequate corticosteroid therapy. B Assess for the predictive features of ischemic neuro-ophthalmic complications of GCA. B 2. Diagnostic investigations Diagnostic imaging: As per ACC 2022 guidelines, obtain prompt evaluation of the entire aorta and branch vessels with MRI or CT, with or without 18F-FDG-positron emission tomography, in patients with large vessel vasculitis. B As per ACR 2021 guidelines: https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 2/11 7/1/23, 12:02 AM Giant cell arteritis Pathway Consider obtaining noninvasive vascular imaging of the large vessels with a clinical assessment to aid in diagnosis in patients with suspected GCA and negative temporal artery biopsy results. C Consider obtaining noninvasive vascular imaging to evaluate large vessel involvement in patients with newly diagnosed GCA. C As per BSR 2020 guidelines: Obtain a confirmatory diagnostic test in patients with suspected GCA. Consider either obtaining an ultrasound of the temporal and axillary arteries or performing a temporal artery biopsy, or both. B Consider obtaining 18F-FDG-positron emission tomography, MRA, CT angiography, or axillary artery ultrasound for the evaluation of the involvement of the aorta and its proximal branches. C As per EULAR 2020 guidelines, obtain ultrasound (1b, A) or MRI to confirm the diagnosis of temporal arteritis. B As per EULAR 2018 guidelines, obtain early imaging in patients with suspected GCA to complement the clinical criteria for diagnosis, assuming high expertise and prompt availability of the imaging technique. Do not delay treatment because of imaging. A Show 7 more As per AHA 2010 guidelines, obtain CT angiography or MRA of the thoracic aorta and branch vessels to assess for aneurysms or arterial occlusion in the initial evaluation of GCA. B Initial investigations: as per BSR 2010 guidelines, obtain the following initial investigations in patients with suspected or confirmed GCA: CBC serum creatinine and urea serum electrolytes LFTs CRP and ESR urinalysis CXR other relevant investigations to exclude mimicking conditions. Assessment of comorbidities: screen patients with large vessel vasculitis for treatment-related and cardiovascular comorbidities. Offer prophylaxis and life-style advice to reduce cardiovascular risk and treatment-related complications. 3. Diagnostic procedures Temporal artery biopsy: As per ACR 2021 guidelines, consider performing an initial unilateral rather than bilateral temporal artery biopsy in patients with suspected GCA. C https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 3/11 7/1/23, 12:02 AM Giant cell arteritis Pathway Show 3 more As per BSR 2020 guidelines, consider either performing a temporal artery biopsy at least 1 cm in length or obtaining an ultrasound of the temporal and axillary arteries, or both, to confirm the diagnosis in patients with suspected GCA. B As per EULAR 2020 guidelines, perform a temporal artery biopsy to confirm the diagnosis of temporal arteritis. B 4. Medical management General principles: manage patients with large vessel vasculitis based on a shared decision between the patient and the rheumatologist, considering efficacy, safety and costs. Setting of care: As per EULAR 2020 guidelines, refer all patients presenting with signs and symptoms suggestive of GCA urgently to a specialist team for further multidisciplinary diagnostic work-up and management. B As per BSR 2010 guidelines, consider referring all patients with GCA urgently for specialist evaluation. C Corticosteroids: As per ACC 2022 guidelines, initiate high-dose corticosteroids as initial medical therapy in patients with active GCA. B As per ACR 2021 guidelines, consider initiating high-dose oral corticosteroids in patients with newly diagnosed GCA without manifestations of cranial ischemia. C Show 5 more As per BSR 2020 guidelines, initiate oral prednisone/prednisolone at an initial dose of 40-60 mg/day in patients with GCA. B Show 4 more As per EULAR 2020 guidelines: Initiate high dose corticosteroids (40-60 mg/day prednisone-equivalent) immediately for induction of remission in patients with active GCA. B Taper corticosteroid dose to a target dose of 15-20 mg/day within 2-3 months and after 1 year to 5 mg/day. B As per SSR 2019 guidelines, initiate corticosteroids at an initial daily dose corresponding to 40- 60 mg of prednisolone in patients with uncomplicated GCA (without jaw claudication or visual complications). E Show 2 more Tocilizumab: As per ACC 2022 guidelines, initiate tocilizumab as adjunctive therapy to corticosteroids, with methotrexate as an alternative, in patients with GCA with evidence of active aortitis. B https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 4/11 7/1/23, 12:02 AM Giant cell arteritis Pathway As per ACR 2021 guidelines, consider initiating tocilizumab in addition to oral corticosteroids in patients with newly diagnosed GCA. B As per BSR 2020 guidelines: Consider initiating tocilizumab in combination with a corticosteroid taper in patients with GCA, especially in patients at high risk of corticosteroid toxicity or presenting with a relapse. B Do not use TNF inhibitors in patients with GCA. D As per EULAR 2020 guidelines, initiate tocilizumab as an adjunctive therapy in selected patients with GCA, including with refractory or relapsing disease, presence or an increased risk of corticosteroid-related adverse effects, and complications. B As per SSR 2019 guidelines, initiate tocilizumab in addition to corticosteroids in patients meeting all of the following criteria: relapse during corticosteroid treatment or relapse after the completion of corticosteroid treatment large vessel arteritis established with biopsy or imaging of large vessels (MRI, positron emission tomography-CT, or CT angiography) clinically active GCA elevated CRP and ESR obvious side effects of corticosteroid treatment or great risk of such side effects from future treatment with corticosteroids. E Show 5 more Methotrexate: As per ACR 2021 guidelines, consider initiating a non-corticosteroid immunosuppressive agent in addition to oral corticosteroids in patients with GCA with active extracranial large vessel involvement. C As per BSR 2020 guidelines: Consider initiating methotrexate in combination with a corticosteroid taper in patients with GCA at high risk of corticosteroid toxicity or presenting with a relapse. C Insufficient evidence to support the use of other oral immunosuppressive agents (including azathioprine, leflunomide, or mycophenolate mofetil) in patients with GCA. I As per EULAR 2018 guidelines, consider initiating methotrexate as an alternative to tocilizumab as an adjunctive therapy in selected patients with GCA, including with refractory or relapsing disease, presence or an increased risk of corticosteroid-related adverse effects, and complications. B Antithrombotics: As per ACR 2021 guidelines, consider initiating aspirin in patients with GCA having critical or flow-limiting involvement of the vertebral or carotid arteries. C As per BSR 2020 guidelines, do not use routine antiplatelet or anticoagulant agents for GCA. As per EULAR 2020 guidelines: https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 5/11 7/1/23, 12:02 AM Giant cell arteritis Pathway Do not use routine antiplatelet or anticoagulant therapy for the treatment of patients with large vessel vasculitis unless it is indicated for other reasons (such as coronary heart disease or cerebrovascular disease etc). D Consider initiating antiplatelet or anticoagulant therapy on an individual basis in special situations, such as vascular ischemic complications or high risk of CVD. C As per SSR 2019 guidelines, consider initiating low-dose aspirin in patients with newly diagnosed GCA, in the absence of contraindications, to reduce the risk of ischemic complications. E Lipid-lowering agents: As per ACR 2021 guidelines, avoid using statins specifically for the treatment of patients with newly diagnosed GCA. D As per BSR 2020 guidelines, do not use routine cholesterol-lowering agents (including statins) for the treatment of patients with GCA. 5. Surgical interventions Reconstructive surgery: As per ACC 2022 guidelines, consider performing elective endovascular or open surgical intervention to treat aortic and branch vessel complications in patients with GCA in remission. C As per ACR 2021 guidelines, decide on the type and timing of intervention in patients requiring surgical vascular intervention for GCA based on a collaborative decision between the vascular surgeon and rheumatologist. As per EULAR 2020 guidelines: Perform elective endovascular interventions or reconstructive surgery in phases of stable remission of large vessel vasculitis. B Refer patients with arterial vessel dissection or critical vascular ischemia to a vascular team urgently. B 6. Specific circumstances Patients with stroke or TIA: initiate immediate oral high-dose corticosteroids to reduce recurrent stroke risk in patients with ischemic stroke or TIA and symptoms attributed to GCA. B Show 2 more 7. Patient education Patient education: As per EULAR 2020 guidelines, ensure that patients have access to education focusing on the impact of large vessel vasculitis, its key warning symptoms and treatment (including treatment- https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 6/11 7/1/23, 12:02 AM Giant cell arteritis Pathway related complications). As per BSR 2010 guidelines, provide education in patients with GCA. B 8. Follow-up and surveillance Assessment of treatment response: As per ACC 2022 guidelines, assess treatment efficacy periodically by monitoring clinical symptoms, inflammatory serum markers (CRP and ESR), and imaging (CT, MRI, or 18F-FDG- positron emission tomography) in patients with active GCA. B As per SSR 2019 guidelines, assess treatment response based on clinical evaluation (medical history and clinical assessment of possible GCA symptoms) combined laboratory tests (ESR, CRP, and blood counts). E Show 2 more Follow-up: As per ACC 2022 guidelines, consider obtaining annual surveillance imaging with CT, MRI, or 18F-FDG-positron emission tomography in patients with GCA and aortic involvement in remission. C As per ACR 2021 guidelines: Obtain long-term clinical monitoring in patients with GCA in apparent clinical remission. B Consider obtaining clinical observation and monitoring without escalation of immunosuppressive therapy in patients with GCA having an increase in levels of inflammation markers alone. C As per EULAR 2020 guidelines, obtain regular follow-up and monitoring of disease activity in patients with large vessel vasculitis, primarily based on symptoms, clinical findings and ESR/CRP. B As per SSR 2019 guidelines: Avoid obtaining imaging in the follow-up and assessment of disease activity after treatment. D Obtain follow-up with CT angiography in patients with known aortic dilatation caused by GCA. E As per EULAR 2018 guidelines, consider obtaining MRA, CT angiography and/or ultrasound for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation and/or aneurysms in patients with GCA. C Show 2 more As per BSR 2010 guidelines, schedule a follow-up assessment at weeks 0, 1, 3, 6, and then at months 3, 6, 9 and 12. Arrange extra unscheduled visits in the event of relapse or adverse events. Show 2 more Management of relapse: https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 7/11 7/1/23, 12:02 AM Giant cell arteritis Pathway As per ACR 2021 guidelines, consider adding a non-corticosteroid immunosuppressive agent in patients with GCA experiencing disease relapse while receiving moderate-to-high-dose corticosteroids. E Show 3 more As per BSR 2020 guidelines: Consider initiating methotrexate in combination with a corticosteroid taper in patients with a relapse. C Consider initiating tocilizumab in combination with a corticosteroid taper in patients with a relapse. B As per EULAR 2020 guidelines, re-institute or escalate dose of corticosteroids as recommended for new onset disease in patients with major relapse (either with signs or symptoms of ischemia or progressive vascular inflammation). B Show 2 more As per SSR 2019 guidelines, consider adding methotrexate in cases of late relapse without major inflammatory activity or with marked corticosteroid side effects, when the patient does not meet the criteria for tocilizumab treatment. E Show 2 more As per BSR 2010 guidelines, refer patients with relapse of GCA for specialist assessment. Show 3 more Clinical findings Patient demographics Symptoms Elderly age Claudication of limb Female sex Cough Northern European Difficulty chewing Dysphagia Past medical history Fatigue Fever Blindness Headache Depression Hearing loss Myocardial infarction Jaw claudication Osteoporosis Jaw pain Polymyalgia rheumatica Loss of appetite Neurological exam Malaise Night sweats Peripheral neuropathy Temporal headache Vision loss Head and neck exam Weight loss Scalp tenderness Vascular exam Tongue claudication https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 8/11 7/1/23, 12:02 AM Giant cell arteritis Pathway Asymmetric pulse Hematological findings Beaded temporal artery Anemia Tender temporal artery WBC count Ocular exam blood platelet count Amaurosis fugax Central vision loss Lab findings Abnormal serum LFTs ESR serum CRP Imaging findings AR Halo sign Likelihood Ratios Pertinent positives The following findings increase the probability of giant cell arteritis in adults. 14 15 Finding LR+ Value Presence of halo sign 9.2 Presence of beaded temporal artery 4.6 History of jaw claudication 4.2 Presence of tender temporal artery 2.6 Show 4 more Pertinent negatives The following findings decrease the probability of giant cell arteritis in adults. 14 15 Finding LR- Value Absence of halo sign 0.5 No history of jaw claudication 0.7 No history of headache 0.7 No history of temporal headache 0.8 Show 4 more References https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 9/11 7/1/23, 12:02 AM Giant cell arteritis Pathway 1. Sarah L Mackie, Christian Dejaco, Simone Appenzeller et al. British Society for Rheumatology guideline on diagnosis and treatment of giant cell arteritis. Rheumatology Oxford). 2020 Mar 1;59 3):e1-e23. Open 2. Mehrdad Maz, Sharon A Chung, Andy Abril et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Care Res Hoboken). 2021 Aug;73 8 1071 1087. Open 3. Bernhard Hellmich, Ana Agueda, Sara Monti et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020 Jan;79 1 19 30. Open 4. B Bienvenu, K H Ly, M Lambert et al. Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis GEFA . Rev Med Interne. 2016 Mar;37 3 154 65. Open 5. Dasgupta B, Borg FA, Hassan N et al. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology Oxford). 2010 Aug;49 8 1594 7. Open 6. Eric M Isselbacher, Ourania Preventza, James Hamilton Black rd et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Nov 2. Open 7. Dawn O Kleindorfer, Amytis Towfighi, Seemant Chaturvedi et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021 Jul;52 7):e364-e467. Open 8. Christian Dejaco, Sofia Ramiro, Christina Duftner et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis. 2018 May;77 5 636 643. Open 9. Turesson C, B rjesson O, Larsson K et al. Swedish Society of Rheumatology 2018 guidelines for investigation, treatment, and follow-up of giant cell arteritis. Scand J Rheumatol. 2019 Jul;48 4 259 265. Open 10. Hiratzka LF, Bakris GL, Beckman JA et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010 Apr 6;121 13):e266 369. Open 11. Weyand CM, Goronzy JJ. Clinical practice. Giant-cell arteritis and polymyalgia rheumatica. N Engl J Med. 2014 Jul 3;371 1 50 7. Open 12. Babigumira JB, Li M, Boudreau DM et al. Estimating the Cost of Illness of Giant Cell Arteritis in the United States. Rheumatol Ther. 2017 Jun;4 1 111 119. Open 13. Weyand CM, Liao YJ, Goronzy JJ. The immunopathology of giant cell arteritis: diagnostic and therapeutic implications. J Neuroophthalmol. 2012 Sep;32 3 259 65. Open 14. Chacko JG, Chacko JA, Salter MW. Review of Giant cell arteritis. Saudi J Ophthalmol. 2015 Jan- Mar;29 1 48 52. Open 15. Smetana GW, Shmerling RH. Does this patient have temporal arteritis?. JAMA. 2002 Jan 2;287 1 92 101. Open https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 10/11 7/1/23, 12:02 AM Giant cell arteritis Pathway 16. Karassa FB, Matsagas MI, Schmidt WA et al. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med. 2005 Mar 1;142 5 359 69. Open 17. Stone JH, Tuckwell K, Dimonaco S et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 Jul 27;377 4 317 328. Open 18. Cristina Ponte, Peter C Grayson, Joanna C Robson et al. 2022 American College of Rheumatology/EULAR Classification Criteria for Giant Cell Arteritis. Arthritis Rheumatol. 2022 Dec;74 12 1881 1889. Open https://web.pathway.md/diseases/recGiLqtcZ9r8gvkM 11/11

Guideline sources The following summarized guidelines for the evaluation and management of giant cell tumor of bone (GCTB) are prepared by our editorial team based on guidelines from the National Comprehensive Cancer Network (NCCN 2021) and the European Reference Network on Genetic Tumour Risk Syndromes (GENTURIS/ERN PaedCan/EURACAN/ESMO 2021). 1 2 Calculator TNM classification for bone can Guidelines 1. Diagnostic investigations History and physical examination: https://web.pathway.md/diseases/recNwQ8EKBfCQAmg3 1/5 7/1/23, 12:02 AM y Giant cell tumor of bone Pathway p y As per ESMO 2021 guidelines, elicit medical history and perform physical examination in the initial work-up of patients with suspected primary bone sarcoma. B As per NCCN 2021 guidelines, elicit history and perform physical examination in the initial evaluation of patients with GCTB. B Imaging for staging: As per ESMO 2021 guidelines: Obtain radiological assessment in the initial work-up of patients with suspected primary bone sarcoma. B Obtain the following imaging modalities as clinically indicated for general staging to assess the extent of distant disease, to detect lung, bone and bone marrow metastases: chest CT bone scintigraphy whole body-MRI 18F-FDG positron emission tomography-CT/MRI. B As per NCCN 2021 guidelines: Obtain the following imaging studies in patients with GCTB: imaging of primary site (such as X-ray, MRI with contrast with or without CT) chest imaging. B Consider obtaining bone scan in patients with GCTB. C 2. Diagnostic procedures Biopsy and histopathology: As per ESMO 2021 guidelines, perform biopsy in the initial work-op of patients with suspected primary bone sarcoma. B Show 2 more As per NCCN 2021 guidelines, perform biopsy to confirm the diagnosis of GCTB. B 3. Medical management Setting of care: as per ESMO 2021 guidelines, manage patients with bone sarcomas at reference centers and/or within reference networks able to provide access to the full spectrum of care and age-specific expertise. B Denosumab: As per ESMO 2021 guidelines, initiate denosumab as standard treatment in patients with unresectable or metastatic GCTB. B Show 3 more As per NCCN 2021 guidelines: https://web.pathway.md/diseases/recNwQ8EKBfCQAmg3 2/5 7/1/23, 12:02 AM Giant cell tumor of bone Pathway Initiate denosumab as a preferred treatment option in patients with localized disease, if resectable with unacceptable morbidity or with unresectable axial lesions. B Consider offering denosumab as a treatment option in patients with unresectable metastatic disease at presentation. C Interferon alpha-2b: Offer interferon alpha-2b as a treatment option in patients with localized disease, if resectable with unacceptable morbidity or with unresectable axial lesions. B Consider offering interferon alpha-2b as a treatment option in patients with unresectable metastatic disease at presentation. C 4. Therapeutic procedures Serial arterial embolization: perform serial arterial embolization as a preferred treatment option in patients with localized disease, if resectable with unacceptable morbidity or with unresectable axial lesions. B Radiotherapy: Offer radiotherapy as a treatment option in patients with localized disease, if resectable with unacceptable morbidity or with unresectable axial lesions. B Consider offering radiotherapy as a treatment option in patients with unresectable metastatic disease at presentation. C 5. Surgical interventions Surgical excision: As per ESMO 2021 guidelines, perform en bloc excision B or intralesional curettage with or without adjuvant therapy in selected patients with GCTB. B As per NCCN 2021 guidelines: Perform excision in patients with localized GCTB, if resectable. B Perform excision of primary tumor in patients with metastatic disease at presentation, if resectable. Consider resecting metastatic sites. B 6. Specific circumstances Patients with malignant transformation: manage patients with malignant transformation as patients with osteosarcoma. B 7. Follow-up and surveillance https://web.pathway.md/diseases/recNwQ8EKBfCQAmg3 3/5 7/1/23, 12:02 AM Giant cell tumor of bone Pathway Assessment of treatment response: obtain follow-up imaging, plain radiographs and CT with or without MRI (both with contrast), to assess treatment response. B Show 2 more Surveillance: As per ESMO 2021 guidelines, consider including the following in the follow-up of patients with high-grade bone sarcomas: physical examination cross-sectional imaging plain radiograph of the primary site CXR/chest CT. C Show 2 more As per NCCN 2021 guidelines, include the following in the surveillance of patients with GCTB: physical examination imaging of surgical site as clinically indicated (X-ray, MRI with contrast with or without CT with contrast) chest imaging every 6-12 months for 4 years, then annually thereafter. B Management of recurrent disease: consider obtaining chest imaging in patients with resectable local recurrence. C Show 3 more Clinical findings Symptoms Past medical history Joint swelling Lung metastasis Localized bone pain Pathological fracture Localized bone swelling Imaging findings Musculoskeletal exam Osteolytic lesion knee ROM spinal ROM wrist ROM References 1. J Sybil Biermann, Angela Hirbe, Warren Chow et al. Bone Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. NCCN. 2021 Oct 8. Open 2. S J Strauss, A M Frezza, N Abecassis et al. Bone sarcomas: ESMO EURACAN GENTURIS ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2021 Dec;32 12 1520 1536. Open https://web.pathway.md/diseases/recNwQ8EKBfCQAmg3 4/5 7/1/23, 12:02 AM Giant cell tumor of bone Pathway 3. Andr s Redondo, Silvia Bagu , Daniel Bernabeu et al. Malignant bone tumors (other than Ewing's): clinical practice guidelines for diagnosis, treatment and follow-up by Spanish Group for Research on Sarcomas GEIS . Cancer Chemother Pharmacol. 2017 Dec;80 6 1113 1131. Open https://web.pathway.md/diseases/recNwQ8EKBfCQAmg3 5/5

Guideline sources The following summarized guidelines for the evaluation and management of glioblastoma are prepared by our editorial team based on guidelines from the American Association of Neurological Surgeons (AANS/CNS 2022; 2014), the European Association of Neuro-Oncology (EANO 2021; 2017), the European Association of Neuro-Oncology (EANO/SNO 2021), the Spanish Association of Medical Oncology (SEOM 2018), the American Society for Radiation Oncology (ASTRO 2016), and the European Society of Medical Oncology (ESMO 2014). 1 2 3 4 5 6 7 8 9 10 11 12 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines https://web.pathway.md/diseases/reckgYogVTBs6efiZ 1/8 6/24/23, 4:21 PM Glioblastoma Pathway 1. Screening and diagnosis Indications for screening: Recognize that screening and prevention have no major role for patients with gliomas. B Refer patients with relevant germline variants or suspected hereditary cancer syndromes for genetic counseling and, subsequently, for possible molecular genetic testing. B 2. Classification and risk stratification Classification: As per EANO 2021 guidelines, use the most recent WHO Classification of Tumors of the CNS for glioma classification, complemented by cIMPACT-NOW. B As per SEOM 2018 guidelines, classify glioblastomas into IDH-wild-type and IDH-mutated depending on the IDH gene mutation status. B 3. Diagnostic investigations Clinical assessment: assess the Karnofsky performance score and neurological function, as well as the patient's age, individual risks, and benefits for clinical decision-making. B Diagnostic imaging: As per EANO 2021 guidelines, obtain MRI without and with gadolinium contrast as the first choice diagnostic imaging modality. B As per SEOM 2018 guidelines: Obtain MRI without and with contrast enhancement as first-line imaging for diagnostic evaluation. B Consider obtaining advanced MRI sequences, including perfusion (cerebral blood volume/permeability), diffusion (DWI/apparent diffusion coefficient), and proton magnetic resonance spectroscopy, to provide information related to hemodynamic, cellular, and metabolism and help to identify glioma subtype and aggressiveness. C 4. Diagnostic procedures Tumor biopsy: As per EANO 2021 guidelines: Perform biopsy or resection as the standard of care in < 70 years old patients with IDH-wild- type glioblastoma and a Karnofsky performance status > 70. B Make clinical decisions without obtaining a tissue diagnosis only in very exceptional situations. B https://web.pathway.md/diseases/reckgYogVTBs6efiZ 2/8 6/24/23, 4:21 PM Glioblastoma Pathway As per ESMO 2014 guidelines, obtain histological confirmation of diagnosis and include sufficient tissue for molecular testing. E Molecular testing, IDH mutation, MGMT promoter methylation, and 1p/19q co-deletion: As per EANO 2021 guidelines, obtain routine immunohistochemistry for mutant IDH-1 R132H protein and nuclear expression of ATRX in the diagnostic evaluation of patients with diffuse gliomas. B Show 2 more As per SEOM 2018 guidelines, obtain MGMT promoter methylation status and IDH mutation testing. B As per ESMO 2014 guidelines, obtain MGMT promoter methylation status, IDH gene mutation, and 1p/19q co-deletion testing depending on the histological and clinical context. E Molecular testing (further testing): obtain combined chromosome 7 gain and chromosome 10 loss (+7/-10 signature), epidermal growth factor receptor amplification, and TERT promoter mutation testing in patients with IDH-wild-type diffuse gliomas lacking microvascular proliferation and necrosis as histological features of WHO grade 4 to allow for a diagnosis of IDH-wild-type glioblastoma. B Show 2 more Molecular testing (repeat testing): do not obtain repeat IDH mutation testing to derive new additional management or prognostic information beyond that derived from the tumor at the initial presentation in adult patients with progressive glioblastoma if the tumor is histologically similar to the primary tumor and the patient's clinical course is as expected. D Show 5 more 5. Medical management Management of initial disease, surgical resection: As per EANO 2021 guidelines: Perform surgical resection as feasible or biopsy followed as the standard of care in < 70 years old patients with IDH-wild-type glioblastoma and a Karnofsky performance score > 70. A Attempt to obtain complete resection B while prioritizing prevention of new permanent neurological deficits over the extent of resection. B As per SEOM 2018 guidelines: Perform surgical resection (maximum safe resection while preserving neurological function) as the first therapeutic approach to reduce the mass effect, obtain tissue for diagnosis, and improve survival in patients with glioblastoma. B Use neuronavigation systems, intraoperative imaging with MRI or ultrasound, and fluorescence dye 5-ALA to improve the extent of resection and improve progression-free survival. A As per ESMO 2014 guidelines, perform surgery to the extent feasible as the first-line therapeutic intervention in all patients with malignant glioma. E https://web.pathway.md/diseases/reckgYogVTBs6efiZ 3/8 6/24/23, 4:21 PM Glioblastoma Pathway Management of initial disease, radiotherapy: As per EANO 2021 guidelines, offer involved-field radiotherapy after resection or biopsy in < 70 years old patients with IDH-wild-type glioblastoma and a Karnofsky performance score > 70. A As per ASTRO 2016 guidelines, consider offering fractionated radiotherapy in individual patients depending on patient characteristics, such as performance status. (Strength of recommendation: Strong, HQE) Recognize that older age and poor performance status are associated with shorter survival in patients with glioblastoma. C Show 5 more Management of initial disease, concomitant chemoradiotherapy: As per EANO 2021 guidelines, offer concomitant radiotherapy and 6 cycles of maintenance temozolomide chemotherapy after resection or biopsy in < 70 years old patients with IDH-wild- type glioblastoma and a Karnofsky performance score > 70. A Show 2 more As per SEOM 2018 guidelines, offer combined treatment with radiotherapy (60 Gy in 30 fractions) and temozolomide (75 mg/m /day during radiotherapy) followed by adjuvant temozolomide (150-200 mg/m /day for 5 consecutive days every 28 days) for 6 cycles in < 70 years old adult patients with newly diagnosed glioblastoma. A Show 2 more As per ASTRO 2016 guidelines, offer fractionated radiotherapy with concurrent and adjuvant temozolomide as the standard of care following biopsy or resection in < 70 years old patients with newly diagnosed glioblastoma. A Show 2 more As per ESMO 2014 guidelines: Offer combined treatment with temozolomide and radiotherapy as the standard of care in patients with glioblastoma. E Consider offering temozolomide monotherapy in elderly patients with MGMT promoter- methylated tumors and hypofractionated radiotherapy alone in elderly patients with MGMT promoter-unmethylated tumors. E Management of initial disease (target volumes for radiotherapy): perform partial brain radiation therapy as the standard treatment paradigm for glioblastoma. A Show 2 more Management of initial disease (tumor-treating fields): consider offering tumor-treating fields in addition to adjuvant temozolomide after combined radiotherapy and temozolomide in patients with newly diagnosed supratentorial glioblastoma. B Management of progressive disease (repeat cytoreductive surgery): perform repeat cytoreductive surgery in symptomatic patients with progressive malignant glioma, recognizing that the expected median survival is 6-17 months following a second procedure. B Management of progressive disease, carmustine-impregnated wafers: As per SEOM 2018 guidelines, consider performing implantation of carmustine-impregnated wafers in patients with progressive glioblastoma. C https://web.pathway.md/diseases/reckgYogVTBs6efiZ 4/8 6/24/23, 4:21 PM Glioblastoma Pathway As per CNS/AANS 2014 guidelines, perform implantation of carmustine-impregnated biodegradable polymer wafers as a surgical adjunct when cytoreductive surgery is indicated in patients with progressive glioblastoma, taking into account the associated toxicities observed with this treatment. B Management of progressive disease (repeat radiotherapy): Offer re-irradiation (conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) for improved local tumor control in adult patients with progressive glioblastoma after first-line combined multimodality treatment with chemotherapy and radiotherapy if the target tumor is amenable to additional radiation. B Offer re-irradiation to maintain or improve the neurological status and quality of life before further tumor progression. B Management of progressive disease (chemotherapy): Offer temozolomide over procarbazine in patients with a first relapse of glioblastoma after having received nitrosourea chemotherapy or no prior cytotoxic chemotherapy at the time of initial therapy. B Consider offering other cytotoxic chemotherapy agents of uncertain benefit in patients with progressive glioblastoma based on the judgment of the treating physician, taking into account the individual patient's prior treatment exposure, systemic health, and the likelihood of tolerance of the toxicities of any given agent. Encourage enrollment in available clinical trials for these cases. C Management of progressive disease (targeted therapy): offer bevacizumab to improve disease control (imaging response and progression-free survival at 6 months) in adult patients with progressive glioblastoma. B Management of symptoms (headache): Administer corticosteroids for the treatment of headaches in patients with glioma. B Consider administering analgesics and co-analgesics for the treatment of headaches in patients with gliomas (in accordance with the WHO cancer pain ladder). C Management of symptoms, seizure: As per EANO/SNO 2021 guidelines, do not administer prophylactic antiepileptic drugs to reduce the risk of seizures in patients with a newly diagnosed brain tumor and no history of seizures. D Show 2 more As per SEOM 2018 guidelines, do not administer prophylactic antiepileptic drugs outside the perioperative period. D As per EANO 2017 guidelines: Offer intranasal midazolam or buccal clonazepam for the management of seizures in the end- of-life phase where the oral route is not an option. B Consider using alternative routes for antiepileptic drug administration in patients with a history of epilepsy developing swallowing difficulties, with the preferred route depending on the local availability of antiepileptic drugs and the place of care. E https://web.pathway.md/diseases/reckgYogVTBs6efiZ 5/8 6/24/23, 4:21 PM Glioblastoma Pathway Management of symptoms (fatigue): insufficient evidence to recommend any pharmacological or nonpharmacological intervention for fatigue in patients with glioma. I Management of symptoms (psychological and cognitive disorders): insufficient evidence to recommend pharmacological interventions, including methylphenidate and donepezil, for mood disorders in patients with glioma. I Consider offering multimodal psychosocial interventions to improve depressive symptoms. I Show 3 more Management of symptoms (delirium): identify and address underlying causes of delirium by adequate symptom control or changes in doses or type of medication. B Show 2 more 6. Perioperative care Postoperative thromboprophylaxis: initiate VTE prophylaxis with LMWH postoperatively within 24 hours, as the perioperative risk of intracranial hypertension increases when prophylaxis is initiated before induction of anesthesia. B Show 2 more Postoperative imaging: Obtain postoperative MRI within 24-48 hours after tumor excision (II, B) to avoid radiological changes related to subacute hemorrhage, ischemia, and inflammation appearing beyond 72 hours, in order to assess the extent of resection and acquire a baseline image for follow-up. B Obtain MRI within 72 hours after complete or partial resection. B 7. Patient education Genetic counseling: refer patients with relevant germline variants or suspected hereditary cancer syndromes for genetic counseling and, subsequently, for possible molecular genetic testing. B 8. Follow-up and surveillance Rehabilitation: Consider offering early postoperative rehabilitation and rehabilitation after tumor-specific treatment. C Consider offering cognitive rehabilitation in patients with glioma, especially in young patients with relatively favorable prognoses. (III) Consider offering cognitive rehabilitation in patients with stable glioma and cognitive complaints and/or deficits. E Surveillance after curative-intent therapy, MRI/MRS: As per EANO 2021 guidelines, suspect pseudoprogression in patients with an increase of abnormalities on neuroimaging in the first months after local therapeutic interventions (including radiotherapy) and after experimental local treatments. B https://web.pathway.md/diseases/reckgYogVTBs6efiZ 6/8 6/24/23, 4:21 PM Glioblastoma Pathway As per SEOM 2018 guidelines, consider viewing an apparent increase of tumor volume on MRI in the first months after local therapeutic interventions (including radiotherapy and experimental local treatments) as pseudoprogression. C As per CNS/AANS 2014 guidelines: Obtain MRI with and without gadolinium enhancement for imaging surveillance to detect the progression of previously diagnosed glioblastoma. B Obtain magnetic resonance spectroscopy as a diagnostic modality to differentiate true tumor progression from treatment-related imaging changes or pseudoprogression in patients with suspected progressive glioblastoma. B Surveillance after curative-intent therapy (PET/SPECT): Obtain single-photon emission CT imaging as a diagnostic modality to differentiate true tumor progression from treatment-related imaging changes or pseudoprogression in patients with suspected progressive glioblastoma. B Do not obtain routine positron emission tomography to identify the progression of glioblastoma. D Management of recurrent disease: As per EANO 2021 guidelines, consider offering surgery and radiotherapy in patients with recurrent IDH-wild-type glioblastoma. C Show 2 more As per SEOM 2018 guidelines, consider offering procarbazine, lomustine, and vincristine or single-agent nitrosourea therapy to achieve tumor control in patients with recurrent glioblastoma. C Show 4 more As per ASTRO 2016 guidelines, consider offering focal re-irradiation (stereotactic radiosurgery, hypofractionated stereotactic radiation therapy, or brachytherapy) in younger patients with recurrent glioblastoma and good performance status, taking into account tumor size and location. C As per AANS 2014 guidelines: Offer repeat cytoreductive surgery in symptomatic patients with locally recurrent malignant glioma, recognizing that the expected median survival is 6-17 months following a second procedure. B Take into account the location of recurrence in eloquent/critical brain regions, Karnofsky performance status, and tumor volume when evaluating patients for a repeat operation. B References 1. Alvin R Cabrera, John P Kirkpatrick, John B Fiveash et al. Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. Pract Radiat Oncol. 2016 Jul-Aug;6 4 217 225. Open https://web.pathway.md/diseases/reckgYogVTBs6efiZ 7/8 6/24/23, 4:21 PM Glioblastoma Pathway 2. Andrea Pace, Linda Dirven, Johan A F Koekkoek et al. European Association for Neuro-Oncology EANO guidelines for palliative care in adults with glioma. Lancet Oncol. 2017 Jun;18 6):e330-e340. Open 3. R Stupp, M Brada, M J van den Bent et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 Suppl 3:iii93 101. Open 4. Michael Weller, Martin van den Bent, Matthias Preusser et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18 3 170 186. Open 5. Jeffrey J Olson, Lakshmi Nayak, D Ryan Ormond et al. The role of cytotoxic chemotherapy in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014 Jul;118 3 501 55. Open 6. M Mart nez-Garcia, J lvarez-Linera, C Carrato et al. SEOM clinical guidelines for diagnosis and treatment of glioblastoma 2017 . Clin Transl Oncol. 2018 Jan;20 1 22 28. Open 7. Timothy Charles Ryken, Steven N Kalkanis, John M Buatti et al. The role of cytoreductive surgery in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014 Jul;118 3 479 88. Open 8. Timothy Charles Ryken, Nafi Aygun, Johnathan Morris et al. The role of imaging in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014 Jul;118 3 435 60. Open 9. Tobias Walbert, Rebecca A Harrison, David Schiff et al. SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neuro Oncol. 2021 Nov 2;23 11 1835 1844. Open 10. Abigail L Goodman, Jos E Vel zquez Vega, Chad Glenn et al. Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of neuropathology in the management of progressive glioblastoma in adults. J Neurooncol. 2022 Jun;158 2 179 224. Open 11. Jeffrey J Olson, Lakshmi Nayak, D Ryan Ormond et al. The role of targeted therapies in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014 Jul;118 3 557 99. Open 12. Samuel Ryu, John M Buatti, Ann Morris et al. The role of radiotherapy in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014 Jul;118 3 489 99. Open https://web.pathway.md/diseases/reckgYogVTBs6efiZ 8/8

Guideline sources The following summarized guidelines for the evaluation and management of gout are prepared by our editorial team based on guidelines from the American College of Rheumatology (ACR 2023; 2020; 2012), the European League Against Rheumatism (EULAR 2022; 2020; 2017), the British Society for Rheumatology (BSR 2017), the Treat-to-target (T2T 2017), the American College of Physicians (ACP 2017), the American College of Radiology (ACR 2017), and the Clinical Pharmacogenetics Implementation Consortium (CPIC 2013). 1 2 3 4 5 6 7 8 9 10 11 12 13 13 14 15 16 16 Definition Gout is a type of inflammatory arthritis characterized by the deposition of monosodium urate monohydrate crystals in synovial fluid and other tissues. 13 https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 1/14 7/1/23, 12:04 AM Gout Pathway Epidemiology Gout is due to persistently elevated blood levels of uric acid (hyperuricemia), which is often multifactorial (increased intake of purine-rich foods, defects in purine metabolism, older age, male sex, obesity, renal failure, diuretics). 16 Pathophysiology In the United States, the prevalence of gout is estimated at 3900 persons per 100,000 population. The incidence of gout is estimated at 400 per 100,000 person-years in men, and 140 per 100,000 person-years in women. 14 15 Disease course In patients with acute gout, deposition of urate monohydrate crystals inside joint cavities initiate an inflammatory response that results in the clinical manifestations of arthritis. Chronic synovitis, bony erosions, cartilage damage, and tophi formation may occur in patients with chronic gout. 16 Prognosis and risk of recurrence The 1-year recurrence rate for acute gout attack in patients who have experienced an attack in the past year is estimated at 69%. 13 Calculator Acute gout diagnosis rule Guidelines 1. Screening and diagnosis Diagnosis: include gout in the differential diagnosis of any adult patient with acute arthritis. B Show 2 more 2. Diagnostic investigations Clinical evaluation: As per EULAR 2020 guidelines, assess for risk factors for chronic hyperuricemia in all patients with gout, specifically CKD, overweight, medications (including diuretics, low-dose aspirin, cyclosporine, tacrolimus), consumption of excess alcohol (particularly beer and spirits), non-diet sodas, meat and shellfish. A https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 2/14 7/1/23, 12:04 AM Gout Pathway As per ACR 2012 guidelines, elicit a history of articular symptoms, and perform a thorough physical exam for signs of gout (such as tophi and acute or chronic synovitis) as part of the clinical evaluation of patients with gout. B Diagnostic imaging: As per EULAR 2020 guidelines, obtain imaging to search for monosodium urate monohydrate crystal deposition and features of any alternative diagnosis when a clinical diagnosis of gout is uncertain and crystal identification is not possible. B Show 2 more As per ACR 2017 guidelines: Obtain radiography as initial imaging in patients with suspected gout. E Obtain ultrasound or CT, including dual-energy CT, to complement radiography in the detection of erosions and tophi. E As per ACR 2012 guidelines: Obtain high-resolution ultrasound, CT or dual energy CT to detect tophi. B Obtain plain radiographic findings to identify findings consistent with tophi, such as characteristic bone erosions. B Genetic testing: Consider HLA-B5801 testing before starting allopurinol in patients with gout of Southeast Asian descent (such as Han Chinese, Korean, Thai) and African American patients, who have a higher prevalence of HLA-B5801. C Do not obtain HLA-B5801 testing in all other patients with gout. D Evaluation for comorbidities: As per EULAR 2020 guidelines, obtain systematic assessment for the presence of associated comorbidities in patients with gout, including obesity, renal impairment, hypertension, ischemic heart disease, HF, diabetes and dyslipidemia. A As per BSR 2017 guidelines, screen for cardiovascular risk factors and comorbid conditions, such as cigarette smoking, hypertension, diabetes mellitus, dyslipidemia, obesity and renal disease, in all patients with gout, review at least annually and manage appropriately. B As per T2T 2017 guidelines: Obtain regular assessment of comorbidities associated with gout, and manage accordingly. B Assess renal function in all patients with gout at the time of diagnosis and then monitor regularly. B As per ACR 2012 guidelines, evaluate for secondary causes of hyperuricemia for all gout patients, and screen for the following specific comorbidities: obesity, dietary factors excessive alcohol intake metabolic syndrome T2DM hypertension https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 3/14 7/1/23, 12:04 AM Gout Pathway hyperlipidemia modifiable risk factors for CAD or stroke serum urate-elevating medications history of urolithiasis CKD, glomerular or interstitial renal disease (e.g., analgesic nephropathy, polycyctsic kidney disease) in selected cases, potential genetic or acquired cause of uric acid overproduction (e.g., inborn error of purine metabolism, or psoriasis, myeloproliferative or lymphoproliferative disease, respectively) lead intoxication. B Screening for chronic infections: screen for HBV infection in all patients eligible for treatment with conventional synthetic, biological, or targeted synthetic DMARDs, immunosuppressants, or corticosteroids (according to dose and duration). B Show 3 more 3. Diagnostic procedures Synovial fluid analysis: As per EULAR 2020 guidelines: Perform synovial fluid aspiration and examination for crystals in any patient with undiagnosed inflammatory arthritis. B Assess for the presence of crystals in synovial fluid or tophus aspirates in all patients with suspected gout, because demonstration of monosodium urate monohydrate crystals allows a definitive diagnosis of gout. B As per ACP 2017 guidelines, perform synovial fluid analysis when clinical judgment indicates that diagnostic testing is necessary in patients with possible acute gout. B 4. Medical management Management of acute flares: As per ACR 2020 guidelines, initiate concomitant anti-inflammatory prophylaxis therapy (such as colchicine, NSAIDs, prednisone/prednisolone) in patients with gout. Select the specific agent of anti-inflammatory prophylaxis based on patient factors. B Show 5 more As per BSR 2017 guidelines, initiate an NSAID at maximum dose or colchicine in doses of 500 g 2-4 times daily as first-line therapy, with the drug choice depending on patient preference, renal function and comorbidities, if not contraindicated. Coprescribe a gastroprotective agent in patients on NSAIDs or COX-2 inhibitors. A Show 3 more https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 4/14 7/1/23, 12:04 AM Gout Pathway As per EULAR 2017 guidelines, treat acute flares of gout as early as possible. Educate fully informed patients to self-medicate at the first warning symptoms. Decide on the drug choice based on the presence of contraindications, the patient's previous experience with treatments, time of initiation after flare onset and the number and type of joints involved. E Show 2 more As per T2T 2017 guidelines, treat acute attacks promptly with anti-inflammatory medications, taking safety issues into consideration. B Indications for urate-lowering therapy: As per ACR 2020 guidelines, initiate urate-lowering therapy in patients with 1 subcutaneous tophi A , or with radiographic damage attributable to gout with any imaging modality. B Show 6 more As per ACP 2017 guidelines, avoid initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks. D As per BSR 2017 guidelines: Discuss and offer urate-lowering therapy in all patients with a diagnosis of gout, particularly in patients with the following: recurring attacks - 2 attacks/year A tophi A chronic gouty arthritis A joint damage A renal impairment, eGFR < 60 mL/min A history of urolithiasis B diuretics use B primary gout starting at a young age. B Initiate urate-lowering therapy ideally after inflammation has settled, as urate-lowering therapy is better discussed when the patient is not in pain. B As per EULAR 2017 guidelines, discuss and consider initiating urate-lowering therapy in the first presentation of all patients with a definite diagnosis of gout. E Show 2 more Treatment targets: As per ACR 2020 guidelines, continue urate-lowering therapy in all patients with gout taking urate-lowering therapy to achieve and maintain an serum urate target of < 6 mg/dL. A Show 2 more As per BSR 2017 guidelines: Set the initial aim of urate-lowering therapy to reduce and maintain the serum urate level 300 mcmol/L to prevent further urate crystal formation and to dissolve away existing crystals. Recognize that the lower the serum urate level the greater the velocity of crystal elimination. B https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 5/14 7/1/23, 12:04 AM Gout Pathway Adjust the dose of urate-lowering therapy to maintain the serum urate level 360 mcmol/L after some years of successful treatment when tophi have resolved and the patient remains free of symptoms, to avoid further crystal deposition and the possibility of adverse effects associated with a very low serum urate level. B As per EULAR 2017 guidelines, maintain serum urate level to < 6 mg/dL (< 360 mcmol/L) in patients on urate-lowering therapy. E Show 2 more As per T2T 2017 guidelines, target and maintain a serum urate level < 6 mg/dL (< 360 mmol/L) in all patients with gout. B Show 2 more Allopurinol: As per ACR 2020 guidelines, select allopurinol over all other urate-lowering agents as the preferred first-line agent for all patients with gout starting any urate-lowering therapy, including in those with CKD stage 3. B Show 2 more As per BSR 2017 guidelines: Initiate allopurinol as first-line urate-lowering therapy at a low dose (50-100 mg/day) and the dose then increased in 100 mg increments approximately every 4 weeks until the serum urate level target has been achieved (maximum dose 900 mg). B Use smaller increments (50 mg) in patients with renal impairment, with a lower maximum dose but the same target urate levels. B As per EULAR 2017 guidelines: Initiate allopurinol as first-line urate-lowering therapy in patients with normal kidney function, starting at a low dose (100 mg/day) and increasing by 100 mg increments every 2-4 weeks if required, to reach the uricemia target. E Adjust the allopurinol maximum dosage to CrCl in patients with renal impairment. Switch allopurinol to febuxostat or benzbromarone, or add benzbromarone to allopurinol, if the serum urate target cannot be achieved at this dose, except in patients with eGFR < 30 mL/min. E As per ACR 2012 guidelines, initiate allopurinol at a maximal dose of 100 mg/day for any patient, and initiate at 50 mg/day in patients with stage 4 or worse CKD. B Xanthine oxidase inhibitors: As per ACR 2020 guidelines, select a xanthine oxidase inhibitor over probenecid for patients with gout and CKD stage 3. B Show 2 more Landmark trials: CARES In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to CV death, nonfatal MI, nonfatal CVA, or UA requiring urgent revascularization. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 6/14 7/1/23, 12:04 AM Gout Pathway White WB et al. N Engl J Med. 2018 Mar 29. As per BSR 2017 guidelines, consider initiating febuxostat (80 mg/day and, if necessary, increase after 4 weeks to 120 mg/day) as an alternative second-line xanthine oxidase inhibitor in patients not tolerating allopurinol or if renal impairment prevents allopurinol dose escalation sufficient to achieve the therapeutic target. B Uricosuric therapy: As per ACR 2020 guidelines: Consider starting probenecid at a low dose (500 mg once or BID) with dose titration in patients with gout. C Do not offer urine alkalinization in patients with gout taking uricosuric treatment. D As per BSR 2017 guidelines, consider initiating uricosuric agents in patients resistant to, or intolerant of, xanthine oxidase inhibitors. Prefer sulfinpyrazone (200-800 mg/day) or probenecid (500-2,000 mg/day) in patients with normal or mildly impaired renal function, or benzbromarone (50-200 mg/day) in patients with mild-to-moderate renal insufficiency. B Show 2 more As per ACR 2012 guidelines, use probenecid as the first choice among uricosurics for urate- lowering therapy monotherapy. B Show 3 more Pegloticase: As per ACR 2020 guidelines: Do not offer pegloticase as first-line therapy for patients with gout. D Do not offer pegloticase in patients with gout for whom xanthine oxidase inhibitor, uricosurics, and other interventions have failed to achieve serum urate target and who have infrequent gout flares (< 2 per year) and no tophi. D As per EULAR 2017 guidelines, initiate pegloticase in patients with crystal-proven, severe debilitating chronic tophaceous gout and poor quality of life, if the serum urate target cannot be reached with any other available drug at the maximal dosage (including combinations). E Anti-inflammatory therapy: As per ACP 2017 guidelines, use corticosteroids, NSAIDs, or colchicine for the treatment patients with acute gout. A As per BSR 2017 guidelines: Consider initiating colchicine 500 g 1-2 times daily as prophylaxis against acute attacks resulting from initiation or uptitration of any urate-lowering therapy and continue for up to 6 months. C Consider initiating a low-dose NSAID or COX-2 inhibitor (with gastroprotection), if not contraindicated, as an alternative in patients not tolerating colchicine. C As per EULAR 2017 guidelines, explain and discuss prophylaxis against flares with the patient. Administer prophylaxis during the first 6 months of urate-lowering therapy. E https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 7/14 7/1/23, 12:04 AM Gout Pathway Show 3 more As per T2T 2017 guidelines, initiate prophylaxis against attacks and continue for at least 6 months after starting urate-lowering therapy. B 5. Nonpharmacologic interventions Discontinuation of contributing medications: discontinue non-essential medications that are associated with elevation in serum urate levels (such as thiazide diuretics, loop diuretics, niacin, and calcineurin inhibitors). B Rest and ice packs: As per ACR 2020 guidelines, advise topical ice as an adjuvant treatment in patients experiencing a gout flare. B As per BSR 2017 guidelines, advise providing rest for the affected joints, elevate and expose in a cool environment. B Advise ice packs B and bed cages as adjuncts to management. B Dietary modifications: As per ACR 2020 guidelines: Advise limiting purine intake in patients with gout, regardless of disease activity. B Advise limiting high-fructose corn syrup in patients with gout, regardless of disease activity. B As per BSR 2017 guidelines, counsel regarding diet in all patients with gout. Encourage a following a well-balanced diet low in fat and added sugars, and high in vegetables and fiber. Advise avoiding sugar-sweetened soft drinks containing fructose, excessive intake of alcoholic drinks and high-purine foods. Encourage inclusion of skimmed milk B and/or low fat yogurt, soy beans and vegetable sources of protein, and cherries in the diet. B As per EULAR 2017 guidelines, advise avoiding sugar-sweetened drinks, heavy meals and excessive intake of meat and seafood in patients with gout. Encourage consuming low-fat dairy products. B As per ACR 2012 guidelines: Advise that patients with gout limit their consumption of purine-rich meat and seafood B as well as high fructose corn syrup sweetened soft drinks and energy drinks B , and encourage consumption of low-fat or non-fat dairy products B Advise that patients with gout reduce consumption of alcohol (particularly beer, but also wine and spirits), and avoid alcohol overuse. B Weight loss: As per ACR 2020 guidelines, advise weight loss in patients with gout who are overweight/obese, regardless of disease activity. B As per BSR 2017 guidelines, encourage dietary modifications to achieve a gradual reduction in body weight and subsequent maintenance in overweight patients with gout. B Exercise: advise regular exercise in patients with gout. B https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 8/14 7/1/23, 12:04 AM Gout Pathway Alcohol intake: as per ACR 2020 guidelines, advise limiting alcohol intake in patients with gout, regardless of disease activity. B Alkohol intake: as per EULAR 2017 guidelines, advise avoiding alcohol (especially beer and spirits) in patients with gout. B Vitamin C: As per ACR 2020 guidelines, do not offer vitamin C supplements to patients with gout, regardless of disease activity. D As per BSR 2017 guidelines, recognize that vitamin C supplements (500-1,500 mg/day) have a weak uricosuric effect. B 6. Specific circumstances Carriers of HLA-B5801: avoid prescribing allopurinol in carriers of the HLA-B5801 allele. D Patients taking antihypertensive medications: As per ACR 2020 guidelines: Consider switching hydrochlorothiazide to an alternate antihypertensive when feasible in patients with gout, regardless of disease activity. C Consider choosing losartan preferentially as an antihypertensive when feasible in patients with gout. C As per BSR 2017 guidelines: Consider switching to an alternative antihypertensive agent in patients receiving diuretic drugs for hypertension, as long as BP is controlled. C Do not use losartan or fenofibrate as a primary urate-lowering therapy, but consider initiating for the treatment of hypertension or dyslipidemia, respectively, as they have a weak uricosuric effect. D As per EULAR 2017 guidelines: Substitute the diuretic in patients with gout receiving loop or thiazide diuretics, if possible. E Consider initiating losartan or CCBs for hypertension and statins or fenifibrate for hyperlipidemia in patients with gout. E Patients taking aspirin: consider not stopping low-dose aspirin in patients with gout (in those who are taking this medication for appropriate indications). D Patients taking fenofibrate: do not add or switch to fenofibrate in patients with gout. D 7. Patient education Patient education: As per BSR 2017 guidelines, educate patients on the importance of initiating treatment for attacks as soon as an attack occurs. Ensure that patients are aware of the importance of https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 9/14 7/1/23, 12:04 AM Gout Pathway continuing any established urate-lowering therapy during an attack. B Show 4 more As per EULAR 2017 guidelines: Inform all patients with gout about the pathophysiology of the disease, the existence of effective treatments, associated comorbidities and the principles of managing acute attacks and eliminating urate crystals through lifelong lowering of serum urate level below a target level. B Provide full information in patients with gout and involve them fully in decision-making concerning the use of urate-lowering therapy. E As per T2T 2017 guidelines: Provide education about all aspects of the disease in patients with gout, and involve the patient fully in shared decision-making. E Make information about gout and its management readily available to patients. B Address modifiable risk factors primarily through patient education and support. B 8. Preventative measures Routine immunizations: consider offering high-dose or adjuvanted influenza vaccination, rather than regular-dose influenza vaccination, in 65 years old patients with rheumatic or musculoskeletal diseases and in 18-65 years old patients with rheumatic or musculoskeletal diseases on immunosuppressive medications. C Show 17 more Prophylaxis for Pneumocystis jirovecii pneumonia: consider administering prophylaxis against P. jirovecii pneumonia in patients initiating high-dose corticosteroids, especially in combination with immunosuppressants and depending on the risk-benefit ratio. C 9. Follow-up and surveillance Indications for specialist referral: Refer patients for specialist consultation in the following situations: unclear etiology of hyperuricemia refractory signs or symptoms of gout difficulty in reaching the target serum urate level, particularly with renal impairment and a trial of xanthine oxidase inhibitor treatment multiple and/or serious adverse events from pharmacologic urate-lowering therapy. B Serum urate monitoring: As per EULAR 2017 guidelines, monitor and maintain a defined serum urate level in patients on urate-lowering therapy. E https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 10/14 7/1/23, 12:04 AM Gout Pathway As per T2T 2017 guidelines, monitor serum urate must regularly and adjust urate-lowering therapy to attain the therapeutic target. B As per ACR 2012 guidelines, monitor serum urate every 2-5 weeks during urate-lowering therapy titration, and obtain follow-up measurements every 6 months once the serum urate target is achieved. B Indications for switching urate-lowering agents: As per ACR 2020 guidelines, consider switching to an alternative urate-lowering agent, if available and consistent with other recommendations in this guideline, in patients with gout taking febuxostat with a history of CVD or a new cardiovascular event. C Show 2 more As per EULAR 2017 guidelines: Switch allopurinol to febuxostat or a uricosuric or combined with a uricosuric, if the serum urate target cannot be reached by an appropriate dose of allopurinol or when allopurinol is not tolerated. E Switch allopurinol to febuxostat or benzbromarone, or add benzbromarone to allopurinol, if the serum urate target cannot be achieved in patients with renal impairment (except in patients with eGFR < 30 mL/min) receiving allopurinol maximum dosage adjusted to CrCl. E Management of refractory disease: attempt upwards dose titration of one xanthine oxidase inhibitor to the maximum appropriate dose. A Clinical findings Symptoms Past medical history Ankle pain CKD Joint pain Diabetes mellitus Joint swelling Obesity Knee pain Social history Family history Alcohol consumption Genetic predispositions Musculoskeletal exam Vital signs Arthritis Hypertension Joint line tenderness Podagra Integument exam Polyarticular synovitis Tophus on pinna Lab findings Histological findings serum uric acid urine uric acid Synovial fluid monosodium urate crystals https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 11/14 7/1/23, 12:04 AM Gout Pathway Urine uric acid crystals Likelihood Ratios Pertinent positives The following findings increase the probability of gout in adults. 16 Finding LR+ Value Presence of synovial fluid monosodium urate crystals 94 Presence of podagra 32 Increased serum uric acid* 3 measuring levels in acute attacks is not recommended, as they can be normal. Pertinent negatives The following findings decrease the probability of gout in adults. 16 Finding LR- Value Absence of podagra 0.04 Absence of synovial fluid monosodium urate crystals 0.2 serum uric acid not increased* 0.4 measuring levels in acute attacks is not recommended, as they can be normal. Studies 2022 STOP GOUT In patients with gout and hyperuricemia, allopurinol was noninferior to febuxostat with respect to the percentage of patients experiencing 1 gout flare at week 49 to 72. James R O'Dell et al. NEJM Evid. 2022 Mar. 2018 CARES In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to CV death, nonfatal MI, nonfatal CVA, or UA requiring urgent revascularization. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. White WB et al. N Engl J Med. 2018 Mar 29. References https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 12/14 7/1/23, 12:04 AM Gout Pathway 1. Michelle Hui, Alison Carr, Stewart Cameron et al. The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology Oxford). 2017 Jul 1;56 7):e1-e20. Open 2. Khanna D, Fitzgerald JD, Khanna PP et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1 systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res Hoboken). 2012 Oct;64 10 1431 46. Open 3. P Richette, M Doherty, E Pascual et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017 Jan;76 1 29 42. Open 4. Pascal Richette, Michael Doherty, Eliseo Pascual et al. 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis. 2020 Jan;79 1 31 38. Open 5. John D FitzGerald, Nicola Dalbeth, Ted Mikuls et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res Hoboken). 2020 Jun;72 6 744 760. Open 6. U Kiltz, J Smolen, T Bardin et al. Treat-to-target T2T recommendations for gout. Ann Rheum Dis. 2017 Apr;76 4 632 638. Open 7. Qaseem A, McLean RM, Starkey M et al. Diagnosis of Acute Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017 Jan 3;166 1 52 57. Open 8. Anne R Bass, Eliza Chakravarty, Elie A Akl et al. 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2023 Jan 4. Online ahead of print. Open 9. Qaseem A, Harris RP, Forciea MA. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017 Jan 3;166 1 58 68. Open 10. George E Fragoulis, Elena Nikiphorou, Mrinalini Dey et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2022 Nov 3;ard-2022 223335. Open 11. Hershfield MS, Callaghan JT, Tassaneeyakul W et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013 Feb;93 2 153 8. Open 12. Expert Panel on Musculoskeletal Imaging:, Jon A Jacobson, Catherine C Roberts et al. ACR Appropriateness Criteria Chronic Extremity Joint Pain-Suspected Inflammatory Arthritis. J Am Coll Radiol. 2017 May;14 5S S81 S89. Open 13. Neogi T. Gout. Ann Intern Med. 2016 Jul 5;165 1 ITC1 ITC16. Open 14. Singh G, Lingala B, Mithal A. Gout and hyperuricaemia in the USA prevalence and trends. Rheumatology Oxford). 2019 Jun 5. pii: kez196. Open 15. Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014 May;40 2 155 75. Open 16. Ragab G, Elshahaly M, Bardin T. Gout: An old disease in new perspective A review. J Adv Res. 2017 Sep;8 5 495 511. Open 17. Zhang W, Doherty M, Pascual E et al. EULAR evidence based recommendations for gout. Part I Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics ESCISIT . Ann Rheum Dis. 2006 Oct;65 10 1301 11. Open https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 13/14 7/1/23, 12:04 AM Gout Pathway 18. Jeff A Simerville, William C Maxted, John J Pahira. Urinalysis: a comprehensive review. Am Fam Physician. 2005 Mar 15;71 6 1153 62. Open 19. Khanna D, Khanna PP, Fitzgerald JD et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2 therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res Hoboken). 2012 Oct;64 10 1447 61. Open 20. Sharan K Rai, J Antonio Avi a-Zubieta, Natalie McCormick et al. The rising prevalence and incidence of gout in British Columbia, Canada: Population-based trends from 2000 to 2012. Semin Arthritis Rheum. 2017 Feb;46 4 451 456. Open 21. A Scuiller, T Pascart, A Bernard et al. Gout]. Rev Med Interne. 2020 Jun;41 6 396 403. Open 22. Francisca Sivera, Mariano Andr s, Neus Quilis. Gout: Diagnosis and treatment. Med Clin Barc). 2017 Mar 22;148 6 271 276. Open 23. James R O'Dell, Mary T Brophy, Michael H Pillinger et al. Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management. NEJM Evid. 2022 Mar;1 3 10.1056/evidoa2100028. Open https://web.pathway.md/diseases/recNUo9eCPgbgtHq6 14/14

Guideline sources The following summarized guidelines for the evaluation and management of granuloma inguinale are prepared by our editorial team based on guidelines from the Center for Disease Control (CDC 1 2021) and the International Union Against Sexually Transmitted Infections (IUSTI/WHO 2010). 2 Guidelines 1. Diagnostic investigations Diagnostic testing: recognize that the causative organism of granuloma inguinale is difficult to culture. E Show 2 more Testing for other STIs: As per CDC 2021 guidelines, test all patients with granuloma inguinale for human immunodeficiency virus. E As per IUSTI 2010 guidelines, obtain testing for human immunodeficiency virus and syphilis in patients with granuloma inguinale. Assessment of sexual partners: https://web.pathway.md/diseases/recwX16CrRdpRlebu 1/3 7/1/23, 12:04 AM Granuloma inguinale Pathway As per CDC 2021 guidelines, evaluate persons having had sexual contact with a patient with granuloma inguinale within the 60 days before onset of the patient's symptoms. E Show 2 more As per IUSTI 2010 guidelines: Recognize that granuloma inguinale is uncommon in partners of index cases. Check sexual contacts in the last 6 months for possible lesions by clinical examination. 2. Medical management Antibiotic therapy: As per CDC 2021 guidelines, administer azithromycin 1 g PO once weekly or 500 mg daily for > 3 weeks and until all lesions have completely healed in patients with granuloma inguinale. E Show 2 more As per IUSTI 2010 guidelines, administer azithromycin 1 g weekly or 500 mg daily as first-line therapy in patients with granuloma inguinale. B Show 3 more 3. Specific circumstances Pregnant patients: As per CDC 2021 guidelines, administer a macrolide regimen (erythromycin or azithromycin) in pregnant and lactating patients with granuloma inguinale. E As per IUSTI 2010 guidelines, consider administering erythromycin 500 mg QID in pregnant patients with granuloma inguinale. C Pediatric patients: Administer a short course of azithromycin 20 mg/kg in pediatric patients with granuloma inguinale. B Administer antibiotic prophylaxis with a 3-day course of azithromycin 20 mg/kg once daily in children born to mothers with granuloma inguinale. B Patients with HIV: administer the same antibiotic regimens in patients with granuloma inguinale and human immunodeficiency virus infection as those used in patients without human immunodeficiency virus infection. E 4. Patient education General counseling: Recognize that patients with granuloma inguinale are often embarrassed or ashamed. Reassure that they have a treatable condition. Ensure that patients take antibiotics until complete healing has been achieved. https://web.pathway.md/diseases/recwX16CrRdpRlebu 2/3 7/1/23, 12:04 AM Granuloma inguinale Pathway 5. Follow-up and surveillance Assessment of treatment response: As per CDC 2021 guidelines: Follow-up patients clinically until signs and symptoms have resolved. E Recognize that relapse can occur 6-18 months after apparently effective therapy. E As per IUSTI 2010 guidelines, perform biopsy to exclude carcinoma if lesions have not resolved by 6 weeks. References 1. Kimberly A Workowski, Laura H Bachmann, Philip A Chan et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021 Jul 23;70 4 1 187. Open 2. N O'Farrell, H Moi, IUSTI/WHO European STD guidelines Editorial Board. European guideline for the management of donovanosis, 2010. Int J STD AIDS. 2010 Sep;21 9 609 10. Open https://web.pathway.md/diseases/recwX16CrRdpRlebu 3/3

Guideline sources The following summarized guidelines for the evaluation and management of granulomatosis with polyangiitis (GPA) are prepared by our editorial team based on guidelines from the European League Against Rheumatism (EULAR 2023), the Vasculitis Foundation (VF/ACR 2021), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021), and the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2019). 1 2 3 4 Calculator ACR/EULAR diagnostic criteria f https://web.pathway.md/diseases/recviPIXECDYZifbb 1/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Guidelines 1. Diagnostic investigations Antineutrophil cytoplasmic antibodies: obtain both proteinase 3-ANCA and myeloperoxidase- ANCA testing, with a high-quality antigen-specific assay as the primary method of testing, in patients with signs and/or symptoms raising suspicion of a diagnosis of ANCA-associated vasculitis. A Serum immunoglobulins: measure serum immunoglobulin concentrations before each course of rituximab to detect secondary immunodeficiency in patients with ANCA-associated vasculitis receiving rituximab. B 2. Diagnostic procedures Biopsy: perform biopsies to assist in establishing a new diagnosis of ANCA-associated vasculitis and for further evaluation of patients suspected of having relapsing vasculitis. B 3. Medical management General principles: As per EULAR 2023 guidelines: Offer multidisciplinary management in centers with, or with ready access to, expertise in vasculitis in patients with ANCA-associated vasculitis. B Offer the best care based on shared decision-making between the patient and the physician, taking efficacy, safety, and costs into account, in patients with ANCA-associated vasculitis. B As per KDIGO 2021 guidelines: Manage patients with ANCA-associated vasculitis at centers with experience in ANCA- associated vasculitis. B Do not delay immunosuppressive therapy while waiting for a kidney biopsy to be performed or reported in patients with a clinical presentation compatible with small-vessel vasculitis and positive or proteinase 3-ANCA and myeloperoxidase-ANCA serology, especially in patients rapidly deteriorating. D Induction of remission: As per EULAR 2023 guidelines, initiate a combination of corticosteroids and either rituximab or cyclophosphamide for induction of remission in patients with new-onset GPA with organ- threatening or life-threatening disease. A Show 3 more Landmark trials: ADVOCATE https://web.pathway.md/diseases/recviPIXECDYZifbb 2/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway In patients with ANCA-associated vasculitis, avacopan was noninferior to prednisone with respect to remission at week 26. David R W Jayne et al. N Engl J Med. 2021 Feb 18. As per KDIGO 2021 guidelines, initiate corticosteroids in combination with cyclophosphamide or rituximab as initial therapy in patients with new-onset ANCA-associated vasculitis. B As per ACR 2021 guidelines, consider initiating methotrexate over cyclophosphamide or rituximab in patients with active, non-severe GPA. C Show 8 more Maintenance of remission: As per EULAR 2023 guidelines: Initiate rituximab for maintenance of remission after induction of remission with either rituximab or cyclophosphamide in patients with GPA. Consider initiating azathioprine or methotrexate as alternatives. B Continue therapy to maintain remission for 24-48 months following induction of remission in patients with new-onset GPA. B Consider continuing therapy for a longer duration in patients with relapse or with an increased risk of relapse, balanced against patient preferences and risks of continuing immunosuppression. B As per KDIGO 2021 guidelines, initiate low-dose corticosteroids and either rituximab or azathioprine as maintenance therapy after induction of remission in patients with GPA. B Show 6 more As per ACR 2021 guidelines, consider initiating rituximab over methotrexate or azathioprine for remission maintenance in patients with severe GPA entered remission after treatment with cyclophosphamide or rituximab. C Show 6 more Anticoagulant therapy: insufficient evidence to recommend an optimal duration of anticoagulation in patients with GPA experiencing venous thrombotic events. I 4. Therapeutic procedures Plasma exchange: As per EULAR 2023 guidelines: Consider performing plasma exchange as part of therapy to induce remission in patients with GPA with a serum creatinine > 300 mcmol/L due to active glomerulonephritis. B Do not perform plasma exchange routinely for the treatment of alveolar hemorrhage in patients with GPA. D As per KDIGO 2021 guidelines: https://web.pathway.md/diseases/recviPIXECDYZifbb 3/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Consider performing plasma exchange in patients with serum creatinine > 5.7 mg/dL (500 mmol/l) requiring dialysis or with rapidly increasing serum creatinine, and in patients with diffuse alveolar hemorrhage having hypoxemia. C Perform plasma exchange in patients with an overlap syndrome of ANCA-associated vasculitis and anti-GBM. B As per ACR 2021 guidelines: Consider avoiding routine plasma exchange in addition to remission induction therapy in patients with GPA and active glomerulonephritis. D Consider avoiding plasma exchange in addition to remission induction therapy in patients with active, severe GPA and alveolar hemorrhage. D Landmark trials: PEXIVAS (plasmapheresis) In patients with severe ANCA-associated vasculitis, plasma exchange was not superior to no plasma exchange with respect to the composite outcome of death from any cause or end- stage kidney disease. Michael Walsh et al. N Engl J Med. 2020 Feb 13. 5. Surgical interventions Kidney transplantation: As per KDIGO 2021 guidelines, delay kidney transplantation until patients are in complete clinical remission for 6 months. Do not delay transplantation because of the persistence of ANCA. B As per ACR 2021 guidelines, consider evaluating patients with GPA in remission and stage 5 CKD for renal transplantation. C 6. Specific circumstances Pediatric patients (diagnosis and classification): Recognize that there are no validated diagnostic criteria for GPA. B Recognize that there are two different classification criteria for GPA: ACR criteria EULAR/PRINTO/PReS endorsed Ankara 2008 criteria. B Use the Ankara 2008 criteria for the classification of GPA in pediatric patients. B Pediatric patients (ANCA testing): obtain ANCA for the diagnosis of ANCA-associated vasculitis. B Show 2 more https://web.pathway.md/diseases/recviPIXECDYZifbb 4/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Pediatric patients (diagnostic imaging): consider obtaining sinus CT or MRI for the diagnosis of GPA. C Show 2 more Pediatric patients (biopsy): attempt histopathological confirmation of the diagnosis of ANCA- associated vasculitis while not delaying treatment in patients with organ- or life-threatening disease. B Show 2 more Pediatric patients (treatment): Consider initiating a biological agent in patients with ANCA-associated vasculitis with critical organ- or life-threatening disease failed standard vasculitis therapy or if concerns exist regarding cyclophosphamide toxicity. Administer B-cell depleting therapy as first-line therapy. C Add co-trimoxazole to help prevent bacterial infection, pneumocystis jiroveci pneumonia, and upper respiratory tract relapses in patients with GPA. B Patients with sinonasal involvement: Consider offering nasal rinses and topical nasal therapies (antibiotics, lubricants, and corticosteroids) in patients with sinonasal involvement in GPA. C Consider performing reconstructive surgery during remission, if desired by the patient, in patients with GPA having nasal septal defects and/or nasal bridge collapse. C Patients with renal involvement: insufficient evidence to support the use of rituximab and corticosteroids in patients presenting with markedly reduced or rapidly declining GFR (serum creatinine > 4 mg/dL; > 354 mmol/L). Prefer cyclophosphamide and corticosteroids for induction therapy, or a combination of rituximab and cyclophosphamide as an alternative. I Show 3 more Patients with respiratory tract involvement: As per KDIGO 2021 guidelines: Consider performing plasma exchange in patients with diffuse alveolar hemorrhage having hypoxemia. C Perform plasma exchange in patients with an overlap syndrome of ANCA-associated vasculitis and anti-GBM. B As per ACR 2021 guidelines, consider initiating immunosuppressive therapy over performing surgical dilation with intralesional corticosteroid injection alone in patients with GPA and actively inflamed subglottic and/or endobronchial tissue with stenosis. C Patients with mass lesions: consider initiating immunosuppressive therapy over performing surgical removal of the mass lesion with immunosuppressive therapy in patients with GPA and mass lesions (such as orbital pseudotumor or masses of the parotid glands, brain, or lungs). C 7. Patient education https://web.pathway.md/diseases/recviPIXECDYZifbb 5/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway General counseling: provide patients with ANCA-associated vasculitis education focusing on the impact of ANCA-associated vasculitis and its prognosis, key warning symptoms, and treatment (including treatment-related complications). B 8. Preventative measures Prophylaxis for Pneumocystis jirovecii pneumonia: Administer TMP-SMX for prophylaxis against P. jirovecii pneumonia and other infections in patients with ANCA-associated vasculitis receiving rituximab, cyclophosphamide, and/or high doses of corticosteroids. B As per ACR 2021 guidelines, consider administering prophylaxis for the prevention of P. jirovecii pneumonia in patients with GPA receiving rituximab or cyclophosphamide. C 9. Follow-up and surveillance Serial clinical assessment: Obtain periodic assessment for treatment-related adverse effects and comorbidities in patients with ANCA-associated vasculitis. Offer prophylaxis and lifestyle advice to reduce treatment- related complications and other comorbidities. B Obtain structured clinical assessment, rather than ANCA and/or CD19-positive B cell testing alone, to inform decisions on changes in treatment in patients with ANCA-associated vasculitis. B Serial laboratory assessment: do not use the persistence of ANCA positivity, an increase in ANCA levels, or a change in ANCA from negative to positive to guide treatment decisions, as those are only modestly predictive of future disease relapse. D Management of refractory disease: As per EULAR 2023 guidelines, obtain a thorough reassessment of disease status and comorbidities and consider offering additional or different treatment in patients with GPA refractory to therapy to induce remission. Manage patients with refractory disease in close conjunction with, or refer to, a center with expertise in vasculitis. B As per KDIGO 2021 guidelines: Consider increasing the dose of corticosteroids (IV or PO), or adding rituximab if cyclophosphamide induction had been used previously, or vice versa, in patients with refractory disease. Consider performing plasma exchange. C Consider performing plasma exchange, in addition to corticosteroids with either cyclophosphamide or rituximab, in patients with diffuse alveolar bleeding with hypoxemia. C As per ACR 2021 guidelines: Consider switching to other therapy over combining two therapies in patients with severe GPA refractory to rituximab or cyclophosphamide for remission induction. C https://web.pathway.md/diseases/recviPIXECDYZifbb 6/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Consider administering IVIG in addition to current therapy in patients with GPA refractory to remission induction therapy. C Management of relapse: As per EULAR 2023 guidelines, initiate a combination of corticosteroids and either rituximab or cyclophosphamide, preferably rituximab, B for induction of remission in patients with relapsing GPA. A As per KDIGO 2021 guidelines, reintroduce corticosteroids in combination with cyclophosphamide or rituximab (preferably rituximab) in patients with relapsing disease (life- or organ-threatening). B As per ACR 2021 guidelines: Consider initiating rituximab over cyclophosphamide for remission re-induction in patients with GPA experienced relapse with severe disease manifestations and not receiving rituximab for remission maintenance. C Consider switching from rituximab to cyclophosphamide over administering additional rituximab for remission re-induction in patients with GPA experienced relapse with severe disease manifestations while receiving rituximab for remission maintenance. C Clinical findings Symptoms Past medical history Abdominal pain Cardiomyopathy Anorexia HF Anosmia Meningitis Arthralgia Raynaud's phenomenon Bloody sputum Recurrent sinusitis Blurred vision Neurological exam Cacosmia Cough Cranial nerve palsy Fever Peripheral neuropathy Headache Sensorineural hearing loss Hearing loss Head and neck exam Hematuria Hemoptysis Conductive hearing loss Limb numbness Nasal crusting Malaise Nasal septal deformation Myalgia Nasal septal perforation Nasal discharge Nasal ulcers Nasal obstruction Oral ulcers Nosebleed Orbital mass Otalgia Otorrhea Pleuritic chest pain Saddle nose deformity https://web.pathway.md/diseases/recviPIXECDYZifbb 7/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Purulent sputum Respiratory exam Rhinitis Seizure Pleuritis Shortness of breath Stridor Vision loss Wheezing Weight loss Genitourinary exam Vital signs Macroscopic hematuria Hypertension Lab findings Ocular exam Urine RBC casts Conjunctivitis ESR Episcleritis serum CRP Retinal hemorrhage serum creatinine Scleritis urine protein Uveitis serum albumin Cardiac exam Serological findings Pericarditis c-ANCA p-ANCA Musculoskeletal exam Endoscopic findings Arthritis Subglottic stenosis Integument exam Blue toes Erythematous painful pinna Palpable purpura Skin nodules Skin ulceration Urticaria Hematological findings Anemia WBC count blood platelet count Imaging findings Cerebral mass Lung nodule Pleural effusion Pulmonary cavity Pulmonary infiltrates https://web.pathway.md/diseases/recviPIXECDYZifbb 8/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway Likelihood Ratios Pertinent positives The following findings increase the probability of granulomatosis with polyangiitis in adults. 4 Finding LR+ Value Positive c-ANCA 5.1 Positive p-ANCA 2.7 Pertinent negatives The following findings decrease the probability of granulomatosis with polyangiitis in adults. 4 Finding LR- Value Negative c-ANCA 0.4 Negative p-ANCA 0.8 Studies 2021 ADVOCATE In patients with ANCA-associated vasculitis, avacopan was noninferior to prednisone with respect to remission at week 26. David R W Jayne et al. N Engl J Med. 2021 Feb 18. 2020 PEXIVAS (corticosteroids) In patients with severe ANCA-associated vasculitis, a reduced-dose corticosteroid regimen was noninferior to a standard-dose corticosteroid regimen with respect to the composite outcome of death from any cause or end-stage kidney disease. Michael Walsh et al. N Engl J Med. 2020 Feb 13. Show 4 more References 1. Sharon A Chung, Carol A Langford, Mehrdad Maz et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021 Aug;73 8 1366 1383. Open 2. Bernhard Hellmich, Beatriz Sanchez-Alamo, Jan H Schirmer et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2023 Mar 16;ard-2022 223764. Open https://web.pathway.md/diseases/recviPIXECDYZifbb 9/10 7/1/23, 12:05 AM Granulomatosis with polyangiitis Pathway 3. Nienke de Graeff, Noortje Groot, Paul Brogan et al. European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative. Rheumatology Oxford). 2019 Apr 1;58 4 656 671. Open 4. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open 5. Hagen EC, Daha MR, Hermans J et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. 1998 Mar;53 3 743 53. Open 6. Seza Ozen, Angela Pistorio, Silvia M Iusan et al. EULAR/PRINTO/PRES criteria for Henoch-Sch nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II Final classification criteria. Ann Rheum Dis. 2010 May;69 5 798 806. Open 7. Pamela M K Lutalo, David P D'Cruz. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). J Autoimmun. Feb-Mar 2014;48 49 94 8. Open 8. Michael Walsh, Peter A Merkel, Chen-Au Peh et al. Plasma Exchange and Glucocorticoids in Severe ANCA Associated Vasculitis. N Engl J Med. 2020 Feb 13;382 7 622 631. Open 9. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 10. Joanna C Robson, Peter C Grayson, Cristina Ponte et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis. 2022 Mar;81 3 315 320. Open 11. Eleana Ntatsaki, David Carruthers, Kuntal Chakravarty et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology Oxford). 2014 Dec;53 12 2306 9. Open https://web.pathway.md/diseases/recviPIXECDYZifbb 10/10

Guideline sources The following summarized guidelines for the evaluation and management of graves' disease (GD) are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the European Thyroid Association (ETA 2022; 2018), and the American Thyroid Association (ATA 2016). 1 2 3 4 5 5 6 6 7 Definition GD is a systemic autoimmune disease that is characterized by production of antibodies to the TSH receptor. 5 Epidemiology GD is caused by autoimmunity rendered by complex interactions between genetic (75-80%)and environmental factors (20-25%). 5 Pathophysiology https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 1/10 7/1/23, 12:05 AM Graves' disease Pathway The annual incidence of GD is estimated at 20-30 cases per 100,000 persons; lifetime risk for women and men is approximately 3% and 0.5%, respectively. 6 Disease course The overproduction of thyroid hormone is caused by thyroid-stimulating immunoglobulins via thyrotropin receptor activation, which results in hypertrophy and hyperplasia of the gland. In addition, the production of cytokines by infiltrating immune cells results in inflammation and altered thyroid cell behavior. The orbital infiltration of immune cells, activation of thyrotropin-insulin-like growth factor 1 receptor complex, signaling of orbital fibroblasts and adipogenesis results in orbital tissue expansion, proptosis, and optic nerve compression. Diffuse goiter, ophthalmopathy, dermopathy, alteration in mental status, and cardiac complications may ensue. 7 Prognosis and risk of recurrence Antithyroid drug therapy is associated with 40-50% remission post 12-18 months treatment; radioactive iodine results in permanent hypothyroidism in >80% cases and a 15-20% risk of inducing/aggravating Graves orbitopathy. 6 Calculator Burch-Wartofsky Point Scale for Guidelines 1. Screening and diagnosis Indications for screening: Consider screening for antithyroid peroxidase and anti-TG antibodies soon after diagnosis in pediatric patients with T1DM. C Measure TSH concentrations at diagnosis when clinically stable or soon after optimizing glycemia. Consider rechecking every 1-2 years or sooner if the initial screening is normal in young patients with positive thyroid antibodies or developing symptoms or signs suggestive of thyroid dysfunction, thyromegaly, an abnormal growth rate, or unexplained glycemic variability. B 2. Diagnostic investigations Thyrotropin receptor antibodies: Obtain TSH receptor autoantibodies for rapid and accurate diagnosis and differential diagnosis of GD. A https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 2/10 7/1/23, 12:05 AM Graves' disease Pathway Consider differentiating TSH receptor autoantibodies functionality, when technically available, as it is helpful and predictive in patients with GD during pregnancy/postpartum and for extrathyroidal manifestations. C Baseline laboratory tests: consider obtaining a baseline CBC, including WBC count with differential, and a liver profile including bilirubin and transaminases before initiating antithyroid drugs. C Diagnostic imaging: Obtain ultrasound, composed of conventional gray-scale analysis and color-flow or power Doppler examination, to support the diagnosis of GD. A Consider obtaining scintigraphy of the thyroid when thyroid nodularity coexists with hyperthyroidism and before radioactive iodine therapy. C 3. Medical management Antithyroid drugs: As per ETA 2018 guidelines, initiatie antithyroid drugs in patients with newly diagnosed GD. A Show 4 more As per ATA 2016 guidelines, initiate methimazole in virtually every patient choosing antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole refusing radioactive iodine therapy or surgery. B Show 3 more Beta-blockers: As per ETA 2018 guidelines, initiate -adrenergic blockers in all suitable patients with GD. A As per ATA 2016 guidelines: Initiate -adrenergic blockers in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with a resting HR > 90 bpm or coexistent CVD. B Consider administering -adrenergic blockers even in asymptomatic patients at increased risk for complications due to worsening of hyperthyroidism (elderly patients and patients with comorbidities), because radioactive iodine therapy can cause a transient exacerbation of hyperthyroidism. C Radioactive iodine: As per ETA 2018 guidelines, consider initiating radioactive iodine therapy in patients with newly diagnosed GD preferring this approach. B Show 6 more As per ATA 2016 guidelines, optimize medical therapy of any comorbid conditions before radioactive iodine therapy. B Show 3 more https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 3/10 7/1/23, 12:05 AM Graves' disease Pathway Antihistamines: administer concurrent antihistamines without stopping the antithyroid drug for the management of minor cutaneous reactions. B Show 2 more Management of thyroid storm: Ensure a multimodality treatment approach in patients with GD with thyroid storm, including: antithyroid drug therapy corticosteroids -adrenergic blockade cooling blankets volume resuscitation nutritional support respiratory care monitoring in an ICU. B Management of subclinical hyperthyroidism: As per ETA 2018 guidelines: Treat subclinical hyperthyroidism in > 65 years old patients with GD with serum TSH levels persistently < 0.1 mIU/L. B Initiate antithyroid drugs as first-line therapy in patients with Graves' subclinical hyperthyroidism. B As per ATA 2016 guidelines, treat subclinical hyperthyroidism if TSH is persistently < 0.1 mU/L in all patients 65 years of age, in patients with cardiac risk factors, heart disease or osteoporosis, in postmenopausal patients not on estrogens or bisphosphonates, and in patients with hyperthyroid symptoms. B Show 3 more 4. Nonpharmacologic interventions Smoking cessation: advise smoking cessation in patients with GD and refer them to a structured smoking cessation program. Identify patients exposed to secondhand smoke and advise of its negative impact, as both firsthand and secondhand smoking increase Graves' orbitopathy risk. B 5. Perioperative care Preoperative care: As per ETA 2018 guidelines, restore euthyroidism by antithyroid drugs before surgery to avoid peri- or postoperative exacerbation of thyrotoxicosis. A Show 2 more As per ATA 2016 guidelines, render patients euthyroid with antithyroid drugs, with or without - adrenergic blockers, before thyroidectomy. B https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 4/10 7/1/23, 12:05 AM Graves' disease Pathway Show 3 more Postoperative care: consider measuring serum calcium with or without intact PTH levels following thyroidectomy, and administer oral calcium and calcitriol supplementation based on these results. Consider administering prophylactic calcium with or without calcitriol prescribed empirically as an alternative strategy. C Show 3 more 6. Surgical interventions Thyroidectomy: As per ETA 2018 guidelines: Consider performing thyroidectomy in patients with newly diagnosed GD preferring this approach. B Perform total thyroidectomy as the procedure of choice by a skilled surgeon with high annual volumes of thyroidectomies, if surgery is selected. A As per ATA 2016 guidelines: Refer the patient to a high-volume thyroid surgeon if surgery is chosen as the primary therapy for GD. B Perform near-total or total thyroidectomy as the procedure of choice if surgery is chosen as the primary therapy for GD. B 7. Specific circumstances Pediatric patients, evaluation: As per ETA 2022 guidelines, obtain WBC count including neutrophil count and LFTs at baseline as both can be affected by the underlying disease process and antithyroid drug therapy. B As per ATA 2016 guidelines, consider obtaining a baseline complete blood cell count, including WBC count with differential, and a liver profile including bilirubin, transaminases, and ALP before initiating antirthyroid drugs. C Pediatric patients, antithyroid drugs: As per ETA 2022 guidelines, initiate prompt treatment in pediatric patients with GD. A Show 7 more As per ATA 2016 guidelines, initiate methimazole as an antirthyroid drug in pediatric patients. B Show 6 more Pediatric patients, beta-blockers: As per ETA 2022 guidelines: Initiatie -adrenergic blockers in patients presenting with marked signs of thyroid hormone excess. Consider discontinuing it once the patient is biochemically euthyroid. B https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 5/10 7/1/23, 12:05 AM Graves' disease Pathway Manage patients with untreated GD on a high dependency or ICU as they can be severely unwell with marked signs of thyroid hormone excess. B As per ATA 2016 guidelines, initiate -adrenergic blockers in pediatric patients experiencing symptoms of hyperthyroidism, especially with a HR > 100 bpm. B Pediatric patients, radioactive iodine: As per ETA 2022 guidelines, consider offering alternative treatment with surgery or radioactive iodine in patients being thyrotoxic despite large doses of carbimazole ( 1.3 mg/kg/day) or methomazole ( 1 mg/kg/day). B Show 6 more As per ATA 2016 guidelines, offer radioactive iodine therapy in pediatric patients if the activity is > 150 mcCi/g (5.55 MBq/g) of thyroid tissue, and in pediatric patients between 5 and 10 years of age if the calculated radioactive iodine administered activity is < 10 mCi (< 370 MBq). B Show 3 more Pediatric patients (immunomodulators): insufficient evidence to recommend immune modulation with new agents such as biologics in the young patients with GD. I Pediatric patients, thyroidectomy: As per ETA 2022 guidelines, consider offering alternative treatment with surgery or radioactive iodine in patients being thyrotoxic despite large doses of carbimazole ( 1.3 mg/kg/day) or methomazole ( 1 mg/kg/day). B Show 5 more As per ATA 2016 guidelines, perform thyroidectomy when definitive therapy is required, the patient is too young for radioactive iodine therapy, and surgery can be performed by a high- volume thyroid surgeon. B Show 2 more Pediatric patients (treatment monitoring): follow-up patients managed with dose titration or block and replace approximately every 4 weeks for the first 3 months and move to 2 and then 3 monthly assessments thereafter depending on the clinical course. B Show 3 more Pediatric patients (management of thyroid nodules): recognize that young patients with GD, like adults, have a slightly higher risk of developing differentiated thyroid cancer. B Show 2 more Pediatric patients (management of orbitopathy): refer pediatric patients with eye symptoms to an orbital specialist, preferably in combined (ophthalmologist/physician) thyroid eye clinics. B Show 3 more Elderly patients: Initiate definitive therapy, usually radioactive iodine, in older patients with AF, HF or cardiac ischemic symptoms precipitated by hyperthyroidism. B Consider initiating long-term methimazole (carbimazole) in older patients with mild GD. C Pregnancy planning: https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 6/10 7/1/23, 12:05 AM Graves' disease Pathway As per ETA 2018 guidelines, provide preconception counseling in female patients with GD of reproductive age, and ensure being stably euthyroid before attempting pregnancy. B Show 3 more As per ATA 2016 guidelines, discuss the possibility and timing of future pregnancy in patients developing hyperthyroidism during their reproductive age range. Consider advising female patients postponing pregnancy until they have become euthyroid with therapy because of the risks of the hyperthyroid state on pregnancy and fetal outcome. B Show 6 more Pregnant patients, evaluation: As per ETA 2018 guidelines: Measure serum TSH receptor antibody levels at the first presentation of pregnancy in all patients with a history of autoimmune thyroid disease, using either a sensitive binding or a functional cell-based bioassay and, if they are elevated, again at 18-22 weeks of gestation. A Monitor the fetus for thyroid dysfunction throughout pregnancy if the maternal TSH receptor antibody concentration remains high (> 3 times the cut-off). A As per ATA 2016 guidelines, diagnose hyperthyroidism in pregnancy based on serum TSH values, and either total T4 and T3 with total T4 and T3 reference ranges increasing to 1.5 times above the nonpregnant range by the second and third trimester or free T4 and total T3 estimations with trimester-specific normal reference ranges. B Show 5 more Pregnant patients, antithyroid drugs: As per ETA 2018 guidelines, administer the lowest possible dose of antithyroid drug during pregnancy and avoid using the block-and-replace antithyroid drug regimen. A Show 4 more As per ATA 2016 guidelines, initiate antithyroid drug therapy in patients with overt hyperthyroidism due to GD during pregnancy. Initiate propylthiouracil when antithyroid drug therapy is given during the first trimester. Initiate methimazole when antithyroid drug therapy is started after the first trimester. B Show 4 more Pregnant patients (thyroidectomy): Recognize that pregnancy is a relative contraindication to thyroidectomy and should only be performed when medical management has been unsuccessful or antithyroid drugs cannot be used. B Perform surgery, when thyroidectomy is necessary for the treatment of hyperthyroidism during pregnancy, during the second trimester if possible. B Breastfeeding: offer lactating patients with GD the same treatments as non-lactating patients. B Show 2 more Patients with immune reconstitution: Do not stop precipitating treatment and do not initiate mandatory definitive therapy for hyperthyroidism in patients with GD precipitated by an immunomodulatory therapy. D https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 7/10 7/1/23, 12:05 AM Graves' disease Pathway Consider obtaining sequential monitoring of serum TSH receptor autoantibodies to guide the duration of antithyroid drug therapy in patients with immune reconstitution GD. C Patients with orbitopathy: As per ETA 2018 guidelines, control hyperthyroidism promptly by antithyroid drugs and maintain stable euthyroidism in patients with Graves' orbitopathy. A Show 4 more As per ATA 2016 guidelines, consider offering radioactive iodine therapy without corticosteroid coverage in patients with inactive Graves' orbitopathy. Reconsider this approach in case of elevated risk for reactivation (high thyroid-stimulation hormone receptor antibody, CAS > 1 and smokers). C Show 5 more 8. Follow-up and surveillance Treatment monitoring: As per ETA 2018 guidelines: Inform patients about the potential side effects of antithyroid drugs and the necessity of informing the physician promptly if they develop jaundice, light-colored stools, dark urine, fever, pharyngitis, or cystitis. B Obtain a differential WBC count in patients taking antithyroid drugs during febrile illness and/or pharyngitis. Assess liver function in patients experiencing jaundice, light-colored stools or dark urine. B As per ATA 2016 guidelines, obtain a differential WBC count during febrile illness and at the onset of pharyngitis in all patients taking antithyroid drugs. B Show 4 more Management of refractory disease: As per ETA 2018 guidelines: Initiate radioactive iodine therapy or perform thyroidectomy as definitive treatment in patients with GD becoming hyperthyroid after completing a first course of antithyroid drugs. B Consider continuing long-term low-dose methimazole in patients not in remission preferring this approach. B As per ATA 2016 guidelines: Consider initiating radioactive iodine therapy or performing thyroidectomy in patients with GD becoming hyperthyroid after completing a course of methimazole. Consider continuing low- dose methimazole treatment for longer than 12-18 months in patients not in remission preferring this approach. C Consider initiating retreatment with radioactive iodine when hyperthyroidism due to GD persists after 6 months following radioactive iodine therapy. Consider offering additional radioactive iodine therapy in selected patients with minimal response 3 months after therapy. C https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 8/10 7/1/23, 12:05 AM Graves' disease Pathway Clinical findings Symptoms Past medical history Amenorrhea Depression Anxiety Neurological exam Change in voice Diarrhea Hyperreflexia Diplopia Tremor Dry eyes Head and neck exam Dysphagia Eye pain Goiter Fatigue Proptosis Globus sensation Thyroid bruit Heat intolerance Increased appetite Lab findings Orthopnea serum free T3 Palpitations serum free T4 Sleeping disorder serum TSH Sweating Watery eyes Weight loss Vital signs Tachycardia Ocular exam Abadie's sign Binocular diplopia Conjunctival injection Exophthalmos Eyelid retraction Griffith's sign Infrequent blinking Joffroy's sign Kocher's sign Lagophthalmos Lid lag on downward gaze Lid lag on upward gaze Von Graefe's sign Widened palpebral fissure https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 9/10 7/1/23, 12:05 AM Graves' disease Pathway Integument exam Acropachy Digital clubbing Onycholysis Palmar erythema Pretibial myxedema Serological findings References 1. Ross DS, Burch HB, Cooper DS et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26 10 1343 1421. Open 2. Christiaan F Mooij, Timothy D Cheetham, Frederik A Verburg et al. 2022 European Thyroid Association Guideline for the management of pediatric Graves disease. Eur Thyroid J. 2022 Jan 1;11 1):e210073. Open 3. Kahaly GJ, Bartalena L, Heged s L et al. 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J. 2018 Aug;7 4 167 186. Open 4. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 5. Wemeau JL, Klein M, Sadoul JL et al. Graves' disease: Introduction, epidemiology, endogenous and environmental pathogenic factors. Ann Endocrinol Paris). 2018 Dec;79 6 599 607. Open 6. Burch HB, Cooper DS. Management of Graves Disease: A Review. JAMA. 2015 Dec 15;314 23 2544 54. Open 7. Smith TJ, Hegedus L. Graves' Disease. N Engl J Med. 2016 Oct 20;375 16 1552 1565. Open 8. Simone De Leo, Sun Y Lee, Lewis E Braverman. Hyperthyroidism. Lancet. 2016 Aug 27;388 10047 906 918. Open https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 10/10

Guideline sources The following summarized guidelines for the evaluation and management of group A streptococcal pharyngitis are prepared by our editorial team based on guidelines from the American Academy of Pediatrics (AAP 2018), the British Medical Journal (BMJ 2017), the American College of Physicians (ACP/CDC 2016), the Infectious Diseases Society of America (IDSA 2012), and the European Society for Microbiology and Infectious Diseases (ESCMID 2012). 1 2 3 4 5 Pathway Calculator Calculator Group A streptococcal pharyngitis FeverPAIN score for streptococc Modified C Diagnosis and management https://web.pathway.md/diseases/recCX4WMvoSFOri2U 1/6 7/1/23, 12:05 AM Group A streptococcal pharyngitis Pathway Guidelines 1. Screening and diagnosis Indications for testing (symptomatic patients): obtain rapid antigen detection test and/or culture for group A Streptococcus in patients with symptoms suggestive of GAS pharyngitis (such as persistent fever, anterior cervical lymphadenopathy, and tonsillar/pharyngeal exudate, or other appropriate combination of symptoms). B Indications for testing (asymptomatic contacts): do not obtain routine testing in asymptomatic household contacts of patients with acute GAS pharyngitis. D 2. Classification and risk stratification Risk assessment: consider using the Centor clinical scoring system to help identify patients with a higher likelihood of group A streptococcal infection B and target antibiotic use, C recognizing that its utility in pediatric patients appears lower than in adults because of the different clinical presentation of sore throat in the first years of life. 3. Diagnostic investigations Rapid antigen detection test: As per ESCMID 2012 guidelines: Consider obtaining a rapid antigen detection test in patients with a high likelihood of streptococcal infections (3-4 Centor criteria). C Do not obtain routine rapid antigen detection test in patients with a lower likelihood of streptococcal infections (0-2 Centor criteria). D As per IDSA 2012 guidelines, obtain a rapid antigen detection test for GAS pharyngitis in most patients with symptoms of acute pharyngitis because the clinical features alone do not reliably discriminate between group A streptococcal and viral pharyngitis, except when overt viral features such as rhinorrhea, cough, oral ulcers, and/or hoarseness are present. A Show 2 more Throat culture: As per ESCMID 2012 guidelines: Do not obtain throat culture for routine diagnosis of acute sore throat to detect group A streptococci. D Do not obtain throat culture after a negative rapid antigen test for the diagnosis of group A streptococci in both pediatric and adult patients. D As per IDSA 2012 guidelines: Obtain a throat culture in pediatric and adolescent patients if the rapid antigen detection test is negative. Do not obtain throat cultures if the rapid antigen detection test is positive. A https://web.pathway.md/diseases/recCX4WMvoSFOri2U 2/6 7/1/23, 12:05 AM Group A streptococcal pharyngitis Pathway Avoid routine use of back-up throat cultures for adults with a negative rapid antigen detection test. D Anti-streptococcal antibodies: do not obtain anti-streptococcal antibody titers in the routine workup of acute pharyngitis, as they reflect past rather than current infection. D Inflammatory markers: do not obtain inflammatory markers (such as ESR, CRP, procalcitonin, anti-DNase B) routinely for the assessment of patients with acute sore throat. D 4. Medical management Antibiotic therapy: As per AAP 2018 guidelines, do not use antibiotics in patients with viral respiratory illnesses, such as viral pharyngitis. D As per ESCMID 2012 guidelines, do not initiate antibiotics to prevent the development of non- suppurative complications (rheumatic fever and acute glomerulonephritis) in low-risk patients (patients with no previous history of rheumatic fever) with acute sore throat. D Show 4 more As per IDSA 2012 guidelines: Initiate an appropriate antibiotic (penicillin or amoxicillin as the drug of choice if not allergic to these agents) at an appropriate dose for a duration likely to eradicate the organism from the pharynx (usually 10 days). A Initiate any of the following regimens in penicillin-allergic patients: a first-generation cephalosporin (if not anaphylactically sensitive) for 10 days clindamycin or clarithromycin for 10 days azithromycin for 5 days. B Analgesics: As per ESCMID 2012 guidelines, offer either ibuprofen or acetaminophen for relief of acute sore throat symptoms. A As per IDSA 2012 guidelines: Consider offering analgesic/antipyretic agents (such as acetaminophen or NSAIDs) as adjunctive therapy for the treatment of moderate-to-severe symptoms or control of high fever associated with GAS pharyngitis. B Avoid using aspirin in pediatric patients with GAS pharyngitis. D Corticosteroids: As per BMJ 2017 guidelines, consider offering corticosteroids in addition to standard care in patients with sore throat. C As per ESCMID 2012 guidelines: Do not offer routine corticosteroids in conjunction with antibiotic therapy for the treatment of patients with acute sore throat. D https://web.pathway.md/diseases/recCX4WMvoSFOri2U 3/6 7/1/23, 12:05 AM Group A streptococcal pharyngitis Pathway Consider offering corticosteroids in adult patients with more severe presentations (such as 3-4 Centor criteria). B As per IDSA 2012 guidelines, do not offer corticosteroids as adjunctive therapy in patients with GAS pharyngitis. D Zinc gluconate: do not use zinc gluconate for the treatment of patients with acute sore throat. D 5. Nonpharmacologic interventions Alternative medicine: insufficient evidence to support the use of herbal treatments and acupuncture as treatments for sore throat. I 6. Specific circumstances Management of chronic GAS carriers: Recognize that recurrent episodes of pharyngitis in patients with laboratory evidence of group A streptococcal infection may represent either: multiple episodes of bona fide recurrent streptococcal pharyngitis at close intervals, or multiple episodes of viral pharyngitis in chronic pharyngeal group A streptococcus carriers. B Do not attempt to identify nor administer antimicrobial therapy in patients with asymptomatic group A streptococcus carriage, as they are unlikely to spread GAS pharyngitis to their close contacts and are at little or no risk for developing suppurative or non-suppurative complications, such as acute rheumatic fever. D Management of asymptomatic household contacts: do not offer routine empiric treatment in asymptomatic household contacts of patients with acute streptococcal pharyngitis. D 7. Preventative measures Tonsillectomy: do not perform tonsillectomy with the sole intent of reducing the frequency of streptococcal pharyngitis. D 8. Follow-up and surveillance Post-treatment throat culture: do not obtain routine follow-up post-treatment throat cultures or rapid antigen detection tests; consider these only in special circumstances. D Clinical findings Patient demographics Symptoms https://web.pathway.md/diseases/recCX4WMvoSFOri2U 4/6 7/1/23, 12:05 AM Group A streptococcal pharyngitis Pathway Children Abdominal pain Dysphagia Past medical history Fever Headache Peritonsillar abscess Malaise Scarlet fever Nausea Upper respiratory tract infection No history of cough Lymphatic exam Odynophagia Throat pain Cervical lymphadenopathy Vomiting Lab findings Head and neck exam ESR Palatine petechiae serum CRP Pharyngeal erythema Pharyngeal exudate Microbiological findings Strawberry tongue rapid streptococcal antigen test Swollen uvula Tonsillar enlargement throat culture for group A streptococci Tonsillar exudate Integument exam Rash Sandpaper-like rash Hematological findings Likelihood Ratios Pertinent positives The following findings increase the probability of group A streptococcal pharyngitis in adults. 6 7 Finding LR+ Value Positive rapid streptococcal antigen test 83 Increased Centor score ( 2) 1 Pertinent negatives The following findings decrease the probability of group A streptococcal pharyngitis in adults. 6 7 https://web.pathway.md/diseases/recCX4WMvoSFOri2U 5/6 7/1/23, 12:05 AM Group A streptococcal pharyngitis Pathway Finding LR- Value Negative throat culture for group A streptococci References Positive EBV point-of-care test 0 0.09 (0.03-0.24) Negative rapid streptococcal antigen test 0.2 1. Shulman ST, Bisno AL, Clegg HW et al. Clinical practice guideline for the diagnosis and management of Centor score not increased (< 2) 0.26 (0.14-0.48) group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012 Nov 15;55 10 1279 82. Open 2. ESCMID Sore Throat Guideline Group, C Pelucchi, L Grigoryan et al. Guideline for the management of acute sore throat. Clin Microbiol Infect. 2012 Apr;18 Suppl 1 1 28. Open 3. Bert Aertgeerts, Thomas Agoritsas, Reed A C Siemieniuk et al. Corticosteroids for sore throat: a clinical practice guideline. BMJ. 2017 Sep 20;358:j4090. Open 4. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2018. Open 5. Aaron M Harris, Lauri A Hicks, Amir Qaseem et al. Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016 Mar 15;164 6 425 34. Open 6. Nawaz H, Smith DS, Mazhari R et al. Concordance of clinical findings and clinical judgment in the diagnosis of streptococcal pharyngitis. Acad Emerg Med. 2000 Oct;7 10 1104 9. Open 7. Simel D, Rennie D. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis. Mayo Clin Proc. 2009 Nov; 84 11 1045. Open 8. McIsaac WJ, Kellner JD, Aufricht P et al. Empirical validation of guidelines for the management of pharyngitis in children and adults. JAMA. 2004 Apr 7;291 13 1587 95. Open 9. Robert Luo, Joanna Sickler, Farnaz Vahidnia et al. Diagnosis and Management of Group a Streptococcal Pharyngitis in the United States, 2011 2015. BMC Infect Dis. 2019 Feb 26;19 1 193. Open 10. Judith M Martin. The Mysteries of Streptococcal Pharyngitis. Curr Treat Options Pediatr. 2015 Jun;1 2 180 189. Open 11. Tim Kenealy. Sore throat. BMJ Clin Evid. 2007 Nov 20;2007 1509. Open 12. Lais Martins Moreira Anjos, Mariana Barros Marcondes, Mariana Ferreira Lima et al. Streptococcal acute pharyngitis. Rev Soc Bras Med Trop. 2014 Jul;47 4 409 13. Open 13. Kapil Bhalla, Parveen Bhardwaj, Ashish Gupta et al. Role of epidemiological risk factors in improving the clinical diagnosis of streptococcal sore throat in pediatric clinical practice. J Family Med Prim Care. 2019 Oct 31;8 10 3130 3135. Open 14. Roger Zoorob, Mohamad A Sidani, Richard D Fremont et al. Antibiotic use in acute upper respiratory tract infections. Am Fam Physician. 2012 Nov 1;86 9 817 22. Open https://web.pathway.md/diseases/recCX4WMvoSFOri2U 6/6

Guideline sources The following summarized guidelines for the evaluation and management of guillain-Barr syndrome (GBS) are prepared by our editorial team based on guidelines from the American Society for Apheresis (ASFA 2019), the American Association of Family Physicians (AAFP 2013), and the American Academy of Neurology (AAN 2011; 2003). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnostic criteria: Use the following diagnostic criteria to establish the diagnosis of GBS: progressive, relatively symmetrical weakness with decreased or absent myotatic reflexes symptoms reached maximal intensity within 4 weeks of onset other possible causes are excluded. B 2. Diagnostic procedures https://web.pathway.md/diseases/recO8rzqWME3KEOd4 1/3 7/1/23, 12:05 AM Guillain-Barr syndrome Pathway Lumbar puncture: perform lumbar puncture in all patients with suspected GBS. Recognize that CSF protein levels may be normal in early disease, but they are elevated in 90% of patients by the end of the second week of symptoms. B 3. Medical management Intravenous immunoglobulin: As per AAFP 2013 guidelines, administer IVIG in patients with GBS requiring assistance with walking within 2 weeks of symptom onset. B As per AAN 2003 guidelines: Administer IVIG in patients with GBS requiring assistance with walking within 2 A or 4 weeks from the onset of neuropathic symptoms. B Recognize that the effects of IVIG and plasmapheresis are equivalent. Corticosteroids: do not use corticosteroids for the treatment of patients with GBS. D Supportive care: Initiate anticoagulation and offer graduated compression stockings to prevent venous thrombosis in hospitalized patients with acute GBS. B Monitor hospitalized patients with acute GBS for autonomic disturbances, including changes in BP and HR (especially bradycardia) and respiratory, bowel, and bladder dysfunction. B 4. Therapeutic procedures Plasmapheresis: As per AAFP 2013 guidelines, perform plasmapheresis (starting within 7 days of symptom onset) as first-line therapy in patients with GBS. A As per AAN 2011 guidelines, perform plasmapheresis in patients with GBS. A As per AAN 2003 guidelines: Perform plasmapheresis in non-ambulant patients within 4 weeks of onset B and in ambulant patients within 2 weeks of onset. B Recognize that the effects of plasmapheresis and IVIG are equivalent. Immunoadsorption: insufficient evidence to recommend immunoadsorption in patients with GBS. I Combination therapy: do not administer sequential treatment with plasmapheresis followed by IVIG D or immunoadsorption followed by IVIG in patients with GBS. D Liquopheresis: insufficient evidence to recommend CSF filtration in patients with GBS. I 5. Specific circumstances https://web.pathway.md/diseases/recO8rzqWME3KEOd4 2/3 7/1/23, 12:05 AM Guillain-Barr syndrome Pathway Pediatric patients: offer plasmapheresis or IVIG in pediatric patients with severe GBS. B Clinical findings Symptoms Past medical history Abdominal pain Recent gastrointestinal infection Constipation Recent upper respiratory infection Excessive sweating Recent vaccination Facial weakness Low back pain Neurological exam Nausea Shortness of breath Ataxia Urinary retention Hyperreflexia Weakness in the legs Hyporeflexia Ophthalmoplegia Vital signs Paraparesis Paraplegia Hypertension Proximal muscle weakness Hypotension Ptosis Lab findings Quadraplegia CSF protein ECG findings Cardiac arrhythmias References 1. R A C Hughes, E F M Wijdicks, R Barohn et al. Practice parameter: immunotherapy for Guillain-Barr syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003 Sep 23;61 6 736 40. Open 2. Anne D Walling, Gretchen Dickson. Guillain-Barr syndrome. Am Fam Physician. 2013 Feb 1;87 3 191 7. Open 3. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 4. Cortese I, Chaudhry V, So YT et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011 Jan 18;76 3 294 300. Open https://web.pathway.md/diseases/recO8rzqWME3KEOd4 3/3

Guideline sources The following summarized guidelines for the evaluation and management of gynecomastia are prepared by our editorial team based on guidelines from the European Academy of Andrology (EAA 2019). 1 Guidelines 1. Diagnostic investigations General principles: consider presence of an underlying pathology in patients with gynecomastia of adulthood. Obtain a detailed investigation even if an apparent reason for gynecomastia of adulthood is identified, including the use of medication known to be associated with gynecomastia. B Show 2 more History taking: elicit a medical history including information on the onset and duration of gynecomastia, sexual development and function, and administration or abuse of substances associated with gynecomastia. B Physical examination: perform a physical examination to detect signs of under-virilization or systemic disease. A Show 2 more https://web.pathway.md/diseases/rec9X3ac2SNEXTP5I 1/3 6/24/23, 4:21 PM Gynecomastia Pathway Diagnostic imaging: Obtain testicular ultrasound to aid genitalia examination, as the detection of a testicular tumor by palpation has low sensitivity. B Obtain breast imaging where the clinical examination is equivocal. B Laboratory testing: Obtain the following laboratory investigations as part of the initial evaluation: testosterone estradiol sex hormone-binding globulin LH FSH TSH prolactin hCG AFP liver and renal function tests. B 2. Diagnostic procedures Core needle biopsy: perform core needle biopsy if the clinical picture is suspicious for a malignant lesion. B 3. Medical management Medical therapy: Offer testosterone only to male patients with proven testosterone deficiency. B Do not use selective estrogen receptor modulators, aromatase inhibitors, or non-aromatizable androgens in the treatment of gynecomastia in general. D 4. Surgical interventions Surgery: offer surgical treatment only for patients with long-lasting gynecomastia, which does not regress spontaneously or following medical therapy. The extent and type of surgery depend on the size of breast enlargement, and the amount of adipose tissue. B 5. Follow-up and surveillance Follow-up: offer watchful waiting after treatment of underlying pathology or discontinue the administration/abuse of substances associated with gynecomastia. B https://web.pathway.md/diseases/rec9X3ac2SNEXTP5I 2/3 6/24/23, 4:21 PM Gynecomastia Pathway References 1. Kanakis GA, Nordkap L, Bang AK et al. EAA clinical practice guidelines-gynecomastia evaluation and management. Andrology. 2019 Nov;7 6 778 793. Open https://web.pathway.md/diseases/rec9X3ac2SNEXTP5I 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hairy cell leukemia (HCL) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2015) and the British Committee for Standards In Haematology (BCSH 2012). 1 2 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Modified A Guidelines 1. Classification and risk stratification https://web.pathway.md/diseases/recBNg1qimnQEtpPf 1/5 6/24/23, 12:31 PM Hairy cell leukemia Pathway Prognosis: Recognize that the following biological factors are associated with poor outcomes: presence of TP53 mutations lack of somatic mutations in the IGVH genes (occur in a minor proportion of patients) VH4-34 family usage (more frequently seen in HCL variant). B Recognize that complete response is associated with a significantly longer disease-free survival than partial response. B 2. Diagnostic investigations Peripheral blood smear: As per ESMO 2015 guidelines, obtain peripheral blood smear and peripheral blood flow cytometry in patients with suspected classical HCL. B As per BCSH 2012 guidelines: Obtain peripheral blood smear for the diagnosis of HCL. B Obtain flow cytometric evaluation (for CD11c, CD25, CD103, and CD123) when liquid material is available. B 3. Diagnostic procedures Bone marrow biopsy: As per ESMO 2015 guidelines: Obtain flow cytometry in bone marrow aspirate and perform bone marrow trephine biopsy with immunohistochemistry in patients with suspected classical HCL. Perform bone marrow examination for the diagnosis, particularly after treatment, to assess response. B Obtain BRAF mutation analysis of exon 15 in difficult cases. B As per BCSH 2012 guidelines, perform bone marrow examination for the diagnosis of HCL. B Show 2 more 4. Medical management Indications for treatment, asymptomatic patients: As per ESMO 2015 guidelines, do not initiate treatment in asymptomatic patients. D Follow-up patients every 3-12 months with complete history, physical examination, CBC, and routine chemistry. D As per BCSH 2012 guidelines, avoid initiating immediate treatment at diagnosis in asymptomatic patients. Obtain active monitoring. D Indications for treatment, symptomatic patients: https://web.pathway.md/diseases/recBNg1qimnQEtpPf 2/5 6/24/23, 12:31 PM Hairy cell leukemia Pathway As per ESMO 2015 guidelines, initiate treatment in patients with symptomatic disease manifested by bulky or progressive, symptomatic splenomegaly cytopenias (Hgb < 10 g/dL and/or platelets < 100 10 /L and/or neutrophils < 1 10 /L), recurrent or severe infections, and/or systemic symptoms. B As per BCSH 2012 guidelines, initiate treatment in patients with symptomatic cytopenia or painful splenomegaly. B Purine analogs: As per ESMO 2015 guidelines: Offer purine analogs (cladribine or pentostatin) as initial treatment in young and fit patients with symptomatic HCL. B Consider administering cladribine at a dose of 0.12-0.15 mg/kg in a 2-hour infusion once weekly over 6 courses. B Administer a second course of cladribine, with or without rituximab, to achieve a complete response at least 6 months after the end of the first course in patients demonstrating a partial response after the first course of cladribine. C As per BCSH 2012 guidelines, offer purine analogs (cladribine or pentostatin) as first-line therapy in patients with HCL. B Interferon-alpha: consider offering interferon-alpha to increase the neutrophil count before nucleoside analog therapy in patients presenting with very severe neutropenia (neutrophil count < 0.2 10 /L). C Growth factors: As per ESMO 2015 guidelines, do not use adjunctive filgrastim routinely with cladribine in the treatment of patients with HCL and severe neutropenia. D As per BCSH 2012 guidelines, do not use growth factors routinely in the treatment of patients with HCL. D 5. Therapeutic procedures Blood product transfusion: administer only irradiated blood products in patients treated with cladribine or pentostatin and requiring transfusion, in order to minimize the risk of transfusion- associated GvHD. B Stem cell transplantation: consider performing allo-SCT in younger, heavily pretreated patients with HCL with multiple relapses and refractory to purine analogs and rituximab. C 6. Surgical interventions Indications for splenectomy: As per ESMO 2015 guidelines, consider performing splenectomy in patients with resistant massive symptomatic splenomegaly (> 10 cm below the costal margin) with accompanied low- level bone marrow infiltration. C https://web.pathway.md/diseases/recBNg1qimnQEtpPf 3/5 6/24/23, 12:31 PM Hairy cell leukemia Pathway Show 3 more As per BCSH 2012 guidelines, consider performing splenectomy in patients with symptomatic splenomegaly, particularly with minimal bone marrow involvement. C 7. Specific circumstances Pregnant patients: initiate treatment in pregnant patients with HCL only when truly warranted. B Show 3 more Patients with hairy cell leukemia variant: As per ESMO 2015 guidelines, offer cladribine (0.15 mg/kg on days 1-5) immediately followed by rituximab (375 mg/m every 8 weeks, beginning day 1) rather than cladribine or rituximab alone as the initial treatment in patients with HCL variant. B Show 4 more As per BCSH 2012 guidelines: Consider offering purine analogs with or without rituximab in selected patients. C Consider performing splenectomy to induce partial remission in selected patients. C 8. Preventative measures Antibiotic prophylaxis: As per ESMO 2015 guidelines, administer prophylactic co-trimoxazole (960 mg 3 times weekly) until the lymphocyte count increases to > 1 10 /L for the prevention of pneumocystis infections in patients with lymphopenia treated with nucleoside analogs. B As per BCSH 2012 guidelines, administer prophylactic co-trimoxazole until the lymphocyte count is 1 10 /L for the prevention of pneumocystis infections in patients treated with cladribine or pentostatin. B Antiviral prophylaxis: As per ESMO 2015 guidelines, administer prophylactic acyclovir (200 mg TID) until the lymphocyte count increases to > 1 10 /L for the prevention of herpes reactivation in patients with lymphopenia treated with nucleoside analogs. B As per BCSH 2012 guidelines, administer prophylactic acyclovir until the lymphocyte count is 1 10 /L for the prevention of herpes reactivation in patients treated with cladribine or pentostatin. B 9. Follow-up and surveillance Assessment of treatment response: As per ESMO 2015 guidelines, perform bone marrow examination for the assessment of response to treatment. B https://web.pathway.md/diseases/recBNg1qimnQEtpPf 4/5 6/24/23, 12:31 PM Hairy cell leukemia Pathway As per BCSH 2012 guidelines: Perform bone marrow examination once the blood count has recovered, typically 4-6 months after cladribine therapy or after 8-9 courses of pentostatin, for the assessment of response to purine analog therapy. B Assess for CD20 as the most useful immunohistochemical stain when assessing remission status post-treatment. B Management of relapsed/refractory disease: As per ESMO 2015 guidelines, offer retreatment with cladribine or pentostatin in patients with a relapse occurring after 12-18 months. B Show 5 more As per BCSH 2012 guidelines, treat residual disease with further purine analog therapy. B Show 2 more References 1. Gail Jones, Nilima Parry-Jones, Bridget Wilkins et al. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol. 2012 Jan;156 2 186 95. Open 2. T Robak, E Matutes, D Catovsky et al. Hairy cell leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v100 7. Open https://web.pathway.md/diseases/recBNg1qimnQEtpPf 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hamstring injury are prepared by our editorial team based on guidelines from the American Physical Therapy Association (APTA 2022), the National Institute for Health and Care Excellence (NICE 2020), and the Italian Society of Muscles, Ligaments and Tendons (ISMuLT 2014). 1 2 3 Calculator Ottawa knee rule Guidelines 1. Screening and diagnosis Diagnosis: diagnose hamstring strain injury in patients presenting with a sudden onset of posterior thigh pain during activity, with pain reproduced when the hamstring is stretched and/or activated, muscle tenderness with palpation, and loss of function. B https://web.pathway.md/diseases/recg2Ora4uJMKLCem 1/4 6/24/23, 12:31 PM Hamstring injury Pathway 2. Diagnostic investigations Physical examination: use a handheld or isokinetic dynamometer to quantify knee flexor strength following hamstring strain injury. A Show 2 more 3. Medical management Analgesics: offer acetaminophen or topical NSAIDs (such as ibuprofen gel) as first-line therapy for pain management. Consider offering oral NSAIDs (such as ibuprofen) if needed. Consider offering short-term codeine as an 'add-on' medication. E 4. Nonpharmacologic interventions Conservative management: Advise on initial 'PRICE' self-management strategies for the first 48- 72 hours after injury: Situation Guidance Protect from further injury (for example, by using a support or high-top, lace-up shoes) Protection Avoid activity for the first 48-72 hours following injury Rest Apply ice wrapped in a damp towel for 15-20 minutes every 2-3 hours during the day for the first 48-72 hours following the injury (not left on whilst asleep) Ice Apply snug (but not tight) compression with a simple elastic bandage or elasticated tubular bandage to help control swelling and support the injury (remove before going to sleep) Compression Keep the injured area elevated and supported on a pillow until the swelling is controlled Elevation Avoid prolonged periods with the leg not elevated if the leg is injured Consider offering a short period of immobilization for a few days after injury for severe sprains and strains. E https://web.pathway.md/diseases/recg2Ora4uJMKLCem 2/4 6/24/23, 12:31 PM Hamstring injury Pathway Walking aids: advise using crutches and avoiding excessive lengthening of the injured muscle in patients with severe lesions. E 5. Preventative measures Injury prevention: offer the Nordic hamstring exercise as part of a hamstring strain injury prevention program, along with other components of warm-up, stretching, stability training, strengthening, and functional movements (sport-specific, agility, and high-speed running). A 6. Follow-up and surveillance Serial clinical assessment: Obtain objective measures of the patient's ability to walk, run, and sprint when documenting changes in activity and participation over the course of treatment. B Use the Functional Assessment Scale for Acute Hamstring Injuries before and after interventions, intended to alleviate the impairments of body function and structure, activity limitations, and participation restrictions in patients diagnosed with an acute hamstring strain injury. B Rehabilitation: As per APTA 2022 guidelines, offer eccentric training to the patient's tolerance, added to stretching, strengthening, stabilization, and progressive running programs, to improve return-to- play time after hamstring strain injury. B Show 2 more As per ISMuLT 2014 guidelines, offer training and rehabilitation programs supervised by an experienced physiotherapist after the first 2-3 days following the injury. Deliver rehabilitation programs in the absence of pain, respecting the healing process, and time of recovery. E Return to play: As per APTA 2022 guidelines, consider assessing the length of muscle tenderness and proximity to the ischial tuberosity to assist in predicting the timing of return to play. C Show 3 more As per NICE 2020 guidelines, advise on safe return to usual activities and sports and provide sources of information and support: start active mobilization and flexibility (ROM) exercises as soon as tolerated without excessive pain consider advising athletes to return to play when there is full, painless range of movement and muscle strength is restored. E References https://web.pathway.md/diseases/recg2Ora4uJMKLCem 3/4 6/24/23, 12:31 PM Hamstring injury Pathway 1. Nicola Maffulli, Francesco Oliva, Antonio Frizziero et al. ISMuLT Guidelines for muscle injuries. Muscles Ligaments Tendons J. 2014 Feb 24;3 4 241 9. Open 2. Robroy L Martin, Michael T Cibulka, Lori A Bolgla et al. Hamstring Strain Injury in Athletes. J Orthop Sports Phys Ther. 2022 Mar;52 3 CPG1 CPG44. Open 3. NICE. Sprains and strains. NHS. 2020 Sep. Open https://web.pathway.md/diseases/recg2Ora4uJMKLCem 4/4

Guideline sources The following summarized guidelines for the management of hand osteoarthritis are prepared by our editorial team based on guidelines from the American College of Rheumatology (ACR 2020) and the European League Against Rheumatism (EULAR 2019). 1 2 Guidelines 1. Medical management General principles: set controlling symptoms as the primary goal for the management of patients with hand OA, such as pain and stiffness, and to optimize hand function, in order to maximize activity, participation and quality of life. B Show 3 more Non-opioid analgesics: As per ACR 2020 guidelines: Offer NSAIDs (topical and oral) in patients with hand OA. A Consider offering acetaminophen in patients with hand OA. C As per EULAR 2019 guidelines: https://web.pathway.md/diseases/recGJNpIVxhQ21thW 1/4 6/24/23, 12:31 PM Hand osteoarthritis Pathway Prefer topical over systemic treatments because of safety reasons. Offer topical NSAIDs as first-choice topical treatment in patients with hand OA. B Consider offering oral analgesics, particularly NSAIDs, for a limited duration for relief of symptoms. B Opioids: Consider offering tramadol in patients with hand OA. C Avoid using non-tramadol opioids in patients with hand OA. Consider offering non-tramadol opioid in certain circumstances, particularly when alternatives have been exhausted. D Duloxetine: consider offering duloxetine in patients with hand OA. C Chondroitin sulfate: As per ACR 2020 guidelines, consider offering chondroitin sulfate in patients with hand OA. B As per EULAR 2019 guidelines, consider offering chondroitin sulfate for pain relief and function improvement in patients with hand OA. B Agents with no evidence for benefit: As per ACR 2020 guidelines: Avoid using the following agents in patients with hand OA: colchicine vitamin D. D Do not use the following agents in patients with hand OA: bisphosphonates glucosamine hydroxychloroquine methotrexate. D As per EULAR 2019 guidelines, do not use conventional or biological DMARDs in patients with hand OA. D 2. Nonpharmacologic interventions Self-management programs: advise participating in self-efficacy and self-management programs in patients with hand OA. A Physical therapy: As per ACR 2020 guidelines, advise exercising in patients with hand OA. A As per EULAR 2019 guidelines, consider advising exercising to improve function and muscle strength and to reduce pain in all patients with hand OA. B Orthoses: As per ACR 2020 guidelines: Offer hand orthoses in patients with first CMC joint OA. A https://web.pathway.md/diseases/recGJNpIVxhQ21thW 2/4 6/24/23, 12:31 PM Hand osteoarthritis Pathway Consider offering hand orthoses in patients with OA in other joints of hand. C As per EULAR 2019 guidelines, consider offering orthoses for symptom relief in patients with thumb base OA. Encourage their long-term use. B Cognitive behavioral therapy: consider offering CBT in patients with hand OA. C Alternative and complementary therapies: consider offering kinesotaping in patients with first CMC joint OA. C Show 3 more 3. Therapeutic procedures Intra-articular corticosteroids: As per ACR 2020 guidelines: Consider administering intra-articular corticosteroid injections in patients with hand OA. C Consider preferring intra-articular corticosteroids over other injections in patients with hand OA. C As per EULAR 2019 guidelines, do not administer intra-articular corticosteroid injections in patients with hand OA, but consider administering in patients with painful interphalangeal joints. D Other intra-articular injections: Avoid administering intra-articular hyaluronic acid in patients with first CMC joint OA. D Do not administer intra-articular TNF inhibitors or IL-1 receptor antagonists in patients with hand OA. D 4. Surgical interventions Indications for surgery: consider performing surgery in patients with structural abnormalities when other treatment modalities have not been sufficiently effective in relieving pain. C Show 2 more 5. Patient education Patient education: Educate all patients with hand OA on the following: nature and course of the disease B self-management principles B treatment options B ergonomic principles B pacing of activity B use of assistive devices. B https://web.pathway.md/diseases/recGJNpIVxhQ21thW 3/4 6/24/23, 12:31 PM Hand osteoarthritis Pathway 6. Follow-up and surveillance Follow-up: ensure a long-term follow-up in patients with hand OA adapted to the patient's individual needs. B References 1. Sharon L Kolasinski, Tuhina Neogi, Marc C Hochberg et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res Hoboken). 2020 Feb;72 2 149 162. Open 2. Margreet Kloppenburg, F line Pb Kroon, Francisco J Blanco et al. 2018 update of the EULAR recommendations for the management of hand osteoarthritis. Ann Rheum Dis. 2019 Jan;78 1 16 24. Open https://web.pathway.md/diseases/recGJNpIVxhQ21thW 4/4

Guideline sources The following summarized guidelines for the evaluation and management of Hashimoto's thyroiditis (HT) are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the European Academy of Dermatology and Venereology (EADV 2021), the Endocrine Society (ES 2020), the British Medical Journal (BMJ 2019), the American Thyroid Association (ATA 2017), the American College of Endocrinology (ACE/AACE 2016), and the American Thyroid Association (ATA/AACE 2012). 1 2 3 4 5 6 7 Guidelines 1. Screening and diagnosis Indications for screening: As per ADA 2023 guidelines: Consider screening for antithyroid peroxidase and anti-TG antibodies soon after diagnosis in pediatric patients with T1DM. C Measure TSH concentrations at diagnosis when clinically stable or soon after optimizing glycemia. Consider rechecking every 1-2 years or sooner if the initial screening is normal in https://web.pathway.md/diseases/rec3VlncUuayFMRMc 1/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway young patients with positive thyroid antibodies or developing symptoms or signs suggestive of thyroid dysfunction, thyromegaly, an abnormal growth rate, or unexplained glycemic variability. B As per AACE 2012 guidelines, consider obtaining screening for hypothyroidism in > 60 years old individuals. B Show 2 more Indications for testing (dyslipidemia): evaluate for and rule out hypothyroidism as the cause of hyperlipidemia before initiating lipid-lowering therapy in patients with hyperlipidemia. A Indications for testing (dermatitis herpetiformis): assess for HT in patients with dermatitis herpetiformis. B Indications for testing (infertility): assess serum TSH concentration in all females seeking care for infertility. B Indications for testing (poor lactation): measure TSH to assess for thyroid dysfunction in females experiencing poor lactation without other identified causes, as maternal hypothyroidism can adversely impact lactation. B 2. Diagnostic investigations Anti-TPO antibodies: measure anti-TPO antibodies in the evaluation of patients with subclinical hypothyroidism. B Show 3 more Thyroid hormone tests: measure serum free T4 (free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti-T4 antibodies) instead of total T4 in the evaluation of hypothyroidism. A Show 2 more 3. Medical management Thyroid replacement therapy, indications, abnormal TSH: As per BMJ 2019 guidelines, do not initiate thyroid replacement therapy in adult patients with subclinical hypothyroidism. D As per ATA/AACE 2012 guidelines: Consider initiating levothyroxine in patients with serum TSH levels > 10 mIU/L, as these patients are at increased risk for HF and cardiovascular mortality. B Consider initiating treatment based on individual factors in patients with TSH levels between the upper limit of a given laboratory's reference range and 10 mIU/L, particularly if patients have symptoms suggestive of hypothyroidism, positive anti-TPO antibodies, or evidence of ASCVD, HF, or associated risk factors for these diseases. B https://web.pathway.md/diseases/rec3VlncUuayFMRMc 2/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway Thyroid replacement therapy (indications, normal TSH): Consider initiating levothyroxine therapy in female patients of childbearing age with serum TSH levels within the reference range for the local laboratory if: serum TSH is > 2.5 mIU/L in patients planning a pregnancy in the immediate future (including assisted reproduction) serum TSH is > 2.5 mIU/L during the first trimester of pregnancy serum TSH is > 3.0 mIU/L during the second trimester of pregnancy serum TSH is > 3.5 mIU/L during the third trimester of pregnancy. C Show 6 more Thyroid replacement therapy (choice of agent and dosing): initiate levothyroxine monotherapy for the treatment of hypothyroidism. A Show 5 more Thyroid replacement therapy (treatment targets): target the normal range of a third-generation TSH assay in nonpregnant patients with hypothyroidism. Consider targeting an ULN of 4.12 mIU/L in iodine-sufficient areas if an ULN for a third-generation TSH assay is not available, and a LLN of 0.45 mIU/L if a LLN is not available. B Management of thyroid nodules: measure anti-TPO antibodies in patients with increased levels of serum TSH. B Recognize that high serum anti-TPO antibody values associated with a firm, diffusely enlarged, or more often atrophic small thyroid, are compatible with HT. B Recognize that a nodular goiter may also harbor HT. B Show 3 more Management of dyslipidemia: avoid treating hyperlipidemia until the patient becomes euthyroid in order to more accurately assess the lipid profile in patients with overt hypothyroidism. D Show 2 more 4. Nonpharmacologic interventions Iodine supplementation (general population): do not use iodine supplementation, including kelp or other iodine-containing functional foods, in the management of hypothyroidism in iodine- sufficient areas. D Iodine supplementation, during pregnancy: As per ATA 2017 guidelines, advise ingestion of approximately 250 g of dietary iodine daily in all pregnant females. A Show 4 more As per ATA/AACE 2012 guidelines, do not use iodine supplementation, including kelp or other iodine-containing functional foods, in the management of hypothyroidism in iodine-sufficient areas. D Iodine supplementation (during breastfeeding): Advise ingestion of approximately 250 g of dietary iodine daily in all breastfeeding females. A https://web.pathway.md/diseases/rec3VlncUuayFMRMc 3/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway Offer daily oral supplements containing 150 g of iodine in breastfeeding females, preferably in the form of potassium iodide (such as present in a multivitamin) because kelp and other forms of seaweed do not provide consistent delivery of daily iodine. Avoid exceeding 500-1,100 g/day of iodine intake during breastfeeding because of concerns about the potential for inducing hypothyroidism in the infant. B Selenium supplementation: do not use selenium for the prevention or treatment of hypothyroidism. D 5. Specific circumstances Pregnant patients (screening): obtain verbal screening for any history of thyroid dysfunction and prior or current use of either thyroid hormone or antithyroid medications in all pregnant patients at the initial prenatal visit. A Show 3 more Pregnant patients, evaluation: As per ATA 2017 guidelines, measure serum TSH before conception in patients treated with levothyroxine and planning pregnancy. Adjust levothyroxine dose to achieve a TSH < 2.5 mU/L. B Show 3 more As per ATA/AACE 2012 guidelines: Measure total T4 or a free T4 index, in addition to TSH, to assess thyroid status during pregnancy. Obtain direct immunoassay measurement of free T4 (because of the wide variation in the results of different free T4 assays) only when method-specific and trimester-specific reference ranges for serum free T4 are available. B Set the target range for TSH in pregnant patients with hypothyroidism based on trimester- specific ranges for the local laboratory. Use the following upper-normal reference ranges if trimester-specific reference ranges are not available in the local laboratory: Situation Guidance 2.5 mIU/L First trimester 3.0 mIU/L Second trimester 3.5 mIU/L. B Third trimester Pregnant patients (management of autoantibodies): consider initiating levothyroxine (at a starting dose of 25-50 g/day) in euthyroid pregnant patients with positive anti-TPO antibodies and a history of pregnancy loss. C Show 2 more Pregnant patients (management of normal TSH levels): Consider initiating levothyroxine therapy in female patients of childbearing age with serum TSH levels within the reference range https://web.pathway.md/diseases/rec3VlncUuayFMRMc 4/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway for the local laboratory if: serum TSH is > 2.5 mIU/L in patients planning a pregnancy in the immediate future (including assisted reproduction) serum TSH is > 2.5 mIU/L during the first trimester of pregnancy serum TSH is > 3.0 mIU/L during the second trimester of pregnancy serum TSH is > 3.5 mIU/L during the third trimester of pregnancy. C Show 3 more Pregnant patients (thyroid replacement therapy): initiate levothyroxine treatment in patients with overt hypothyroidism during pregnancy. B Show 5 more Pregnant patients, treatment targets: As per ATA 2017 guidelines, consider targetting a TSH in the lower half of the trimester-specific reference range. Consider targetting maternal TSH levels < 2.5 mU/L when trimester-specific reference ranges are not available. C As per ATA/AACE 2012 guidelines, measure serum TSH promptly after conception in pregnant patients with hypothyroidism being treated with levothyroxine, and adjust levothyroxine dose with a TSH goal of < 2.5 mIU/L during the first trimester., B < 3 mIU/L during the second trimester, and < 3.5 mIU/L during the third trimester. B Pregnant patients, monitoring: As per ATA 2017 guidelines, monitor patients with overt and subclinical hypothyroidism (treated or untreated) or patients at risk for hypothyroidism (such as euthyroid patients with positive anti- TPO or anti-TG antibodies, post-hemithyroidectomy, or patients treated with radioactive iodine) with a serum TSH measurement approximately every 4 weeks until midgestation and at least once near 30 weeks of gestation. A As per ATA/AACE 2012 guidelines, obtain monitoring every 4 weeks in the first 20 weeks of pregnancy for the development of hypothyroidism in patients with positive levels of serum anti- TPO antibodies or with a serum TSH > 2.5 mIU/L not being treated with levothyroxine. B Pregnant patients (postpartum): reduce the dose of levothyroxine following delivery to the patient's preconception dose. Obtain additional thyroid function testing at approximately 6 weeks postpartum. B Show 4 more Breastfeeding patients: measure TSH to assess for thyroid dysfunction in females experiencing poor lactation without other identified causes, as maternal hypothyroidism can adversely impact lactation. B Show 4 more Patients with infertility: measure serum TSH concentration in all female patients seeking care for infertility. B Show 6 more https://web.pathway.md/diseases/rec3VlncUuayFMRMc 5/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway Patients with combined adrenal insufficiency: initiate corticosteroids before treatment with levothyroxine in patients with combined adrenal insufficiency and hypothyroidism. B 6. Patient education General counseling: As per ATA 2017 guidelines: Advise patients receiving levothyroxine therapy to independently increase their dose of levothyroxine by 20-30% (such as taking 2 additional tablets weekly of the current daily levothyroxine dosage) and urgently notify their caregiver for prompt testing and further evaluation in case of a suspected or confirmed pregnancy (positive home pregnancy test). A Counsel treated hypothyroid female patients of reproductive age regarding the likelihood of increased demand for levothyroxine during pregnancy. Advise such patients to contact their caregiver immediately upon a confirmed or suspected pregnancy. A As per AACE 2012 guidelines: Advise patients to take levothyroxine with water consistently 30-60 minutes before breakfast or at bedtime 4 hours after the last meal, and not take it with substances or medications interfering with its absorption. B Inform patients taking dietary supplements and nutraceuticals for hypothyroidism that commercially available thyroid-enhancing products are not a remedy for hypothyroidism and counsel about the potential side effects of various preparations, particularly those containing iodine or sympathomimetic amines as well as those marked as "thyroid support" since they could be adulterated with levothyroxine or T3. B 7. Follow-up and surveillance Indications for specialist referral: Manage most patients with primary hypothyroidism by non- endocrinologist physicians familiar with the diagnosis and treatment of hypothyroidism. Refer patients with hypothyroidism meeting any of the following criteria for a consultation with an endocrinologist: infant and pediatric patients female patient planning conception pregnant patients patients difficult to render and maintain in a euthyroid state cardiac disease presence of goiter, nodule, or other structural changes in the thyroid gland presence of other endocrine diseases, such as adrenal or pituitary disorders unusual constellation of thyroid function test results unusual causes of hypothyroidism, such as induced by agents interfering with the absorption of levothyroxine, impacting thyroid gland hormone production or secretion, affecting the https://web.pathway.md/diseases/rec3VlncUuayFMRMc 6/7 6/24/23, 12:31 PM Hashimoto's thyroiditis Pathway hypothalamic-pituitary-thyroid axis (directly or indirectly), increasing clearance, or peripherally impacting metabolism. B Serial laboratory assessment: measure serum TSH at 4-8 weeks after initiating treatment or after a change in dose. Obtain periodic TSH measurements, once an adequate replacement dose has been determined, after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise. B Show 2 more References 1. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 2. Erik K Alexander, Elizabeth N Pearce, Gregory A Brent et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27 3 315 389. Open 3. Garber JR, Cobin RH, Gharib H et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18 6 988 1028. Open 4. G E Bekkering, T Agoritsas, L Lytvyn et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019 May 14;365:l2006. Open 5. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 6. Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guideline for the Diagnosis and Treatment of Postmenopausal Osteoporosis 2016. Endocr Pract. 2016 Sep 2;22 Suppl 4 1 42. Open 7. A G r g, E Antiga, M Caproni et al. S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology EADV . J Eur Acad Dermatol Venereol. 2021 Jun;35 6 1251 1277. Open https://web.pathway.md/diseases/rec3VlncUuayFMRMc 7/7

Guideline sources The following summarized guidelines for the evaluation and management of healthcare-associated ventriculitis and meningitis (HAVM) are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2017). 1 Guidelines 1. Screening and diagnosis Clinical presentation (patients with CSF shunts): interpret new headache, nausea, lethargy, and/or a change in mental status as suggestive of CSF shunt infection. B Show 2 more Clinical presentation (patients with intrathecal pumps): consider new fever and drainage from the surgical site to be suggestive of wound infection in patients with intrathecal infusion pumps. C Clinical presentation (patients with recent trauma or neurosurgery): in the setting of recent trauma or neurosurgery, new headache, fever, evidence of meningeal irritation, seizures, and/or worsening mental status are suggestive of ventriculitis or meningitis. B Clinical presentation (patients with external ventricular drains): https://web.pathway.md/diseases/recLZPSS31H6qTBn1 1/3 6/24/23, 12:31 PM Healthcare-associated ventriculitis and meningitis Pathway Suspect HAVM in patients with with external ventricular drains who develop new or worsening altered mental status. B Suspect HAVM in patients with with external ventricular drains who develop fever and increased WBC count. B 2. Diagnostic investigations CSF biochemical testing: recognize that abnormalities of CSF cell count, glucose, and/or protein may not be reliable indicators of infection in patients with HAVM. B CSF microbiological testing: avoid excluding CNS infection on the sole basis of a negative CSF Gram stain, especially in patients who have received previous antimicrobial therapy. D CSF cultures: Obtain CSF cultures to establish the diagnosis of HAVM. A Hold cultures for at least 10 days in an attempt to identify organisms such as P. acnes in patients with CSF shunts or drains and negative initial CSF cultures. A Neuroimaging: obtain neuroimaging in patients with suspected HAVM. B 3. Medical management Empiric antibiotic therapy: administer vancomycin plus an anti-pseudomonal -lactam (such as cefepime, ceftazidime, or meropenem) as empiric antibiotic therapy for HAVM. B Interpretation of CSF cultures: diagnose HAVM based on CSF pleocytosis with a positive culture and symptoms of infection. A Show 2 more Intraventricular antimicrobial therapy: consider intraventricular antimicrobial therapy to patients with HAVM in whom the infection responds poorly to systemic antimicrobial therapy alone. B 4. Specific circumstances Patients with Staphylococcus infection: administer nafcillin or oxacillin for treatment of infection caused by MSSA (strong, moderate). If the patient cannot receive -lactam agents, consider desensitizing the patient or prescribing vancomycin as an alternative agent. B Show 4 more Patients with Pseudomonas infection: Administer cefepime, ceftazidime, or meropenem as the recommended therapy to treat infection caused by Pseudomonas species. B Use aztreonam or a fluoroquinolone as alternative agents for isolates with in vitro activity. B Patients with Acinetobacter infection: Administer meropenem to treat infection caused by Acinetobacter species. B https://web.pathway.md/diseases/recLZPSS31H6qTBn1 2/3 6/24/23, 12:31 PM Healthcare-associated ventriculitis and meningitis Pathway Use colistimethate sodium or polymyxin B for strains that demonstrate carbapenem resistance. Either agent is administered by the intravenous and intraventricular routes. B Patients with Gram negative bacilli infection: treat infection caused by Gram-negative bacilli using agents that achieve good CNS penetration, and adjust therapy based on in-vitro susceptibility testing. B Patients with Propionibacterium infection: administer penicillin G for treatment of infection caused by P. acnes. B Patients with fungal infection: Administer liposomal amphotericin B, often combined with 5-flucytosine, to treat HAVM caused by Candida species, based on in vitro susceptibility testing. B Consider switching to fluconazole once the patient shows clinical improvement, if the isolated species is susceptible. C References 1. Tunkel AR, Hasbun R, Bhimraj A et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis. 2017 Feb 14. Open 2. Chanunya Srihawan, Rodrigo Lopez Castelblanco, Lucrecia Salazar et al. Clinical Characteristics and Predictors of Adverse Outcome in Adult and Pediatric Patients With Healthcare-Associated Ventriculitis and Meningitis. Open Forum Infect Dis. 2016 Apr 13;3 2):ofw077. Open https://web.pathway.md/diseases/recLZPSS31H6qTBn1 3/3

Guideline sources The following summarized guidelines for the evaluation and management of heart failure are prepared by our editorial team based on guidelines from the Heart Failure Society of America (HFSA/AHA/ACC 2022), the European Society of Cardiology (ESC 2022; 2021), the The Japanese Society for Vascular Surgery (JSVS/JSCVS/JATS/JCS 2022), the European Society of Cardiology (ESC/ERS 2022), the American College of Emergency Physicians (ACEP 2022), the Canadian Cardiovascular Society (CCS 2022), the American Heart Association (AHA/HRS/ACC 2018), the American College of Preventive Medicine (ACPM/PCNA/ABC/ASPC/ASH/AAPA/AGS/AHA/NMA/ACC/APhA 2018), the American Heart https://web.pathway.md/diseases/rectslm30dGoeF3RH 1/28 6/24/23, 12:32 PM Heart failure Pathway Association (AHA/ACC 2017; 2013), and the American College of Endocrinology (ACE/AACE 2016). 1 2 3 4 5 6 7 8 9 10 11 12 13 13 13 13 13 14 15 Definition HF is a clinical syndrome that results from structural or functional impairment of filling or ejection of blood from the heart. HF can be associated with either reduced ejection fraction ( 40%), preserved ejection fraction ( 50%), or borderline ejection fraction (41-50%). 13 Epidemiology The most common causes of HF include ischemic heart disease, hypertensive heart disease, valvular and rheumatic heart disease, genetic cardiomyopathies, and congenital heart disease. 13 Pathophysiology In the United States, the age and sex-adjusted incidence of HF is estimated at 219.3 cases per 100,000 person-years. Its prevalence is estimated at 1915 persons per 100,000 population. 13 14 Disease course Clinical manifestations relate to pulmonary edema (dyspnea, orthopnea, paroxysmal nocturnal dyspnea), peripheral edema (ankle swelling, abdominal bloating), and activation of inflammatory pathways (early satiety, cachexia). Severe HF leads to manifestations related to hypoperfusion, spanning from mild fatigue and exertional intolerance to cardiogenic shock. 15 Prognosis and risk of recurrence The 1-year and 5-year mortality associated with HF are estimated at 20.2% and 56.2%, respectively. Death is due to non-cardiovascular events in over 50% of patients. 13 13 CalculatorAssessment of diastolic dysfunc CalculatorAssessment of diastolic functio CalculatorKillip class Guidelines 1. Classification and risk stratification Risk stratification: consider using validated multivariable risk scores to estimate subsequent risk of incident HF in the general population and mortality in ambulatory or hospitalized patients with HF. C https://web.pathway.md/diseases/rectslm30dGoeF3RH 2/28 6/24/23, 12:32 PM Heart failure Pathway 2. Diagnostic investigations Clinical evaluation: Elicit a thorough history and perform physical examination in patients presenting with HF in order to: direct diagnostic strategies to uncover specific causes likely to warrant disease-specific management B identify cardiac and noncardiac disorders, lifestyle and behavioral factors and social determinants of health likely to cause or accelerate the development or progression of HF. B Show 5 more Laboratory evaluation: As per ACC 2022 guidelines: Evaluate for the specific cause of HF using additional laboratory testing for appropriate management of patients presenting with HF. B Obtain the following laboratory tests to optimize management of patients with HF: CBC urinalysis serum electrolytes BUN serum creatinine glucose lipid profile LFTs iron studies TSH. B As per ESC 2021 guidelines, obtain the following routine blood tests for comorbidities in all patients with suspected chronic HF: CBC electrolytes BUN thyroid function tests fasting glucose and Hgb A1C lipids iron status (transferrin saturation and ferritin). B Electrocardiogram: As per ACC 2022 guidelines, obtain a 12-lead ECG at the initial encounter in all patients presenting with HF, to optimize management. B As per ESC 2021 guidelines, obtain 12-lead ECG in all patients with suspected chronic HF. B Cardiopulmonary exercise testing: https://web.pathway.md/diseases/rectslm30dGoeF3RH 3/28 6/24/23, 12:32 PM Heart failure Pathway As per ACC 2022 guidelines, obtain cardiopulmonary exercise testing to determine appropriateness of advanced treatments (such as LV assist device, heart transplant) in selected ambulatory patients with HF. B Show 2 more As per ESC 2021 guidelines, consider obtaining exercise testing to detect reversible myocardial ischemia and investigate the cause of dyspnea. C Show 3 more Natriuretic peptide biomarkers: consider obtaining BNP or N-terminal pro-BNP to support a diagnosis or exclusion of HF in patients presenting with dyspnea. B Show 4 more Chest radiography: As per ACC 2022 guidelines, obtain a CXR to assess heart size and pulmonary congestion and to detect alternative cardiac, pulmonary and other diseases likely to cause or contribute to the symptoms in patients with suspected or new-onset HF or presenting with acute decompensated HF. B As per ESC 2021 guidelines, obtain CXR to assess for comorbidities in all patients with suspected chronic HF. B Transthoracic echocardiogram: As per ACC 2022 guidelines, obtain TTE in the initial evaluation to assess cardiac structure and function in patients with suspected or newly diagnosed HF. B Show 2 more As per ESC 2021 guidelines, obtain TTE in all patients with suspected chronic HF. B Advanced cardiac imaging: As per ACC 2022 guidelines, obtain alternative imaging such as cardiac MRI, cardiac CT, or radionuclide imaging for assessment of LV ejection fraction, if echocardiography is inadequate. B Show 3 more As per ESC 2021 guidelines, obtain cardiac MRI for the assessment of myocardial structure and function in patients with poor echocardiogram acoustic windows. B Show 4 more Lung ultrasound: obtain point-of-care lung ultrasound as an imaging modality in conjunction with medical history and physical examination to diagnose acute HF syndrome when diagnostic uncertainty exists. B Psychosocial assessment: consider screening adult patients with HF for depression, social isolation, frailty and low health literacy as risk factors for poor self-care to improve management. C Show 2 more 3. Diagnostic procedures https://web.pathway.md/diseases/rectslm30dGoeF3RH 4/28 6/24/23, 12:32 PM Heart failure Pathway Coronary angiography: As per ESC 2021 guidelines: Perform invasive coronary angiography in patients with angina despite pharmacological therapy or symptomatic ventricular arrhythmias. B Consider performing invasive coronary angiography in patients with HF with reduced ejection fraction with an intermediate-to-high pretest probability of coronary artery disease and the presence of ischemia in noninvasive stress tests. C As per ACC 2017 guidelines, consider performing coronary angiography in patients eligible for revascularization when ischemia may be contributing to HF. C Right heart catheterization: perform right heart catheterization in patients with severe HF being evaluated for heart transplantation or mechanical circulatory support. B Show 3 more Endomyocardial biopsy: As per ACC 2022 guidelines: Do not perform endomyocardial biopsy in patients undergoing routine evaluation of HF because of the risk of complications. D Consider performing endomyocardial biopsy when a specific diagnosis is suspected that would influence therapy in patients with HF. C As per ESC 2021 guidelines, consider performing endomyocardial biopsy in patients with rapidly progressive HF despite standard therapy, if there is a probability of a specific diagnosis to be confirmed only in myocardial samples. C 4. Respiratory support Supplemental oxygen: administer oxygen to correct hypoxemia in patients with SpO < 90% or PaO < 60 mmHg. B Mechanical ventilation: Perform intubation for progressive respiratory failure persisting in spite of oxygen administration or noninvasive ventilation. B Consider initiating noninvasive positive pressure ventilation in patients with respiratory distress (respiratory rate > 25 breaths/min, SpO < 90%) and starting as soon as possible to decrease respiratory distress and reduce the rate of mechanical endotracheal intubation. C 5. Medical management General principles: As per ACC 2022 guidelines, provide multidisciplinary cate in patients with HF to: facilitate the implementation of guideline-directed medical therapy address potential barriers to self-care https://web.pathway.md/diseases/rectslm30dGoeF3RH 5/28 6/24/23, 12:32 PM Heart failure Pathway reduce the risk of subsequent re-hospitalization for HF improve survival. A Show 7 more As per ESC 2021 guidelines, enroll patients with HF in a multidisciplinary HF management program to reduce the risk of HF hospitalization and mortality. A Renin-angiotensin system inhibitors: As per ESC 2022 guidelines, initiate ACEIs/ARBs/angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists in all patients with HF with reduced ejection fraction. A As per ACC 2022 guidelines, initiate angiotensin receptor-neprilysin inhibitors to reduce morbidity and mortality in patients with HF with reduced ejection fraction and NYHA class II-III symptoms. A Show 7 more Landmark trials: V-HeFT II In male patients with HF and LV dilation or an LV ejection fraction < 45%, enalapril was superior to hydralazine-isosorbide dinitrate arm with respect to death at 2 years. Cohn JN et al. N Engl J Med. 1991 Aug 1. As per ESC 2021 guidelines, initiate ACEIs to reduce the risk of HF hospitalization and death in patients with NYHA class II-IV HF with reduced ejection fraction with reduced ejection fraction (LV ejection fraction 40%). A Show 2 more As per AHA 2018 guidelines, initiate mineralocorticoid receptor antagonists and either ACEIs, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors to reduce sudden cardiac death and all-cause mortality in patients with HF with reduced ejection fraction (LV ejection fraction 40%). A Aldosterone receptor antagonists: As per ACC 2022 guidelines, initiate mineralocorticoid receptor antagonists (spironolactone or eplerenone) to reduce morbidity and mortality in patients with HF with reduced ejection fraction and NYHA class II-IV symptoms, if estimated GFR is > 30 mL/min/1.73 m and serum potassium is < 5.0 mEq/L. Obtain careful monitoring of potassium, renal function and diuretic dosing at initiation and closely monitor thereafter to minimize risk of hyperkalemia and renal insufficiency. A Show 2 more Landmark trials: TOPCAT In patients with HF and a preserved LV ejection fraction, spironolactone was not superior to placebo with respect to death from cardiovascular causes, aborted cardiac arrest, or https://web.pathway.md/diseases/rectslm30dGoeF3RH 6/28 6/24/23, 12:32 PM Heart failure Pathway hospitalization for HF. Pitt B et al. N Engl J Med. 2014 Apr 10. As per ESC 2021 guidelines, initiate mineralocorticoid receptor antagonists to reduce the risk of HF hospitalization and death in patients with NYHA class II-IV HF with reduced ejection fraction with reduced ejection fraction (LV ejection fraction 40%). A Hydralazine and isosorbide dinitrate: As per ACC 2022 guidelines, initiate the combination of hydralazine and isosorbide dinitrate to improve symptoms and reduce morbidity and mortality in patients self-identified as African American with NYHA class III-IV HF with reduced ejection fraction receiving optimal medical therapy. A Show 2 more Landmark trials: V-HeFT In patients with chronic HF and LV ejection fraction < 45%, the combination of hydralazine and isosorbide dinitrate reduced mortality 2 years (25.6% vs. 34.3%, p<0.028; RRR 34%) as compared with prazosin or with placebo. LV ejection fraction rose significantly in the group treated with hydralazine/isosorbide dinitrate, but not in the placebo or prazosin groups. Cohn JN et al. N Engl J Med. 1986 Jun 12. As per ESC 2021 guidelines: Consider initiating hydralazine and isosorbide dinitrate to reduce the risk of HF hospitalization and death in self-identified black patients with LV ejection fraction 35% or with an LV ejection fraction < 45% combined with a dilated left ventricle in NYHA class III-IV despite treatment with an ACEI (or angiotensin receptor-neprilysin inhibitor), a -blocker and an mineralocorticoid receptor antagonist. C Consider initiating hydralazine and isosorbide dinitrate to reduce the risk of death in patients with symptomatic HF with reduced ejection fraction unable to tolerate any of ACEIs, angiotensin-receptor blockers or angiotensin receptor-neprilysin inhibitors (or they are contraindicated). C Beta-blockers: As per ESC 2022 guidelines, initiate -blockers in all patients with HF with reduced ejection fraction. A As per ACC 2022 guidelines: Initiate one of the three beta blockers proven to reduce mortality (bisoprolol, carvedilol, sustained-release metoprolol succinate) to reduce mortality and hospitalizations in patients with HF with reduced ejection fraction with current or previous symptoms. A Recognize that -blocker therapy provides high economic value in patients with HF with reduced ejection fraction with current or previous symptoms. A https://web.pathway.md/diseases/rectslm30dGoeF3RH 7/28 6/24/23, 12:32 PM Heart failure Pathway Landmark trials: COMET In patients chronic HF (NYHA II-IV), previous cardiovascular admission, and LV ejection fraction < 35% on optimal medical treatment, carvedilol was superior to metoprolol with respect to a all-cause death. Poole-Wilson PA et al. Lancet. 2003 Jul 5. As per ESC 2021 guidelines, initiate -blockers to reduce the risk of HF hospitalization and death in patients with stable NYHA class II-IV HF with reduced ejection fraction with reduced ejection fraction (LV ejection fraction 40%). A As per AHA 2018 guidelines, initiate -blockers to reduce sudden cardiac death and all-cause mortality in patients with HF with reduced ejection fraction (LV ejection fraction 40%). A Calcium channel blockers: do not use dihydropyridine D or nondihydropyridine CCBs in patients with HF with reduced ejection fraction. D Ivabradine: As per ACC 2022 guidelines, consider initiating ivabradine to reduce HF hospitalizations and cardiovascular death in patients with symptomatic (NYHA class II-III) stable chronic HF with reduced ejection fraction (LV ejection fraction 35%) receiving guideline-directed medical therapy including a beta blocker at maximum tolerated dose and having sinus rhythm with a HR of 70 bpm at rest. C Landmark trials: SHIFT In patients with symptomatic HF and a left-ventricular ejection fraction < 35% who were in sinus rhythm with HR 70 beats/min and had been admitted to hospital for HF within the previous year, ivabradine was superior to placebo with respect to cardiovascular death or hospital admission for worsening HF. Swedberg K et al. Lancet. 2010 Sep 11. As per ESC 2021 guidelines: Consider initiating ivabradine to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with LV ejection fraction 35%, in sinus rhythm and a resting HR 70 bpm despite treatment with an evidence-based dose of -blocker (or maximum tolerated dose below that), ACEI or angiotensin receptor-neprilysin inhibitor and an mineralocorticoid receptor antagonist. C Consider initiating ivabradine to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with LV ejection fraction 35%, in sinus rhythm and a resting HR 70 bpm unable to tolerate or having contraindications to a -blocker. Initiate ACEIs (or https://web.pathway.md/diseases/rectslm30dGoeF3RH 8/28 6/24/23, 12:32 PM Heart failure Pathway angiotensin receptor-neprilysin inhibitors) and mineralocorticoid receptor antagonists in these patients. C Diuretics: As per ACEP 2022 guidelines: Consider initiating early diuretics when indicated for emergency department patients with acute HF syndrome to reduce the length of stay and in-hospital mortality. C Verify the diagnosis of acute HF syndrome with volume overload before administering diuretics to avoid causing harm in patients with an alternative diagnosis. B As per ACC 2022 guidelines: Initiate diuretics to relieve congestion, improve symptoms and prevent worsening HF in patients with HF having fluid retention. B Reserve adding thiazide (such as metolazone) to treatment with a loop diuretic for patients with HF and congestive symptoms not responding to moderate- or high-dose loop diuretics, to minimize electrolyte abnormalities. B Landmark trials: TRANSFORM-HF In in-hospital patients with new or worsening HF, torsemide was not superior to furosemide with respect to death from all causes. Frederik H Verbrugge et al. Eur Heart J Acute Cardiovasc Care. 2022 Dec 27. As per ESC 2021 guidelines, initiate diuretics to alleviate HF symptoms, improve exercise capacity and reduce HF hospitalizations in patients with NYHA class II-IV HF with reduced ejection fraction with reduced ejection fraction (LV ejection fraction 40%) with signs and/or symptoms of congestion. B Digoxin: As per ACC 2022 guidelines, consider initiating digoxin to decrease hospitalizations for HF in patients with symptomatic HF with reduced ejection fraction despite guideline-directed medical therapy or unable to tolerate guideline-directed medical therapy. C Landmark trials: DIG In patients with an LV ejection fraction 0.45 being treated with diuretics and ACE inhibitors, digoxin was not superior to placebo with respect to death from all causes. Digitalis Investigation Group. N Engl J Med. 1997 Feb 20. As per ESC 2021 guidelines, consider initiating digoxin to reduce the risk of hospitalization (both all-cause and HF hospitalizations) in patients with symptomatic HF with reduced ejection https://web.pathway.md/diseases/rectslm30dGoeF3RH 9/28 6/24/23, 12:32 PM Heart failure Pathway fraction in sinus rhythm despite treatment with an ACEI (or angiotensin receptor-neprilysin inhibitor), a -blocker and a mineralocorticoid receptor antagonist. C Sodium-glucose cotransporter-2 inhibitors: As per CCS 2022 guidelines: Initiate SGLT-2 inhibitors to reduce all-cause and cardiovascular mortality, hospitalization for HF, and the composite endpoint of significant decline in estimated GFR, progression to end- stage kidney disease, or death due to kidney disease in adult patients with HF and LV ejection fraction 40%. B Initiate SGLT-2 inhibitors to reduce hospitalization for HF in adult patients with HF and LV ejection fraction > 40%. B Landmark trials: EMPULSE In patients with a primary diagnosis of acute de novo or decompensated chronic HF regardless of LV ejection fraction, empagliflozin was superior to placebo with respect to clinical benefit at day 90. Adriaan A Voors et al. Nat Med. 2022 Mar. As per ESC 2022 guidelines, initiate SGLT-2 inhibitors in all patients with HF with reduced ejection fraction. A As per ACC 2022 guidelines: Initiate SGLT-2 inhibitors to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of T2DM in patients with symptomatic chronic HF with reduced ejection fraction. A Recognize that SGLT-2 inhibitor therapy provides intermediate economic value in patients with symptomatic chronic HF with reduced ejection fraction. A Landmark trials: DAPA-HF In adult patients with NYHA class II, III, or IV HF and an ejection fraction < 40%, dapagliflozin was superior to placebo with respect to worsening HF or cardiovascular death. John J V McMurray et al. N Engl J Med. 2019 Nov 21. As per ESC 2021 guidelines: Initiate dapagliflozin or empagliflozin to reduce the risk of HF hospitalization and death in patients with NYHA class II-IV HF with reduced ejection fraction with reduced ejection fraction (LV ejection fraction 40%). A Initiate SGLT-2 inhibitors (dapagliflozin, empagliflozin, and sotagliflozin) to reduce hospitalizations for HF and cardiovascular death in patients with T2DM mellitus and HF with https://web.pathway.md/diseases/rectslm30dGoeF3RH 10/28 6/24/23, 12:32 PM Heart failure Pathway reduced ejection fraction. A Landmark trials: EMPEROR-Reduced In adult patients with chronic HF and an ejection fraction 40% who were receiving recommended therapy, empagliflozin was superior to placebo with respect to cardiovascular death or hospitalization for worsening HF. Milton Packer et al. N Engl J Med. 2020 Oct 8. Soluble guanylate cyclase stimulators: As per ACC 2022 guidelines, consider initiating an oral soluble guanylate cyclase stimulator (vericiguat) to reduce HF hospitalization and cardiovascular death in selected high-risk patients with HF with reduced ejection fraction and recent worsening of HF already on guideline-directed medical therapy. C As per ESC 2021 guidelines, consider initiating vericiguat to reduce the risk of cardiovascular mortality or HF hospitalization in patients with NYHA class II-IV HF with reduced ejection fraction (LVEF 40%) with worsening HF despite treatment with an ACEI (or angiotensin receptor- neprilysin inhibitor), a -blocker and an mineralocorticoid receptor antagonist. C Anticoagulation therapy: do not initiate anticoagulation in patients with chronic HF with reduced ejection fraction without a specific indication, such as VTE, AF, a previous thromboembolic event or a cardioembolic source. D Medications to avoid: recognize that class IC antiarrhythmic medications and dronedarone may increase the risk of mortality in patients with HF with reduced ejection fraction. B Show 3 more Management of pre-HF: initiate ACEIs to prevent symptomatic HF and reduce mortality in patients with LV ejection fraction 40%. A Show 7 more Management of HFmrEF: As per ACC 2022 guidelines: Consider initiating SGLT-2 inhibitors to decrease HF hospitalizations and cardiovascular mortality in patients with HF with mildly reduced ejection fraction. C Consider initiating the following agents in patients with current or previous symptomatic HF with mildly reduced ejection fraction (LV ejection fraction 41-49%) to reduce the risk of HF hospitalization and cardiovascular mortality, particularly among patients with LV ejection fraction on the lower end of this spectrum: evidence-based -blockers for HF with reduced ejection fraction angiotensin receptor-neprilysin inhibitors ACEIs ARBs https://web.pathway.md/diseases/rectslm30dGoeF3RH 11/28 6/24/23, 12:32 PM Heart failure Pathway mineralocorticoid receptor antagonists. C Landmark trials: DELIVER In patients with HF and a LV ejection fraction > 40%, dapagliflozin was superior to placebo with respect to worsening HF or cardiovascular death. Scott D Solomon et al. N Engl J Med. 2022 Sep 22. As per ESC 2021 guidelines: Initiate diuretics to alleviate symptoms and signs in patients with congestion and HF with mildly reduced ejection fraction. B Consider initiating the following agents to reduce the risk of HF hospitalization and death in patients with HF with mildly reduced ejection fraction: ACEIs, angiotensin-receptor blockers or sacubitril/valsartan mineralocorticoid receptor antagonists -blockers. C Management of HFimpEF: continue guideline-directed medical therapy to prevent relapse of HF and LV dysfunction in patients with HF with improved ejection fraction after treatment, even in patients becoming asymptomatic. B Management of HFpEF: As per ACC 2022 guidelines, titrate medication to attain BP targets in accordance with published clinical practice guidelines to prevent morbidity in patients with HFpEF and hypertension. B Show 6 more Landmark trials: EMPEROR-Preserved In patients with NYHA class II-IV HF and an ejection fraction > 40%, empagliflozin was superior to placebo with respect to cardiovascular death or hospitalization for HF. Stefan D Anker et al. N Engl J Med. 2021 Oct 14. As per ESC 2021 guidelines: Screen for and treat etiologies and cardiovascular and non-cardiovascular comorbidities in patients with HFpEF. B Initiate diuretics to alleviate symptoms and signs in patients with HFpEF with congestion. B Management of hypertension: As per AHA 2022 guidelines: Titrate guideline-directed medical therapy to the maximally tolerated target dose in patients with HF with reduced ejection fraction and hypertension. B https://web.pathway.md/diseases/rectslm30dGoeF3RH 12/28 6/24/23, 12:32 PM Heart failure Pathway Titrate medication to attain BP targets in accordance with published clinical practice guidelines to prevent morbidity in patients with HFpEF and hypertension. B As per JCS 2022 guidelines: Consider offering proactive use of medications, mainly cardioprotective antihypertensive agents, to achieve a mean BP < 90 mmHg (< 80 mmHg if tolerated) in patients with HF. C Encourage and educate patients to measure their BP at home and to record it as a daily self- management goal. B As per AAPA 2018 guidelines, titrate guideline-directed medical therapy titrated to attain a BP of < 130/80 mmHg in adult patients with HF with reduced ejection fraction and hypertension. B Show 3 more Management of atrial fibrillation, anticoagulation: As per HFSA/ACC/AHA 2022 guidelines, initiate chronic anticoagulant therapy in patients with chronic HF with permanent-persistent-paroxysmal AF and a CHA2DS2-VASc score of 2 (for males) and 3 (for females). A Show 4 more As per ESC 2021 guidelines, initiate long-term oral anticoagulation in all patients with AF, HF and CHA2DS2-VASc score 2 in males or 3 in females. A Show 2 more Management of atrial fibrillation (rate control): Consider initiating -blockers for short- and long-term rate control in patients with HF and AF. C Consider initiating digoxin when the ventricular rate remains high despite -blockers or when - blockers are contraindicated or not tolerated. C Management of atrial fibrillation (cardioversion): Perform urgent electrical cardioversion in patients with acute worsening of HF presenting with rapid ventricular rates and hemodynamic instability. B Consider performing cardioversion if there is an association between AF and worsening of HF symptoms despite optimal medical treatment. C Management of atrial fibrillation, catheter ablation: As per HFSA/ACC/AHA 2022 guidelines: Consider performing AF ablation to improve symptoms and quality of life in patients with HF and symptoms caused by AF. C Consider performing atrioventricular nodal ablation with implantation of a cardiac resynchronization therapy device in patients with AF and LV ejection fraction 50%, if a rhythm control strategy fails or is not desired and ventricular rates remain rapid despite medical therapy. C As per ESC 2021 guidelines, consider performing catheter ablation for the prevention or treatment of AF if there is a clear association between paroxysmal or persistent AF and worsening of HF symptoms persisting despite medical therapy. C Management of valvular heart disease: https://web.pathway.md/diseases/rectslm30dGoeF3RH 13/28 6/24/23, 12:32 PM Heart failure Pathway Manage VHD in a multidisciplinary manner in accordance with clinical practice guidelines for VHD to prevent worsening of HF and adverse clinical outcomes in patients with HF. B Optimize guideline-directed medical therapy before any intervention for secondary MR related to LV dysfunction in patients with chronic severe secondary MR and HF with reduced ejection fraction. B Management of hyperkalemia: insufficient evidence to support the use of potassium binders (patiromer, sodium zirconium cyclosilicate) to improve outcomes in patients with HF experiencing hyperkalemia (serum potassium level 5.5 mEq/L) while taking a RAAS inhibitor. I Management of anemia: As per ACC 2022 guidelines: Consider initiating IV iron replacement to improve functional status and quality of life in patients with HF with reduced ejection fraction and iron deficiency with or without anemia. C Do not use ESAs to improve morbidity and mortality in patients with HF and anemia. D Landmark trials: FAIR-HF In patients with chronic HF, reduced LV ejection fraction, and iron deficiency, with or without anemia, ferric carboxymaltose was superior to placebo with respect to the percentage of patients achieving good or moderate improvement on the self-reported Patient Global Assessment at 24 weeks. Anker SD et al. N Engl J Med. 2009 Dec 17. As per ESC 2021 guidelines, obtain periodic screening for anemia and iron deficiency with a CBC, serum ferritin concentration and transferrin saturation in all patients with HF. B Show 3 more Management of sleep disorders: consider obtaining a formal sleep assessment in patients with HF and suspicion of sleep-disordered breathing to confirm the diagnosis and differentiate between obstructive and central sleep apnea. C Show 2 more 6. Inpatient care General principles: continue and optimize preexisting guideline-directed medical therapy to improve outcomes, unless contraindicated, in patients with HF with reduced ejection fraction requiring hospitalization. B Show 6 more Invasive hemodynamic monitoring: Do not obtain routine invasive hemodynamic monitoring in patients with HF. D Consider obtaining invasive hemodynamic monitoring to guide management in selected patients with HF with persistent or worsening symptoms, signs, diagnostic parameters and, if https://web.pathway.md/diseases/rectslm30dGoeF3RH 14/28 6/24/23, 12:32 PM Heart failure Pathway hemodynamics are uncertain. C Venous thromboprophylaxis: As per ACC 2022 guidelines, administer venous thromboprophylaxis to prevent venous thromboembolic disease in patients hospitalized with HF. B As per ESC 2021 guidelines, administer thromboprophylaxis, such as with low-molecular-weight heparin, to reduce the risk of DVT and pulmonary embolism in patients not already anticoagulated and with no contraindication to anticoagulation. A Intravenous diuretics: As per ACC 2022 guidelines, administer prompt IV loop diuretics to improve symptoms and reduce morbidity in patients with HF admitted with evidence of significant fluid overload. B Show 3 more Landmark trials: ADVOR In patients with acute decompensated HF, clinical signs of volume overload, and N-terminal pro-BNP level > 1,000 pg/mL or BNP level > 250 pg/mL, acetazolamide was superior to placebo with respect to successful decongestion at 3 days. Wilfried Mullens et al. N Engl J Med. 2022 Sep 29. As per ESC 2021 guidelines: Administer IV loop diuretics to improve symptoms in all patients with acute HF admitted with signs/symptoms of fluid overload. B Consider combining a loop diuretic with a thiazide-type diuretic in patients with resistant edema not responding to an increase in loop diuretic doses. C Updated evidence: CLOROTIC In hospitalized adult patients with acute decompensated HF, hydrochlorothiazide was superior to placebo with respect to weight reduction at 72 hours. Joan Carles Trull s et al. Eur Heart J. 2022 Nov 24. As per ACC 2017 guidelines, obtain daily serum electrolytes, urea nitrogen, and creatinine measurements during the use of IV diuretics or active titration of HF medications. B Intravenous inotropes: As per ACC 2022 guidelines, consider administering continuous IV inotropic support as "bridge therapy" in patients with advanced (stage D) HF refractory to guideline-directed medical therapy and device therapy being eligible for and awaiting mechanical circulatory support or cardiac transplantation. C Show 2 more https://web.pathway.md/diseases/rectslm30dGoeF3RH 15/28 6/24/23, 12:32 PM Heart failure Pathway As per ESC 2021 guidelines, do not administer routine inotropic agents because of safety concerns unless the patient has symptomatic hypotension and evidence of hypoperfusion. D Show 2 more Intravenous nitrates: As per ACEP 2022 guidelines, consider administering high-dose nitroglycerin in patients with acute HF syndrome and elevated BP. C As per ACC 2022 guidelines, consider administering IV nitroglycerin or nitroprusside as an adjuvant to diuretic therapy to relieve dyspnea in patients admitted with decompensated HF, in the absence of systemic hypotension. C As per ESC 2021 guidelines, consider administering IV vasodilators as initial therapy to improve symptoms and reduce congestion in patients with acute HF and systolic BP > 110 mmHg. C Opioids: do not use routine opioids unless in selected patients with severe/intractable pain or anxiety. D Management of cardiogenic shock (general principles): Consider managing patients with cardiogenic shock by a multidisciplinary team experienced in shock. C Consider placing a pulmonary artery line to define hemodynamic subsets and appropriate management strategies in patients presenting with cardiogenic shock. C Management of cardiogenic shock, inotropes and vasopressors: As per HFSA/ACC/AHA 2022 guidelines, administer IV inotropic support to maintain systemic perfusion and preserve end-organ performance in patients with cardiogenic shock. B As per ESC 2021 guidelines, consider administering a vasopressor, preferably norepinephrine, to increase BP and vital organ perfusion in patients with cardiogenic shock. C Management of cardiogenic shock, mechanical circulatory support: As per HFSA/ACC/AHA 2022 guidelines: Consider triaging patients not rapidly responding to initial shock measures to centers providing temporary mechanical circulatory support to optimize management. C Consider initiating temporary mechanical circulatory support in patients with cardiogenic shock when end-organ function cannot be maintained by pharmacologic means to support cardiac function. C As per ESC 2021 guidelines, consider initiating short-term mechanical circulatory support in patients with cardiogenic shock as a bridge to recovery, bridge to decision, bridge to bridge or to treat the cause of cardiogenic shock or long-term mechanical circulatory support or transplantation. C Management of cardiogenic shock (intra-aortic balloon pump): Consider performing intra-aortic balloon pump therapy in patients with cardiogenic shock as a bridge to recovery, bridge to decision, bridge to bridge including the treatment of cardiogenic shock (mechanical complication of acute myocardial infarction) or long-term mechanical circulatory support or transplantation. C https://web.pathway.md/diseases/rectslm30dGoeF3RH 16/28 6/24/23, 12:32 PM Heart failure Pathway Do not perform intra-aortic balloon pump therapy routinely in patients with post-myocardial infarction cardiogenic shock. D Management of cardiogenic shock (coronary revascularization): transfer suitable patients with STEMI developing cardiogenic shock or acute severe HF, irrespective of the time delay from myocardial infarction onset, immediately to a PCI-capable hospital for coronary angiography. B Show 6 more 7. Nonpharmacologic interventions Lifestyle modifications: As per AHA 2017 guidelines, control or avoid other conditions likely to lead or contribute to HF, including obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents. B As per AACE 2016 guidelines, do not offer weight loss for the expressed purpose of preventing cardiovascular events or to extend life in patients with congestive HF, although evidence suggests that weight loss can improve myocardial function and congestive HF symptomatology in the short term. D Self-management programs: Offer self-management strategies in patients with HF to reduce the risk of HF hospitalization and mortality. A Offer either home-based and/or clinic-based programs to improve outcomes and to reduce the risk of HF hospitalization and mortality. A Exercise: As per ACC 2022 guidelines, advise participating in exercise training or practicing regular physical activity to improve functional status, exercise performance and quality of life in patients with HF able to participate. A As per ESC 2021 guidelines, advise exercising in all patients able in order to improve exercise capacity, quality of life and reduce HF hospitalization. A Cardiac rehabilitation: As per ACC 2022 guidelines, consider offering participation in cardiac rehabilitation programs to improve functional capacity, exercise tolerance and health-related quality of life in patients with HF. C As per ESC 2021 guidelines, consider offering a supervised, exercise-based, cardiac rehabilitation program in patients with more severe disease, frailty or with comorbidities. C Fluid and sodium restriction: Advise avoiding excessive sodium intake to reduce congestive symptoms in patients with stage C HF. B Insufficient evidence to recommend fluid restriction to reduce congestive symptoms in patients with advanced HF and hyponatremia. I https://web.pathway.md/diseases/rectslm30dGoeF3RH 17/28 6/24/23, 12:32 PM Heart failure Pathway Landmark trials: SODIUM-HF In adult patients with chronic HF receiving optimally tolerated medical treatment, reduced sodium intake was not superior to usual sodium intake with respect to a composite of admission to hospital for cardiovascular causes, emergency department visit for cardiovascular causes, or death from all causes at 12 months. Justin A Ezekowitz et al. Lancet. 2022 Apr 9. Nutritional supplements: Consider offering omega-3 PUFA supplementation as adjunctive therapy to reduce mortality and cardiovascular hospitalizations in patients with HF and NYHA class II-IV symptoms. C Do not offer vitamins, nutritional supplements or hormonal therapy in patients with HF with reduced ejection fraction other than to correct specific deficiencies. D 8. Therapeutic procedures Cardiac resynchronization therapy: As per ACC 2022 guidelines, perform cardiac resynchronization therapy to reduce total mortality and hospitalizations and improve symptoms and quality of life in patients with LV ejection fraction 35%, sinus rhythm, LBBB with a QRS duration 150 ms and NYHA class II, III or ambulatory IV symptoms on guideline-directed medical therapy. B Show 10 more As per ESC 2021 guidelines, perform cardiac resynchronization therapy to improve symptoms and reduce morbidity and mortality in symptomatic patients with HF in sinus rhythm with a QRS duration 150 ms and LBBB QRS morphology and with LV ejection fraction 35% despite optimal medical therapy. A Show 6 more Implantable cardioverter-defibrillator: As per ACC 2022 guidelines, perform placement of an ICD for primary prevention of sudden cardiac death to reduce total mortality in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction with LV ejection fraction 35% and NYHA class II-III symptoms on chronic guideline-directed medical therapy having a reasonable expectation of meaningful survival for > 1 year. A Show 4 more As per ESC 2021 guidelines, perform placement of an ICD to reduce the risk of sudden death and all-cause mortality in patients recovered from a ventricular arrhythmia causing hemodynamic instability and expected to survive for > 1 year with good functional status, in the absence of reversible causes or unless the ventricular arrhythmia has occurred < 48 hours after a myocardial infarction. A Show 6 more

Show 2 more https://web.pathway.md/diseases/rectslm30dGoeF3RH 15/28 6/24/23, 12:32 PM Heart failure Pathway As per ESC 2021 guidelines, do not administer routine inotropic agents because of safety concerns unless the patient has symptomatic hypotension and evidence of hypoperfusion. D Show 2 more Intravenous nitrates: As per ACEP 2022 guidelines, consider administering high-dose nitroglycerin in patients with acute HF syndrome and elevated BP. C As per ACC 2022 guidelines, consider administering IV nitroglycerin or nitroprusside as an adjuvant to diuretic therapy to relieve dyspnea in patients admitted with decompensated HF, in the absence of systemic hypotension. C As per ESC 2021 guidelines, consider administering IV vasodilators as initial therapy to improve symptoms and reduce congestion in patients with acute HF and systolic BP > 110 mmHg. C Opioids: do not use routine opioids unless in selected patients with severe/intractable pain or anxiety. D Management of cardiogenic shock (general principles): Consider managing patients with cardiogenic shock by a multidisciplinary team experienced in shock. C Consider placing a pulmonary artery line to define hemodynamic subsets and appropriate management strategies in patients presenting with cardiogenic shock. C Management of cardiogenic shock, inotropes and vasopressors: As per HFSA/ACC/AHA 2022 guidelines, administer IV inotropic support to maintain systemic perfusion and preserve end-organ performance in patients with cardiogenic shock. B As per ESC 2021 guidelines, consider administering a vasopressor, preferably norepinephrine, to increase BP and vital organ perfusion in patients with cardiogenic shock. C Management of cardiogenic shock, mechanical circulatory support: As per HFSA/ACC/AHA 2022 guidelines: Consider triaging patients not rapidly responding to initial shock measures to centers providing temporary mechanical circulatory support to optimize management. C Consider initiating temporary mechanical circulatory support in patients with cardiogenic shock when end-organ function cannot be maintained by pharmacologic means to support cardiac function. C As per ESC 2021 guidelines, consider initiating short-term mechanical circulatory support in patients with cardiogenic shock as a bridge to recovery, bridge to decision, bridge to bridge or to treat the cause of cardiogenic shock or long-term mechanical circulatory support or transplantation. C Management of cardiogenic shock (intra-aortic balloon pump): Consider performing intra-aortic balloon pump therapy in patients with cardiogenic shock as a bridge to recovery, bridge to decision, bridge to bridge including the treatment of cardiogenic shock (mechanical complication of acute myocardial infarction) or long-term mechanical circulatory support or transplantation. C https://web.pathway.md/diseases/rectslm30dGoeF3RH 16/28 6/24/23, 12:32 PM Heart failure Pathway Do not perform intra-aortic balloon pump therapy routinely in patients with post-myocardial infarction cardiogenic shock. D Management of cardiogenic shock (coronary revascularization): transfer suitable patients with STEMI developing cardiogenic shock or acute severe HF, irrespective of the time delay from myocardial infarction onset, immediately to a PCI-capable hospital for coronary angiography. B Show 6 more 7. Nonpharmacologic interventions Lifestyle modifications: As per AHA 2017 guidelines, control or avoid other conditions likely to lead or contribute to HF, including obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents. B As per AACE 2016 guidelines, do not offer weight loss for the expressed purpose of preventing cardiovascular events or to extend life in patients with congestive HF, although evidence suggests that weight loss can improve myocardial function and congestive HF symptomatology in the short term. D Self-management programs: Offer self-management strategies in patients with HF to reduce the risk of HF hospitalization and mortality. A Offer either home-based and/or clinic-based programs to improve outcomes and to reduce the risk of HF hospitalization and mortality. A Exercise: As per ACC 2022 guidelines, advise participating in exercise training or practicing regular physical activity to improve functional status, exercise performance and quality of life in patients with HF able to participate. A As per ESC 2021 guidelines, advise exercising in all patients able in order to improve exercise capacity, quality of life and reduce HF hospitalization. A Cardiac rehabilitation: As per ACC 2022 guidelines, consider offering participation in cardiac rehabilitation programs to improve functional capacity, exercise tolerance and health-related quality of life in patients with HF. C As per ESC 2021 guidelines, consider offering a supervised, exercise-based, cardiac rehabilitation program in patients with more severe disease, frailty or with comorbidities. C Fluid and sodium restriction: Advise avoiding excessive sodium intake to reduce congestive symptoms in patients with stage C HF. B Insufficient evidence to recommend fluid restriction to reduce congestive symptoms in patients with advanced HF and hyponatremia. I https://web.pathway.md/diseases/rectslm30dGoeF3RH 17/28 6/24/23, 12:32 PM Heart failure Pathway Landmark trials: SODIUM-HF In adult patients with chronic HF receiving optimally tolerated medical treatment, reduced sodium intake was not superior to usual sodium intake with respect to a composite of admission to hospital for cardiovascular causes, emergency department visit for cardiovascular causes, or death from all causes at 12 months. Justin A Ezekowitz et al. Lancet. 2022 Apr 9. Nutritional supplements: Consider offering omega-3 PUFA supplementation as adjunctive therapy to reduce mortality and cardiovascular hospitalizations in patients with HF and NYHA class II-IV symptoms. C Do not offer vitamins, nutritional supplements or hormonal therapy in patients with HF with reduced ejection fraction other than to correct specific deficiencies. D 8. Therapeutic procedures Cardiac resynchronization therapy: As per ACC 2022 guidelines, perform cardiac resynchronization therapy to reduce total mortality and hospitalizations and improve symptoms and quality of life in patients with LV ejection fraction 35%, sinus rhythm, LBBB with a QRS duration 150 ms and NYHA class II, III or ambulatory IV symptoms on guideline-directed medical therapy. B Show 10 more As per ESC 2021 guidelines, perform cardiac resynchronization therapy to improve symptoms and reduce morbidity and mortality in symptomatic patients with HF in sinus rhythm with a QRS duration 150 ms and LBBB QRS morphology and with LV ejection fraction 35% despite optimal medical therapy. A Show 6 more Implantable cardioverter-defibrillator: As per ACC 2022 guidelines, perform placement of an ICD for primary prevention of sudden cardiac death to reduce total mortality in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction with LV ejection fraction 35% and NYHA class II-III symptoms on chronic guideline-directed medical therapy having a reasonable expectation of meaningful survival for > 1 year. A Show 4 more As per ESC 2021 guidelines, perform placement of an ICD to reduce the risk of sudden death and all-cause mortality in patients recovered from a ventricular arrhythmia causing hemodynamic instability and expected to survive for > 1 year with good functional status, in the absence of reversible causes or unless the ventricular arrhythmia has occurred < 48 hours after a myocardial infarction. A Show 6 more As per AHA 2018 guidelines: https://web.pathway.md/diseases/rectslm30dGoeF3RH 18/28 6/24/23, 12:32 PM Heart failure Pathway Consider performing placement of an ICD in patients with ventricular arrhythmias and HF with reduced ejection fraction awaiting heart transplantation and otherwise not qualifying for an ICD (such as NYHA class IV and/or use of inotropes) with a plan to discharge home. C Consider performing placement of an ICD in patients with a LV assist device and sustained ventricular arrhythmia. C Mechanical circulatory support: As per ACC 2022 guidelines, initiate mechanical circulatory support in carefully selected patients with stage D HF and reduced LV ejection fraction if definitive management is planned or cardiac recovery is anticipated. B As per JCS 2022 guidelines, consider performing placement of an implantable LV assist device to improve prognosis and quality of life in patients with stage D HF with reduced ejection fraction ineligible for heart transplantation. C As per ESC 2021 guidelines, ensure that patients eligible for long-term mechanical circulatory support have good compliance, appropriate capacity for device handling, and psychosocial support. B Show 2 more Percutaneous coronary intervention: As per ESC 2021 guidelines, consider performing coronary revascularization to relieve persistent symptoms of angina (or an angina-equivalent) in patients with HF with reduced ejection fraction, chronic coronary syndrome and coronary anatomy suitable for revascularization, despite optimal medical therapy including anti-anginal drugs. C Show 2 more As per ACC 2017 guidelines: Perform coronary artery revascularization via CABG surgery or percutaneous intervention in patients with HF and angina despite medical therapy with a suitable coronary anatomy, especially for a left main stenosis (> 50%) or left main equivalent disease. B Consider performing coronary artery revascularization in patients with coronary artery disease if symptoms (angina) or demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite guideline-directed medical therapy. C Renal replacement therapy: As per ESC 2021 guidelines: Consider performing RRT in patients with refractory volume overload and end-stage kidney failure. C Consider performing ultrafiltration in patients with refractory volume overload unresponsive to diuretic treatment. C As per ACC 2017 guidelines: Consider performing ultrafiltration in patients with obvious volume overload to alleviate congestive symptoms and restore fluid balance. C Consider performing ultrafiltration in patients with refractory congestion not responding to medical therapy. C https://web.pathway.md/diseases/rectslm30dGoeF3RH 19/28 6/24/23, 12:32 PM Heart failure Pathway 9. Surgical interventions Coronary artery bypass graft: As per ACC 2022 guidelines, consider performing surgical revascularization in conjunction with guideline-directed medical therapy to improve symptoms, cardiovascular hospitalizations and long-term all-cause mortality in selected patients with HF, reduced ejection fraction ( 35%) and suitable coronary anatomy. B As per ESC 2021 guidelines, consider performing CABG as the first-choice revascularization strategy in patients suitable for surgery. especially in patients with diabetes and multivessel disease. C Show 3 more LV aneurysmectomy: consider performing LV reconstructive surgery or LV aneurysmectomy in carefully selected patients with HF with reduced ejection fraction for specific indications, including intractable HF and ventricular arrhythmias. C Aortic valve surgery: As per ESC 2021 guidelines: Perform aortic valve intervention, TAVI or SAVR, to reduce mortality and improve symptoms in patients with HF and severe high gradient aortic stenosis. B Choose between TAVI and SAVR by the heart team according to individual patient preference and features, including age, surgical risk, clinical, anatomical and procedural aspects, weighing the risks and benefits of each approach. B As per AHA 2017 guidelines: Consider performing SAVR in patients with critical aortic stenosis and a predicted surgical mortality of 10%. C Consider performing TAVR after careful candidate consideration in patients with critical aortic stenosis deemed inoperable. C Mitral valve surgery: As per ESC 2021 guidelines, consider performing percutaneous edge-to-edge mitral valve repair in carefully selected patients with secondary MR ineligible for surgery, not requiring coronary revascularization, being symptomatic despite optimal medical therapy, and fulfilling criteria for reducing HF hospitalizations. C Show 2 more As per AHA 2017 guidelines, consider performing transcatheter mitral valve repair or mitral valve surgery for functional mitral insufficiency only after careful candidate selection and with a background of guideline-directed medical therapy. C Heart transplantation: As per ACC 2022 guidelines: Offer cardiac transplantation to improve survival and quality of life in selected patients with advanced HF despite guideline-directed medical therapy. B https://web.pathway.md/diseases/rectslm30dGoeF3RH 20/28 6/24/23, 12:32 PM Heart failure Pathway Recognize that cardiac transplantation provides intermediate economic value in patients with advanced (stage D) HF despite guideline-directed medical therapy. B As per ESC 2021 guidelines, offer heart transplantation in patients with advanced HF refractory to medical/device therapy and not having absolute contraindications. B 10. Specific circumstances Pregnant patients: provide patient-centered counseling regarding contraception and the risks of cardiovascular deterioration during pregnancy in patients with a history of HF or cardiomyopathy including previous peripartum cardiomyopathy. B Show 2 more Patients with cardiac amyloidosis (evaluation): screen for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and sFLC in patients with a clinical suspicion for cardiac amyloidosis. B Show 2 more Patients with cardiac amyloidosis, management: As per HFSA/ACC/AHA 2022 guidelines, initiate transthyretin tetramer stabilizer therapy (tafamidis) to reduce cardiovascular morbidity and mortality in selected patients with wild-type or variant transthyretin cardiac amyloidosis and NYHA class I-III HF symptoms. B Show 2 more Landmark trials: ATTR-ACT In patients with transthyretin amyloid cardiomyopathy, tafamidis, as compared to placebo, reduced all-cause mortality (29.5% vs. 42.9%; HR 0.70, 95% CI 0.51-0.96) and reduced the rate of cardiovascular-related hospitalizations (0.48 per year vs. 0.70 per year; RR 0.68, 95% CI 0.56-0.81). Tafamidis also reduced the decline in distance for the 6 minute walk test (p < 0.001) and reduced the rate of decline in KCCQ-OS score (p < 0.001). The incidence and types of adverse events were similar in the two groups. Maurer MS et al. N Engl J Med. 2018 Sep 13. As per ESC 2021 guidelines: Initiate tafamidis to reduce symptoms, cardiovascular hospitalization and mortality in patients with genetic testing proven hereditary transthyretin cardiac amyloidosis and NYHA class I or II symptoms. B Initiate tafamidis to reduce symptoms, cardiovascular hospitalization and mortality in patients with wild-type transthyretin cardiac amyloidosis and NYHA class I or II symptoms. B Patients with cancer therapy-related HF: As per ACC 2022 guidelines, consider obtaining pre-therapy evaluation of cardiac function to establish baseline cardiac function and guide the choice of cancer therapy in patients with https://web.pathway.md/diseases/rectslm30dGoeF3RH 21/28 6/24/23, 12:32 PM Heart failure Pathway cardiovascular risk factors or known cardiac disease being considered for potentially cardiotoxic anticancer therapies. C Show 5 more As per ESC 2021 guidelines, obtain cardiovascular evaluation in patients with cancer at increased risk for cardiotoxicity defined by a history or risk factors of CVD, previous cardiotoxicity or exposure to cardiotoxic agents before scheduled anticancer therapy, preferably by a cardiologist with experience/interest in cardio-oncology. B Show 2 more Patients with pulmonary hypertension: consider obtaining additional testing with exercise or fluid challenge to uncover post-capillary pulmonary hypertension in patients with pulmonary hypertension at right heart catheterization, a borderline pulmonary arterial wedge pressure (13-15 mmHg), and features of HFpEF. C Show 3 more 11. Patient education General counseling: As per AHA 2022 guidelines, provide specific education and support to facilitate self-care in a multidisciplinary manner in patients with HF. B As per JCS 2022 guidelines, encourage and educate patients to measure their BP at home and to record it as a daily self-management goal. B Genetic counseling: Consider referring selected patients with non-ischemic cardiomyopathy for genetic counseling and testing to identify conditions likely to guide treatment in patients and family members. C Offer genetic screening and counseling in first-degree relatives of selected patients with genetic or inherited cardiomyopathies to detect cardiac disease and prompt consideration of treatments to decrease HF progression and sudden death. B 12. Preventative measures Primary prevention: As per ACC 2022 guidelines, advise following a healthy lifestyle habits to reduce future risk of HF in general population, including: regular physical activity maintaining normal weight healthy dietary patterns avoiding smoking. B Show 3 more Landmark trials: STOP-HF https://web.pathway.md/diseases/rectslm30dGoeF3RH 22/28 6/24/23, 12:32 PM Heart failure Pathway In patients with cardiovascular risk factors, screening with BNP was superior to no routine BNP screening with respect to LV dysfunction with or without HF. Ledwidge M et al. JAMA. 2013 Jul 3. As per ESC 2021 guidelines, counsel patients against sedentary habit, obesity, cigarette smoking and alcohol abuse to prevent or delay the onset of HF. B Show 4 more Immunizations: As per ACC 2022 guidelines, consider offering vaccination against respiratory illnesses to reduce mortality in patients with HF. C As per ESC 2021 guidelines, consider offering influenza and pneumococcal vaccinations in patients with HF to prevent HF hospitalizations. C 13. Follow-up and surveillance Telemonitoring: consider offering noninvasive home telemonitoring to reduce the risk of recurrent cardiovascular and HF hospitalizations and cardiovascular death in patients with HF. C Wireless implantable hemodynamic monitoring: As per ACC 2022 guidelines: Insufficient evidence regarding the usefulness of wireless monitoring of pulmonary artery pressure by an implanted hemodynamic monitor to reduce the risk of subsequent HF hospitalizations in selected adult patients with NYHA class III HF and history of a HF hospitalization in the past year or elevated natriuretic peptide levels on maximally tolerated stable doses of guideline-directed medical therapy with optimal device therapy. I Insufficient evidence regarding the usefulness of wireless monitoring of the pulmonary artery pressure by an implanted hemodynamic monitor in patients with NYHA class III HF with a HF hospitalization within the previous year. I As per ESC 2021 guidelines, consider performing placement of a wireless hemodynamic monitoring system for pulmonary artery pressure monitoring to improve clinical outcomes in symptomatic patients with HF. C Discharge from hospital: As per ACEP 2022 guidelines, do not rely on current acute HF syndrome risk stratification tools alone to determine which patients may be discharged directly home from the emergency department. D Show 3 more As per ACC 2022 guidelines, provide patient-centered discharge instructions with a clear plan for transitional care before hospital discharge in patients hospitalized with worsening HF. B As per ESC 2021 guidelines: https://web.pathway.md/diseases/rectslm30dGoeF3RH 23/28 6/24/23, 12:32 PM Heart failure Pathway Obtain careful evaluation in patients hospitalized for HF to exclude persistent signs of congestion before discharge and to optimize oral treatment. B Initiate evidence-based oral medical treatment before discharge. B Follow-up after hospital discharge: As per ACC 2022 guidelines, consider obtaining an early follow-up, generally within 7 days of hospital discharge, to optimize care and reduce re-hospitalization in patients discharged after hospitalization for worsening HF. C As per ESC 2021 guidelines, obtain an early follow-up at 12 weeks after discharge to assess signs of congestion, drug tolerance and start and/or uptitrate evidence-based therapy. B Palliative care: provide palliative and supportive care, including high-quality communication, conveyance of prognosis, clarifying goals of care, shared decision-making, symptom management and caregiver support, to improve quality of life and relieve suffering in all patients with HF. B Show 4 more 14. Quality improvement Performance measures: Use performance measures based on professionally developed clinical practice guidelines with the goal of improving quality of care in patients with HF. B Consider participating in quality improvement programs, including patient registries providing benchmark feedback on nationally endorsed, clinical practice guideline-based quality and performance measures in improving the quality of care for patients with HF. C Likelihood Ratios Pertinent positives The following findings increase the probability of heart failure in adults. 1 1 1 1 1 Finding LR+ Value History of exertional dyspnea 5 Presence of abdominojugular reflux 4.4 (1.8-10) Presence of myocardial infarction 4.3 Presence of third heart sound 4 history of myocardial infarction, previous diagnosis of heart failure, orthopnea or paroxysmal nocturnal dyspnea, Q-wave or intraventricular conduction delay, or a chest radiograph abnormality (cardiomegaly, pulmonary venous hypertension, or edema) Show 10 more Pertinent negatives The following findings decrease the probability of heart failure in adults. 1 1 1 1 1 https://web.pathway.md/diseases/rectslm30dGoeF3RH 24/28 6/24/23, 12:32 PM Heart failure Pathway Finding LR- Value Absence of any abnormal finding on ECG 0.03 (0.01-0.10) Absence of BNP 37 pg/mL and no clinical finding of HF 0.04 (0.01-0.30) blood B-type natriuretic peptide not increased 0.1 Absence of BNP > 37 pg/mL and no clinical finding of HF* 0.23 (0.06-0.92) history of myocardial infarction, previous diagnosis of heart failure, orthopnea or paroxysmal nocturnal dyspnea, Q-wave or intraventricular conduction delay, or a chest radiograph abnormality (cardiomegaly, pulmonary venous hypertension, or edema) Show 10 more References 1. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jan 29;61 4):e78 140. Open 2. Theresa A McDonagh, Marco Metra, Marianna Adamo et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42 36 3599 3726. Open 3. W Timothy Garvey, Jeffrey I Mechanick, Elise M Brett et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3 1 203. Open 4. Paul A Heidenreich, Biykem Bozkurt, David Aguilar et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Apr 1;101161CIR0000000000001063. Open 5. Katja Zeppenfeld, Jacob Tfelt-Hansen, Marta de Riva et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022 Aug 26;ehac262. Open 6. Minoru Ono, Osamu Yamaguchi, Tomohito Ohtani et al. JCS/JSCVS/JATS/JSVS 2021 Guideline on Implantable Left Ventricular Assist Device for Patients With Advanced Heart Failure. Circ J. 2022 May 25;86 6 1024 1058. Open 7. Sana M Al-Khatib, William G Stevenson, Michael J Ackerman et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2018 Sep 25;138 13):e272-e391. Open 8. Nishimura RA, Otto CM, Bonow RO et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017 Jun 20;135 25):e1159-e1195. Open https://web.pathway.md/diseases/rectslm30dGoeF3RH 25/28 6/24/23, 12:32 PM Heart failure Pathway 9. Marc Humbert, Gabor Kovacs, Marius M Hoeper et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43 38 3618 3731. Open 10. Paul K Whelton, Robert M Carey, Wilbert S Aronow 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: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71 6):e13-e115. Open 11. American College of Emergency Physicians Clinical Policies Subcommittee Writing Committee) on Acute Heart Failure Syndromes. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Acute Heart Failure Syndromes: Approved by ACEP Board of Directors, June 23, 2022. Ann Emerg Med. 2022 Oct;80 4):e31-e59. Open 12. G B John Mancini, Eileen O'Meara, Shelley Zieroth et al. 2022 Canadian Cardiovascular Society Guideline for Use of GLP 1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults. Can J Cardiol. 2022 Aug;38 8 1153 1167. Open 13. Ziaeian B, Fonarow GC, . Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016 Jun;13 6 368 78. Open 14. Komanduri S, Jadhao Y, Guduru SS et al. Prevalence and risk factors of heart failure in the USA NHANES 2013 2014 epidemiological follow-up study. J Community Hosp Intern Med Perspect. 2017 Mar 31;7 1 15 20. Open 15. Metra M, Teerlink JR. Heart failure. Lancet. 2017 Oct 28;390 10106 1981 1995. Open 16. Konstam MA, Kiernan MS, Bernstein D et al. Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2018 May 15;137 20):e578-e622. Open 17. 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. Circulation. 2017 Aug 8;136 6):e137-e161. Open 18. Anker SD, Comin Colet J, Filippatos G et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009 Dec 17;361 25 2436 48. Open 19. Yancy CW, Januzzi JL Jr, Allen LA et al. 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018 Jan 16;71 2 201 230. Open 20. Bozkurt B, . What Is New in Heart Failure Management in 2017? Update on ACC/AHA Heart Failure Guidelines. Curr Cardiol Rep. 2018 Apr 17;20 6 39. Open 21. Atherton JJ, Sindone A, De Pasquale CG et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of heart failure 2018. Med J Aust. 2018 Oct 15;209 8 363 369. Open 22. Simone Frea, Stefano Pidello, Alessandra Volpe et al. Diuretic treatment in high-risk acute decompensation of advanced chronic heart failure-bolus intermittent vs. continuous infusion of furosemide: a randomized controlled trial. Clin Res Cardiol. 2020 Apr;109 4 417 425. Open https://web.pathway.md/diseases/rectslm30dGoeF3RH 26/28 6/24/23, 12:32 PM Heart failure Pathway 23. Eileen O'Meara, Michael McDonald, Michael Chan et al. CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis. Can J Cardiol. 2020 Feb;36 2 159 169. Open 24. Ali Ahmed. American College of Cardiology/American Heart Association Chronic Heart Failure Evaluation and Management guidelines: relevance to the geriatric practice. J Am Geriatr Soc. 2003 Jan;51 1 123 6. Open 25. John J V McMurray, Scott D Solomon, Silvio E Inzucchi et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381 21 1995 2008. Open 26. Charlene Bredy, Margherita Ministeri, Alexander Kempny et al. New York Heart Association NYHA classification in adults with congenital heart disease: relation to objective measures of exercise and outcome. Eur Heart J Qual Care Clin Outcomes. 2018 Jan 1;4 1 51 58. Open 27. Ian G Stiell, Jeffrey J Perry, Catherine M Clement et al. Prospective and Explicit Clinical Validation of the Ottawa Heart Failure Risk Scale, With and Without Use of Quantitative NT-proBNP. Acad Emerg Med. 2017 Mar;24 3 316 327. Open 28. L Goldman, B Hashimoto, E F Cook et al. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981 Dec;64 6 1227 34. Open 29. Stefan D Anker, Javed Butler, Gerasimos Filippatos et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385 16 1451 1461. Open 30. Barry M Massie, Peter E Carson, John J McMurray et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Dec 4;359 23 2456 67. Open 31. Justin A Ezekowitz, Eloisa Colin-Ramirez, Heather Ross et al. Reduction of dietary sodium to less than 100 mmol in heart failure SODIUM HF an international, open-label, randomised, controlled trial. Lancet. 2022 Apr 9;399 10333 1391 1400. Open 32. Justin A Ezekowitz, Eileen O'Meara, Michael A McDonald et al. 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. Can J Cardiol. 2017 Nov;33 11 1342 1433. Open 33. Milton Packer, Stefan D Anker, Javed Butler et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383 15 1413 1424. Open 34. Adriaan A Voors, Christiane E Angermann, John R Teerlink et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022 Mar;28 3 568 574. Open 35. Scott D Solomon, John J V McMurray, Brian Claggett et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387 12 1089 1098. Open 36. Alexandre Mebazaa, Beth Davison, Ovidiu Chioncel et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure STRONG HF a multinational, open-label, randomised, trial. Lancet. 2022 Dec 3;400 10367 1938 1952. Open 37. Frederik H Verbrugge, Venu Menon. Torsemide comparison with furosemide for management of heart failure TRANSFORM HF trial. Eur Heart J Acute Cardiovasc Care. 2022 Dec 27;11 12 931 932. Open https://web.pathway.md/diseases/rectslm30dGoeF3RH 27/28 6/24/23, 12:32 PM Heart failure Pathway 38. Julio N ez, Pau Ll cer, Vicente Bertomeu-Gonz lez et al. Carbohydrate Antigen-125 Guided Therapy in Acute Heart Failure: CHANCE HF A Randomized Study. JACC Heart Fail. 2016 Nov;4 11 833 843. Open https://web.pathway.md/diseases/rectslm30dGoeF3RH 28/28

Guideline sources The following summarized guidelines for the evaluation and management of heat-related illness are prepared by our editorial team based on guidelines from the Wilderness Medical Society (WMS 2019). 1 Guidelines 1. Classification and risk stratification Risk assessment: use the wet-bulb globe temperature index for the assessment of heat risk. A Show 2 more 2. Diagnostic investigations Temperature measurement: Prefer rectal temperature measurement, when available, as the most accurate measurement of core hyperthermia compared to axillary, oral, or aural thermometry. B Do not delay empiric cooling for heat stroke by a measurement value that may be below the diagnostic threshold of 40 C in hyperthermic patients with an altered sensorium. D Screening for comorbidities: screen for significant preexisting medical conditions. B https://web.pathway.md/diseases/recbZqB6WmRb8jeJF 1/3 6/24/23, 12:31 PM Heat-related illness Pathway g p g g Cardiac evaluation: obtain cardiac evaluation in patients with recurrent episodes of heat syncope inconsistent with exercise-associated collapse or other clear explanation. B 3. Medical management Goals of cooling: cool patients with heat stroke to a target temperature of no less than 39 C. B Rehydration: Minimize dehydration in patients with heat illness. B Administer IV fluids for rehydration in patients with exertional heat stroke. B Intravenous cold fluids: Administer cold IV fluids as an adjunctive cooling method in patients with heat stroke. B Do not use intravascular cooling catheters or cold water lavage for primary treatment od patients with heat stroke. D Antipyretics: avoid using antipyretics in patients with heat illness. D Dantrolene: do not use dantrolene for the treatment of heat stroke. D 4. Nonpharmacologic interventions Passive cooling: offer passive cooling measures to minimize thermal strain and maximize heat loss. B Immersive cooling: offer cold water immersion as the optimal cooling method in the field management of patients with heat stroke. A Show 2 more Evaporative cooling: Consider offering evaporative or convective cooling as an adjunct cooling method in the field treatment if cold water immersion is unavailable. B Consider offering evaporative and convective cooling in classic heat stroke in the hospital setting. Do not use evaporative and convective cooling for exertional heat stroke, unless effective conductive cooling is not available. B Ice packs: apply ice packs to cover the entire body. Apply chemical cold packs, if used, to the cheeks, palms, and soles rather than the skin covering the major vessels. B 5. Preventative measures Acclimatization: advise allowing for acclimatization with 1-2 hours/day of heat-exposed exertion for at least 8 days. B Clothing: advise assessing and modifying clothing and equipment for a given activity as needed to optimize evaporative, convective, conductive, and radiative heat exchange or isolation, taking https://web.pathway.md/diseases/recbZqB6WmRb8jeJF 2/3 6/24/23, 12:31 PM Heat-related illness Pathway into account the mechanisms of heat accumulation or dissipation dominating during the activity. B Hydration: Ensure adequate hydration before activity. B Ensure ongoing rehydration with a "drink to thirst" approach sufficient to prevent > 2% loss of body weight. B Aerobic exercise: promote regular aerobic activity before heat exposure. B Avoidance of drugs affecting thermoregulation: advise minimizing the use of medications likely to affect the thermoregulatory response. B References 1. Grant S Lipman, Flavio G Gaudio, Kurt P Eifling et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Heat Illness: 2019 Update. Wilderness Environ Med. 2019 Dec;30 4S S33 S46. Open 2. Lipman GS, Eifling KP, Ellis MA et al. Wilderness Medical Society Practice Guidelines for the Prevention and Treatment of Heat Illness. Wilderness Environ Med. 2014 Dec;25 4 Suppl):S55 65. Open https://web.pathway.md/diseases/recbZqB6WmRb8jeJF 3/3

Guideline sources The following summarized guidelines for the evaluation and management of Helicobacter pylori infection are prepared by our editorial team based on guidelines from the Italian Society of Digestive Endoscopy (SIDE/SIGE 2022), the American Gastroenterological Association (AGA 2021; 2020), the World Society of Emergency Surgery (WSES 2020), the American Society for Clinical Pathology (ASCP 2019), the European Society for the Study of Coeliac Disease (ESsCD 2019), the American College of Gastroenterology (ACG/CAG 2017), the Maastricht V/Florence Consensus Report (Maastricht V/Florence 2017), the American College of Gastroenterology (ACG 2017; 2013; 2007), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN/NASPGHAN 2017), the Canadian Association of Gastroenterologists (CAG 2016), and the American Society for Gastrointestinal Endoscopy (ASGE 2010). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 18 19 Definition https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 1/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway H. pylori is a Gram-negative bacterium that causes chronic infection and inflammation of the stomach and duodenum. 16 Epidemiology H. pylori infection is transmitted via the fecal-oral and oral-oral routes; horizontal transmission, and environmental transmission through contaminated water also occurs. 18 Pathophysiology The overall prevalence of H. pylori infection is estimated at 30.7% in the United States. However, the distribution is heterogeneous with a higher prevalence in immigrants from high-risk areas (Latin America, Asia). 17 Disease course H. pylori infection is associated with an increased risk of various gastrointestinal diseases including functional dyspepsia, gastritis, peptic ulcer disease, gastric intestinal metaplasia, and gastric cancer. 18 Prognosis and risk of recurrence Although successful eradication of H. pylori infection prevents the development and progression of H. pylori-associated diseases, the efficacy of treatment regimens has decreased due to increased antibiotic resistance. Globally, the annual recurrence, reinfection, and recrudescence rate of H. pylori is 4.3%, 3.1%, and 2.2%, respectively. 19 Guidelines 1. Screening and diagnosis Epidemiology: As per ACG 2017 guidelines: Recognize that H. pylori is a chronic condition and is usually acquired in childhood. B Recognize that the incidence and prevalence of H. pylori infection are generally higher among people born outside North America. Recognize that the prevalence of the infection within North America is higher in certain racial and ethnic groups, the socially disadvantaged, and people who have immigrated to North America. B Recognize that H. pylori resistance rates to antibiotics are increasing in most parts of the world. B Differential diagnosis: exclude H. pylori gastritis before making a reliable diagnosis of functional dyspepsia. A Indications for testing, dyspepsia: https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 2/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway As per SIDE/SIGE 2022 guidelines, test for and eradicate H. pylori infection in < 50 years old patients with uninvestigated dyspepsia without alarm symptoms. B As per ACG 2017 guidelines, consider testing for H. pylori infection (with noninvasive methods) in < 60 years old patients with uninvestigated dyspepsia in the absence of alarm features. B As per CAG/ACG 2017 guidelines, test for (with noninvasive methods) and eradicate H. pylori infection in < 60 years old patients with dyspepsia. A Indications for testing, PUD: As per SIDE/SIGE 2022 guidelines, test for and eradicate H. pylori infection in patients taking NSAIDs or aspirin with a history of peptic ulcer. Initial eradication ideally before starting NSAIDs or aspirin therapy to prevent complicated and uncomplicated peptic ulcers. B As per WSES 2020 guidelines, test for H. pylori infection in all patients with bleeding peptic ulcer. B As per ACG 2017 guidelines, test for H. pylori infection in all patients with active peptic ulcer disease, or a past history of peptic ulcer disease (unless the previous cure of H. pylori infection has been documented). A Test for H. pylori infection in aspirin and NSAID users with a history of peptic ulcer. B As per ASGE 2010 guidelines, test for H. pylori infection in all patients with peptic ulcer disease because it is a common etiology. B Indications for testing (NSAID use): Test for and eradicate H. pylori infection in patients initiating chronic treatment with an NSAID. B Consider testing for and eradicating H. pylori infection in patients taking long-term low-dose aspirin, to reduce the risk of ulcer bleeding. C Indications for testing (lymphocytic gastritis): insufficient evidence to recommend routine testing and treatment for H. pylori infection in patients with lymphocytic gastritis. I Indications for testing, GERD: As per SIDE/SIGE 2022 guidelines, eradicate H. pylori infection in patients with GERD on PPI therapy. B As per ACG 2017 guidelines, do not test for H. pylori infection in patients with typical symptoms of GERD without a history of peptic ulcer disease. Treat if tested and found to be positive. D As per ACG 2013 guidelines, do not test for H. pylori infection in patients with GERD. Do not offer eradication therapy routinely as part of antireflux therapy. D Indications for testing, neoplasia: As per AGA 2020 guidelines, test for and eradicate H. pylori infection in patients with gastric intestinal metaplasia. B As per ACG 2017 guidelines, test for H. pylori infection in all patients with low-grade gastric MALT lymphoma, or a history of endoscopic resection of early gastric cancer. B Show 2 more https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 3/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway Indications for testing (celiac disease): recognize that H. pylori infection is frequently associated with Marsh 1 intestinal histology and its eradication may lead to normalization of duodenal intraepithelial lymphocyte count. Consider testing for H. pylori infection (with serology or concomitant gastric biopsies) in patients with celiac disease and suspected concomitant H. pylori infection. A Indications for testing (hyperemesis gravidarum): insufficient evidence to recommend routine testing and treatment for H. pylori infection in patients with hyperemesis gravidarum. I Indications for testing, hematological conditions: As per SIDE/SIGE 2022 guidelines, test for and eradicate H. pylori infection in patients with iron, vitamin B12 deficiency anemia, or idiopathic thrombocytopenia. B As per AGA 2020 guidelines, consider testing (with noninvasive methods) for and eradicating H. pylori infection in patients with iron deficiency anemia without other identifiable etiology after upper and lower gastrointestinal endoscopy. C As per ACG 2017 guidelines, test for and eradicate H. pylori infection in patients with unexplained iron deficiency anemia despite an appropriate evaluation, B and in adult patients with immune thrombocytopenia. B Test for and eradicate H. pylori in patients with unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura, and vitamin B12 deficiency. B 2. Diagnostic investigations Choice of diagnostic test: As per SIGE 2022 guidelines, obtain urea breath test or monoclonal ELISA stool antigen test for noninvasive diagnosis of H. pylori infection, both in pre- and post-therapy settings. A Show 2 more As per ASCP 2019 guidelines: Obtain fecal antigen test or urea breath test for the diagnosis of H. pylori infection. B Do not obtain H. pylori serology for the diagnosis of H. pylori infection. D Obtain urea breath test as the first-line noninvasive test in the context of a "test-and-treat strategy". Consider obtaining stool antigen testing as the next option. B Show 3 more As per ACG 2007 guidelines, decide on the choice of the test based on whether the patient requires evaluation with upper endoscopy and an understanding of the strengths, weaknesses, and costs of the individual tests. Show 5 more Culture and sensitivity: As per SIGE 2022 guidelines, consider obtaining culture testing only after multiple treatment failures to choose the most appropriate therapy. C https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 4/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway As per AGA 2021 guidelines, consider obtaining H. pylori susceptibility testing to guide the selection of subsequent regimens after two failed therapies with confirmed patient adherence. C Obtain clarithromycin susceptibility testing (either by a standard antibiogram after culture or by a molecular test directly on the gastric biopsy specimen) when a standard clarithromycin-based regimen is considered as the first-line therapy, except in populations or regions with well- documented low clarithromycin resistance (< 15%). B Obtain culture and standard antimicrobial susceptibility testing after a first failure if endoscopy is performed to tailor the treatment, except if a bismuth-based quadruple therapy is considered. B 3. Diagnostic procedures Biopsy: As per SIGE 2022 guidelines, perform histological examination for the diagnosis of H. pylori infection, both in pre- and post-eradication settings, if there is an indication to perform upper gastrointestinal endoscopy with gastric biopsies. Obtain immunohistochemical analysis only in rare cases, such as when chronic/atrophic gastritis is present. B Take two biopsies from the antrum (greater and lesser curvature 3 cm proximal to the pyloric region) and two biopsies from the middle of the body as a minimum standard for the assessment of H. pylori gastritis. Consider taking an additional biopsy from the incisura for the detection of precancerous lesions. B Show 2 more 4. Medical management General principles: As per ACG 2017 guidelines: Recognize that the main determinants of successful H. pylori eradication are the choice of regimen, the patient's adherence to a multi-drug regimen with frequent side effects, and the sensitivity of the H. pylori strain to the combination of antibiotics administered. B Elicit a history of any previous antibiotic exposure and take this information into consideration when choosing a treatment regimen for H. pylori. B Consider employing a test-and-treat strategy for uninvestigated dyspepsia taking into account the regional H. pylori prevalence and cost-benefit considerations. Do not use this strategy in patients with alarm symptoms or older patients. B Show 4 more As per CAG 2016 guidelines, take into account the local antibiotic resistance patterns when deciding on first-line antibiotic therapy in patients with H. pylori infection. B First-line regimens: https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 5/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway As per SIGE 2022 guidelines, administer bismuth-based quadruple therapy, concomitant therapy, or sequential therapy as first-line therapy in patients with H. pylori infection. Consider administering a 14-day standard triple therapy only in areas with proven low clarithromycin resistance (< 15%). B As per ACG 2017 guidelines, administer clarithromycin triple therapy (PPI, clarithromycin, and amoxicillin/metronidazole) for 14 days as first-line therapy in patients with no previous history of macrolide exposure for any reason in regions with a low (< 15%) clarithromycin resistance. B Show 3 more Administer a clarithromycin-based triple regimen for 14 days B as first-line empirical therapy in areas with low clarithromycin resistance. Administer bismuth-containing quadruple therapy as an alternative. A Show 4 more As per CAG 2016 guidelines, administer any of the following regimens for 14 days as first-line therapy in patients with H. pylori infection: Situation Guidance PPI, amoxicillin, and clarithromycin B Clarithromycin triple therapy PPI, bismuth, metronidazole, and tetracycline B Traditional bismuth quadruple therapy PPI, amoxicillin, metronidazole, and clarithromycin B Non-bismuth quadruple therapy Show 2 more Management of treatment failure, evaluation: As per SIDE/SIGE 2022 guidelines, obtain upper gastrointestinal endoscopy followed by culture and antimicrobial susceptibility testing to tailor treatment in case of third-line therapy failure. B As per AGA 2021 guidelines, recognize that the usual cause of refractory H. pylori infection (persistent infection after attempting eradication therapy) is antibiotic resistance. Conduct a thorough review of prior antibiotic exposures. B Show 3 more Obtain culture and standard antimicrobial susceptibility testing after a first failure if endoscopy is performed to tailor the treatment, except if a bismuth-based quadruple therapy is considered. B Obtain culture with susceptibility testing or molecular determination of genotype resistance to guide treatment after failure of second-line therapy. B Management of treatment failure (decision to treat): ensure shared decision-making regarding ongoing attempts to eradicate H. pylori in some cases. Weight the potential benefits of H. pylori eradication 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. B https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 6/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway Management of treatment failure, choice of regimen: As per SIDE/SIGE 2022 guidelines, administer a levofloxacin-containing regimen as second-line therapy when first-line therapy with single-capsule bismuth quadruple regimen failed, particularly in patients previously exposed to clarithromycin or in a geographical area of known high dual resistance. Asminisrer single-capsule bismuth quadruple therapy as second-line therapy if a clarithromycin-containing regimen was used as the first-line therapy. B Show 2 more As per AGA 2021 guidelines, avoid using clarithromycin- or levofloxacin-based regimens if there is a history of any treatment with macrolides or fluoroquinolones, respectively, given the high likelihood of resistance. D Show 6 more As per ACG 2017 guidelines, avoid using antibiotics previously used by the patient in cases of persistent H. pylori infection. D Show 6 more Administer a bismuth-containing quadruple therapy or a fluoroquinolone-containing triple or quadruple therapy as second-line therapy after failure of clarithromycin triple therapy (PPI, amoxicillin, and clarithromycin). B Show 5 more As per CAG 2016 guidelines, administer bismuth quadruple therapy (consisting of a PPI, bismuth, metronidazole, and tetracycline for 14 days) as an option for subsequent therapy in patients failed to respond to clarithromycin-containing H. pylori eradication therapy. B Show 5 more Management of treatment failure (adjunctive therapies): do not offer adjunctive therapies, including probiotics, for the treatment of refractory H. pylori infection. D 5. Nonpharmacologic interventions Probiotics: As per SIGE 2022 guidelines, consider offering probiotics in addition to eradication therapy to reduce the rate of side effects associated with the eradication therapy. C As per CAG 2016 guidelines, do not offer probiotics in addition to eradication therapy for the purpose of increasing eradication rates or reducing adverse events in patients with H. pylori infection. D 6. Specific circumstances Patients with penicillin allergy: As per AGA 2021 guidelines, consider obtaining penicillin allergy testing in patients labeled as having this allergy, in the absence of a history of anaphylaxis, in order to delist penicillin as an allergy and potentially enable its use. C https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 7/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway As per ACG 2017 guidelines, recognize that most patients with a history of penicillin allergy do not have true penicillin hypersensitivity. Consider obtaining penicillin allergy testing after failing the first-line therapy, since the vast majority can ultimately be safely given amoxicillin-containing salvage regimens. B Consider administering clarithromycin triple therapy (PPI, metronidazole, and clarithromycin) as first-line therapy in patients with penicillin allergy in areas of low clarithromycin resistance. Prefer bismuth quadruple therapy in areas of high clarithromycin resistance. C Consider administering a fluoroquinolone-containing regimen as an empirical second-line rescue option in patients with penicillin allergy. C Pediatric patients (diagnosis): diagnose H. pylori infection based on either positive culture or H. pylori gastritis on histopathology with at least 1 other positive biopsy-based test. A Pediatric patients (testing): determine the underlying cause of the symptoms and not solely the presence of H. pylori infection as the primary goal of clinical investigation of gastrointestinal symptoms. Show 9 more Pediatric patients (management): consider offering treatment after careful discussion with the patient/parents if H. pylori infection is an incidental finding at endoscopy. C Pediatric patients (counseling): explain to the family of pediatric patients with H. pylori infection the importance of adherence to the anti-H. pylori therapy to enhance successful eradication. B Pediatric patients (follow-up): Evaluate the effectiveness of first-line therapy in national/regional centers. B Assess the outcome of anti-H. pylori therapy at least 4 weeks after completion of therapy B with any of the following tests: 13C-urea breath test 2-step monoclonal stool H. pylori antigen test. A Pediatric patients (treatment failure): individualize the rescue therapy by taking into account antibiotic susceptibility data, the age of the patient, and available antimicrobial options when H. pylori treatment fails. B 7. Patient education General counseling: recognize that eradication regimens for H. pylori are complex and might not be fully comprehended by patients. B Show 2 more 8. Follow-up and surveillance Post-eradication testing: https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 8/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway As per SIGE 2022 guidelines, obtain urea breath test or monoclonal ELISA stool antigen test in the post-therapy setting. A Show 2 more As per ACG 2017 guidelines, obtain urea breath test, fecal antigen test, or biopsy-based testing B to prove eradication in all patients at least 4 weeks after the completion of antibiotic therapy and after interruption of PPI for 2 weeks. B Obtain urea breath test, or monoclonal stool antigen test as an alternative, for confirmation of H. pylori eradication at least 4 weeks after completion of therapy. A Do not obtain a rapid urease test for the assessment of H. pylori eradication after treatment. D 9. Quality improvement Local susceptibility assessment: As per AGA 2021 guidelines, compile 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). Make aggregated data publicly available to guide the local selection of H. pylori eradication therapy. B As per ACG 2017 guidelines, attempt to document local, regional, and national patterns of resistance in order to guide the appropriate selection of H. pylori therapy. B Recognize that susceptibility-based results simultaneously provide results both for the individual patient and the population. B Likelihood Ratios Pertinent positives The following findings increase the probability of Helicobacter pylori infection in adults. -1 Finding LR+ Value Positive urea breath test 11.6 Positive rapid urease testing 9.6 Presence of H. pylori 7 Positive stool H. pylori antigen 2.9 does not differentiate between current and prior infection Show 1 more Pertinent negatives The following findings decrease the probability of Helicobacter pylori infection in adults. -1 Finding LR- Value Negative urea breath test 0.1 Negative serum anti-H. pylori antibodies* 0.2 https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 9/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway Negative stool H. pylori antigen 0.2 Absence of H. pylori 0.3 does not differentiate between current and prior infection Show 1 more References 1. Paul Moayyedi, Brian E Lacy, Christopher N Andrews et al. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol. 2017 Jul;112 7 988 1013. Open 2. Marco Romano, Antonietta Gerarda Gravina, Leonardo Henry Eusebi et al. Management of Helicobacter pylori infection: Guidelines of the Italian Society of Gastroenterology SIGE and the Italian Society of Digestive Endoscopy SIED . Dig Liver Dis. 2022 Sep;54 9 1153 1161. Open 3. Fallone CA, Chiba N, van Zanten SV et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterology. 2016 Jul;151 1 51 69.e14. Open 4. P Malfertheiner, F Megraud, C A O'Morain et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut. 2017 Jan;66 1 6 30. Open 5. Chey WD, Leontiadis GI, Howden CW et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017 Feb;112 2 212 239. Open 6. Shailja C Shah, Prasad G Iyer, Steven F Moss. AGA Clinical Practice Update on the Management of Refractory Helicobacter pylori Infection: Expert Review. Gastroenterology. 2021 Apr;160 5 1831 1841. Open 7. ASGE Standards of Practice Committee, Subhas Banerjee, Brooks D Cash et al. The role of endoscopy in the management of patients with peptic ulcer disease. Gastrointest Endosc. 2010 Apr;71 4 663 8. Open 8. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2019. Open 9. Nicola L Jones, Sibylle Koletzko, Karen Goodman et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents Update 2016 . J Pediatr Gastroenterol Nutr. 2017 Jun;64 6 991 1003. Open 10. Abdulbaqi Al-Toma, Umberto Volta, Renata Auricchio et al. European Society for the Study of Coeliac Disease ESsCD guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019 Jun;7 5 583 613. Open 11. Antonio Tarasconi, Federico Coccolini, Walter L Biffl et al. Perforated and bleeding peptic ulcer: WSES guidelines. World J Emerg Surg. 2020 Jan 7;15 3. Open 12. Samir Gupta, Dan Li, Hashem B El Serag et al. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology. 2020 Feb;158 3 693 702. Open 13. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108 3 308 28. Open https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 10/11 6/24/23, 12:31 PM Helicobacter pylori infection Pathway 14. Cynthia W Ko, Shazia M Siddique, Amit Patel et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020 Sep;159 3 1085 1094. Open 15. Chey WD, Wong BC, Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007 Aug;102 8 1808 25. Open 16. Fischbach W, Malfertheiner P. Helicobacter Pylori Infection. Dtsch Arztebl Int. 2018 Jun 22;115 25 429 436. Open 17. Myers J, Atwood JE, Forbes S et al. Effect of fructose 1,6-diphosphate infusion on the hormonal response to exercise. Med Sci Sports Exerc. 1990 Feb;22 1 102 5. Open 18. Watari J, Chen N, Amenta PS et al. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol. 2014 May 14;20 18 5461 73. Open 19. Hu Y, Wan JH, Li XY et al. Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. Aliment Pharmacol Ther. 2017 Nov;46 9 773 779. Open 20. Laura E Targownik, Deborah A Fisher, Sameer D Saini. AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology. 2022 Feb 16;S0016 5085 21 04083 X. Open 21. Barbara Farrell, Kevin Pottie, Wade Thompson et al. Deprescribing proton pump inhibitors: Evidence- based clinical practice guideline. Can Fam Physician. 2017 May;63 5 354 364. Open https://web.pathway.md/diseases/recBlcLq2Gd1rW3fw 11/11

Guideline sources The following summarized guidelines for the evaluation and management of HELLP syndrome are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2021), the European Association for the Study of the Liver (EASL 2017), the American College of Gastroenterology (ACG 2016), the Italian Association for the Study of the Liver (AISF 2016), and the Society of Obstetricians and Gynaecologists of Canada (SOGC 2014). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Indications for monitoring: obtain close monitoring for the development of eclampsia and HELLP syndrome in patients with preeclampsia. E 2. Diagnostic investigations Initial evaluation: https://web.pathway.md/diseases/recKa9ufB6qegaEBp 1/3 6/24/23, 12:31 PM HELLP syndrome Pathway As per AASLD 2021 guidelines, obtain abdominal imaging to rule out hepatic hemorrhage, infarct, or rupture in patients with suspected HELLP syndrome. E As per ACG 2016 guidelines, obtain standard workup in a pregnant patient presenting with abnormal liver tests as with any non-pregnant patient. B 3. Medical management Corticosteroids: As per AISF 2016 guidelines, administer corticosteroids to promote fetal lung maturity in patients with HELLP syndrome between 24 and 34 weeks of gestation. Consider planning delivery 24 hours after corticosteroids administration. A As per SOGC 2014 guidelines, do not administer corticosteroids for the treatment of HELLP syndrome. D 4. Therapeutic procedures Platelet transfusion: As per ACG 2016 guidelines, consider administering platelet transfusion to 40,000-50,000 cells/ L before delivery, especially if C-section is likely. C As per SOGC 2014 guidelines, administer platelet transfusion in patients with HELLP syndrome with a platelet count of < 20 109/L, regardless of mode of delivery. B Show 3 more Delivery: As per AASLD 2021 guidelines, perform expeditious deliver after maternal stabilization in patients with suspected HELLP syndrome or eclampsia. E As per ACG 2016 guidelines, perform prompt delivery for the management of HELLP syndrome, especially after 34 weeks gestation. B As per AISF 2016 guidelines, perform delivery of the fetus as first-line treatment of HELLP syndrome before 24 or after 32 weeks of gestation and in presence of maternal-fetal complications. B Plasmapheresis: do not perform plasma exchange or plasmapheresis for HELLP syndrome, particularly within the first 4 days postpartum. D 5. Specific circumstances Patients with acute liver failure: As per AASLD 2021 guidelines, transfer patients with HELLP syndrome complicated by hepatic rupture or ALF to a transplant center for evaluation. E https://web.pathway.md/diseases/recKa9ufB6qegaEBp 2/3 6/24/23, 12:31 PM HELLP syndrome Pathway As per EASL 2017 guidelines, perform prompt delivery of the fetus as the treatment of choice in patients with HELLP syndrome and acute fatty liver of pregnancy, especially in case of elevated lactate levels and hepatic encephalopathy. Offer screening for putative fatty acid defects. B 6. Follow-up and surveillance Breastfeeding: recognize that breastfeeding is not contraindicated in patients with HELLP syndrome on antihypertensive therapy, including nifedipine, labetalol, atenolol, methyldopa, captopril, and enalapril. B References 1. Magee LA, Pels A, Helewa M et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can. 2014 May;36 5 416 41. Open 2. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 3. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 4. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 5. Wendon, J, Cordoba J et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017 May;66 5 1047 1081. Open 6. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 7. Laura A Magee, Graeme N Smith, Christine Bloch et al. Guideline No. 426 Hypertensive Disorders of Pregnancy: Diagnosis, Prediction, Prevention, and Management. J Obstet Gynaecol Can. 2022 May;44 5 547 571.e1. Open https://web.pathway.md/diseases/recKa9ufB6qegaEBp 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hemophagocytic lymphohistiocytosis (HLH) are prepared by our editorial team based on guidelines from the Histiocyte Society (HS 2019). 1 1 3 4 5 5 Definition HLH is a severe hyperinflammatory syndrome caused by aberrant activation of macrophages and cytotoxic T cells. 1 Epidemiology Primary HLH is due to genetic abnormalities (including perforin and syntaxin mutations), while secondary HLH is due to underlying conditions such as infections (notably, EBV, CMV, parvovirus B19, human immunodeficiency virus, and HHV-6), autoimmune/rheumatologic disease, malignancy, or metabolic conditions. Secondary HLH caused by rheumatologic disease is often termed "macrophage activating syndrome," and has been reported in association with adult-onset Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, Sj gren's syndrome, and SLE. 4 Pathophysiology The incidence of HLH is estimated at 0.1 cases per 100,000 person-years. 3 https://web.pathway.md/diseases/reclLNJCDurXzGWE8 1/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Disease course Key clinical manigestations include fever, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias. In addition, elevated liver enzymes, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen. 5 Prognosis and risk of recurrence Mortality has been reported to vary from 8-22% in rheumatologic HLH to 18-24% in EBV associated HLH. 5 Calculator Diagnostic criteria for hemopha Guidelines 1. Screening and diagnosis Indications for testing: test for HLH in critically ill patients with persistent fever, cytopenias, and organomegaly, particularly in confirmed or presumed cases of sepsis, sepsis-like syndromes, and/or evolving multiorgan failure. E Diagnostic criteria: as per HS 2019 guidelines, use the HLH-2004 diagnostic criteria in conjunction with clinical judgment and the patient's history in order to establish a diagnosis of HLH in adults. E 2. Classification and risk stratification Classification: As per HS 2019 guidelines: Recognize that primary and secondary hemophagocytic syndromes, including macrophage activating syndrome, are hyperferritinemic, hyperinflammatory syndromes with a common terminal pathway but with different pathogenetic roots. E Recognize that malignancy-associated HLH may present as one of two distinct entities: malignancy-triggered HLH, as a presenting feature of the malignancy at diagnosis or at relapse HLH during chemotherapy, in most cases induced by infections. E 3. Diagnostic investigations https://web.pathway.md/diseases/reclLNJCDurXzGWE8 2/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Evaluation for etiology: conduct a meticulous search for an underlying trigger in patients with HLH, including occult malignancies, despite ongoing HLH treatment. E Show 3 more Genetic testing: consider obtaining functional assessment of lymphocyte cytotoxicity and guided genetic testing, while not delaying the clinical decision to initiate treatmen, to detect potential genetic predisposition to HLH in patients with HLHt. E 4. Medical management General principles: As per HS 2019 guidelines: Recognize that the variable severity of HLH, including macrophage activating syndrome, demands graded intensity and length of treatment. Tailor treatment to control hyperinflammation and treat identified disease triggers. E Recognize that treatment of macrophage activating syndrome is different from that recommended for HLH, as a result of partial pathogenetic diversity. E HLH-94 regimen: recognize that HLH-94 treatment components (consisting of corticosteroids, typically dexamethasone, cyclosporine A, intrathecal therapy, and etoposide) are highly effective in treating hyperinflammation in adult patients with HLH, However, do not use a "1-size-fits-all protocol because o, the heterogeneity of adult HLH. E Management of HLH due to intracellular infections: as per HS 2019 guidelines, initiate specific antimicrobial treatment for HLH induced by intracellular infections, such as tuberculosis, leishmaniasis, or rickettsial disease. Avoid using HLH-94-like treatment. E Management of refractory/relapsing HLH: Recognize that secondary infections are a major cause of fatality and may erroneously be diagnosed as disease relapse. E Administer combined chemotherapy and consolidation with allo-SCT for salvage treatment of eligible adult patients with refractory/relapsing HLH. E Likelihood Ratios Pertinent positives The following findings increase the probability of hemophagocytic lymphohistiocytosis in adults. 1 5 Finding LR+ Value Increased serum soluble IL-2 receptor (> 10,000 u/ml) 6.0 (1.9-18.7) Decreased serum glycosylated ferritin fraction (< 25%) 3.6 (1.2-12.3) Increased serum soluble IL-2 receptor (> 2,400 u/ml) 2.7 (1.8-4.0) https://web.pathway.md/diseases/reclLNJCDurXzGWE8 3/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Increased serum ferritin (> 10,000 g/L) 2.6 (1.6-4.4) Show 1 more Pertinent negatives The following findings decrease the probability of hemophagocytic lymphohistiocytosis in adults. 1 5 Finding LR- Value serum ferritin not increased ( 500 g/L) 0.01 (0.0-0.01) serum soluble IL-2 receptor not increased ( 2,400 u/ml) 0.01 (0.0-0.01) serum glycosylated ferritin fraction not decreased ( 25%) 0.2 (0.1-0.8) serum ferritin not increased ( 10,000 g/L) 0.3 (0.2-0.6) Show 1 more References 1. La Ros e P, Horne A, Hines M et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019 Jun 6;133 23 2465 2477. Open 2. Kai Lehmberg, Kim E Nichols, Jan-Inge Henter et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015 Aug;100 8 997 1004. Open 3. Delaney A, Mai C, Smoots A et al. Population-Based Surveillance of Birth Defects Potentially Related to Zika Virus Infection 15 States and U.S. Territories, 2016. MMWR Morb Mortal Wkly Rep. 2018 Jan 26;67 3 91 96. Open 4. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014 Jun 12;5 69 86. Open 5. Kleynberg RL, Schiller GJ. Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol. 2012 Nov;10 11 726 32. Open 6. Hayden A, Lin M, Park S et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017 Dec 6;1 26 2529 2534. Open https://web.pathway.md/diseases/reclLNJCDurXzGWE8 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hemorrhoids are prepared by our editorial team based on guidelines from the World Society of Emergency Surgery (WSES/AAST 2021), the American College of Gastroenterology (ACG 2021; 2014), the American Society of Colon and Rectal Surgeons (ASCRS 2018), and the American Association of Family Physicians (AAFP 2018). 1 2 3 4 5 Calculator Goligher's classification of inter Guidelines 1. Diagnostic investigations Clinical assessment: As per WSES 2021 guidelines: https://web.pathway.md/diseases/recl7RHiPmqgaSl0E 1/5 6/24/23, 12:31 PM Hemorrhoids Pathway Consider eliciting a focused medical history and performing a complete physical examination, including DRE, to rule out other causes of lower gastrointestinal bleeding in patients with suspected bleeding hemorrhoids. C Consider performing anoscopy as part of the physical examination in patients with complicated hemorrhoids, whenever feasible and well tolerated. C As per ASCRS 2018 guidelines, elicit a disease-specific history and perform a physical examination emphasizing the degree and duration of symptoms and risk factors. B As per ACG 2014 guidelines, elicit history and perform physical examination for the diagnosis of hemorrhoids. B Laboratory tests: consider checking vital signs and obtaining Hgb, hematocrit and coagulation studies to evaluate the severity of bleeding in patients with suspected bleeding hemorrhoids. C Show 2 more Diagnostic imaging: Consider obtaining CT, MRI or endoanal ultrasound in patients with suspected complicated hemorrhoids only if there is suspicion of concomitant anorectal diseases (sepsis/abscess, IBD, neoplasm). C Insufficient evidence to recommend obtaining angiography in patients with complicated hemorrhoids. I 2. Diagnostic procedures Colonoscopy: As per WSES 2021 guidelines, consider performing colonoscopy in patients with complicated hemorrhoids if there is a concern for IBD or cancer arising from patient personal and family history or from physical examination. C As per ASCRS 2018 guidelines, perform complete endoscopic evaluation of the colon in selected patients with symptomatic hemorrhoids and rectal bleeding. B As per ACG 2014 guidelines, perform endoscopy to confirm the source of bleeding in patients with hemorrhoids and rectal bleeding. B 3. Medical management Pharmacotherapy: As per WSES 2021 guidelines, consider offering flavonoids to relieve symptoms in patients with complicated hemorrhoids. C Show 2 more As per ASCRS 2018 guidelines, consider offering medical therapy, representing a heterogeneous group of treatment options, in patients with hemorrhoids with an expectation of minimal harm and a decent potential for relief. C https://web.pathway.md/diseases/recl7RHiPmqgaSl0E 2/5 6/24/23, 12:31 PM Hemorrhoids Pathway 4. Nonpharmacologic interventions Dietary modifications: As per WSES 2021 guidelines, advise dietary and lifestyle modifications (increased fiber and water intake together with adequate bathroom habits) as first-line therapy in patients with complicated hemorrhoids. B As per ACG 2021 guidelines, advise dietary modifications consisting of adequate fluid and fiber intake and minimizing straining at defecation as first-line therapy in patients with symptomatic hemorrhoids. B As per AAFP 2018 guidelines, advise increasing fiber intake as an effective first-line, non- surgical treatment in patients with hemorrhoids. A As per ASCRS 2018 guidelines, advise dietary modifications consisting of adequate fluid and fiber intake and counsel regarding defecation habits as the primary first-line therapy in patients with symptomatic hemorrhoid disease. B 5. Therapeutic procedures Office-based procedures: As per WSES 2021 guidelines, insufficient evidence to recommend performing office-based procedures (rubber band ligation, sclerotherapy, infrared coagulation) in patients with complicated hemorrhoids. I As per ACG 2021 guidelines, perform office-based procedures, such as a rubber band ligation or infrared coagulation, sclerotherapy, and bipolar coagulation as alternatives, in patients with symptomatic grade I-II internal hemorrhoids failed medical therapy. B Updated evidence: MoLish In patients with symptomatic hemorrhoids, modified ligation procedure was superior to stapled hemorrhoidectomy with respect to cure rate at 6 months. Haibo Yang et al. BJS Open. 2022 May 2. As per AAFP 2018 guidelines, consider performing rubber band ligation as the preferred office- based procedure in patients with grade I-III hemorrhoids. B As per ASCRS 2018 guidelines, consider performing office-based procedures, such as banding, sclerotherapy, and infrared coagulation, in patients with grade I and II and selected patients with grade III internal hemorrhoids failed medical treatment. Recognize that hemorrhoid banding is typically the most effective option. B 6. Surgical interventions https://web.pathway.md/diseases/recl7RHiPmqgaSl0E 3/5 6/24/23, 12:31 PM Hemorrhoids Pathway Early excision of thrombosed external hemorrhoids: As per WSES 2021 guidelines: Decide between nonoperative management and early surgical excision in patients with thrombosed hemorrhoids based on local expertise and patient's preference. B Avoid performing incision and drainage of the thrombus in patients with thrombosed hemorrhoids. D As per ACG 2021 guidelines, perform either surgical excision or incision and evacuation of the thrombus in patients with acutely thrombosed external hemorrhoids if seen within the first 4 days. B As per AAFP 2018 guidelines, perform surgical excision of thrombosed hemorrhoids in most patients presenting within 2-3 days of symptom onset. B As per ASCRS 2018 guidelines, consider performing early surgical excision in selected patients with thrombosed external hemorrhoids. C Excisional hemorrhoidectomy: As per ACG 2021 guidelines, consider performing excisional hemorrhoidectomy in patients with symptomatic grade III hemorrhoids. C As per AAFP 2018 guidelines: Perform excisional (conventional) hemorrhoidectomy for the treatment of patients with grade III-IV, recurrent, or highly symptomatic hemorrhoids. A Recognize that the use of LigaSure during conventional hemorrhoidectomy leads to decreased pain in the immediate postoperative period. A As per ASCRS 2018 guidelines: Perform hemorrhoidectomy typically in patients with symptoms resulting from external hemorrhoids or combined internal and external hemorrhoids with prolapse (grade III-IV). A Prescribe a multimodality pain regimen in patients undergoing surgical hemorrhoidectomy to reduce narcotic usage and promote a faster recovery. B Stapled hemorrhoidopexy: recognize that stapled hemorrhoidopexy results in more frequent recurrence of symptoms and prolapse than conventional hemorrhoidectomy. A Hemorrhoidal artery ligation: As per ACG 2021 guidelines, consider performing Doppler-guided procedures such as hemorrhoidal artery ligations in patients with symptomatic grade III hemorrhoids. C As per AAFP 2018 guidelines, recognize that hemorrhoidal artery ligation is an emerging therapy with early outcomes similar to conventional hemorrhoidectomy in patients with grade II- III hemorrhoids. B References 1. Davis BR, Lee-Kong SA, Migaly J et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Hemorrhoids. Dis Colon Rectum. 2018 Mar;61 3 284 292. https://web.pathway.md/diseases/recl7RHiPmqgaSl0E 4/5 6/24/23, 12:31 PM Hemorrhoids Pathway Open 2. Antonio Tarasconi, Gennaro Perrone, Justin Davies et al. Anorectal emergencies: WSES AAST guidelines. World J Emerg Surg. 2021 Sep 16;16 1 48. Open 3. Arnold Wald, Adil E Bharucha, Berkeley Limketkai et al. ACG Clinical Guidelines: Management of Benign Anorectal Disorders. Am J Gastroenterol. 2021 Oct 1;116 10 1987 2008. Open 4. Timothy Mott, Kelly Latimer, Chad Edwards. Hemorrhoids: Diagnosis and Treatment Options. Am Fam Physician. 2018 Feb 1;97 3 172 179. Open 5. Wald A, Bharucha AE, Cosman BC et al. ACG clinical guideline: management of benign anorectal disorders. Am J Gastroenterol. 2014 Aug;109 8 1141 57. Open 6. Robert S Sandler, Anne F Peery. Rethinking What We Know About Hemorrhoids. Clin Gastroenterol Hepatol. 2019 Jan;17 1 8 15. Open 7. Varut Lohsiriwat. Hemorrhoids: from basic pathophysiology to clinical management. World J Gastroenterol. 2012 May 7;18 17 2009 17. Open 8. Anne F Peery, Robert S Sandler, Joseph A Galanko et al. Risk Factors for Hemorrhoids on Screening Colonoscopy. PLoS One. 2015 Sep 25;10 9):e0139100. Open 9. R M Kluiber, B G Wolff. Evaluation of anemia caused by hemorrhoidal bleeding. Dis Colon Rectum. 1994 Oct;37 10 1006 7. Open 10. Haibo Yang, Zhan Shi, Wei Chen et al. Modified ligation procedure for prolapsed haemorrhoids versus stapled haemorrhoidectomy for the management of symptomatic haemorrhoids MoLish): randomized clinical trial. BJS Open. 2022 May 2;6 3):zrac064. Open https://web.pathway.md/diseases/recl7RHiPmqgaSl0E 5/5

Guideline sources The following summarized guidelines for the evaluation and management of henoch-Sch nlein purpura (HSP) are prepared by our editorial team based on guidelines from the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2019) and the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2012). 1 2 Calculator Calculator EULAR/PRINTO/PRES criteria for Severity grading for IgA vasculiti Guidelines 1. Classification and risk stratification https://web.pathway.md/diseases/reciVsOBWLsaejtOa 1/4 6/24/23, 12:31 PM Henoch-Sch nlein purpura Pathway Classification: use the EULAR/PRINTO/PReS-endorsed Ankara 2008 criteria for the classification of IgA vasculitis (formerly known as HSP). B 2. Diagnostic investigations Evaluation for renal involvement: obtain estimated GFR measurement and urinalysis (for hematuria and urine protein/urine creatinine ratio or urine albumin/urine creatinine ratio) for the evaluation of renal involvement in patients with IgA vasculitis. B Abdominal ultrasound: obtain abdominal ultrasound by a specialist with pediatric expertise to exclude intestinal intussusception in patients with severe abdominal pain. B 3. Diagnostic procedures Skin biopsy: perform skin biopsy with specific immunofluorescence stating for IgA in patients with atypical rash and/or to exclude alternative diagnosis. B Show 2 more Kidney biopsy: Perform renal biopsy in patients with IgA vasculitis with: severe proteinuria (> 250 mg/mmol for at least 4 weeks) persistent moderate proteinuria (100-250 mg/mmol) impaired GFR. B Consider performing renal biopsy in patients with IgA vasculitis with a shorter duration of severe proteinuria (> 250 mg/mmol for < 4 weeks). C 4. Medical management Corticosteroids: Initiate corticosteroids in patients with IgA vasculitis for the treatment of: orchitis cerebral vasculitis pulmonary hemorrhage other severe organ- or life-threatening vasculitis manifestations. B Show 3 more Analgesics: Prescribe adequate analgesia in patients with IgA vasculitis-associated arthropathy or abdominal pain. B Recognize that NSAIDs are not contraindicated if the renal function is normal. B 5. Specific circumstances https://web.pathway.md/diseases/reciVsOBWLsaejtOa 2/4 6/24/23, 12:31 PM Henoch-Sch nlein purpura Pathway Patients with IgA nephritis, ACEIs and ARBs: As per SHARE initiative 2019 guidelines, consider administering ACEIs to prevent/limit secondary glomerular injury in patients with IgA nephritis with persistent proteinuria. C As per KDIGO 2012 guidelines, consider administering ACEIs or ARBs in patients with HSP nephritis and persistent proteinuria > 0.5-1 g/day/1.73 m . C Patients with IgA nephritis, corticosteroids: As per SHARE initiative 2019 guidelines, administer oral prednisone as first-line therapy in patients with mild IgA nephritis. B Show 2 more As per KDIGO 2012 guidelines, consider administering a 6-month course of corticosteroid therapy in patients with HSP nephritis with GFR > 50 ml/min/1.73 m and persistent proteinuria > 1 g/day after a trial of ACEIs or ARBs. C Patients with IgA nephritis (immunosuppressants): consider administering azathioprine or mycophenolate mofetil as second-line therapy in patients with IgA nephritis following renal biopsy. C Show 2 more Patients with IgA nephritis (combination therapy): Administer IV cyclophosphamide with pulsed methylprednisolone and/or oral prednisolone as first-line therapy in patients with severe IgA nephritis. B Consider administering azathioprine or mycophenolate mofetil in combination with corticosteroids as maintenance therapy in patients with severe IgA nephritis. C Patients with crescentic nephritis: consider treating patients with crescentic HSP and nephrotic syndrome and/or deteriorating kidney function using the same treatment regimens as for crescentic IgA nephropathy. C 6. Preventative measures Prevention of IgA nephritis: As per SHARE initiative 2019 guidelines, do not administer prophylactic corticosteroids to prevent the development of IgA vasculitis-associated nephritis. D As per KDIGO 2012 guidelines, do not administer corticosteroids for the prevention of HSP nephritis. D 7. Follow-up and surveillance Indications for specialist consultation: Consult with a pediatric nephrologist: if the patient with IgA vasculitis has moderate proteinuria and/or impaired GFR when starting treatment for IgA nephritis. B https://web.pathway.md/diseases/reciVsOBWLsaejtOa 3/4 6/24/23, 12:31 PM Henoch-Sch nlein purpura Pathway References 1. KDIGO. Chapter 11 Henoch-Sch nlein purpura nephritis. Kidney Int Suppl 2011 . 2012 Jun;2 2 218 220. Open 2. Seza Ozen, Stephen D Marks, Paul Brogan et al. European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative. Rheumatology Oxford). 2019 Sep 1;58 9 1607 1616. Open 3. Priyank Yagnik, Apurva Jain, Jason K Amponsah et al. National Trends in the Epidemiology and Resource Use for Henoch-Sch nlein Purpura IgA Vasculitis) Hospitalizations in the United States From 2006 to 2014. Hosp Pediatr. 2019 Nov;9 11 888 896. Open 4. Louise Oni, Sunil Sampath. Childhood IgA Vasculitis Henoch Schonlein Purpura)-Advances and Knowledge Gaps. Front Pediatr. 2019 Jun 27;7 257. Open 5. Alexander Tracy, Anuradhaa Subramanian, Nicola J Adderley et al. Cardiovascular, thromboembolic and renal outcomes in IgA vasculitis Henoch-Sch nlein purpura): a retrospective cohort study using routinely collected primary care data. Ann Rheum Dis. 2019 Feb;78 2 261 269. Open 6. Seza Ozen, Angela Pistorio, Silvia M Iusan et al. EULAR/PRINTO/PRES criteria for Henoch-Sch nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II Final classification criteria. Ann Rheum Dis. 2010 May;69 5 798 806. Open 7. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open https://web.pathway.md/diseases/reciVsOBWLsaejtOa 4/4

Guideline sources The following summarized guidelines for the evaluation and management of heparin-induced thrombocytopenia (HIT) are prepared by our editorial team based on guidelines from the Society for Cardiovascular Angiography and Interventions (SCAI/AHA/ACC 2022), the French Working Group on Perioperative Hemostasis (GIHP 2020), the European Society of Cardiology (ESC/EACTS 2019), the Canadian Association of Interventional Cardiology (CAIC 2019), the American Society of Hematology (ASH 2018), the Society for Vascular Surgery (SVS 2018), the European Society of Cardiology (ESC 2018), the Canadian Consensus Group on Venous Thromboembolism in Cancer (CCG-VTEC 2015), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2014), the American College of Chest Physicians (ACCP 2012), the British Committee for Standards In Haematology (BCSH 2012), and the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2012). 1 2 3 4 5 6 7 8 9 10 11 12 https://web.pathway.md/diseases/recR76V6DESBdk0f1 1/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway Calculator4Ts score for heparin-induced t Guidelines 1. Screening and diagnosis Indications for monitoring, baseline platelet count: As per GIHP 2020 guidelines, obtain baseline measurement of platelet count before initiating heparin (or alternatively as soon as possible after the first injection, before day 4), whether UFH or LMWH. E As per ACCP 2012 guidelines, obtain baseline measurement of platelet count before initiating heparin or LMWH in patients exposed to heparin within the past 100 days. Repeat platelet count measurement 24 hours later, if feasible. E As per BCSH 2012 guidelines, obtain baseline measurement of platelet count in patients receiving any heparin. B Indications for monitoring, low risk: As per GIHP 2020 guidelines, consider obtaining platelet count monitoring in patients at low risk of HIT. E As per ASH 2018 guidelines, avoid obtaining platelet count monitoring to screen for HIT in patients at low risk (< 0.1%). D As per ACCP 2012 guidelines, avoid obtaining platelet count monitoring in patients at low risk (< 1%) of HIT. D As per BCSH 2012 guidelines, do not obtain routine platelet monitoring in medical patients and obstetric patients receiving heparin. D Indications for monitoring, moderate-to-high risk: As per GIHP 2020 guidelines: Consider obtaining platelet count monitoring 1-2 times a week from day 4 to day 14 of treatment, and then once weekly for 1 month if heparin therapy is continued, in patients at intermediate risk of HIT. E Consider obtaining platelet count monitoring 2-3 times a week from day 4 to day 14 of treatment, and then once weekly for 1 month if heparin therapy is continued, in patients at high risk of HIT. E As per ASH 2018 guidelines, consider obtaining platelet count monitoring in patients at intermediate (0.1-1.0%) or high risk (> 1.0%) of HIT. C Show 2 more https://web.pathway.md/diseases/recR76V6DESBdk0f1 2/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway As per ACCP 2012 guidelines, consider obtaining platelet count monitoring every 2-3 days from day 4 to day 14 if the risk of HIT is > 1%. C Indications for monitoring (after surgery): obtain platelet count monitoring every 2-3 days from day 4 to day 14 or until heparin is stopped in postoperative patients, including obstetric cases, receiving UFH. B Show 3 more Indications for monitoring, recent heparin exposure: As per ASH 2018 guidelines, consider obtaining platelet count monitoring starting from day 0 (the day heparin is initiated) if the patient has received heparin in the previous 30 days. C As per ACCP 2012 guidelines, obtain baseline measurement of platelet count before initiating heparin or LMWH in patients exposed to heparin within the past 100 days. Repeat platelet count measurement 24 hours later, if feasible. E As per BCSH 2012 guidelines, obtain platelet count measurement 24 hours after initiating heparin in postoperative patients (including cardiopulmonary bypass) receiving any type of heparin and having a history of heparin exposure within the past 100 days. B Indications for testing, low pretest probability: As per GIHP 2020 guidelines, do not obtain specific laboratory evaluation for the exclusion of HIT in patients with low (4T 3) pretest probability. Obtain close monitoring of platelet count to search for an etiology of thrombocytopenia. D As per ASH 2018 guidelines, do not obtain laboratory testing in patients with low pretest probability based on the 4Ts score. D As per BCSH 2012 guidelines, do not obtain laboratory evaluation for the exclusion of HIT in patients with low pretest probability. D Indications for testing, moderate-to-high pretest probability: As per GIHP 2020 guidelines, obtain biological tests to detect anti-PF4 antibodies in patients with intermediate (4T = 4-5) or high (4T 6) pretest probability. E Show 2 more As per ASH 2018 guidelines, obtain an immunoassay in patients with an intermediate or high pretest probability based on the 4Ts score. B Consider obtaining a functional assay, if available, either locally or as a send-out test to a reference laboratory, in patients with positive immunoassay results. B As per BCSH 2012 guidelines, obtain laboratory testing in patients with an intermediate or high pretest probability of HIT. B Indications for testing, acute systemic reaction: As per GIHP 2020 guidelines, consider obtaining platelet count monitoring in all patients receiving heparin and experiencing an unexpected clinical event (onset or aggravation of venous or arterial thrombosis, skin necrosis, or unusual reaction after heparin injection, such as chills, low BP, dyspnea, amnesia), regardless of the risk of HIT. E https://web.pathway.md/diseases/recR76V6DESBdk0f1 3/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway As per ACCP 2012 guidelines, consider obtaining platelet count measurement in patients presenting with acute systemic reactions within 30 minutes of an IV heparin bolus. E As per BCSH 2012 guidelines, suspect and assess for HIT in patients with new thrombosis, skin allergy, or any other rarer manifestations of HIT developing between day 4 and day 14 of heparin administration. B Diagnosis: As per GIHP 2020 guidelines, consider excluding HIT based on a low (4T 3) pretest probability without specific bioassays. Obtain close monitoring of platelet count to search for an etiology of thrombocytopenia. E Show 3 more As per BCSH 2012 guidelines, suspect HIT if the platelet count falls by 30% between days 4 and 14 of heparin administration. B Show 4 more 2. Classification and risk stratification Pretest probability: As per GIHP 2020 guidelines: Use the 4T score (outside a cardiac surgery context) to determine the clinical probability of HIT in patients with suspected HIT. E Consider classifying the risk of HIT during heparin administration into three groups: Situation Guidance Treatment with LMWH in medicine (except cancer), obstetrics (except surgery including C-section), or in the course of minor trauma Low (< 0.1%) Treatment with fondaparinux Isolated UFH injection for an endovascular procedure or simple surgery Treatment with UFH or LMWH lasting > 1 month Prophylactic treatment with UFH in medicine/obstetrics Intermediate (0.1-1%) Prophylactic treatment with LMWH in patients with cancer or severe trauma or in postoperative care (including cardiac surgery) Prophylactic treatment with UFH in surgery (including circulatory assistance) or for High (> 1%) https://web.pathway.md/diseases/recR76V6DESBdk0f1 4/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway RRT All curative treatments with UFH in medicine/surgery/obstetrics. E As per ASH 2018 guidelines, use the 4Ts score rather than a gestalt approach to estimate the probability of HIT in patients with suspected HIT. B Classification: Consider classifying HIT into three stages: Situation Guidance Diagnosed within the last month Acute HIT Anti-PF4 antibodies most often present with a high thrombotic risk Diagnosed 1-3 months ago Subacute HIT Anti-PF4 antibodies often present with a low titer Diagnosed > 3 months ago Previous history of HIT Anti-PF4 antibodies most often are undetectable. E 3. Diagnostic investigations Immunoassays: As per GIHP 2020 guidelines: Consider obtaining anti-PF4 antibodies as soon as possible in patients with suspected HIT with intermediate or high clinical probability. E Obtain biological tests to detect anti-PF4 antibodies in patients with intermediate (4T = 4-5) or high (4T 6) pretest probability. E As per ASH 2018 guidelines, obtain an immunoassay in patients with suspected HIT with an intermediate or high pretest probability based on the 4Ts score. B As per BCSH 2012 guidelines: Obtain an antigen assay of high sensitivity in non-expert laboratories. Measure only the IgG class. Report actual optical density, degree of inhibition by high dose heparin, and the cut-off point for a positive test rather than simply the test as positive or negative. B Do not obtain platelet aggregation assays using platelet-rich plasma because of lack of sensitivity. D Platelet function tests: As per GIHP 2020 guidelines, obtain a platelet function test to confirm the diagnosis of HIT in patients with intermediate or high clinical probability and a significant titer of anti-PF4 antibodies. https://web.pathway.md/diseases/recR76V6DESBdk0f1 5/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway E As per ASH 2018 guidelines, consider obtaining a functional assay, if available, either locally or as a send-out test to a reference laboratory, in patients with suspected HIT with positive immunoassay results. C As per BCSH 2012 guidelines, recognize that platelet activation assays using washed platelets (heparin-induced platelet activation assay and serotonin release assay) have a higher sensitivity than platelet aggregation assays using platelet-rich plasma and are regarded as the reference standard, but are technically demanding. Restrict their use to experienced laboratories. B Screening for asymptomatic DVT: Consider obtaining bilateral lower-extremity compression ultrasound to screen for asymptomatic proximal deep vein thrombosis in patients with acute isolated HIT. C Consider obtaining upper-extremity ultrasound in the limb with the catheter to screen for asymptomatic deep vein thrombosis in patients with acute isolated HIT and an upper-extremity central venous catheter. Avoid obtaining upper-extremity ultrasound in limbs without central venous catheters. C 4. Medical management Continuation of heparin: As per GIHP 2020 guidelines, consider continuing or resuming heparin therapy, with close monitoring of platelet count, after the exclusion of HIT based on the absence of anti-PF4 antibodies in patients with intermediate clinical probability. E As per ASH 2018 guidelines, do not discontinue heparin empirically in patients with suspected HIT with a low probability score. D Discontinuation of heparin: As per GIHP 2020 guidelines, discontinue heparin immediately (without waiting for the results of biological tests) and initiate a non-heparin anticoagulant at curative doses in patients with a high (4T 6, or extracorporeal circulation with biphasic platelet count progression profile) clinical probability of HIT. E As per ASH 2018 guidelines, discontinue heparin in patients with an intermediate probability of HIT with no other indications for therapeutic-intensity anticoagulation. B Consider initiating a non-heparin anticoagulant at prophylactic or therapeutic doses in patients with or without a high risk of bleeding, respectively. B Show 4 more As per BCSH 2012 guidelines: Discontinue heparin and initiate full-dose anticoagulation with an alternative anticoagulant in patients with suspected (non-low pretest probability) or confirmed HIT. B Take the risks and benefits of treatment with an alternative anticoagulant into consideration when making clinical decisions. B Initiation of non-heparin anticoagulants, HIT without thrombosis, general principles: https://web.pathway.md/diseases/recR76V6DESBdk0f1 6/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway As per GIHP 2020 guidelines: Initiate a non-heparin anticoagulant (such as argatroban, bivalirudin, danaparoid, fondaparinux, or a DOAC) as an alternative anticoagulant in the acute phase of HIT. E Consider initiating any available non-heparin anticoagulant in stable patients with acute HIT with no severe renal or hepatic impairment and no risk of bleeding (absence of comorbidity or recent or expected invasive procedure in the short-term). E As per ASH 2018 guidelines: Initiate a non-heparin anticoagulant at therapeutic intensity, rather than prophylactic intensity dosing, in patients with acute isolated HIT. (strong recommendation, moderate certainty in the evidence about effects. B Consider initiating argatroban, bivalirudin, danaparoid, fondaparinux, or a DOAC when a non- heparin anticoagulant is being selected. C As per CCG-VTEC 2015 guidelines, initiate a non-heparin agent (including lepirudin, argatroban, and danaparoid; off-label agents include bivalirudin and fondaparinux) in patients with strongly suspected or confirmed HIT without thrombosis. A Initiation of non-heparin anticoagulants, HIT without thrombosis, direct thrombin and factor Xa inhibitors: As per GIHP 2020 guidelines, administer IV danaparoid at curative doses (not at prophylactic doses) and monitor anti-Xa activity with a specific calibration curve in patients with HIT. Replace danaparoid with another anticoagulant if the platelet count is not corrected or if a thrombosis under danaparoid appears or spreads. E Show 5 more As per ACCP 2012 guidelines: Initiate lepirudin, argatroban, or danaparoid over the continuation of heparin/LMWH or initiation/continuation of vitamin K antagonists in patients with isolated HIT (HIT without thrombosis). B Consider initiating argatroban, lepirudin, or danaparoid over other non-heparin anticoagulants in patients with isolated HIT (HIT without thrombosis) with normal renal function. C As per BCSH 2012 guidelines, initiate danaparoid at therapeutic doses, but not prophylactic doses, as a suitable alternative anticoagulant in patients with HIT. B Consider obtaining an anti-Xa assay with specific danaparoid calibrators to monitor the anticoagulant effect of danaparoid in patients > 90 kg or with a GFR < 30 mL/min. B Show 2 more Initiation of non-heparin anticoagulants, HIT without thrombosis, direct oral anticoagulants: As per GIHP 2020 guidelines, consider initiating a DOAC (without specific biological monitoring) as a first-line alternative anticoagulant (due to the simplicity of its use), after the use of danaparoid or argatroban, in stable patients with acute HIT. E As per ASH 2018 guidelines: Consider initiating a DOAC when a non-heparin anticoagulant is being selected in patients with acute isolated HIT. C https://web.pathway.md/diseases/recR76V6DESBdk0f1 7/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway Consider initiating a DOAC (dabigatran, rivaroxaban, or apixaban) rather than a vitamin K antagonist in patients with subacute HIT A. C Initiation of non-heparin anticoagulants, HIT without thrombosis, vitamin K antagonists: As per GIHP 2020 guidelines, initiate vitamin K antagonists as a supplement to parenteral treatment in the acute phase of HIT only when the platelet count is corrected (> 150, 000/ L). E As per ASH 2018 guidelines, do not initiate vitamin K antagonists before platelet count recovery (usually 150, 000/ L) in patients with acute isolated HIT. D As per CCG-VTEC 2015 guidelines, do not initiate warfarin in patients with strongly suspected or confirmed HIT until after the platelet count has substantially recovered ( 150, 000/ L). D As per BCSH 2012 guidelines: Do not initiate warfarin until the platelet count has recovered to the normal range. Continue the alternative anticoagulant until the INR is therapeutic when introducing warfarin. Recognize that argatroban affects the INR and take this into consideration when using this drug. Ensure a minimum overlap of 5 days between non-heparin anticoagulants and vitamin K antagonist therapy. D Administer IV vitamin K for reversal if the patient has received a vitamin K antagonist at the time of diagnosis. B Initiation of non-heparin anticoagulants, HIT with thrombosis, general principles: As per ASH 2018 guidelines: Initiate a non-heparin anticoagulant at therapeutic intensity, rather than prophylactic intensity dosing, (strong recommendation, very low certainty in the evidence about effects) in patients with acute HIT complicated by thrombosis. B Consider initiating argatroban, bivalirudin, danaparoid, fondaparinux, or a DOAC when a non- heparin anticoagulant is being selected. C As per CCG-VTEC 2015 guidelines, initiate a non-heparin agent (including lepirudin, argatroban, and danaparoid; off-label agents include bivalirudin and fondaparinux) in patients with strongly suspected or confirmed HIT complicated by thrombosis. A Initiation of non-heparin anticoagulants, HIT with thrombosis, direct thrombin and factor Xa inhibitors: As per GIHP 2020 guidelines: Replace danaparoid with another anticoagulant when a thrombosis under danaparoid appears or spreads. E Consider administering injectable argatroban or bivalirudin, combined with strict biological monitoring, in patients with acute severe HIT (massive pulmonary embolism, extensive or arterial thrombosis, venous gangrene, coagulopathy of consumption). E As per ACCP 2012 guidelines, initiate non-heparin anticoagulants, in particular lepirudin, argatroban, or danaparoid, over the continuation of heparin or LMWH or initiation/continuation of vitamin K antagonists in patients with HIT complicated by thrombosis. B Consider initiating https://web.pathway.md/diseases/recR76V6DESBdk0f1 8/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway lepirudin, argatroban, or danaparoid over other non-heparin anticoagulants in patients with normal renal function. B Initiation of non-heparin anticoagulants, HIT with thrombosis, vitamin K antagonists: As per ASH 2018 guidelines, do not initiate vitamin K antagonists before platelet count recovery (usually 150, 000/ L) in patients with acute HIT complicated by thrombosis. D As per ACCP 2012 guidelines, do not initiate vitamin K antagonist until platelets have substantially recovered (usually to at least 150, 000/ L). Start vitamin K antagonists initially at low doses (maximum 5 mg of warfarin or 6 mg phenprocoumon) in patients with strongly suspected or confirmed HIT. D Show 2 more Duration of anticoagulation: As per ASH 2018 guidelines, consider continuing anticoagulation at least until platelet count recovery (usually 150, 000/ L) in patients with acute isolated HIT and no asymptomatic deep vein thrombosis identified by screening compression ultrasound. Avoid continuing treatment for 3 months unless HIT persists without platelet count recovery. C As per ACCP 2012 guidelines, consider continuing alternative anticoagulant therapy (including vitamin K antagonists) for 4 months in patients with isolated HIT and for 3 weeks in patients with HIT complicated by thrombosis. E As per BCSH 2012 guidelines, continue therapeutic anticoagulation for 4 months after HIT without a thrombotic complication B and for 3 weeks following HIT with a thrombotic complication. A Antiplatelet therapy: As per GIHP 2020 guidelines, do not use oral antiplatelet agents for the treatment of patients with acute HIT. D As per ASH 2018 guidelines, avoid using antiplatelet agents in combination with non-heparin anticoagulants in patients with acute HIT (whether acute isolated HIT or complicated by thrombosis) and no other indication for antiplatelet therapy. D Intravenous immunoglobulin: do not use IVIGs as first-line therapy in the acute phase of HIT. D 5. Therapeutic procedures Platelet transfusion: As per GIHP 2020 guidelines, do not administer platelet transfusion in the acute phase of HIT in the absence of life-threatening or functional bleeding. D As per ASH 2018 guidelines, avoid administering platelet transfusions routinely in patients with acute HIT, whether acute isolated HIT or complicated by thrombosis, at average bleeding risk. D https://web.pathway.md/diseases/recR76V6DESBdk0f1 9/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway As per ACCP 2012 guidelines, consider administering platelet transfusions in patients with severe thrombocytopenia only in case of bleeding or when performing an invasive procedure with a high risk of bleeding. C As per BCSH 2012 guidelines, consider administering platelet transfusions in the event of bleeding C but not for prophylaxis. B Inferior vena cava filter placement: As per GIHP 2020 guidelines, do not insert an IVC filter in the acute phase of HIT. D As per ASH 2018 guidelines, do not insert an IVC filter routinely in patients with acute HIT, whether acute isolated HIT or complicated by thrombosis. D 6. Specific circumstances Pediatric patients: Consider using the same procedures for monitoring platelet counts in pediatric patients treated with heparin as in adult patients. E Initiate sodium danaparoid or argatroban, with rigorous dose adjustment based on weight and bioassay results, in pediatric patients with HIT. E Pregnant patients, management: As per GIHP 2020 guidelines, consider preferring danaparoid, or fondaparinux if danaparoid is not available, in pregnant patients with HIT. E As per ACCP 2012 guidelines, consider initiating danaparoid over other non-heparin anticoagulants in pregnant patients with acute or subacute HIT. Consider initiating lepirudin or fondaparinux only when danaparoid is not available. C As per BCSH 2012 guidelines, initiate a non-cross-reacting anticoagulant (danaparoid, where available, or fondaparinux) in pregnant patients with HIT. B Pregnant patients (diagnosis): Recognize that HIT in pregnant women is extremely rare. B Obtain baseline measurement platelet count, and repeat testing a week later, to screen for HIT in pregnant patients initiated on therapeutic LMWH. B Patients with hepatic impairment: Initiate argatroban at 1 g/kg/min and reduce it to 0.5 g/kg/min in patients with moderate hepatic failure (Child-Pugh B). E Consider initiating bivalirudin, danaparoid, or fondaparinux in patients with acute HIT with severe hepatic impairment (Child-Pugh C). Do not use argatroban in patients with severe hepatic impairment. E Patients with renal impairment: As per GIHP 2020 guidelines: Initiate argatroban for HIT in patients with severe renal failure (CrCl < 30 mL/min). E https://web.pathway.md/diseases/recR76V6DESBdk0f1 10/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway Do not use danaparoid as first-line therapy in patients with severe renal failure. D As per ACCP 2012 guidelines, consider initiating argatroban over other non-heparin anticoagulants in patients with renal impairment. C As per BCSH 2012 guidelines, consider obtaining an anti-Xa assay with specific danaparoid calibrators to monitor the anticoagulant effect of danaparoid in patients with a GFR < 30 mL/min. C Patients requiring renal replacement therapy: As per GIHP 2020 guidelines: Consider using citrate or argatroban as the preferred treatment for circuit anticoagulation for RRT in the case of HIT. E Consider administering citrate or argatroban as the preferred treatment for circuit anticoagulation in patients with HIT undergoing RRT. E As per ASH 2018 guidelines: Consider administering argatroban, danaparoid, or bivalirudin rather than other non-heparin anticoagulants in patients with acute HIT receiving RRT and requiring anticoagulation to prevent thrombosis of the dialysis circuitry. C Consider administering regional citrate rather than heparin or other non-heparin anticoagulants in patients with subacute HIT A, subacute HIT B, or remote HIT receiving RRT, not otherwise receiving anticoagulation, and requiring anticoagulation to prevent thrombosis of the dialysis circuit. C As per ACCP 2012 guidelines: Consider administering argatroban or danaparoid over other non-heparin anticoagulants in patients with acute or subacute HIT requiring RRT. C Consider administering regional citrate over heparin or LMWH in patients with a previous history of HIT requiring ongoing RRT or catheter locking. C As per KDIGO 2012 guidelines: Administer direct thrombin inhibitors (such as argatroban) or factor Xa inhibitors (such as danaparoid or fondaparinux) during RRT in patients with HIT. B Consider administering argatroban rather than other thrombin or factor Xa inhibitors during RRT in patients with HIT without severe liver failure. C Patients requiring PCI: As per ACC 2022 guidelines, initiate bivalirudin or argatroban to replace UFH to avoid thrombotic complications in patients with HIT undergoing PCI. B As per GIHP 2020 guidelines, consider initiating bivalirudin or an analog, or argatroban if it fails, in patients with acute HIT requiring transluminal angioplasty for ACS . E As per CAIC 2019 guidelines, initiate bivalirudin over UFH or LMWH for procedural anticoagulation in patients with STEMI and a history of HIT undergoing primary PCI. B As per ESC 2019 guidelines, initiate bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/hour for up to 4 hours after the procedure) in patients with HIT undergoing PCI. B https://web.pathway.md/diseases/recR76V6DESBdk0f1 11/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway As per ASH 2018 guidelines: Consider initiating bivalirudin rather than other non-heparin anticoagulants in patients with acute HIT or subacute HIT A requiring PCI. C Consider initiating bivalirudin rather than UFH in patients with subacute HIT B or remote HIT requiring PCI. C As per ESC 2018 guidelines, initiate bivalirudin as the anticoagulant agent of choice in patients with HIT undergoing primary PCI. B As per ACCP 2012 guidelines: Consider initiating bivalirudin C or argatroban over other non-heparin anticoagulants in patients with acute or subacute HIT requiring PCI. C Offer the same treatment in patients with a history of HIT requiring cardiac catheterization or PCIs as in patients with acute or subacute HIT. As per BCSH 2012 guidelines, initiate bivalirudin in patients with previous or present HIT requiring coronary intervention, including angiography and PCI. B Patients requiring cardiac surgery: As per GIHP 2020 guidelines, consider obtaining an ELISA for anti-PF4 antibodies before any cardiac surgery in patients with a documented history of HIT. E Show 2 more As per ASH 2018 guidelines, delay surgery until the patient has subacute HIT B or remote HIT, if feasible, in patients with acute HIT or subacute HIT A requiring cardiovascular surgery. Show 2 more As per SVS 2018 guidelines, administer a thrombin inhibitor, such as bivalirudin or argatroban, as an alternative to heparin in patients with a history of HIT undergoing open surgical repair of an AAA. B As per ACCP 2012 guidelines, consider administering bivalirudin over other non-heparin anticoagulants and over heparin plus antiplatelet agents in patients with acute (thrombocytopenic, antibody-positive HIT) or subacute (platelets recovered, but still antibody- positive HIT) HIT requiring urgent cardiac surgery. C Show 2 more As per BCSH 2012 guidelines, administer intraoperative UFH in preference to other anticoagulants in antibody-negative (usually after > 100 days) patients with previous HIT requiring cardiac surgery. Initiate an anticoagulant other than UFH or LMWH for pre- and postoperative anticoagulation. B Patients requiring non-cardiac surgery: consider postponing any surgery beyond the first month following the diagnosis of acute HIT (< 1 month) if this does not generate a major vital or functional risk for the patient. Define the modalities during a multidisciplinary consultation. E Show 2 more Patients with non-HIT related thrombosis: consider initiating fondaparinux at full therapeutic doses until the transition to vitamin K antagonists in patients with a past history of HIT presenting https://web.pathway.md/diseases/recR76V6DESBdk0f1 12/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway with an acute thrombosis (not related to HIT) and normal renal function. C 7. Preventative measures Secondary prevention: As per GIHP 2020 guidelines, consider initiating an OAC (vitamin K antagonist or DOAC) or fondaparinux in patients with a history of HIT requiring prophylactic or curative anticoagulation. Consider initiating argatroban, bivalirudin, or danaparoid only when OACs and fondaparinux are contraindicated. E As per ASH 2018 guidelines, initiate a non-heparin anticoagulant (such as apixaban, dabigatran, danaparoid, edoxaban, fondaparinux, rivaroxaban, or a vitamin K antagonist) rather than UFH or LMWH in patients with remote HIT requiring VTE treatment or prophylaxis. B 8. Quality improvement Documentation: consider obtaining a hemostasis consultation within 3 months of the diagnosis of HIT and provide a card attesting this complication, specifying the results of the biological tests, and recommending the exclusion of all heparin treatment to the patient. E Medical alert bracelet: Consider offering carrying or wearing an emergency identifier (such as an emergency pendant or bracelet) in patients with a history of HIT in the past 3 months. C Avoid offering carrying or wearing an emergency identifier in patients with a history of HIT > 3 months ago. D References 1. Lori-Ann Linkins, Antonio L Dans, Lisa K Moores et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141 2 Suppl):e495S- e530S. Open 2. Adam Cuker, Gowthami M Arepally, Beng H Chong et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018 Nov 27;2 22 3360 3392. Open 3. Yves Gruel, Emmanuel De Maistre, Claire Pouplard et al. Diagnosis and management of heparin-induced thrombocytopenia. Anaesth Crit Care Pain Med. 2020 Apr;39 2 291 310. Open 4. Jennifer S Lawton, Jacqueline E Tamis-Holland, Sripal Bangalore et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Jan 18;145 3):e18-e114. Open https://web.pathway.md/diseases/recR76V6DESBdk0f1 13/14 6/24/23, 12:31 PM Heparin-induced thrombocytopenia Pathway 5. Henry Watson, Simon Davidson, David Keeling et al. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012 Dec;159 5 528 40. Open 6. J C Easaw, M A Shea-Budgell, C M J Wu et al. Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2 treatment. Curr Oncol. 2015 Apr;22 2 144 55. Open 7. Elliot L Chaikof, Ronald L Dalman, Mark K Eskandari et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg. 2018 Jan;67 1 2 77.e2. Open 8. Arif Khwaja. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120 4):c179 84. Open 9. Miguel Sousa-Uva, Franz-Josef Neumann, Anders Ahlsson et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur J Cardiothorac Surg. 2019 Jan 1;55 1 4 90. Open 10. Wong GC, Welsford M, Ainsworth C et al. 2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion. Can J Cardiol. 2019 Feb;35 2 107 132. Open 11. Chan WS, Rey E, Kent NE et al. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can. 2014 Jun;36 6 527 53. Open 12. Borja Ibanez, Stefan James, Stefan Agewall et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology ESC . Eur Heart J. 2018 Jan 7;39 2 119 177. Open 13. American Society of Hematology. Choosing Wisely ASH recommendations. Choosing Wisely. 2014. Open 14. Mark Andrew Crowther, Deborah J Cook, Martin Albert et al. The 4Ts scoring system for heparin- induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care. 2010 Jun;25 2 287 93. Open 15. Steven Coutre, MDMark Crowther, MD et al. Management of heparin-induced thrombocytopenia. UpToDate.Management of heparin-induced thrombocytopenia.2021. Open 16. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open https://web.pathway.md/diseases/recR76V6DESBdk0f1 14/14

Guideline sources The following summarized guidelines for the evaluation and management of hepatic adenoma are prepared by our editorial team based on guidelines from the Enhanced Recovery After Surgery Society (ERASS 2023), the American College of Radiology (ACR 2020), the European Federation of Societies for Ultrasound (EFSU 2020), the European Association for the Study of the Liver (EASL 2019; 2016), and the American College of Gastroenterology (ACG 2016; 2014). 1 2 3 4 5 6 7 Guidelines 1. Classification and risk stratification Risk factors: recognize that oral contraceptives may be considered risk factors for the development of hepatic adenoma. B https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 1/6 6/24/23, 12:40 PM Hepatic adenoma Pathway Show 2 more 2. Diagnostic investigations Contrast-enhanced ultrasound: As per ACR 2020 guidelines: Obtain contrast-enhanced abdominal ultrasound of an indeterminate > 1 cm liver lesion on initial ultrasound in patients with a normal liver with no suspicion or evidence of extrahepatic malignancy or underlying liver disease. B Obtain contrast-enhanced abdominal ultrasound of an incidental liver lesion > 1 cm on initial ultrasound, non-contrast or single-phase CT, or non-contrast MRI in patients with known chronic liver disease. B As per EFSU 2020 guidelines, obtain liver ultrasound using B-mode and Doppler mode before obtaining contrast-enhanced ultrasound to characterize focal liver lesions. B Show 14 more Cross-sectional imaging: As per ACR 2020 guidelines, obtain contrast-enhanced multiphase CT, contrast-enhanced MRI, or contrast-enhanced ultrasound of an indeterminate > 1 cm liver lesion on initial ultrasound in patients with a normal liver with no suspicion or evidence of extrahepatic malignancy or underlying liver disease. B Show 7 more As per EASL 2016 guidelines: Prefer MRI as it is superior to all other imaging modalities and due to its intrinsic properties to detect fat and vascular spaces it offers an opportunity to subtype hepatocellular adenoma up to 80%. B Recognize that MRI can identify hepatocyte nuclear factor-1 alpha hepatocellular adenoma and inflammatory hepatocellular adenoma with > 90% specificity, whereas identification of - catenin-activated hepatocellular adenoma and its distinction with unclassified hepatocellular adenoma and HCC is not possible by any imaging technique. B 3. Diagnostic procedures Liver biopsy: perform a liver biopsy in patients with inconclusive imaging findings and if a biopsy is deemed necessary to make treatment decisions. B 4. Medical management Indications for treatment: As per EASL 2016 guidelines: Decide on the treatment based on gender, size, and pattern of progression. B https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 2/6 6/24/23, 12:40 PM Hepatic adenoma Pathway Decide on the management of patients with multiple hepatocellular adenomas based on the size of the largest tumor. B As per ACG 2014 guidelines, offer operative or nonoperative management in patients with hepatocellular adenoma 5 cm because of the risk of rupture and malignancy. B 5. Therapeutic procedures Embolization: perform embolization of a bleeding hepatocellular adenoma with hemodynamic instability. B 6. Perioperative care Preoperative care (counseling): Provide preoperative information and counseling regarding the upcoming liver surgery. Consider using brochures and multimedia support to improve verbal counseling. B Advise preoperative smoking cessation at least 4 weeks before hepatectomy. Advise alcohol cessation in heavy drinkers (> 24 g/day for females or > 36 g/day for males) 4-8 weeks before surgery. A Preoperative care (nutrition): obtain a nutritional assessment before liver surgery. Administer enteral supplementation at least 7-14 days before surgery to optimize nutritional status in malnourished patients (weight loss > 10% or > 5% over 3 months and reduced BMI or a low fat- free mass index). A Show 2 more Preoperative care (rehabilitation): offer prehabilitation in high-risk patients (elderly, malnourished or overweight patients, smokers, or patients with psychological disorders) before liver surgery. Initiate prehabilitation 4-6 weeks before the operation depending upon the urgency of surgery. Insufficient evidence to recommend the content (physical exercises, dietary interventions, or anxiety reduction exercises) and duration of the prehabilitation program for liver surgery. B Preoperative care (biliary drainage): perform biliary drainage in the cholestatic liver (> 50 mmol/L). Avoid performing surgery until the bilirubin level drops < 50 mmol/L. B Preoperative care (antibiotic prophylaxis): administer antibiotic prophylaxis (such as cefazolin) within 60 minutes before surgical incision with no extension into the postoperative period. Consider administering a targeted antibiotic preemptive regimen based on preoperative bile culture in case of complex liver surgery with biliary reconstruction. B Preoperative care (corticosteroids): administer a preoperative dose of corticosteroids (methylprednisolone 500 mg). Insufficient evidence for its use in diabetic patients undergoing liver surgery. B Preoperative care (preanesthetic medication): avoid administering long-acting anxiolytic drugs, particularly in the elderly. D https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 3/6 6/24/23, 12:40 PM Hepatic adenoma Pathway Show 3 more Intraoperative care (anesthesia and analgesia): Administer multimodal analgesia, including the potential use of intrathecal opioids, both for open A and laparoscopic surgery. B Recognize that thoracic epidural analgesia can provide excellent analgesia for open liver surgery but has significant disadvantages. Do not use regional anesthesia techniques in laparoscopic surgery as multimodal analgesia combined with judicious IV opioids provide functional analgesia. Perform continuous local anesthetic wound infiltration to provide lower complication rates and overall equivalent analgesia to thoracic epidural analgesia. Perform local anesthetic transversus abdominis plane blockade as a supplement to standard analgesia to improve pain control and reduce opioid usage. A Intraoperative care (temperature management): maintain perioperative normothermia with multimodal temperature management (including circulating water garments or forced warm air) during open and minimally invasive liver surgery. B Intraoperative care (fluid management): Maintain low central venous pressure (< 5 cmH O) with close monitoring during hepatic transection. A Prefer balanced crystalloids over 0.9% saline or colloids for fluid maintenance. Provide goal- directed fluid therapy to optimize cardiac output and end-organ perfusion, recognizing that this may be particularly beneficial after the intraoperative liver resection during a low central venous pressure state to restore tissue perfusion, with patients having comorbidities and reduced cardiac function benefiting the most. A Postoperative care (thromboprophylaxis): administer routine postoperative LMWH or UFH to reduce the risk of thromboembolic events unless exceptional circumstances make this unsafe. Use intermittent pneumatic compression devices to reduce this risk further. B Postoperative care (early mobilization): initiate early mobilization (out of bed) after liver surgery from the operative day until hospital discharge. Insufficient evidence regarding the optimal duration of mobilization. B Postoperative care (nutrition): implement early oral intake with a normal diet after hepatectomy. Assess the individualized needs for artificial nutrition in malnourished patients, patients with complications causing several days of fasting, and patients with liver cirrhosis. Prefer enteral administration for artificial nutrition. A Show 2 more Postoperative care (antiemetics): use a multimodal approach to postoperative nausea and vomiting. Administer postoperative nausea and vomiting prophylaxis with at least 2 antiemetic drugs, such as dexamethasone and ondansetron. A Postoperative care (laxatives): insufficient evidence to support the routine use of postoperative laxatives, gum chewing, herbal medicine, or decoction to stimulate bowel movement after liver surgery. I https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 4/6 6/24/23, 12:40 PM Hepatic adenoma Pathway 7. Surgical interventions Surgical resection (indications): perform resection in patients with hepatocellular adenoma irrespective of size in males and in any instance of proven -catenin mutation. B Show 3 more Liver transplantation: do not offer liver transplantation in patients with multiple hepatocellular adenomas. Consider offering liver transplantation in patients with underlying liver disease. D Surgical resection (technical considerations): perform liver resection laparoscopically, in trained teams and when clinically appropriate, to reduce the postoperative length of stay and complication rates. B Show 3 more 8. Specific circumstances Pregnant patients: monitor hepatic adenomas with ultrasound during pregnancy for growth. Refer patients with large adenomas (> 5 cm) for resection before pregnancy. B 9. Patient education General counseling: As per EASL 2016 guidelines, advise lifestyle changes such as discontinuation of oral contraceptives as well as weight loss upon hepatocellular adenoma diagnosis. B As per ACG 2014 guidelines: Advise avoiding oral contraceptives, hormone-containing intrauterine devices, and anabolic steroids in patients with hepatocellular adenoma. B Counsel patients that pregnancy is not generally contraindicated in hepatocellular adenoma < 5 cm and offer an individualized approach in these patients. B 10. Follow-up and surveillance Serial imaging assessment: As per EASL 2016 guidelines, reassess female patients with lesions < 5 cm at 1 year, and annually thereafter. B As per ACG 2014 guidelines, obtain follow-up CT or MRI at 6-12-month intervals in patients with lesions suspected of being hepatocellular adenoma, if no therapeutic intervention is pursued. Decide on the duration of monitoring based on the growth patterns and stability of the lesion over time. B References https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 5/6 6/24/23, 12:40 PM Hepatic adenoma Pathway 1. Marrero JA, Ahn J, Rajender Reddy K et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014 Sep;109 9 1328 47. Open 2. Ga tan-Romain Joliat, Kosuke Kobayashi, Kiyoshi Hasegawa et al. Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery ERAS Society Recommendations 2022. World J Surg. 2023 Jan;47 1 11 34. Open 3. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 4. Expert Panel on Gastrointestinal Imaging, Victoria Chernyak, Jeanne M Horowitz et al. ACR Appropriateness Criteria Liver Lesion-Initial Characterization. J Am Coll Radiol. 2020 Nov;17 11S S429 S446. Open 5. European Association for the Study of the Liver EASL . EASL Clinical Practice Guidelines on the management of benign liver tumours. J Hepatol. 2016 Aug;65 2 386 98. Open 6. European Association for the Study of the Liver, Clinical Practice Guideline Panel: Chair, Panel members et al. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019 Jun;70 6 1222 1261. Open 7. Christoph F Dietrich, Christian P llson Nols e, Richard G Barr et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound CEUS in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020 Oct;46 10 2579 2604. Open 8. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open https://web.pathway.md/diseases/recJem7gvtVJ5xwBl 6/6

Guideline sources The following summarized guidelines for the evaluation and management of hepatic artery aneurysm are prepared by our editorial team based on guidelines from the Society for Vascular Surgery (SVS 2020). 1 Guidelines 1. Diagnostic investigations Diagnostic imaging: Obtain CT angiography as the diagnostic tool of choice in patients with suspected hepatic artery aneurysm. B Obtain mesenteric angiography for preoperative planning of patients with hepatic artery aneurysm considered for intervention. B Screening for other aneurysms: Consider obtaining abdominal axial imaging to screen for concomitant intra-abdominal aneurysms if CT angiography has not obtained at the time of hepatic artery aneurysm diagnosis. C Consider obtaining one-time screening CT angiography or MRA of the head, neck and chest in patients with nonatherosclerotic causes of hepatic artery aneurysm. C https://web.pathway.md/diseases/rectSqCrDBU1EYeH9 1/2 6/24/23, 12:41 PM Hepatic artery aneurysm Pathway 2. Therapeutic procedures Indications for repair: repair all hepatic artery pseudoaneurysms, regardless of cause, as soon as the diagnosis is made, given the high propensity of rupture and significant antecedent mortality. A Show 3 more Choice of repair: perform an endovascular intervention as the first approach, if anatomically feasible (if this approach maintains arterial circulation to the liver), in all patients with hepatic artery aneurysms. A Show 2 more 3. Follow-up and surveillance Surveillance imaging: consider obtaining annual follow-up with CT angiography or non-contrast- enhanced CT to monitor patients with asymptomatic hepatic artery aneurysm. C References 1. Rabih A Chaer, Christopher J Abularrage, Dawn M Coleman et al. The Society for Vascular Surgery clinical practice guidelines on the management of visceral aneurysms. J Vasc Surg. 2020 Jul;72 1S 3S 39S. Open https://web.pathway.md/diseases/rectSqCrDBU1EYeH9 2/2

Guideline sources The following summarized guidelines for the evaluation and management of hepatic cyst are prepared by our editorial team based on guidelines from the European Association for the Study of the Liver (EASL 2022) and the American College of Gastroenterology (ACG 2014). 1 2 Guidelines 1. Diagnostic investigations Diagnostic imaging: As per EASL 2022 guidelines, obtain ultrasound as the first-line imaging for the diagnosis of hepatic cysts. B Show 2 more As per ACG 2014 guidelines, obtain CT or MRI for further evaluation of a hepatic cyst identified on ultrasound with septations, fenestrations, calcifications, irregular walls, or daughter cysts. B Evaluation of mucinous cystic neoplasms: View a combination of 1 major and 1 minor feature as worrisome features for mucinous cystic neoplasms of the liver: major features: thick septation, nodularity https://web.pathway.md/diseases/recINRFlhaXp4fSIT 1/3 6/24/23, 12:40 PM Hepatic cyst Pathway minor features: upstream biliary dilatation, thin septations, internal hemorrhage, perfusional change, < 3 coexistent hepatic cysts. B Show 3 more Evaluation of cyst infection: diagnose definite hepatic cyst infection in the presence of neutrophil debris and/or microorganisms in cyst aspirate. B Show 2 more Evaluation of cyst hemorrhage: consider obtaining imaging to detect intracystic hemorrhage in patients with sudden and severe abdominal pain. C Show 2 more Evaluation of Caroli disease/syndrome: evaluate for congenital hepatic fibrosis to differentiate Caroli disease from Caroli syndrome in patients with multiple segmental cystic or saccular dilatations of bile ducts. B 2. Therapeutic procedures Drainage: As per EASL 2022 guidelines, offer the best locally available volume-reducing therapy for the treatment of symptomatic simple hepatic cysts without biliary communication. B As per ACG 2014 guidelines, do not perform aspiration of asymptomatic simple hepatic cysts. D 3. Surgical interventions Laparoscopic deroofing: consider performing laparoscopic deroofing rather than aspiration and sclerotherapy, dictated based on the availability of local expertise, in symptomatic patients with simple hepatic cysts. C 4. Specific circumstances Patients with cyst infection (antibiotic therapy): administer fluoroquinolones and third- generation cephalosporins for 4-6 weeks B as empirical first-line antibiotics in patients with hepatic cyst infection. B Patients with cyst infection (secondary prophylaxis): Do not administer secondary prophylaxis for hepatic cyst infection. D Insufficient evidence to recommend selective decontamination of the digestive tract to prevent hepatic cyst infection. I Patients with cyst hemorrhage: interrupt anticoagulants temporarily in patients with hepatic cyst hemorrhage B , and consider resuming 7-15 days after the onset of hepatic cyst hemorrhage. B https://web.pathway.md/diseases/recINRFlhaXp4fSIT 2/3 6/24/23, 12:40 PM Hepatic cyst Pathway Patients with cyst infection (drainage): Perform drainage of infected hepatic cysts in the presence of any of the following features: persistence of temperature > 38.5 C after 48 hours on empirical antibiotic therapy isolation of pathogens unresponsive to antibiotic therapy from a cyst aspirate severe immunocompromise CT or MRI detecting gas in a cyst large infected hepatic cysts. B Patients with mucinous cystic neoplasms: perform surgical resection, aiming for complete resection, as the gold standard for the management of patients with suspected mucinous cystic neoplasms. B Patients with biliary hamartomas: obtain MRI with heavily T2-weighted sequences and magnetic resonance cholangiography sequences for the diagnosis of biliary hamartomas. B Show 2 more Patients with Caroli disease/syndrome: Consider obtaining surveillance for cholangiocarcinoma with MRCP every 12 months after diagnosis in patients with Caroli disease and syndrome. C Consider referring patients with Caroli disease or syndrome with recurrent cholangitis for liver transplantation in the presence of bilobar involvement or monolobar involvement in combination with liver fibrosis or portal hypertension when the possibility of liver resection has been excluded. B 5. Follow-up and surveillance Serial imaging assessment: do not monitor asymptomatic patients with simple hepatic cysts or peribiliary cysts. D Show 2 more Expectant management: observe asymptomatic patients with simple hepatic cysts with expectant management. B References 1. European Association for the Study of the Live. EASL Clinical Practice Guidelines on the management of cystic liver diseases. EASL. 2022 Jun. Open 2. Marrero JA, Ahn J, Rajender Reddy K et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014 Sep;109 9 1328 47. Open https://web.pathway.md/diseases/recINRFlhaXp4fSIT 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hepatic encephalopathy (HE) are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2023), the European Association for the Study of the Liver (EASL 2022; 2018), the Baveno VII Consensus Workshop (Baveno VII 2022), the Italian Association for the Study of the Liver (AISF 2019), and the European Association for the Study of the Liver (EASL/AASLD 2014). 1 2 3 4 5 6 7 7 8 8 9 10 11 Definition https://web.pathway.md/diseases/reciwA55EyqDknXId 1/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway HE is a reversible neuropsychiatric abnormality found in patients with chronic liver disease and/or portosystemic shunting. 7 Epidemiology The pathophysiology of HE is multifactorial and involves agents such as ammonia, inflammatory cytokines, manganese deposition in the basal ganglia, and benzodiazepine-like compounds. Fecal microbiota and aromatic amino acids also play a role. 7 Pathophysiology In the United States, the incidence of hospital admission for HE is approximately 30 cases per 100,000 person-years. In patients with decompensated cirrhosis, the prevalence of HE is up to 20%. 8 9 Disease course HE is associated with clinical manifestations of neuronal dysfunction (delirium, seizures). If untreated, severe HE may result in brain edema, coma, and death. 10 Prognosis and risk of recurrence The in-hospital mortality of patients with HE is estimated at 14.1-15.6%. Patients with cirrhosis who develop HE have an estimated 1-year survival probability of 42% and 3-year survival probability of 23%. 8 11 CalculatorGlasgow Coma Scale GCS CalculatorWest-Haven criteria for hepatic Guidelines 1. Screening and diagnosis Screening for covert hepatic encephalopathy: As per EASL 2022 guidelines, screen patients with cirrhosis and no history of overt HE for covert HE with validated (with available experience/tools and local norms) tests. B As per AISF 2019 guidelines: Screen for covert HE using the Animal Naming Test (the number of animals listed in 60 seconds) in all patients with cirrhosis. B Screen for minimal HE using combined neuropsychological and neurophysiological indices in patients with a job and lifestyle requiring high standards of functioning. B https://web.pathway.md/diseases/reciwA55EyqDknXId 2/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Diagnosis: As per AISF 2019 guidelines, exclude other causes of mental impairment through systematic and careful evaluation in order to diagnose type A HE. B As per AASLD 2014 guidelines, diagnose HE by excluding other causes of brain dysfunction. Obtain a diagnostic workup considering other disorders able to alter brain function and mimic HE. A Show 2 more Differential diagnosis: As per EASL 2022 guidelines: Identify alternative or additional causes of neuropsychiatric impairment in patients with suspected HE, to improve prognostic accuracy and the results of treatment. B Recognize that features of covert HE and mild cognitive impairment of an etiology other than liver dysfunction show significant overlap. B As per AISF 2019 guidelines, conduct a differential diagnosis with particular attention to dementing disorders in case of a lack of response to treatment in patients with minimal or covert HE. B 2. Classification and risk stratification Classification: As per EASL 2022 guidelines, classify HE according to the underlying condition: Situation Guidance ALF Type A Portosystemic shunt Type B Cirrhosis. B Type C Show 5 more As per AISF 2019 guidelines, classify HE according to the following criteria: Situation Guidance Type A Underlying condition Type B Type C Covert Severity of mental alteration Overt Episodic Time course of mental alteration https://web.pathway.md/diseases/reciwA55EyqDknXId 3/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Recurrent Persistent Yes, and if so, which ones Presence of precipitating and facilitating events No. B As per AASLD 2014 guidelines, classify HE according to the type of underlying disease, severity of manifestations, time course, and precipitating factors. A Severity grading: As per EASL 2022 guidelines, use the West Haven criteria for grading the HE in patients with at least temporal disorientation (from West Haven grades 2). Add the Glasgow coma scale in patients with grades III-IV West Haven criteria. B As per AISF 2019 guidelines, consider using a combination of the West Haven criteria, the presence/absence of flapping tremor, and the Glasgow Coma Scale to grade type C, overt HE. C As per AASLD 2014 guidelines: Grade overt HE according to the West-Haven criteria and the GCS. B Classify HE into various stages of severity, reflecting the degree of self-sufficiency and the need for care. B 3. Diagnostic investigations Serum ammonia levels: As per EASL 2022 guidelines, obtain serum ammonia level measurement in patients with delirium/encephalopathy and liver disease, as a normal value brings the diagnosis of HE into question. B As per AISF 2019 guidelines, obtain venous blood ammonia level measurement as part of the workup in all forms of new-onset unexplained delirium to aid in identifying unrecognized type B HE. B As per AASLD 2014 guidelines, recognize that increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with chronic liver disease. Obtain diagnostic reevaluation in case of a normal value. B Neurophysiological testing: As per EASL 2022 guidelines, obtain a neuropsychological/neurophysiological or therapeutic test for the diagnosis of covert HE in patients with no or mild neuropsychiatric abnormalities (not meeting the criteria for the diagnosis of HE grades 2 based on the West Haven criteria). B As per AASLD 2014 guidelines, consider obtaining neurophysiological and psychometric tests by experienced examiners for the diagnosis and grading of minimal HE and covert HE. C Brain imaging: As per EASL 2022 guidelines: https://web.pathway.md/diseases/reciwA55EyqDknXId 4/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Obtain brain CT or MRI in patients with delirium/encephalopathy and liver disease in case of diagnostic doubts or nonresponse to treatment. B Recognize that no cerebral imaging proves a diagnosis of HE. B As per AISF 2019 guidelines, obtain brain imaging to rule out alternative or coexisting causes of brain damage only in the following situations: unusual clinical profile abrupt/severe onset of symptoms focal neurological signs limited or no response to treatment of the precipitant and/or ammonia-lowering treatment over the first 12-24 hours. B Abdominal imaging: Obtain abdominal CT angiography to identify non-cirrhotic portal hypertension and portosystemic shunts in patients with hyperammonemia in the absence of significant liver damage. B Obtain Doppler ultrasound, and abdominal CT angiography if ultrasound is negative, for the assessment of spontaneous portosystemic shunts in patients with persistent or highly recurrent HE. B 4. Respiratory support Mechanical ventilation: consider intubating patients with grades III-IV HE. C 5. Medical management Setting of care: As per EASL 2022 guidelines: Admit patients with grades 3-4 overt HE to the ICU as they are at risk of aspiration. B Admit patients with HE to the ICU based on clinical judgment as there is no single marker that can identify patients who will benefit from ICU admission. B As per AISF 2019 guidelines, admit patients with high-grade overt HE at risk or unable to protect their airways to the ICU. B Management of precipitating factors: As per EASL 2022 guidelines: Assess and manage precipitating factors in patients with HE. B Attempt to control the progression of the underlying liver disease in patients with HE. B As per AISF 2019 guidelines, identify any facilitating and precipitating events once there is a working diagnosis of type C overt HE. B As per AASLD 2014 guidelines, identify and treat precipitating factors in patients with HE. A https://web.pathway.md/diseases/reciwA55EyqDknXId 5/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Indications for treatment: As per EASL 2022 guidelines, consider initiating anti-HE treatment for the purposes of differential diagnosis and to prevent overt HE in patients with covert HE. B As per AISF 2019 guidelines, treat episodes of spontaneous or precipitated overt HE. B Show 2 more As per AASLD 2014 guidelines: Treat all episodes of overt HE, whether spontaneous or precipitated. A Treat minimal HE and covert HE episodes only on a case-by-case basis. B Nonabsorbable disaccharides: As per EASL 2022 guidelines, administer nonabsorbable disaccharides for the treatment of patients with covert HE. B As per AASLD 2014 guidelines, administer lactulose as first-line therapy for episodic overt HE. B Landmark trials: Rifaximin plus lactulose for hepatic encephalopathy In patients with overt hepatic encephalopathy, lactulose and rifaximin were superior to lactulose only with respect to complete reversal of hepatic encephalopathy. Sharma BC et al. Am J Gastroenterol. 2013 Sep. Oral branched-chain amino acids: Consider administering oral branched-chain amino acid supplementation to achieve and maintain recommended nitrogen intake in patients intolerant to dietary protein. C Consider administering oral branched-chain amino acids as an alternative or additional agent for the treatment of patients with HE not responding to conventional therapy. B Intravenous L-ornithine L-aspartate: consider administering IV L-ornithine L-aspartate as an alternative or additional agent in patients with HE not responding to conventional therapy. B Dopaminergic agents: administer dopaminergic agents for the treatment of patients with cirrhosis-related Parkinsonism. B Antibiotic therapy: consider administering neomycin C or metronidazole as an alternative option in patients with HE. C Landmark trials: Rifaximin plus lactulose for hepatic encephalopathy In patients with overt hepatic encephalopathy, lactulose and rifaximin were superior to lactulose only with respect to complete reversal of hepatic encephalopathy. Sharma BC et al. Am J Gastroenterol. 2013 Sep. https://web.pathway.md/diseases/reciwA55EyqDknXId 6/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Diuretic therapy: avoid diuretic therapy in patients with persistent overt HE. D Discontinuation of treatment: consider discontinuing anti-HE therapy on an individual basis in patients with a history of overt HE, improved liver function and nutritional status, and controlled precipitant factors. C 6. Inpatient care Serial clinical assessment: assess for signs of intracranial hypertension at regular intervals and monitor for intracranial pressure and manage according to available pertinent guidelines. B 7. Nonpharmacologic interventions Dietary modifications: As per EASL 2022 guidelines, consider replacing animal protein with vegetable and dairy protein in patients with recurrent/persistent HE, taking into account the patient's tolerance, provided that overall protein intake is not compromised. C As per AISF 2019 guidelines: Do not reduce protein intake/administration. D Do not replace meat with vegetables (pulses) and/or dairy protein, except in patients truly intolerant to meat protein. D As per AASLD 2014 guidelines: Ensure a daily energy intake of 35-40 kcal/kg of ideal body weight and a daily protein intake of 1.2-1.5 g/kg. B Offer small meals or liquid nutritional supplements evenly distributed throughout the day and a late-night snack. B Vitamin and micronutrient supplements: As per EASL 2022 guidelines: Treat demonstrated or suspected vitamin/micronutrient deficiencies in patients with HE as they can compound HE. B Do not administer zinc supplementation routinely in patients with HE. D As per AISF 2019 guidelines: Treat vitamin and micronutrient deficiencies as they may worsen mental function and confound the diagnosis of HE. B Consider initiating zinc supplementation in patients with type C, overt HE with documented zinc deficiency. C 8. Therapeutic procedures https://web.pathway.md/diseases/reciwA55EyqDknXId 7/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Albumin dialysis: consider performing albumin dialysis to ameliorate HE in patients with liver failure and overt HE. C Occlusion of portosystemic shunts: As per EASL 2022 guidelines, consider performing obliteration of accessible portosystemic shunts in stable patients with cirrhosis with recurrent/persistent HE (despite adequate medical treatment) with a Model for End-stage Liver Disease score < 11. C As per AISF 2019 guidelines: Perform surgical shunt reduction/obliteration in patients with persistent or highly recurrent type C, overt HE. B Assess the feasibility, pros and cons of shunt obliteration in patients with type B HE as this has the potential to cure the disease. B Liver support system: do not use liver support systems for the treatment of patients with type A HE. D Fecal microbiota transplantation: do not perform fecal microbiota transplantation routinely in patients with recurrent/persistent HE. D 9. Perioperative care Pre-TIPS prophylaxis: Consider administering rifaximin for prophylaxis of HE before non-urgent TIPS placement in patients with cirrhosis and previous episodes of overt HE. B Assess for the presence and/or history of overt and covert HE in patients scheduled for a non- urgent TIPS placement. Recognize that one single episode of HE is not an absolute contraindication, especially if precipitated by bleeding. B 10. Surgical interventions Liver transplantation: As per EASL 2022 guidelines, consider performing liver transplantation in patients with recurrent/persistent HE. Refer patients promptly to a center for evaluation in case of the first episode of overt HE. B Show 2 more As per AISF 2019 guidelines, use a combination of clinical and imaging criteria examined by a multidisciplinary expert team to recognize irreversible brain damage in patients with severe coma, in order to avoid futile liver transplantation. B Show 2 more As per AASLD 2014 guidelines, evaluate patients with intractable overt HE and liver failure for liver transplantation. A https://web.pathway.md/diseases/reciwA55EyqDknXId 8/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway 11. Specific circumstances Patients with acute-on-chronic liver failure: consider administering nonabsorbable disaccharides in critically ill patients with acute-on-chronic liver failure and overt HE. C Show 4 more 12. Patient education General counseling: counsel patients with a history of overt HE episode about the risks associated with driving and the appropriateness of formal driving assessment with the relevant authorities. B 13. Preventative measures Avoidance of precipitating factors: Avoid worsening/decompensation of the underlying liver disease, if possible, for the prevention of overt HE. D Avoid and manage precipitants, such as infection, constipation, and dehydration, for the prevention of overt HE. D Primary prevention: As per EASL 2022 guidelines, consider removing the blood from the gastrointestinal tract promptly with lactulose or mannitol by nasogastric tube, or lactulose enemas to prevent HE in patients presenting with gastrointestinal bleeding. B As per AISF 2019 guidelines, do not offer primary prophylaxis for the prevention of overt HE, with the exception of rapid removal of blood from the gastrointestinal tract after an upper gastrointestinal bleeding. D Secondary prevention: As per Baveno VII 2022 guidelines: Administer rifaximin for the secondary prophylaxis of HE. A Consider administering rifaximin for prophylaxis of overt HE in patients with previous overt HE undergoing elective TIPS placement. C As per EASL 2022 guidelines: Initiate lactulose as secondary prophylaxis after the first episode of overt HE, and titrate to obtain 2-3 bowel movements per day. A Initiate rifaximin as an adjunct to lactulose for secondary prophylaxis after 1 additional episode of overt HE within 6 months of the first one. B As per AISF 2019 guidelines, address the recurrence of HE as it is frequent, costly, and potentially preventable. B Show 3 more https://web.pathway.md/diseases/reciwA55EyqDknXId 9/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway Likelihood Ratios Pertinent positives The following findings increase the probability of hepatic encephalopathy in adults. 1 1 Finding LR+ Value Increased serum arterial ammonia 1.3 Increased serum venous ammonia 1.1 Pertinent negatives The following findings decrease the probability of hepatic encephalopathy in adults. 1 1 Finding LR- Value serum arterial ammonia not increased 0.4 serum venous ammonia not increased 0.9 References 1. Sara Montagnese, Francesco Paolo Russo, Piero Amodio et al. Hepatic encephalopathy 2018 A clinical practice guideline by the Italian Association for the Study of the Liver AISF . Dig Liver Dis. 2019 Feb;51 2 190 205. Open 2. Vilstrup H, Amodio P, Bajaj J et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60 2 715 35. Open 3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. EASL. 2022 Jun. Open 4. Roberto de Franchis, Jaime Bosch, Guadalupe Garcia-Tsao et al. Baveno VII Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76 4 959 974. Open 5. Rahul Nanchal, Ram Subramanian, Waleed Alhazzani et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations. Crit Care Med. 2023 May 1;51 5 657 676. Open 6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 7. Elwir S, Rahimi RS. Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. J Clin Transl Hepatol. 2017 Jun 28;5 2 142 151. Open 8. Stepanova M, Mishra A, Venkatesan C et al. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol. 2012 Sep;10 9 1034 41.e1. Open 9. Acharya C, Bajaj JS. Current Management of Hepatic Encephalopathy. Am J Gastroenterol. 2018 Nov;113 11 1600 1612. Open https://web.pathway.md/diseases/reciwA55EyqDknXId 10/11 6/24/23, 12:41 PM Hepatic encephalopathy Pathway 10. Wijdicks EF. Hepatic Encephalopathy. N Engl J Med. 2016 Oct 27;375 17 1660 1670. Open 11. Bustamante J, Rimola A, Ventura PJ et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999 May;30 5 890 5. Open 12. American Association for the Study of Liver Diseases. Choosing Wisely AASLD recommendations. Choosing Wisely. 2014. Open 13. Karin Weissenborn. Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles. Drugs. 2019 Feb;79 Suppl 1 5 9. Open https://web.pathway.md/diseases/reciwA55EyqDknXId 11/11

Guideline sources The following summarized guidelines for the evaluation and management of hepatic hemangioma are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2020), the European Federation of Societies for Ultrasound (EFSU 2020), the European Association for the Study of the Liver (EASL 2016), and the American College of Gastroenterology (ACG 2016; 2014). 1 2 3 4 5 Guidelines 1. Diagnostic investigations Contrast-enhanced ultrasound: As per ACR 2020 guidelines: Obtain contrast-enhanced abdominal ultrasound of an indeterminate > 1 cm liver lesion on initial ultrasound in patients with a normal liver with no suspicion or evidence of extrahepatic malignancy or underlying liver disease. B Obtain contrast-enhanced abdominal ultrasound of an incidental liver lesion > 1 cm on initial ultrasound, non-contrast or single-phase CT, or non-contrast MRI in patients with known chronic liver disease. B https://web.pathway.md/diseases/recZPcRcjiO2GFdbJ 1/3 6/24/23, 12:41 PM Hepatic hemangioma Pathway As per EFSU 2020 guidelines, obtain liver ultrasound using B-mode and Doppler mode before obtaining contrast-enhanced ultrasound to characterize focal liver lesions. B Show 14 more As per EASL 2016 guidelines: Obtain contrast-enhanced imaging (such as contrast-enhanced ultrasound) in patients with an oncological condition or an underlying liver disease. B Confirm the diagnosis with contrast-enhanced imaging based on a typical vascular profile characterized by peripheral and globular enhancement in the arterial phase followed by a central enhancement in the delayed phases. B Cross-sectional imaging: As per ACR 2020 guidelines, obtain contrast-enhanced multiphase CT, contrast-enhanced MRI, or contrast-enhanced ultrasound of an indeterminate > 1 cm liver lesion on initial ultrasound in patients with a normal liver with no suspicion or evidence of extrahepatic malignancy or underlying liver disease. B Show 7 more As per EASL 2016 guidelines, suspect hepatic hemangioma in the presence of a hyperechoic lesion in patients with a normal and healthy liver. Obtain ultrasound to confirm the diagnosis with typical imaging features (homogeneous hyperechoic, sharp margin, posterior enhancement, and absence of halo sign) in a lesion < 3 cm. B Show 2 more As per ACG 2014 guidelines, obtain MRI or CT for the diagnosis of hepatic hemangioma. B 2. Diagnostic procedures Liver biopsy: avoid performing a liver biopsy in the presence of radiologic features suggestive of hepatic hemangioma. D 3. Medical management Indications for treatment: As per EASL 2016 guidelines, offer conservative management in patients with typical cases of hepatic hemangioma. B As per ACG 2014 guidelines, do not offer any intervention for asymptomatic hepatic hemangiomas regardless of size. D 4. Specific circumstances Pregnant patients: do not obtain routine imaging or surveillance for asymptomatic hemangioma during pregnancy. D https://web.pathway.md/diseases/recZPcRcjiO2GFdbJ 2/3 6/24/23, 12:41 PM Hepatic hemangioma Pathway 5. Patient education General counseling: As per EASL 2016 guidelines, counsel patients that pregnancy and the use of oral contraceptives are not contraindicated in hepatic hemangioma. B As per ACG 2014 guidelines, counsel patients that pregnancy and the use of oral contraceptives or anabolic steroids are not contraindicated in hepatic hemangioma. B 6. Follow-up and surveillance Indications for referral: As per EASL 2016 guidelines, refer patients to benign liver tumor multidisciplinary team in the presence of Kasabach-Merrit syndrome, growing lesions, or lesions symptomatic by compression. B As per ACG 2014 guidelines, consider referring symptomatic patients with impaired quality of life to an experienced team for operative or nonoperative management. C Serial imaging assessment: do not obtain follow-up imaging in patients with typical cases of hepatic hemangioma due to its benign course. D References 1. Expert Panel on Gastrointestinal Imaging, Victoria Chernyak, Jeanne M Horowitz et al. ACR Appropriateness Criteria Liver Lesion-Initial Characterization. J Am Coll Radiol. 2020 Nov;17 11S S429 S446. Open 2. European Association for the Study of the Liver EASL . EASL Clinical Practice Guidelines on the management of benign liver tumours. J Hepatol. 2016 Aug;65 2 386 98. Open 3. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 4. Marrero JA, Ahn J, Rajender Reddy K et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol. 2014 Sep;109 9 1328 47. Open 5. Christoph F Dietrich, Christian P llson Nols e, Richard G Barr et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound CEUS in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020 Oct;46 10 2579 2604. Open 6. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open https://web.pathway.md/diseases/recZPcRcjiO2GFdbJ 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hepatic hydrothorax are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2021), the British Association for the Study of the Liver (BASL/BSG 2021), and the European Association for the Study of the Liver (EASL 2010). 1 2 3 Guidelines 1. Diagnostic procedures Diagnostic thoracocentesis: perform a diagnostic thoracocentesis in patients with suspected spontaneous bacterial empyema with inoculation of fluid into blood culture bottles. A 2. Medical management Diuretic therapy: initiate diuretics as first-line therapy in patients with hepatic hydrothorax. E 3. Nonpharmacologic interventions https://web.pathway.md/diseases/recdXbU8zPfHX7Q3O 1/3 6/24/23, 12:41 PM Hepatic hydrothorax Pathway Salt restriction: advise dietary sodium restriction as first-line therapy in patients with hepatic hydrothorax. E 4. Therapeutic procedures Therapeutic thoracocentesis: perform thoracentesis as required in the initial treatment of patients with hepatic hydrothorax. E Percutaneous drainage: avoid inserting a chest tube for hepatic hydrothorax. Consider inserting indwelling tunneled catheters in carefully selected patients not responding to medical therapy and being candidates for TIPS. D Transjugular intrahepatic portosystemic shunt: As per AASLD 2021 guidelines, consider performing TIPS placement in selected patients as second-line therapy for refractory hepatic hydrothorax. E As per BSG 2021 guidelines: Consider performing TIPS placement in patients with hepatic hydrothorax, after discussion with the multidisciplinary team. B Consider offering alternative palliative interventions in patients with hepatic hydrothorax not undergoing TIPS placement and/or liver transplant evaluation. B As per EASL 2010 guidelines, consider TIPS placement in selected patients with recurrent symptomatic hepatic hydrothorax. C 5. Surgical interventions Liver transplantation: consider performing liver transplantation in patients with hepatic hydrothorax. E 6. Specific circumstances Patients with spontaneous bacterial empyema: manage spontaneous bacterial empyema similarly as SBP. References 1. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53 3 397 417. Open 2. Scott W Biggins, Paulo Angeli, Guadalupe Garcia-Tsao et al. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug;74 2 1014 1048. Open https://web.pathway.md/diseases/recdXbU8zPfHX7Q3O 2/3 6/24/23, 12:41 PM Hepatic hydrothorax Pathway 3. Guruprasad P Aithal, Naaventhan Palaniyappan, Louise China et al. Guidelines on the management of ascites in cirrhosis. Gut. 2021 Jan;70 1 9 29. Open 4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 5. Ricardo Badillo, Don C Rockey. Hepatic hydrothorax: clinical features, management, and outcomes in 77 patients and review of the literature. Medicine Baltimore). 2014 May;93 3 135 142. Open 6. Yong Lv, Guohong Han, Daiming Fan. Hepatic Hydrothorax. Ann Hepatol. January-February 2018;17 1 33 46. Open 7. Salim R Surani, Yamely Mendez, Humayun Anjum et al. Pulmonary complications of hepatic diseases. World J Gastroenterol. 2016 Jul 14;22 26 6008 15. Open https://web.pathway.md/diseases/recdXbU8zPfHX7Q3O 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hepatic veno-occlusive disease are prepared by our editorial team based on guidelines from the European Association for the Study of the Liver (EASL 2016) and the British Society for Haematology (BSH/BSBMT 2013). 1 2 Calculator Pathway Calculator Baltimore criteria for diagnosis o Hepatic veno-occlusive disease Seattle cr Diagnosis and management Guidelines 1. Screening and diagnosis Clinical presentation: suspect VOD in patients in whom liver disease occurs in the context of prior HSCT, chemotherapy for cancer, or immunosuppression for solid organ transplantation or IBD. B https://web.pathway.md/diseases/recsc7DxcVPDZdf0T 1/4 6/24/23, 12:41 PM Hepatic veno-occlusive disease Pathway Diagnostic criteria: use the modified Seattle or Baltimore criteria to establish the diagnosis of VOD. A Risk factors: assess patients for risk factors for VOD, and address these risk factors prior to HSCT. A 2. Diagnostic investigations Ultrasound: obtain an abdominal ultrasound in patients with suspected VOD, to assist in the exclusion of other disease. B Plasminogen activator inhibitor 1 levels: consider avoiding routine measurement of plasminogen activator inhibitor 1 levels in the evaluation for VOD. D 3. Diagnostic procedures Liver biopsy: As per EASL 2016 guidelines, obtain a transjugular liver biopsy and measurement of portal venous pressures in patients who do not meet clinical criteria of sinusoidal obstruction syndrome, or when other diagnoses have to be excluded. A As per BCSH 2013 guidelines, obtain a transjugular liver biopsy for patients in whom the diagnosis of VOD is unclear, and there is a need to exclude other diagnoses. B 4. Medical management Supportive care: provide supportive care for the treatment of complications of established VOD. B Defibrotide: administer defibrotide for the treatment of VOD in adults and children. B Methylprednisolone: consider administering methylprednisolone for the treatment of VOD, while taking into account the potential risks of infection. C Fluid balance: ensure judicious fluid balance management in patients with VOD. B Tissue plasminogen activator: avoid tPA for the treatment of VOD, due to the associated risk of hemorrhage. D N-acetylcysteine: avoid routine use of N-acetylcysteine in the treatment of VOD, due to lack of efficacy. D 5. Preventative measures Defibrotide: https://web.pathway.md/diseases/recsc7DxcVPDZdf0T 2/4 6/24/23, 12:41 PM Hepatic veno-occlusive disease Pathway As per EASL 2016 guidelines, administer defibrotide to prevent VOD in patients undergoing HSCT. B As per BSH 2013 guidelines, consider administering a course of defibrotide (6.25 mg/kg IV QID) to prevent VOD in adults undergoing allo-SCT who meet 1 of the following criteria: preexisting hepatic disease second myeloablative transplant allogeneic transplant for leukemia beyond second relapse conditioning with busulfan-containing regimens prior treatment with gemtuzumab ozogamicin diagnosis of primary hemophagocytic lymphohistiocytosis adrenoleucodystrophy or osteopetrosis. C Prostaglandin E1: avoid using prostaglandin E1 in the prophylaxis of VOD, due to lack of efficacy and toxicity. D Pentoxifylline: avoid using pentoxifylline for the prophylaxis of VOD due to lack of efficacy. D Ursodeoxycholic acid: consider administering UDCA as an option for the prophylaxis of VOD. C Anticoagulants: consider avoiding unfractionated or LMWH to prevent VOD, due to the risk of increased toxicity. D 6. Follow-up and surveillance Indications for specialist referral: obtain early consultation with critical care and hepatology specialists in patients with VOD, and consider other treatment options including TIPS or liver transplantation. B References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016 Jan;64 1 179 202. Open 2. Dignan FL, Wynn RF, Hadzic N et al. BCSH/BSBMT guideline: diagnosis and management of veno- occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 2013 Nov;163 4 444 57. Open 3. Chien-Chang Lee, Hsiu-Hao Chang, Meng-Yao Lu et al. The incidence and risk factors of hepatic veno- occlusive disease after hematopoietic stem cell transplantation in Taiwan. Ann Hematol. 2019 Mar;98 3 745 752. Open 4. Zhun Cao, Kathleen F Villa, Craig B Lipkin et al. Burden of illness associated with sinusoidal obstruction syndrome/veno-occlusive disease in patients with hematopoietic stem cell transplantation. J Med Econ. 2017 Aug;20 8 871 883. Open https://web.pathway.md/diseases/recsc7DxcVPDZdf0T 3/4 6/24/23, 12:41 PM Hepatic veno-occlusive disease Pathway 5. Jason A Coppell, Paul G Richardson, Robert Soiffer et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010 Feb;16 2 157 68. Open https://web.pathway.md/diseases/recsc7DxcVPDZdf0T 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hepatitis B virus infection are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA/CDC/NIH/HIVMA 2023), the Center for Disease Control (CDC 2022), the American Association for the Study of Liver Diseases (AASLD 2021; 2018; 2014), the World Health Organization (WHO 2020; 2015), the American Society of Clinical Oncology (ASCO 2020), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN/NASPGHAN 2020), the U.S. Preventive Services Task Force (USPSTF 2020; 2019), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2020; 2017), the European Association for the Study of the Liver (EASL 2017), the American College of Physicians (ACP/CDC 2017), the Italian Association for the Study of the Liver (AISF 2016), the American College of Gastroenterology (ACG 2016), and the American Gastroenterological Association (AGA 2015). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 CalculatorChild Pugh score for mortality in CalculatorRisk estimation for hepatocellula https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 1/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Guidelines 1. Screening and diagnosis Indications for screening, persons at risk: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, screen for HBV infection (with HBsAg, total HBcAb, and HBsAb) in patients with human immunodeficiency virus infection. A As per USPSTF 2020 guidelines, screen for HBV infection in adolescents and adults at increased risk for infection. B As per CDC/ACP 2017 guidelines, screen for HBV infection (with HBsAg, HBcAb, and HBsAb) in high-risk persons, including: persons born in countries with 2% HBV prevalence MSM injection drug users incarcerated persons patients with elevated ALT levels ( 19 IU/L in females and 30 IU/L in males) patients requiring immunosuppressive therapy patients with end-stage renal disease (including receiving hemodialysis) blood and tissue donors pregnant females infants born to HBV-infected mothers household and sexual contacts of HBV-infected patients patients with HCV infection patients with human immunodeficiency virus infection. B As per AGA 2015 guidelines: Screen for HBV (with HBsAg and HBcAb, followed by a sensitive HBV DNA test if positive) in moderate-to-high-risk patients on immunosuppressive medical therapy. B Avoid screening for HBV infection routinely in low-risk patients on immunosuppressive medical therapy. D Indications for screening, pregnancy: As per AASLD 2021 guidelines, screen all pregnant females for HBsAg. E As per WHO 2020 guidelines, screen all pregnant for HBsAg at least once and as early as possible in the pregnancy. B As per USPSTF 2019 guidelines, screen for HBV infection in pregnant females at their first prenatal visit. A https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 2/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway As per EASL 2017 guidelines, screen for HBsAg in the first trimester of pregnancy. A As per SOGC 2017 guidelines, screen pregnant females for HBV infection with HBsAg in early pregnancy. A Show 2 more As per AISF 2016 guidelines, screen all pregnant females for HBsAg A and, if positive, test for HBeAg/HBeAb and HBV-DNA. B Indications for screening (before anticancer therapy): test for HBV with 3 tests (HBsAg, HBcAb total immunoglobulin or IgG, and HBsAb) before or at the beginning of treatment in all patients with cancer anticipating systemic anticancer therapy while not delaying initiation of treatment. A 2. Diagnostic investigations Pretreatment evaluation: assess baseline renal function and baseline risk for renal dysfunction in all patients before initiating tenofovir or entecavir therapy. E 3. Medical management Management of acute HBV hepatitis: Do not initiate specific treatment in most (> 95%) adult patients with acute HBV because they will fully recover spontaneously. D Initiate nucleoside/nucleotide analogs only in patients with severe acute hepatitis B, characterized by coagulopathy or protracted course, and assess for liver transplantation. B Indications for antiviral therapy: As per AASLD 2018 guidelines, initiate antiviral therapy to decrease the risk of liver-related complications in adult patients with immune-active chronic hepatitis B (HBeAg-negative or - positive). B Show 2 more As per EASL 2017 guidelines, initiate treatment in all patients with HBeAg-positive or -negative chronic hepatitis B defined by HBV DNA > 2,000 IU/mL, ALT > ULN, and/or at least moderate liver necroinflammation or fibrosis. A Show 4 more As per WHO 2015 guidelines, initiate treatment in all patients with chronic hepatitis B and clinical evidence of compensated or decompensated cirrhosis (or cirrhosis based on APRI score > 2 in adults) regardless of ALT levels, HBeAg status, or HBV DNA levels. B Show 4 more Goals of antiviral therapy: set induction of long-term suppression of HBV DNA levels as the main endpoint of all current treatment strategies. A Show 3 more Choice of antiviral regimens: https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 3/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway As per AASLD 2018 guidelines, initiate pegylated interferon, entecavir, or tenofovir as preferred initial therapy in adult patients with immune-active chronic hepatitis B. B As per EASL 2017 guidelines, initiate long-term potent nucleoside/nucleotide analogs with a high barrier to resistance as the treatment of choice regardless of the severity of the liver disease. A Initiate nucleoside/nucleotide analogs with a high barrier to resistance in patients with decompensated cirrhosis irrespective of the level of HBV replication, and assess for liver transplantation. B Show 9 more As per WHO 2015 guidelines, initiate nucleoside/nucleotide analogs with a high barrier to drug resistance (tenofovir or entecavir), if antiviral therapy is indicated, in all adult patients. B Show 2 more Maintenance therapy: As per AASLD 2018 guidelines, consider discontinuing nucleoside/nucleotide analog therapy after a period of treatment consolidation in hepatitis B e-antigen-positive adult patients without cirrhosis but with chronic hepatitis B seroconverted to HBeAb on therapy. C Show 6 more As per EASL 2017 guidelines, discontinue nucleoside/nucleotide analogs after confirmed HBsAg loss, with or without HBsAb seroconversion. B Show 7 more As per WHO 2015 guidelines, continue treatment with nucleoside/nucleotide analogs for lifelong in all patients with cirrhosis based on clinical evidence (or APRI score > 2 in adults). Do not discontinue antiviral therapy because of the risk of reactivation which can cause severe acute- on-chronic liver injury. B Show 2 more Management of treatment failure: As per EASL 2017 guidelines, check compliance to nucleoside/nucleotide analog therapy in all cases of treatment failure. B Show 2 more As per WHO 2015 guidelines, switch to tenofovir if the patient is not responding to lamivudine, entecavir, adefovir, or telbivudine. B Management of relapse: re-initiate treatment in patients with consistent signs of reactivation (HBsAg or HBeAg becoming positive, ALT level increase, or HBV DNA becoming detectable again). B 4. Surgical interventions Liver transplantation, pre-transplant antiviral therapy: As per EASL 2017 guidelines, initiate nucleoside/nucleotide analogs in all patients with HBV- related liver disease on the transplant waiting list. B https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 4/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway As per AASLD 2014 guidelines, initiate antiviral therapy in patients with HBV liver disease to suppress HBV replication before liver transplantation. B Liver transplantation (post-transplant antiviral prophylaxis): initiate a combination of hepatitis B IgAnd a potent nucleoside/nucleotide analog after liver transplantation for the prevention of HBV recurrence. B Show 2 more 5. Specific circumstances Pregnant patients, indications for screening: As per AASLD 2021 guidelines, screen all pregnant females for HBsAg. E As per WHO 2020 guidelines, screen all pregnant for HBsAg at least once and as early as possible in the pregnancy. B As per USPSTF 2019 guidelines, screen for HBV infection in pregnant females at their first prenatal visit. A As per EASL 2017 guidelines, screen for HBsAg in the first trimester of pregnancy. A As per SOGC 2017 guidelines, screen pregnant females for HBV infection with HBsAg in early pregnancy. A Show 2 more As per AISF 2016 guidelines, screen all pregnant females for HBsAg A and, if positive, test for HBeAg/HBeAb and HBV-DNA. B Pregnant patients (immunization of the mother): offer recombinant hepatitis B vaccine series in unvaccinated HBsAg-negative patients at high risk for acquiring hepatitis B infection. Recognize that pregnancy is not a contraindication for immunization against hepatitis B. B Pregnant patients (indications for testing): obtain testing for common etiologies of acute liver injury including viral hepatitis (HAV, HBV, HBV, and HSV) in pregnant patients presenting with acute hepatitis. B Pregnant patients, laboratory testing: As per AASLD 2021 guidelines, assess HBV DNA level in the second trimester in HBsAg- positive pregnant patients. E As per SOGC 2017 guidelines, obtain testing for HBeAg, HBV DNA level, and ALT during pregnancy for the purposes of maternal health and perinatal HBV transmission risk stratification in HBsAg-positive pregnant patients. A Pregnant patients (liver imaging): obtain liver ultrasound during pregnancy for the purposes of maternal health and perinatal HBV transmission risk stratification in HBsAg-positive pregnant patients. B Pregnant patients, antiviral therapy: As per AASLD 2021 guidelines: https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 5/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Initiate antiviral therapy (preferably tenofovir disoproxil fumarate) at 28-32 weeks of gestation to reduce the risk of mother-to-child transmission when maternal HBV DNA is > 200,000 IU/mL. Consider discontinuing antiviral therapy at delivery or up to 3 months postpartum. E Monitor ALT and HBV DNA levels for 6 months postpartum or after cessation of antiviral therapy. E As per SOGC 2020 guidelines, consider initiating antiviral therapy with tenofovir to decrease the vertical transmission risk in patients with chronic hepatitis B infection and a significant viral load (> 200,000 IU/mL or > 10 copies/mL). B As per WHO 2020 guidelines, initiate tenofovir prophylaxis (starting at 28 weeks of gestation until at least birth) to prevent mother-to-child transmission of HBV in HBsAg-positive pregnant patients with HBV DNA levels 200,000 IU/mL. Consider obtaining HBeAg testing as an alternative to HBV DNA testing, if antenatal HBV DNA testing is not available, to determine eligibility for tenofovir prophylaxis. B As per AASLD 2018 guidelines, consider initiating antiviral therapy to reduce the risk of perinatal transmission of HBV in HBsAg-positive pregnant patients with HBV DNA levels > 200,000 IU/mL. C Do not initiate antiviral therapy in patients with HBV DNA levels 200,000 IU/mL. B As per EASL 2017 guidelines, consider delaying therapy until the child is born in patients of childbearing age without advanced fibrosis planning a pregnancy in the near future. C Show 3 more As per SOGC 2017 guidelines, consider initiating antiviral therapy (starting at 28-32 weeks of gestation and continuing until delivery), in collaboration with an adult infectious disease/gastroenterology or hepatology specialist, for the prevention of perinatal transmission in patients with hepatitis B DNA viral loads level > 200,000 IU/mL (> 10 copies/mL). C As per ACG 2016 guidelines, initiate antiviral therapy with tenofovir or telbivudine in the third trimester of pregnancy in patients with chronic hepatitis B with a high viral load ( 200,000 IU/mL) to reduce perinatal transmission of HBV. B As per AISF 2016 guidelines: Consider initiating early antiviral therapy in patients with advanced liver fibrosis (F3-4). Initiate tenofovir as the preferred drug due to its high genetic barrier, safety, and potency. Continue treatment after delivery. B Initiate nucleoside/nucleotide analogs to minimize the risk of vertical transmission in pregnant patients with serum HBV DNA levels 10 IU/mL. B Initiate tenofovir or telbivudine as the drugs of choice started no later than 32 weeks of gestation. B Consider initiating lamivudine as an alternative option. B . Discontinue treatment 0-4 weeks after delivery. Insufficient evidence regarding the safety of continuing treatment during breastfeeding. B Pregnant patients, counseling: As per AASLD 2021 guidelines, counsel HBsAg-positive pregnant patients on the increased risk of mother-to-child-transmission with invasive pregnancy procedures, such as amniocentesis. E As per SOGC 2017 guidelines, counsel HBsAg-positive pregnant patients on the prevention of HBV transmission to sexual partners and household contacts. B https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 6/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Show 2 more Pregnant patients, fetal evaluation: As per SOGC 2020 guidelines, obtain noninvasive methods of fetal aneuploidy risk assessment (maternal serum placental analytes with or without nuchal translucency, detailed ultrasound, and maternal serum cell-free placental DNA as first- or second-tier screening test) in patients with chronic hepatitis B infection. B Show 3 more As per SOGC 2017 guidelines, obtain noninvasive screening for aneuploidy before invasive testing in HBsAg-positive patients. B Pregnant patients, delivery: As per SOGC 2017 guidelines: Do not perform a C-section for the sole purpose of reducing the risk of perinatal transmission of HBV. D Avoid performing intrapartum invasive procedures (such as fetal ECG and scalp lactate), if possible, to avoid increasing the infant's risk of percutaneous HBV exposure. D As per ACG 2016 guidelines, do not perform elective C-section in HBV-positive pregnant patients to prevent fetal infection. D Pregnant patients, immunization of the infant: As per SOGC 2017 guidelines: Administer hepatitis B vaccination in all infants. Administer hepatitis B immunoglobulin within the first 12 hours of life in all infants born to HBsAg-positive mothers. A Encourage families to complete the infant immunization series for HBV according to local infant vaccination schedule and obtain serological confirmation of protection after completion of the series, no sooner than 9-12 months of age. A As per ACG 2016 guidelines, administer active-passive immunoprophylaxis with hepatitis B IgAnd the HBV vaccination series in all infants born to HBV-infected mothers to prevent perinatal transmission. B As per AISF 2016 guidelines, administer vaccination to prevent HBV transmission. Administer hepatitis B immunoglobulin in infants born to HBsAg-positive mothers to prevent HBV vertical transmission. A As per AISF 2016 guidelines, administer standard prophylaxis with hepatitis B vaccination and anti-HBsAg immunoglobulins in all infants born to HBsAg-positive mothers within 12 hours after delivery. A Pregnant patients, breastfeeding: As per AASLD 2021 guidelines, recognize that breastfeeding is not contraindicated, even in patients continuing antiviral therapy. E As per EASL 2017 guidelines, recognize that breastfeeding is not contraindicated in HBsAg- positive untreated patients or in patients on tenofovir disoproxil fumarate-based treatment or prophylaxis. B https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 7/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway As per SOGC 2017 guidelines, encourage breastfeeding in mothers with chronic hepatitis B infection wishing to breastfeed as it does not pose an additional risk of HBV infection, even without neonatal vaccination. B As per ACG 2016 guidelines, advise breastfeeding as recommended for infant health in patients with chronic hepatitis B. B Pediatric patients (screening): screen for HBV infection in adolescents at increased risk for infection. B Pediatric patients, antiviral therapy: As per AASLD 2018 guidelines, do not initiate antiviral therapy in HBeAg-positive pediatric (aged 2-18 years) patients with persistently normal ALT regardless of HBV DNA level. D As per EASL 2017 guidelines: Recognize that the course of the disease is generally mild in pediatric patients and most of them do not meet standard treatment indications. Consider offering treatment with caution. B Consider initiating entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, or pegylated interferon alfa in pediatric and adolescent patients meeting treatment criteria. C As per WHO 2015 guidelines, initiate treatment in all pediatric and adolescent patients with chronic hepatitis B and clinical evidence of compensated or decompensated cirrhosis (or cirrhosis based on APRI score > 2 in adults) regardless of ALT levels, HBeAg status, or HBV DNA levels. B Show 3 more Pediatric patients (monitoring): obtain careful monitoring of growth in pediatric patients on long- term tenofovir or entecavir therapy. B Pediatric patients (patients with HIV co-infection): Initiate antiretroviral therapy in all pediatric patients with HBV/human immunodeficiency virus co- infection irrespective of CD4 cell count. E Initiate tenofovir disoproxil fumarate or tenofovir alafenamide-based antiretroviral regimens in pediatric patients with HBV/human immunodeficiency virus co-infection. E Pediatric patients, patients on immunosuppressive therapy: As per NASPGHAN/ESPGHAN 2020 guidelines, test for HBV (with HBsAg, HBsAb, and HBcAb) in all pediatric patients at risk of HBV reactivation. E Show 6 more As per EASL 2017 guidelines, test for HBV markers before immunosuppression in all candidates for chemotherapy and immunosuppressive therapy. A Show 2 more Pediatric patients (liver transplant recipients): initiate antiviral therapy as soon as possible before liver transplantation with the aim of achieving an undetectable HBV DNA level at the time of transplantation in HBsAg-positive liver transplant recipients with detectable serum HBV DNA. E Show 4 more https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 8/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Pediatric patients (non-liver transplant recipients): initiate lifelong antiviral therapy with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide in HBsAg-positive non-liver solid transplant recipients. E Show 3 more Pediatric patients (hematologic stem cell transplant recipients): consider stratifying the risk of HBV reactivation in pediatric and adolescent patients into the following broad groups: high risk (> 10%), moderate risk (1-10%), and low risk (< 1%). Classify patients undergoing bone marrow or hematologic stem cell or solid organ transplantation as at high risk of HBV reactivation. E Show 2 more Patients with renal impairment: As per AASLD 2018 guidelines, insufficient evidence to recommend in preference between entecavir or tenofovir regarding potential long-term risks of renal and bone complications. I As per EASL 2017 guidelines, screen for HBV markers in all dialysis and renal transplant recipients. B Show 3 more Patients with malignancy: test for HBV with 3 tests (HBsAg, HBcAb total immunoglobulin or IgG, and HBsAb) before or at the beginning of treatment in all patients with cancer anticipating systemic anticancer therapy while not delaying initiation of treatment. A Show 5 more Patients with HDV co-infection: initiate pegylated interferon alfa for at least 48 weeks as the treatment of choice in patients with HBV/hepatitis D virus co-infection and compensated liver disease. A Show 2 more Patients with HCV co-infection: recognize that treatment of HCV infection with direct-acting antivirals may cause reactivation of HBV. Initiate nucleoside/nucleoside analog therapy in patients fulfilling the standard criteria for HBV treatment. B Show 2 more Patients with HIV co-infection: As per EASL 2017 guidelines: Initiate antiretroviral therapy in all patients with HBV/human immunodeficiency virus co- infection irrespective of CD4 cell count. B Initiate a tenofovir disoproxil fumarate- A or tenofovir alafenamide-based regimen in patients with HBV/human immunodeficiency virus co-infection. B As per WHO 2015 guidelines, initiate antiretroviral therapy in HBV/human immunodeficiency virus-coinfected patients with evidence of severe chronic liver disease regardless of CD4 cell count, and with a CD4 cell count 500 cells/mm regardless of the stage of liver disease. B Show 2 more Patients on immunosuppressive therapy: screen for HBV (with HBsAg and HBcAb, followed by a sensitive HBV DNA test if positive) in moderate-to-high-risk patients on immunosuppressive medical therapy. B https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 9/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Show 8 more Patients with extrahepatic manifestations: Initiate nucleoside/nucleotide analog therapy in patients with replicative HBV infection and extrahepatic manifestations. B Do not use pegylated interferon alfa in patients with immune-related extrahepatic manifestations. D 6. Preventative measures Immunizations, infants: As per WHO 2020 guidelines, administer the first dose of the hepatitis B vaccine in all infants as soon as possible after birth, preferably within 24 hours, followed by 2-3 doses to complete the primary series. E As per ACG 2016 guidelines, administer active-passive immunoprophylaxis with hepatitis B IgAnd the HBV vaccination series in all infants born to HBV-infected mothers to prevent perinatal transmission. B As per AISF 2016 guidelines, administer standard prophylaxis with hepatitis B vaccination and anti-HBsAg immunoglobulins within 12 hours after delivery in all infants born to HBsAg-positive mothers. A Immunizations, adults: As per CDC 2022 guidelines: Offer vaccination against HBV in adults aged 19-59 years and adults aged 60 years with the following risk factors for hepatitis B: Situation Guidance Sex partners of persons testing positive for HBsAg Persons at risk for infection by sexual exposure Sexually active persons not in a long-term, mutually monogamous relationship (such as persons with > 1 sex partner during the previous 6 months) Persons seeking evaluation or treatment for a STI MSM Persons with current or recent injection drug use Persons at risk for infection by percutaneous or mucosal exposure to blood Household contacts of persons testing positive for HBsAg Residents and staff members of facilities for persons with developmental disabilities https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 10/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Healthcare and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids Patients on maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, and predialysis patients Patients with diabetes at the discretion of the treating clinician International travelers to countries with high or intermediate levels of endemic HBV infection (HBsAg prevalence of 2%) Other Patients with HCV infection Patients with chronic liver disease (including, but not limited to, patients with cirrhosis, fatty liver disease, alcoholic liver disease, AIH, and an ALT or AST level > 2 the ULN) Patients with human immunodeficiency virus infection Incarcerated persons. E Consider offering vaccination against HBV in adults aged 60 years without known risk factors for hepatitis B. E As per CDC/ACP 2017 guidelines, offer vaccination against HBV in all unvaccinated adults (including pregnant females) at risk for infection, including: history of sexual, percutaneous, or mucosal exposure healthcare and public safety workers at risk for blood exposure adult patients with chronic liver disease, end-stage renal disease (including receiving hemodialysis), or human immunodeficiency virus infection travelers to HBV-endemic regions adults seeking protection from HBV infection. B 7. Follow-up and surveillance Monitoring of untreated patients: As per EASL 2017 guidelines, follow-up < 30 years old patients with HBeAg-positive chronic HBV infection not meeting criteria for treatment initiation at least every 3-6 months. B Show 2 more https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 11/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway As per WHO 2015 guidelines, obtain continued monitoring in all patients with chronic hepatitis B not meeting the criteria for treatment initiation to determine if antiviral therapy may be indicated in the future to prevent progressive liver disease, including: 30 years old patients with HBV DNA levels > 20,000 IU/mL, persistently normal ALT levels, and without cirrhosis HBeAgn-negative 30 years old patients with HBV DNA levels fluctuating between 2,000- 20,000 IU/mL or intermittently abnormal ALT levels and without cirrhosis 30 years old patients with persistently normal ALT levels and without cirrhosis, regardless of HBeAg-negative status, if HBV DNA testing is not available. E Show 2 more Monitoring of treatment response: As per AASLD 2018 guidelines, monitor ALT levels at least every 6 months in adult patients with immune-tolerant chronic hepatitis B to monitor for potential transition to immune-active or immune-inactive chronic hepatitis B. B As per EASL 2017 guidelines, obtain periodic assessments of ALT and serum HBV DNA in all patients treated with nucleoside/nucleotide analogs. A Show 3 more As per WHO 2015 guidelines: Monitor the following at least annually: ALT level (and AST for APRI), HBsAg, HBeAg, and HBV DNA levels (where HBV DNA testing is available) noninvasive tests (APRI score or FibroScan) to assess for the presence of cirrhosis in patients without cirrhosis at baseline adherence to treatment regularly and at each visit. B Obtain more frequent monitoring (at least every 3 months for the first year) in the following circumstances: patients with more advanced disease (compensated or decompensated cirrhosis) patients with human immunodeficiency virus co-infection during the first year of treatment to assess treatment response and adherence where treatment adherence is a concern after discontinuation of treatment. B Monitoring of treatment adverse effects: As per EASL 2017 guidelines, obtain renal function monitoring at least with estimated GFR and serum phosphate levels in patients at risk of renal disease treated with any nucleoside/nucleotide analogs and in all patients treated with tenofovir disoproxil fumarate regardless of renal risks. B Show 3 more As per WHO 2015 guidelines, monitor renal function annually in patients on long-term tenofovir or entecavir therapy. B https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 12/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Surveillance for hepatocellular carcinoma: As per EASL 2017 guidelines, obtain HCC surveillance in all patients with cirrhosis and in patients with moderate or high HCC risk scores at the onset of nucleoside/nucleotide analog therapy. B Show 2 more As per WHO 2015 guidelines: Obtain routine surveillance for HCC with abdominal ultrasound and AFP testing every 6 months in patients with cirrhosis regardless of age or other risk factors and in patients with a family history of HCC. B Obtain routine surveillance for HCC with abdominal ultrasound and AFP testing every 6 months in > 40 years old patients (a lower age may apply according to the regional incidence of HCC) with HBV DNA level > 2,000 IU/mL (where HBV DNA testing is available) in the absence of clinical evidence of cirrhosis (or based on APRI score 2). B 8. Quality improvement Healthcare workers: Do not disqualify persons from the practice or study of surgery, dentistry, medicine, or allied health fields based on HBV infection alone. D Consider initiating nucleoside/nucleotide analogs to reduce transmission risk in healthcare workers performing exposure-prone procedures with serum HBV DNA > 200 IU/mL. C References 1. Eliana Castillo, Kellie Murphy, Julie van Schalkwyk. No. 342 Hepatitis B and Pregnancy. J Obstet Gynaecol Can. 2017 Mar;39 3 181 190. Open 2. No authors listed. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015. Open 3. Norah A Terrault, Anna S F Lok, Brian J McMahon et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67 4 1560 1599. Open 4. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67 2 370 398. Open 5. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 6. No authors listed. Prevention of Mother-to-Child Transmission of Hepatitis B Virus: Guidelines on Antiviral Prophylaxis in Pregnancy. Geneva: World Health Organization; 2020. Open 7. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 8. Reddy KR, Beavers KL, Hammond SP et al. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 13/14 6/24/23, 12:41 PM Hepatitis B virus infection Pathway Gastroenterology. 2015 Jan;148 1 215 9. Open 9. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 10. Jessica P Hwang, Jordan J Feld, Sarah P Hammond et al. Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update. J Clin Oncol. 2020 Nov 1;38 31 3698 3715. Open 11. Giuseppe Indolfi, Mona Abdel-Hady, Sanjay Bansal et al. Management of Hepatitis B Virus Infection and Prevention of Hepatitis B Virus Reactivation in Children With Acquired Immunodeficiencies or Undergoing Immune Suppressive, Cytotoxic, or Biological Modifier Therapies. J Pediatr Gastroenterol Nutr. 2020 Apr;70 4 527 538. Open 12. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 13. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 14. US Preventive Services Task Force, Alex H Krist, Karina W Davidson et al. Screening for Hepatitis B Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020 Dec 15;324 23 2415 2422. Open 15. R Douglas Wilson. Guideline No. 409 Intrauterine Fetal Diagnostic Testing in Women with Chronic Viral Infections. J Obstet Gynaecol Can. 2020 Dec;42 12 1555 1562.e1. Open 16. US Preventive Services Task Force, Douglas K Owens, Karina W Davidson et al. Screening for Hepatitis B Virus Infection in Pregnant Women: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2019 Jul 23;322 4 349 354. Open 17. Drake LA, Dinehart SM, Farmer ER et al. Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2017 Dec 5;167 11 794 804. Open 18. Mark K Weng, Mona Doshani, Mohammed A Khan et al. Universal Hepatitis B Vaccination in Adults Aged 19 59 Years: Updated Recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep. 2022 Apr 1;71 13 477 483. Open 19. Terrault NA, Bzowej NH, Chang KM et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan;63 1 261 83. Open https://web.pathway.md/diseases/rectTxvoSS1Qsiskg 14/14

Guideline sources The following summarized guidelines for the evaluation and management of hepatitis C are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2022), the World Health Organization (WHO 2022), the American College of Emergency Physicians (ACEP 2021), the Infectious Diseases Society of America (IDSA/AASLD 2020), and the U.S. Preventive Services Task Force (USPSTF 2013). 1 2 3 4 5 6 6 6 7 8 8 9 Definition Hepatitis C is an infectious disease caused by HCV that is characterized by progressive liver damage and polymorphous extrahepatic manifestations. 6 Epidemiology HCV, an RNA virus of the Flaviviridae family, infects hepatocytes and evades the immune system, causing oxidative stress, inflammation and fibrosis, which can progress to cirrhosis, hepatic decompensation, HCC, and death. 6 Pathophysiology https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 1/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Pathophysiology The prevalence of hepatitis C in the United States adult population is estimated at 1.0% (current infection) and 1.7% (current or past infection). 7 Disease course Approximately 15-20% of patients who are infected will progress to cirrhosis over a 20-year period. The risk of HCC in cirrhotic patients (without successful treatment) is 3% per year. 8 8 Prognosis and risk of recurrence The mortality rate ratio of patients with HCV infection, as compared with the general population, is estimated at 2.3 (95% CI, 2.2-2.5). Cure rates with modern antiviral therapy are > 90% for chronic HCV infection. 6 9 CalculatorChild Pugh score for mortality in Guidelines 1. Screening and diagnosis Indications for screening: As per AASLD 2020 guidelines, obtain one-time, routine opt-out HCV testing in all persons 18 years of age. B Show 4 more As per USPSTF 2013 guidelines: Screen for HCV infection in patients at high risk for infection. B Offer one-time screening for HCV infection in patients born between 1945 and 1965. B 2. Diagnostic investigations Initial laboratory tests: As per WHO 2022 guidelines, obtain quantitative or qualitative nucleic acid testing directly following a positive HCV antibody serological test result for the detection of HCV RNA as the preferred strategy to diagnose viremic infection. B Show 7 more As per AASLD 2020 guidelines, obtain HCV antibodies with reflex HCV-RNA PCR for initial HCV testing. B https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 2/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Show 4 more Viral genotyping: As per ACEP 2021 guidelines, do not obtain HCV genotyping when treating with pangenotypic medications unless planning glecaprevir-pibrentasvir therapy. D As per AASLD 2020 guidelines, consider obtaining HCV genotyping if it may alter treatment recommendations. B Evaluation for liver fibrosis: As per ACEP 2021 guidelines: Do not obtain invasive testing to establish the degree of fibrosis. D Consider obtaining inexpensive laboratory tests to identify patients with cirrhosis. C As per AASLD 2020 guidelines, obtain evaluation for advanced fibrosis using noninvasive tests (serum panels, elastography) or liver biopsy, if required, in all patients with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy, and to determine the need for initiating additional measures for cirrhosis management (such as HCC screening). B Evaluation for other coinfections: obtain evaluation for other conditions accelerating liver fibrosis, including hepatitis B and human immunodeficiency virus in all patients with active HCV infection. B Evaluation of renal function: Assess all patients for kidney disease (with urinalysis and estimated GFR) at the time of HCV infection diagnosis. B Obtain repeated screening in patients remaining nucleic acid testing-positive if there is no evidence of kidney disease at initial evaluation. Pretreatment evaluation: evaluate potential drug-drug interactions with concomitant medications before starting direct-acting antiviral therapy. Discontinue an interaction co-medication or switch to an alternative with less risk for potential interaction during HCV treatment, if possible. B Show 4 more Resistance-associated substitution testing: obtain non-structural protein 5A resistance- associated substitution testing in genotype 1a-infected, treatment-na ve or -experienced patients being candidates for elbasvir/grazoprevir therapy. Consider switching to a different regimen if present. B Show 2 more 3. Diagnostic procedures Kidney biopsy: consider managing patients with HCV infection with a typical presentation of immune-complex proliferative glomerulonephritis without a confirmatory kidney biopsy. Consider performing a biopsy in certain clinical circumstances. 4. Medical management https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 3/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway General principles: As per WHO 2022 guidelines, initiate any of the following pangenotypic direct-acting antiviral regimens in all adult, B adolescent, B and 3 years old pediatric patients with chronic hepatitis C infection, regardless of the disease stage: sofosbuvir/daclatasvir for 12 weeks sofosbuvir/velpatasvir for 12 weeks glecaprevir/pibrentasvir for 8 weeks. B As per ACEP 2021 guidelines, ensure simplification of treatment and monitoring to enable patients with uncomplicated HCV infection to receive treatment in primary care settings. B As per AASLD 2020 guidelines, set a goal of treatment to reduce all-cause mortality and liver- related health adverse consequences, including end-stage liver disease and HCC, by the achievement of virologic cure as evidenced by a sustained virologic response in patients with HCV infection. B Show 5 more Antiviral therapy, genotype 1a: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 1a HCV infection without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks in patients without baseline non-structural protein 5A resistance-associated substitutions for elbasvir B glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 8 weeks in patients without human immunodeficiency virus infection and if HCV-RNA level is < 6 million IU/mL B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 1b: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 1b HCV infection without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks B glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 8 weeks in patients without human immunodeficiency virus and if HCV-RNA level is < 6 million IU/mL B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 2: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 2 HCV infection without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 4/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Antiviral therapy, genotype 3: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 3 HCV infection without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 4 more Antiviral therapy, genotype 4: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 4 without cirrhosis: elbasvir 50 mg/grazoprevir 100 mg for 12 weeks glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more Antiviral therapy, genotype 5 or 6: Administer any of the following daily fixed-dose combination regimens in patients with na ve genotype 5 or 6 HCV infection with or without compensated cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg 12 weeks. B Show 2 more Antiviral therapy, prior failures: administer daily fixed-dose combination of sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg for 12 weeks in patients with HCV infection with or without compensated cirrhosis failed sofosbuvir-based treatment. B Show 4 more Indications for treatment discontinuation: discontinue direct-acting antiviral therapy in patients with an increase in ALT 10-fold from baseline at any time during treatment (especially with signs or symptoms of liver inflammation or increasing conjugated bilirubin, ALP, or INR). B Show 2 more 5. Specific circumstances Pediatric patients (laboratory testing): obtain HCV antibodies in all 18 months pediatric patients born to females with HCV infection. B Show 6 more Pediatric patients (preventative measures and counseling): inform parents that HCV is not transmitted by casual contact and pediatric patients with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions. B Show 5 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 5/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Pediatric patients (antiviral therapy): initiate direct-acting antiviral treatment with an approved regimen in all 3 years old pediatric and adolescent patients with HCV infection regardless of disease severity. B Show 5 more Pediatric patients (follow-up): obtain disease severity assessment using routine laboratory testing and physical examination and evolving noninvasive modalities (elastography, imaging, or serum fibrosis markers) in all pediatric patients with chronic HCV infection. B Show 2 more Patients contemplating pregnancy: counsel female patients with HCV infection and cirrhosis about the increased risk of adverse maternal and perinatal outcomes. B Show 6 more Pregnant patients: obtain HCV infection testing with each pregnancy, ideally at the initial visit in all pregnant patients as part of prenatal care. B Show 7 more Men who have sex with men: obtain annual HCV testing in sexually active adolescent and adult MSM with human immunodeficiency virus. Consider obtaining more frequent testing depending on the precedence of high-risk sexual or drug use practices. B Show 4 more Patients injecting drugs: obtain annual HCV testing in patients injecting drugs with no prior testing or past negative testing and subsequent injection drug use. Consider obtaining more frequent testing depending on the level of risk. B Show 5 more Patients in jails and prisons: jails and prisons should implement opt-out HCV testing consisting of HCV antibody testing followed by confirmatory HCV-RNA testing if the antibody is positive. B Show 4 more Patients with chronic kidney disease (screening for HCV infection): screen all patients for HCV infection at the time of initial evaluation of CKD. B Obtain an immunoassay followed by nucleic acid testing if the immunoassay is positive. B Show 8 more Patients with chronic kidney disease (screening for other infections): screen for HAV, HBV, and human immunodeficiency virus in all patients with HCV infection (whether nucleic acid testing-positive or not) and CKD. Offer vaccination against HAV and HBV if appropriate. B Show 3 more Patients with chronic kidney disease (liver testing): assess for liver fibrosis in patients with CKD and HCV infection, B initially with noninvasive methods. B Show 2 more Patients with chronic kidney disease, antiviral regimens: As per KDIGO 2022 guidelines, assess all patients with CKD (G1-G5), on dialysis (G5D), and kidney transplant recipients (G1T-G5T) with HCV for direct-acting antiviral-based therapy. B Show 4 more https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 6/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway As per IDSA/AASLD 2020 guidelines, do not adjust doses of direct-acting antiviral therapy when using recommended regimens in patients with stage 1, 2, or 3 D and 4 or 5 CKD, except consider adjusting ribavirin dose in patients with stage 3, 4, or 5 CKD. D Patients with chronic kidney disease (management of glomerular disease): consider managing patients with HCV infection with a typical presentation of immune-complex proliferative glomerulonephritis without a confirmatory kidney biopsy. Consider performing a biopsy in certain clinical circumstances. Show 6 more Patients with chronic kidney disease (kidney transplantation): offer kidney transplantation as the best therapeutic option in patients with CKD stage G5 irrespective of the presence of HCV infection. B Show 6 more Patients with chronic kidney disease (follow-up): obtain regular monitoring to assess kidney disease progression in all patients with CKD with a history of HCV infection, whether nucleic acid testing-positive or not. B Kidney transplant recipients: As per KDIGO 2022 guidelines, evaluate kidney transplant recipients being treated with direct- acting antivirals for the need for dose adjustment of concomitant immunosuppressants. B Show 4 more As per AASLD 2020 guidelines, administer any of the following daily fixed-dose combination regimens in treatment-na ve and non-direct-acting-antiviral-experienced patients with kidney transplant with genotype 1-6 HCV infection with or without compensated cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 12 weeks B ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks in patients with genotype 1, 4, 5, or 6 HCV infection B sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 2 more Patients receiving organs of HCV-infected patients: As per KDIGO 2022 guidelines, screen all kidney donors for HCV infection with both immunoassay and nucleic acid testing (if available). B Show 4 more As per AASLD 2020 guidelines, include the following elements in the informed consent: risk of transmission from an HCV-viremic donor (and with a public health service-defined increased risk donor, the potential risks for other viral infections) risk of liver disease if HCV treatment is not available or treatment is unsuccessful risk of graft failure risk of extrahepatic complications, such as HCV-associated renal disease risk of HCV transmission to a partner benefits, specifically reduced waiting time and possibly lower waiting list mortality https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 7/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway other unknown long-term consequences (hepatic and extrahepatic) of HCV exposure (even if cure is attained). B Show 5 more Patients with acute HCV infection: obtain HCV antibodies and HCV-RNA in patients with suspected acute HCV infection due to exposure, clinical presentation, or elevated aminotransferase levels. B Show 5 more Patients with HBV coinfection: obtain HBsAg for assessment of active HBV coinfection and HBV core antibodies and HBV surface antibodies for assessment of prior infection in all patients initiating direct-acting antiviral therapy for HCV infection. B Show 2 more Patients with HIV coinfection: treat and re-treat patients with human immunodeficiency and HCV coinfection the same as patients without human immunodeficiency virus infection after recognizing and managing interactions with antiretroviral medications. B Show 23 more 6. Patient education General counseling: provide education and interventions in all patients with HCV infection aimed at reducing liver disease progression and preventing HCV transmission. B Show 3 more 7. Preventative measures Immunizations: Administer vaccination against hepatitis A and hepatitis B in all susceptible patients with HCV infection. B Administer vaccination against pneumococcal infection in all patients with cirrhosis. B Prevention of transmission in hemodialysis units: ensure that hemodialysis facilities adhere to standard infection control procedures including hygienic precautions effectively preventing the transfer of blood and blood-contaminated fluids between patients to prevent transmission of blood-borne pathogens. B Show 7 more 8. Follow-up and surveillance Treatment monitoring: As per ACEP 2021 guidelines: Consider limiting laboratory monitoring to the beginning and end of the treatment in adult patients without cirrhosis or with compensated cirrhosis. C https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 8/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway Obtain closer monitoring in patients with decompensated cirrhosis. B As per AASLD 2020 guidelines, ensure clinic visits or telephone contact as clinically indicated during treatment to ensure medication adherence, and to monitor for adverse events and potential drug-drug interactions, especially with newly prescribed medications. B Show 6 more Post-treatment follow-up (patients achieved sustained virologic response): monitor patients without cirrhosis in the same way as persons never infected with HCV. B Show 6 more Post-treatment follow-up (patients failed sustained virologic response): initiate retreatment with recommended regimens in patients with chronic HCV. B Show 3 more Management of recurrence after liver transplantation: Administer any of the following daily fixed-dose combination regimens in treatment-na ve and -experienced patients with genotype 1-6 HCV infection in the allograft without cirrhosis: glecaprevir 300 mg/pibrentasvir 120 mg for 12 weeks ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks in patients with genotype 1, 4, 5, or 6 HCV infection sofosbuvir 400 mg/velpatasvir 100 mg for 12 weeks. B Show 3 more References 1. Kidney Disease: Improving Global Outcomes KDIGO Hepatitis C Work Group. KDIGO 2022 Clinical Practice Guideline FOR the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int. 2022 Dec;102 6S S129 S205. Open 2. Marc G Ghany, Timothy R Morgan, AASLD IDSA Hepatitis C Guidance Panel. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Hepatology. 2020 Feb;71 2 686 721. Open 3. George M Abraham, Adam J Obley, Linda L Humphrey et al. World Health Organization Guidelines on Treatment of Hepatitis C Virus Infection: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Jan;174 1 98 100. Open 4. No authors listed. Updated recommendations on treatment of adolescents and children with chronic HCV infection, and HCV simplified service delivery and diagnostics. Geneva: World Health Organization; 2022. Open 5. Moyer VA. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Sep 3;159 5 349 57. Open 6. Manns MP, Buti M, Gane E et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017 Mar 2;3 17006. Open 7. Hofmeister MG, Rosenthal EM, Barker LK et al. Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013 2016. Hepatology. 2019 Mar;69 3 1020 1031. Open https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 9/10 6/24/23, 12:41 PM Hepatitis C virus infection Pathway 8. Kim A. Hepatitis C Virus. Ann Intern Med. 2016 Sep 6;165 5 ITC33 ITC48. Open 9. Ireland G, Mandal S, Hickman M et al. Mortality rates among individuals diagnosed with hepatitis C virus HCV ; an observational cohort study, England, 2008 to 2016. Euro Surveill. 2019 Jul;24 30 . Open 10. Kidney Disease: Improving Global Outcomes KDIGO . KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2008 Apr; 109 S1 99. Open 11. Grad R, Thombs BD, Tonelli M et al. Recommendations on hepatitis C screening for adults. CMAJ. 2017 Apr 24;189 16 E594 E604. Open 12. Kaplan JE, Benson C, Holmes KK et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 Apr 10;58 RR 4 1 207. Open 13. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2019. Open 14. Muir AJ, Gong L, Johnson SG et al. Clinical Pharmacogenetics Implementation Consortium CPIC guidelines for IFNL3 IL28B genotype and PEG interferon- -based regimens. Clin Pharmacol Ther. 2014 Feb;95 2 141 6. Open 15. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 16. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 17. Kidney Disease: Improving Global Outcomes KDIGO Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl 2011 . 2018 Oct;8 3 91 165. Open 18. European Association for the Study of the Liver, Clinical Practice Guidelines Panel: Chair, EASL Governing Board representative. EASL recommendations on treatment of hepatitis C Final update of the series. J Hepatol. 2020 Nov;73 5 1170 1218. Open 19. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 20. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 21. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 22. R Douglas Wilson. Guideline No. 409 Intrauterine Fetal Diagnostic Testing in Women with Chronic Viral Infections. J Obstet Gynaecol Can. 2020 Dec;42 12 1555 1562.e1. Open https://web.pathway.md/diseases/rec6kvLzFTxqzyttj 10/10

Guideline sources The following summarized guidelines for the evaluation and management of hepatitis E are prepared by our editorial team based on guidelines from the European Association for the Study of the Liver (EASL 2018). 1 Guidelines 1. Screening and diagnosis Indications for testing: test for HEV infection in all patients with symptoms consistent with acute hepatitis. A 2. Diagnostic investigations Laboratory testing: use a combination of serology and NAT testing to diagnose HEV infection. A 3. Diagnostic procedures https://web.pathway.md/diseases/rec7KptJdWUxYyGmX 1/3 6/24/23, 12:41 PM Hepatitis E virus infection Pathway Kidney biopsy: consider renal biopsy for patients with acute or chronic HEV infection who develop new onset proteinuria. C 4. Medical management Indications for treatment: Consider ribavirin treatment in patients with severe acute hepatitis E or acute-on-chronic liver failure. C Consider antiviral treatment for patients with chronic hepatitis E infection infection and associated glomerular disease. C Duration of treatment: complete 12 weeks of ribavirin monotherapy in patients with persisting HEV replication three months after detection of HEV RNA. B Show 3 more Management of non-response to treatment: consider administering PEGylated interferon-alpha for the treatment of hepatitis E infection in liver transplant recipients who show no response to ribavirin. C 5. Nonpharmacologic interventions Dietary modifications: Advise immunocompromised patients, as well as those with chronic liver diseases, to avoid consumption of undercooked meat (pork, wild boar and venison) and shellfish. B Consider advising that immunocompromised patients consume meat only if it has been thoroughly cooked to temperatures of at least 70 degree C. C 6. Specific circumstances Pregnant patients: admit pregnant women with HEV genotype 1 or 2 infection to a high- dependency unit, and transfer to a liver transplant unit if liver failure occurs. A Immunosuppressed patients: decrease immunosuppression at diagnosis of chronic HEV infection in solid organ transplant recipients, if possible. B References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018 Jun;68 6 1256 1271. Open 2. Kamar N, Bendall R, Legrand-Abravanel F et al. Hepatitis E. Lancet. 2012 Jun 30;379 9835 2477 2488. Open https://web.pathway.md/diseases/rec7KptJdWUxYyGmX 2/3 6/24/23, 12:41 PM Hepatitis E virus infection Pathway 3. Ivo Ditah, Fausta Ditah, Pardha Devaki et al. Current epidemiology of hepatitis E virus infection in the United States: low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatology. 2014 Sep;60 3 815 22. Open 4. Liza Bronner Murrison, Kenneth E Sherman. The Enigma of Hepatitis E Virus. Gastroenterol Hepatol N Y . 2017 Aug;13 8 484 491. Open 5. Glynn W Webb, Harry R Dalton. Hepatitis E an underestimated emerging threat. Ther Adv Infect Dis. 2019 Apr 3;6 2049936119837162. Open 6. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 7. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/rec7KptJdWUxYyGmX 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hepatocellular carcinoma are prepared by our editorial team based on guidelines from the Enhanced Recovery After Surgery Society (ERASS 2023), the American Association for the Study of Liver Diseases (AASLD 2023), the Asian Pacific Association for the Study of the Liver (APASL 2023), the American Gastroenterological Association (AGA 2022), the American Society for Radiation Oncology (ASTRO 2022), the European Association for the Study of the Liver (EASL 2022; 2020; 2018), the American Society of Clinical Oncology (ASCO 2020), the European Federation of Societies for Ultrasound (EFSU 2020), and the European Society of Medical Oncology (ESMO 2018). 1 2 3 4 5 6 7 8 9 10 11 12 12 12 13 14 15 16 Definition HCC is a disease occurring due to malignant transformation of normal hepatocytes within the liver parenchyma. 12 https://web.pathway.md/diseases/recURgzrLYpU9qco8 1/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Epidemiology The risk factors that induce malignant transformation of normal hepatocytes include chronic infections of HBV and/or HCV, aflatoxin toxin, cirrhosis, or consumption of large amounts of alcohol. Underlying liver cirrhosis is present in about 80-90% of patients. 14 Pathophysiology HCC accounts for 75-85% of all liver malignancies. In the United States, the incidence of HCC is estimated at 7.7 cases per 100,000 person-years. 12 13 Disease course Clinical manifestations relate to local mass effect (abdominal pain, distension, loss of appetite, palpable masses), hepatic dysfunction (jaundice, ascites, gastrointestinal bleeding, splenomegaly, and encephalopathy), and constitutional effects of malignancy. 15 Prognosis and risk of recurrence Multiple treatment modalities exist; however, only orthotopic liver transplantation or surgical resection is curative. The overall prognosis for HCC in the United States is poor with a 2-year survival < 50% and a 5-year survival of only 10%. 12 16 CalculatorEastern Cooperative Oncology G CalculatorKarnofsky performance status s CalculatorLiver deco Guidelines 1. Screening and diagnosis Epidemiology: the prevalence of hapatocellular carcinoma is increasing both in Europe and worldwide; it is amongst the leading causes of cancer death globally. A Indications for screening, liver cirrhosis: As per AASLD 2023 guidelines, obtain surveillance for HCC in patients with Child-Pugh A-B cirrhosis of any etiology or Child-Pugh C cirrhosis eligible for liver transplantation. B Do not obtain surveillance in patients with Child-Pugh C cirrhosis ineligible for liver transplantation. B As per EASL 2022 guidelines, consider obtaining screening for hepatobiliary malignancy every 6 months in patients with PSC in the presence of cirrhosis. C As per EASL 2018 guidelines, obtain surveillance for HCC in high-risk patients, B including patients with cirrhosis, Child-Pugh stages A-B, B or Child-Pugh stage C, awaiting liver https://web.pathway.md/diseases/recURgzrLYpU9qco8 2/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway transplantation. B Show 2 more As per ESMO 2018 guidelines: Obtain surveillance for HCC in all patients with cirrhosis, irrespective of the etiology, as long as liver function and comorbidities allow curative or palliative treatments. B Obtain surveillance for HCC in patients at risk for HCC with abdominal ultrasound every 6 months with or without AFP. A Indications for screening (hemochromatosis): obtain surveillance for HCC with 6-monthly ultrasound, with or without AFP testing, in patients with cirrhosis due to hemochromatosis. Obtain surveillance only if a diagnosis of HCC will alter management. A Indications for screening, viral hepatitis: As per AASLD 2023 guidelines: Obtain surveillance for HCC in patients with chronic HBV infection without cirrhosis. B Do not obtain routine surveillance for HCC in patients with HCV infection post-sustained virological response with advanced fibrosis but without cirrhosis. D As per EASL 2018 guidelines, obtain surveillance for HCC in patients with HBV infection (without cirrhosis) at intermediate or high risk of HCC (according to PAGE-B classes for Caucasian subjects, respectively 10-17 and 18 score points). B As per ESMO 2018 guidelines, obtain surveillance for HCC in hepatitis virus-infected patients without cirrhosis, especially in HBV carriers with serum viral load > 10,000 copies/mL or HCV- infected patients with bridging fibrosis (F3). B Indications for screening (occupational liver disease): consider obtaining ultrasound surveillance for the development of liver neoplasms in workers exposed to high levels of vinyl chloride monomer in the past, that is until the mid-1970s, as defined by their job title (reactor cleaners). C Indications for screening, NAFLD: As per AASLD 2023 guidelines, do not obtain routine surveillance for HCC in patients with nonalcoholic fatty liver disease with advanced fibrosis but without cirrhosis. D As per EASL 2018 guidelines, insufficient evidence regarding the role of HCC surveillance in patients with nonalcoholic fatty liver disease without cirrhosis. I Indications for screening, liver transplant candidates: As per AASLD 2023 guidelines: Obtain semiannual surveillance for HCC in all patients listed for liver transplantation because identifying early-stage HCC changes the priority for transplantation. B Do not obtain surveillance for HCC in patients with life-limiting comorbid conditions not treatable by liver transplantation or other directed therapies. D As per EASL 2018 guidelines, implement surveillance programs for HCC in patients on the waiting list for liver transplantation to detect and manage tumor occurrence or tumor response and to help define priority policies for transplantation. B https://web.pathway.md/diseases/recURgzrLYpU9qco8 3/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Choice of screening tests: As per AASLD 2023 guidelines, obtain liver ultrasound and AFP measurement approximately every 6 months for HCC surveillance. B Assess and report ultrasound visualization, given its impact on recommended recall procedures. B Show 3 more As per EFSU 2020 guidelines, do not obtain contrast-enhanced ultrasound routinely for HCC surveillance in at-risk patients. D As per EASL 2018 guidelines, do not use tumor biomarkers alone (including AFP, lectin-reactive fraction of AFP, and des-gamma-carboxy prothrombin) for routine surveillance for early HCC. D Diagnostic criteria: As per AASLD 2023 guidelines, diagnose HCC based on noninvasive imaging criteria and/or pathology in at-risk patients with cirrhosis or chronic HBV infection. A Show 3 more As per EASL 2018 guidelines: Diagnose HCC based on noninvasive criteria and/or pathology in patients with cirrhosis. A Diagnose HCC based on pathology in patients without cirrhosis. B As per ESMO 2018 guidelines, diagnose HCC based on histological analysis and/or contrast- enhanced imaging findings. B Show 2 more 2. Classification and risk stratification Staging: As per AASLD 2023 guidelines: Assess and document tumor staging, including tumor burden, degree of liver dysfunction, and ECOG performance status, at the time of initial treatment evaluation in patients with HCC. B Use the Barcelona Liver Clinic Cancer system for HCC staging. B As per EASL 2018 guidelines, use the Barcelona Liver Clinic Cancer staging system for treatment allocation and prognostication in patients with HCC. A As per ESMO 2018 guidelines, assess tumor extent, AFP level, liver function, portal pressure, and clinical performance status for the staging of HCC to determine outcome and planning of optimal therapy. B Show 3 more 3. Diagnostic investigations Diagnostic imaging, CT/MRI: As per AASLD 2023 guidelines, obtain either dynamic contrast-enhanced MRI or multiphasic CT for noninvasive diagnosis of HCC. A https://web.pathway.md/diseases/recURgzrLYpU9qco8 4/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Show 2 more As per EASL 2018 guidelines, obtain CT or MRI as first-line imaging evaluation for HCC due to their higher sensitivity and ability to visualize the entire liver. A As per ESMO 2018 guidelines: Consider obtaining MRI (based on techniques such as DWI and the use of hepatobiliary contrast agents) to identify and stratify nodules as high-risk nodules (either HCC not displaying the typical imaging hallmarks features or high-grade dysplastic nodules). C Consider obtaining contrast-enhanced ultrasound as a suitable noninvasive technique for diagnosing hepatocellular in patients with liver cirrhosis. C Diagnostic imaging (CEUS): Consider obtaining contrast-enhanced ultrasound as first-line imaging for characterizing focal liver lesions to establish a diagnosis of malignancy (contrast-enhanced ultrasound LR-M) or, specifically, HCC (contrast-enhanced ultrasound LR-5) in patients with liver cirrhosis. C Consider obtaining contrast-enhanced ultrasound to assess the probability of HCC when CT or MRI is inconclusive, especially in focal liver lesions in the cirrhotic liver unsuitable for biopsy. C Tumor biomarkers: avoid obtaining biomarkers, including AFP alone, to diagnose HCC. D Evaluation for portal hypertension: assess for portal hypertension by the presence of esophageal varices and/or splenomegaly with blood platelet counts of 100 10 cells/L suggesting clinically important portal hypertension (or based on invasive measured by the transjugular route: hepatic venous pressure gradient > 10 mmHg). B Imaging for staging, CT/MRI: As per AASLD 2023 guidelines: Obtain multiphase CT or contrast-enhanced MRI of the abdomen for staging in all patients with HCC. B Obtain non-contrast CT of the chest to evaluate for metastatic disease in patients with HCC beyond Barcelona Liver Clinic Cancer stage 0. B As per EFSU 2020 guidelines, obtain CT or MRI for accurate staging unless contraindicated. B Imaging for staging (CEUS): do not obtain contrast-enhanced ultrasound routinely for staging HCC. D Imaging for staging, PET: As per AASLD 2023 guidelines, avoid obtaining routine positron emission tomography and bone scan for staging, given low sensitivity for HCC. D As per ESMO 2018 guidelines, insufficient evidence to recommend obtaining FDG-positron emission tomography for staging. I 4. Diagnostic procedures Liver biopsy: https://web.pathway.md/diseases/recURgzrLYpU9qco8 5/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway As per AASLD 2023 guidelines, consider performing biopsy over repeat imaging in patients with an LR-4 observation if an immediate diagnosis would impact management decisions. B Show 3 more As per EASL 2018 guidelines: Perform a tissue biopsy to confirm the diagnosis of HCC in patients without cirrhosis. B Repeat tissue biopsy in patients with inconclusive histological or discordant findings, or in cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC. B As per ESMO 2018 guidelines, use standard (H&E) and special stains (such as reticulin), and immunohistochemistry if required, for histopathological diagnosis of tumor biopsies. E Show 2 more Ancillary testing: obtain immunohistochemistry in unclear cases. Obtain CD34 immunohistochemistry to assess capillarization of sinusoids. B Show 2 more 5. Medical management General principles: As per AASLD 2023 guidelines, discuss and manage cases of HCC in a multidisciplinary care setting. B As per EASL 2018 guidelines, discuss cases of HCC in multidisciplinary teams to fully capture and tailor individualized treatment options. B Expectant management: Consider monitoring patients with decompensated cirrhosis developing T1 HCC eligible for liver transplantation with cross-sectional imaging at least every 3 months until criteria are met for Model for End-Stage Liver Disease exception before pursuing locoregional therapy. C Consider offering immediate locoregional therapy in patients with decompensated cirrhosis developing T1 HCC with significantly elevated AFP levels or if the patient is not otherwise eligible for liver transplantation. C Neoadjuvant therapy: As per AASLD 2023 guidelines, avoid offering neoadjuvant systemic therapies in patients undergoing liver resection outside a clinical trial setting. D As per EASL 2018 guidelines, do not offer neoadjuvant therapy in patients with HCC because it has not been proven to improve the outcome of patients treated with resection. D Adjuvant therapy: As per AASLD 2023 guidelines, offer adjuvant immune checkpoint inhibitor-based systemic therapy in patients at high risk of recurrence after liver resection or local ablation. B As per AGA 2022 guidelines: https://web.pathway.md/diseases/recURgzrLYpU9qco8 6/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Avoid offering adjuvant sorafenib therapy in patients with HCC undergoing curative surgical resection, curative local ablation, D or transarterial chemoembolization locoregional therapy. D Avoid offering adjuvant bevacizumab therapy in patients with HCC undergoing transarterial chemoembolization locoregional therapy. D As per EASL 2018 guidelines, do not offer adjuvant therapy in patients with HCC because it has not been proven to improve the outcome of patients treated with resection. D As per ESMO 2018 guidelines, do not offer adjuvant therapy in patients with HCC after orthotopic liver transplantation, liver resection, or local ablation. D Landmark trials: STORM In patients with HCC with a complete radiological response after surgical resection or local ablation, sorafenib was not superior to placebo with respect to median recurrence-free survival. Jordi Bruix et al. Lancet Oncol. 2015 Oct. Primary systemic therapy, first-line therapy: As per AASLD 2023 guidelines, consider offering systemic therapy in patients with intermediate HCC unsuitable for or refractory to locoregional therapies due to contraindications, worsening hepatic dysfunction, progression of HCC, or lack of objective response. B Show 4 more Landmark trials: HIMALAYA (STRIDE) In patients with unresectable HCC and no previous systemic treatment, STRIDE was superior to sorafenib with respect to median overall survival. Ghassan K. Abou-Alfa et al. NEJM Evid. 2022. As per AGA 2022 guidelines, consider offering sorafenib in patients with HCC with preserved liver function ineligible for locoregional therapy/resection or with metastatic disease. C Show 3 more As per ASCO 2020 guidelines, consider offering atezolizumab plus bevacizumab as first-line therapy in most patients with advanced HCC, Child-Pugh class A, ECOG performance status 0- 1, and following management of esophageal varices, when present, according to institutional guidelines. B Show 2 more Landmark trials: IMbrave 150 https://web.pathway.md/diseases/recURgzrLYpU9qco8 7/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway In patients with unresectable HCC who had not previously received systemic treatment, atezolizumab-bevacizumab was superior to sorafenib with respect to overall survival at 12 months. Richard S Finn et al. N Engl J Med. 2020 May 14. As per EASL 2018 guidelines: Offer sorafenib as the standard first-line systemic therapy for HCC in patients with well- preserved liver function (Child-Pugh A) and advanced tumors (BCLC stage C), or earlier stage tumors progressing despite or unsuitable for locoregional therapies. A Offer lenvatinib as another first-line option in patients with well-preserved liver function (Child- Pugh A class), good performance status, and with advanced tumors (BCLC-C without main portal vein invasion), or tumors progressing despite or unsuitable for locoregional therapies. A As per ESMO 2018 guidelines, do not offer chemotherapy as the standard of care in patients with advanced HCC. D Show 3 more Primary systemic therapy, second-line therapy: As per AASLD 2023 guidelines, consider offering second-line therapy in patients with preserved liver function (Child-Pugh A or well-selected Child-Pugh B cirrhosis), ECOG performance status 0-1 developing HCC progression or intolerance with first-line systemic therapy. B Show 3 more As per AGA 2022 guidelines, consider offering regorafenib in patients with HCC with preserved liver function ineligible for locoregional therapy or with metastatic disease with progressive disease on sorafenib. C Show 3 more As per ASCO 2020 guidelines: Consider offering second-line therapy with a TKI (sorafenib, lenvatinib, cabozantinib, or regorafenib) following first-line therapy with atezolizumab plus bevacizumab. C Consider offering second-line therapy with another TKI (cabozantinib or regorafenib), ramucirumab (AFP 400 ng/mL), or atezolizumab plus bevacizumab in appropriate candidates following first-line therapy with sorafenib or lenvatinib. C As per EASL 2018 guidelines, offer regorafenib as second-line therapy in patients tolerating and progressing on sorafenib and with well-preserved liver function (Child-Pugh A class) and good performance status. A As per ESMO 2018 guidelines, consider offering cabozantinib in patients with progressive disease on 1-2 systemic therapies with well-preserved liver function and ECOG performance status. B Show 2 more Management of pain: consider using acetaminophen (maximum dose: 3 g per day, PO) to manage pain of mild intensity in patients with HCC in the context of cirrhosis. C https://web.pathway.md/diseases/recURgzrLYpU9qco8 8/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Show 2 more Palliative care: As per AASLD 2023 guidelines, offer advance care planning in all patients receiving palliative- intent therapy or best supportive care for HCC, regardless of transplant eligibility. B As per EASL 2018 guidelines: Provide supportive care (including pain management, nutritional and psychological support) to patients with BCLC stage D HCC ineligible for liver transplantation. B Consider offering palliative radiotherapy for bone metastases causing pain or at significant risk of spontaneous secondary fracture. C 6. Nonpharmacologic interventions Psychosocial and nutritional support: provide psycho-oncological support and counseling on adequate nutrition according to the patients' condition. B 7. Therapeutic procedures Local ablation: As per AASLD 2023 guidelines: Perform local ablative therapies with curative intent in patients with solitary tumors 5 cm ineligible for or declining surgical therapy. A Consider performing thermal ablation (radiofrequency or microwave ablation) in patients with early-stage HCC 3 cm ineligible for or declining surgery. B As per EASL 2018 guidelines, perform thermal ablation with radiofrequency in patients with Barcelona Liver Clinic Cancer stage 0-A tumors ineligible for surgery. A Show 4 more As per ESMO 2018 guidelines: Consider performing local ablation in cases of a long-anticipated waiting time (> 3 months) for liver transplantation to minimize the risk of tumor progression and to offer a bridge to transplant. C Consider performing radiofrequency ablation or microwave ablation as first-line therapy in very early-stage disease (Barcelona Liver Clinic Cancer stage 0). B Transarterial therapies: As per AASLD 2023 guidelines, perform transarterial chemoembolization in patients with Barcelona Liver Clinic Cancer stage B HCC. A Consider performing radioembolization as an alternative therapy to chemoembolization. B Show 2 more As per EASL 2018 guidelines, perform transarterial chemoembolization in suitable patients with BCLC stage B HCC. A https://web.pathway.md/diseases/recURgzrLYpU9qco8 9/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Show 3 more As per ESMO 2018 guidelines, consider performing transarterial chemoembolization in cases of a long-anticipated waiting time (> 3 months) for liver transplantation to minimize the risk of tumor progression and to offer a bridge to transplant. C Show 2 more External beam radiation therapy, indications: As per AASLD 2023 guidelines, consider offering targeted radioembolization (radiation segmentectomy) or EBRT as alternative therapies to thermal ablation in patients with Barcelona Liver Clinic Cancer stage A HCC ineligible for surgical resection, including tumors > 3 cm in size. B As per ASTRO 2022 guidelines, offer EBRT as a potential first-line single therapy option in patients with liver-confined HCC ineligible for curative options (surgery or thermal ablation) and being considered for catheter-based therapies. B Show 7 more As per ESMO 2018 guidelines: Consider offering high conformal high-dose-rate radioablation or stereotactic body radiotherapy as alternatives for the ablation of tumors with a high risk of local failure after thermal ablation due to location. C Do not offer stereotactic body radiotherapy as first-line therapy in patients in intermediate or advanced stages. D External beam radiation therapy (technical considerations): administer dose-escalated ultra- or moderately hypofractionated external beam radiation therapy with choice of regimen based on tumor location, underlying liver function, and available technology in patients with liver-confined HCC, if external beam radiation therapy is recommended. B Show 4 more 8. Perioperative care Preoperative care (counseling): Provide preoperative information and counseling regarding the upcoming liver surgery. Consider using brochures and multimedia support to improve verbal counseling. B Advise preoperative smoking cessation at least 4 weeks before hepatectomy. Advise alcohol cessation in heavy drinkers (> 24 g/day for females or > 36 g/day for males) 4-8 weeks before surgery. A Preoperative care (nutrition): obtain a nutritional assessment before liver surgery. Administer enteral supplementation at least 7-14 days before surgery to optimize nutritional status in malnourished patients (weight loss > 10% or > 5% over 3 months and reduced BMI or a low fat- free mass index). A Show 2 more https://web.pathway.md/diseases/recURgzrLYpU9qco8 10/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Preoperative care (rehabilitation): offer prehabilitation in high-risk patients (elderly, malnourished or overweight patients, smokers, or patients with psychological disorders) before liver surgery. Initiate prehabilitation 4-6 weeks before the operation depending upon the urgency of surgery. Insufficient evidence to recommend the content (physical exercises, dietary interventions, or anxiety reduction exercises) and duration of the prehabilitation program for liver surgery. B Preoperative care (biliary drainage): perform biliary drainage in the cholestatic liver (> 50 mmol/L). Prefer percutaneous over endoscopic biliary drainage in perihilar cholangiocarcinoma. Avoid performing surgery until the bilirubin level drops < 50 mmol/L. B Preoperative care (antibiotic prophylaxis): administer antibiotic prophylaxis (such as cefazolin) within 60 minutes before surgical incision with no extension into the postoperative period. Consider administering a targeted antibiotic preemptive regimen based on preoperative bile culture in case of complex liver surgery with biliary reconstruction. B Preoperative care (corticosteroids): administer a preoperative dose of corticosteroids (methylprednisolone 500 mg). Insufficient evidence for its use in diabetic patients undergoing liver surgery. B Preoperative care (preanesthetic medication): avoid administering long-acting anxiolytic drugs, particularly in the elderly. D Show 3 more Intraoperative care (anesthesia and analgesia): Administer multimodal analgesia, including the potential use of intrathecal opioids, both for open A and laparoscopic surgery. B Recognize that thoracic epidural analgesia can provide excellent analgesia for open liver surgery but has significant disadvantages. Do not use regional anesthesia techniques in laparoscopic surgery as multimodal analgesia combined with judicious IV opioids provide functional analgesia. Perform continuous local anesthetic wound infiltration to provide lower complication rates and overall equivalent analgesia to thoracic epidural analgesia. Perform local anesthetic transversus abdominis plane blockade as a supplement to standard analgesia to improve pain control and reduce opioid usage. A Intraoperative care (fluid management): Maintain low central venous pressure (< 5 cmH O) with close monitoring during hepatic transection. A Prefer balanced crystalloids over 0.9% saline or colloids for fluid maintenance. Provide goal- directed fluid therapy to optimize cardiac output and end-organ perfusion, recognizing that this may be particularly beneficial after the intraoperative liver resection during a low central venous pressure state to restore tissue perfusion, with patients having comorbidities and reduced cardiac function benefiting the most. A Intraoperative care (temperature management): maintain perioperative normothermia with multimodal temperature management (including circulating water garments or forced warm air) during open and minimally invasive liver surgery. B https://web.pathway.md/diseases/recURgzrLYpU9qco8 11/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway Postoperative care (thromboprophylaxis): administer routine postoperative LMWH or UFH to reduce the risk of thromboembolic events unless exceptional circumstances make this unsafe. Use intermittent pneumatic compression devices to reduce this risk further. B Postoperative care (early mobilization): initiate early mobilization (out of bed) after liver surgery from the operative day until hospital discharge. Insufficient evidence regarding the optimal duration of mobilization. B Postoperative care (nutrition): implement early oral intake with a normal diet after hepatectomy. Assess the individualized needs for artificial nutrition in malnourished patients, patients with complications causing several days of fasting, and patients with liver cirrhosis. Prefer enteral administration for artificial nutrition. A Show 2 more Postoperative care (antiemetics): use a multimodal approach to postoperative nausea and vomiting. Administer postoperative nausea and vomiting prophylaxis with at least 2 antiemetic drugs, such as dexamethasone and ondansetron. A Postoperative care (laxatives): insufficient evidence to support the routine use of postoperative laxatives, gum chewing, herbal medicine, or decoction to stimulate bowel movement after liver surgery. I 9. Surgical interventions Surgical resection, indications: As per AASLD 2023 guidelines, perform surgical resection in patients with localized HCC without underlying cirrhosis. B Consider performing surgical resection in patients with cirrhosis with limited tumor burden, well-compensated cirrhosis without clinically significant portal hypertension, and an adequate future liver remnant. B As per EASL 2018 guidelines, perform surgical resection in patients with HCC arising on a non- cirrhotic liver. B Show 4 more As per ESMO 2018 guidelines, perform minor/major liver resection in patients with Child-Pugh A without immanent portal hypertension. B Show 2 more Surgical resection, technical considerations: As per AASLD 2023 guidelines, consider performing minimally invasive liver resection (laparoscopic or robotic) to enhance recovery and lower the risk of perioperative morbidity in selected patients. C As per ERASS 2023 guidelines, perform liver resection laparoscopically, in trained teams and when clinically appropriate, to reduce the postoperative length of stay and complication rates. B Show 3 more https://web.pathway.md/diseases/recURgzrLYpU9qco8 12/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway As per EASL 2018 guidelines, consider performing liver resection via laparoscopic/minimally invasive approaches in properly trained centers, especially for tumors in anterolateral and superficial locations. C As per ESMO 2018 guidelines, prefer a laparoscopic approach for liver resection in patients with cirrhosis. B Liver transplantation, indications: As per AASLD 2023 guidelines, offer liver transplantation in transplant-eligible patients with early-stage HCC occurring in the setting of clinically significant portal hypertension and/or decompensated cirrhosis. B Show 2 more As per EASL 2018 guidelines, offer liver transplantation as a first-line treatment option in patients with HCC meeting Milan criteria but unsuitable for resection. A Show 2 more As per ESMO 2018 guidelines, use the Milan criteria (1 lesion < 5 cm; alternatively, up to 3 lesions, each < 3 cm; no extrahepatic manifestations; no evidence of macrovascular invasion) for the selection of patients with HCC for orthotopic liver transplantation. B Show 2 more Liver transplantation, bridging therapy: As per AASLD 2023 guidelines, consider offering pre-transplant locoregional bridging therapy in patients with adequate hepatic reserve being evaluated or listed for liver transplantation to reduce the risk of waitlist dropout in the context of anticipated prolonged wait times for transplant. B Show 2 more As per ASTRO 2022 guidelines, consider offering ultra- or moderately hypofractionated EBRT as a bridge to transplant in patients with HCC being potential candidates for orthotopic liver transplantation. C As per ESMO 2018 guidelines, consider offering resection, local ablation, or transarterial chemoembolization in cases of a long-anticipated waiting time (> 3 months) for liver transplantation to minimize the risk of tumor progression and to offer a bridge to transplant. C 10. Preventative measures Public health measures: As per AASLD 2023 guidelines: Implement interventions such as best practice alerts or outreach programs to increase HCC surveillance adherence, given the underuse of surveillance in clinical practice. B Implement public health policies and interventions to address the significant mortality of HCC. B As per EASL 2018 guidelines, implement public health policies to decrease HBV and HCV transmission, counteract chronic alcohol abuse, and encourage healthy lifestyles preventing https://web.pathway.md/diseases/recURgzrLYpU9qco8 13/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway obesity and metabolic syndrome. B Hepatitis B immunization: As per AASLD 2023 guidelines, administer vaccination for HBV infection in all newborns and high-risk adults failed to receive vaccination at birth to reduce the risk of HCC. B As per EASL 2018 guidelines, immunize newborns and high-risk patients against hepatitis B to decrease the risk of HCC. A As per ESMO 2018 guidelines, implement universal vaccination at birth against HBV to prevent chronic liver disease and HCC. A Management of viral hepatitis: As per AASLD 2023 guidelines, initiate antiviral treatment for HBV and HCV infections according to current evidence-based clinical practice guidelines. Suppress HBV and eradicate HCV infection to decrease the risk of HCC development in patients with chronic viral hepatitis. B As per EASL 2018 guidelines: Initiate antiviral therapy to maintain HBV suppression in patients with chronic HBV infection or to sustain the viral response in patients with HCV infection to prevent progression to cirrhosis and HCC. A Initiate antiviral therapy in patients with cirrhosis and chronic HBV infection or HCV infection to prevent cirrhosis progression and decompensation. B As per ESMO 2018 guidelines, initiate early antiviral treatment of viral HBV and HCV infections to prevent chronic liver disease and HCC. B Chemoprevention: do not use chemoprevention therapies, such as statins, aspirin, and metformin, solely to reduce the risk of HCC. D Lifestyle modifications: counsel patients with chronic liver disease to maintain a healthy weight, adopt a balanced diet, avoid tobacco and alcohol use, and achieve adequate control of comorbid conditions, including components of the metabolic syndrome, as a healthy lifestyle has multiple benefits and may decrease the risk of HCC. B Coffee: consider advising coffee consumption in patients with chronic liver disease as it has been associated with decreased risk of HCC development. C 11. Follow-up and surveillance Surveillance for hepatic nodules: As per AASLD 2023 guidelines, consider obtaining repeat short-interval ultrasound and AFP measurement in approximately 3-6 months in patients with a < 1 cm lesion on ultrasound. B Consider returning to semiannual surveillance with ultrasound and AFP if the lesion is stable for 2 follow-up ultrasounds. C Show 4 more As per EASL 2018 guidelines, obtain surveillance ultrasound at 4-month intervals in the first year in high-risk patients with hepatic nodules measuring < 1 cm in diameter. Consider returning https://web.pathway.md/diseases/recURgzrLYpU9qco8 14/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway surveillance to the usual 6-month interval if there is no increase in the size or number of nodules. B Assessment of treatment response: As per EASL 2018 guidelines: Use mRECIST criteria to assess the response to loco-regional therapies for HCC. B Use mRECIST and RECIST1.1 criteria to assess the response to systemic therapies for HCC. B As per ESMO 2018 guidelines: Obtain dynamic CT or MRI for the assessment of viable tumor, defined as uptake of contrast agent in the arterial phase. B Consider using the mRECIST to include not only tumor diameters but also lesion viability in therapy decision-making. Use the mRECIST for the assessment of response to locoregional therapies. C Post-treatment follow-up: As per AASLD 2023 guidelines: Obtain routine postoperative surveillance with contrast-enhanced multiphasic CT or MRI every 3-6 months to detect recurrence in all patients with HCC following liver resection. B Consider obtaining post-transplant surveillance with multiphasic contrast-enhanced abdominal CT or MRI and chest CT to detect recurrence in patients with HCC following liver transplantation. B As per EASL 2018 guidelines, obtain follow-up (every 3-4 months for the first year) in patients after curative-intent liver resection because of high rates of treatable recurrence. A As per ESMO 2018 guidelines: Obtain clinical evaluation of liver decompensation and dynamic CT or MRI every 3 months during the first 2 years and every 6 months thereafter for early detection of recurrence in patients treated with radical treatments (resection or radiofrequency ablation). B Obtain clinical evaluation for signs of liver decompensation and dynamic CT or MRI every 3 months for tumor progression to guide therapy decisions in patients with more advanced stages of HCC treated with transarterial chemoembolization or systemic therapy. B Management of recurrence: As per AASLD 2023 guidelines: Consider offering post-progression treatment after adjuvant therapy based on the recurrence pattern. C Avoid using immune checkpoint inhibitors in patients with recurrent HCC after liver transplantation, given the increased risk of graft loss and death. D Consider offering sorafenib or lenvatinib as first-line therapy in these patients. As per ASTRO 2022 guidelines, consider offering palliative hypofractionated EBRT directed to the liver and/or macrovascular tumor thrombus, alone or sequenced with systemic therapy or catheter-based therapies, in patients with symptomatic locally advanced HCC. C https://web.pathway.md/diseases/recURgzrLYpU9qco8 15/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway References 1. Grace L. Su, Osama Altayar, Robert O Shea et al. AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma. Gastroenterology. 2022 Mar;163 3 920 934. Open 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69 1 182 236. Open 3. Ga tan-Romain Joliat, Kosuke Kobayashi, Kiyoshi Hasegawa et al. Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery ERAS Society Recommendations 2022. World J Surg. 2023 Jan;47 1 11 34. Open 4. A Vogel, A Cervantes, I Chau et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Suppl 4):iv238-iv255. Open 5. Amit G Singal, Josep M Llovet, Mark Yarchoan et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023 May 22. Online ahead of print. Open 6. John D Gordan, Erin B Kennedy, Ghassan K Abou-Alfa et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020 Dec 20;38 36 4317 4345. Open 7. Smith Apisarnthanarax, Aisling Barry, Minsong Cao et al. External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. Jan-Feb 2022;12 1 28 51. Open 8. Christoph F Dietrich, Christian P llson Nols e, Richard G Barr et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound CEUS in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020 Oct;46 10 2579 2604. Open 9. Darrell H G Crawford, Grant A Ramm, Kim R Bridle et al. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int. 2023 Apr 17. Open 10. Massimo Colombo. EASL clinical practice guidelines for the management of occupational liver diseases. Liver Int. 2020 Feb;40 Suppl 1 136 141. Open 11. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on Sclerosing Cholangitis. J Hepatol. 2022 May 31;S0168 8278 22 00326 9. Open 12. Ogunwobi OO, Harricharran T, Huaman J et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019 May 21;25 19 2279 2293. Open 13. Rahman R, Hammoud GM, Almashhrawi AA et al. Primary hepatocellular carcinoma and metabolic syndrome: An update. World J Gastrointest Oncol. 2013 Sep 15;5 9 186 94. Open 14. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog. 2017 May 29;16 1. Open 15. Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM et al. Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev. 2017 Apr 1;18 4 863 872. Open 16. Balogh J, Victor D rd, Asham EH et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016 Oct 5;3 41 53. eCollection 2016. Open https://web.pathway.md/diseases/recURgzrLYpU9qco8 16/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway 17. Liu R, Wakabayashi G, Kim HJ et al. International consensus statement on robotic hepatectomy surgery in 2018. World J Gastroenterol. 2019 Mar 28;25 12 1432 1444. Open 18. Davide Citterio, Antonio Facciorusso, Carlo Sposito et al. Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma. JAMA Surg. 2016 Sep 1;151 9 846 53. Open 19. Hwai-I Yang, Man-Fung Yuen, Henry Lik-Yuen Chan et al. Risk estimation for hepatocellular carcinoma

Initiate antiviral therapy in patients with cirrhosis and chronic HBV infection or HCV infection to prevent cirrhosis progression and decompensation. B As per ESMO 2018 guidelines, initiate early antiviral treatment of viral HBV and HCV infections to prevent chronic liver disease and HCC. B Chemoprevention: do not use chemoprevention therapies, such as statins, aspirin, and metformin, solely to reduce the risk of HCC. D Lifestyle modifications: counsel patients with chronic liver disease to maintain a healthy weight, adopt a balanced diet, avoid tobacco and alcohol use, and achieve adequate control of comorbid conditions, including components of the metabolic syndrome, as a healthy lifestyle has multiple benefits and may decrease the risk of HCC. B Coffee: consider advising coffee consumption in patients with chronic liver disease as it has been associated with decreased risk of HCC development. C 11. Follow-up and surveillance Surveillance for hepatic nodules: As per AASLD 2023 guidelines, consider obtaining repeat short-interval ultrasound and AFP measurement in approximately 3-6 months in patients with a < 1 cm lesion on ultrasound. B Consider returning to semiannual surveillance with ultrasound and AFP if the lesion is stable for 2 follow-up ultrasounds. C Show 4 more As per EASL 2018 guidelines, obtain surveillance ultrasound at 4-month intervals in the first year in high-risk patients with hepatic nodules measuring < 1 cm in diameter. Consider returning https://web.pathway.md/diseases/recURgzrLYpU9qco8 14/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway surveillance to the usual 6-month interval if there is no increase in the size or number of nodules. B Assessment of treatment response: As per EASL 2018 guidelines: Use mRECIST criteria to assess the response to loco-regional therapies for HCC. B Use mRECIST and RECIST1.1 criteria to assess the response to systemic therapies for HCC. B As per ESMO 2018 guidelines: Obtain dynamic CT or MRI for the assessment of viable tumor, defined as uptake of contrast agent in the arterial phase. B Consider using the mRECIST to include not only tumor diameters but also lesion viability in therapy decision-making. Use the mRECIST for the assessment of response to locoregional therapies. C Post-treatment follow-up: As per AASLD 2023 guidelines: Obtain routine postoperative surveillance with contrast-enhanced multiphasic CT or MRI every 3-6 months to detect recurrence in all patients with HCC following liver resection. B Consider obtaining post-transplant surveillance with multiphasic contrast-enhanced abdominal CT or MRI and chest CT to detect recurrence in patients with HCC following liver transplantation. B As per EASL 2018 guidelines, obtain follow-up (every 3-4 months for the first year) in patients after curative-intent liver resection because of high rates of treatable recurrence. A As per ESMO 2018 guidelines: Obtain clinical evaluation of liver decompensation and dynamic CT or MRI every 3 months during the first 2 years and every 6 months thereafter for early detection of recurrence in patients treated with radical treatments (resection or radiofrequency ablation). B Obtain clinical evaluation for signs of liver decompensation and dynamic CT or MRI every 3 months for tumor progression to guide therapy decisions in patients with more advanced stages of HCC treated with transarterial chemoembolization or systemic therapy. B Management of recurrence: As per AASLD 2023 guidelines: Consider offering post-progression treatment after adjuvant therapy based on the recurrence pattern. C Avoid using immune checkpoint inhibitors in patients with recurrent HCC after liver transplantation, given the increased risk of graft loss and death. D Consider offering sorafenib or lenvatinib as first-line therapy in these patients. As per ASTRO 2022 guidelines, consider offering palliative hypofractionated EBRT directed to the liver and/or macrovascular tumor thrombus, alone or sequenced with systemic therapy or catheter-based therapies, in patients with symptomatic locally advanced HCC. C https://web.pathway.md/diseases/recURgzrLYpU9qco8 15/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway References 1. Grace L. Su, Osama Altayar, Robert O Shea et al. AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma. Gastroenterology. 2022 Mar;163 3 920 934. Open 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69 1 182 236. Open 3. Ga tan-Romain Joliat, Kosuke Kobayashi, Kiyoshi Hasegawa et al. Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery ERAS Society Recommendations 2022. World J Surg. 2023 Jan;47 1 11 34. Open 4. A Vogel, A Cervantes, I Chau et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Suppl 4):iv238-iv255. Open 5. Amit G Singal, Josep M Llovet, Mark Yarchoan et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023 May 22. Online ahead of print. Open 6. John D Gordan, Erin B Kennedy, Ghassan K Abou-Alfa et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020 Dec 20;38 36 4317 4345. Open 7. Smith Apisarnthanarax, Aisling Barry, Minsong Cao et al. External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. Jan-Feb 2022;12 1 28 51. Open 8. Christoph F Dietrich, Christian P llson Nols e, Richard G Barr et al. Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound CEUS in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020 Oct;46 10 2579 2604. Open 9. Darrell H G Crawford, Grant A Ramm, Kim R Bridle et al. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int. 2023 Apr 17. Open 10. Massimo Colombo. EASL clinical practice guidelines for the management of occupational liver diseases. Liver Int. 2020 Feb;40 Suppl 1 136 141. Open 11. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on Sclerosing Cholangitis. J Hepatol. 2022 May 31;S0168 8278 22 00326 9. Open 12. Ogunwobi OO, Harricharran T, Huaman J et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019 May 21;25 19 2279 2293. Open 13. Rahman R, Hammoud GM, Almashhrawi AA et al. Primary hepatocellular carcinoma and metabolic syndrome: An update. World J Gastrointest Oncol. 2013 Sep 15;5 9 186 94. Open 14. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog. 2017 May 29;16 1. Open 15. Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM et al. Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev. 2017 Apr 1;18 4 863 872. Open 16. Balogh J, Victor D rd, Asham EH et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016 Oct 5;3 41 53. eCollection 2016. Open https://web.pathway.md/diseases/recURgzrLYpU9qco8 16/17 6/24/23, 12:42 PM Hepatocellular carcinoma Pathway 17. Liu R, Wakabayashi G, Kim HJ et al. International consensus statement on robotic hepatectomy surgery in 2018. World J Gastroenterol. 2019 Mar 28;25 12 1432 1444. Open 18. Davide Citterio, Antonio Facciorusso, Carlo Sposito et al. Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma. JAMA Surg. 2016 Sep 1;151 9 846 53. Open 19. Hwai-I Yang, Man-Fung Yuen, Henry Lik-Yuen Chan et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B REACH B development and validation of a predictive score. Lancet Oncol. 2011 Jun;12 6 568 74. Open 20. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 21. Julie K Heimbach, Laura M Kulik, Richard S Finn et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018 Jan;67 1 358 380. Open 22. Al B Benson, Michael I D'Angelica, Daniel E Abbott et al. Hepatobiliary Cancers, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. NCCN. 2022 Jul 15. Open 23. Expert Panel on Gastrointestinal Imaging, Victoria Chernyak, Jeanne M Horowitz et al. ACR Appropriateness Criteria Liver Lesion-Initial Characterization. J Am Coll Radiol. 2020 Nov;17 11S S429 S446. Open 24. Jorge A Marrero, Laura M Kulik, Claude B Sirlin et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018 Aug;68 2 723 750. Open 25. Ghassan K. Abou-Alfa, M.D., M.B.A. et al. Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1 8 . Open 26. Jordi Bruix, Tadatoshi Takayama, Vincenzo Mazzaferro et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation STORM a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015 Oct;16 13 1344 54. Open 27. Richard S Finn, Shukui Qin, Masafumi Ikeda et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382 20 1894 1905. Open 28. Ronan J Kelly, Katherine Bever, Joseph Chao et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer. 2023 Jun;11 6):e006658. Open https://web.pathway.md/diseases/recURgzrLYpU9qco8 17/17

Guideline sources The following summarized guidelines for the evaluation and management of hepatopulmonary syndrome (HPS) are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2020), the European Association for the Study of the Liver (EASL 2018), and the International Liver Transplantation Society (ILTS 2016). 1 2 3 Guidelines 1. Screening and diagnosis Indications for testing: As per EASL 2018 guidelines, evaluate patients with the hallmarks of chronic liver disease for HPS in the presence of tachypnea and polypnea, digital clubbing, and/or cyanosis. B As per ILTS 2016 guidelines, obtain screening for HPS, especially in liver transplant candidates, since its clinical presentation may be variable, adversely influencing the quality of life and https://web.pathway.md/diseases/rectEmLOKI8HSRbNu 1/5 6/24/23, 12:41 PM Hepatopulmonary syndrome Pathway survival. B Diagnostic criteria: use the ERS diagnostic criteria for the diagnosis of HPS in research and clinical settings. B 2. Classification and risk stratification Severity assessment: consider using the ERS severity classification of HPS in research and clinical settings. C 3. Diagnostic investigations Pulse oximetry: As per EASL 2018 guidelines, obtain pulse oximetry to screen for HPS in adult patients. B As per ILTS 2016 guidelines, consider obtaining pulse oximetry (O2 saturation < 96%) as a reasonable screening test to detect hypoxemia in adult patients otherwise suitable for liver transplantation. Obtain sequential pulse oximetry for oxygenation monitoring. B Blood gas analysis: As per EASL 2018 guidelines, obtain arterial blood gas analysis in patients with SpO < 96%. Obtain further investigations in patients with a PaO < 80 mmHg and/or an alveolar-arterial oxygen gradient 15 mmHg in ambient air ( 20 mmHg in 65 years old patients). B As per ILTS 2016 guidelines, obtain arterial blood gas analysis for the diagnosis of HPS. B Contrast echocardiography: As per EASL 2018 guidelines: Obtain contrast (microbubble) echocardiography to characterize HPS. B Consider obtaining a contrast-enhanced TEE to definitively exclude intracardiac shunts. C As per ILTS 2016 guidelines, consider obtaining a contrast-enhanced TTE as an optimal screening test and criterion for detection of intrapulmonary vascular dilatation. B Macroaggregated albumin lung perfusion scan: As per EASL 2018 guidelines: Obtain macroaggregated albumin scan as a complementary tool to quantify the degree of shunting in patients with severe hypoxemia and coexistent intrinsic lung disease or to assess the prognosis in patients with HPS and very severe hypoxemia (PaO < 50 mmHg). B Recognize that neither contrast echocardiography nor macroaggregated albumin scan can definitively differentiate discrete arteriovenous communications from diffuse precapillary and capillary dilatations or cardiac shunts. B As per ILTS 2016 guidelines, consider obtaining a macroaggregated albumin scan to clarify the contribution of HPS-related hypoxemia in coexistent intrinsic cardiopulmonary disease. B https://web.pathway.md/diseases/rectEmLOKI8HSRbNu 2/5 6/24/23, 12:41 PM Hepatopulmonary syndrome Pathway Pulmonary angiography: perform pulmonary angiography only in patients with the severe hypoxemia (PaO < 60 mmHg), poorly responsive to administration of 100% oxygen, and if there is a strong suspicion of arteriovenous communications amenable to embolization. B 4. Respiratory support Oxygen therapy: As per SCCM 2020 guidelines, provide supportive care with supplemental oxygen in the management of patients with HPS, pending possible liver transplantation. E As per EASL 2018 guidelines, initiate long-term oxygen therapy in patients with HPS and severe hypoxemia, recognizing that there is insufficient evidence regarding its effectiveness, tolerance, cost-effectiveness, compliance, and effects on survival rates. B 5. Medical management Pharmacotherapy: As per EASL 2018 guidelines, insufficient evidence regarding the use of medical therapy for the treatment of patients with HPS. I As per ILTS 2016 guidelines, recognize that aside from supplemental oxygen (rest, exercise, and sleep) no medical therapies are definitively established or FDA approved for HPS. B 6. Therapeutic procedures Transjugular intrahepatic portosystemic shunt: As per EASL 2018 guidelines, insufficient evidence to recommend TIPS placement for the treatment of patients with HPS. I As per ILTS 2016 guidelines, insufficient evidence to recommend portal decompression with TIPS in adult patients with HPS. I Coil embolization: consider performing coil embolization in rare cases to improve oxygenation in selected patients with HPS. C Extracorporeal membrane oxygenation: consider performing ECMO as a bridge to liver transplantation and to reduce the need for mechanical ventilation in patients with severe HPS. C 7. Perioperative care Introperative oxygen monitoring: Obtain continuous monitoring of mixed venous oxygen saturation. Consider performing venovenous bypass if the mixed venous oxygen saturation falls < 65% on vascular exclusion of the liver. B https://web.pathway.md/diseases/rectEmLOKI8HSRbNu 3/5 6/24/23, 12:41 PM Hepatopulmonary syndrome Pathway Recognize that intraoperative oxygenation is not adversely affected by different anesthetic deliveries. B Postoperative oxygen therapy: perform early extubation to prevent ventilator-associated pneumonia. B Show 5 more Postoperative fluid management: initiate goal-directed fluid therapy to avoid fluid overload and pulmonary congestion. B Postoperative imaging: do not obtain routine post-transplantation contrast-enhanced TTE unless clinically indicated. D 8. Surgical interventions Liver transplantation: As per EASL 2018 guidelines: Evaluate patients with HPS and PaO < 60 mmHg for liver transplantation since it is the only effective treatment for HPS. B Obtain arterial blood gas analysis every 6 months to facilitate prioritization of liver transplantation since severe hypoxemia (PaO < 45-50 mmHg) is associated with increased post-liver transplantation mortality. B As per ILTS 2016 guidelines: Consider performing liver transplantation in patients with severe hypoxemia due to HPS (PaO < 60 mmHg). B Use standard model for end-stage liver disease exception scores if PaO is < 60 mmHg due to HPS. Consider using increased model for end-stage liver disease exception scores (higher model for end-stage liver disease points) if PaO is < 50 mmHg. B 9. Specific circumstances Pediatric patients: consider correcting congenital portosystemic shunts in pediatric patients. C References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 2. Michael J Krowka, Michael B Fallon, Steven M Kawut et al. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation. 2016 Jul;100 7 1440 52. Open 3. Rahul Nanchal, Ram Subramanian, Constantine J Karvellas et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Cardiovascular, Endocrine, Hematologic, Pulmonary https://web.pathway.md/diseases/rectEmLOKI8HSRbNu 4/5 6/24/23, 12:41 PM Hepatopulmonary syndrome Pathway and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48 3 415 419. Open https://web.pathway.md/diseases/rectEmLOKI8HSRbNu 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hepatorenal syndrome (HRS) are prepared by our editorial team based on guidelines from the American College of Gastroenterology (ACG 2022), the American Association for the Study of Liver Diseases (AASLD 2021; 2017; 2014), the Society of Critical Care Medicine (SCCM 2020), and the European Association for the Study of the Liver (EASL 2018; 2010). 1 2 3 4 5 6 7 CalculatorDiagnostic criteria for hepatoren Guidelines 1. Screening and diagnosis https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 1/6 6/24/23, 12:41 PM Hepatorenal syndrome Pathway Differential diagnosis: As per AASLD 2021 guidelines: Evaluate and treat precipitating factors of AKI, such as fluid loss, bacterial infections, hemodynamic instability, potentially nephrotoxic agents (particularly NSAIDs). E Use the consensus criteria for the differential diagnosis of AKI, HRS and acute tubular necrosis. E As per EASL 2018 guidelines: Differentiate between pre-renal AKI, HRS, intrinsic, particularly acute tubular necrosis, and post-renal AKI. B Consider obtaining urinary neutrophil gelatinase-associated lipocalin to distinguish between acute tubular necrosis and HRS as kidney biopsy is rarely performed in the setting of AKI. C As per EASL 2010 guidelines: Exclude other common causes of renal failure (including hypovolemia, shock, parenchymal renal diseases, and use of nephrotoxic drugs) in patients with cirrhosis before a diagnosis of HRS is made. B Suspect parenchymal renal diseases in patients with significant proteinuria or microhematuria, or if renal ultrasound demonstrates abnormalities in kidney size. B Diagnostic criteria: as per EASL 2018 guidelines, diagnose HRS-AKI based on the revised ICA criteria. B 2. Classification and risk stratification Classification: Classify HRS into two types: type 1 HRS: characterized by a rapid and progressive impairment in renal function (increase in serum creatinine 100% compared to baseline, to a level > 2.5 mg/dL, within 2 weeks) type 2 HRS: characterized by a stable or less progressive impairment in renal function. A 3. Diagnostic procedures Kidney biopsy: consider performing kidney biopsy in patients with suspected parenchymal renal disease in order to orient further management, including the potential need for combined liver and kidney transplantation. B 4. Medical management General principles: decide on the management (including initiation of vasoconstrictor therapy and RRT) by a multidisciplinary team including specialists in hepatology, nephrology, critical care, and transplant surgery, if possible, given the complexity of patients with suspected HRS-AKI. E Vasoactive agents: https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 2/6 6/24/23, 12:41 PM Hepatorenal syndrome Pathway As per ACG 2022 guidelines, consider initiating terlipressin C or norepinephrine to improve renal function in hospitalized patients with cirrhosis and HRS-AKI without high-grade acute-on- chronic liver failure or major cardiopulmonary or vascular disease. C Landmark trials: CONFIRM In adult patients with type 1 hepatorenal syndrome, terlipressin was superior to placebo with respect to verified reversal of hepatorenal syndrome. Florence Wong et al. N Engl J Med. 2021 Mar 4. As per AASLD 2021 guidelines: Initiate vasoconstrictor drugs in combination with albumin as the treatment of choice in patients with HRS-AKI. Administer terlipressin either as IV bolus or continuous IV infusion as the preferred drug. E Administer norepinephrine if terlipressin is not available. Consider initiating a trial of oral midodrine (5-15 mg per os every 8 hours) in combination with octreotide (100-200 g every 8 hours or 50 g/hour IV) if neither terlipressin nor norepinephrine can be used. E As per SCCM 2020 guidelines, initiate vasopressors in critically ill patients with acute-on-chronic liver failure developing HRS. B As per EASL 2018 guidelines, initiate vasoconstrictors and albumin expeditiously in all patients meeting the current definition of AKI-HRS stage > 1A. B Show 3 more Albumin: administer albumin solution (20%) at the dose 20-40 g/day. Consider obtaining serial measurements of central venous pressure or other measures of assessing central blood volume, apart from routine monitoring, to prevent circulatory overload by optimizing the fluid balance and titrating the albumin dose. B Antibiotic therapy: Identify bacterial infection promptly by blood, urine, and ascitic fluid cultures, and administer antibiotics as appropriate. Continue prophylactic antibiotics, if previously prescribed, in patients without signs of infection. B Insufficient evidence to support the use of antibiotics as empirical treatment for unproven infection in patients presenting with type 1 HRS. I Management of beta-blockers: decrease or temporarily hold nonselective -blockers in patients with refractory ascites and HRS. Consider re-introducing if clinical status improves. E Management of diuretics: Discontinue all diuretics at the initial evaluation and diagnosis of HRS. A Consider administering furosemide to maintain urine output and treat central volume overload if present. Do not use spironolactone because of the high risk of life-threatening hyperkalemia. B https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 3/6 6/24/23, 12:41 PM Hepatorenal syndrome Pathway 5. Therapeutic procedures Renal replacement therapy: As per AASLD 2021 guidelines: Initiate RRT in candidates for liver transplantation with worsening renal function or electrolyte disturbances or increasing volume overload unresponsive to vasoconstrictor therapy. E Initiate RRT with a clear endpoint in mind in patients not being candidates for liver transplantation. E As per EASL 2018 guidelines, decide on initiating RRT based on the individual severity of illness. B Therapeutic paracentesis: consider performing large-volume paracentesis with albumin in patients with tense ascites, despite the paucity of data on the use of paracentesis in patients with HRS. B Transjugular intrahepatic portosystemic shunt: Insufficient evidence to recommend TIPS placement in patients with HRS-AKI. I Consider placing a TIPS in selected patients with HRS outside the criteria of AKI. C 6. Surgical interventions Liver transplantation: As per AASLD 2021 guidelines: Consider obtaining urgent evaluation for liver transplantation in all patients with cirrhosis and AKI because of the high short-term mortality even in responders to vasoconstrictors. E Consider performing simultaneous liver-kidney transplantation in patients not expected to recover kidney function post-transplantation. E As per EASL 2018 guidelines: Perform liver transplantation as the best therapeutic option in patients with HRS regardless of the response to medical therapy. A Consider performing liver-kidney transplantation in patients with significant CKD or with sustained AKI including HRS-AKI with no response to medical therapy. B As per AASLD 2014 guidelines, obtain prompt evaluation for liver transplantation in potential liver transplant candidates with worsening renal dysfunction or other evidence of rapid hepatic decompensation. B 7. Preventative measures Norfloxacin: initiate norfloxacin 400 mg/day as SBP prophylaxis to prevent HRS-AKI. A Albumin: administer albumin (1.5 g/kg at diagnosis and 1 g/kg on day 3) in patients with SBP to prevent AKI. A https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 4/6 6/24/23, 12:41 PM Hepatorenal syndrome Pathway 8. Follow-up and surveillance Serial clinical assessment: As per AASLD 2021 guidelines, obtain close monitoring for side effects of vasoconstrictors and albumin, including ischemic complications and pulmonary edema. E As per EASL 2018 guidelines, recognize that adverse events related to terlipressin and norepinephrine include ischemic and cardiovascular events. Obtain a careful clinical screening including an ECG before treatment initiation. A Show 2 more Assessment of treatment response: As per AASLD 2021 guidelines: Define response to terlipressin or norepinephrine as creatinine decrease to < 1.5 mg/dL or return to within 0.3 mg/dL of baseline over a maximum of 14 days. Discontinue therapy if creatinine remains at or above the pretreatment level over 4 days with the maximum tolerated doses of the vasoconstrictor. E Retreat recurrence as it may occur after treatment discontinuation. E As per EASL 2018 guidelines, define complete response to treatment as a final serum creatinine level within 0.3 mg/dL (26.5 mcmol/L) from the baseline value and partial response as the regression of AKI stage to a final serum creatinine level 0.3 mg/dL (26.5 mcmol/L) from the baseline value. B Show 2 more References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 2. Scott W Biggins, Paulo Angeli, Guadalupe Garcia-Tsao et al. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug;74 2 1014 1048. Open 3. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53 3 397 417. Open 4. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 5. Rahul Nanchal, Ram Subramanian, Constantine J Karvellas et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48 3 415 419. Open 6. Jasmohan S Bajaj, Jacqueline G O'Leary, Jennifer C Lai et al. Acute-on-Chronic Liver Failure Clinical Guidelines. Am J Gastroenterol. 2022 Jan 10. Open https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 5/6 6/24/23, 12:41 PM Hepatorenal syndrome Pathway 7. Garcia-Tsao G, Abraldes JG, Berzigotti A et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017 Jan;65 1 310 335. Open 8. Khurram Jamil, Xingyue Huang, Belinda Lovelace et al. The burden of illness of hepatorenal syndrome HRS in the United States: a retrospective analysis of electronic health records. J Med Econ. 2019 May;22 5 421 429. Open 9. G Low, G J M Alexander, D J Lomas. Hepatorenal syndrome: aetiology, diagnosis, and treatment. Gastroenterol Res Pract. 2015;2015 207012. Open 10. J Bradford Rice, Alan G White, Philip Galebach et al. The burden of hepatorenal syndrome among commercially insured and Medicare patients in the United States. Curr Med Res Opin. 2017 Aug;33 8 1473 1480. Open 11. Florence Wong, S Chris Pappas, Michael P Curry et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021 Mar 4;384 9 818 828. Open https://web.pathway.md/diseases/recEXDsu3o2GGbP4N 6/6

Guideline sources The following summarized guidelines for the evaluation and management of hereditary angioedema (HAE) are prepared by our editorial team based on guidelines from the European Academy of Allergy and Clinical Immunology (EAACI/WAO 2022) and the European Academy of Allergy and Clinical Immunology (EAACI/AAAAI 2013). 1 2 Guidelines 1. Screening and diagnosis Pathogenesis: Recognize that: HAE is an autosomal dominant disease, and most patients with HAE have a positive family history of angioedema A HAE is caused by mutations in the serine protease inhibitor C1 resulting in a serine protease inhibitor C1 functional deficiency B most cases of HAE result from a deficiency of the serine protease inhibitor C1 inhibitor B primary mediator of swelling in patients with HAE is bradykinin. A Clinical presentation: Recognize that: https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 1/4 6/24/23, 12:41 PM Hereditary angioedema Pathway disease severity is highly variable, as characterized by episodic rather than continuous swelling B a precipitating cause for most attacks is unknown stress and trauma are recognized as precipitants B HAE is characterized by relatively prolonged attacks B attacks of swelling generally involve the extremities, abdomen, genitourinary tract, face, oropharynx, or larynx and follow a stereotypical pattern in which the swelling worsens over 24 hours, peaks, and then slowly resolves over the following 48-72 hours A attacks can be preceded by a prodrome B onset of swelling in patients with HAE most often begins during childhood and frequently worsens around puberty B HAE attacks are associated with significant potential morbidity and potential mortality. A Diagnosis: Recognize that two forms of HAE are indistinguishable clinically and require laboratory testing for diagnostic confirmation: type I HAE presents with low serine protease inhibitor C1 antigenic and functional levels type II HAE presents with normal serine protease inhibitor C1 antigenic levels but decreased serine protease inhibitor C1 inhibitor functional levels. A Diagnose type I or type II HAE based on low serine protease inhibitor C1 antigenic or functional levels, decreased C4 levels and generally normal C1q levels. A Screening of family relatives: screen family members of patients for HAE. B 2. Diagnostic investigations Blood tests: Assess blood C1 inhibitor function, C1 inhibitor protein, and C4 levels in all patients with suspected HAE. B Consider repeating testing for C1 inhibitor function, C1 inhibitor protein, and C4 in patients tested positive, to confirm the diagnosis of HAE-1/2. C Genetic tests: assess for known mutations underlying HAE with normal C1 inhibitor levels in patients with suspected HAE having normal C1 inhibitor levels. B 3. Medical management General principles: ensure that all patients have an action plan. B Show 3 more Management of acute attacks: As per WAO 2022 guidelines, offer on-demand treatment in all patients presenting with an acute attack. B https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 2/4 6/24/23, 12:41 PM Hereditary angioedema Pathway Show 4 more As per AAAAI 2013 guidelines, do not use epinephrine, corticosteroids and antihistamines for the treatment of patients with HAE. D Show 4 more Prophylactic treatment: As per WAO 2022 guidelines, ensure that all patients have sufficient medication for on-demand treatment of at least 2 attacks and carry on-demand medication at all times. B Show 8 more As per AAAAI 2013 guidelines, consider administering FFP, serine protease inhibitor C1 inhibitor replacement or short-term, high-dose anabolic androgen therapy as short-term prophylaxis in patients with HAE. C Show 5 more 4. Nonpharmacologic interventions Avoidance of triggers: As per WAO 2022 guidelines, educate all patients about triggers likely to induce attacks. B As per AAAAI 2013 guidelines, offer adjunctive strategies, such as avoidance of ACEIs and estrogen therapy as feasible, and stress reduction to decrease the frequency and severity of HAE attacks. B 5. Specific circumstances Pregnant patients: As per WAO 2022 guidelines, prefer plasma-derived C1 inhibitors during pregnancy and lactation. B As per AAAAI 2013 guidelines: Recognize that pregnancy may be associated with an increase in the frequency and severity of HAE episodes. B Prefer plasma-derived C1 inhibitor for long-term prophylaxis recognizing that androgens are contraindicated in pregnancy. B Pediatric patients: Test children from HAE-affected families and all offspring of an affected parent as soon as possible. B Administer C1 inhibitor or icatibant for the treatment of attacks in < 12 years old pediatric patients with HAE. A Patients with normal C1 inhibitor levels: Recognize that: https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 3/4 6/24/23, 12:41 PM Hereditary angioedema Pathway familial recurrent angioedema characterized by normal C1 inhibitor function might represent HAE with normal C1 inhibitor levels, but there are no agreed upon criteria for diagnosing HAE with normal C1 inhibitor levels at this time some kindreds with HAE with normal C1 inhibitor levels appear to require high estrogen levels for the angioedema to manifest HAE with normal C1 inhibitor levels can be caused by increased bradykinin signaling. B Consider offering drugs developed for patients with HAE with reduced C1 inhibitor function in patients with HAE with normal C1 inhibitor levels. C Patients with acquired angioedema: Recognize that acquired C1 inhibitor deficiency: results from enhanced catabolism of C1 inhibitor B might be associated with C1 inhibitor autoantibodies with or without an underlying condition such as lymphoma B has clinical characteristics similar to those in HAE attacks. B Show 2 more Patients with ACEI-associated angioedema: recognize that ACEIs are associated with angioedema in approximately 0.1-0.7% of patients and ARBs have been associated with angioedema less commonly. A Show 3 more References 1. Bruce L Zuraw, Jonathan A Bernstein, David M Lang et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013 Jun;131 6 1491 3. Open 2. Marcus Maurer, Markus Magerl, Stephen Betschel et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022 Jul;77 7 1961 1990. Open https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hereditary breast and ovarian cancer (HBOC) are prepared by our editorial team based on guidelines from the U.S. Preventive Services Task Force (USPSTF 2014) and the National Society of Genetic Counselors (NSGC 2013). 1 2 Calculator Calculator Calculator Eastern Cooperative Oncology G FIGO staging for ovarian cancer Karnofsky Guidelines 1. Screening and diagnosis Indications for screening: As per USPSTF 2014 guidelines: Screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes such as BRCA1 or BRCA2. B https://web.pathway.md/diseases/recLD1PXcWPEPbK9p 1/3 6/24/23, 12:41 PM Hereditary breast and ovarian cancer Pathway Avoid routine BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes. D As per USPSTF 2014 guidelines: Screen for mutations in breast cancer susceptibility genes (including BRCA1 or BRCA2) in women who have family members with breast, ovarian, tubal, or peritoneal cancer. Use a screening tool designed to identify a family history that may be associated with an increased risk. B Provide genetic counseling and, if indicated after counseling, BRCA testing in women with positive screening results. B 2. Diagnostic investigations Genetic testing: consult published guidelines regarding the appropriateness of genetic testing, and address a more tailored approach to medical management. Risk assessment: follow the standards of care for accurate risk assessment when identifying individuals at risk for breast and/or ovarian cancers. Consider established models and published data to estimate the individual's risk of developing cancer, as this will assist in determining appropriate management. E 3. Patient education Genetic counseling: As per USPSTF 2014 guidelines: Provide genetic counseling and, if indicated after counseling, BRCA testing for women with positive screening results. B Avoid routine genetic counseling for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes. D As per NSGC 2013 guidelines, provide access to resources including scientific information, psychosocial support, and advocacy as part of the genetics consultation for patients with suspected HBOC. E References 1. Moyer VA. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Feb 18;160 4 271 81. Open 2. Berliner JL, Fay AM, Cummings SA et al. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns. 2013 Apr;22 2 155 63. Open 3. Anne Grabenstetter, Conxi Lazaro, Gulisa Turashvili. Editorial: Hereditary Breast and Ovarian Cancer: Current Concepts of Prevention and Treatment. Front Oncol. 2020 Dec 2;10 618369. Open https://web.pathway.md/diseases/recLD1PXcWPEPbK9p 2/3 6/24/23, 12:41 PM Hereditary breast and ovarian cancer Pathway 4. Samantha Greenberg, Saundra S Buys, Sandra L Edwards et al. Population prevalence of individuals meeting criteria for hereditary breast and ovarian cancer testing. Cancer Med. 2019 Nov;8 15 6789 6798. Open 5. Anna fverholm, Zakaria Einbeigi, Antonia Wigermo et al. Increased Overall Mortality Even after Risk Reducing Surgery for BRCA Positive Women in Western Sweden. Genes Basel). 2019 Dec 16;10 12 1046. Open 6. Megan Marshall, Sheila Solomon. Hereditary breast-ovarian cancer: clinical findings and medical management. Plast Surg Nurs. Jul-Sep 2007;27 3 124 7. Open 7. Michelle Jacobson, Marcus Bernardini, Mara L Sobel et al. No. 366 Gynaecologic Management of Hereditary Breast and Ovarian Cancer. J Obstet Gynaecol Can. 2018 Nov;40 11 1497 1510. Open 8. S Paluch-Shimon, F Cardoso, C Sessa et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. 2016 Sep;27(suppl 5):v103-v110. Open https://web.pathway.md/diseases/recLD1PXcWPEPbK9p 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hereditary hemochromatosis (HH) are prepared by our editorial team based on guidelines from the Asian Pacific Association for the Study of the Liver (APASL 2023), the European Association for the Study of the Liver (EASL 2022; 2010), the American College of Gastroenterology (ACG 2019), the British Society for Haematology (BSH 2018), the European Thyroid Association (ETA 2018), and the American Association for the Study of Liver Diseases (AASLD 2011). 1 2 3 4 5 6 7 Guidelines 1. Screening and diagnosis Indications for screening, general population: As per APASL 2023 guidelines, do not obtain screening for HH in the general population. D https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 1/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway s pe S 0 3 gu de es, do ot obta sc ee g o t e ge e a popu at o As per BSH 2018 guidelines, do not obtain unselected population screening for HFE gene mutation. D As per AASLD 2011 guidelines, do not obtain screening for HH in the average-risk population. D As per EASL 2010 guidelines, do not obtain genetic screening for HFE hemochromatosis because disease penetrance is low and iron overload progresses only in a minority of C282Y homozygotes. D Indications for screening, family relatives: As per APASL 2023 guidelines, obtain screening (including genetic testing) in first-degree relatives (without phenotypic expression) of patients with HFE p.Cys282Tyr/p.His63Asp variants. B As per EASL 2022 guidelines: Obtain screening in adult first-degree relatives (focusing on siblings as they are at the highest risk of hemochromatosis) of patients with rare variants in hemochromatosis genes. B Obtain screening in adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis. B As per ACG 2019 guidelines, obtain screening for HH in family members (particularly first- degree relatives) of patients diagnosed with HH. B As per BSH 2018 guidelines, obtain laboratory screening (CBC, LFTs, serum ferritin, transferrin saturation, and HFE genotyping) in first-degree relatives of patients diagnosed with HFE hemochromatosis. B As per AASLD 2011 guidelines, obtain screening for HH in first-degree relatives of patients with HFE-related HH to detect early disease and prevent complications. B As per EASL 2010 guidelines, obtain genetic screening in siblings of patients with HFE hemochromatosis. Consider screening other first-degree relatives. B Indications for testing: As per APASL 2023 guidelines, obtain testing (serum transferrin saturation, serum ferritin levels, and genetic testing) in patients of European descent with any clinical symptoms or signs compatible with the diagnosis or a family history of iron overload. Measure serum ferritin concentration and transferrin saturation in patients with symptoms, signs, or biochemical abnormalities consistent with hemochromatosis. A As per EASL 2022 guidelines, obtain clinical assessment and biochemical testing for hemochromatosis (serum ferritin and transferrin saturation) in patients with increased liver iron evident on liver biopsy or MRI. B As per AASLD 2011 guidelines: Evaluate patients with abnormal iron studies as patients with hemochromatosis, even without symptoms. B Evaluate all patients with evidence of liver disease for hemochromatosis. B https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 2/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per EASL 2010 guidelines: Consider obtaining HFE genotyping in patients with unexplained chronic liver disease and increased transferrin saturation, B porphyria cutanea tarda B , well-defined chondrocalcinosis, HCC, or T1DM. C Do not obtain routine HFE genotyping in patients with unexplained arthritis or arthralgia D or T2DM. D 2. Diagnostic investigations Clinical assessment: assess patients with HFE hemochromatosis for end-organ complications, including diabetes mellitus, joint disease, endocrine deficiencies, cardiac disease, porphyria cutanea tarda, and osteoporosis, before initiating treatment with phlebotomy. B Iron panel: As per APASL 2023 guidelines: Obtain serum ferritin and transferrin saturation as initial tests for hemochromatosis. A Measure hepatic iron concentration using available validated methods, including chemical estimation, in all patients with hemochromatosis and serum ferritin levels > 1,000 g/L. A As per EASL 2022 guidelines, assess serum iron parameters, including transferrin saturation and serum ferritin, as the first step in testing for hemochromatosis. B Show 2 more As per BSH 2018 guidelines, obtain a CBC, LFTs, serum ferritin and transferrin saturation in patients of North European ancestry with clinical features suggestive of genetic hemochromatosis. B As per AASLD 2011 guidelines, obtain a combination of transferrin saturation and ferritin rather than relying on a single test in patients with suggestive symptoms, physical findings, or family history of hemochromatosis. B As per EASL 2010 guidelines, measure fasting transferrin saturation and serum ferritin in patients with suspected iron overload. B As per EASL 2010 guidelines, obtain a CBC, LFTs, serum ferritin, and transferrin saturation in all confirmed C282Y homozygotes. Show 2 more Magnetic resonance imaging: As per APASL 2023 guidelines: Consider obtaining MRI after initial laboratory testing to assess the level of hepatic iron loading. B Measure hepatic iron concentration using available validated methods, including MRI, in all patients with hemochromatosis and serum ferritin levels > 1,000 g/L. A As per EASL 2022 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 3/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Obtain MRI to quantify hepatic iron concentrations and to assess extrahepatic organ involvement in patients with an unclear cause of hyperferritinemia, biochemical iron overload (increased transferrin saturation and ferritin), or positive liver iron staining. B Consider obtaining MRI for detection and noninvasive quantification of iron, and to evaluate the distribution of iron in the liver in patients with suspected or confirmed iron overload disorder. E As per ACG 2019 guidelines, consider obtaining a non-contrast-enhanced MRI (in conjunction with software used for the estimation of hepatic iron concentration) in order to noninvasively measure hepatic iron concentration in the non-C282Y homozygote with suspected HH. C Assessment of liver fibrosis: As per APASL 2023 guidelines, consider obtaining a noninvasive assessment of liver fibrosis after initial laboratory testing. B Show 2 more As per EASL 2022 guidelines, assess all patients with hemochromatosis noninvasively for the presence of liver fibrosis at diagnosis to guide appropriate treatment and follow-up. B Show 3 more Evaluation for extrahepatic manifestations: As per EASL 2022 guidelines, evaluate clinically patients with hemochromatosis for extrahepatic manifestations, including: skeletal (joint pain, arthritis, osteoporosis, fractures) endocrine (diabetes) reproductive or sexual dysfunction (erectile dysfunction, loss of libido, or amenorrhea). B Show 4 more As per ETA 2018 guidelines, evaluate for central hypothyroidism in all patients with hemochromatosis or iron overload, particularly in the presence of hypothyroid manifestations. B Genetic testing: As per APASL 2023 guidelines, obtain genetic testing for hemochromatosis if both serum ferritin and transferrin saturation are elevated. A Show 3 more As per EASL 2022 guidelines, obtain genetic testing for hemochromatosis, after informed consent for genetic testing has been obtained, in patients with clinical and biochemical signs of hemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation. B Show 4 more As per ACG 2019 guidelines: Counsel individuals with H63D or S65C mutation in the absence of C282Y mutation that they are not at increased risk of iron overload. B Avoid obtaining further genetic testing in patients with iron overload tested negative for the C282Y and H63D alleles. D https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 4/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per BSH 2018 guidelines: Test for HFE hemochromatosis in all adult patients of North European ancestry with raised serum ferritin of unclear etiology (> 300 g/L in males or > 200 g/L in females) and elevated random transferrin saturation (> 50% in males or > 40% in females), and normal CBC. B Test for rare iron loading genotypes or digenic inheritance in non-C282Y homozygotes with significant iron loading as confirmed by MRI and/or liver biopsy. B As per AASLD 2011 guidelines, obtain HFE mutation analysis if either of iron studies is abnormal (transferrin saturation 45% or ferritin above the ULN). B As per EASL 2010 guidelines, obtain HFE testing for the C282Y and H63D polymorphism in all patients with otherwise unexplained increased serum ferritin and increased transferrin saturation. B Obtain HFE testing only in patients with increased transferrin saturation. A Show 2 more 3. Diagnostic procedures Liver biopsy: As per APASL 2023 guidelines: Consider performing a liver biopsy after initial laboratory testing to assess the level of hepatic iron loading and liver fibrosis. B Consider performing a liver biopsy to assess for advanced hepatic fibrosis in patients with verified HFE-hemochromatosis with any of the following noninvasive markers: serum ferritin > 1,000 g/L B hepatic iron concentration > 200 mcmol/g by magnetic resonance methods B AST-to-platelet ratio index > 0.44 FIB-4 index > 1.1 mobilizable iron stores > 9.6 g B transient elastography liver stiffness measurement > 13.9 kPa. B As per EASL 2022 guidelines, consider performing a liver biopsy to assess liver fibrosis if serum ferritin is > 1,000 g/L or liver enzymes are increased. B Show 2 more As per ACG 2019 guidelines, perform a liver biopsy to determine hepatic iron concentration if there is a concomitant need to stage hepatic fibrosis or evaluate for alternate liver diseases. B As per BSH 2018 guidelines: Do not perform a liver biopsy for the diagnosis of HFE hemochromatosis. D Consider performing a liver biopsy in patients with HFE hemochromatosis, serum ferritin > 1,000 g/L and/or elevated transaminases to assess the severity of fibrosis. Consider using transient elastography to select which patients from this group require a liver biopsy. C As per AASLD 2011 guidelines, perform a liver biopsy to stage the degree of liver disease in C282Y homozygotes or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 5/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway ferritin is > 1,000 g/L. B Show 2 more 4. Medical management General principles: As per APASL 2023 guidelines, evaluate the phenotype of p.Cys282Tyr/p.His63Asp compound heterozygous patients and identify factors that may alter serum iron indices and/or increase hepatic iron stores or cofactors for liver disease expressivity. A As per EASL 2022 guidelines, guide the management of patients with p.C282Y/p.H63D compound heterozygosity or p.H63D homozygosity by their phenotypic presentation and the presence of additional risk factors, not the genotype alone. B Show 2 more Treatment targets: As per APASL 2023 guidelines: Target ferritin level of 50 g/L in the de-ironing phase and 50-100 g/L in the maintenance phase. A Measure Hgb at every venesection and serum ferritin at every fourth venesection during the induction phase until the serum ferritin concentration reaches 200 g/L. Measure serum ferritin at each venesection after that. Measure serum ferritin 2-3 times per year and adjust the venesection schedule accordingly during the maintenance phase. A As per EASL 2022 guidelines: Set a target of serum ferritin of 50 g/L, but not lower to avoid iron deficiency, for iron depletion during the induction phase of phlebotomy. B Consider maintaining serum ferritin with some flexibility in the range of 50-100 g/L in the maintenance phase. C As per BSH 2018 guidelines, target serum ferritin levels of approximately 20-30 g/L and transferrin saturation < 50% with phlebotomy. Monitor CBC weekly and serum ferritin and/or transferrin saturation monthly during phlebotomy. B As per AASLD 2011 guidelines, target a ferritin level of 50-100 g/L with phlebotomy. B Iron chelation therapy: As per APASL 2023 guidelines, initiate iron chelation as an alternative to phlebotomy/erythrocytapheresis in patients unable to tolerate the procedure for medical or personal reasons. B As per EASL 2022 guidelines, initiate iron depletion therapy as first-line therapy in patients with hemochromatosis and evidence of iron overload. B Show 2 more As per ACG 2019 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 6/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Do not use chelation as first-line therapy in patients with HH, given the effectiveness of phlebotomy, the associated side effects of chelation including hepatic and renal toxicity, and the relatively small sample size of clinical trials supporting chelation. D Initiate iron chelation therapy for the treatment of HH in patients intolerant or refractory to phlebotomy or when phlebotomy has the potential for harm, such as in patients with severe anemia or congestive HF. B As per AASLD 2011 guidelines, initiate iron chelation with either deferoxamine mesylate or deferasirox in iron overloaded patients with dyserythropoietic syndromes or chronic hemolytic anemia. B Hepcidin agonists: insufficient evidence to support the use of hepcidin-based therapy. I Proton-pump inhibitors: do not use of PPIs routinely as the primary treatment of HH. D Management of complications: manage complications of hemochromatosis, such as liver cirrhosis, diabetes, arthropathy, hypogonadism, or porphyria cutanea tarda, regardless of whether or not hemochromatosis is the underlying cause and whether there is symptomatic relief or improvement during phlebotomy. B 5. Nonpharmacologic interventions Dietary modifications: As per APASL 2023 guidelines, advise adopting a healthy lifestyle, including maintaining normal body weight and limiting alcohol consumption, in patients with hemochromatosis. Do not restrict dietary iron intake but advise avoiding iron supplements. B As per EASL 2022 guidelines, do not off dietary modifications as a substitute for iron removal therapy. D Show 5 more As per AASLD 2011 guidelines, avoid advising any dietary adjustments during HH treatment. Avoid using vitamin C and iron supplements. D 6. Therapeutic procedures Therapeutic phlebotomy: As per APASL 2023 guidelines: Perform phlebotomy in patients with p.Cys282Tyr/p.His63Asp compound heterozygosity or p.His63Asp homozygosity with significant iron loading. Consider performing phlebotomy in patients with mild iron overload if symptomatic. A Initiate a venesection program in patients with elevated serum ferritin concentration. A As per EASL 2022 guidelines, perform therapeutic phlebotomy as first-line therapy for iron depletion. https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 7/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway As per ACG 2019 guidelines, perform phlebotomy as first-line treatment in patients diagnosed with HH, as determined by C282Y homozygosity or C282Y/H63D compound heterozygosity. B As per BSH 2018 guidelines, perform weekly phlebotomy in all fit patients with genetic hemochromatosis with biochemical evidence of iron loading, until serum ferritin is approximately 20-30 g/L and transferrin saturation < 50%. Monitor CBC weekly and serum ferritin and/or transferrin saturation monthly during this phase of phlebotomy. B As per AASLD 2011 guidelines, perform therapeutic phlebotomy weekly (as tolerated) in patients with hemochromatosis and iron overload. B Show 3 more As per EASL 2010 guidelines, perform phlebotomy in patients with HFE hemochromatosis and evidence of iron overload. B Show 3 more Erythrocytapheresis: As per APASL 2023 guidelines, consider performing erythrocytapheresis in patients having problems with symptoms from hypovolemia from phlebotomy, with cardiac morbidity, hypoproteinemia, and/or thrombocytopenia. B As per EASL 2022 guidelines, consider performing erythrocytapheresis as an alternative to therapeutic phlebotomy if available, recognizing that it is cost-effective in the induction phase because fewer interventions are required. Consider performing personalized erythrocytapheresis as the preferred treatment in selected patients. 7. Surgical interventions Liver transplantation: As per APASL 2023 guidelines, offer liver transplantation in patients with decompensated liver disease and/or HCC. Recognize that the risk of recurrence of hepatic iron loading is very low after liver transplantation and take into consideration the alternative causes should it occur. A As per ACG 2019 guidelines, consider offering liver transplantation in patients with HH with decompensated cirrhosis or HCC. B 8. Specific circumstances Young patients: Obtain genetic testing for HFE- and non-HFE-hemochromatosis in < 30 years old patients presenting with iron overload. Obtain an accurate assessment of the degree of iron overload affecting the liver and heart. B Perform early phlebotomy for the best prognosis. B Pregnant patients: As per APASL 2023 guidelines: https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 8/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway Monitor iron studies in patients with hemochromatosis contemplating pregnancy and ensure avoidance of iron deficiency. B Consider stopping phlebotomy during pregnancy with continuing monitoring iron studies. B As per EASL 2022 guidelines, ensure that patients with hemochromatosis planning to get pregnant do not have iron deficiency. B Show 2 more 9. Preventative measures Hepatitis A and B vaccination: consider providing hepatitis A and B immunization in patients with HFE hemochromatosis despite ongoing evidence of iron overload, to minimize the risk of additional complications. C 10. Follow-up and surveillance Indications for specialist referral: As per EASL 2022 guidelines, refer patients with evidence of significant, unexplained iron overload for assessment by a specialist in iron disorders. B As per BSH 2018 guidelines, refer patients with genetic hemochromatosis and serum ferritin > 1,000 g/L or raised transaminases to a hepatologist for fibrosis assessment and exclusion of cirrhosis. B As per EASL 2010 guidelines, refer all patients with serum ferritin > 1,000 g/L and/or abnormal LFTs to a hepatologist for fibrosis assessment (with elastography) to exclude the presence of cirrhosis. B Serial ferritin monitoring: As per APASL 2023 guidelines, measure serum ferritin and transferrin saturation no more frequently than once a year and up to once every 5 years, especially if previously stable and not rising in patients found to be homozygous for the HFE p.Cys282Tyr pathogenic variant or compound heterozygous for p.Cys282Tyr/p.His63Asp with normal serum ferritin. Avoid obtaining testing beyond annually as it presents a higher risk of patients forgetting to undertake this test, recognizing that it is unlikely that serum ferritin would increase from the normal range to a dangerously high level in 12 months. B Show 2 more As per AASLD 2011 guidelines, monitor patients with hemochromatosis and iron overload for reaccumulation of iron and perform maintenance phlebotomy. B As per EASL 2010 guidelines, consider monitoring ferritin annually in C282Y homozygotes without evidence for iron overload, and instituting treatment when ferritin rises above normal. C Surveillance for hepatocellular carcinoma: As per APASL 2023 guidelines, obtain surveillance for HCC with 6-monthly ultrasound, with or without AFP testing, in patients with cirrhosis due to hemochromatosis. Obtain surveillance only https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 9/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway if a diagnosis of HCC will alter management. A As per EASL 2022 guidelines, obtain screening for HCC every 6 months in patients with hemochromatosis and cirrhosis (on biopsy METAVIR F4, Ishak scoring system stage 6, or on elastography), regardless of iron depletion. B Show 6 more As per ACG 2019 guidelines, avoid obtaining routine surveillance for HCC in patients with HH with stage 3 fibrosis. D As per BSH 2018 guidelines, obtain monitoring for HCC with hepatic ultrasound and measurement of serum AFP every 6 months in patients with hemochromatosis and cirrhosis. B As per EASL 2010 guidelines, obtain monitoring with AFP and hepatic ultrasound every 6 months in patients with confirmed cirrhosis. B Likelihood Ratios Pertinent positives The following findings increase the probability of hereditary hemochromatosis in adults. 1 1 1 Finding LR+ Value Presence of C282Y homozygosity 68.3 Decreased serum unbound iron binding capacity (< 28 g/dL) 18.3 Increased serum transferrin saturation (> 46%) 12.8 Increased serum total transferrin 11.3 Show 1 more Pertinent negatives The following findings decrease the probability of hereditary hemochromatosis in adults. 1 1 1 1 Finding LR- Value T2 relaxation rate not increased 0.1 serum total transferrin not increased 0.1 Absence of C282Y homozygosity 0.2 serum unbound iron binding capacity not decreased ( 28 g/dL) 0.3 Show 2 more References 1. European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010 Jul;53 1 3 22. Open https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 10/11 6/24/23, 12:41 PM Hereditary hemochromatosis Pathway 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. Hepatol. 2022 Aug;77 2 479 502. Open 3. Bruce R Bacon, Paul C Adams, Kris V Kowdley et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul;54 1 328 43. Open 4. Darrell H G Crawford, Grant A Ramm, Kim R Bridle et al. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int. 2023 Apr 17. Open 5. Fitzsimons EJ, Cullis JO, Thomas DW et al. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br J Haematol. 2018 May;181 3 293 303. Open 6. Kris V Kowdley, Kyle E Brown, Joseph Ahn et al. ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol. 2019 Aug;114 8 1202 1218. Open 7. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 8. American College of Medical Genetics. Choosing Wisely ACMG recommendations. Choosing Wisely. 2016. Open 9. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 10. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 11. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recBiLsP1YUdVbc7N 11/11

Guideline sources The following summarized guidelines for the evaluation and management of hereditary hemorrhagic telangiectasia are prepared by our editorial team based on guidelines from the Hereditary Haemorrhagic Telangiectasia Working Group (HHT-WG 2020), the American College of Gastroenterology (ACG 2020; 2015), and the European Association for the Study of the Liver (EASL 2016). 1 2 3 4 Calculator Cura ao Criteria for hereditary h Guidelines https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 1/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway 1. Screening and diagnosis Indications for screening: As per HHT-WG 2020 guidelines, screen asymptomatic children of a parent with HHT for HHT with genetic testing. A As per ACG 2015 guidelines, consider screening SMAD4 mutation carriers for HHT. C Diagnosis: As per HHT-WG 2020 guidelines, diagnose HHT using the Cura ao criteria or by identification of a causative mutation. B Show 2 more As per EASL 2016 guidelines, suspect the diagnosis of HHT in patients with diffuse liver VMs (either complicated or not). B 2. Classification and risk stratification Severity grading: Grade the severity of HHT-related gastrointestinal bleeding according to the following framework (Hgb goals should reflect age, gender, symptoms, and comorbidities): Situation Guidance Hgb goal is met with oral iron Mild Hgb goal is met with IV iron Moderate Hgb goal is not met despite adequate iron replacement, or blood transfusions are required. B Severe Prognostic assessment: estimate the prognosis of liver VMs using available predictors to identify patients requiring closer monitoring. B 3. Diagnostic investigations Genetic testing: Refer patients for genetic testing for HHT: to identify the causative mutation in a family with clinically confirmed HHT to establish the diagnosis in relatives of a patient with a known causative mutation, including asymptomatic or minimally symptomatic patients and patients desiring prenatal testing to assist establishing the diagnosis in patients not meeting clinical diagnostic criteria. B Consider SMAD4 testing to identify the causative mutation in patients tested negative for ENG and ACVRL1 coding sequence mutations. C https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 2/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway Diagnostic imaging: As per HHT-WG 2020 guidelines, consider obtaining contrast TTE as initial screening test for pulmonary AVMs. C Show 2 more As per EASL 2016 guidelines, obtain Doppler ultrasound as first-line imaging for the diagnosis and staging of liver VMs. Obtain multiphase CT to investigate symptomatic liver VMs if Doppler ultrasound is unavailable. A Show 2 more Evaluation for vascular malformations, liver: As per ACG 2020 guidelines, do not obtain routine screening for liver VMs in patients with HHT. Insufficient evidence to support that making a diagnosis in an asymptomatic patient has clinical benefits or prevents death. D Show 3 more As per HHT-WG 2020 guidelines, offer screening for liver VMs in adult patients with definite or suspected HHT. B Evaluation for vascular malformations (pulmonary): screen all patients with possible or confirmed HHT for pulmonary AVMs. B Show 3 more Evaluation for vascular malformations (brain): Consider screening for brain VMs with MRI in adult patients with possible or definite HHT using a protocol with and without contrast administration and using sequences that detect blood products, to maximize sensitivity. C Screen for brain VMs at the time of presentation/diagnosis of asymptomatic pediatric patients with HHT or at risk for HHT. B Evaluation for iron deficiency and anemia: Test the following patients with HHT for iron deficiency and anemia: all adult patients, regardless of symptoms all pediatric patients with recurrent bleeding and/or symptoms of anemia. A Consider evaluating for additional causes of anemia in the setting of an inadequate response to iron replacement. B 4. Diagnostic procedures Upper and lower gastrointestinal endoscopy: perform upper gastrointestinal endoscopy as first- line diagnostic modality in patients with suspected HHT-related bleeding. B Show 2 more Liver biopsy: As per EASL 2016 guidelines: Avoid performing liver biopsy for the diagnosis of hepatic VMs related to HHT. D https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 3/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway Acknowledge the risk of increased bleeding with percutaneous transcapsular liver biopsy when liver biopsy is pursued for other reasons. A 5. Medical management Topical therapies for epistaxis: advise using moisturizing topical therapies that humidifying the nasal mucosa to reduce epistaxis in patients with HHT-related epistaxis. B Anticoagulation and antiplatelet therapy: Administer anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when indicated in patients with HHT with consideration of their individualized bleeding risks. Be aware that bleeding in HHT is not an absolute contraindication for these therapies. B Avoid dual antiplatelet therapy and/or combination of antiplatelet therapy and anticoagulation where possible in patients with HHT. D Antifibrinolytic therapy: Consider administering oral tranexamic acid for the management of epistaxis not responding to moisturizing topical therapies in patients with HHT. B Consider administering oral antifibrinolytics for the treatment of patients with mild HHT-related gastrointestinal bleeding. C Antiangiogenic therapy: Consider administering systemic antiangiogenic agents for the management of epistaxis in patients with HHT failed to respond to moisturizing topical therapies, ablative therapies, and/or tranexamic acid. B Consider administering IV bevacizumab or other systemic antiangiogenic agents for the management of patients with moderate-to-severe HHT-related gastrointestinal bleeding. B Iron replacement: Offer iron replacement for the treatment of patients with HHT and iron deficiency/anemia as follows: initial therapy with oral iron IV iron replacement when oral is not effective, not absorbed, or not tolerated, or in severe anemia. B Consider evaluating for additional causes of anemia in the setting of an inadequate response to iron replacement. B 6. Therapeutic procedures Red blood cell transfusion: Perform RBC transfusions in patients with HHT in the following settings: hemodynamic instability/shock comorbidities requiring a higher Hgb target https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 4/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway need to increase the Hgb acutely, such as before surgery or during pregnancy inability to maintain an adequate Hgb despite frequent iron infusions. B Endoscopic argon plasma coagulation: perform endoscopic argon plasma coagulation in patients with HHT only during endoscopy. B Transcatheter embolotherapy: As per HHT-WG 2020 guidelines, perform transcatheter embolotherapy for the treatment of pulmonary AVMs in patients with HHT. B As per EASL 2016 guidelines, seek advice from a medical team with expertise in HHT before making any decisions regarding the treatment of liver VMs, and notably orthotopic liver transplantation. A Show 2 more 7. Surgical interventions Surgical management of epistaxis (ablative therapies): consider performing ablative therapies for nasal telangiectasias, including laser treatment, radiofrequency ablation, electrosurgery, and sclerotherapy, in patients with HHT failed to respond to moisturizing topical therapies. C Surgical management of epistaxis (septodermoplasty): consider performing septodermoplasty for the management of epistaxis in patients with HHT failed to sufficiently respond to moisturizing topical therapies, ablative therapies, and/or tranexamic acid. C Surgical management of epistaxis (nasal closure): consider performing nasal closure for the management of epistaxis in patients with HHT failed to sufficiently respond to moisturizing topical therapies, ablative therapies, and/or tranexamic acid. B Liver transplantation: As per HHT-WG 2020 guidelines, refer patients with HHT with symptomatic complications of liver VMs, specifically with refractory high-output HF, biliary ischemia, or complicated portal hypertension, for consideration of liver transplantation. B As per EASL 2016 guidelines, seek advice from a medical team with expertise in HHT before making any decisions regarding the treatment of liver VMs, and notably orthotopic liver transplantation. A Show 2 more 8. Specific circumstances Patients with vascular malformations, liver: As per ACG 2020 guidelines, offer standard medical therapy for each complication of liver VMs in patients with HHT, which results in symptom resolution in the majority. B Show 4 more https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 5/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway As per HHT-WG 2020 guidelines, estimate the prognosis of liver VMs using available predictors to identify patients requiring closer monitoring. B Show 4 more Patients with vascular malformations (pulmonary): perform transcatheter embolotherapy for the treatment of pulmonary AVMs in patients with HHT. B Show 3 more Patients with vascular malformations (brain): consider providing definitive treatment for adult patients presenting with an acute hemorrhage secondary to a brain VM, in a center with neurovascular expertise. B Show 2 more Pregnant patients: As per ACG 2020 guidelines, pay special attention in female patients with HHT and liver VMs becoming pregnant, due to anticipated hemodynamic stress. B As per HHT-WG 2020 guidelines, obtain unenhanced MRI in pregnant patients with symptoms suggestive of brain VMs. B Show 5 more Pediatric patients: offer genetic testing for HHT in asymptomatic children of a parent with HHT. A Show 6 more 9. Patient education Preconception and prenatal counseling: discuss preconception and prenatal diagnostic options, including preimplantation genetic diagnosis, with patients with HHT. B References 1. Marie E Faughnan, Johannes J Mager, Steven W Hetts et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020 Dec 15;173 12 989 1001. Open 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016 Jan;64 1 179 202. Open 3. Douglas A Simonetto, Ashwani K Singal, Guadalupe Garcia-Tsao et al. ACG Clinical Guideline: Disorders of the Hepatic and Mesenteric Circulation. Am J Gastroenterol. 2020 Jan;115 1 18 40. Open 4. Sapna Syngal, Randall E Brand, James M Church et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110 2 223 62; quiz 263. Open 5. Andrew M Ferry, Alex E Wright, Gwen Baillargeon et al. Epidemiology and Trends of Hereditary Hemorrhagic Telangiectasia in the United States. Am J Rhinol Allergy. 2020 Mar;34 2 230 237. Open https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 6/7 6/24/23, 12:41 PM Hereditary hemorrhagic telangiectasia Pathway 6. Athena Kritharis, Hanny Al-Samkari, David J Kuter. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective. Haematologica. 2018 Sep;103 9 1433 1443. Open 7. James W Donaldson, Tricia M McKeever, Ian P Hall et al. Complications and mortality in hereditary hemorrhagic telangiectasia: A population-based study. Neurology. 2015 May 5;84 18 1886 93. Open 8. C L Shovlin, A E Guttmacher, E Buscarini et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91 1 66 7. Open 9. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/rec7GXA0GMsYiIKiE 7/7

Guideline sources The following summarized guidelines for the evaluation and management of herpes zoster (HZ) are prepared by our editorial team based on guidelines from the Center for Disease Control (CDC 2022; 2018), the German Herpes Management Forum (GHMF 2020), the American Society of Transplantation (AST 2019), the National Advisory Committee on Immunization (NACI 2018), the American Association of Family Physicians (AAFP 2017), the European Academy of Dermatology and Venereology (EADV/EDF 2017), the American College of Obstetricians and Gynecologists (ACOG 2015), and the Infectious Diseases Society of America (IDSA 2014). 1 2 3 4 5 6 7 8 9 10 Guidelines 1. Screening and diagnosis Diagnosis: diagnose HZ clinically without laboratory confirmation in patients with classical unilateral HZ of the thoracic or lumbar dermatomes. B https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 1/9 6/24/23, 12:41 PM Herpes zoster Pathway 2. Diagnostic investigations Laboratory testing: As per GHMF 2020 guidelines, do not obtain laboratory confirmation in patients with HZ with a typical clinical presentation. Obtain laboratory confirmation in all other cases using VZV PCR or HSV-VZV PCR from swabs, aqueous humor, CSF, serum or plasma. D Show 5 more As per AAFP 2017 guidelines, obtain PCR of vesicle or other fluids for the diagnosis of HZ, if laboratory confirmation is needed, although HZ typically is diagnosed clinically. B As per EADV 2017 guidelines, consider obtaining viral antigen detection or molecular-based techniques (PCR) in patients with diagnostic uncertainty, particularly to distinguish HZ of the face and genital areas from zosteriform HSV-infection. C Show 4 more As per IDSA 2014 guidelines, consider obtaining peripheral blood PCR for VZV to help establishing the diagnosis of disseminated infection in patients with unexplained skin lesions. C HIV testing: As per GHMF 2020 guidelines, obtain testing for human immunodeficiency virus infection in < 50 years old patients with HZ. B As per EADV 2017 guidelines, obtain testing for human immunodeficiency virus infection in younger patients (possible cut-off 50 years of age) exhibiting widespread multidermatomal or recurrent HZ, particularly if lesions are simultaneously present in different disease stages and/or if other risk factors for human immunodeficiency virus seropositivity are present. B Neuroimaging: As per GHMF 2020 guidelines, obtain emergency MRI or CT in patients with neurological symptoms extending beyond cranial nerves VII and VIII or in patients with impaired consciousness. B As per EADV 2017 guidelines: Obtain acute MRI in patients with HZ and any neurological signs outside the VII and VIII nerves (such as a VI nerve palsy) or if there is any change in the level of consciousness. B Consider obtaining CT in patients with HZ with loss of > 2 points on the GCS. C Evaluation for complications: As per GHMF 2020 guidelines, assess for hemorrhagic/necrotic lesions, satellite lesions and aberrant vesicles, multisegmental or generalized cutaneous involvement, decreased overall health, and signs of meningism in all patients with HZ. B Show 3 more As per EADV 2017 guidelines, assess for the presence of hemorrhagic/necrotizing lesions, satellite lesions (aberrant vesicles), multisegmental or generalized cutaneous involvement, simultaneous presence of lesions in different developmental stages, altered general status and meningeal signs in patient presenting with HZ. B Show 3 more https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 2/9 6/24/23, 12:41 PM Herpes zoster Pathway Evaluation for malignancy: As per GHMF 2020 guidelines, do not screen for malignancy in patients with HZ with a typical clinical course. D As per EADV 2017 guidelines, avoid obtaining investigations for cancer only based on the occurrence of HZ. D Assessment of pain: As per GHMF 2020 guidelines, distinguish between nociceptive and neuropathic pain. B Show 2 more As per EADV 2017 guidelines: Assess pain intensity by a validated pain assessment scale, such as VAS, NRS (0 = no pain, 10 = worst possible pain). B Consider assessing patient satisfaction with pain management (NRS: 0 = not satisfied to 10 = very satisfied). C 3. Diagnostic procedures Lumbar puncture: As per GHMF 2020 guidelines, ensure co-treatment by a neurologist and perform a lumbar puncture in patients with HZ-associated neurological symptoms. B As per EADV 2017 guidelines, perform lumbar puncture in patients with HZ with neurological symptoms and/or signs. B Biopsy: As per GHMF 2020 guidelines, perform a diagnostic biopsy (regular histology) in patients with atypical cutaneous manifestations, such as lichenoid, verrucous, granulomatous, and follicular lesions. B As per EADV 2017 guidelines, perform biopsy of lesions without ulceration and obtain a swab when ulceration is present in patients with atypical mucocutaneous manifestations including lichenoid, verrucous, granulomatous and follicular lesions. B 4. Medical management Systemic antiviral therapy: As per GHMF 2020 guidelines, initiate systemic antiviral therapy in patients with HZ with any of the following: age 50 years moderate-to-severe pain hemorrhagic or necrotic lesions aberrant vesicles/satellite lesions head and neck region involvement https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 3/9 6/24/23, 12:41 PM Herpes zoster Pathway mucocutaneous involvement multisegmental involvement immunosuppression predisposing skin diseases (such as atopic dermatitis) pediatric and adolescent patients on long-term topical corticosteroid treatment. B Show 5 more As per AAFP 2017 guidelines, initiate acyclovir, valacyclovir, or famciclovir ideally within 72 hours of the appearance of the rash to decrease the duration of symptoms and severity of pain in patients with HZ. B As per EADV 2017 guidelines, initiate antiviral therapy in patients with: HZ of any localization and 50 years of age HZ of the head and/or neck area HZ of any localization with, moderate-to-severe zoster-associated pain, hemorrhagic or necrotizing lesions, > 1 segment involved, aberrant vesicles/satellite lesions, or involvement of mucous membranes HZ and immunocompromised states HZ and severe predisposing skin diseases (such as atopic dermatitis) HZ in pediatric and adolescent patients under long-term treatment with salicylic acid or corticosteroids. B Show 5 more As per IDSA 2014 guidelines: Initiate acyclovir in patients with suspected or confirmed cutaneous or disseminated VZV infection. B Add IV acyclovir to the antimicrobial regimen in patients with suspected or confirmed cutaneous or disseminated VZV infection. B Topical antiviral therapy: As per GHMF 2020 guidelines, do not use topical antiviral therapy for cutaneous HZ. D As per EADV 2017 guidelines, insufficient evidence to support the use of local antiviral preparations for the treatment of patients with cutaneous HZ. I Consider selecting a topical treatment according to the current status of the skin lesions. I Topical antiseptics: consider offering stage-adjusted topical treatment, including antiseptic gels for crusted vesicles, and cooling, anti-inflammatory or antiseptic solutions for fresh vesicles, in patients with HZ. C Management of herpes zoster ophthalmicus: As per GHMF 2020 guidelines, ensure co-treatment by an ophthalmologist to rule out ocular involvement in patients with HZ ophthalmicus. B Show 4 more As per EADV 2017 guidelines, initiate IV acyclovir as induction treatment (10 mg/kg bodyweight 3 /d for 7-10 days) followed by oral acyclovir (800 mg 5 /d for 3-4 months) in patients with https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 4/9 6/24/23, 12:41 PM Herpes zoster Pathway acute retinal necrosis (as complication of HZ ophthalmicus). B Show 3 more Management of herpes zoster oticus: As per GHMF 2020 guidelines: Ensure co-treatment by an ENT specialist and a neurologist in patients with HZ oticus, particularly if there is facial nerve and/or vestibulocochlear nerve involvement. B Administer combination treatment consisting of IV acyclovir and systemic corticosteroids in patients with HZ oticus and facial nerve involvement (Ramsay Hunt syndrome), severe pain, and/or paralysis of multiple cranial nerves. B As per EADV 2017 guidelines, consider initiating combination therapy of IV acyclovir with systemic corticosteroids in patients with HZ oticus with involvement of the facial nerve (Ramsay Hunt syndrome) or with severe pain and multiple cranial nerve palsies. C Pain management, acute pain: As per GHMF 2020 guidelines, administer systemic analgesics for early treatment of HZ- associated pain. B Show 3 more As per EADV/EDF 2017 guidelines, administer early systemic analgesics for the treatment of acute zoster-associated pain. B Show 2 more Pain management, postherpetic neuralgia: As per GHMF 2020 guidelines, ensure co-treatment by a pain specialist in case of persistent pain despite pain management (4 weeks after the resolution of skin lesions). B As per AAFP 2017 guidelines: Offer capsaicin 8% patches applied for 30-90 minutes for pain relief in patients with postherpetic neuralgia. A Consider offering the following agents for pain relief in patients with postherpetic neuralgia: gabapentin pregabalin amitriptyline nortriptyline desipramine. B 5. Specific circumstances Pregnant patients: As per GHMF 2020 guidelines: Do not use systemic antiviral therapy during pregnancy in the absence of risk factors for a complicated disease course. D https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 5/9 6/24/23, 12:41 PM Herpes zoster Pathway Initiate systemic antiviral therapy with acyclovir during pregnancy only for complicated disease courses. B As per EADV 2017 guidelines: Avoid using antiviral therapy in pregnant patients in the absence of the risk of complications. D Consider initiating antiviral therapy, preferably with acyclovir, in pregnant patients in the presence of risk factors for complicated courses of disease, if the potential benefits to the mother outweigh the potential risks to the fetus. C Pediatric patients: As per GHMF 2020 guidelines: Do not use systemic antiviral therapy in pediatric patients with HZ in the absence of risk factors for complications. D Consider initiating systemic antiviral therapy in pediatric patients with HZ in the presence of risk factors for a complicated disease course, if the therapeutic benefits outweigh any potential risks. C As per EADV 2017 guidelines: Avoid using antiviral therapy in pediatric patients in the absence of the risk of complications. D Consider initiating antiviral therapy in pediatric patients in the presence of risk factors for complicated courses of disease, if the potential benefits of the treatment outweigh the potential risks. C Patients with impaired renal function: As per GHMF 2020 guidelines: Assess creatinine levels at the initiation of oral antiviral therapy with acyclovir, famciclovir, or valacyclovir in patients with known or suspected CKD. B Administer oral brivudine (if oral antiviral treatment is indicated) or IV acyclovir (if intravenous antiviral treatment is indicated) at a dose adjusted to renal function in patients with impaired renal function. B As per EADV 2017 guidelines: Consider assessing creatinine levels in patients with known or suspected renal insufficiency at the time of initiation of antiviral therapy with acyclovir, famciclovir, or valacyclovir. C Administer oral brivudin (if oral antiviral therapy is indicated) or IV acyclovir with dosage adaptation (if IV treatment is indicated) in patients with renal function impairment. B Solid organ transplant recipients (screening for previous infection): obtain VZV serology during the pre-transplant evaluation to screen solid organ transplant candidates for prior VZV infection. B Solid organ transplant recipients (laboratory tests): obtain laboratory confirmation of HZ in solid organ transplant recipients, even though clinical presentations often allow for a presumptive clinical diagnosis. B Show 2 more https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 6/9 6/24/23, 12:41 PM Herpes zoster Pathway Solid organ transplant recipients (antiviral therapy): administer IV acyclovir in post-transplant patients developing primary varicella, due to the risk of severe complications. B Show 4 more Solid organ transplant recipients (pre-transplant vaccination): administer the live-attenuated vaccine in VZV seronegative transplant candidates at least 4 weeks prior to transplantation, provided no contraindications are present. B Show 2 more Solid organ transplant recipients (post-transplant vaccination): Do not use the live-virus varicella vaccine in the post-transplant period. D Consider offering the live virus varicella vaccine with caution in selected seronegative patients receiving low level immunosuppression in the post transplant period. D Consider offering the adjuvanted subunit vaccine for the prevention of HZ in selected kidney transplant recipients at low risk for rejection. C Solid organ transplant recipients (post-transplant antiviral prophylaxis): Administer short-term prophylaxis with acyclovir or valacyclovir in HSV- and VZV-seropositive patients not receiving CMV prophylaxis (or receiving letermovir prophylaxis). A Administer short-term prophylaxis with acyclovir or valacyclovir in VZV-seropositive, HSV- seronegative patients not receiving CMV prophylaxis (or receiving letermovir prophylaxis). B Solid organ transplant recipients (post-exposure prophylaxis): administer post-exposure prophylaxis after a significant exposure in seronegative transplant recipients. A Show 2 more Solid organ transplant recipients (infection control): place all immunosuppressed patients admitted to the hospital with varicella or HZ on airborne and contact isolation precautions. B Show 2 more 6. Preventative measures Immunization, immunocompetent adults: As per CDC 2018 guidelines, offer recombinant zoster vaccine for the prevention of HZ in immunocompetent adults aged 60 years. E Show 9 more As per NACI 2018 guidelines, offer recombinant zoster vaccine in 50 years old adults without contraindications to the vaccine, including if previously vaccinated with zoster vaccine live A , or had a previous episode of HZ. B Show 3 more Immunization, immunocompromised adults: As per CDC 2022 guidelines, offer 2 doses of recombinant zoster vaccine in 19 years old immunocompromised patients, regardless of the previous history of HZ or previous receipt of zoster vaccine live. E Show 3 more https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 7/9 6/24/23, 12:41 PM Herpes zoster Pathway As per CDC 2018 guidelines, offer recombinant zoster vaccine in patients taking low-dose immunosuppressive therapy (such as < 20 mg/day of prednisone or equivalent or using inhaled or topical corticosteroids) and patients anticipating immunosuppression or having recovered from an immunocompromising illness. E As per NACI 2018 guidelines, consider offering recombinant zoster vaccine (not zoster vaccine live) in 50 years old immunocompromised adults on a case-by-case basis. B Patient isolation: consider placing patients in a shared room with other patients with documented immunity to VZV if single-room isolation is not feasible and following an individual risk assessment. 7. Follow-up and surveillance Indications for referral: As per EADV 2017 guidelines, consult with an ophthalmologist for patients with HZ ophthalmicus to exclude complicated courses. B Show 2 more As per EADV 2017 guidelines, refer patients with persisting pain (such as after 4 weeks after the resolution of skin lesions) to a pain specialist. B Patients with resistant disease: Suspect clinical resistance of VZV infection if drug therapy failures after 10-21 days, particularly in patients presenting with verrucous VZV infection. B Consider obtaining VZV genotyping to provide information on the appearance of acyclovir or other antiviral resistant variants. C References 1. Gerd E Gross, Lisa Eisert, Hans Wilhelm Doerr et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia. J Dtsch Dermatol Ges. 2020 Jan;18 1 55 78. Open 2. Aaron Saguil, Shawn Kane, Michael Mercado et al. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. Am Fam Physician. 2017 Nov 15;96 10 656 663. Open 3. R N Werner, A F Nikkels, B Marinovi et al. European consensus-based (S2k) Guideline on the Management of Herpes Zoster - guided by the European Dermatology Forum EDF in cooperation with the European Academy of Dermatology and Venereology EADV , Part 2 Treatment. J Eur Acad Dermatol Venereol. 2017 Jan;31 1 20 29. Open 4. Steven A Pergam, Ajit P Limaye, AST Infectious Diseases Community of Practice. Varicella zoster virus in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33 9):e13622. Open 5. R Warrington, S Ismail, National Advisory Committee on Immunization NACI . Summary of the NACI Update on Herpes Zoster Vaccines. Can Commun Dis Rep. 2018 Sep 6;44 9 220 225. Open https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 8/9 6/24/23, 12:41 PM Herpes zoster Pathway 6. R N Werner, A F Nikkels, B Marinovi et al. European consensus-based (S2k) Guideline on the Management of Herpes Zoster - guided by the European Dermatology Forum EDF in cooperation with the European Academy of Dermatology and Venereology EADV , Part 1 Diagnosis. J Eur Acad Dermatol Venereol. 2017 Jan;31 1 9 19. Open 7. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59 2):e10 52. Open 8. Kathleen L Dooling, Angela Guo, Manisha Patel et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep. 2018 Jan 26;67 3 103 108. Open 9. No authors listed. Practice bulletin no. 151 Cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy. Obstet Gynecol. 2015 Jun;125 6 1510 1525. Open 10. Tara C Anderson, Nina B Masters, Angela Guo et al. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged 19 Years: Recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep. 2022 Jan 21;71 3 80 84. Open https://web.pathway.md/diseases/recZEWlD6HYvbSJRU 9/9

Guideline sources The following summarized guidelines for the evaluation and management of hiatal hernia are prepared by our editorial team based on guidelines from the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES 2013). 1 Guidelines 1. Classification and risk stratification Classification: Classify hiatal hernias into the following types: Situation Guidance Sliding hernias - the GEJ migrates above the diaphragm, the stomach remains in its usual longitudinal alignment and the fundus remains below the GEJ Type I Pure paraesophageal hernias - the GEJ remains in its normal anatomic position, but a portion of the fundus herniates through the Type II https://web.pathway.md/diseases/recOcTmIRvMcd65LM 1/3 6/24/23, 12:44 PM Hiatal hernia Pathway diaphragmatic hiatus adjacent to the esophagus A combination of types I and II, with both the GEJ and the fundus herniating through the hiatus, and the fundus lies above the GEJ Type III Hiatal hernias with the presence of a structure other than stomach (such as the omentum, colon, or small bowel) within the hernial sac. Type IV 2. Diagnostic investigations Diagnostic strategy: recognize that hiatal hernia can be diagnosed by various modalities. Obtain only investigations that will alter the management. B 3. Surgical interventions Indications for surgery: avoid repairing type I hernias in the absence of reflux disease. D Show 3 more Choice of surgical approach: Perform surgical repair of hiatal hernias by a transabdominal or transthoracic approach, preferring a laparoscopic approach in the majority of cases. B Recognize that a laparoscopic approach is as effective as open transabdominal approach and leads to less perioperative morbidity and shorter hospital stay than an open approach. B Technical considerations for surgery (hernial sac dissection): dissect the hernial sac away from mediastinal structures during paraesophageal hiatal hernia repair B , preferably followed by excision. B Technical considerations for surgery (mesh use): Use a mesh for reinforcement of large hiatal hernia repairs to decrease the risk of short-term recurrence. B Insufficient evidence to recommend either for or against the use of mesh at the hiatus. I Technical considerations for surgery (fundoplication): perform fundoplication during repair of a sliding type hiatal hernia to address reflux. B Show 2 more Technical considerations for surgery (esophageal length): return the GEJ to an infradiaphragmatic position during hiatal hernia repair. B Show 2 more Technical considerations for surgery (gastropexy): https://web.pathway.md/diseases/recOcTmIRvMcd65LM 2/3 6/24/23, 12:44 PM Hiatal hernia Pathway Consider performing gastropexy in addition to hiatal repair. B Consider performing gastropexy alone without hiatal hernia repair as a safe alternative in high- risk patients, recognizing that this approach can lead to high recurrence rates. C Technical considerations for surgery (gastrotomy tube): consider inserting a gastrostomy tube to facilitate postoperative care in selected patients. B 4. Specific circumstances Patients undergoing bariatric surgery: repair any hiatal hernia detected during Roux-en-Y gastric bypass, sleeve gastrectomy, and adjustable gastric band placement. B Pediatric patients (indications for surgery): perform surgical repair of symptomatic hiatal hernias in pediatric patients. Consider using a laparoscopic approach. Recognize that the patient's age and size of hernia are not up-front contraindications to laparoscopy. B Pediatric patients (technical considerations for surgery): perform concomitant antireflux procedure for gastroesophageal reflux. B Show 3 more 5. Follow-up and surveillance Postoperative care: do not obtain routine postoperative contrast studies in asymptomatic patients after hiatal hernia repair. D Show 2 more Revisional surgery: consider performing revisional surgery with a laparoscopic approach by experienced surgeons for recurrent hiatal hernia repair. B References 1. Kohn GP, Price RR, DeMeester SR et al. Guidelines for the management of hiatal hernia. Surg Endosc. 2013 Dec;27 12 4409 28. Open 2. Jong Jin Hyun, Young-Tae Bak. Clinical significance of hiatal hernia. Gut Liver. 2011 Sep;5 3 267 77. Open 3. Sabine Roman, Peter J Kahrilas. The diagnosis and management of hiatus hernia. BMJ. 2014 Oct 23;349:g6154. Open 4. Ryan E. Smith, Rai Dilawar Shahjehan. Hiatal Hernia. In: StatPearls Internet]. Treasure Island FL StatPearls Publishing; 2021 Jan. 2020 Sep 1. Open 5. Peter J Kahrilas, Hyon C Kim, John E Pandolfino. Approaches to the diagnosis and grading of hiatal hernia. Best Pract Res Clin Gastroenterol. 2008;22 4 601 16. Open https://web.pathway.md/diseases/recOcTmIRvMcd65LM 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hidradenitis suppurativa are prepared by our editorial team based on guidelines from the United States Hidradenitis Suppurativa Foundation (USHSF/CHSF 2019) and the British Association of Dermatologists (BAD 2019). 1 2 3 4 4 4 5 6 7 8 Definition Hidradenitis suppurativa is a chronic inflammatory skin condition characterized by painful, suppurative lesions in apocrine gland-bearing areas. 4 Epidemiology Hidradenitis suppurativa is caused by immune dysregulation in the terminal follicular epithelium and is thought to occur due to a combination of genetic predisposition and environmental factors. 7 Pathophysiology https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 1/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway Estimates of the prevalence of hidradenitis suppurativa globally range from 0.03% to 4%. The incidence of hidradenitis suppurativa in the United States is 8.6 per 100,000 population/year. 5 6 Disease course The dysregulated innate and adaptive immune response leads to perifollicular inflammation, hyperkeratosis, and occlusion of hair follicles in apocrine gland-bearing areas. Spillage of sebum and debris occurs due to rupture of dilated hair follicles, triggering an inflammatory response and the development of painful, inflamed nodules, abscesses, fistulas, and sinus tracts. 8 Prognosis and risk of recurrence Hidradenitis suppurativa is associated with increased all-cause mortality (incidence rate ratio 1.35, 95% CI, 1.15-1.59). Recurrence rates vary according to treatment, with rates of 13%, 22%, and 27% reported following wide excision, local excision, and deroofing, respectively. 4 4 Guidelines 1. Classification and risk stratification Severity grading: As per BAD 2019 guidelines, document the Hurley stage at baseline for the worst-affected region in all patients with hidradenitis suppurativa: Situation Guidance Abscess formation, single or multiple, without sinus tracts and cicatrization Stage I Recurrent abscesses with tract formation and cicatrization, single or multiple, widely separated lesions Stage II Diffuse or near-diffuse involvement, or multiple interconnected tracts and abscesses across the entire area. E Stage III As per USHSF 2019 guidelines, use the following to assess disease severity: hurley staging inflammatory lesion counts (abscesses and inflammatory lesions) clinical performance evaluation. B Show 2 more 2. Diagnostic investigations https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 2/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway Laboratory tests: Do not obtain routine microbiologic testing unless signs of secondary infection such as surrounding cellulitis or fever are present. Recognize that a negative culture may support a diagnosis of hidradenitis suppurativa based on consensus-derived diagnostic criteria. D Do not obtain biomarker or genetic testing in patients with hidradenitis suppurativa. D Screening for comorbidities: As per BAD 2019 guidelines: Screen patients with hidradenitis suppurativa for associated comorbidities including depression, anxiety and cardiovascular risk factors (diabetes, hypertension, hyperlipidemia and central obesity). Refer patients with persistent gastrointestinal symptoms for IBD screening. E Monitor for the following conditions in patients with long-standing, moderate-to-severe hidradenitis suppurativa: fistulating gastrointestinal disease inflammatory arthritis genital lymphedema cutaneous SCC anemia. E As per USHSF 2019 guidelines, screen for smoking, diabetes, metabolic syndrome, depression/anxiety B , follicular occlusion tetrad B , and SCC of HS-affected skin B Show 2 more 3. Medical management General principles: Manage patients with hidradenitis suppurativa via a multidisciplinary team approach, particularly when considering surgical interventions. E Consider referring patients with Hurley stage III (severe) disease immediately to dermatology secondary care. E Antibiotics, systemic: As per BAD 2019 guidelines, administer oral tetracyclines such as doxycycline or lymecycline for at least 12 weeks in patients with hidradenitis suppurativa, considering treatment breaks to assess need for ongoing therapy and to limit the risk of antimicrobial resistance. A Show 3 more As per CHSF/USHSF 2019 guidelines, administer tetracyclines for 12 weeks or as long-term maintenance when appropriate in patients with mild-to-moderate hidradenitis suppurativa. B Show 6 more Antibiotics, topical: https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 3/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway As per BAD 2019 guidelines, consider offering clindamycin 1% solution in patients with hidradenitis suppurativa. C As per CHSF/USHSF 2019 guidelines, consider offering topical clindamycin to reduce pustules in patients with hidradenitis suppurativa, but recognize that it carries a high risk of bacterial resistance. C Antiandrogen therapy: As per BAD 2019 guidelines: Consider offering metformin in patients with hidradenitis suppurativa with concomitant diabetes mellitus, and in female patients with PCOS or pregnancy. E Insufficient evidence to support the use of the following agents in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy: cyproterone ethinyloestradiol with cyproterone acetate ethinyloestradiol with norgestrel finasteride spironolactone. I As per USHSF 2019 guidelines: Consider administering the following hormonal agents in appropriate female patients with hidradenitis suppurativa, either as monotherapy for mild-to-moderate disease or in combination with other agents for more severe disease: estrogen-containing combined oral contraceptives (C, II) finasteride (C, III) cyproterone acetate spironolactone (C, III) metformin. (C, III) (Ungraded). Avoid progestogen-only contraceptives as they may worsen hidradenitis suppurativa. Retinoids: As per BAD 2019 guidelines, consider administering acitretin 0.3-0.5 mg/kg/day in male and non-fertile female patients with hidradenitis suppurativa unresponsive to antibiotics. C Show 2 more As per USHSF 2019 guidelines, consider administering isotretinoin only as second- or third-line therapy, or in patients with severe concomitant acne. C Show 2 more Corticosteroids: As per BAD 2019 guidelines, insufficient evidence to support the use of hydrocortisone or oral prednisolone in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy. I As per USHSF 2019 guidelines: https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 4/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway Consider administering short-term pulse corticosteroid therapy in patients with acute flares or to bridge patients to other treatment. C Consider administering long-term systemic corticosteroids tapered to the lowest possible dose as adjunct therapy in patients with severe hidradenitis suppurativa with suboptimal response to standard therapy. Consider administering as low-dose adjunctive therapy or pulse dosing for acute flares or to bridge to other treatment. C Other immunosuppressants: As per BAD 2019 guidelines, insufficient evidence to support the use of the following immunosuppressants in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy: azathioprine ciclosporin methotrexate colchicine. I As per USHSF 2019 guidelines, consider administering colchicine in combination with minocycline in patients with refractory mild-to-moderate hidradenitis suppurativa. C Show 2 more Biologic agents: As per BAD 2019 guidelines, offer adalimumab 40 mg weekly in patients with moderate-to- severe hidradenitis suppurativa unresponsive to conventional systemic therapy. A Show 3 more As per USHSF 2019 guidelines, offer adalimumab to improve disease severity and quality of life in patients with moderate-to-severe hidradenitis suppuratova. A Show 4 more Agents with no evidence for benefit: Insufficient evidence to support the use of the following agents in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy: staphage lysate atorvastatin tolmetin sodium fumaric acid esters. I Pain management: achieve disease control as the first-line method for pain management in patients with hidradenitis suppurativa. B Show 2 more 4. Nonpharmacologic interventions Lifestyle modifications: As per BAD 2019 guidelines, refer patients with hidradenitis suppurativa to smoking cessation and weight management services, if relevant. E https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 5/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway As per USHSF 2019 guidelines, advise smoking cessation. B Show 2 more Supplements: As per BAD 2019 guidelines, insufficient evidence to support the use of oral zinc in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy. I As per USHSF 2019 guidelines, consider offering oral zinc supplements. C 5. Therapeutic procedures Intralesional corticosteroids: As per BAD 2019 guidelines, consider administering intralesional corticosteroid injections in carefully selected hidradenitis suppurativa lesions during the acute phase. C As per USHSF 2019 guidelines, consider administering intralesional corticosteroid injections in the inflamed lesions for short-term control of hidradenitis suppurativa flares. Laser and light therapies: As per BAD 2019 guidelines, insufficient evidence to recommend the following therapies in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy: laser therapy photodynamic therapy phototherapy photochemotherapy. I As per USHSF 2019 guidelines, offer Nd-YAG laser for patients with Hurley stage I disease and Hurley stage II and III disease. B Show 3 more Therapies with no evidence for benefit: As per BAD 2019 guidelines, insufficient evidence to recommend the following therapies in patients with hidradenitis suppurativa unresponsive to conventional systemic therapy: external beam radiation therapy hyperbaric oxygen therapy. Show 2 more As per USHSF 2019 guidelines, recognize that external beam radiation therapy and photodynamic therapy have a limited role in the management of patients with hidradenitis suppurativa. B 6. Perioperative care Perioperative medical therapy: continue medical therapy in the perioperative period as it is likely to be beneficial and poses minimal risk of increased postoperative complications. B https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 6/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway 7. Surgical interventions Surgery: perform deroofing or excision for recurrent nodules and tunnels. B Show 2 more Wound care: ensure wound healing following surgery through secondary intention, primary closure, delayed primary closure, flaps, grafts, and/or skin substitutes. B Show 4 more 8. Specific circumstances Pregnant patients: Offer topical treatments, procedures, and safe systemic agents in pregnant patients with hidradenitis suppuratova. Avoid using retinoids, hormonal agents, most systemic antibiotics, and most immunosuppressive medications in pregnant patients with hidradenitis suppuratova. 9. Patient education Patient education: provide a patient information leaflet in all patients with hidradenitis suppurativa. E 10. Follow-up and surveillance Assessment of treatment response: measure treatment response using recognized instruments for pain and quality of life, including an inflammatory lesion count for patients on adalimumab therapy. E References 1. Ali Alikhan, Christopher Sayed, Afsaneh Alavi et al. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part II Topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019 Jul;81 1 91 101. Open 2. J R Ingram, F Collier, D Brown et al. British Association of Dermatologists guidelines for the management of hidradenitis suppurativa (acne inversa) 2018. Br J Dermatol. 2019 May;180 5 1009 1017. Open 3. Alikhan A, Sayed C, Alavi A et al. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part I Diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019 Jul;81 1 76 90. Open https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 7/8 6/24/23, 12:45 PM Hidradenitis suppurativa Pathway 4. Saunte DML, Jemec GBE. Hidradenitis Suppurativa: Advances in Diagnosis and Treatment. JAMA. 2017 Nov 28;318 20 2019 2032. Open 5. Calao M, Wilson JL, Spelman L et al. Hidradenitis Suppurativa HS prevalence, demographics and management pathways in Australia: A population-based cross-sectional study. PLoS One. 2018 Jul 24;13 7):e0200683. Open 6. Garg A, Lavian J, Lin G et al. Incidence of hidradenitis suppurativa in the United States: A sex- and age- adjusted population analysis. J Am Acad Dermatol. 2017 Jul;77 1 118 122. Open 7. Napolitano M, Megna M, Timoshchuk EA et al. Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment. Clin Cosmet Investig Dermatol. 2017 Apr 19;10 105 115. Open 8. Vinkel C, Thomsen SF, . Hidradenitis Suppurativa: Causes, Features, and Current Treatments. J Clin Aesthet Dermatol. 2018 Oct;11 10 17 23. Open https://web.pathway.md/diseases/recLhlEqiLh0BxVCU 8/8

Guideline sources The following summarized guidelines for the evaluation and management of hip fracture are prepared by our editorial team based on guidelines from the Eastern Association for the Surgery of Trauma (EAST/AOTA 2023), the American College of Physicians (ACP 2023), the American Academy of Orthopaedic Surgeons (AAOS 2022), the World Falls Guidelines (WFG 2022), the American College of Obstetricians and Gynecologists (ACOG 2022; 2021), the American Association of Family Physicians (AAFP 2022), the Academy of Orthopaedic Physical Therapy (AOPT 2021), the American College of Endocrinology (ACE/AACE 2020), the Endocrine Society (ES 2020), the American College of Radiology (ACR 2019), the Danish Health Authority (DHA 2018), the U.S. Preventive Services Task Force (USPSTF 2018), the Eastern Association for the Surgery of Trauma (EAST 2016), and the Osteoporosis Canada Foundation (OC 2010). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Guidelines 1. Diagnostic investigations Diagnostic imaging: https://web.pathway.md/diseases/recRdaocxVoiEsSMc 1/9 6/24/23, 12:45 PM Hip fracture Pathway As per AAFP 2022 guidelines, obtain cross-table lateral hip and anteroposterior pelvis radiography as initial evaluation for suspected hip fracture. B As per ACR 2019 guidelines: Obtain hip and pelvis X-rays as initial imaging of the hip with acute pain, fall or minor trauma, and suspected fracture. B Obtain hip and pelvis MRI or CT as subsequent imaging for evaluating acute hip pain from a fall or minor trauma with negative X-ray and suspected fracture. B Functional tests: Perform a musculoskeletal examination using the following tests and tools: assessment of knee extension strength in all settings B the Verbal Rating Scale for pain in all settings B the Gait Speed Test, documenting comfortable or maximum speed, walking aid, and rolling start or static start in all settings in patients not requiring human assistance B the Cumulated Ambulation Score to measure basic mobility in the acute and post-acute clinical settings until independent ambulation has been reached B the Timed Up and Go Test, documenting comfortable or maximum speed and walking-aid use, to measure mobility and risk for falls in all settings in patients not requiring human assistance B the New Mobility Score to assess the pre-fracture status in the early period/inpatient setting and the current status and recovery of pre-fracture status in the post-acute and community settings B the Falls Efficacy Scale-International to measure concern about falling in all settings. B Consider using the following tools in all settings: the Short Physical Performance Battery, recognizing that completion may not be feasible in the early postoperative period depending on ability the Activity Measure for Post-Acute Care using the 3-level version of the EuroQol-5 dimensions scale to measure health-related quality of life the 10-item physical functioning scale of the Medical Outcomes Study 36-Item Short-Form Health Survey to measure physical functioning the Medical Outcomes Study 36-Item Short-Form Health Survey to measure health-related quality of life. C 2. Medical management Management of pain: As per EAST 2023 guidelines: Consider administering NSAIDs (such as ketorolac) for pain management in adult patients with a traumatic fracture. C https://web.pathway.md/diseases/recRdaocxVoiEsSMc 2/9 6/24/23, 12:45 PM Hip fracture Pathway Insufficient evidence to recommend for the preference of selective NSAIDs (COX-2 inhibitors) or nonselective NSAIDs. I As per AOPT 2021 guidelines: Implement strategies to minimize fracture-related pain during physical therapy sessions to optimize the patient's mobility. Consider offering the following strategies for nonpharmacological pain management: appropriate timing of medication consultation with the interprofessional team psychologically informed physical therapy approaches. E Consider offering electrical stimulation for pain if it is not sufficiently managed with usual strategies. C Management of osteoporosis, indications: As per ACOG 2022 guidelines, initiate pharmacotherapy for osteoporosis in patients at high risk of fracture. A As per ACE/AACE 2020 guidelines, initiate pharmacologic therapy in patients with osteopenia or low bone mass and a history of a fragility fracture of the hip or spine. A Show 2 more As per ES 2020 guidelines, initiate pharmacotherapy in postmenopausal patients with osteoporosis at high risk of fractures, especially in patients with a recent fracture. A Management of osteoporosis, regimens: As per ACP 2023 guidelines, initiate bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in postmenopausal patients with primary osteoporosis. A Show 4 more As per ACOG 2022 guidelines, initiate bisphosphonates as initial therapy in most postmenopausal patients at increased risk of fracture. A Show 5 more As per ACE/AACE 2020 guidelines, initiate alendronate, risedronate, or zoledronate as initial therapy to reduce hip, non-vertebral, and spine fractures in most postmenopausal patients with osteoporosis at high risk of fracture. A Show 5 more As per ES 2020 guidelines, initiate bisphosphonates (alendronate, risedronate, zoledronic acid, or ibandronate) as initial therapy to reduce fracture risk in postmenopausal patients with osteoporosis at high risk of fractures. A Show 10 more As per OC 2010 guidelines, initiate alendronate, risedronate, zoledronic acid, or denosumab as first-line therapy for the prevention of fractures in menopausal females requiring treatment for osteoporosis. A Show 17 more Management of osteoporosis, duration: https://web.pathway.md/diseases/recRdaocxVoiEsSMc 3/9 6/24/23, 12:45 PM Hip fracture Pathway As per ACOG 2022 guidelines, consider discontinuing bisphosphonates to allow a drug holiday for low-to-moderate risk postmenopausal patients being stable after 5 years of treatment with oral bisphosphonates or after 3 years of therapy with IV zoledronic acid. Consider continuing treatment for longer durations of up to 10 years for oral bisphosphonates or up to 6 years for IV zoledronic acid in patients at high risk of fracture. C As per ACE/AACE 2020 guidelines, limit treatment with abaloparatide and teriparatide to 2 years and follow abaloparatide or teriparatide therapy with a bisphosphonate or denosumab. A Show 6 more 3. Inpatient care Prevention of inpatient complications: provide multicomponent nonpharmacological intervention programs delivered by an interprofessional team (including physicians, nurses, and possibly other healthcare professionals) for the entire hospitalization to prevent delirium in at-risk older adult patients undergoing hip surgery. B Show 2 more 4. Perioperative care Preoperative analgesia: administer multimodal analgesia incorporating preoperative nerve block for pain after hip fracture. A Preoperative traction: do not perform routine preoperative traction in older patients with hip fractures. D Perioperative antibiotics: administer antibiotics with activity against S. aureus 1-2 hours before hip surgery and 24 hours postoperatively. A Perioperative thromboprophylaxis: As per AAFP 2022 guidelines, administer chemoprophylaxis over mechanical prophylaxis alone, as patients with hip fractures are at high risk of VTE caused by immobility. A As per AAOS 2022 guidelines, administer VTE prophylaxis in older patients with hip fractures. B Perioperative blood transfusion: As per AAFP 2022 guidelines, set a Hgb level of 8 g/dL as the threshold for blood transfusion in asymptomatic postoperative patients with a hip fracture unless cardiac contraindications exist. B As per AAOS 2022 guidelines: Consider setting a blood transfusion threshold of 8 g/dL in asymptomatic postoperative patients. C Administer tranexamic acid to reduce blood loss and blood transfusion in older patients with hip fractures. A https://web.pathway.md/diseases/recRdaocxVoiEsSMc 4/9 6/24/23, 12:45 PM Hip fracture Pathway 5. Surgical interventions Surgical management, timing: As per AAFP 2022 guidelines, perform surgery for a hip fracture within 24-48 hours of injury unless a delay is needed to stabilize comorbidities, recognizing that early operative management improves pain control, decreases the length of hospitalization, and reduces complications. B As per AAOS 2022 guidelines, consider performing hip fracture surgery in older patients within 24-48 hours of admission for better outcomes. C Surgical management (anesthesia): administer either spinal or general anesthesia in older patients with hip fractures. A Surgical management (approach): perform arthroplasty over fixation in older patients with unstable (displaced) femoral neck fractures. A Show 4 more Surgical management (technical considerations): use cemented femoral stems in older patients undergoing arthroplasty for femoral neck fracture. A Show 5 more 6. Preventative measures Prevention of falls (general principles): Incorporate the individual's values and preferences in the care plan developed to prevent falls and related injuries. A Include both the individual's and their caregivers' perspectives when creating fall prevention care plans for older adults with cognitive impairment. B Advise on how to maintain safe mobility and optimize physical functioning in older patients at low risk of falls, taking into consideration the individual's circumstances, priorities, preferences, and resources. Reinforce health promotion/prevention messaging relevant to falls and fracture risks, including physical activity, lifestyle habits, and nutrition, including vitamin D intake. E Prevention of falls, environmental modifications: As per WFG 2022 guidelines, provide counseling for modifications of the physical home environment for fall hazards as part of a multidomain falls prevention intervention. A As per ACOG 2021 guidelines, offer fall prevention strategies, including weight-bearing and muscle-strengthening exercises, in patients at risk of falls. E As per DHA 2018 guidelines, consider offering changes to improve the safety in the home environment of elderly adults at risk of falls living at home. C As per EAST 2016 guidelines, consider offering physical environment modification to prevent falls in frail elderly people. C Prevention of falls, exercise interventions: As per WFG 2022 guidelines, offer an exercise program based on an individual assessment. E https://web.pathway.md/diseases/recRdaocxVoiEsSMc 5/9 6/24/23, 12:45 PM Hip fracture Pathway Show 6 more As per DHA 2018 guidelines: Consider offering balance training in elderly adults at risk of falls living at home or in institutional care. C Consider offering movement concepts, such as Tai Chi, yoga, dance, or dance-like training in elderly adults at risk of falls living at home. C As per DHA 2018 guidelines, offer fall prevention strategies, including weight-bearing and muscle-strengthening exercises, in patients at risk of falls. E As per USPSTF 2018 guidelines, offer exercise interventions to prevent falls in community- dwelling 65 years old adults at increased risk for falls. B As per EAST 2016 guidelines, consider offering evidence-based exercise programs for frail elderly individuals. C As per OC 2010 guidelines, consider offering exercises focusing on balance, such as Tai Chi, or on balance and gait training in individuals at risk of falls. B Prevention of falls, multifactorial interventions: As per WFG 2022 guidelines, offer multidomain interventions, informed by a multiprofessional, multifactorial falls risk assessment, in community-dwelling older adults at high risk of falls. A As per ACOG 2021 guidelines, offer fall prevention strategies, including individualized multifactorial interventions such as vision assessment and treatment, balance training, and environmental assessment and modification, in patients at risk of falls. E As per USPSTF 2018 guidelines, offer multifactorial interventions to prevent falls in selective groups of 65 years old community-dwelling individuals at increased risk for falls. B Prevention of falls (vestibular rehabilitation): consider offering vestibular rehabilitation in elderly patients with diagnosed vestibular dysfunction. C Prevention of falls, vitamin D/calcium supplementation: As per USPSTF 2018 guidelines, do not use vitamin D supplements for the prevention of falls in community-dwelling 65 years old adults. D As per EAST 2016 guidelines, consider offering vitamin D and calcium supplementation for the prevention of fall-related injuries in frail elderly individuals. C Prevention of falls, medication review: As per WFG 2022 guidelines: Assess for fall history and the risk of falls before prescribing potential fall risk-increasing drugs in older adults. A Obtain a medication review and deprescribe fall risk-increasing drugs as part of multidomain fall prevention interventions. A Use a validated, structured screening and assessment tool to identify fall risk-increasing drugs when conducting a general medication review or medication review targeted to fall prevention. B As per DHA 2018 guidelines: https://web.pathway.md/diseases/recRdaocxVoiEsSMc 6/9 6/24/23, 12:45 PM Hip fracture Pathway Discontinue benzodiazepines in elderly adults in case of > 4 weeks of use, since benzodiazepines increase the risk of falls. B Keep selective serotonin receptor inhibitors only upon due consideration and only if non- pharmacological treatment has been ineffective, in > 65 years old adults with moderate depression, since selective serotonin receptor inhibitors may increase the risk of falling and the effect on depression and quality of life is likely to be negligible. B Hip protectors: As per EAST 2016 guidelines, consider offering hip protectors in frail elderly individuals in the appropriate environment. C As per OC 2010 guidelines, consider offering hip protectors in older adults at high risk for fracture residing in long-term care facilities. C 7. Follow-up and surveillance Serial clinical assessment: assess and document hip extensor and abductor muscle strength in post-acute clinical settings. B Show 5 more Discharge from hospital: Ensure a safe transfer of postoperative patients with hip fractures from the hospital to the community involving physical therapists in the interprofessional assessment and planning. E Obtain evaluation by the facility or home care physical therapist within 72 hours of transfer of care in patients with continued impairments and functional deficits after hip fracture (including patients in nursing homes). E Postoperative rehabilitation: As per AAFP 2022 guidelines: Offer early rehabilitation and weight-bearing within 24 hours postoperatively to improve mobility outcomes. A Ensure non-weight-bearing status and complete activity cessation while awaiting definitive imaging in patients with a suspected femoral neck stress fracture to reduce the risk of conversion to complete fracture. B As per AAOS 2022 guidelines, consider offering immediate, full weight-bearing to tolerance in older patients after surgery. C As per WSES 2022 guidelines, offer an individualized and progressive exercise program to improve mobility, including standing up, balance, walking, and climbing stairs, as a fall prevention strategy in older adults after sustaining a hip fracture. A Commence such programs in the hospital B and continue in the community. B As per AOPT 2021 guidelines, set individual goals for recovery of function, including independent basic mobility, achieving the prior level of function, return to pre-fracture residence, and activities to support long-term well-being. Review and revise goals throughout the continuum of care. E https://web.pathway.md/diseases/recRdaocxVoiEsSMc 7/9 6/24/23, 12:45 PM Hip fracture Pathway Show 9 more References 1. Mary I O'Connor, Julie A Switzer. AAOS Clinical Practice Guideline Summary: Management of Hip Fractures in Older Adults. J Am Acad Orthop Surg. 2022 Oct 15;30 20):e1291-e1296. Open 2. Danish Health Authority. National clinical guideline for the prevention of falls in elderly people: Quick guide. Sundhedsstyrelsen. 2018 Apr. Open 3. Patrick B Murphy, George Kasotakis, Elliott R Haut et al. Efficacy and safety of non-steroidal anti- inflammatory drugs NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association. Trauma Surg Acute Care Open. 2023 Feb 21;8 1):e001056. Open 4. Pauline M Camacho, Steven M Petak, Neil Binkley et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS 2020 UPDATE. Endocr Pract. 2020 May;26 Suppl 1 1 46. Open 5. US Preventive Services Task Force, Grossman DC, Curry SJ et al. Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Apr 24;319 16 1696 1704. Open 6. Manuel Montero-Odasso, Nathalie van der Velde, Finbarr C Martin et al. World guidelines for falls prevention and management for older adults: a global initiative. Age Ageing. 2022 Sep 2;51 9):afac205. Open 7. American College of Obstetricians and Gynecologists Committee on Clinical Practice Guidelines Gynecology. Osteoporosis Prevention, Screening, and Diagnosis: ACOG Clinical Practice Guideline No. 1. Obstet Gynecol. 2021 Sep 1;138 3 494 506. Open 8. Papaioannou A, Morin S, Cheung AM et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010 Nov 23;182 17 1864 73. Open 9. Christine M McDonough, Marcie Harris-Hayes, Morten Tange Kristensen et al. Physical Therapy Management of Older Adults With Hip Fracture. J Orthop Sports Phys Ther. 2021 Feb;51 2 CPG1 CPG81. Open 10. American College of Obstetricians and Gynecologists Committee on Clinical Practice Guidelines Gynecology. Management of Postmenopausal Osteoporosis: ACOG Clinical Practice Guideline No. 2. Obstet Gynecol. 2022 Apr;139 4 698 717. Open 11. Jeremy D Schroeder, Sean P Turner, Emily Buck. Hip Fractures: Diagnosis and Management. Am Fam Physician. 2022 Dec. Open 12. Amir Qaseem, Lauri A Hicks, Itziar Etxeandia-Ikobaltzeta et al. Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023 Jan 3. Online ahead of print. Open 13. Crandall M, Duncan T, Mallat A et al. Prevention of fall-related injuries in the elderly: An Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2016 Jul;81 1 196 206. Open https://web.pathway.md/diseases/recRdaocxVoiEsSMc 8/9 6/24/23, 12:45 PM Hip fracture Pathway 14. Dolores Shoback, Clifford J Rosen, Dennis M Black et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update. J Clin Endocrinol Metab. 2020 Mar 1;105 3):dgaa048. Open 15. Expert Panel on Musculoskeletal Imaging, Andrew B Ross, Kenneth S Lee et al. ACR Appropriateness Criteria Acute Hip Pain-Suspected Fracture. J Am Coll Radiol. 2019 May;16 5S S18 S25. Open 16. Moyer VA. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 May 7;158 9 691 6. Open 17. Expert Panel on Pediatric Imaging, Nabile M Safdar, Cynthia K Rigsby et al. ACR Appropriateness Criteria Acutely Limping Child Up To Age 5. J Am Coll Radiol. 2018 Nov;15 11S S252 S262. Open https://web.pathway.md/diseases/recRdaocxVoiEsSMc 9/9

Guideline sources The following summarized guidelines for the management of hip osteoarthritis are prepared by our editorial team based on guidelines from the American College of Rheumatology (ACR/AAHKS 2023), the American College of Rheumatology (ACR 2020), and the American Academy of Orthopaedic Surgeons (AAOS 2017). 1 2 3 Calculator Calculator Gurd and Wilson criteria for fat e Schonfeld's criteria for fat embol Guidelines 1. Medical management Non-opioid analgesics: As per ACR 2020 guidelines: Offer NSAIDs (topical and oral) in patients with hip OA. A https://web.pathway.md/diseases/recLpSfsK5Ex3P8PR 1/5 6/24/23, 12:44 PM Hip osteoarthritis Pathway Consider offering acetaminophen in patients with hip OA. C As per AAOS 2017 guidelines, offer NSAIDs to improve short-term pain, function, or both in patients with symptomatic hip OA. A Opioids: As per ACR 2020 guidelines: Consider offering tramadol in patients with hip OA. C Avoid using non-tramadol opioids in patients with hip OA. Consider offering non-tramadol opioid in certain circumstances, particularly when alternatives have been exhausted. D Duloxetine: consider offering duloxetine in patients with hip OA. C Agents with no evidence for benefit: As per ACR 2020 guidelines: Avoid using the following agents in patients with hip OA: colchicine vitamin D. D Do not use the following agents in patients with hip OA: bisphosphonates glucosamine chondroitin sulfate, and combination products containing glucosamine and chondroitin sulfate hydroxychloroquine methotrexate. D As per AAOS 2017 guidelines, avoid using glucosamine sulfate for improving function, reducing stiffness and decreasing pain in patients with symptomatic hip OA. D 2. Nonpharmacologic interventions Weight loss: advise losing weight in overweight and obese patients with hip OA. A Self-management programs: advise participating in self-efficacy and self-management programs in patients with hip OA. A Physical therapy: As per ACR 2020 guidelines: Advise exercising in patients with hip OA. A Consider advising balance exercises in patients with hip OA. C As per AAOS 2017 guidelines, offer physical therapy to improve function and reduce pain in patients with hip OA with mild-to-moderate symptoms. A Walking canes: advise using walking canes in patients with hip OA if the disease in one or both hips causes a sufficiently large impact on ambulation, joint stability, or pain. A https://web.pathway.md/diseases/recLpSfsK5Ex3P8PR 2/5 6/24/23, 12:44 PM Hip osteoarthritis Pathway Footwear: avoid using modified shoes, lateral and medial wedged insoles in patients with hip OA. D Cognitive behavioral therapy: consider offering CBT in patients with hip OA. C Alternative and complementary therapies: advise practicing Tai chi in patients with hip OA. A Show 2 more 3. Therapeutic procedures Intra-articular corticosteroids: As per ACR 2020 guidelines, administer intra-articular corticosteroid injections in patients with hip OA. A Show 2 more As per AAOS 2017 guidelines, administer intra-articular corticosteroid injections to improve function and reduce short-term pain in patients with symptomatic hip OA. A Other intra-articular injections: As per ACR 2020 guidelines: Avoid administering the following agents intra-articularly in patients with hip OA: botulinum toxin prolotherapy. D Do not administer the following agents intra-articularly in patients with hip OA: hyaluronic acid stem cells TNF inhibitors IL-1 receptor antagonists platelet rich plasma. D As per AAOS 2017 guidelines, do not administer intra-articular hyaluronic acid injections in patients with symptomatic hip OA. D Transcutaneous electrical nerve stimulation: do not perform transcutaneous electrical stimulation in patients with hip OA. D 4. Perioperative care Preoperative risk assessment: consider using risk assessment tools to assist in predicting adverse events, assessing surgical risks and educating patients with symptomatic hip OA undergoing total hip arthroplasty. C Preoperative physical therapy: consider offering preoperative physical therapy to improve early function in patients with symptomatic hip OA after total hip arthroplasty. C https://web.pathway.md/diseases/recLpSfsK5Ex3P8PR 3/5 6/24/23, 12:44 PM Hip osteoarthritis Pathway Intraoperative tranexamic acid: consider administering IV or topical tranexamic acid to reduce blood loss in patients undergoing total hip arthroplasty. C 5. Surgical interventions Total hip arthroplasty (timing): consider performing elective hip arthroplasty without delay, rather than delaying for 3 months, or for a trial of physical therapy, (Low) NSAIDs, intra-articular corticosteroid injections, viscosupplementation injections, or braces and/or ambulatory aids, in patients with radiographically moderate-to-severe OA with moderate-to-severe pain or loss of function eligible for elective total joint arthroplasty decided through a shared decision-making process and completed 1 trial of appropriate nonoperative therapy. (Very low). C Show 4 more Total hip arthroplasty (prognostic factors): Recognize that obesity is associated with the following outcomes in patients with symptomatic hip OA undergoing total hip arthroplasty: lower absolute outcome scores B similar levels of patient satisfaction B relative improvement in pain and function B increased rates of postoperative dislocation, superficial wound infection, and blood loss. B Show 4 more Total hip arthroplasty (surgical approach): recognize that there are no clinically significant differences in patient-oriented outcomes related to the surgical approach in patients with symptomatic hip OA undergoing total hip arthroplasty. B Anesthesia: consider performing neuraxial anesthesia over general anesthesia to reduce the rate of complications in patients with symptomatic hip OA undergoing total hip arthroplasty. C 6. Follow-up and surveillance Postoperative physical therapy: consider offering postoperative physical therapy to improve early function in patients with symptomatic hip OA undergone total hip arthroplasty. C References 1. No authors listed. Management of Osteoarthritis of the Hip: Evidence-Based Clinical Practice Guideline. AAOS. 2017 Mar 13. Open 2. Sharon L Kolasinski, Tuhina Neogi, Marc C Hochberg et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res Hoboken). 2020 Feb;72 2 149 162. Open 3. American College of Rheumatology, American Association of Hip and Knee Surgeons. 2023 American College of Rheumatology ACR and American Association of Hip and Knee Surgeons AAHKS Clinical https://web.pathway.md/diseases/recLpSfsK5Ex3P8PR 4/5 6/24/23, 12:44 PM Hip osteoarthritis Pathway Practice Guideline for the Optimal Timing of Elective Total Hip or Knee Arthroplasty for Patients with Symptomatic Moderate to Severe Osteoarthritis or Osteonecrosis Who Have Failed Nonoperative Therapy. ACR. 2023 Mar 8. Open https://web.pathway.md/diseases/recLpSfsK5Ex3P8PR 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hirschsprung disease are prepared by our editorial team based on guidelines from the European Reference Network for Rare Inherited and Congenital Anomalies (ERNICA 2020). 1 Calculator Hirschsprung's Associated Enter Guidelines 1. Screening and diagnosis Diagnosis: diagnose Hirschsprung's disease based on representative rectal histology. Confirm the diagnosis before performing pull-through surgery. B https://web.pathway.md/diseases/reczQKoF1jKDWSuBG 1/4 6/24/23, 12:44 PM Hirschsprung disease Pathway 2. Diagnostic investigations Genetic analysis: Consider obtaining genetic testing of RET in patients with non-syndromic Hirschsprung's disease. C Refer patients with syndromic Hirschsprung's disease for genetic consultation and screening for the specific gene associated with the syndromic phenotype. B 3. Diagnostic procedures Rectal biopsy: perform rectal biopsy if the clinical history and physical signs are suggestive of Hirschsprung's disease. B Show 2 more 4. Perioperative care Pre-operative management: administer rectal saline irrigations 1-3 times daily to decompress the bowel until the definitive pull-through surgery. B Show 3 more Post-operative management: provide specialist pediatric and nursing care during the early postoperative period, and ensure availability of anesthesia consultation. B Show 2 more 5. Surgical interventions Pull-through surgery (indications): perform pull-through surgery in stable and well-growing patients with Hirschsprung's disease, if the bowel has been sufficiently decompressed. B Pull-through surgery (technical considerations): preserve anal canal during pull-through surgery. B Show 2 more Pull-through surgery (setting): Perform pull-through surgery in centers with at least two pediatric colorectal surgeons and pathological, radiological and anesthetic expertise, including pediatric and neonatal intensive care and specialized nursing 24/7. B Ensure that the centers performing pull-through surgery for Hirschsprung's disease: have the capabilities to manage the entire care pathway B demonstrate active involvement in quality control and improvement B perform the type of pull-through surgery in which they have the most experience, including management of postoperative complications and follow-up. B https://web.pathway.md/diseases/reczQKoF1jKDWSuBG 2/4 6/24/23, 12:44 PM Hirschsprung disease Pathway 6. Specific circumstances Patients with Hirschsprung's associated enterocolitis: suspect the diagnosis of Hirschsprung's associated enterocolitis in patients with explosive diarrhea, foul-smelling stool and/or HAEC score of 4. B Show 6 more 7. Follow-up and surveillance Management of persistent fecal incontinence: Consider evaluating pediatric patients > 4 years old with fecal incontinence and normal intellectual development, including: elicit stooling history and pattern to evaluate for tendency to constipation or diarrhea, and involuntary passage of flatus elicit dietary history and growth perform examination under anesthesia with or without anorectal manometry to assess the integrity of the anal canal, sphincter complex and dentate line, and for the presence of rolled muscle cuff, stricture or rectal spur obtain contrast enema to evaluate for colonic dilatation, rectal spur, constipation, or a twisted pull-through with or without obtaining endorectal ultrasound to assess for sphincter defects. B Show 4 more Management of persistent obstructive symptoms: Obtain further evaluation in pediatric patients with persistent obstructive symptoms following pull-through surgery including: perform rectal examination and obtain contrast enema to rule out a mechanical cause and to assess for colonic dilatation review the histology of the proximal margins of the originally resected bowel repeat rectal biopsies to ensure normal innervation of the pulled-through bowel. B Show 3 more Long-term follow-up: obtain regular follow-up to adulthood in pediatric patients with Hirscgprung's disease within the context of an interdisciplinary care team, led by a pediatric surgeon. B Show 2 more References 1. Kristiina Kyrklund, Cornelius E. J. Sloots, [ ] et al. ERNICA guidelines for the management of rectosigmoid Hirschsprung s disease. Orphanet J Rare Dis. 2020; 15 164. Open 2. Aimee C Pastor, Fahima Osman, Daniel H Teitelbaum et al. Development of a standardized definition for Hirschsprung's-associated enterocolitis: a Delphi analysis. J Pediatr Surg. 2009 Jan;44 1 251 6. Open https://web.pathway.md/diseases/reczQKoF1jKDWSuBG 3/4 6/24/23, 12:44 PM Hirschsprung disease Pathway https://web.pathway.md/diseases/reczQKoF1jKDWSuBG 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hirsutism are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2018), the American College of Obstetricians and Gynecologists (ACOG 2018), and the Society of Obstetricians and Gynaecologists of Canada (SOGC 2017). 1 2 3 Guidelines 1. Screening and diagnosis Etiology: recognize that insulin resistance and hyperinsulinemia may lead to hyperandrogenism in patients with PCOS. B Show 2 more 2. Classification and risk stratification Classification: Consider classifying hirsutism into 1 of 3 following groups based on etiology: https://web.pathway.md/diseases/recFbebjJD55qgBNf 1/5 6/24/23, 12:44 PM Hirsutism Pathway hyperandrogenic hirsutism (including PCOS or androgen-secreting tumors) non-androgenic hirsutism (including medication-induced hirsutism) idiopathic hirsutism. C Severity assessment: Consider using the Ferriman-Gallwey score in the assessment of hirsutism to help quantify the problem and help assess response to treatment, with a score of 8 representing excessive hair growth, and classify into the following categories: Situation Guidance Mild hirsutism < 15 Moderate 16-25 Severe. C > 25 3. Diagnostic investigations Initial evaluation: Elicit a focused history, perform a physical examination and obtain appropriate investigations to differentiate among the possible etiologies in the evaluation of patients presenting with hirsutism. B Obtain a comprehensive evaluation and, when applicable, explore the long-term health sequelae of hyperandrogenism and PCOS, including abnormal uterine bleeding, infertility and metabolic syndrome. B Serum testosterone levels: As per ES 2018 guidelines, consider obtaining androgen level measurement in all patients with an abnormal hirsutism score. C Show 2 more As per SOGC 2017 guidelines, obtain total testosterone in patients with moderate-to-severe hirsutism, although the benefit in mild hirsutism is questionable. Obtain additional testing in patients with irregular menses and/or signs of hyperandrogenism or other endocrinopathies. B Screening for non-classic CAH: Consider obtaining early morning 17-hydroxyprogesterone levels in the follicular phase (or on a random day) to screen for nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in patients with hyperandrogenemia and amenorrhea or infrequent menses. C Consider obtaining early morning 17-hydroxyprogesterone levels to screen for nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in patients with hirsutism at high risk of congenital adrenal hyperplasia (positive family history, member of a high-risk ethnic group), even if serum total and free testosterone are normal. C https://web.pathway.md/diseases/recFbebjJD55qgBNf 2/5 6/24/23, 12:44 PM Hirsutism Pathway 4. Medical management General principles: As per ES 2018 guidelines, recognize that there is no clear primary treatment for hirsutism in patients with PCOS. B As per ES 2018 guidelines, consider initiating pharmacological therapy in most patients with patient-important hirsutism despite cosmetic measures. Consider offering direct hair removal methods in patients desiring additional cosmetic benefit. Consider offering either approach in patients with mild hirsutism with no evidence of an endocrine disorder. C Show 2 more As per SOGC 2017 guidelines, offer multimodal treatment including physical hair removal techniques and medical therapies in patients with hirsutism. Offer at least 6 month of medical therapy to see a significant improvement in hirsutism. B Systemic antiandrogen therapy: As per ES 2018 guidelines, avoid using antiandrogen monotherapy as initial therapy (because of the teratogenic potential of these medications) in most patients with hirsutism unless patients use adequate contraception. D Show 2 more As per SOGC 2017 guidelines, consider initiating antiandrogen therapy in patients with moderate-to-severe hirsutism or to ensure an optimal response in milder hirsutism, depending on patient's goals of treatment. B Show 2 more Topical antiandrogen therapy: avoid using topical antiandrogen therapy in patients with hirsutism. D Oral contraceptives: As per ES 2018 guidelines, consider offering oral contraceptives as initial therapy for the treatment of patient-important hirsutism in the majority of patients with hirsutism not seeking fertility. C Show 3 more As per SOGC 2017 guidelines, offer combined hormonal contraceptives, if not contraindicated, as first-line therapy in all patients with hirsutism desiring treatment. A Combination therapy: Consider initiating combination therapy with an oral contraceptive and antiandrogen in patients with severe hirsutism causing emotional distress and/or in patients used oral contraceptives in the past not resulted in sufficient improvement. Avoid initiating combination therapy as a standard first-line approach. C Consider adding an antiandrogen if patient-important hirsutism remains despite 6 months of monotherapy with an oral contraceptive. C Topical eflornithine cream: https://web.pathway.md/diseases/recFbebjJD55qgBNf 3/5 6/24/23, 12:44 PM Hirsutism Pathway As per ACOG 2018 guidelines, consider adding eflornithine to laser treatment for the treatment of hirsutism. B As per ES 2018 guidelines, consider adding eflornithine topical cream during treatment in patients desiring more rapid response to photoepilation. C Insulin-lowering drugs: avoid using insulin-lowering drugs for the sole indication of treating hirsutism. D Gonadotropin-releasing hormone agonists: avoid using GnRH agonists except in patients with severe forms of hyperandrogenemia (such as ovarian hyperthecosis) having a suboptimal response to oral contraceptives and antiandrogens. D 5. Nonpharmacologic interventions Lifestyle modifications: advise lifestyle changes in patients with hirsutism and obesity, including patients with PCOS. B 6. Therapeutic procedures Hair removal: As per ES 2018 guidelines, consider offering photoepilation in patients choosing hair removal therapy with unwanted auburn, brown or black hair, and electrolysis in patients with white or blonde hair. C Show 2 more As per SOGC 2017 guidelines: Offer laser hair removal and electrolysis for permanent hair reduction, recognizing that hair growth tends to recur after stopping medical therapy. B Consider offering mechanical hair removal and/or topical therapy as first-line therapy or as an adjuvant to medical therapy. B 7. Specific circumstances Adolescent patients: recognize that adolescents may present with hirsutism but the diagnosis of PCOS in young patients is controversial given that the diagnostic features of PCOS may be normal pubertal physiologic events. B 8. Follow-up and surveillance Indications for specialist referral: Refer patients to an endocrinologist or reproductive endocrinologist for evaluation in the presence of any of the following: virilization https://web.pathway.md/diseases/recFbebjJD55qgBNf 4/5 6/24/23, 12:44 PM Hirsutism Pathway serum testosterone or DHEA sulfate levels more than twice the ULN signs or symptoms of Cushing's syndrome early menstrual phase serum 17-hydroxyprogesterone levels > 6 nmol/L. B References 1. Kimberly Liu, Tarek Motan, Paul Claman. No. 350 Hirsutism: Evaluation and Treatment. J Obstet Gynaecol Can. 2017 Nov;39 11 1054 1068. Open 2. Martin KA, Anderson RR, Chang RJ et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Apr 1;103 4 1233 1257. Open 3. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins Gynecology. ACOG Practice Bulletin No. 194 Polycystic Ovary Syndrome. Obstet Gynecol. 2018 Jun;131 6):e157-e171. Open https://web.pathway.md/diseases/recFbebjJD55qgBNf 5/5

Guideline sources The following summarized guidelines for the evaluation and management of histoplasmosis are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA/CDC/NIH/HIVMA 2023), the European Confederation of Medical Mycology (ECMM/ISHAM 2021), the Pan American Health Organization (PAHO/WHO 2020), the American Thoracic Society (ATS 2011), and the Infectious Diseases Society of America (IDSA 2007). 1 2 3 4 5 Guidelines 1. Classification and risk stratification Severity assessment: Define severe or moderately severe histoplasmosis as the presence of at least one sign or symptom involving vital organs: respiratory or circulatory failure neurological signs renal failure coagulation anomalies https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 1/7 6/24/23, 12:45 PM Histoplasmosis Pathway general alteration of the WHO performance status > 2, in which the person is confined to a bed or chair for more than half the waking hours and only capable of limited self-care. Define mild-to-moderate histoplasmosis as signs and symptoms not including the above features defining severe or moderately severe histoplasmosis. 2. Diagnostic investigations Antigen testing: obtain circulating Histoplasma antigens for the diagnosis of disseminated histoplasmosis in patients with human immunodeficiency virus infection. B 3. Diagnostic procedures Histopathological analysis: obtain tissue for the histopathological diagnosis of histoplasmosis using fungal stains (Grocott methenamine silver staining) and fungal culture whenever possible. E 4. Medical management Management of acute pulmonary histoplasmosis, mild-to-moderate: As per ATS 2011 guidelines, do not initiate antifungal treatment in asymptomatic patients. D Show 2 more As per IDSA 2007 guidelines: Avoid initiating antifungal treatment in patients with mild-to-moderate pulmonary histoplasmosis. D Administer itraconazole 200 mg TID for 3 days and then 200 mg once daily or BID for 6-12 weeks in patients continuing to experience symptoms for > 1 month. B Management of acute pulmonary histoplasmosis, severe: As per ATS 2011 guidelines: Administer amphotericin B 0.7 mg/kg/day until clinical improvement is observed or until a cumulative dose of 2 g of amphotericin B is reached in patients with severe pulmonary histoplasmosis, such as patients with life-threatening pulmonary infections, including severe gas-exchange abnormality, severe toxicity, and rapid progression. B Consider initiating maintenance itraconazole 200 mg BID for at least 12 weeks in patients improving clinically after initial treatment with amphotericin B. B Consider administering adjunctive systemic corticosteroids (prednisone 40-60 mg/day or equivalent for 1-2 weeks) in patients with severe pulmonary histoplasmosis with diffuse pulmonary infiltrates or massive granulomatous mediastinitis. C As per IDSA 2007 guidelines: Administer lipid formulation of amphotericin B (3.0-5.0 mg/kg/day IV for 1-2 weeks, followed by itraconazole 200 mg TID for 3 days and then 200 mg BID, for a total of 12 weeks) in patients https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 2/7 6/24/23, 12:45 PM Histoplasmosis Pathway with moderately severe to severe acute pulmonary histoplasmosis. Administer deoxycholate formulation of amphotericin B (0.7-1.0 mg/kg/day IV) as an alternative to a lipid formulation in patients at low risk for nephrotoxicity. B Administer methylprednisolone (0.5-1.0 mg/kg/day IV) during the first 1-2 weeks of antifungal therapy in patients developing respiratory complications, including hypoxemia or significant respiratory distress. B Management of progressive disseminated histoplasmosis: administer liposomal amphotericin B 3.0 mg/kg/day for 1-2 weeks, followed by oral itraconazole 200 mg TID for 3 days and then 200 mg BID, for a total of at least 12 months, in patients moderately severe to severe disease. A Show 6 more Management of chronic cavitary pulmonary histoplasmosis: Initiate itraconazole 200 mg TID for 3 days and then once daily or BID for at least 1 year in patients with chronic cavitary pulmonary histoplasmosis. B Measure blood levels of itraconazole after the patient has been receiving it for at least 2 weeks to ensure adequate drug exposure. B Management of pulmonary nodules: As per ATS 2011 guidelines, do not initiate antifungal treatment in asymptomatic patients with pulmonary nodules if Histoplasma cannot be cultured. D As per IDSA 2007 guidelines, do not initiate antifungal treatment in patients with pulmonary nodules (histoplasmomas). D Management of broncholithiasis: As per ATS 2011 guidelines, do not use antifungals in most patients with broncholithiasis. D Show 2 more As per IDSA 2007 guidelines: Do not initiate antifungal treatment in patients with broncholithiasis. D Perform bronchoscopic or surgical removal of the broncholith. B Management of pericarditis: administer NSAIDs in patients with mild pericarditis. B Show 3 more Management of mediastinal lymphadenitis: avoid initiating antifungal treatment in patients with mediastinal lymphadenitis. D Show 2 more Management of mediastinal granuloma: Avoid initiating antifungal treatment in patients with mediastinal granuloma. D Administer itraconazole 200 mg TID for 3 days and then once daily or BID for 6-12 weeks in symptomatic patients. B Management of fibrosing mediastinitis: As per ATS 2011 guidelines: Administer itraconazole 200 mg BID for 12 weeks in patients with fibrosing mediastinitis. Consider administering longer treatment, up to 12 months, in patients with radiographic or https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 3/7 6/24/23, 12:45 PM Histoplasmosis Pathway physiologic improvement after an initial 12 weeks of therapy. B Do not use antifibrotic agents or systemic corticosteroids. B Consider performing placement of intravascular stents, C bronchoplasty, and/or placement of endobronchial stents, if appropriate expertise is available, in selected patients with fibrosing mediastinitis and severe vascular or airway compromise. Consider using removable stents initially if a decision is made to place a stent. C As per IDSA 2007 guidelines, do not initiate antifungal treatment in patients with mediastinal fibrosis. D Show 2 more Management of CNS histoplasmosis: Administer liposomal amphotericin B (5.0 mg/kg/day for a total of 175 mg/kg given over 4-6 weeks) followed by itraconazole (200 mg BID or TID) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels. B Monitor blood levels of itraconazole to ensure adequate drug exposure. B Management of rheumatologic syndromes: administer NSAIDs in patients with mild symptoms. B Show 2 more 5. Specific circumstances Pediatric patients: apply the same treatment indications and regimens in pediatric patients similar to adult patients, except that amphotericin B deoxycholate (1.0 mg/kg/day) is usually well tolerated and lipid preparations are not preferred. B Show 7 more Pregnant patients: Administer lipid formulation amphotericin B (3.0-5.0 mg/kg/day for 4-6 weeks) in pregnant patients. Administer deoxycholate formulation of amphotericin B (0.7-1.0 mg/kg daily) as an alternative to a lipid formulation in patients at low risk for nephrotoxicity. B Initiate treatment with amphotericin B deoxycholate (1.0 mg/kg/day for 4 weeks) if the newborn shows evidence of infection. B Patients with HIV, primary prophylaxis: As per IDSA/HIVMA/CDC/NIH 2023 guidelines, initiate primary prophylaxis in patients with a cluster of differentiation count < 150 cells/mm and at high risk because of occupational exposure or residence in a community with a hyperendemic rate of histoplasmosis (> 10 cases/100 patient-years). B Show 3 more As per IDSA 2007 guidelines: Initiate primary prophylaxis with itraconazole (200 mg daily) in patients with human immunodeficiency virus infection with a cluster of differentiation count < 150 cells/mm in https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 4/7 6/24/23, 12:45 PM Histoplasmosis Pathway specific areas of endemicity where the incidence of histoplasmosis is > 10 cases per 100 patient-years. A Consider initiating primary prophylaxis with itraconazole (200 mg daily) in specific circumstances in other immunosuppressed patients. C Patients with HIV, management of mild-to-moderate pulmonary disease: As per IDSA/HIVMA/CDC/NIH 2023 guidelines: Administer itraconazole 200 mg PO TID for 3 days, then 200 mg PO BID for 12 months, B with dose adjustment based on interactions with antiretroviral therapy and itraconazole serum concentration, as the preferred induction and maintenance therapy in patients with less severe disseminated disease. B Administer any of the following as alternative therapy: posaconazole, ER tablet 300 mg PO BID for 1 day, then 300 mg PO once daily B voriconazole 400 mg PO BID for 1 day, then 200 mg PO BID B fluconazole 800 mg PO once daily. B As per ISHAM/ECMM 2021 guidelines, administer itraconazole for induction therapy in patients with less severe infection. E As per WHO/PAHO 2020 guidelines, administer itraconazole 200 mg TID for 3 days and then 200 mg BID in patients with human immunodeficiency virus and mild-to-moderate histoplasmosis. B As per ATS 2011 guidelines, administer itraconazole 200 mg TID for 3 days, followed by 200 mg BID for 12 months, in patients with mild-to-moderate histoplasmosis. B Patients with HIV, management of severe pulmonary disease: As per IDSA/HIVMA/CDC/NIH 2023 guidelines: Administer liposomal amphotericin B 3 mg/kg IV daily as the preferred induction therapy for 2 weeks or until clinically improved in patients with moderately severe to severe disseminated disease. A Administer amphotericin B lipid complex 5 mg/kg IV daily as an alternative therapy. B Initiate itraconazole 200 mg PO thrice times daily for 3 days, then BID for 12 months, B with dosage adjustment based on interactions with antiretroviral therapy and itraconazole serum concentration, as maintenance therapy. B As per ISHAM/ECMM 2021 guidelines, administer liposomal amphotericin B as first-line induction therapy in patients with advanced human immunodeficiency virus infection and moderate- to- severe histoplasmosis. Administer other amphotericin B formulations if liposomal amphotericin B is not available. E As per WHO/PAHO 2020 guidelines, initiate antiretroviral therapy as soon as possible in patients with disseminated histoplasmosis if CNS involvement is not suspected or proven. B Show 4 more As per ATS 2011 guidelines, administer amphotericin B 0.7-1.0 mg/kg/day (or a lipid formulation of amphotericin 3-5 mg/kg/day) until clinical improvement is observed or a cumulative dose of 2 g of amphotericin B is reached in patients with severe progressive disseminated histoplasmosis https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 5/7 6/24/23, 12:45 PM Histoplasmosis Pathway requiring hospitalization. Consider administering itraconazole 200 mg BID for 12 months in patients improving clinically after initial treatment with amphotericin B. B Show 3 more Patients with HIV (management of chronic pulmonary disease): Initiate itraconazole 200 mg BID for 12-24 months in patients with chronic pulmonary histoplasmosis. B Initiate amphotericin B over itraconazole as initial therapy in patients with severe chronic pulmonary histoplasmosis. B Patients with HIV (management of meningeal disease): administer liposomal amphotericin B 5 mg/kg IV daily as induction therapy (4-6 weeks) for the management of meningeal disease in immunocompromised patients. B Show 2 more Patients with HIV (therapeutic drug monitoring): measure itraconazole serum concentrations in all patients after 2 weeks of therapy to ensure adequate absorption and to assess changes in hepatic metabolism due to drug interactions. B Patients with HIV (management of TB coinfection): treat tuberculosis according to the WHO guidelines in patients with human immunodeficiency virus with tuberculosis and histoplasmosis coinfection. B Patients with HIV (secondary prophylaxis): Initiate long-term suppressive therapy in patients with any of the following: severe disseminated or CNS infection after completing 12 months of treatment B relapse despite appropriate initial therapy. B Show 4 more 6. Preventative measures Antifungal prophylaxis: As per ATS 2023 guidelines, initiate primary prophylaxis in patients with a cluster of differentiation count < 150 cells/mm and at high risk because of occupational exposure or residence in a community with a hyperendemic rate of histoplasmosis (> 10 cases/100 patient- years). B Show 3 more As per IDSA 2007 guidelines: Initiate prophylaxis with itraconazole (200 mg/day) in patients with human immunodeficiency virus infection and a CD4 count < 150 cells/ L residing in areas with an incidence of histoplasmosis of > 10 cases per 100 patient-years. A Consider initiating prophylaxis with itraconazole (200 mg/day) in specific circumstances in other immunosuppressed patients. C https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 6/7 6/24/23, 12:45 PM Histoplasmosis Pathway References 1. L Joseph Wheat, Alison G Freifeld, Martin B Kleiman et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007 Oct 1;45 7 807 25. Open 2. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 3. Andrew H Limper, Kenneth S Knox, George A Sarosi et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183 1 96 128. Open 4. George R Thompson rd, Thuy Le, Ariya Chindamporn et al. Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology. Lancet Infect Dis. 2021 Dec;21 12):e364-e374. Open 5. No authors listed. Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV Internet]. Geneva: World Health Organization; 2020. Open 6. James H Diaz. Environmental and Wilderness-Related Risk Factors for Histoplasmosis: More Than Bats in Caves. Wilderness Environ Med. 2018 Dec;29 4 531 540. Open 7. Paige A Armstrong, Brendan R Jackson, Dirk Haselow et al. Multistate Epidemiology of Histoplasmosis, United States, 2011 2014. Emerg Infect Dis. 2018 Mar;24 3 425 431. Open https://web.pathway.md/diseases/recuIBHLjJKnZaHrS 7/7

Guideline sources The following summarized guidelines for the evaluation and management of HIV-associated malignancies are prepared by our editorial team based on guidelines from the British HIV Association (BHIVA 2014). 1 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines 1. Diagnostic investigations Evaluation for Kaposi sarcoma: Confirm Kaposi sarcoma histologically. B Consider avoiding routine CT scans, bronchoscopy or gastrointestinal endoscopy in the absence of symptoms. D https://web.pathway.md/diseases/recwxqzfYkJIRiFly 1/4 6/24/23, 12:31 PM HIV-associated malignancies Pathway Evaluation for Castleman's disease: consider obtaining histological confirmation by immunocytochemical staining for HHV-8 and IgM lambda. C Evaluation for anal cancer: perform examination under anesthetic of the anal canal and rectum with biopsy in all suspected cases. B 2. Medical management Highly active antiretroviral therapy: initiate HAART in all patients diagnosed with Kaposi sarcoma. B Irradiation of blood products: use irradiated blood products for patients with human immunodeficiency virus infection and Hodgkin's lymphoma who require blood products. B 3. Specific circumstances Patients with Kaposi's sarcoma: initiate chemotherapy along with HAART for patients with T1 advanced stage Kaposi's sarcoma. B Show 3 more Patients with Hodgkin's lymphoma: administer doxorubicin, bleomycin, vinblastine, and dacarbazine 2-4 + involved field radiation therapy 20-30 Gy for early-favorable Hodgkin's lymphoma. B Patients with diffuse large-B cell lymphoma: administer chemotherapy regimens (such as CHOP or EPOCH) used in human immunodeficiency virus-negative patients for first-line treatment of diffuse large-B cell lymphoma in human immunodeficiency virus-positive patients. B Show 3 more Patients with Burkitt's lymphoma: administer first-line treatment of Burkitt's lymphoma in human immunodeficiency virus-infected individuals with regimens such as cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). B Patients with multicentric Castleman's disease: administer rituximab as the first-line treatment for multicentric Castleman's disease. B Patients with primary central nervous system lymphoma: place all patients with primary CNS lymphoma on HAART if not already on it. B Patients with primary effusion lymphoma: consider offering first-line treatment of primary effusion lymphoma in human immunodeficiency virus-infected individuals with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimens. No comparative studies have been performed and there is no optimal gold-standard therapy. C Patients with plasmablastic lymphoma: initiate HAART with systemic anthracycline-containing chemotherapy as first-line therapy for patients with plasmablastic lymphoma. B https://web.pathway.md/diseases/recwxqzfYkJIRiFly 2/4 6/24/23, 12:31 PM HIV-associated malignancies Pathway Patients with relapsed/refractory aggressive lymphoma: administer a second-line chemotherapy regimen (level of evidence 1C), which may contain platinum, to patients deemed fit for intensive chemotherapy with relapsed/refractory aggressive AIDS-related lymphoma. B Patients with anal cancer: administer chemoradiotherapy with 5-fluorouracil and mitomycin C. A Patients with cervical intraepithelial neoplasia and cervical cancer: advise all women newly diagnosed with human immunodeficiency virus to have cervical surveillance performed by, or in conjunction with, the medical team managing their human immunodeficiency virus infection (level of evidence 1B). Perform an initial colposcopy and annual cytology if resources permit. B Patients with non-AIDS-defining malignancies: consider treating germ cell tumours of the testis in an identical manner regardless of human immunodeficiency virus status. C 4. Preventative measures Immunizations: Provide influenza immunization to all patients with HIV-associated malignancies on an annual basis. B Provide pneumococcal immunization and HBV immunization. B Prophylaxis against opportunistic infections: initiate prophylaxis against P. jirovecii pneumonia in patients with HIV and a CD4 cell count < 200 cells/uL. A 5. Follow-up and surveillance Indications for referral to specialized centers: refer all patients with HIV and malignancy to centers that have developed expertise in the management of these diseases. B Consideration for enrolment in clinical trials: screen all patients for enrolment in clinical trials, if appropriate. B Monitoring for patients with Hodgkin's lymphoma: perform assessment of response after treatment bypositron emission tomography scan and bone marrow biopsy. B Monitoring for patients with multicentric Castleman's disease: consider a rise in plasma HHV8 level to be predictive of relapse. C References 1. Bower M, Palfreeman A, Alfa-Wali M et al. British HIV Association guidelines for HIV-associated malignancies 2014. HIV Med. 2014 Mar;15 Suppl 2 1 92. Open 2. Robert Yarchoan, Thomas S Uldrick. HIV Associated Cancers and Related Diseases. N Engl J Med. 2018 Mar 15;378 11 1029 1041. Open https://web.pathway.md/diseases/recwxqzfYkJIRiFly 3/4 6/24/23, 12:31 PM HIV-associated malignancies Pathway 3. Edgar P Simard, Ruth M Pfeiffer, Eric A Engels. Mortality due to cancer among people with AIDS a novel approach using registry-linkage data and population attributable risk methods. AIDS. 2012 Jun 19;26 10 1311 8. Open https://web.pathway.md/diseases/recwxqzfYkJIRiFly 4/4

Guideline sources The following summarized guidelines for the evaluation and management of Hodgkin's lymphoma (HL) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2014). 2 5 6 7 8 8 Definition HL is a rare lymphatic neoplasm, typically of B-cell origin, characterized by large malignant lymphoid cells, and Reed-Sternberg cells. 5 Epidemiology HL is most frequently caused by the EBV. Other causes include tuberculosis and genetic factors (HLA class II polymorphisms). 7 Pathophysiology HL incidence in the United States is estimated at 3.23 per 100,000 people per year. 6 Disease course https://web.pathway.md/diseases/recbCbpohsw9AgeZT 1/5 6/24/23, 12:45 PM Hodgkin's lymphoma Pathway Clinical manifestations include painless lymphadenopathy enlarging over months, mainly involving the mediastinum, left neck node, right neck node, splenic, axillary, abdominal, hilar, or inguinofemoral nodes in descending order. The clinically occult disease is characterized by severe unremitting pruritus without obvious skin pathology. B symptoms include fever, night sweats, and unexplained weight loss > 10% of body weight. Alcohol-induced lymph node pain is highly specific for HL. 8 Prognosis and risk of recurrence Prognosis is determined by disease stage (i.e. best prognosis in early-stage HL) and pathology (i.e. better prognosis in Nodular sclerosis cHL). 8 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines 1. Classification and risk stratification Severity classification: Classify patients with early-stage HL as having favorable or unfavorable disease. A Classify patients with advanced stage HL using the Hasenclever/International Prognostic Score. A 2. Diagnostic investigations Pretreatment blood tests: obtain pre-treatment blood evaluation, which should include human immunodeficiency virus serology. A Computed tomography of the neck to pelvis: obtain staging with contrast-enhanced CT of the neck to pelvis. A Pretreatment positron emission tomography: obtain positron emission tomography/CT for pre- treatment staging when clinically feasible. B Interim positron emission tomography: obtain interim positron emission tomography as it is highly predictive of outcome in patients treated with adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine. A 3. Diagnostic procedures https://web.pathway.md/diseases/recbCbpohsw9AgeZT 2/5 6/24/23, 12:45 PM Hodgkin's lymphoma Pathway Tissue biopsy: perform biopsy assessment or close clinical/radiological surveillance for early progression in patients who remain positron emission tomography-positive on completion of therapy. B 4. Medical management ABVD regimen: administer doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and radiotherapy (20 Gy) as standard of care in patients with favorable early stage HL. A Concurrent chemoradiation: initiate 4 3 adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine and 30 Gy radiotherapy as the standard of care for unfavorable early stage HL. A Radiotherapy: avoid omitting radiotherapy in patients presenting with bulky disease. D BEACOPP regimen: administer either 6-8 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine or six cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) to patients 16-60 years of age with advanced stage HL. A Irradiated blood products: administer irradiated blood products for life. B 5. Nonpharmacologic interventions Lifestyle modification: offer regular lifestyle advice to reduce secondary neoplasms and cardiovascular risk. Advise complete avoidance of smoking and carefully manage cardiovascular risk factors, such as hypertension, diabetes mellitus and dyslipidemia. B 6. Therapeutic procedures Pretreatment semen cryopreservation: offer pre-treatment semen cryopreservation, if possible, to male patients with HL. A 7. Specific circumstances Pregnant patients: co-manage patients closely with a specialized obstetric/fetal medicine unit. B Show 4 more Elderly patients: assess elderly patients formally to receive combination chemotherapy with a comorbidity assessment tool, to distinguish frail' from non-frail' patients. B 8. Follow-up and surveillance Indications for specialist referral: consider pre-treatment consultation with a fertility specialist for female patients with HL. B https://web.pathway.md/diseases/recbCbpohsw9AgeZT 3/5 6/24/23, 12:45 PM Hodgkin's lymphoma Pathway Serial clinical assessment: follow patients with intermittent outpatient clinical review for 2-5 years following first-line therapy. B Serial imaging assessment: routine surveillance CT or positron emission tomography/CT imaging have no proven role in patients who are otherwise well following first line therapy. B Screening for secondary malignancies: educate hodgkin's lymphoma patients that they are at an increased lifetime risk of second neoplasms, cardiovascular and pulmonary disease and infertility. A Serial laboratory assessment: monitor thyroid function regularly in patients who have had radiotherapy to the neck and upper mediastinum. A References 1. Eichenauer DA, Aleman BMP, Andr M et al. Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Suppl 4):iv19-iv29. Open 2. Follows GA, Ardeshna KM, Barrington SF et al. Guidelines for the first line management of classical Hodgkin lymphoma. Br J Haematol. 2014 Jul;166 1 34 49. Open 3. Hoppe RT, Advani RH, Ai WZ et al. NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018. J Natl Compr Canc Netw. 2018 Mar;16 3 245 254. Open 4. Eichenauer DA, Engert A, Andr M et al. Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 Suppl 3:iii70 5. Open 5. Stephen M Ansell. Hodgkin Lymphoma: Diagnosis and Treatment. 2015 Nov;90 11 1574 83.2015 Nov;90 11 1574 83. Open 6. Linghui Zhou, Yujiao Deng, Na Li et al. Global, regional, and national burden of Hodgkin lymphoma from 1990 to 2017 estimates from the 2017 Global Burden of Disease study. 2019 Oct 22;12 1 107.2019 Oct 22;12 1 107. Open 7. Massimiliano Salati, Marina Cesaretti, Matteo Macchia et al. Epidemiological Overview of Hodgkin Lymphoma across the Mediterranean Basin. 2014 Jul 1;6 1):e2014048.2014 Jul 1;6 1):e2014048. Open 8. Satish Shanbhag, Richard F Ambinder. Hodgkin lymphoma: A review and update on recent progress. 2018 Mar;68 2 116 132.2018 Mar;68 2 116 132. Open 9. Collins GP, Parker AN, Pocock C et al. Guideline on the management of primary resistant and relapsed classical Hodgkin lymphoma. Br J Haematol. 2014 Jan;164 1 39 52. Open 10. Hoppe RT, Advani RH, Ai WZ et al. NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018. J Natl Compr Canc Netw. 2018 Mar;16 3 245 254. Open 11. Satish Shanbhag, Richard F Ambinder. Hodgkin lymphoma: A review and update on recent progress. CA Cancer J Clin. 2018 Mar;68 2 116 132. Open 12. Massimiliano Salati, Marina Cesaretti, Matteo Macchia et al. Epidemiological Overview of Hodgkin Lymphoma across the Mediterranean Basin. Mediterr J Hematol Infect Dis. 2014 Jul 1;6 1):e2014048. Open https://web.pathway.md/diseases/recbCbpohsw9AgeZT 4/5 6/24/23, 12:45 PM Hodgkin's lymphoma Pathway 13. Pareen Shenoy, Alison Maggioncalda, Neha Malik et al. Incidence patterns and outcomes for hodgkin lymphoma patients in the United States. Adv Hematol. 2011;2011 725219. Open 14. David Perez-Callejo, Lorea Zurutuza, Ana Royuela et al. Long-term follow up of Hodgkin lymphoma. Oncotarget. 2018 Feb 3;9 14 11638 11645. Open 15. Richard T Hoppe, Ranjana H Advani, Weiyun Z Ai et al. Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020 Jun;18 6 755 781. Open 16. M Hutchings, M Ladetto, C Buske et al. ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients. Ann Oncol. 2018 Aug 1;29 8 1687 1700. Open 17. Abraham S Kanate, Ambuj Kumar, Peter Dreger et al. Maintenance Therapies for Hodgkin and Non- Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol. 2019 May 1;5 5 715 722. Open 18. Steven H Kroft, Cordelia E Sever, Adam Bagg et al. Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists. Arch Pathol Lab Med. 2021 Mar 1;145 3 269 290. Open 19. C Buske, M Hutchings, M Ladetto et al. ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018 Mar 1;29 3 544 562. Open 20. David J Straus, Monika D ugosz-Danecka, Joseph M Connors et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma ECHELON 1 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8 6):e410-e421. Open https://web.pathway.md/diseases/recbCbpohsw9AgeZT 5/5

Guideline sources The following summarized guidelines for the evaluation and management of home oxygen are prepared by our editorial team based on guidelines from the British Thoracic Society (BTS 2015). 1 Guidelines 1. Screening and diagnosis Indications for assessment: refer patients with a resting oxygen saturation of 92% for a blood gas assessment in order to assess eligibility for long-term oxygen therapy. B Show 2 more 2. Diagnostic investigations Blood gas analysis: obtain an arterial blood gas in patients being assessed for long-term oxygen therapy. A Show 2 more Pulse oximetry: https://web.pathway.md/diseases/recnoQqrXqiEQL0qE 1/5 6/24/23, 12:44 PM Home oxygen Pathway Avoid using pulse oximetry alone to assess the need for long-term oxygen therapy. D Consider using a combination of capillary blood gas and pulse oximetry to assess the need for long-term oxygen therapy in patients in whom arterial blood gas sampling is not possible. Some patients may receive long-term oxygen therapy unnecessarily using this approach, but it is unlikely that any patient would be inappropriately denied long-term oxygen therapy. 3. Medical management General principles: order long-term oxygen therapy for a minimum of 15 hours per day; up to 24 hours per day may be of additional benefit. B Show 2 more Assessment of stability: Avoid ordering long-term oxygen therapy at the time of an acute exacerbation of a patient's underlying condition. Consider assessing patients for long-term oxygen therapy after < 8 weeks of stability, if they exacerbate frequently and are unable to achieve a period of stability lasting 8 weeks. If long- term oxygen therapy is ordered for such patients, they should be counselled that oxygen therapy may no longer be required once they achieve a more stable state. Smoking cessation: Advise smoking cessation prior to ordering home oxygen, and at each follow-up visit if the patient continues to smoke. B Inform patients that the benefit of long-term oxygen therapy may be reduced if tobacco use is not discontinued. B Oxygen delivery device: Use nasal cannulae as the oxygen delivery device of choice for patients requiring home oxygen therapy. Some patients may benefit from or prefer a Venturi mask system. B Consider using a Venturi mask as the oxygen delivery device in patients in whom there are concerns about existing or developing hypercapnic respiratory failure, in patients with a high resting respiratory rate, or in patients with cognitive impairment. Oxygen humidification: Order humidified oxygen for patients receiving oxygen via a tracheostomy. Avoid routinely ordering humidification of home oxygen for patients who do not have tracheostomies. D Oxygen carrying equipment: offer wheeled devices or backpacks to patients in whom these devices can improve ambulation and quality of life. B Nocturnal oxygen therapy: avoid offering nocturnal oxygen therapy to patients with COPD who have nocturnal hypoxemia, but fail to meet criteria for long-term oxygen therapy. D Ambulatory oxygen therapy: offer ambulatory oxygen therapy to patients who are undertaking exercise in the context of a pulmonary rehabilitation program. B https://web.pathway.md/diseases/recnoQqrXqiEQL0qE 2/5 6/24/23, 12:44 PM Home oxygen Pathway Show 2 more Palliative oxygen therapy: Avoid offering palliative oxygen therapy to patients with intractable breathlessness who are not hypoxemic, or have mild hypoxemia above established thresholds (SpO 92%). D Assess patients with intractable breathlessness due to cancer or end-stage cardiorespiratory disease for a trial of treatment with opioids from an appropriately trained healthcare professional. A Short-burst oxygen therapy: avoid offering short-burst oxygen therapy for use prior to or following exercise in patients with COPD. D 4. Specific circumstances Patients with chronic obstructive pulmonary disease: offer long-term oxygen therapy to patients with stable COPD and a resting PaO 55 mmHg (7.3 kPa). A Show 2 more Patients with interstitial lung disease: Offer long-term oxygen therapy to patients with ILD and a resting PaO 55 mmHg (7.3 kPa). B Offer long-term oxygen therapy to patients with ILD, a resting PaO 60 mmHg (8 kPa), and either peripheral edema, polycythemia (hematocrit 55%), or evidence of pulmonary hypertension. B Patients with cystic fibrosis: Offer long-term oxygen therapy to patients with cystic fibrosis and a resting PaO 55 mmHg (7.3 kPa). B Offer long-term oxygen therapy to patients with cystic fibrosis, a resting PaO 60 mmHg (8 kPa), and either peripheral edema, polycythemia (hematocrit 55%), or evidence of pulmonary hypertension. B Patients with pulmonary hypertension: offer long-term oxygen therapy to patients with pulmonary hypertension (including idiopathic pulmonary hypertension) and a resting PaO 60 mmHg (8 kPa). B Patients with neuromuscular or chest wall disorders: offer noninvasive ventilation as the treatment of choice for patients with hypercapnic respiratory failure due to chest wall or neuromuscular disease. Consider additional long-term oxygen therapy in patients in whom hypoxemia is not corrected with noninvasive ventilation. B Patients with heart failure (long-term oxygen therapy): Offer long-term oxygen therapy to patients with advanced cardiac failure and a resting PaO 55 mmHg (7.3 kPa). B Offer long-term oxygen therapy to patients with advanced cardiac failure, a resting PaO 60 mmHg (8 kPa), and evidence of peripheral edema, polycythemia (hematocrit 55%), or pulmonary hypertension. B https://web.pathway.md/diseases/recnoQqrXqiEQL0qE 3/5 6/24/23, 12:44 PM Home oxygen Pathway Patients with heart failure (nocturnal oxygen therapy): consider offering nocturnal oxygen therapy to patients with severe HF who do not fulfill indications for long-term oxygen therapy, but have evidence of sleep disordered breathing leading to daytime symptoms, after other causes of nocturnal desaturation have been excluded and HF treatment has been optimized. Consider noninvasive ventilatory support in this patient population. C Patients with obstructive sleep apnea: Avoid ordering nocturnal oxygen therapy alone in patients with obstructive sleep apnea, obesity hypoventilation syndrome, or overlap syndrome. D Combine oxygen with noninvasive ventilatory support in patients with evidence of established ventilatory failure in whom oxygen is indicated. B Patients who smoke: Assess the risks of offering long-term oxygen therapy to active smokers on a case-by-case basis, taking into account the patient's attitude toward risks, smoking behavior, and a home visit to assess the patient's home situation. Consider not offering long-term oxygen therapy to patients who continue to smoke if the risks are too high. Give particular consideration to risks to children and risks to neighbors in multiple occupancy dwellings. Avoid prescribing therapy where there is reasonable doubt. 5. Patient education General counseling: arrange for the patient to receive formal education on long-term oxygen therapy by a specialist home oxygen assessment team, in order to ensure compliance with therapy. B Oxygen transport: inform patients that oxygen cylinders should be secured with a seat belt, in the foot-well, or car boot, possibly using a cylinder box, when transported in cars or trucks. Liquid oxygen should always be transported in an upright position. A warning triangle may be displayed and insurance companies should be informed. Safe oxygen use: provide written information on the dangers of using home oxygen within the vicinity of any naked flame, such as pilot lights, cookers, gas fires, and candles. B Show 2 more 6. Follow-up and surveillance Assessment of treatment response: obtain an arterial blood gas after oxygen titration is complete in patients under long-term oxygen therapy, in order to determine whether adequate oxygenation has been achieved without precipitating respiratory acidosis and/or worsening hypercapnia. B Show 3 more Follow-up clinical assessment: schedule follow-up within 4 weeks in patients who develop respiratory acidosis and/or a rise in PaCO of > 7.5 mmHg (> 1 kPa) during assessment for long- https://web.pathway.md/diseases/recnoQqrXqiEQL0qE 4/5 6/24/23, 12:44 PM Home oxygen Pathway term oxygen therapy, as they may have clinically unstable disease. Show 2 more Follow-up home visits: Schedule a home visit within 4 weeks, conducted by a specialist nurse or healthcare professional with experience of domiciliary oxygen therapy, for all patients in whom long-term oxygen therapy is initiated. The visit provides an opportunity to highlight potential risks and should be used to reinforce education and offer support to the patient and carer. Compliance may be checked, along with smoking status, symptoms of hypercapnia and oxygen saturations on oxygen to check that oxygen is therapeutic. Ensure that follow-up visits are conducted by a specialist home oxygen assessment team with the necessary skills to deliver patient education and manage withdrawal of home oxygen. B References 1. Hardinge M, Annandale J, Bourne S et al. British Thoracic Society guidelines for home oxygen use in adults. Thorax. 2015 Jun;70 Suppl 1:i1 43. Open 2. Susan S Jacobs, Jerry A Krishnan, David J Lederer et al. Home Oxygen Therapy for Adults with Chronic Lung Disease. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2020 Nov 15;202 10):e121-e141. Open 3. Sagrario Mayoralas Alises, Catia Caneiras, Salvador D az-Lobato. A telephone-based survey of current trends, habits and beliefs in patients receiving portable oxygen therapy in Madrid, Spain. ERJ Open Res. 2019 May 20;5 2 00059 2018. Open https://web.pathway.md/diseases/recnoQqrXqiEQL0qE 5/5

Guideline sources The following summarized guidelines for the management of hospital-acquired pneumonia (HAP) are prepared by our editorial team based on guidelines from the European Society of Intensive Care Medicine (ESICM/ALAT/ERS/ESCMID 2017), the Infectious Diseases Society of America (IDSA/ATS 2016), and the Infectious Diseases Society of America (IDSA 2011). 1 2 3 4 4 5 6 7 Definition HAP (nosocomial pneumonia) is a lower respiratory infection occurring in patients at least 48 hours after admission to the hospital, or within 14 days after discharge from the hospital. 4 Epidemiology The three main infection routes include inhalation (most common), aspiration and hematogenous dissemination (rare). HAP is most frequently caused by S. aureus (especially, methicillin-resistant S. aureus), Pseudomonas species (especially P. aeruginosa), Acinetobacter species, E. coli, and Klebsiella species (including ESBL-producing and extensively drug-resistant Enterobacteriaceae). Other pathogens include S. maltophilia, Chryseobacterium species, E. meningoseptica. 6 Pathophysiology The incidence of HAP (HAP) in the United States is estimated at 363 per 100,000 patient-days. 5 Disease course https://web.pathway.md/diseases/recnrmysH538ONOB7 1/6 6/24/23, 12:45 PM Hospital-acquired pneumonia Pathway Clinical manifestations of HAP are similar to community-acquired pneumonia. Typical pneumonia is characterized by severe malaise, fever, chills, productive cough with purulent sputum (yellow- greenish), dyspnea, and pleuritic chest pain associated with rales and increased tactile fremitus. Atypical HAP presents with extrapulmonary manifestations (eg. myalgia, nervous system impairment, and gastrointestinal symptoms). 4 Prognosis and risk of recurrence Prognosis of HAP is highly dependent on risk factors and comorbidities. However, multidrug- resistant HAP is associated with higher mortality. 7 Guidelines 1. Medical management Initiation of treatment: use clinical criteria alone to decide whether or not to initiate antibiotic therapy in patients with suspected HAP. B Show 2 more Empiric antibiotic therapy, general principles: As per ALAT/ESCMID/ESICM/ERS 2017 guidelines, consider initiating narrow-spectrum antibiotics (ertapenem, ceftriaxone, cefotaxime, moxifloxacin, or levofloxacin) in patients with suspected low risk of resistance (without septic shock, no other risk factors for multidrug- resistant bacteria, and not in hospitals with a high background rate of resistant pathogens) and early-onset HAP. C Show 2 more As per ATS/IDSA 2016 guidelines: Initiate antibiotics with activity against S. aureus, P. aeruginosa, and other Gram-negative bacilli for empiric treatment of patients with HAP. B Consider determining antibiotic dosing using pharmacokinetic and pharmacodynamic data, rather than the manufacturer's prescribing information, in patients with HAP. C Empiric antibiotic therapy (MSSA coverage): Consider administering antibiotics with activity against methicillin-sensitive S. aureus (piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem) for initial empiric treatment of patients with HAP with no risk factors for MRSA infection and not being at high risk of mortality. C Avoid using oxacillin, nafcillin, or cefazolin for empiric therapy if one of the above agents is administered. D Empiric antibiotic therapy, MRSA coverage: As per ATS/IDSA 2016 guidelines: Consider administering an antibiotic with activity against MRSA in patients with HAP at high risk of mortality or with one of the following risk factors for MRSA infection: https://web.pathway.md/diseases/recnrmysH538ONOB7 2/6 6/24/23, 12:45 PM Hospital-acquired pneumonia Pathway prior IV antibiotic use within 90 days hospitalization in a unit where > 20% of S. aureus isolates are methicillin-resistant hospitalization in a unit where the prevalence of MRSA is not known. C Administer vancomycin or linezolid in patients with HAP requiring empiric coverage for MRSA. B As per IDSA 2011 guidelines, consider administering a loading dose of 25-30 mg/kg (actual body weight) of vancomycin in patients with HAP with suspected MRSA infection, may be considered. Consider prolonging the infusion time to 2 hours and administering an H1RA before administration of the loading dose given the risk of red man syndrome and possible anaphylaxis associated with large doses of vancomycin. C Empiric antibiotic therapy (Pseudomonas coverage): Consider administering antibiotics from 2 different classes with activity against P. aeruginosa in patients with HAP at high risk of mortality or risk factors for Pseudomonas or other Gram- negative infection (such as prior IV antibiotic use within 90 days). C Do not use an aminoglycoside as the sole empiric antipseudomonal agent in patients with HAP. D Definitive antibiotic therapy (general principles): Tailor antibiotic therapy to the susceptibility data of the etiological pathogen once microbiological and clinical response data become available (usually day 3). E Consider continuing treatment with a single agent based on culture results if the initial treatment was a combination therapy, and consider maintaining definitive combination treatment based on sensitivities in patients with extensively drug-resistant (susceptible to only 1-2 classes of antibiotics)/pandrug-resistant (not susceptible to any antibiotics) nonfermenting Gram-negative bacteria and carbapenem-resistant Enterobacteriaceae isolates. C Definitive antibiotic therapy (MSSA): administer oxacillin, nafcillin, or cefazolin in patients with HAP due to MSSA. B Definitive antibiotic therapy, MRSA: As per ATS/IDSA 2016 guidelines, administer either vancomycin or linezolid in patients with HAP due to MRSA. B As per IDSA 2011 guidelines, administer IV vancomycin or PO/IV linezolid 600 mg BID B or PO/IV clindamycin 600 mg TID B , if the strain is susceptible, for 7-21 days depending on the extent of infection in patients with healthcare-associated pneumonia due to MRSA. B Show 4 more Definitive antibiotic therapy (Pseudomonas aeruginosa): decide on the choice of an antibiotic for definitive therapy based on the results of antimicrobial susceptibility testing in patients with HAP due to P. aeruginosa. B Show 3 more Definitive antibiotic therapy (ESBL-producing pathogens): decide on the choice of an antibiotic for definitive therapy based on the results of antimicrobial susceptibility testing and patient-specific factors in patients with HAP due to ESBL-producing Gram-negative bacilli. B https://web.pathway.md/diseases/recnrmysH538ONOB7 3/6 6/24/23, 12:45 PM Hospital-acquired pneumonia Pathway Definitive antibiotic therapy (carbapenem-resistant pathogens): Administer intravenous polymyxins (colistin or polymyxin B) in patients with HAP due to a carbapenem-resistant pathogen sensitive only to polymyxins. B Consider administering adjunctive inhaled colistin in patients with HAP due to a carbapenem- resistant pathogen sensitive only to polymyxins. C Definitive antibiotic therapy (Acinetobacter species): consider administering either a carbapenem or ampicillin/sulbactam, if the isolate is susceptible to these agents, as definitive antibiotic therapy in patients with HAP due to Acinetobacter species. C Show 4 more Duration of treatment: As per ERS 2017 guidelines, consider completing a 7-8-day course of antibiotic therapy in nonventilated patients with HAP without immunodeficiency, cystic fibrosis, empyema, lung abscess, cavitation, or necrotizing pneumonia and with a good clinical response to therapy, as well as in patients with nonfermenting Gram-negative pathogens, Acinetobacter species, and MRSA with a good clinical response. C Show 2 more As per IDSA 2016 guidelines, complete a 7-day course of antimicrobial therapy in patients with HAP. B Show 3 more 2. Inpatient care Serial clinical assessment: Obtain routine bedside clinical assessment with the following in patients with HAP receiving antibiotic therapy E : temperature monitoring measurement of tracheobronchial secretion volume culture and purulence assessment of tracheobronchial secretions evaluation for CXR resolution WBC count paO2/FiO assessment of 1 clinical scores, such as CPIS, ODIN, SOFA, SAPS II, and APACHE II. Serial laboratory assessment: do not obtain biomarkers (such as CRP, procalcitonin, copeptin, and mid-regional pro-atrial natriuretic peptide) routinely in addition to bedside clinical assessment to predict adverse outcomes and clinical response at 72-96 hours in patients with HAP receiving antibiotic therapy. D Show 2 more 3. Quality improvement https://web.pathway.md/diseases/recnrmysH538ONOB7 4/6 6/24/23, 12:45 PM Hospital-acquired pneumonia Pathway Local susceptibility assessments: ensure regular generation and dissemination of local antibiograms in all hospitals, ideally tailored to their HAP population, if possible. References 1. Catherine Liu, Arnold Bayer, Sara E Cosgrove et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children. Clin Infect Dis. 2011 Feb 1;52 3):e18 55. Open 2. Kalil AC, Metersky ML, Klompas M et al. Management of Adults With Hospital-acquired and Ventilator- associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63 5):e61-e111. Open 3. Antoni Torres, Michael S Niederman, Jean Chastre et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia HAP /ventilator-associated pneumonia VAP of the European Respiratory Society ERS , European Society of Intensive Care Medicine ESICM , European Society of Clinical Microbiology and Infectious Diseases ESCMID and Asociaci n Latinoamericana del T rax ALAT . Eur Respir J. 2017 Sep 10;50 3 1700582. Open 4. Charles W Lanks, Ali I Musani, David W Hsia. Community-acquired Pneumonia and Hospital-acquired Pneumonia. 2019 May;103 3 487 501.2019 May;103 3 487 501. Open 5. Karen K Giuliano, Dian Baker, Barbara Quinn. The epidemiology of nonventilator hospital-acquired pneumonia in the United States. 2018 Mar;46 3 322 327.2018 Mar;46 3 322 327. Open 6. Shio-Shin Jean, Yin-Chun Chang, Wei-Cheng Lin et al. Epidemiology, Treatment, and Prevention of Nosocomial Bacterial Pneumonia. J Clin Med. 2020 Jan 19;9 1 275. Open 7. Renato Seligman, Luis Francisco Ramos-Lima, Vivian do Amaral Oliveira et al. Risk factors for infection with multidrug-resistant bacteria in non-ventilated patients with hospital-acquired pneumonia. May-Jun 2013;39 3 339 48.May-Jun 2013;39 3 339 48. Open 8. Karen K Giuliano, Dian Baker, Barbara Quinn. The epidemiology of nonventilator hospital-acquired pneumonia in the United States. Am J Infect Control. 2018 Mar;46 3 322 327. Open 9. Fei Qi, Guo-Xin Zhang, Dan-Yang She et al. Healthcare-associated Pneumonia: Clinical Features and Retrospective Analysis Over 10 Years. Chin Med J Engl). 2015 Oct 20;128 20 2707 13. Open 10. Shio-Shin Jean, Yin-Chun Chang, Wei-Cheng Lin et al. Epidemiology, Treatment, and Prevention of Nosocomial Bacterial Pneumonia. 2020 Jan 19;9 1 275.2020 Jan 19;9 1 275. Open 11. M B Drakulovic, A Torres, T T Bauer et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999 Nov 27;354 9193 1851 8. Open 12. Marc Leone, Lila Bouadma, B la d Bouhemad et al. Hospital-acquired pneumonia in ICU. Anaesth Crit Care Pain Med. 2018 Feb;37 1 83 98. Open 13. Antoine Roquilly, Bruno Francois, Olivier Huet et al. Interferon gamma-1b for the prevention of hospital- acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial. Intensive Care Med. 2023 Apr 18;1 15. Open https://web.pathway.md/diseases/recnrmysH538ONOB7 5/6 6/24/23, 12:45 PM Hospital-acquired pneumonia Pathway https://web.pathway.md/diseases/recnrmysH538ONOB7 6/6

Guideline sources The following summarized guidelines for the evaluation and management of human immunodeficiency virus infection (HIV) are prepared by our editorial team based on guidelines from the Center for Disease Control (CDC 2021), the International AIDS Society (IAS 2018), the Clinical Pharmacogenetics Implementation Consortium (CPIC 2014), and the U.S. Preventive Services Task Force (USPSTF 2013). 1 2 3 4 5 6 6 7 8 9 10 Definition HIV is a chronic viral disease that, if untreated, leads to progressive T cell depletion with resultant infectious and oncological complications. 6 Epidemiology Human immunodeficiency virus type 1 is responsible for the vast majority of infections, while human immunodeficiency type 2 is relatively uncommon and follows a more indolent course. 8 Pathophysiology https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 1/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway In the United States, the incidence and prevalence of human immunodeficiency virus are estimated at 18.0 cases per 100,000 person-years and 380.9 persons per 100,000 population, respectively. 7 Disease course Infection begins by invasion of the target cells in a mucosa, following which the infection spreads to the lymphoid system. In untreated patients, the destruction of human immunodeficiency virus- infected CD4 T cells results in immunodeficiency and chronic inflammation. CD4 T cell counts of < 350 cells/ L are associated with an increased risk of complications such as varicella-zoster, tuberculosis, and other severe bacterial infections. The risk of opportunistic infections, such as pneumocystis pneumonia and esophageal candidiasis, increases with CD4 T cell counts of < 250 cells/ L. CD4 T cells count < 100 cells/ L result in an increased risk of coccidioidomycosis, cryptococcosis, CMV infection, histoplasmosis, progressive multifocal leukoencephalopathy, disseminated mycobacterium avium complex, brain toxoplasmosis, human immunodeficiency virus- associated wasting syndrome, and finally death. 6 Prognosis and risk of recurrence The standardized mortality rate ratio of patients with HIV is estimated at 3.97 (95% CI 3.01-5.24) in patients who have never received antiretroviral therapy, and 2.76 (95% CI 2.25-3.39) in patients who have been treated with antiretroviral therapy. The 2-year and 10-year survival rates of patients diagnosed with AIDS are 82% and 26%, respectively. 9 10 Calculator Calculator CKD prediction in HIV patients Denver HIV risk score Guidelines 1. Screening and diagnosis Indications for screening: As per IAS 2018 guidelines, screen for HIV at least once in all individuals who have ever been sexually active. B Show 2 more As per USPSTF 2013 guidelines: Screen adolescents and adults 15 to 65 years of age for HIV. Screen younger adolescents and older adults who are at an increased risk. A https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 2/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway Screen all pregnant women for human immunodeficiency virus, including those who present in labor who are untested and whose human immunodeficiency virus status is unknown. A As per USPSTF 2013 guidelines: Screen for HIV in patients 15-65 years of age. A Screen for HIV in patients < 15 years of age and patients > 65 years of age who are at increased risk. A 2. Diagnostic investigations Initial and confirmatory testing: Use assays that can detect recent HIV (either an instrument-based combination antigen/antibody assay or a combination of a stand-alone antibody assay and nucleic acid testing) to screen for HIV. B Obtain confirmatory measurement of human immunodeficiency virus RNA levels in patients with positive screening results. A Baseline laboratory investigations: Obtain the following laboratory testing prior to initiating antiretroviral therapy: human immunodeficiency virus RNA level CD4 cell count reverse transcriptase and protease genotype complete blood cell count kidney and LFTs lipid levels, glucose level, and pregnancy status screening for hepatitis A, B, and C, tuberculosis, and STIs. A Testing for HLA-B5701: Obtain testing for HLA-B5701 allele before initiating abacavir. A Avoid abacavir in patients who test positive for HLA-B5701. D Bone mineral density testing: obtain baseline bone mineral density testing in postmenopausal women and in all patients > 50 years of age. B Evaluation for comorbidities: implement age- and risk-appropriate screening for STIs at various anatomical sites, anal or cervical dysplasia, tuberculosis, general health, and medication toxicity. B Show 2 more 3. Medical management General principles: initiate antiretroviral therapy as soon as possible after diagnosis, including immediately after diagnosis, unless the patient is not ready to commit to starting therapy. A https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 3/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway Initial ART regimens: Choose among the following initial regimens for the treatment of HIV: bictegravir/tenofovir alafenamide/emtricitabine A dolutegravir/abacavir/Lamivudine A dolutegravir plus tenofovir alafenamide/emtricitabine A Updated evidence: ATLAS-2M (152-week results) In adults living with human immunodeficiency virus-1 infection, every 8 weeks dosing was noninferior to every 4 weeks dosing with respect to a HIV-1 RNA 50 copies/mL at week 152. Edgar T Overton et al. Clin Infect Dis. 2023 Jan 20. ART initiation (rapid start): initiate antiretroviral therapy, including rapid start, for all infected ambulatory patients committed to starting antiretroviral therapy, unless the patient has symptoms that suggest an opportunistic infection for which immediate antiretroviral therapy is contraindicated, or for those with unclear human immunodeficiency virus diagnosis. B Show 2 more ART initiation (opportunistic infections): initiate antiretroviral therapy within the first 2 weeks after diagnosis for most opportunistic infections. A Show 2 more ART switching (virologic failure): obtain resistance testing in patients with virologic failure, while taking the failing antiretroviral therapy regimen or within 4 weeks of stopping. B Prophylaxis for opportunistic infections: initiate primary prophylaxis for Pneumocystis pneumonia should be initiated for patients with CD4 cell counts below 200/ L. A Show 2 more 4. Specific circumstances Pregnant patients: advise individuals with HIV who are pregnant to initiate antiretroviral therapy as soon as possible, for their own health and to reduce transmission to the infant. A Show 3 more Patients with HBV co-infection: treat patients who are co-infected with human immunodeficiency virus and HBV with a regimen that contains 2 drugs active against HBV, usually tenofovir alafenamide or tenofovir disoproxil fumarate plus lamivudine or emtricitabine, in addition to a third antiretroviral therapy drug. B Patients with HCV co-infection: treat patients with human immunodeficiency virus who are co- infected with HCV using antiretroviral regimens that have minimal drug interactions with HCV therapies, such as dolutegravir/abacavir/lamivudine, dolutegravir/tenofovir alafenamide/emtricitabine, bictegravir/tenofovir alafenamide/emtricitabine, or raltegravir plus tenofovir alafenamide/emtricitabine. B https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 4/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway Patients with osteoporosis: Avoid tenofovir disoproxil fumarate for patients with osteopenia or osteoporosis. D Switch proactively from tenofovir disoproxil fumarate to tenofovir alafenamide for patients at high risk of renal or bone toxicity. B Patients with kidney disease: avoid tenofovir disoproxil fumarate for individuals with or at risk for kidney disease. D Show 2 more Patients with tuberculosis: treat patients with human immunodeficiency infection taking rifamycin-basedd antituberculosis therapy with 2 NRTIs (excluding tenofovir alafenamide) plus one of the following: efavirenz (600 mg daily), raltegravir (800 mg BID), or dolutegravir (50 mg BID). A Patients with substance use disorders: initiate opioid substitution therapy in patients with human immunodeficiency virus who are opioid-dependent. A Patients who are carriers of HLA-B57:01: avoid abacavir in patients who are carriers of HLA- B57:01. D 5. Patient education Sexual behaviour counseling: remind HIV-seropositive and HIV-negative individuals that condoms are required to prevent acquisition of non-HIV STIs. B 6. Preventative measures Pre-exposure prophylaxis: As per CDC 2021 guidelines, inform all sexually active adult and adolescent individuals about human immunodeficiency virus pre-exposure prophylaxis. B Show 10 more As per IAS 2018 guidelines, offer pre-exposure prophylaxis for populations whose annual HIV incidence is at least 2%. B Landmark trials: ANRS IPERGAY In men who have unprotected anal sex with men and who are at high risk for HIV infection, truvada was superior to placebo with respect to the incidence of human immunodeficiency virus 1 infection. Molina JM et al. N Engl J Med. 2015 Dec 3. Post-exposure prophylaxis: provide access to pre-exposure prophylaxis in patients who have completed post-exposure prophylaxis for a recent exposure, and are at risk of ongoing exposure. https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 5/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway B 7. Follow-up and surveillance Follow-up STI screening: perform quarterly screening for asymptomatic STIs in patient populations with high rates of bacterial STIs and incomplete condom use. B Follow-up viral load monitoring: measure viral load at 4-6 weeks after starting a new antiretroviral therapy regimen. B Follow-up CD4 cell count monitoring: measure CD4 cell counts every 6 months until cell counts are > 250 cells/ L for at least 1 year with concomitant viral suppression. B Linkage to care and adherence monitoring: monitor time to care linkage, retention in care, reengagement in care, antiretroviral therapy adherence, and rates of viral suppression, in all care settings and at a population level. B Likelihood Ratios Pertinent positives The following findings increase the probability of human immunodeficiency virus infection in adults. -1 Finding LR+ Value History of genital ulcer 5.4 (2.5-12) History of weight loss 4.7 (2.1-7.2) History of vomiting 4.6 (2.5-8.0) History of swollen lymph nodes 4.6 (1.3-8.0) Show 15 more Pertinent negatives The following findings decrease the probability of human immunodeficiency virus infection in adults. -1 Finding LR- Value Absence of generalized lymphadenopathy 0.70 (0.49-0.92) No history of fever 0.74 (0.64-0.84) No history of myalgia or arthralgia 0.79 (0.57-0.92) Absence of inguinal lymphadenopathy 0.82 (0.69-0.92) Show 20 more References 1. Saag MS, Benson CA, Gandhi RT et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2018 Jul https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 6/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway 24;320 4 379 396. Open 2. US Preventive Services Task Force. Human Immunodeficiency Virus HIV Infection: Screening USPSTF . USPSTF. 2013. Open 3. Martin MA, Hoffman JM, Freimuth RR et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA B Genotype and Abacavir Dosing: 2014 update. Clin Pharmacol Ther. 2014 May;95 5 499 500. Open 4. Centers for Disease Control and Prevention. PREEXPOSURE PROPHYLAXIS FOR THE PREVENTION OF HIV INFECTION IN THE UNITED STATES 2021 UPDATE A CLINICAL PRACTICE GUIDELINE. CDC. 2021. Open 5. Moyer VA. Screening for HIV U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013 Jul 2;159 1 51 60. Open 6. Deeks SG, Overbaugh J, Phillips A et al. HIV infection. Nat Rev Dis Primers. 2015 Oct 1;1 15035. Open 7. Singh S, Song R, Johnson AS et al. HIV Incidence, Prevalence, and Undiagnosed Infections in U.S. Men Who Have Sex With Men. Ann Intern Med. 2018 May 15;168 10 685 694. Open 8. Schwartz SA, Nair MP. Current concepts in human immunodeficiency virus infection and AIDS. Clin Diagn Lab Immunol. 1999 May;6 3 295 305. Open 9. Eyawo O, Franco-Villalobos C, Hull MW et al. Changes in mortality rates and causes of death in a population-based cohort of persons living with and without HIV from 1996 to 2012. BMC Infect Dis. 2017 Feb 27;17 1 174. Open 10. Poorolajal J, Hooshmand E, Mahjub H et al. Survival rate of AIDS disease and mortality in HIV-infected patients: a meta-analysis. Public Health. 2016 Oct;139 3 12. Open 11. International Advisory Panel on HIV Care Continuum Optimization. IAPAC Guidelines for Optimizing the HIV Care Continuum for Adults and Adolescents. J Int Assoc Provid AIDS Care. 2015 Nov-Dec;14 Suppl 1 S3 S34. Open 12. Seem DL, Lee I, Umscheid CA et al. PHS guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep. 2013 Jul;128 4 247 343. Open 13. Wilkins E, Nelson M, Agarwal K et al. British HIV Association guidelines for the management of hepatitis viruses in adults infected with HIV 2013. HIV Med. 2013 Nov;14 Suppl 4 1 71. Open 14. Birbeck GL, French JA, Perucca E et al. Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. Neurology. 2012 Jan 10;78 2 139 45. Open 15. Martin MA, Klein TE, Dong BJ et al. Clinical pharmacogenetics implementation consortium guidelines for HLA B genotype and abacavir dosing. Clin Pharmacol Ther. 2012 Apr;91 4 734 8. Open 16. HIV Medicine Association. Choosing Wisely HMA recommendations. Choosing Wisely. 2016. Open 17. No authors listed. BHIVA/BASHH guidelines on the use of HIV pre-exposure prophylaxis PrEP 2018. HIV Med. 2019 Mar;20 Suppl 2:s2-s80. Open 18. US Preventive Services Task Force, Owens DK, Davidson KW et al. Preexposure Prophylaxis for the Prevention of HIV Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2019 https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 7/8 6/24/23, 12:45 PM Human immunodeficiency virus infection Pathway Jun 11;321 22 2203 2213. Open 19. No authors listed. BHIVA/BASHH guidelines on the use of HIV pre-exposure prophylaxis PrEP 2018. HIV Med. 2019 Mar;20 Suppl 2:s2-s80. Open 20. Angel A. Justiz Vaillant Peter G. Gulick. HIV Disease Current Practice. In: StatPearls Internet]. Treasure Island FL StatPearls Publishing; 2021 Jan. 2020 Dec 30. Open 21. US Preventive Services Task Force, Douglas K Owens, Karina W Davidson et al. Screening for HIV Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2019 Jun 18;321 23 2326 2336. Open 22. Viviana Simon, David D Ho, Quarraisha Abdool Karim. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet. 2006 Aug 5;368 9534 489 504. Open 23. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Open 24. R Douglas Wilson. Guideline No. 409 Intrauterine Fetal Diagnostic Testing in Women with Chronic Viral Infections. J Obstet Gynaecol Can. 2020 Dec;42 12 1555 1562.e1. Open 25. Giuseppe Indolfi, Mona Abdel-Hady, Sanjay Bansal et al. Management of Hepatitis B Virus Infection and Prevention of Hepatitis B Virus Reactivation in Children With Acquired Immunodeficiencies or Undergoing Immune Suppressive, Cytotoxic, or Biological Modifier Therapies. J Pediatr Gastroenterol Nutr. 2020 Apr;70 4 527 538. Open 26. Naokatsu Ando, Daisuke Mizushima, Kazumi Omata et al. Combination of Amoxicillin 3,000 mg and Probenecid versus 1,500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients with HIV an Open- Label, Randomized, Controlled, Non-Inferiority Trial. Clin Infect Dis. 2023 May 9;ciad278. Open https://web.pathway.md/diseases/recQ0DpI3qRwt7qOo 8/8

Guideline sources The following summarized guidelines for the evaluation and management of Huntington's disease (HD) are prepared by our editorial team based on guidelines from the American Academy of Neurology (AAN 2020; 2012), the European Huntington's Disease Network (EHDN 2019), and the Huntington's Disease Expert Group (HD-EG 2018). 1 2 3 4 5 6 6 7 8 Definition HD is an adult-onset, autosomal dominant inherited neurodegenerative disorder characterized by the progressive development of chorea, psychiatric symptoms, and cognitive impairment. 5 Epidemiology Primary neuropathophysiology occurs in the neostriatum with atrophy, neuronal loss and gliosis in the caudate nucleus, thalamus, and, ultimately, the cortex. HD is caused by a cytosine-adenine- guanine (CAG) trinucleotide repeat expansion at the 5' end of the huntingtin gene. 6 Pathophysiology The cumulative incidence rate of HD in the United States is estimated at 1.22 per 100,000 persons (95% CI 1.53-1.65). Mean age at onset ranges from 35-44 years. 6 Disease course https://web.pathway.md/diseases/recD8XAEAPBsmglJb 1/6 6/24/23, 12:44 PM Huntington's disease Pathway Initial clinical manifestations include motor dysfunction (chorea, athetosis, oculomotor disorders), hyperreflexia and hyperhidrosis. Advanced stages progress to movement dysfunction (dystonia, rigidity, bradykinesia, dysarthria, gait disturbance, facial grimacing), cognitive decline (dementia), and psychiatric disturbances (major depressive disorder, psychosis, obsessive-compulsive symptoms, suicidal ideation). Additionally, ataxic gait and seizure may occur. 7 Prognosis and risk of recurrence Huntington disease progresses to disability, and eventually death approximately 15-20 years after onset. Intercurrent illnesses such as aspiration pneumonia are the most common cause of death. 8 Guidelines 1. Diagnostic investigations Clinical assessment: Elicit symptoms from patients with HD when possible, and collateral information from carers. E Assess for comorbid medical conditions, medications, environmental factors, and coexisting psychiatric symptoms of HD contributing to the presenting symptoms. E 2. Medical management General principles: decide on drug choice in HD depending on coexisting symptoms and the stage of the disease. E Show 2 more Management of chorea: As per EHDN 2019 guidelines, consider initiating drug treatment if chorea causes distress or discomfort. Prefer monotherapy for chorea management because combination therapy increases the risk of adverse effects and may complicate the management of non-motor symptoms. Show 2 more As per AAN 2012 guidelines, offer tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) in patients with HD, if treatment of chorea is required. B Show 5 more Management of dystonia and rigidity: offer active and passive physiotherapy as a preventive measure to maintain the range of joint motion, limit postural and musculoskeletal deformities, and prevent the development of contractures. B Show 5 more Management of motor deterioration: https://web.pathway.md/diseases/recD8XAEAPBsmglJb 2/6 6/24/23, 12:44 PM Huntington's disease Pathway As per AAN 2020 guidelines, offer aerobic exercise (moderate intensity, 55-90% HR maximum) paired with upper and lower body strengthening 3 times weekly for a minimum of 12 weeks to improve fitness and to stabilize or improve motor function in patients with HD. B As per EHDN 2019 guidelines, offer physiotherapy and/or personalized exercise programs, in combination with pharmacological treatments, for overall functional ability, motor function, and independence in HD. B Show 2 more Management of gait disturbance: As per AAN 2020 guidelines, offer one-on-one supervised gait training to improve spatiotemporal measures of gait (such as walking speed and step length) in patients with HD. B Show 3 more As per EHDN 2019 guidelines, initiate interventions for gait and balance as early as possible and continue and adapt throughout the progression of the disease. B Offer physiotherapy B and falls prevention programs, gait, core stability, and balance interventions, B and attentional training. Show 3 more Management of dysphagia: obtain regular assessments of swallowing disorders throughout the progression of the disease, and refer to a speech and language therapist as soon as the disorders appear. B Show 6 more Management of respiratory muscle weakness: as per AAN 2020 guidelines, consider offering breathing exercises, including inspiratory and expiratory training, to improve respiratory muscle strength and cough effectiveness in patients with HD. C Management of respiratory decline: as per EHDN 2019 guidelines, consider offering a home- based respiratory muscle training program to improve pulmonary function, recognizing that it has only a small effect on swallowing function, dyspnea, and exercise capacity. C Management of bruxism: consider injecting botulin toxin A into the masseter muscles as first-line therapy for bruxism. C Show 5 more Management of dental pain: provide verbal and written instructions on how to provide good oral hygiene at home. B Show 3 more Management of urinary incontinence: assess for a precipitating factor (urinary infection, prostate disease) in case of urinary incontinence. Assess for the presence of diurnal unexpected complete urination (complete and sudden bladder emptying, without urge) and consider offering carbamazepine for it. B Show 3 more Management of sexual disorders: attempt to identify sexual disorders and determine their triggers and their impact on relationships. Consider offering psychological support and/or referral https://web.pathway.md/diseases/recD8XAEAPBsmglJb 3/6 6/24/23, 12:44 PM Huntington's disease Pathway to a specialist in psychosexual disorders. Show 4 more Management of cognitive impairment: consider offering multiple rehabilitation strategies (speech therapy, occupational therapy, cognitive and psychomotricity) to improve or stabilize transitorily cognitive functions. C Management of akathisia and irritability: assess for an iatrogenic cause of akathisia as a priority. Recognize that tetrabenazine B , neuroleptics, and SSRIs may cause akathisia in HD. Consider reducing the dose or changing the treatment. Show 3 more Management of communication difficulties: reassess changing communication needs throughout the course of the disease to plan effective management strategies. B Obtain a comprehensive assessment of language and other factors, such as mood, motivation, and behavior, during monitoring since communication disorders in HD is variable. Show 2 more Management of depression and anxiety: As per EHDN 2019 guidelines, recognize that treatment of anxiety and depression may help to improve executive function and cognitive stimulation through rehabilitation may improve planning and initiation more specifically. (Grade C) Monitor sedative drugs and neuroleptics closely as they impair executive functions and attention. Show 7 more As per HD-EG 2018 guidelines, treat coexisting psychiatric symptoms or comorbid medical conditions and modify environmental factors contributing to anxiety. E Show 6 more Management of apathy: differentiate apathy from the impaired ability of the patient to perform motor or cognitive tasks. E Show 4 more Management of sleep disorders: treat comorbid medical conditions, coexisting psychiatric symptoms, pain, or substance use contributing to sleep disturbance in HD. Assess and adjust the dosing schedule of drugs contributing either to daytime sleepiness or nocturnal insomnia. E Show 5 more Management of perseveration: Consider offering SSRIs if pharmacological treatment is required for perseverative symptoms, particularlt when symptoms are associated with anxiety. Offer olanzapine or risperidone for ideational perseverations, particularly when associated with irritability. C Offer psychological intervention, such as CBT, in non-cognitively impaired patients since true obsessive-compulsive phenomena are sensitive to psychological intervention. Offer SSRIs as first-line therapy, if pharmacological treatment is required for obsessive-compulsive phenomena. B Management of hallucinations: search for and interrupt the use of psychotropic agents in case of hallucinations and delusions. B https://web.pathway.md/diseases/recD8XAEAPBsmglJb 4/6 6/24/23, 12:44 PM Huntington's disease Pathway Show 4 more Management of agitation: identify and treat comorbid medical conditions precipitating acute agitation including infectious, metabolic, toxic, drug-related, substance use, or other medical causes of acute psychosis/delirium. E Show 7 more Management of psychosis: identify and treat comorbid medical conditions precipitating the acute onset of psychotic symptoms, including infectious, metabolic, toxic, drug-related, substance use, or other medical or acute psychosis/delirium. E Show 5 more 3. Nonpharmacologic interventions Nutritional support: ensure good nutritional care in the management of patients with HD. Obtain early assessment by a dietitian or nutritionist and regular timely reviews of nutritional needs. Take into consideration factors such as swallowing ability, cognitive changes, behavior, mood, and general functional ability to determine possible other causes of weight loss. B Ensure a multidisciplinary approach and consider including a speech-language therapist and an occupational therapist to assist with swallowing, positioning, and feeding aids. Use screening tools for malnutrition such as the MUST. Show 3 more 4. Patient education General counseling: Provide education about the nature and presentations of symptoms in HD. E Provide information about methods that may be helpful for modifying symptom triggers. E References 1. Anne-Catherine Bachoud-L vi, Joaquim Ferreira, Renaud Massart et al. International Guidelines for the Treatment of Huntington's Disease. Front Neurol. 2019 Jul 3;10 710. Open 2. Karen E Anderson, Erik van Duijn, David Craufurd et al. Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders. J Huntingtons Dis. 2018;7 3 355 366. Open 3. Lori Quinn, Deb Kegelmeyer, Anne Kloos et al. Clinical recommendations to guide physical therapy practice for Huntington disease. Neurology. 2020 Feb 4;94 5 217 228. Open 4. Melissa J Armstrong, Janis M Miyasaki, American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2012 Aug 7;79 6 597 603. Open https://web.pathway.md/diseases/recD8XAEAPBsmglJb 5/6 6/24/23, 12:45 PM Huntington's disease Pathway 5. Francis O Walker. Huntington's disease. 2007 Jan 20;369 9557 218 28.2007 Jan 20;369 9557 218 28. Open 6. Emilie Bruzelius, Joseph Scarpa, Yiyi Zhao et al. Huntington's disease in the United States: Variation by demographic and socioeconomic factors. Mov Disord. 2019 Jun;34 6 858 865. Open 7. Raymund A C Roos. Huntington's disease: a clinical review. 2010 Dec 20;5 40.2010 Dec 20;5 40. Open 8. Filipe Brogueira Rodrigues, Daisy Abreu, Joana Dam sio et al. Survival, Mortality, Causes and Places of Death in a European Huntington's Disease Prospective Cohort. Mov Disord Clin Pract. 2017 May 26;4 5 737 742. Open 9. Raymund A C Roos. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010 Dec 20;5 40. Open 10. Emilie Bruzelius, Joseph Scarpa, Yiyi Zhao et al. Huntington's disease in the United States: Variation by demographic and socioeconomic factors. 2019 Jun;34 6 858 865.2019 Jun;34 6 858 865. Open 11. Filipe Brogueira Rodrigues, Daisy Abreu, Joana Damasio et al. Survival, Mortality, Causes and Places of Death in a European Huntington's Disease Prospective Cohort. 2017 May 26;4 5 737 742.2017 May 26;4 5 737 742. Open https://web.pathway.md/diseases/recD8XAEAPBsmglJb 6/6

Guideline sources The following summarized guidelines for the evaluation and management of hydrocele are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022). 1 Guidelines 1. Diagnostic investigations Assessment of contralateral disease: elicit history and perform physical examination at the time of initial evaluation to assess for contralateral disease. B Scrotal ultrasound: obtain scrotal ultrasound in case of doubt about the character of an intrascrotal mass. B 2. Surgical interventions Timing of surgery: Observe the majority of infant patients with hydrocele for 12 months before considering surgical treatment because of the tendency for spontaneous resolution. B Perform early surgery if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology. B https://web.pathway.md/diseases/recFwbzrHVXtHxd0b 1/2 6/24/23, 12:44 PM Hydrocele Pathway Technical considerations for surgery: perform ligation of the patent processus vaginalis via inguinal incision with distal stump left open in pediatric patients with hydrocele. B Show 2 more References 1. Lisette A 't Hoen, Guy Bogaert, Christian Radmayr et al. EAU guidelines on Paediatric Urology. EAU. 2022 Mar. Open https://web.pathway.md/diseases/recFwbzrHVXtHxd0b 2/2

Guideline sources The following summarized guidelines for the evaluation and management of hypercalcemia of malignancy (HCM) are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2022). 1 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines 1. Diagnostic investigations Assessment of renal function: assess renal function (CrCl or estimated GFR) before administering IV bisphosphonates in adult patients with HCM. E 2. Medical management Antiresorptive therapies: https://web.pathway.md/diseases/recqRDcPcXPh2eIXa 1/2 6/24/23, 12:44 PM Hypercalcemia of malignancy Pathway Initiate treatment with an IV bisphosphonate or denosumab in adult patients with HCM. B Consider preferring denosumab over intravenous bisphosphonates. B Consider initiating a combination of calcitonin and an IV bisphosphonate or denosumab as initial therapy in adult patients with severe HCM (serum calcium > 14 mg/dL; 3.5 mmol/L). C Intravenous fluids: provide adequate hydration with IV fluids as first-line therapy in adults with HCM while awaiting the effect of antiresorptive drugs. Tailor therapy according to cardiac function. E 3. Specific circumstances Patients with renal insufficiency: administer renal dosing of zoledronic acid over 30-60 minutes or renal dosing of pamidronate over 2-24 hours in adult patients with HCM and renal insufficiency (defined as CrCl < 60 mL/min) treated with IV bisphosphonates. E Patients with calcitriol-secreting tumor: consider administering an IV bisphosphonate or denosumab in adult patients with HCM from tumors associated with high calcitriol levels, such as lymphomas, already receiving corticosteroid therapy but continuing to have severe or symptomatic hypercalcemia. C Patients with parathyroid carcinoma: consider administering a calcimimetic, an IV bisphosphonate, or denosumab in adult patients with hypercalcemia due to parathyroid carcinoma. C Show 3 more 4. Follow-up and surveillance Serial clinical and laboratory assessment: monitor dental hygiene and oral health, including visual examination of the mouth, in the context of the provision of antiresorptive therapy in adult patients with HCM. E Show 2 more Management of refractory/recurrent hypercalcemia: consider administering denosumab in adult patients with refractory/recurrent HCM on IV bisphosphonate therapy. C References 1. Ghada El-Hajj Fuleihan, Gregory A Clines, Mimi I Hu et al. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Dec 21:dgac621. Open https://web.pathway.md/diseases/recqRDcPcXPh2eIXa 2/2

Guideline sources The following summarized guidelines for the evaluation and management of hypercapnic respiratory failure are prepared by our editorial team based on guidelines from the European Respiratory Society (ERS 2017) and the British Thoracic Society (BTS/ICS 2016). 1 2 3 3 3 3 4 Definition Hypercapnic respiratory failure (Type II Respiratory Failure) is a state of reduced alveolar ventilation with subsequent respiratory acidosis (PaCO >50 mmHg). 3 Epidemiology Hypercapnic respiratory failure is most frequently caused by drug overdose, COPD (COPD), obesity hypoventilation syndrome, obstructive sleep apnea (OSA), and the overlap syndrome of COPD and OSA. 3 Pathophysiology The overall prevalence of hypercapnic respiratory failure in patients with severe COPD is approximately 25%. 4 Disease course https://web.pathway.md/diseases/recwW4gUdPXoAtErL 1/4 6/24/23, 12:45 PM Hypercapnic respiratory failure Pathway Acute hypercapnic respiratory failure develops rapidly (within minutes to hours). Clinical manifestations include increasing dyspnea, lethargy, hypoxemic, disorientation, tachycardia, altered mental status, hypoventilation, hyperinflation, and need for ventilatory support. The disease decreases the quality of life with increased risk of readmission and longer periods of hospital stay. 3 Prognosis and risk of recurrence Hypercapnic respiratory failure in hospitalized patients is associated with significant mortality (36%). 3 Guidelines 1. Classification and risk stratification Prognostic tools: consider the use of validated tools to inform discussion regarding prognosis and appropriateness of invasive mechanical ventilation, keeping in mind that such tools are poorly predictive for individual patient use. C 2. Medical management Patients with COPD exacerbation: As per ERS 2017 guidelines, initiate bilevel noninvasive ventilation for patients with acute respiratory failure due to an acute exacerbation of COPD that leads to respiratory acidosis (pH 7.35). A Show 2 more As per BTS 2016 guidelines, initiate noninvasive ventilation in patients with an acute exacerbation of COPD with persistent respiratory acidosis (pH < 7.35 and PaCO > 6.5 kPa or 49 mmHg) despite optimal medical therapy. A Show 3 more Patients with acute asthma: avoid using noninvasive ventilation in patients with acute hypercapnic respiratory failure caused by an acute asthma exacerbation. D Patients with bronchiectasis: initiate noninvasive ventilation in patients with non-cystic fibrosis bronchiectasis following the indications used for acute exacerbations of COPD. B Show 2 more Patients with cystic fibrosis: Use noninvasive ventilation as a first-line strategy in patients with cystic fibrosis in whom ventilatory support is needed. B Provide specialized physiotherapy to aid sputum clearance in patients with cystic fibrosis. B Patients with restrictive lung disease: https://web.pathway.md/diseases/recwW4gUdPXoAtErL 2/4 6/24/23, 12:45 PM Hypercapnic respiratory failure Pathway Provide a trial of noninvasive as a first-line strategy in almost all patients with hypercapnia and chest wall or neuromuscular disease who are acutely unwell. B Consider noninvasive ventilation in patients with chest wall or neuromuscular disease when vital capacity is < 1L and respiratory rate is > 20, even if normocapnic. C Patients with neuromuscular disease: involve senior staff in decision-making for patients with chest wall or neuromuscular disease, in conjunction with home mechanical ventilation specialists, if experience is limited, and especially when the appropriateness of invasive mechanical ventilation is questioned. B Patients with obesity hypoventilation syndrome: initiate noninvasive ventilation in patients with obesity hypoventilation syndrome following the indications used for acute exacerbations of COPD. B 3. Inpatient care General principles: treat the precipitant cause of acute hypercapnic respiratory failure, normalize pH, correct chronic hypercapnia and address fluid overload. B Noninvasive ventilation strategy: use pressure-targeted ventilators as the devices of choice for acute noninvasive ventilation. B Show 2 more Invasive ventilation strategy: minimize dynamic hyperinflation by prolonging expiratory time and setting a low frequency during controlled ventilation. B Show 2 more Oxygenation targets: adjust the FiO to achieve SaO 88-92% in patients with acute hypercapnic respiratory failure treated with noninvasive ventilation. A Sedative agents (noninvasive ventilation): use sedation only with close monitoring in patients on noninvasive mechanical ventilation. B Sedative agents (mechanical ventilation): titrate sedation to a specific level of alertness in patients on invasive mechanical ventilation. B Volume status optimization: consider a BNP-directed fluid management strategy in patients with known LV dysfunction. C Assessment for extubation: use 30-minute spontaneous breathing trials to assess suitability for extubation. B Weaning of ventilatory support: Establish spontaneous breathing as soon as possible in all causes of acute hypercapnic respiratory failure. B Undertake daily assessment of the readiness for weaning of ventilatory support. B Monitoring for ventilator asynchrony: assess patients with agitation for ventilator asynchrony. B https://web.pathway.md/diseases/recwW4gUdPXoAtErL 3/4 6/24/23, 12:45 PM Hypercapnic respiratory failure Pathway 4. Therapeutic procedures Tracheostomy: consider mini-tracheostomy to aid secretion clearance in patients with weak cough due to neuromuscular/chest wall disease, or in patients with excessive airway secretions such as in COPD or cystic fibrosis. C Extracorporeal CO2 removal: consider extracorporeal CO removal when severe hypercapnic acidosis persists despite attempts to optimize invasive mechanical ventilation using lung protective strategies. C Show 2 more 5. Follow-up and surveillance Post-extubation care: consider prophylactic use of noninvasive ventilation to provide post- extubation support in patients with identified risk factors for extubation failure. C Palliative care: ensure the timely availability of palliative care services when providing mechanical ventilation. B Quality improvement: operate noninvasive ventilation services under a single clinical lead having formal working links with the ICU. B References 1. Davidson AC, Banham S, Elliott M et al. BTS/ICS guideline for the ventilatory management of acute hypercapnic respiratory failure in adults. Thorax. 2016 Apr;71 Suppl 2:ii1 35. Open 2. Rochwerg B, Brochard L, Elliott MW et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017 Aug 31;50 2 . pii: 1602426. Open 3. Amber J Meservey, Michael C Burton, Jeffrey Priest et al. Risk of Readmission and Mortality Following Hospitalization with Hypercapnic Respiratory Failure. Lung. 2020 Feb;198 1 121 134. Open 4. Michael Dreher, Pierre-Charles Neuzeret, Wolfram Windisch et al. Prevalence Of Chronic Hypercapnia In Severe Chronic Obstructive Pulmonary Disease: Data From The HOmeVent Registry. 2019 Oct 18;14 2377 2384.2019 Oct 18;14 2377 2384. Open 5. Michael Dreher, Pierre-Charles Neuzeret, Wolfram Windisch et al. Prevalence Of Chronic Hypercapnia In Severe Chronic Obstructive Pulmonary Disease: Data From The HOmeVent Registry. Int J Chron Obstruct Pulmon Dis. 2019 Oct 18;14 2377 2384. Open 6. Janice Wang, Astha Chichra, Seth Koenig. An unusual cause of acute hypercapneic respiratory failure. Clin Med Insights Circ Respir Pulm Med. 2011;5 81 5. Open 7. Amber J Meservey, Michael C Burton, Jeffrey Priest et al. Risk of Readmission and Mortality Following Hospitalization with Hypercapnic Respiratory Failure. 2020 Feb;198 1 121 134.2020 Feb;198 1 121 134. Open https://web.pathway.md/diseases/recwW4gUdPXoAtErL 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hyperemesis gravidarum (HG) are prepared by our editorial team based on guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG 2019). 1 Calculator Pregnancy Unique-Quantificatio Guidelines 1. Screening and diagnosis Diagnosis: diagnose HG if protracted NVOP is present with the triad of > 5% pre-pregnancy weight loss, dehydration and electrolyte imbalance. B https://web.pathway.md/diseases/recw71AkdMBOlT6MB 1/4 6/24/23, 12:45 PM Hyperemesis gravidarum Pathway Differential diagnosis: elicit clinical history, perform focused examination and investigations to exclude other pathological causes. B 2. Classification and risk stratification Severity grading: consider using an objective and validated index of nausea and vomiting such as the PUQE score to classify the severity of NVOP. C 3. Diagnostic investigations Initial evaluation: be aware of the features in history, examination and investigation assisting in the assessment, diagnosing and monitoring of the severity of HG. B 4. Medical management Setting of care: Consider managing patients in an inpatient setting if 1 of the following present: continued nausea and vomiting and inability to keep down oral antiemetics continued nausea and vomiting associated with ketonuria and/or weight loss (> 5% of body weight), despite oral antiemetics confirmed or suspected comorbidities, such as UTI and inability to tolerate oral antibiotics. C Multidisciplinary management: consider involving other professionals, such as midwives, nurses, dietitians, pharmacists, endocrinologists, nutritionists and gastroenterologists, and a mental health team, including a psychiatrist, in the care of patients with HG. C Antiemetics: offer antiemetics such as H1RAs and phenothiazines as first-line therapy in patients with HG. B Show 6 more Rehydration therapy: use normal saline with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, for IV hydration in patients with HG. B Show 2 more Corticosteroids: reserve corticosteroids for cases where standard therapies have failed. A Diazepam: do not use diazepam for the management of patients with HG. D Acid-reducing agents: consider offering H2RAs or PPIs in patients with HG developing GERD, esophagitis or gastritis. C Thromboprophylaxis: offer thromboprophylaxis with LMWH in patients admitted with HG, unless there are specific contraindications such as active bleeding. Consider discontinuing thromboprophylaxis upon discharge. B 5. Nonpharmacologic interventions https://web.pathway.md/diseases/recw71AkdMBOlT6MB 2/4 6/24/23, 12:45 PM Hyperemesis gravidarum Pathway Nutrition: consider offering enteral or parenteral treatment with a multidisciplinary approach when all other medical therapies have failed. C Supplements: offer thiamine supplements (either PO or IV) in all patients admitted with prolonged vomiting, especially before administration of dextrose or parenteral nutrition. B Show 2 more Acupuncture: consider reassuring patients that acustimulations are safe in pregnancy. C Hypnosis: do not offer hypnotic therapies for the management of patients with HG. D Psychosocial care: address the severity of symptoms in relation to the patient's quality of life and social situation, as the quality of life can be adversely affected by HG. B Show 3 more Rest: advise patients to rest as required to alleviate symptoms. B 6. Therapeutic procedures Termination of pregnancy: attempt all therapeutic measures before offering termination of a wanted pregnancy. B 7. Follow-up and surveillance Follow-up: Prepare an individualized management plan for patients with HG when they are discharged from hospital. B Offer serial scans to monitor fetal growth in patients with HG experiencing continued symptoms into the late second or the third trimester. B Future pregnancies: Inform patients with previous HG that there is a risk of recurrence in future pregnancies. B Advise early use of lifestyle/dietary modifications and antiemetics that were found to be useful in the index pregnancy to reduce the risk of HG in the current pregnancy. B References 1. Ioannis Tsakiridis, Apostolos Mamopoulos, Apostolos Athanasiadis et al. The Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum. Obstet Gynecol Surv. 2019 Mar;74 3 161 169. Open 2. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 3. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recw71AkdMBOlT6MB 3/4 6/24/23, 12:45 PM Hyperemesis gravidarum Pathway 4. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open https://web.pathway.md/diseases/recw71AkdMBOlT6MB 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hyperkalemia are prepared by our editorial team based on guidelines from the United Kingdom Kidney Association (UKKA 2020), the American Association of Family Physicians (AAFP 2015), and the Guidelines and Audit Implementation Network (GAIN 2014). 1 1 1 1 2 3 5 5 Definition Hyperkalemia refers to the presence of serum potassium levels > 5.0 mmol/L. 1 Epidemiology Hyperkalemia is caused by excess potassium intake, impaired potassium excretion, or transcellular shifts. The etiology of hyperkalemia is often multifactorial, with impaired renal function, medication use, and hyperglycemia as the most common contributors. 1 Pathophysiology https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 1/8 6/24/23, 12:45 PM Hyperkalemia Pathway In the United States, the prevalence of hyperkalemia is estimated at 1550 per 100,000 population. 5 Disease course Manifestations of severe hyperkalemia include muscle weakness, ascending paralysis, heart palpitations, and paresthesias. Typical electrocardiographic changes include peaked T waves, P- wave flattening, PR-interval prolongation, widening of the QRS complex, and sine waves. 5 Prognosis and risk of recurrence Severe untreated hyperkalemia can lead to malignant cardiac arrhythmias and cardiac arres. 1 Guidelines 1. Screening and diagnosis Indications for screening: obtain regular blood monitoring at a frequency (2-4 times per year) depending on the level of renal function and degree of proteinuria in patients with CKD, HF and/or diabetes being at risk for hyperkalemia. B Indications for repeated testing: As per UKKA 2020 guidelines: Obtain repeated serum K+ within 3 days or as soon as feasible if an episode of mild hyperkalemia (K+ 5.5-5.9 mmol/L) was detected unexpectedly in the community. B Obtain repeated serum K+ within 1 day if an episode of moderate hyperkalemia (K+ 6.0-6.4 mmol/L) was detected in the community. B As per GAIN 2014 guidelines, obtain a repeat serum potassium urgently in order to exclude pseudohyperkalemia, especially if hyperkalemia is an unexpected or isolated finding. E 2. Classification and risk stratification Severity grading: As per UKKA 2020 guidelines, use an early warning scoring system for urgent clinical assessment to assess the level of acuity in all patients with known or suspected hyperkalemia. B As per GAIN 2014 guidelines, classify the severity of hyperkalemia as follows: Situation Guidance Potassium 5.5-5.9 mmol/L Mild Potassium 6.0-6.5 mmol/L Moderate Severe https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 2/8 6/24/23, 12:45 PM Hyperkalemia Pathway Potassium 6.5 mmol/L or serum potassium 5.5mmol/L with ECG changes or symptoms (muscle weakness, flaccid paralysis, palpitations, or paresthesias). E 3. Diagnostic investigations Assessment for underlying cause: As per UKKA 2020 guidelines, elicit a comprehensive medical and drug history and perform a clinical examination to determine the cause of hyperkalemia in all patients presenting with hyperkalemia. B As per GAIN 2014 guidelines: Elicit a thorough medical history focusing on a history of renal disease and determination of the medications or fluids prescribed. E Perform a physical examination for causes of post-renal obstruction, such as bladder distension or prostatic hypertrophy. Catheterise if appropriate. E Laboratory tests: measure K+ from an arterial or venous blood sample using a point-of-care blood gas analyzer in emergencies whilst awaiting the results from a formal laboratory measurement. B Show 2 more Electrocardiography: As per UKKA 2020 guidelines, obtain urgent 12-lead ECG in all hospitalized patients with a serum K+ 6.0 mmol/L. B As per GAIN 2014 guidelines, obtain a 12-lead ECG in all patients with hyperkalemia. E 4. Medical management Indications for outpatient treatment: Initiate interventions to lower serum potassium in patients with a serum K+ 5.5 mmol/L. B Guide outpatient treatment of hyperkalemia by its severity and clinical condition of the patient. B Indications for urgent treatment: As per UKKA 2020 guidelines, admit patients with severe hyperkalemia (K+ 6.5 mmol/L) detected in the community for urgent hospital assessment and treatment. A Show 3 more As per AAFP 2015 guidelines, initiate urgent treatment for hyperkalemia in patients with any of the following: serum potassium > 6.5 mmol/L https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 3/8 6/24/23, 12:45 PM Hyperkalemia Pathway ECG changes physical signs or symptoms possible rapid-onset hyperkalemia underlying kidney disease, heart disease, or cirrhosis. B As per GAIN 2014 guidelines, initiate urgent treatment if the serum potassium is 6.5 mmol/L or hyperkalemia is accompanied by ECG changes or symptoms. E Discontinuation of contributing medications: As per UKKA 2020 guidelines: Withhold RAAS inhibitors during acute intercurrent illness (such as sepsis, hypovolemia and/or AKI) at all severities of hyperkalemia. B Discontinue RAAS inhibitors in patients with serum K+ 6 mmol/L not meeting the criteria for treatment with patiromer or sodium zirconium cyclosilicate. B As per GAIN 2014 guidelines: Discontinue all medications that can contribute to hyperkalemia, including: ACEIs ARBs potassium-retaining diuretics potassium-containing laxatives. E Discontinue -blockers and digoxin, if safe and feasible, as they prevent intracellular buffering of potassium and reduce the effectiveness of insulin-glucose and -2 agonists. E Intravenous calcium: As per UKKA 2020 guidelines, administer IV calcium chloride or calcium gluconate at an equivalent dose (6.8 mmol) in patients with hyperkalemia in the presence of ECG evidence of hyperkalemia. B As per AAFP 2015 guidelines, administer IV calcium in patients with manifestations of hyperkalemia on electriocardiogram. B As per GAIN 2014 guidelines: Administer 10 ml of IV calcium gluconate 10% over 2 minutes in patients with hyperkalemia with ECG abnormalities. E Consider administering additional 10 ml of IV calcium gluconate 10% every 10 minutes if improvement does not occur, until the ECG normalizes. Recognize that patients may require up to 50 ml of IV calcium gluconate and the effect of this intervention is transient (approximately 30-60 minutes). E Intracellular shifting, insulin/glucose: As per UKKA 2020 guidelines, administer insulin/glucose (10 units soluble insulin in 25 g glucose) by IV infusion for the treatment of severe hyperkalemia (K+ 6.5 mmol/L). B Show 2 more As per GAIN 2014 guidelines, administer 10 units of rapid-acting insulin combined with 50 mL of 50% glucose solution (25 g of glucose) by slow IV injection over 5 minutes. Recognize that the https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 4/8 6/24/23, 12:45 PM Hyperkalemia Pathway potassium-lowering effect occurs within 15 minutes and lasts at least 60 minutes, and the reduction in potassium observed ranges from 0.6 to 1.0 mmol/L. E Show 4 more Intracellular shifting, salbutamol: As per UKKA 2020 guidelines, administer nebulized salbutamol 10-20 mg as an adjuvant therapy in patients with severe hyperkalemia (K+ 6.5 mmol/L). B Show 2 more As per GAIN 2014 guidelines: Administer salbutamol (10 mg via nebulisation). Potassium-lowering effects occurs within 15- 30 minutes and lasts at least 2 hours. The reduction in potassium observed ranges from 0.5 to 1.0 mmol/L. E Avoid using salbutamol as a single agent for the treatment of hyperkalemia, as it may not lower potassium in all patients. Response is weakned in patients taking -blockers, digoxin, and in patients on chronic dialysis. D Intracellular shifting, bicarbonate: As per UKKA 2020 guidelines: Administer sodium bicarbonate in patients with CKD with a serum bicarbonate level < 22 mmol/L with or without hyperkalemia. B Do not administer routine IV sodium bicarbonate infusion for acute treatment of patients with hyperkalemia. D As per GAIN 2014 guidelines, consider not using hypertonic sodium bicarbonate as a treatment for hyperkalemia, as many studies show that sodium bicarbonate fails to lower the serum potassium. D Gastrointestinal excretion (sodium polystyrene): consider using sodium polystyrene sulfonate (Kayexalate) to lower total body potassium in patients with subacute hyperkalemia. C Gastrointestinal excretion (sodium zirconium cyclosilicate): Administer sodium zirconium cyclosilicate as an option for the management of persistent hyperkalemia with a confirmed serum K+ 6.0 mmol/L in patients with CKD stage 3b-5 (not on dialysis) or HF receiving a suboptimal dose of RAAS inhibitors. Administer sodium zirconium cyclosilicate only in secondary care. A Discontinte sodium zirconium cyclosilicate if renin-angiotensin-aldosterone-system inhibitors are stopped. A Gastrointestinal excretion (calcium polystyrene): Consider administering calcium resonium as a short-term measure to lower serum potassium to a level of 5 mmol/L in patients with mild-to-moderate hyperkalemia. C Avoid using calcium resonium for emergency management of patients with severe hyperkalemia, but consider administering it in patients with moderate hyperkalemia. D Gastrointestinal excretion (patiromer): administer patiromer as an option for the management of persistent hyperkalemia with a confirmed serum K+ 6.0 mmol/L in outpatients with CKD stage https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 5/8 6/24/23, 12:45 PM Hyperkalemia Pathway 3b-5 (not on dialysis) or HF receiving a suboptimal dose or not receiving RAAS inhibitors due to hyperkalemia. Administer patiromer only in secondary care. A Show 2 more Renal excretion (loop diuretics): consider administering loop diuretics as an adjunct therapy in non-oliguric and volume replete patients with chronic hyperkalemia. C 5. Inpatient care Laboratory monitoring: As per UKKA 2020 guidelines, monitor serum K+ closely in all patients with hyperkalemia to assess efficacy of treatment and to monitor for rebound hyperkalemia after the initial response to treatment wanes. B Show 3 more As per GAIN 2014 guidelines, monitor urea, electrolytes and glucose at regular intervals. Consider additional blood investigations, including blood gas analysis, as appropriate. E Cardiac monitoring: As per UKKA 2020 guidelines, obtain a minimum of continuous 3-lead ECG monitoring, ideally in a higher dependency setting, in all patients with a serum K+ 6.5 mmol/L, patients with features of hyperkalemia on 12-lead ECG, and in patients with a serum K+ 6.0-6.4 mmol/L if clinically unwell or rapid rise in serum K+ is anticipated. B As per GAIN 2014 guidelines, initiate cardiac monitoring in patients with severe hyperkalemia (serum potassium 6.5 mmol/L). E Show 2 more 6. Nonpharmacologic interventions Low-potassium diet: As per UKKA 2020 guidelines: Advise a low potassium diet in outpatients with persistent hyperkalemia with a serum K+ > 5.5 mmol/L. B Administer a low potassium diet in hospitalized patients with moderate-to-severe hyperkalemia. B As per GAIN 2014 guidelines, place the patient on a low potassium diet, avoiding fruit juice, fruits, chocolate, fruit gums, biscuits, coffee or potatoes. E 7. Therapeutic procedures Hemodialysis: As per UKKA 2020 guidelines, decide on timing, suitability and modality for initiation of RRT urgently by a nephrologist or critical care specialist in patients with life threatening hyperkalemia, https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 6/8 6/24/23, 12:45 PM Hyperkalemia Pathway either from the outset or resistant to initial medical therapy. B As per GAIN 2014 guidelines, consider initiating hemodialysis in patients with severe hypokalemia in whom other first-line agents have been unsuccessful, or if there is ongoing tissue damage and continued release of intracellular potassium is expected. E 8. Specific circumstances Patients on RAASi therapy: obtain urea and electrolytes before initiating ACEI or ARB. Be cautious if serum K+ is > 5.0 mmol/L. A Show 4 more Patients on digoxin: Administer IV calcium slowly (e.g. over 20 minutes) in patients taking digoxin in whom IV calcium is indicated, as as rapid calcium administration may precipitate myocardial digoxin toxicity. E Consider initiating hemodialysis and administration of digoxin antibody fragments in patients with hyperkalemia due to digoxin toxicity. Consult with a local expert. E Patients on hemodialysis: perform urgent dialysis in hemodialysis patients with severe hyperkalemia (K+ 6.5 mmol/L). A Show 3 more Patients with cardiac arrest (diagnosis): suspect hyperkalemia in all patients with cardiac arrest, as part of identifying and treating a reversible cause using the 4Hs (hypoxia, hypokalemia/hyperkalemia, hypothermia/hyperthermia, hypovolemia) and 4Ts (tension pneumothorax, tamponade, thrombosis, toxins) approach. A Patients with cardiac arrest (prevention): Treat hyperkalemia urgently in patients with severe hyperkalemia (K+ 6.5 mmol/L) and in patients with ECG changes suggestive of severe hyperkalemia. B Obtain continuous cardiac monitoring in patients with severe cardiac hyperkalemia (K+ 6.5 mmol/L) in a setting appropriate for the level of care required. B Patients with cardiac arrest (management): use a treatment algorithm providing guidance on the medical therapies and the need for initiation of RRT during CPR for the management of patients with cardiac arrest attributable to hyperkalemia. B Show 4 more Patients with cardiac arrest (resuscitation): use standard advanced life support practice in patients with cardiac arrest requiring dialysis. A Show 2 more 9. Preventative measures https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 7/8 6/24/23, 12:45 PM Hyperkalemia Pathway Prevention: monitor renal function in patients at risk of hyperkalemia with known CKD, HF, diabetes or taking RAAS inhibitors. A Show 3 more 10. Follow-up and surveillance Referral to renal/critical care services: consider referring patients with severe hyperkalemia (K+ 6.5 mmol/L) to their local renal or critical care team for an urgent opinion, guided by the clinical scenario and its persistence after initial medical treatment. C Show 6 more References 1. Anthony J Viera, Noah Wouk. Potassium Disorders: Hypokalemia and Hyperkalemia. Am Fam Physician. 2015 Sep 15;92 6 487 95. Open 2. Annette Alfonzo, Alexander Harrison, Richard Baines et al. Clinical Practice Guidelines Treatment of Acute Hyperkalaemia in Adults. The Renal Association. 2020 Jun. Open 3. McVeigh G, Maxwell P, O'Donell S et al. Guidelines for the Treatment of Hyperkalaemia in Adults. GAIN Sub-Group on the Treatment of Hyperkalaemia in Adults. Open 4. Ashish R Panchal, Jason A Bartos, Jos G Caba as et al. Part 3 Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142 16_suppl_2 S366 S468. Open 5. Keith A Betts, J Michael Woolley, Fan Mu et al. The prevalence of hyperkalemia in the United States. Curr Med Res Opin. 2018 Jun;34 6 971 978. Open https://web.pathway.md/diseases/recU1AS4qWgwSAVUQ 8/8

Guideline sources The following summarized guidelines for the evaluation and management of hyperoxaluria are prepared by our editorial team based on guidelines from the European Hyperoxaluria Consortium (OxalEurope/ERKNet 2023), the Canadian Urological Association (CUA 2022), the European Association of Urology (EAU 2021), the American Society of Anesthesiologists (ASA/ACE/OS/AACE/ASMBS/OMA 2020), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2020), the American College of Endocrinology (ACE/AACE 2016), the American Urological Association (AUA 2014), and the American Association for the Study of Liver Diseases (AASLD 2014). 1 2 3 4 5 6 7 8 Guidelines 1. Screening and diagnosis Indications for testing: obtain metabolic testing including urinary oxalate assessment (with one or two 24-hour urine collections obtained on a random diet) in patients with recurrent https://web.pathway.md/diseases/recURu9iv10sfKMhE 1/5 6/24/23, 12:45 PM Hyperoxaluria Pathway nephrolithiasis, or in high-risk or interested patients with a first episode of nephrolithiasis. B 2. Diagnostic investigations Urine oxalate studies: assess urinary oxalate excretion, along with creatinine, by 24-hour urine collection. B Consider obtaining spot urine collections instead of 24-hour urine collections, where clinically necessary, provided that oxalate assessment is expressed as the oxalate-to- creatinine ratio. B Show 4 more Plasma oxalate levels: measure plasma oxalate levels only in patients with CKD stage 4. B Interpret plasma oxalate levels on the basis of reference values, taking the impact of kidney failure into account. B Genetic testing: obtain genetic testing in all patients with high clinical and/or biochemical suspicion of primary hyperoxaluria. B Show 2 more 3. Medical management RNA interference therapy: consider weighing the benefit of RNA interference therapy against its potential long-term risks in patients with primary hyperoxaluria type 1. C Show 7 more 4. Nonpharmacologic interventions Dietary oxalate restriction: As per ERKNet 2023 guidelines: Initiate conservative therapy promptly in all patients with suspected primary hyperoxaluria. B Offer a balanced diet in patients with primary hyperoxaluria, avoiding only foods containing extremely high levels of oxalate. B As per CUA 2022 guidelines, advise minimization of high-oxalate foods in patients with hyperoxaluria. Consider offering a diet high in fiber, fruits, and vegetables as a protective measure against stone formation. B As per EAU 2021 guidelines, advise oxalate restriction for the prevention of kidney stone formation in patients with hyperoxaluria. Advise reducing dietary fat and oxalate in patients with enteric hyperoxaluria. B Fluid intake: Initiate hyperhydration (3.5-4 L/day in adult and 2-3 L/m BSA in pediatric patients, consumed throughout 24 hours) in all patients with suspected primary hyperoxaluria and preserved kidney function. B https://web.pathway.md/diseases/recURu9iv10sfKMhE 2/5 6/24/23, 12:45 PM Hyperoxaluria Pathway Monitor hyperhydration based on urinary markers at a frequency depending on disease severity. B Pyridoxine supplementation: As per CUA 2022 guidelines, consider initiating pyridoxine supplementation to lower urinary oxalate levels in patients with hyperoxaluria, if dietary modification has been unsuccessful. C As per EAU 2021 guidelines, initiate pyridoxine for the prevention of kidney stone formation in patients with primary hyperoxaluria. A Potassium supplementation: initiate oral supplementation of potassium citrate (0.1-0.15 g/kg) in patients with preserved kidney function. B 5. Therapeutic procedures Kidney stone removal: consider performing percutaneous nephrolithotomy or ureteroscopy rather than external shock wave lithotripsy for stone removal in patients with primary hyperoxaluria. C Dialysis: consider performing kidney replacement therapy before kidney failure has developed in patients with primary hyperoxaluria type 1 at high risk of systemic oxalosis because of the high plasma oxalate values or patients already having comorbidities. C Show 3 more 6. Surgical interventions Kidney transplantation: As per ERKNet 2023 guidelines, decide on performing either sequential or simultaneous liver and kidney transplantation based on the clinical situation and the preference of the local surgeon. B Show 3 more As per KDIGO 2020 guidelines, consider performing combined or sequential liver-kidney transplantation in eligible patients with primary hyperoxaluria type 1. C Show 2 more As per AASLD 2014 guidelines, consider performing combined liver and kidney transplantation in patients with primary hyperoxaluria and end-stage renal disease not responding to medical therapy. B Liver transplantation: As per ERKNet 2023 guidelines, perform liver transplantation with complete removal of the native liver in patients with primary hyperoxaluria. B Show 4 more As per AASLD 2014 guidelines, consider performing preemptive liver transplantation (before the development of advanced renal disease) or combined liver and kidney transplantation in the https://web.pathway.md/diseases/recURu9iv10sfKMhE 3/5 6/24/23, 12:45 PM Hyperoxaluria Pathway setting of end-stage renal disease in patients with primary hyperoxaluria not responding to medical therapy. B 7. Specific circumstances Patients with infantile oxalosis: define infantile oxalosis as stage 5D CKD due to primary hyperoxaluria before the age of 1 year. B Show 3 more Patients with enteric hyperoxaluria: As per CUA 2022 guidelines, offer elemental calcium or calcium citrate taken with meals to bind with dietary oxalate and reduce its intestinal absorption in patients with enteric hyperoxaluria. B As per EAU 2021 guidelines, offer alkaline citrates and calcium supplements for the prevention of kidney stones in patients with enteric hyperoxaluria. Advise reducing dietary fat and oxalate intake. B As per AACE 2020 guidelines, advise avoiding dehydration, B adopting a low-oxalate meal plan, B and offer oral calcium B and potassium citrate therapy B for the management of oxalosis and calcium oxalate stones occurred after bariatric surgery. Consider offering probiotics containing Oxalobacter formigenes to improve renal oxalate excretion and improve supersaturation levels. B Patients with hyperuricosuria: initiate allopurinol in patients with recurrent calcium oxalate stones with hyperuricosuria and normal urinary calcium. B 8. Preventative measures Medications to avoid: As per CUA 2022 guidelines, do not use vitamin C supplementation of > 1,000 mg/day because of the associated risk of hyperoxaluria and nephrolithiasis. D As per AACE 2016 guidelines, do not use orlistat in patients with, or at risk of, oxalate nephropathy. D 9. Follow-up and surveillance Assessment of treatment response: Assess pyridoxine responsiveness in all patients with primary hyperoxaluria type 1 and titrate its dose based on urinary oxalate excretion. B Consider continuing RNA interference therapy and other specific new therapies based on annual re-evaluation of biochemical and clinical efficacy. C Imaging surveillance: consider obtaining lifelong imaging surveillance in patients with primary hyperoxaluria. C https://web.pathway.md/diseases/recURu9iv10sfKMhE 4/5 6/24/23, 12:45 PM Hyperoxaluria Pathway References 1. Jaap W Groothoff, Ella Metry, Lisa Deesker et al. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat Rev Nephrol. 2023 Jan 5. Open 2. C T rk, A. Neisius, A. Pet k et al. EAU Guidelines on Urolithiasis. EAU Guidelines. 2021 Mar. Open 3. Pearle MS, Goldfarb DS, Assimos DG et al. Medical management of kidney stones: AUA guideline. J Urol. 2014 Aug;192 2 316 24. Open 4. Naeem Bhojani, Jennifer Bjazevic, Brendan Wallace et al. Update 2022 Canadian Urological Association guideline: Evaluation and medical management of the kidney stone patient. Can Urol Assoc J. 2022 Mar 11. Open 5. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 6. W Timothy Garvey, Jeffrey I Mechanick, Elise M Brett et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3 1 203. Open 7. Jeffrey I Mechanick, Caroline Apovian, Stacy Brethauer et al. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity Silver Spring). 2020 Apr;28 4 O1 O58. Open 8. Steven J Chadban, Curie Ahn, David A Axelrod et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104 4S1 Suppl 1 S11 S103. Open https://web.pathway.md/diseases/recURu9iv10sfKMhE 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hyperprolactinemia are prepared by our editorial team based on guidelines from the European Society of Endocrinology (ESE 2021), the European Thyroid Association (ETA 2018), and the Endocrine Society (ES 2011). 1 2 3 Guidelines 1. Screening and diagnosis Diagnosis: obtain a single measurement of serum prolactin for the diagnosis of hyperprolactinemia and confirm the diagnosis with a level above the ULN as long as the serum sample is obtained without excessive venipuncture stress. A Differential diagnosis: Exclude the following causes in patients with symptomatic non- physiological hyperprolactinemia: medication use renal failure hypothyroidism parasellar tumors. A https://web.pathway.md/diseases/rechvfZS1fT3Z9dog 1/4 6/24/23, 12:45 PM Hyperprolactinemia Pathway pa ase a tu o s 2. Diagnostic investigations Serum prolactin levels: obtain a single measurement of serum prolactin for the diagnosis of hyperprolactinemia. A Show 3 more Screening for central hypothyroidism: obtain screening for central hypothyroidism in patients with hyperprolactinemia and hypothyroid manifestations. A 3. Medical management Dopamine agonists: initiate dopamine agonist therapy to lower prolactin levels, decrease tumor size, and restore gonadal function in patients with symptomatic prolactin-secreting microadenomas or macroadenomas. A Show 7 more Oral contraceptives: consider initiating oral contraceptives for the treatment of patients with amenorrhea caused by a microadenoma. C 4. Therapeutic procedures Radiotherapy: consider offering radiation therapy in patients failed surgical treatment or with aggressive or malignant prolactinomas. C 5. Surgical interventions Transsphenoidal surgery: consider performing transsphenoidal surgery in symptomatic patients with prolactinomas not tolerating high doses of cabergoline or not responsive to dopamine agonist therapy. C 6. Specific circumstances Patients contemplating pregnancy: As per ESE 2021 guidelines, manage female patients of reproductive age contemplating pregnancy with a diagnosis of pituitary adenoma, functioning or nonfunctioning, by an endocrinologist. B Show 3 more As per ES 2011 guidelines: Counsel female patients with a macroprolactinoma not showing pituitary tumor shrinkage during dopamine agonist therapy or not tolerating bromocriptine or cabergoline about the https://web.pathway.md/diseases/rechvfZS1fT3Z9dog 2/4 6/24/23, 12:45 PM Hyperprolactinemia Pathway potential benefits of surgical resection before attempting pregnancy. B Instruct female patients with prolactinomas to discontinue dopamine agonist therapy as soon as pregnancy is identified. B Pregnant patients, monitoring: As per ESE 2021 guidelines, do not measure prolactin during pregnancy. D Show 4 more As per ES 2011 guidelines, do not assess serum prolactin levels during pregnancy in patients with prolactinomas. D Show 2 more Pregnant patients, management: As per ESE 2021 guidelines, discontinue dopamine agonists once pregnancy is established. Consider continuing dopamine agonists for a longer gestational period in specific circumstances. B Show 3 more As per ES 2011 guidelines: Consider continuing dopaminergic therapy throughout the pregnancy in selected patients with macroadenomas with no prior history of undergoing surgery or radiation therapy, especially if the tumor is invasive or is abutting the optic chiasm. B Initiate bromocriptine therapy in patients experiencing symptomatic growth of a prolactinoma during pregnancy. B Pregnant patients (delivery and breastfeeding): consider providing standard obstetrical care with close maternal and fetal surveillance in pregnant patients with pituitary adenomas. C Show 2 more Patients with drug-induced hyperprolactinemia: consider discontinuing medication for 3 days or substituting with an alternative followed by re-measurement of serum prolactin in symptomatic patients with suspected drug-induced hyperprolactinemia. C Show 6 more Patients with malignant prolactinoma: Consider offering radiation therapy in patients with aggressive or malignant prolactinomas. C Consider offering temozolomide in patients with malignant prolactinomas. C References 1. A Luger, L H A Broersen, N R Biermasz et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021 Aug 23;185 3 G1 G33. Open 2. Melmed S, Casanueva FF, Hoffman AR et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96 2 273 88. Open 3. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open https://web.pathway.md/diseases/rechvfZS1fT3Z9dog 3/4 6/24/23, 12:45 PM Hyperprolactinemia Pathway 4. A Luger, L H A Broersen, N R Biermasz et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021 Aug 23;185 3 G1 G33. Open https://web.pathway.md/diseases/rechvfZS1fT3Z9dog 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hypersensitivity pneumonitis (HP) are prepared by our editorial team based on guidelines from the American College of Chest Physicians (ACCP 2021), the Latin American Thoracic Association (ALAT/JRS/ATS 2020), the American Thoracic Society (ATS 2011), and the British Thoracic Society (BTS/TSANZ/ITS 2008). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnosis: As per ACCP 2021 guidelines, consider using clinical improvement with antigen avoidance, if an inciting antigen is identified and then completely avoided, to support the diagnosis in patients with suspected HP. Avoid relying solely on the lack of clinical improvement with antigen avoidance to rule out the diagnosis of HP. C Show 2 more https://web.pathway.md/diseases/recAKcR8Fglc9M2hN 1/4 6/24/23, 12:45 PM Hypersensitivity pneumonitis Pathway As per BTS 2008 guidelines, recognize that the diagnosis of HP requires a high index of suspicion and in difficult cases an integrated multidisciplinary approach is essential. B 2. Classification and risk stratification Classification: Consider classifying patients with suspected HP based on the likelihood of an occupational or environmental inciting antigen exposure. C Consider classifying the disease as fibrotic or non-fibrotic based on the presence or absence of fibrosis on HRCT of the chest in patients with either newly diagnosed or a working diagnosis of HP. C 3. Diagnostic investigations General principles: Consider using a multidisciplinary discussion for diagnostic decision-making in patients with suspected HP. C Consider including an occupational medicine specialist and an environmental hygienist in the multidisciplinary diagnostic workup in patients with suspected HP, if the inciting antigen is thought to be related to an occupational exposure especially if the source of exposure is obscure or unverified. E Exposure history: consider eliciting a thorough clinical history of exposures focused on establishing the type, extent, and temporal relationship of exposures to symptoms in patients with suspected HP. E Antigen-specific antibodies: As per ACCP 2021 guidelines, avoid relying solely on serum antigen-specific IgG or IgA to confirm or rule out the diagnosis in patients with suspected HP. D As per ATS 2020 guidelines, consider obtaining serum IgG targeting potential antigens associated with HP in patients with newly identified ILD if differential diagnosis includes non- fibrotic or fibrotic HP. C Antigen-specific lymphocyte proliferation testing: avoid obtaining antigen-specific lymphocyte proliferation testing to support the diagnosis in patients with suspected pneumonitis. D Computed tomography: consider integrating HRCT findings characteristic of HP with clinical findings to support the diagnosis in patients with suspected HP, but do not use CT findings in isolation to make a definite diagnosis. C 4. Diagnostic procedures Bronchoalveolar lavage: https://web.pathway.md/diseases/recAKcR8Fglc9M2hN 2/4 6/24/23, 12:45 PM Hypersensitivity pneumonitis Pathway As per ACCP 2021 guidelines, do not perform routine BAL fluid analysis to confirm the diagnosis in patients with suspected HP having a compelling exposure history within the appropriate clinical context and a chest HRCT pattern typical for HP. D As per ATS 2020 guidelines: Perform BAL with lymphocyte cellular analysis in patients with newly identified ILD if differential diagnosis includes non-fibrotic HP. B Consider performing BAL with lymphocyte cellular analysis in patients with newly identified ILD if differential diagnosis includes fibrotic HP. C As per BTS 2008 guidelines, recognize that typical BAL cellular profiles may allow a diagnosis of HP with greater confidence, if the diagnosis is uncertain after clinical assessment and HRCT. B Inhalation challenge testing: avoid performing antigen-specific inhalation challenge testing to support the diagnosis in patients with suspected HP. D Lung biopsy: As per ACCP 2021 guidelines: Consider performing histological lung biopsy for additional diagnostic evaluation in patients with suspected HP if all available data such as clinical, laboratory and radiologic findings along with bronchoscopic results do not yield a confident diagnosis and results may help guide management. C Consider integrating biopsy findings with clinical and radiological findings to support the diagnosis in patients with suspected HP in the context of multidisciplinary discussion. C As per ATS 2020 guidelines, consider performing transbronchial forceps lung biopsy in patients with newly identified ILD if differential diagnosis includes non-fibrotic HP. C Show 4 more 5. Medical management Corticosteroids: consider offering corticosteroids for the management of patients with severe or progressive HP. C 6. Nonpharmacologic interventions Avoidance of causative antigens: offer avoiding of the causative antigens, when identified, as the most important and effective aspect of management. B 7. Specific circumstances Patients with hypersensitivity pneumonitis related to Aspergillus: Advise avoidance of Aspergillus exposure in patients with HP related to Aspergillus and, when necessary, initiate corticosteroid therapy up to 60 mg/day, tapering over 1 month. B https://web.pathway.md/diseases/recAKcR8Fglc9M2hN 3/4 6/24/23, 12:45 PM Hypersensitivity pneumonitis Pathway Do not use antifungal therapy in patients with HP related to Aspergillus. D References 1. Ganesh Raghu, Martine Remy-Jardin, Christopher J Ryerson et al. Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2020 Aug 1;202 3):e36-e69. Open 2. Evans R Fern ndez P rez, William D Travis, David A Lynch et al. Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report. Chest. 2021 Aug;160 2):e97- e156. Open 3. B Bradley, H M Branley, J J Egan Irish Thoracic Society) et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008 Sep;63 Suppl 5:v1 58. Open 4. Andrew H Limper, Kenneth S Knox, George A Sarosi et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183 1 96 128. Open 5. Jonathan P Parsons, Teal S Hallstrand, John G Mastronarde et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2013 May 1;187 9 1016 27. Open https://web.pathway.md/diseases/recAKcR8Fglc9M2hN 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hypersensitivity reactions to chemotherapy are prepared by our editorial team based on guidelines from the European Academy of Allergy and Clinical Immunology (EAACI 2022), the European Society of Medical Oncology (ESMO 2017), and the Comit de l' volution de la pratique en oncologie (CEPO 2014). 1 2 3 Guidelines 1. Screening and diagnosis Pathogenesis: Recognize the pathogenetic mechanisms of hypersensitivity reactions to different chemotherapeutic agents: Situation Guidance IgE-mediated reactions in some immediate, often severe cases B Platinum compounds https://web.pathway.md/diseases/recXCuhDZ7scNuvWY 1/5 6/24/23, 12:45 PM Hypersensitivity reactions to chemotherapy Pathway Direct activation of complement system by the drug in the majority of cases Taxanes IgE-mediated reactions in some cases B Immunologic and non-immunologic mechanisms. B Epipodophyllotoxins 2. Classification and risk stratification Risk factors: take into account other risk factors apart from being aware of the potential risk of an infusion reaction of a specific drug, when delivering anticancer drugs, and during which course it is most likely to happen. B Show 2 more Severity grading: as per ESMO 2017 guidelines, grade adverse reactions in a standardized way to evaluate the severity of an infusion reaction. B 3. Diagnostic investigations Skin testing: As per EAACI 2022 guidelines, recognize that skin testing is the most readily available diagnostic test. B Show 3 more As per CEPO 2014 guidelines, consider obtaining skin testing (prick and intradermal) in patients with suspected hypersensitivity to platinum drugs, whenever possible. Obtain the test at least 2- 6 weeks after a hypersensitivity reaction. C Show 2 more Drug provocation test: Obtain drug provocation testing as the gold standard for the diagnosis of hypersensitivity reactions to drugs A , and to help avoid a significant number of patients from unnecessary drug desensitizations. B Recognize that drug provocation testing is a high-risk technique and benefits from dedicated spaces and expert personnel, while has a good safety profile when performed in specialist centers. B In vitro IgE testing: consider obtaining in vitro detection of specific IgE for platinum compounds for the diagnosis of hypersensitivity reactions to these drugs. C Tryptase and histamine tests: do not obtain serum tryptase, serum and urine histamine tests in patients with anaphylaxis, as these tests are not universally available, not carried out on an emergency basis and not specific for anaphylaxis. D https://web.pathway.md/diseases/recXCuhDZ7scNuvWY 2/5 6/24/23, 12:45 PM Hypersensitivity reactions to chemotherapy Pathway 4. Medical management Observation: Recognize that prompt recognition and immediate medical attention are essential. Recognize that some patients feel odd or uncomfortable or express a need to urinate or defecate before an infusion reaction. Pay serious attention to those symptoms and evaluate the patient by measuring BP and pulse rate. B Initial supportive therapy: discontinue the administration of medication caused infusion reaction. B Show 10 more Management of anaphylaxis: administer epinephrine immediately at a dose of 0.01 mg/kg, 1 mg/mL dilution to a maximum total dose of 0.5 mL, intramuscularly into the lateral thigh muscle in patients fulfilling any of the three criteria of anaphylaxis. B Consider repeated administration every 5-15 minutes. B Administer IV epinephrine after a failure of a prompt response with severe hypotension or cardiac arrest. B Show 6 more Drug desensitization: As per EAACI 2022 guidelines, perform rapid drug desensitization in patients with immediate reactions, anaphylaxis and delayed reactions non-severe cutaneous adverse reactions. B Show 2 more As per ESMO 2017 guidelines, consider performing desensitization in patients with grade 3/4 infusion reaction caused by carboplatin, oxaliplatin, docetaxel, anthracyclines, or etoposide. C As per CEPO 2014 guidelines, consider using a multi-step desensitization protocol in case of a positive skin test for platinum drugs or a type I hypersensitivity reaction, if treatment cannot be substituted and if stopping treatment would affect the patient's survival. C Show 6 more 5. Nonpharmacologic interventions Psychological support: Provide psychological intervention to alleviate symptoms of uncertainty related to a potential infusion reaction with anticancer drugs. B Provide psychological support and have a complete, informative discussion with the patient about the potential benefits of continuing with the drug and the risk of infusion reaction recurrence. B 6. Preventative measures Preparation before drug delivery: elicit a medical history, ask about previous allergic disorders, atopic status and concomitant treatments before the administration of any drug. B https://web.pathway.md/diseases/recXCuhDZ7scNuvWY 3/5 6/24/23, 12:45 PM Hypersensitivity reactions to chemotherapy Pathway Show 2 more Premedication: As per EAACI 2022 guidelines, administer premedication with corticosteroids and antihistamines (such as dexametasone 20 mg and chlorpheniramine 10 mg IV 1 hour before chemotherapy) for the prevention of moderate-to-severe infusion reactions to taxanes. B Show 2 more As per ESMO 2017 guidelines, administer premedication with corticosteroids and antihistamines in patients before taxane B , asparaginase and etoposide infusion. B Show 6 more As per CEPO 2014 guidelines: Do not administer routine premedication with corticosteroids and antihistamines before platinum agents infusion. D Administer routine premedication with corticosteroids and H1RAs and H1RAs before taxanes infusion. A Rate of administration: as per ESMO 2017 guidelines, slow the infusion rate of anthracyclines. B Show 5 more Prevention of future episodes: attempt to establish, based on the precipitating drug and the characteristics of the event, the steps that could be taken to prevent future episodes following any infusion reaction episode. B 7. Follow-up and surveillance Post-reaction monitoring: obtain close observation for 24 hours after a severe reaction. Monitor vital signs and control recurrence symptoms. B Show 3 more Rechallenge: decide on restoring treatment based on the severity and nature of the reaction as well as clinical factors such as the risk of a serious recurrent reaction and the potential clinical benefit of further treatment. B Show 2 more 8. Quality improvement Reporting: ensure accurate documentation of the infusion reaction episode, including pre-infusion assessments, an appropriate description and grading of the infusion reaction (according to accepted classifications such as CTCAE), and how it was managed. B References https://web.pathway.md/diseases/recXCuhDZ7scNuvWY 4/5 6/24/23, 12:45 PM Hypersensitivity reactions to chemotherapy Pathway 1. S Rosell , I Blasco, L Garc a Fabregat et al. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017 Jul 1;28(suppl_4):iv100-iv118. Open 2. J Boulanger, J N Boursiquot, G Cournoyer et al. Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations. Curr Oncol. 2014 Aug;21 4):e630 41. Open 3. Mauro Pagani, Sevim Bavbek, Emilio Alvarez-Cuesta et al. Hypersensitivity reactions to chemotherapy: an EAACI Position Paper. Allergy. 2022 Feb;77 2 388 403. Open 4. David A Khan, Aleena Banerji, Kimberly G Blumenthal et al. Drug Allergy: A 2022 Practice Parameter Update. J Allergy Clin Immunol. 2022 Sep 16;S0091 6749 22 01186 1. Open https://web.pathway.md/diseases/recXCuhDZ7scNuvWY 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hypertension (HTN) are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the American Association of Family Physicians (AAFP 2022), the Heart Failure Society of America (HFSA/AHA/ACC 2022), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021), the U.S. Preventive Services Task Force (USPSTF 2021; 2020), the Hypertension Canada Guidelines (Hypertension Canada 2020), the European Society of Cardiology (ESC/ESH 2018), the American College of Preventive Medicine (ACPM/PCNA/ABC/ASPC/ASH/AAPA/AGS/AHA/NMA/ACC/APhA 2018), the American College of Physicians (ACP/AAFP 2017), the American College of Endocrinology (ACE/AACE 2016), the Endocrine Society (ES 2015), and the Joint National Committee (JNC 2014). 1 2 3 3 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Definition According to the 2017 ACC/AHA, elevated BP (BP) is defined as systolic pressure between 120 and 129 mm Hg and diastolic pressure less than 80 mm Hg. Stage 1 HTN is defined as systolic BP https://web.pathway.md/diseases/reclWZaqSp36TX3eN 1/18 6/24/23, 12:46 PM Hypertension Pathway greater than 130 mm Hg or diastolic BP greater than 80 mm Hg. 3 Epidemiology Primary HTN etiology is multifactorial and most frequently associated with a combination of environmental (unhealthy diet, increased sodium intake, insufficient potassium intake, inadequate physical activity, overweight/obesity) and genetic factors (multiple risk alleles, gene-gene interactions, fetal programming, epigenetic mechanisms). Secondary HTN etiology includes primary aldosteronism, renal HTN, renal parenchymal disease, pheochromocytoma/paraganglioma, Cushing's syndrome, hypothyroidism, hyperthyroidism, hypercalcemia and primary hyperparathyroidism, congenital adrenal hyperplasia, acromegaly, coarctation of the aorta, and medication or recreational drug use (amphetamines, cocaine, phencyclidine). White-coat HTN and isolated systolic HTN are essential subtypes. 14 Pathophysiology HTN is highly prevalent worldwide. The prevalence of HTN in the United States is estimated at 31,900 per 100,000 adults based on the 140/90-mm Hg cutoff. Rates are highest in African Americans and increase with age. 3 Disease course HTN is mostly asymptomatic until an acute hypertensive crisis or end-organ complications occur. Manifestations of end-organ damage in HTN include motor or sensory deficit (brain); hypertensive retinopathy (retina); and AF, arrhythmias, pulmonary congestion and peripheral edema (heart). Secondary HTN presents with symptoms of the causal condition, for example, abdominal bruit in renal artery stenosis or abdominal masses in polycystic kidney disease. A fourth heart sound is often the earliest sign of hypertensive heart disease. HTN decreases health-related quality of life. 15 Prognosis and risk of recurrence Prognosis is highly dependant on the BP and end-organ damage. Higher BP and more severe retinopathy or organ damage are associated with a worse prognosis. Untreated or treatment- resistant HTN leads to lower survival rates. However, effective BP control raises 10-year survival rates to 70%. 16 CalculatorNYHA functional classification f Guidelines https://web.pathway.md/diseases/reclWZaqSp36TX3eN 2/18 6/24/23, 12:46 PM Hypertension Pathway 1. Screening and diagnosis Indications for screening, adults: As per USPSTF 2021 guidelines, obtain screening for HTN with office BP measurement in 18 years old adults. Obtain BP measurements outside of the clinical setting for diagnostic confirmation before starting treatment. A As per ESH/ESC 2018 guidelines, obtain screening for HTN with a measurement of office BP in all adult patients 18 years of age. Record the BP results in the patient's medical file and inform them about their BP. B As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, screen for HTN in adults 18 years of age. A Indications for screening (pediatrics): insufficient evidence to assess the balance of benefits and harms of screening for high BP in children and adolescents. I Screening for white coat hypertension: consider obtaining daytime ambulatory BP monitoring or home BP monitoring to screen for white coat HTN in adult patients with untreated systolic BP > 130 mmHg but < 160 mmHg or diastolic BP > 80 mmHg but < 100 mmHg. C 2. Classification and risk stratification Staging: As per ESC 2018 guidelines, classify BP as optimal, normal, or high-normal, or grades 1-3 HTN, according to office BP. B As per ACC 2018 guidelines, classify BP as follows, in order to assist in appropriate prevention and treatment of high BP: normal (systolic BP < 120 mmHg and diastolic BP < 80 mmHg) elevated (systolic BP 120-129 mmHg and diastolic BP < 80 mmHg) stage 1 HTN (systolic BP 130-139 mmHg or diastolic BP 80-89 mmHg) stage 2 HTN (systolic BP 140 mmHg or diastolic BP 90 mmHg). B Cardiovascular risk stratification: As per CHEP 2020 guidelines, assess global cardiovascular risk in patients with HTN. Consider obtaining multifactorial risk assessment models to: predict more accurately a patient's global cardiovascular risk A help engage patients in conversations about health behavior change to lower BP B use antihypertensive therapy more efficiently. B Show 2 more As per ESC 2018 guidelines, obtain cardiovascular risk assessment with the SCORE system in patients with HTN not already at high or very high risk due to established CVD, renal disease, or diabetes. B https://web.pathway.md/diseases/reclWZaqSp36TX3eN 3/18 6/24/23, 12:46 PM Hypertension Pathway 3. Diagnostic investigations Office blood pressure measurement: As per KDIGO 2021 guidelines, obtain standardized office BP measurement in preference to routine office BP measurement for the management of high BP in adult patients. B Show 3 more As per ESC 2018 guidelines, repeat office BP measurements on more than one visit, except when HTN is severe (grade 3 and especially in high-risk patients). Record three BP measurements at each visit, 1-2 min apart, and perform additional measurements if the first two readings differ by > 10 mmHg. Recognize that the patient's BP is the average of the last two BP readings. B Out-of-office blood pressure measurement: As per KDIGO 2021 guidelines, consider obtaining out-of-office BP measurements with ambulatory BP monitoring or home BP monitoring to complement standardized office BP readings for the management of high BP. C As per CHEP 2020 guidelines, obtain ambulatory BP monitoring or home BP monitoring for follow-up of patients with demonstrated white coat effect. B Show 4 more As per ESC 2018 guidelines, obtain out-of-office BP measurement with ambulatory BP monitoring and/or home BP monitoring, provided that these measurements are logistically and economically feasible. B As per ACC 2018 guidelines, obtain out-of-office BP measurements to confirm the diagnosis of HTN and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions. A Show 2 more Initial investigations: As per CHEP 2020 guidelines, obtain the following routine tests for the evaluation of all patients with HTN: urinalysis blood chemistry (potassium, sodium, and creatinine) fasting blood glucose and/or Hgb A1C serum total cholesterol, LDL, high-density lipoprotein, non-HDL-C, and triglycerides. B Show 4 more As per ACC 2018 guidelines: Obtain the following tests in patients newly diagnosed with HTN: CBC serum creatinine with estimated GFR serum sodium, potassium, calcium lipid profile https://web.pathway.md/diseases/reclWZaqSp36TX3eN 4/18 6/24/23, 12:46 PM Hypertension Pathway fasting blood glucose TSH urinalysis ECG. Consider obtaining uric acid and urinary albumin to creatinine ratio on a case-by-case basis in patients with newly diagnosed HTN. Echocardiography: As per CHEP 2020 guidelines, do not obtain routine echocardiographic evaluation in patients with HTN. D Show 3 more As per ACC 2018 guidelines, consider obtaining echocardiography on a case-by-case basis in patients with newly diagnosed HTN. Evaluation for modifiable risk factors: As per CHEP 2020 guidelines, measure height, weight, and waist circumference and calculate BMI in all adults. B As per ACC 2018 guidelines, screen for and manage other modifiable CVD risk factors in adults with HTN. B Evaluation for drug or alcohol use: Assess for use of the following substances in patients with HTN: sodium-containing antacids; caffeine; nicotine (smoking); alcohol; nonsteroidal anti-inflammatory agents; oral contraceptives; cyclosporine or tacrolimus; sympathomimetics (decongestants, anorectics); cocaine, amphetamines and other illicit drugs; neuropsychiatric agents; ESAs; clonidine withdrawal; and herbal agents (Ma Huang, ephedra). B Obtain a toxicology screen to evaluate for drug or alcohol abuse in patients with HTN and symptoms suggestive of illicit drug use. B Evaluation for obstructive sleep apnea: Obtain a screening test for obstructive apnea (such as the Berlin Questionnaire, Epworth Sleepiness Score, or overnight oximetry) in patients with HTN meeting any of the following criteria: resistant HTN loss of normal nocturnal BP fall snoring, fitful sleep, breathing pauses during sleep daytime sleepiness obesity, Mallampati class III-IV. B Evaluation for renovascular disease: Obtain renal duplex Doppler ultrasound, MRA, or abdominal CT to evaluate for renovascular disease in patients meeting with HTN meeting any of the following criteria: resistant HTN, or increasingly difficult to control HTN of abrupt onset or worsening flash pulmonary edema https://web.pathway.md/diseases/reclWZaqSp36TX3eN 5/18 6/24/23, 12:46 PM Hypertension Pathway early-onset HTN, especially in women abdominal systolic-diastolic bruit bruits over other arteries. B Evaluation for renal parenchymal disease: Obtain renal ultrasound to evaluate for renal parenchymal disease in patients with HTN meeting any of the following criteria: history of UTIs or obstruction symptoms of hematuria, urinary frequency and nocturia history of analgesic abuse family history of polycystic kidney disease elevated serum creatinine, or abnormal urinalysis abdominal mass (polycystic kidney disease). B Evaluation for primary hyperaldosteronism: Screen for primary hyperaldosteronism in patients meeting any of the following criteria: resistant HTN spontaneous hypokalemia marked diuretic-induced hypokalemia incidentally discovered adrenal mass family history of early-onset HTN stroke at < 40 years of age. B Use plasma aldosterone to renin activity ratio as the first-line test for primary hyperaldosteronism in adults. B Evaluation for pheochromocytoma: Obtain 24-h urinary fractionated metanephrines (or plasma metanephrines under standard conditions) to screen for pheochromocytoma in patients with HTN meeting any of the following criteria: resistant HTN or paroxysmal HTN BP lability, headache, sweating, palpitations, pallor positive family history of pheochromocytoma/paraganglioma adrenal incidentaloma skin stigmata of neurofibromatosis (caf -au-lait spots; neurofibromas) orthostatic hypotension. B Evaluation for aortic coarctation: Obtain echocardiography to screen for aortic coarctation in patients with HTN meeting any of the following criteria: young patient with HTN (< 30 years of age) BP higher in upper extremities than in lower extremities absent femoral pulses continuous murmur over patient's back, chest, or abdominal bruit left thoracotomy scar (postoperative). B https://web.pathway.md/diseases/reclWZaqSp36TX3eN 6/18 6/24/23, 12:46 PM Hypertension Pathway Evaluation for thyroid disease: Obtain a TSH to screen for hypothyroidism in patients with HTN meeting any of the following criteria: dry skin; cold intolerance; constipation; hoarseness; weight gain delayed ankle reflex; periorbital puffiness; coarse skin; cold skin; slow movement; goiter. B Obtain a serum TSH to screen for hyperthyroidism in patients with HTN meeting any of the following criteria: warm, moist skin; heat intolerance; nervousness; tremulousness; insomnia; weight loss; diarrhea; proximal muscle weakness lid lag; fine tremor of the outstretched hands; warm, moist skin. B Evaluation for hyperparathyroidism: obtain a serum PTH to screen for primary hyperparathyroidism in patients with HTN and hypercalcemia. B Evaluation for congenital adrenal hyperplasia: Obtain screening for congenital adrenal hyperplasia in patients with HTN meeting any of the following criteria: HTN and hypokalemia; signs of virilization (11- -OH) incomplete masculinization (17-alpha-OH). B Evaluation for acromegaly: Obtain a serum GH level to screen for acromegaly in patients with HTN who meet any of the following criteria: enlarging shoe, glove, or hat size headache, visual disturbances concomitant diabetes mellitus acral features or frontal bossing. B Genetic testing: avoid routine genetic testing for hypertensive patients. D 4. Medical management Indications for treatment, general population: As per Hypertension Canada 2020 guidelines, initiate antihypertensive therapy for average diastolic BP measurements of 100 mmHg or average systolic BP measurements of 160 mmHg in patients without macrovascular target organ damage or other cardiovascular risk factors. A Show 2 more As per ESH/ESC 2018 guidelines: Initiate BP-lowering pharmacotherapy promptly in patients with grade 2-3 HTN at any level of cardiovascular risk, simultaneously with the initiation of lifestyle changes. A Avoid withdrawing BP-lowering pharmacotherapy on the basis of age, even when patients attain an age of 80 years, provided that treatment is well tolerated. D https://web.pathway.md/diseases/reclWZaqSp36TX3eN 7/18 6/24/23, 12:46 PM Hypertension Pathway As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, initiate BP-lowering therapy for the primary prevention of CVD in adults with a systolic BP 140 mmHg or a diastolic BP 90 mmHg with an estimated 10-year ASCVD risk < 10%. B Indications for treatment (>= 60 years old patients): initiate treatment in adults 60 years of age with systolic BP persistently 150 mmHg to achieve a target systolic BP of < 150 mmHg to reduce the risk for mortality, stroke, and cardiac events. A Goals of treatment, general population: As per AAFP 2022 guidelines: Treat adult patients with HTN to a standard BP target (< 140/90 mmHg) to reduce the risk of all-cause and cardiovascular mortality. A Consider treating adult patients with HTN to a lower BP target (< 135/85 mmHg) to reduce the risk of myocardial infarction. C As per Hypertension Canada 2020 guidelines, treat adult patients with HTN to a systolic BP goal of < 140 mmHg B and a diastolic BP goal of < 90 mmHg. A As per JNC 2014 guidelines: Treat adult patients with HTN, both aged 18-29 B and 30-59 years, to lower BP to a goal of diastolic BP < 90 mmHg. A Treat adult patients with HTN aged < 60 years to lower BP to a goal of systolic BP < 140 mmHg. B Goals of treatment (>= 60 years old patients): Consider initiating or intensifying pharmacologic treatment to achieve a target systolic BP of < 140 mmHg with the goal of reducing the risk for stroke or cardiac event in selected 60 years old patients at high cardiovascular risk, based on individualized assessment. C Set treatment goals based on a periodic discussion of the benefits and harms of specific BP targets with the patient. Consider initiating or intensifying pharmacologic treatment to achieve a target systolic BP of < 140 mmHg with the goal of reducing the risk for stroke or cardiac events in 60 years old patients with a history of stroke or TIA. C Set treatment goals based on a periodic discussion of the benefits and harms of specific BP targets with the patient. Goals of treatment (patients at high CV risk): target a BP < 130/80 mmHg in adult patients with HTN and known CVD or 10-year ASCVD event risk 10%. B Show 4 more Updated evidence: SPRINT (secondary analysis) In patients 50 years of age with hypertension and increased cardiovascular risk, intensive BP control was not superior to standard BP control with respect to the rate of death from cardiovascular causes at a follow-up of 8.8 years. Byron C Jaeger et al. JAMA Cardiol. 2022 Nov 1. https://web.pathway.md/diseases/reclWZaqSp36TX3eN 8/18 6/24/23, 12:46 PM Hypertension Pathway Choice of antihypertensive (general principles): use once daily medication dosing, rather than multiple times daily, in order to improve adherence to antihypertensive therapy. B Show 2 more Choice of antihypertensive, initial therapy: As per Hypertension Canada 2020 guidelines, initiate treatment with either monotherapy or a single-pill combination, with choices including: monotherapy: a thiazide/thiazide-like diuretic, A preferably longer-acting B ; a -blocker, particularly in < 60 years old patients B ; an ACEI, particularly in nonblack patients B ; an ARB B ; a long-acting CCB B single-pill combinations: an ACEI with a CCB A ; an ARB with a CCB B ; an ACEI or ARB with a diuretic B Show 2 more As per ESH/ESC 2018 guidelines, initiate combination treatment as initial therapy in most patients with HTN. Prefer combinations of a RAAS blocker (either an ACEI or an ARB) with a CCB or diuretic. Consider using other combinations of the five major classes. Combine - blockers with any of the other major drug classes when there are specific clinical situations, such as angina, post-myocardial infarction, HF, or HR control. A Show 2 more As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, initiate antihypertensive drug therapy with thiazide diuretics, CCBs, ACEIs, or ARBs as first-line agents. A Show 2 more Landmark trials: ALLHAT In patients aged 55 years with hypertension and at least 1 other coronary artery disease risk factor, treatment with one of three antihypertensive agent classes (amlodipine, lisinopril or chlorthalidone) did not result in any significant differences in major adverse cardiovascular events (fatal CHD or nonfatal myocardial infarction). The RRs for amlodipine (6-year rate, 11.3%) and lisinopril (6-year rate, 11.4%) were 0.98, 95% CI 0.90-1.07 and 0.99, 95% CI 0.91-1.08, respectively, when compared with chlorthalidone (6-year rate, 11.5%). The measurement of 5-year systolic BP was significantly higher with amlodipine (0.8 mmHg, p = 0.3) and lisinopril (2 mmHg, p < 0.001) therapy, as compared with chlorthalidone; the 5-year diastolic BP was significantly lower with amlodipine (0.8 mmHg, p < 0.001). The effect of treatment with amlodipine was similar to chlorthalidone in relation to all measured aspects of CHD and CVD adverse events, except for higher 6-year rate of HF with amlodipine (10.2% vs. 7.7%). On comparing the effects of treatment of lisinopril with chlorthalidone, lisinopril was associated with higher 6-year rates of combined CVD (33.3% vs. 30.9%), stroke (6.3% vs. 5.6%) and HF (8.7% vs. 7.7%). https://web.pathway.md/diseases/reclWZaqSp36TX3eN 9/18 6/24/23, 12:46 PM Hypertension Pathway ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA. 2002 Dec 18. Choice of antihypertensive, subsequent therapy: As per Hypertension Canada 2020 guidelines, add additional antihypertensive drugs if target BP levels are not achieved with standard-dose monotherapy. B Choose add-on drugs from first- line choices, such as thiazide/thiazide-like diuretics or CCBs with either ACEIs, ARBs, or - blockers. B Be cautious when combining a nondihydropyridine CCB and a -blocker. B Do not combine an ACEI and an ARB. A Show 2 more As per ESH/ESC 2018 guidelines, increase treatment to a three-drug combination, usually a RAAS blocker with a CCB and thiazide/thiazide-like diuretics, preferably as a single-pill combination, if BP is not controlled with a two-drug combination. A Show 2 more Landmark trials: PATHWAY-2 (spironolactone vs. placebo) In patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months, spironolactone was superior to placebo with respect to reduction in home systolic BP through week 6 to week 12. Bryan Williams et al. Lancet. 2015 Nov 21. Management of hypertensive emergencies: admit adults with a hypertensive emergency to an ICU for continuous monitoring of BP and target organ damage and for parenteral administration of an appropriate agent. B Statin therapy: As per CHEP 2020 guidelines, initiate statin therapy in patients with HTN with 3 cardiovascular risk factors or with established atherosclerotic disease. A As per ESC 2018 guidelines, initiate statins in patients at high or very high cardiovascular risk. B Antiplatelet therapy: Avoid initiating aspirin for primary prevention in patients without CVD. D Initiate antiplatelet therapy, particularly low-dose aspirin, for secondary prevention in patients with HTN. A 5. Nonpharmacologic interventions Lifestyle modifications: As per ESC 2018 guidelines: https://web.pathway.md/diseases/reclWZaqSp36TX3eN 10/18 6/24/23, 12:46 PM Hypertension Pathway Recommend BP-lowering drug treatment and lifestyle interventions in fit older patients > 65 years but not > 80 years of age, when systolic BP is in the grade 1 range (such as 140-159 mmHg), provided that treatment is well tolerated. A Advise lifestyle changes in patients with high-normal BP (such as 130-139/85-89 mmHg). A As per ACC 2018 guidelines, offer effective behavioral and motivational strategies for adults with HTN to achieve a healthy lifestyle including tobacco cessation, weight loss, moderation in alcohol intake, increased physical activity, reduced sodium intake, and consumption of a healthy diet. B Dietary modifications: As per CHEP 2020 guidelines: Advise adopting a diet emphasizing fruits, vegetables, low-fat dairy products, whole grain foods rich in dietary fiber, protein from plant sources, and reduced in saturated fat and cholesterol in patients with HTN and nonhypertensive individuals at increased risk of developing HTN. B Advise increasing dietary potassium intake to reduce BP in patients not at risk of hyperkalemia. A As per ESC 2018 guidelines, encourage increased consumption of vegetables, fresh fruits, fish, nuts, and unsaturated fatty acids; low consumption of red meat; and consumption of low-fat dairy products. A As per ACC 2018 guidelines: Advise adopting a heart-healthy diet, such as the Dietary Approaches to Stop HTN diet, in order to achieve a desirable weight in adult patients with elevated BP or HTN. A Advise increasing intake of potassium, preferably via dietary modification, in adult patients with elevated BP or HTN unless contraindicated by the presence of CKD or the use of drugs reducing potassium excretion. A Salt restriction: As per CHEP 2020 guidelines, consider reducing sodium intake to 2 g (5 g of salt or 87 mmol of sodium) per day to prevent HTN in nonhypertensive individuals and reduce BP in adult patients with HTN. B As per ESC 2018 guidelines, advise restricting salt intake to < 5 g per day. A As per ACC 2018 guidelines, advise reducing sodium intake in adult patients with elevated BP or HTN. A Alcohol restriction: As per CHEP 2020 guidelines: Advise abstaining from alcohol or reducing alcohol intake to 2 drinks per day prevent HTN in healthy adults. B Advise reducing alcohol intake to decrease BP in adult patients with HTN drinking 2 drinks per day. Advise reducing alcohol intake to 2 drinks per day to decrease BP in adult patients with HTN drinking 6 drinks per day. A https://web.pathway.md/diseases/reclWZaqSp36TX3eN 11/18 6/24/23, 12:46 PM Hypertension Pathway As per ESC 2018 guidelines: Restrict alcohol consumption to < 14 units per week for males and < 8 units per week for females. A Advise against binge drinking. B As per ACC 2018 guidelines, advise limiting alcohol consumption ( 2 standard drinks per day foe males and 1 standard drink per day for females) in patients with elevated BP or HTN. A Weight loss: As per CHEP 2020 guidelines: Advise maintaining a healthy body weight (BMI 18.5-24.9) and waist circumference (< 102 cm for males and < 88 cm for females) for nonhypertensive individuals to prevent HTN (Grade C) and for hypertensive patients to reduce BP. B Offer weight loss in all patients with HTN and overweight. Offer a multidisciplinary approach for weight loss, including dietary education, increased physical activity, and behavioral intervention. B As per ESC 2018 guidelines, advise controlling body weight to avoid obesity (such as BMI > 30 kg/m or waist circumference > 102 cm in males and > 88 cm in females) and aim for a healthy BMI (about 20-25 kg/m ) and waist circumference values (< 94 cm in males and < 80 cm in females) to reduce BP and cardiovascular risks. A As per ACC 2018 guidelines, advise losing weight to reduce BP in adult patients with elevated BP or HTN with obesity or overweight. A Exercising: As per CHEP 2020 guidelines: Advise practicing moderate-intensity dynamic exercise, such as walking, jogging, cycling, or swimming, for 4-7 days per week (30-60 minutes in total) in addition to the routine activities of daily living to reduce BP in patients with HTN and to reduce the possibility of becoming hypertensive in nonhypertensive individuals. B Do not discourage practicing resistance or weight training exercise (such as free-weight lifting, fixed-weight lifting, or handgrip exercise) in patients with systolic BP/diastolic BP of 140- 159/90-99 mmHg as it does not adversely influence BP. D As per ESC 2018 guidelines, advise practicing regular aerobic exercises ( 30 minutes of moderate dynamic exercise on 5-7 days per week) in adult patients with HTN. A As per ACC 2018 guidelines, advise increasing the level of physical activity with a structured exercise program in adult patients with elevated BP or HTN. A Smoking cessation: As per CHEP 2020 guidelines: Update tobacco use status on a regular basis in all patients with HTN and advise to quit smoking. B Offer pharmacologic therapy (such as varenicline, bupropion, nicotine replacement therapy) in all smokers with a goal of smoking cessation. B https://web.pathway.md/diseases/reclWZaqSp36TX3eN 12/18 6/24/23, 12:46 PM Hypertension Pathway As per ESC 2018 guidelines, advise smoking cessation, provide supportive care, and refer to smoking cessation programs. B Stress management: Consider offering stress management in patients with HTN if stress appears to be contributing to high BP. C Offer individualized cognitive-behavioral interventions when relaxation techniques are used. B Supplements: do not offer supplementation of calcium or magnesium for the prevention or treatment of HTN. D Telehealth interventions: consider using telehealth strategies as adjuncts to other interventions shown to reduce BP for adults with HTN. B Adjuncts to control of hypertension: consider using performance measures in combination with other quality improvement strategies at patient-, provider-, and system-based levels to facilitate optimal HTN control. C 6. Therapeutic procedures Renal artery revascularization: consider referring patients with renal artery stenosis for consideration of renal artery revascularization when medical management has failed (refractory HTN, worsening renal function, and/or intractable HF) and when renal artery stenosis is due to nonatherosclerotic disease, including FMD. C Device-based therapies: avoid using device-based therapies for the routine treatment of HTN, unless in the context of clinical studies and RCTs, until further evidence regarding their safety and efficacy becomes available. D 7. Perioperative care Perioperative management of antihypertensives: continue -blockers in patients with HTN undergoing major surgery who have been on -blockers chronically. B Show 4 more 8. Specific circumstances Elderly patients: As per ESC 2018 guidelines, recommend BP-lowering drug treatment and lifestyle interventions in fit older patients with HTN even if > 80 years of age when systolic BP 160 mmHg. A As per AHA 2018 guidelines, treat HTN with a systolic BP treatment goal of < 130 mmHg for noninstitutionalized ambulatory community-dwelling adults 65 years of age with an average systolic BP 130 mmHg. A As per JNC 2014 guidelines: https://web.pathway.md/diseases/reclWZaqSp36TX3eN 13/18 6/24/23, 12:46 PM Hypertension Pathway Initiate pharmacologic treatment in the general population aged 60 years to lower BP at systolic BP 150 mmHg or diastolic BP 90 mmHg and treat to a goal of systolic BP < 150 mmHg and diastolic BP < 90 mmHg. A Do not adjust treatment in the general population aged 60 years if pharmacotherapy for high BP results in lower achieved systolic BP (< 140 mmHg) and treatment is well tolerated and without adverse effects on health or quality of life. D Pregnant patients: Transition women with HTN who become pregnant or are planning to conceive to treatment with methyldopa, nifedipine, and/or labetalol. B Avoid prescribing ACEIs, ARBs, or direct renin inhibitors in women with HTN who become pregnant. D Patients of black background: use a thiazide-type diuretic or CCB for initial antihypertensive treatment in black adults with HTN but without HF or CKD, including those with diabetes mellitus. B Patients with stage 1 hypertension: As per ESC 2018 guidelines, in patients with grade 1 HTN: advise lifestyle interventions to determine if this will normalize BP. (Class : I, LOE : B) administer BP-lowering drug treatment in patients with grade 1 HTN at low-moderate-risk and without evidence of HTN-mediated organ damage, if the patient remains hypertensive after a period of lifestyle intervention initiate drug treatment promptly with simultaneous lifestyle interventions, in patients with grade 1 HTN at high risk or with evidence of HTN-mediated organ damage. (Class : I, LOE : A). A As per ACC 2018 guidelines, manage adults with an elevated BP or stage 1 HTN who have an estimated 10-year ASCVD risk < 10% with nonpharmacological therapy and repeat BP evaluation within 3 to 6 months. B Patients with obesity: As per AACE 2016 guidelines, prefer orlistat, lorcaserin, phentermine/topiramate ER, and liraglutide 3 mg in patients with existing HTN. (Grade B; BEL 1) Obtain careful monitoring of HR in patients receiving liraglutide 3 mg and phentermine/topiramate ER. A Show 2 more As per ES 2015 guidelines: Do not use sympathomimetic agents phentermine and diethylpropion in patients with uncontrolled HTN or a history of heart disease. D Consider offering non-sympathomimetic agents (such as lorcaserin and/or orlistat) as weight loss pharmacotherapy in patients with CVD. C Patients with diabetes mellitus (screening): measure BP at every routine clinical visit. Confirm BP using multiple readings, when possible, in patients found to have elevated BP (systolic BP 120-129 mmHg and diastolic < 80 mmHg), including measurements on a separate day, to diagnose HTN. Diagnose HTN in case of a systolic BP 130mmHg or a diastolic BP 80 mmHg based on an average of 2 measurements obtained on 2 occasions. A https://web.pathway.md/diseases/reclWZaqSp36TX3eN 14/18 6/24/23, 12:46 PM Hypertension Pathway Show 2 more Patients with diabetes mellitus (lifestyle modifications): advise lifestyle interventions in patients with BP > 120/80 mmHg, consisting of weight loss when indicated, a Dietary Approaches to Stop HTN-style eating pattern including reducing sodium and increasing potassium intake, moderation of alcohol intake, and increased physical activity. A Patients with diabetes mellitus, BP targets: As per ADA 2023 guidelines, individualize BP targets in patients with diabetes and HTN through a shared decision-making process addressing cardiovascular risk, potential adverse effects of antihypertensive medications, and patient preferences. B Show 2 more As per Hypertension Canada 2020 guidelines, treat HTN in patients with diabetes mellitus targeting systolic BP of < 130 mmHg B and diastolic BP of < 80 mmHg. A As per JNC 2014 guidelines, initiate pharmacologic treatment in adult patients with diabetes mellitus to lower BP at systolic BP 140 mmHg or diastolic BP 90 mmHg and treat to a goal of systolic BP < 140 mmHg and goal diastolic BP < 90 mmHg. B Patients with diabetes mellitus, pharmacotherapy: As per ADA 2023 guidelines, initiate and titrated pharmacologic therapy to achieve BP goal of < 130/80 mmHg in patients with confirmed office-based BP 130/80 mmHg. A Show 6 more As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, initiate antihypertensive drug treatment at a BP 130/80 mmHg with a treatment goal of < 130/80 mmHg in adults with diabetes mellitus and HTN. B As per JNC 2014 guidelines: Initiate a thiazide-type diuretic, CCB, ACEI, or ARB as initial antihypertensive treatment in the general nonblack population, including patients with diabetes mellitus. B Initiate a thiazide-type diuretic or CCB as initial antihypertensive treatment in the general black population B , including patients with diabetes. B Patients with diabetes mellitus (pediatric patients): measure BP in young patients with T2DM at every visit. Consider obtaining ambulatory BP monitoring in young patients with high BP (BP 90th percentile for age, gender, and height or, in adolescents aged 13 years, 120/80 mmHg) on 3 separate measurements. B Show 3 more Patients with chronic kidney disease (lifestyle modifications): consider advising patients with HTN and CKD to target a sodium intake of < 2 g of sodium per day (or < 90 mmol of sodium per day or < 5 g of sodium chloride per day). C Show 5 more Patients with chronic kidney disease, antihypertensives: As per KDIGO 2021 guidelines, consider targeting systolic BP of < 120 mmHg, when tolerated, using standardized office BP measurement in adult patients with HTN and CKD. C Show 8 more https://web.pathway.md/diseases/reclWZaqSp36TX3eN 15/18 6/24/23, 12:46 PM Hypertension Pathway As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, treat adults with HTN and CKD to a BP goal of < 130/80 mmHg. B Show 2 more As per JNC 2014 guidelines: Initiate pharmacologic treatment in adult patients with CKD to lower BP at systolic BP 140 mmHg or diastolic BP 90 mmHg and treat to the goal of systolic BP < 140 mmHg and diastolic BP < 90 mmHg. B Initiate an ACEI or ARB as the initial (or add-on) antihypertensive treatment to improve kidney outcomes in adult patients with CKD regardless of race or diabetes status. B Patients with coronary artery disease: Aim for a BP target of < 130/80 mmHg in adults with stable ischemic heart disease and HTN. B Treat adults with stable ischemic heart disease and HTN (BP 130/80 mmHg) with medications for compelling indications (e.g., -blockers, ACEIs, or ARBs for previous myocardial infarction or stable angina) as first-line therapy, with the addition of other drugs (e.g., dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists) as needed to further control HTN. B Patients with heart failure, reduced EF: As per HFSA/ACC/AHA 2022 guidelines, titrate guideline-directed medical therapy to the maximally tolerated target dose in patients with HF with reduced ejection fraction and HTN. B As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, administer guideline-directed medical therapy titrated to attain a BP of < 130/80 mmHg in adults with HF with reduced ejection fraction and HTN. B Patients with heart failure, preserved EF: As per HFSA/ACC/AHA 2022 guidelines, titrate medication to attain BP targets in accordance with published clinical practice guidelines to prevent morbidity in patients with HFpEF and HTN. B As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines: Initiate diuretics to control HTN in adults with HFpEF who present with symptoms of volume overload. B Initiate ACEIs or ARBs and -blockers titrated to attain a systolic BP of < 130 mmHg in adults with HFpEF and persistent HTN after management of volume overload. B Patients with stroke or TIA: Resume antihypertensive treatment after a few days in patients with HTN who experience a stroke or transient ischemic, in order to reduce the risk of recurrent stroke and other vascular events. A Lower BP slowly to < 185/110 mmHg before initiating thrombolytic therapy in adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous tPA. B Patients with acute intracerebral hemorrhage: https://web.pathway.md/diseases/reclWZaqSp36TX3eN 16/18 6/24/23, 12:46 PM Hypertension Pathway Consider initiating a continuous intravenous antihypertensive drug infusion with close BP monitoring to lower systolic BP in adults with intracerebral hemorrhage who present with systolic BP > 220 mmHg. C Avoid immediate lowering of systolic BP to < 140 mmHg in adults with spontaneous intracerebral hemorrhage who present within 6 hours of the acute event and have a systolic BP 150 mmHg-220 mmHg, given the lack of demonstrated benefit and evidence of potential harm. D Patients with valvular heart disease: Initiate pharmacological treatment for HTN in adults with asymptomatic aortic stenosis, starting at low doses, and gradually titrating upward as needed. B Consider using agents that do not slow the HR (avoid -blockers) in patients with HTN and chronic aortic insufficiency. C Patients with thoracic aortic disease: use -blockers as the preferred antihypertensive agents in patients with HTN and thoracic aortic disease. B Patients with peripheral artery disease: treat adults with HTN and PAD similarly to patients with HTN who do not have PAD. B Patients with atrial fibrillation: consider ARBs in patients with AF to prevent recurrence. C Patients with obstructive sleep apnea: insufficient evidence to establish the efficacy of CPAP to reduce BP in adults with HTN and obstructive sleep apnea. I Renal transplant recipients: consider treating patients with HTN to a BP goal of < 130/80 mmHg after kidney transplantation. B 9. Follow-up and surveillance Indications for specialist referral: As per ACC 2018 guidelines: Refer adults with HTN and a positive screening test for primary aldosteronism to a HTN specialist or endocrinologist for further evaluation and treatment. B Consider referring patients with secondary HTN to a HTN specialist with relevant expertise. C As per JNC 2014 guidelines, consider referring patients to a HTN specialist if BP goal cannot be attained using the recommended strategy or for the management of complicated patients requiring additional clinical consultation. C Assessment of treatment response: As per ESC 2018 guidelines, reduce BP to < 140/90 mmHg as the first objective of treatment in all patients, and provided that the treatment is well tolerated, target treated BP values to 130/80 mmHg in most patients. A Show 2 more

https://web.pathway.md/diseases/reclWZaqSp36TX3eN 14/18 6/24/23, 12:46 PM Hypertension Pathway Show 2 more Patients with diabetes mellitus (lifestyle modifications): advise lifestyle interventions in patients with BP > 120/80 mmHg, consisting of weight loss when indicated, a Dietary Approaches to Stop HTN-style eating pattern including reducing sodium and increasing potassium intake, moderation of alcohol intake, and increased physical activity. A Patients with diabetes mellitus, BP targets: As per ADA 2023 guidelines, individualize BP targets in patients with diabetes and HTN through a shared decision-making process addressing cardiovascular risk, potential adverse effects of antihypertensive medications, and patient preferences. B Show 2 more As per Hypertension Canada 2020 guidelines, treat HTN in patients with diabetes mellitus targeting systolic BP of < 130 mmHg B and diastolic BP of < 80 mmHg. A As per JNC 2014 guidelines, initiate pharmacologic treatment in adult patients with diabetes mellitus to lower BP at systolic BP 140 mmHg or diastolic BP 90 mmHg and treat to a goal of systolic BP < 140 mmHg and goal diastolic BP < 90 mmHg. B Patients with diabetes mellitus, pharmacotherapy: As per ADA 2023 guidelines, initiate and titrated pharmacologic therapy to achieve BP goal of < 130/80 mmHg in patients with confirmed office-based BP 130/80 mmHg. A Show 6 more As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, initiate antihypertensive drug treatment at a BP 130/80 mmHg with a treatment goal of < 130/80 mmHg in adults with diabetes mellitus and HTN. B As per JNC 2014 guidelines: Initiate a thiazide-type diuretic, CCB, ACEI, or ARB as initial antihypertensive treatment in the general nonblack population, including patients with diabetes mellitus. B Initiate a thiazide-type diuretic or CCB as initial antihypertensive treatment in the general black population B , including patients with diabetes. B Patients with diabetes mellitus (pediatric patients): measure BP in young patients with T2DM at every visit. Consider obtaining ambulatory BP monitoring in young patients with high BP (BP 90th percentile for age, gender, and height or, in adolescents aged 13 years, 120/80 mmHg) on 3 separate measurements. B Show 3 more Patients with chronic kidney disease (lifestyle modifications): consider advising patients with HTN and CKD to target a sodium intake of < 2 g of sodium per day (or < 90 mmol of sodium per day or < 5 g of sodium chloride per day). C Show 5 more Patients with chronic kidney disease, antihypertensives: As per KDIGO 2021 guidelines, consider targeting systolic BP of < 120 mmHg, when tolerated, using standardized office BP measurement in adult patients with HTN and CKD. C Show 8 more https://web.pathway.md/diseases/reclWZaqSp36TX3eN 15/18 6/24/23, 12:46 PM Hypertension Pathway As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, treat adults with HTN and CKD to a BP goal of < 130/80 mmHg. B Show 2 more As per JNC 2014 guidelines: Initiate pharmacologic treatment in adult patients with CKD to lower BP at systolic BP 140 mmHg or diastolic BP 90 mmHg and treat to the goal of systolic BP < 140 mmHg and diastolic BP < 90 mmHg. B Initiate an ACEI or ARB as the initial (or add-on) antihypertensive treatment to improve kidney outcomes in adult patients with CKD regardless of race or diabetes status. B Patients with coronary artery disease: Aim for a BP target of < 130/80 mmHg in adults with stable ischemic heart disease and HTN. B Treat adults with stable ischemic heart disease and HTN (BP 130/80 mmHg) with medications for compelling indications (e.g., -blockers, ACEIs, or ARBs for previous myocardial infarction or stable angina) as first-line therapy, with the addition of other drugs (e.g., dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists) as needed to further control HTN. B Patients with heart failure, reduced EF: As per HFSA/ACC/AHA 2022 guidelines, titrate guideline-directed medical therapy to the maximally tolerated target dose in patients with HF with reduced ejection fraction and HTN. B As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines, administer guideline-directed medical therapy titrated to attain a BP of < 130/80 mmHg in adults with HF with reduced ejection fraction and HTN. B Patients with heart failure, preserved EF: As per HFSA/ACC/AHA 2022 guidelines, titrate medication to attain BP targets in accordance with published clinical practice guidelines to prevent morbidity in patients with HFpEF and HTN. B As per PCNA/NMA/ASPC/ASH/APhA/AGS/ACPM/ABC/AAPA/AHA/ACC 2018 guidelines: Initiate diuretics to control HTN in adults with HFpEF who present with symptoms of volume overload. B Initiate ACEIs or ARBs and -blockers titrated to attain a systolic BP of < 130 mmHg in adults with HFpEF and persistent HTN after management of volume overload. B Patients with stroke or TIA: Resume antihypertensive treatment after a few days in patients with HTN who experience a stroke or transient ischemic, in order to reduce the risk of recurrent stroke and other vascular events. A Lower BP slowly to < 185/110 mmHg before initiating thrombolytic therapy in adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous tPA. B Patients with acute intracerebral hemorrhage: https://web.pathway.md/diseases/reclWZaqSp36TX3eN 16/18 6/24/23, 12:46 PM Hypertension Pathway Consider initiating a continuous intravenous antihypertensive drug infusion with close BP monitoring to lower systolic BP in adults with intracerebral hemorrhage who present with systolic BP > 220 mmHg. C Avoid immediate lowering of systolic BP to < 140 mmHg in adults with spontaneous intracerebral hemorrhage who present within 6 hours of the acute event and have a systolic BP 150 mmHg-220 mmHg, given the lack of demonstrated benefit and evidence of potential harm. D Patients with valvular heart disease: Initiate pharmacological treatment for HTN in adults with asymptomatic aortic stenosis, starting at low doses, and gradually titrating upward as needed. B Consider using agents that do not slow the HR (avoid -blockers) in patients with HTN and chronic aortic insufficiency. C Patients with thoracic aortic disease: use -blockers as the preferred antihypertensive agents in patients with HTN and thoracic aortic disease. B Patients with peripheral artery disease: treat adults with HTN and PAD similarly to patients with HTN who do not have PAD. B Patients with atrial fibrillation: consider ARBs in patients with AF to prevent recurrence. C Patients with obstructive sleep apnea: insufficient evidence to establish the efficacy of CPAP to reduce BP in adults with HTN and obstructive sleep apnea. I Renal transplant recipients: consider treating patients with HTN to a BP goal of < 130/80 mmHg after kidney transplantation. B 9. Follow-up and surveillance Indications for specialist referral: As per ACC 2018 guidelines: Refer adults with HTN and a positive screening test for primary aldosteronism to a HTN specialist or endocrinologist for further evaluation and treatment. B Consider referring patients with secondary HTN to a HTN specialist with relevant expertise. C As per JNC 2014 guidelines, consider referring patients to a HTN specialist if BP goal cannot be attained using the recommended strategy or for the management of complicated patients requiring additional clinical consultation. C Assessment of treatment response: As per ESC 2018 guidelines, reduce BP to < 140/90 mmHg as the first objective of treatment in all patients, and provided that the treatment is well tolerated, target treated BP values to 130/80 mmHg in most patients. A Show 2 more As per ACC 2018 guidelines, perform a follow-up evaluation of adherence and response to treatment at monthly intervals until control is achieved for adults initiating a new or adjusted drug https://web.pathway.md/diseases/reclWZaqSp36TX3eN 17/18 6/24/23, 12:46 PM Hypertension Pathway regimen for HTN. B As per JNC 2014 guidelines, increase the dose of the initial drug or add a second drug from one of the classes (thiazide-type diuretic, CCB, ACEI, or ARB) if goal BP is not reached within a month of treatment. Continue to assess BP and adjust the treatment regimen until goal BP is reached. B Show 2 more References 1. Doreen M Rabi, Kerry A McBrien, Ruth Sapir-Pichhadze et al. Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2020 May;36 5 596 624. Open 2. Williams B, Mancia G, Spiering W et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39 33 3021 3104. Open 3. Paul K Whelton, Robert M Carey, Wilbert S Aronow 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: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71 6):e13-e115. Open 4. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee JNC 8 . JAMA. 2014 Feb 5;311 5 507 20. Open 5. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017 Mar 21;166 6 430 437. Open 6. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 7. Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Feb;100 2 342 62. Open 8. Kidney Disease: Improving Global Outcomes KDIGO Blood Pressure Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021 Mar;99 3S S1 S87. Open 9. Sarah Coles, Lynn Fisher, Kenneth W Lin et al. Blood Pressure Targets in Adults With Hypertension: A Clinical Practice Guideline From the AAFP. Am Fam Physician. 2022 Dec;106 6 Online. Open 10. W Timothy Garvey, Jeffrey I Mechanick, Elise M Brett et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3 1 203. Open 11. US Preventive Services Task Force, Alex H Krist, Karina W Davidson et al. Screening for High Blood Pressure in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. https://web.pathway.md/diseases/reclWZaqSp36TX3eN 18/18

Guideline sources The following summarized guidelines for the evaluation and management of hyperthyroidism are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2020) and the American Thyroid Association (ATA 2016). 1 2 3 4 4 5 6 7 Definition Hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormone. 3 Epidemiology Causes of hyperthyroidism include increased synthesis of thyroid hormones (e.g. Grave's disease), release of preformed thyroid hormones due to destruction of thyroid tissue (e.g. thyroiditis), and exogenous thyroid hormone intake. 5 Pathophysiology https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 1/7 6/24/23, 12:45 PM Hyperthyroidism Pathway In the United States, the prevalence of hyperthyroidism is estimated at 13000 per 100,000 population. In Europe, the prevalence of hyperthyroidism is estimated at 800 per 100,000 population. 4 4 Disease course Hyperthyroidism leads to a higher incidence of AF and atrial flutter, and, at least partly by that mechanism, a higher risk of cerebral arterial thrombosis. Hyperthyroidism additionally leads to increased bone turnover and a negative bone balance. 6 7 Guidelines 1. Diagnostic investigations Initial evaluation: Determine the etiology of thyrotoxicosis. If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, perform diagnostic testing including: measurement of thyrotropin receptor antibodies determination of the radioactive iodine uptake, or measurement of thyroidal blood flow on ultrasound. B Obtain a 123I or 99mTc pertechnetate scan when the clinical presentation suggests a toxic adenoma or a toxic multinodular goiter. B Thyroid antibodies: measure TSH receptor antibody levels when the etiology of hyperthyroidism in pregnancy is uncertain. B Lipid profile: re-evaluate lipid panel in patients with hyperthyroidism after reaching euthyroid state. A 2. Medical management Antithyroid drugs (general principles): consider a baseline CBC, including WBC count with differential, and a liver profile including bilirubin and transaminases prior to initiating anti-thyroid drug therapy for Graves' disease. C Antithyroid drugs (pregnant patients): avoid treating transient hCG-mediated TSH suppression in early pregnancy with antithyroid drug therapy. D Beta-adrenergic blockers: administer -adrenergic blockade in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting HRs in excess of 90 bpm or coexistent CVD. B Potassium iodide: insufficient evidence to recommend potassium iodide for the treatment of hyperthyroidism; potassium iodide may be of benefit in select patients with hyperthyroidism due to Graves' disease, those who have adverse reactions to antithyroid drugs, and those who have a https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 2/7 6/24/23, 12:45 PM Hyperthyroidism Pathway contraindication or aversion to radioactive iodine therapy or aversion to repeat radioactive iodine therapy, or surgery. I Antihistamine therapy: manage minor cutaneous reactions with concurrent antihistamine therapy without stopping the antithyroid drug. Manage the persistent symptomatic minor side effects of antithyroid medication by cessation of the medication and changing to radioactive iodine or surgery, or switching to the other antithyroid drug when radioactive iodine or surgery are not options. In the case of a serious allergic reaction, avoid prescribing the alternative drug. B Management of Graves' disease: treat patients with overt Graves' hyperthyroidism with any of the following modalities: radioactive iodine therapy, antithyroid drugs, or thyroidectomy. B Management of toxic multinodular goiter: consider treating patients with overtly toxic multinodular goiter or toxic adenoma with radioactive iodine therapy or thyroidectomy. On occasion, long-term, low-dose treatment with methimazole may be appropriate. C Management of subclinical hyperthyroidism: Treat subclinical hyperthyroidism when TSH is persistently < 0.1 mU/L in the following clinical settings: patients 65 years of age patients with cardiac risk factors, heart disease or osteoporosis postmenopausal women who are not on estrogens or bisphosphonates patients with symptoms. B Management of thyroid nodules: evaluate and manage according to recently published guidelines regarding thyroid nodules in euthyroid individuals if a thyroid nodule is discovered in a patient with Graves' disease. B 3. Nonpharmacologic interventions Smoking cessation: advise smoking cessation in patients with Graves' disease and refer them to a structured smoking cessation program. Identify patients exposed to secondhand smoke and advise of its negative impact, as both firsthand and secondhand smoking increase Graves' orbitopathy risk. B 4. Therapeutic procedures Radioactive iodine ablation (Graves' disease): optimize the treatment of comorbidities prior to radioactive iodine therapy. B Radioactive iodide ablation (toxic goiter and adenoma): administer sufficient activity of radioactive iodine in a single application to alleviate hyperthyroidism in patients with toxic multinodular goiter. B Radioactive iodine ablatiom (pediatric patients): consider pretreatment with methimazole and -adrenergic blockade until total T4 and/or free T4 normalize before proceeding with radioactive https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 3/7 6/24/23, 12:45 PM Hyperthyroidism Pathway iodine treatment in children with Graves' disease having total T4 levels of > 20 g/dL or free T4 > 5 ng/dL who are to receive radioactive iodine therapy. C Ethanol and radiofrequency ablation: insufficient evidence to assess benefits and risks of alternative therapies such as ethanol or radiofrequency ablation of toxic adenoma and toxic multinodular goiter; these therapies can be considered in select patients in whom radioactive iodine, surgery, and long-term antithyroid drug are inappropriate, contraindicated, or refused, and expertise in these procedures is available. I 5. Perioperative care Pre-RAI corticosteroid coverage: insufficient evidence to recommend for or against the use of prophylactic corticosteroids in smokers who receive radioactive iodine and have no evidence of Graves' ophtalmopathy. I Pre-thyroidectomy care (Graves' disease): render patients euthyroid prior to the procedure with antithyroid drug pretreatment, with or without -adrenergic blockade if surgery is chosen as treatment for Graves' disease. Give a potassium iodide-containing preparation in the immediate preoperative period. B Post-thyroidectomy care in Graves disease: consider undertaking alternative strategies for management of calcium levels: serum calcium with or without intact PTH levels can be measured, and oral calcium and calcitriol supplementation administered based on these results, or prophylactic calcium with or without calcitriol prescribed empirically, following thyroidectomy for Graves' disease. C Post-thyroidectomy care (toxic multinodular goitre): measure serum calcium with or without intact PTH levels, and administer oral calcium and calcitriol supplementation based on the results, following thyroidectomy for toxic multinodular goiter. B 6. Surgical interventions Thyroidectomy for Graves' disease: perform near-total or total thyroidectomy as the procedure of choice if surgery is chosen as the primary therapy for Graves' disease. B Thyroidectomy for toxic multinodular goitre: render patients with overt hyperthyroidism euthyroid prior to the procedure with methimazole pretreatment, with or without -adrenergic blockade if surgery is chosen as treatment for toxic multinodular goiter or toxic adenoma. Avoid using preoperative iodine in this setting. B Thyroidectomy in pediatric patients: render children with Graves' disease undergoing thyroidectomy euthyroid with the use of methimazole. Give a potassium iodide-containing preparation in the immediate preoperative period. B Thyroidectomy for pregnant patients: use thyroidectomy only when medical management has been unsuccessful or antithyroid drugs cannot be used because pregnancy is a relative contraindication to thyroidectomy. B https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 4/7 6/24/23, 12:45 PM Hyperthyroidism Pathway Thyroidectomy for amiodarone-induced thyrotoxicosis: perform thyroidectomy in patients with amiodarone-induced thyrotoxicosis who are unresponsive to aggressive medical therapy with methimazole and corticosteroids. B 7. Specific circumstances Pregnant patients: diagnose hyperthyroidism in pregnancy using serum TSH values, and either total thyroxine and T3 with total thyroxine and T3 reference ranges increasing to 1.5 times above the nonpregnant range by the second and third trimester or free thyroxine and total T3 estimations with trimester-specific normal reference ranges. B Show 2 more Pediatric patients: treat children with Graves' disease with methimazole, radioactive iodine therapy, or thyroidectomy. Avoid radioactive iodine therapy in very young children < 5 years of age. Radioactive iodine therapy in children is acceptable if the activity is > 150 Ci/g (5.55 MBq/g) of thyroid tissue, and for children between 5 and 10 years of age if the calculated radioactive iodine administered activity is < 10 mCi (< 370 MBq). Choose thyroidectomy when definitive therapy is required, the child is too young for radioactive iodine, and surgery can be performed by a high-volume thyroid surgeon. B Patients with iodine-induced thyrotoxicosis: avoid routine administration of antithyroid drugs before iodinated contrast media exposure for all patients. D Patients with postpartum thyroiditis: perform selective diagnostic studies to distinguish postpartum destructive thyroiditis from postpartum Graves' disease in women developing thyrotoxicosis after delivery. B Patients with Graves' opthalmopathy: consider radioactive iodine therapy, antithyroid drugs, and thyroidectomy as equally acceptable therapeutic options in patients with Graves' hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease. B Patients with amiodarone-induced thyrotoxicosis: consider monitoring thyroid function tests before and within the first 3 months following the initiation of amiodarone therapy, and at 3- to 6- month intervals thereafter. C Patients with thyrotoxicosis due to destructive thyroiditis: treat patients with mild symptomatic subacute thyroiditis initially with -adrenergic-blocking drugs and nonsteroidal anti-inflammatory agents. Use corticosteroids instead of NSAIDs when patients fail to respond or present initially with moderate-to-severe pain and/or thyrotoxic symptoms. B Patients with other causes of thyrotoxicosis: monitor patients taking medications known to cause thyrotoxicosis, including interferon-a, IL-2, TKIs, and lithium, clinically and biochemically at 6-month intervals for the development of thyroid dysfunction. Evaluate patients who develop thyrotoxicosis to determine etiology and treat accordingly. B https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 5/7 6/24/23, 12:45 PM Hyperthyroidism Pathway 8. Patient education Counseling for radioactive iodide ablation: provide written advice concerning radiation safety precautions following treatment when administering radioactive iodine, and select an alternative therapy if the precautions cannot be followed. B 9. Follow-up and surveillance Monitoring of patients on antithyroid drugs: obtain a differential WBC count during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medication to exclude agranulocytosis. B References 1. Ross DS, Burch HB, Cooper DS et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26 10 1343 1421. Open 2. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 3. David S Cooper. Hyperthyroidism. 2003 Aug 9;362 9382 459 68.2003 Aug 9;362 9382 459 68. Open 4. De Leo S, Lee SY, Braverman LE . Hyperthyroidism. Lancet. 2016 Aug 27;388 10047 906 918. Open 5. Lea Slahor. CME Thyrotoxicosis and Thyroiditis]. 2018;107 22 1187 1192.2018;107 22 1187 1192. Open 6. Laura P B Elbers, Alessandro Squizzato, Victor E A Gerdes. Thyroid Disorders and Hemostasis. 2018 Oct;44 7 676 682.2018 Oct;44 7 676 682. Open 7. Medea Amashukeli, Maka Korinteli, Tamar Zerekidze et al. The negative correlation between thyrotropin receptor-stimulating antibodies and bone mineral density in postmenopausal patients with Graves' disease. 2013 Jun;61 5 842 7.2013 Jun;61 5 842 7. Open 8. Erik K Alexander, Elizabeth N Pearce, Gregory A Brent et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27 3 315 389. Open 9. LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015 May 5;162 9 641 50. Open 10. Simone De Leo, Sun Y Lee, Lewis E Braverman. Hyperthyroidism. Lancet. 2016 Aug 27;388 10047 906 918. Open 11. Mark P J Vanderpump. The epidemiology of thyroid disease. Br Med Bull. 2011;99 39 51. Open 12. Douglas S Ross, Henry B Burch, David S Cooper et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 6/7 6/24/23, 12:45 PM Hyperthyroidism Pathway Oct;26 10 1343 1421. Open https://web.pathway.md/diseases/recDEwiYN0ZUgdOP7 7/7

Guideline sources The following summarized guidelines for the evaluation and management of hypertriglyceridemia are prepared by our editorial team based on guidelines from the European Society of Cardiology (ESC/EAS 2020), the Endocrine Society (ES 2020; 2012), and the American College of Preventive Medicine (ACPM/ADA/PCNA/ABC/ASPC/AAPA/AGS/AHA/ACC/APhA 2019). 1 2 3 4 5 5 6 7 8 Definition Hypertriglyceridemia is defined as fasting triglycerides 150 mg/dL, which is associated with an increased risk for coronary heart disease. 5 Epidemiology Underlying pathophysiology occurs through abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis; dysfunctional LPL-mediated lipolysis or impaired remnant clearance. Primary etiology includes genetic mutations (LPL, APOC3, APOA5 genes), while secondary etiologies may consist of obesity, metabolic syndrome, diabetes, alcohol use, renal disease, pregnancy, and nonalcoholic fatty liver disorder. 6 Pathophysiology https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 1/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway The prevalence of hypertriglyceridemia in the United States is estimated at 29% in men and 21% in women. 5 Disease course Clinical manifestations include eruptive cutaneous xanthomata, lipemia retinalis, tuberous xanthoma, palmar crease xanthomas, hepatosplenomegaly, focal neurologic symptoms (irritability), and recurrent epigastric pain with an increased risk of pancreatitis seen mostly with both familial chylomicronemia and primary mixed hyperlipidemia. Hypertriglyceridemia is associated with an increased risk of coronary heart disease, T2DM mellitus, and acute pancreatitis with a reduction in health-related quality of life. 7 Prognosis and risk of recurrence Hypertriglyceridemia with high (150-500 mg/dL) and very high levels (> 500 mg/dL) is associated with increased risk of all-cause mortality with hazard ratio of 1.49 (95% CI 1.36-1.63, p < 0.001) and 3.08 (95% CI 1.46-6.50, p < 0.01), respectively. 8 Guidelines 1. Screening and diagnosis Indications for screening: screen adults for hypertriglyceridemia with measurement of serum triglycerides as part of a lipid panel at least every 5 years. B Diagnosis: base the diagnosis of hypertriglyceridemia on fasting rather than nonfasting triglyceride levels. B 2. Diagnostic investigations Initial evaluation: evaluate patients with elevation of fasting triglycerides for secondary causes of hypertriglyceridemia, including endocrine conditions and medications. Focus treatment on such secondary causes. B Lipoprotein levels: Avoid routine measurement of lipoprotein particle heterogeneity in patients with hypertriglyceridemia. D Consider measuring ApoB or lipoprotein A levels, whereas measurement of other apolipoprotein levels has little clinical value. C 3. Medical management General principles: https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 2/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway As per ES 2020 guidelines, initiate pharmacologic treatment as adjunct to dietary modifications and exercise to prevent pancreatitis in adult patients with fasting triglyceride levels > 500 mg/dL (5.6 mmol/L). B As per AHA 2019 guidelines, address and treat lifestyle factors (such as obesity and metabolic syndrome), secondary factors (such as diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides in 20 years old adult patients with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175-499 mg/dL; 2.0-5.6 mmol/L). A Show 3 more As per ES 2012 guidelines: Target a non-HDL-C level in agreement with published guidelines in patients with moderate hypertriglyceridemia. B Consider initiating the following drug classes alone or in combination with statins as treatment options in patients with moderately to severely elevated triglyceride levels: fibrates niacin n-3 fatty acids. C Fibrates: As per ESC 2020 guidelines: Consider adding fenofibrate or bezafibrate to statins for primary prevention in patients with triglyceride levels of > 2.3 mmol/L (> 200 mg/dL) achieved LDL cholesterol goal. C Consider adding fenofibrate or bezafibrate to statins in high risk patients with triglyceride levels of > 2.3 mmol/L (> 200 mg/dL) achieved LDL cholesterol goal. C Updated evidence: PROMINENT In patients with T2DM, mild-to-moderate hypertriglyceridemia, and high-density lipoprotein cholesterol levels 40 mg/dL, pemafibrate was not superior to placebo with respect to the composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Aruna Das Pradhan et al. N Engl J Med. 2022 Nov 24. As per AHA 2019 guidelines, consider initiating fibrates if necessary to prevent acute pancreatitis in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. C As per ES 2012 guidelines, initiate fibrates as first-line therapy to reduce triglycerides in patients at risk for triglyceride-induced pancreatitis. B Polyunsaturated fatty acids: https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 3/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway As per ES 2020 guidelines, consider adding n-3 PUFAs (icosapent ethyl 2 2 g/day) in high or very high risk patients with triglyceride levels of 1.5-5.6 mmol/L (135-499 mg/dL) despite statin treatment. C As per ES 2020 guidelines, consider adding eicosapentaenoic acid ethyl ester to reduce the risk of CVD in adult patients with moderate hypertriglyceridemia (> 150 mg/dL; > 1.7 mmol/L) on statins and with either ASCVD or diabetes plus 2 additional risk factors. C As per AHA 2019 guidelines, advise consuming omega-3 fatty acids in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. B Statins: As per ESC 2020 guidelines, initiate statins as first-line therapy to reduce cardiovascular risk in high risk patients with hypertriglyceridemia (triglyceride levels > 2.3 mmol/L; > 200 mg/dL). B As per AHA 2019 guidelines: Consider initiating statin therapy in 40-75 years old adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.6 mmol/L) and ASCVD risk of 7.5%. C Consider intensifying statin therapy in 40-75 years old adult patients with moderate-to-severe hypertriglyceridemia and ASCVD risk of 7.5% if triglyceride levels are persistently elevated despite addressing lifestyle and secondary factors. C As per ES 2012 guidelines: Avoid using statins as monotherapy in patients with severe or very severe hypertriglyceridemia. D Consider initiating statins for the treatment of patients with moderate hypertriglyceridemia, when indicated to modify the cardiovascular risks. B Bile acid sequestrants: consider measuring triglyceride levels before and after starting a bile acid sequestrant in patients with elevated triglycerides (> 150-499 mg/dL; 1.7-5.6 mmol/L). C 4. Nonpharmacologic interventions Lifestyle modification: As per AHA 2019 guidelines, advise implementing a very low-fat diet, avoiding refined carbohydrates and alcohol in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. B As per ES 2012 guidelines, advise dietary modification, physical activity, and weight reduction programs as first-line therapy in overweight and obese patients with mild-to-moderate hypertriglyceridemia. B https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 4/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway 5. Specific circumstances Patients with triglyceride-induced pancreatitis: Avoid performing acute plasmapheresis as first-line therapy to reduce triglyceride levels in patients with triglyceride-induced pancreatitis. D Avoid administering routine insulin infusion in patients with triglyceride-induced pancreatitis not having diabetes. D References 1. Lars Berglund, John D. Brunzell, Anne C. Goldberg et al. Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012 Sep; 97 9 2969 2989. Open 2. Fran ois Mach, Colin Baigent, Alberico L Catapano et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41 1 111 188. Open 3. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 4. Scott M Grundy, Neil J Stone, Alison L Bailey et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139 25):e1082-e1143. Open 5. Wenjun Fan, Sephy Philip, Craig Granowitz et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. Jan-Feb 2019;13 1 100 108.Jan-Feb 2019;13 1 100 108. Open 6. H C Hassing, R P Surendran, H L Mooij et al. Pathophysiology of hypertriglyceridemia. 2012 May;1821 5 826 32.2012 May;1821 5 826 32. Open 7. George Yuan, Khalid Z Al-Shali, Robert A Hegele. Hypertriglyceridemia: its etiology, effects and treatment. 2007 Apr 10;176 8 1113 20.2007 Apr 10;176 8 1113 20. Open 8. Marcello Arca, Chiara Veronesi, Laura D'Erasmo et al. Association of Hypertriglyceridemia with All-Cause Mortality and Atherosclerotic Cardiovascular Events in a Low-Risk Italian Population: The TG REAL Retrospective Cohort Analysis. 2020 Oct 20;9 19):e015801.2020 Oct 20;9 19):e015801. Open 9. Ann C Skulas-Ray, Peter W F Wilson, William S Harris et al. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019 Sep 17;140 12):e673-e691. Open 10. Mahya Faghih, Vikesh K Singh. Do Elevated Triglycerides Truly Trigger Acute Pancreatitis?. Dig Dis Sci. 2019 Mar;64 3 616 618. Open 11. Susan Xiaoqin Lin, Mercedes Carnethon, Moyses Szklo et al. Racial/ethnic differences in the association of triglycerides with other metabolic syndrome components: the Multi-Ethnic Study of Atherosclerosis. Metab Syndr Relat Disord. 2011 Feb;9 1 35 40. Open https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 5/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway 12. Wenjun Fan, Sephy Philip, Craig Granowitz et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. Jan-Feb 2019;13 1 100 108. Open 13. Margaret D Carroll, David A Lacher, Paul D Sorlie et al. Trends in serum lipids and lipoproteins of adults, 1960 2002. JAMA. 2005 Oct 12;294 14 1773 81. Open 14. Lauren Elizabeth Kleess, Natasa Janicic. SEVERE HYPERTRIGLYCERIDEMIA IN PREGNANCY A CASE REPORT AND REVIEW OF THE LITERATURE. AACE Clin Case Rep. 2018 Oct 5;5 2):e99-e103. Open 15. George Yuan, Khalid Z Al-Shali, Robert A Hegele. Hypertriglyceridemia: its etiology, effects and treatment. CMA. 2007 Apr 10;176 8 1113 20. Open 16. Sujani Poonuru, Sumedha R Pathak, Hemender S Vats et al. Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin. Clin Med Res. 2011 Mar;9 1 38 41. Open 17. Bertha Wong, Teik C Ooi, Erin Keely. Severe gestational hypertriglyceridemia: A practical approach for clinicians. Obstet Med. 2015 Dec;8 4 158 67. Open 18. Klaus G Parhofer, Ulrich Laufs. The Diagnosis and Treatment of Hypertriglyceridemia. Dtsch Arztebl Int. 2019 Dec 6;116 49 825 832. Open 19. Marcello Arca, Chiara Veronesi, Laura D'Erasmo et al. Association of Hypertriglyceridemia with All- Cause Mortality and Atherosclerotic Cardiovascular Events in a Low-Risk Italian Population: The TG REAL Retrospective Cohort Analysis. J Am Heart Assoc. 2020 Oct 20;9 19):e015801. Open https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 6/6

Guideline sources The following summarized guidelines for the evaluation and management of hypertrophic cardiomyopathy are prepared by our editorial team based on guidelines from the European Society of Cardiology (ESC 2022; 2018; 2014), the American Heart Association (AHA/ACC 2020), and the American Heart Association (AHA/HRS/ACC 2019; 2018). 1 2 3 4 5 6 7 7 7 8 9 Definition Hypertrophic cardiomyopathy is a genetic disorder characterized by LV hypertrophy and a non- dilated left ventricle with preserved or increased ejection fraction. 7 Epidemiology Hypertrophic cardiomyopathy is most frequently caused by genetic mutations in genes ( -myosin heavy chain [MYH7] and myosin binding protein C [MYBPC3]) encoding sarcomere proteins. LV hypertrophy leads to diastolic dysfunction, reduced systolic output volume, decreased peripheral https://web.pathway.md/diseases/recp2rCpGQe4lzw9C 1/4 6/24/23, 12:45 PM Hypertrophic cardiomyopathy Pathway and myocardial perfusion, cardiac arrhythmia and/or HF and finally increased risk of sudden cardiac death. 7 Pathophysiology The prevalence of hypertrophic cardiomyopathy in the United States is low, with an estimated 200 cases per 100,000 population. HCM incidence is bimodal (peak incidence in the second decade and third decade of life). 8 Disease course Clinical manifestations include symptoms due to increased LV end-diastolic pressure (exertional dyspnea, exercise intolerance, orthopnea, peripheral edema, and HFpEF), LV outflow obstruction (exertional or immediately post-exertional syncope, ventricular arrhythmia), chest pain, palpitations, VT. Disease progression may lead to AF, hypertension, valvular disease, HF, and sudden cardiac death. 7 Prognosis and risk of recurrence Hypertrophic cardiomyopathy is associated with an annual mortality rate of 0.5%, and mortality is higher in children. However, sudden cardiac death is often the first clinical manifestation. 9 Calculator Calculator Calculator CHA DS VASc score for stroke CHADS score for stroke risk in a NYHA fun Guidelines 1. Screening and diagnosis Screening of family relatives, clinical and genetic testing: As per ACC/AHA 2020 guidelines, obtain a 12-lead ECG as part of screening in first-degree relatives of patients with hypertrophic cardiomyopathy. Obtain a TTE as part of the initial family screening and periodic follow-up in first-degree relatives of patients with hypertrophic cardiomyopathy. B Show 3 more As per HRS/ACC/AHA 2018 guidelines: Obtain an ECG and echocardiography in first-degree relatives of patients with hypertrophic cardiomyopathy. B Provide genetic counseling and obtain mutation-specific genetic testing in first-degree relatives of patients with hypertrophic cardiomyopathy due to a known causative mutation. B https://web.pathway.md/diseases/recp2rCpGQe4lzw9C 2/4 6/24/23, 12:45 PM Hypertrophic cardiomyopathy Pathway As per ESC 2014 guidelines, obtain cascade genetic screening, after pretest counseling, in first- degree adult relatives of patients with a definite disease-causing mutation. B Show 4 more Screening of family relatives, follow-up: As per ACC/AHA 2020 guidelines, do not obtain ongoing clinical screening in genotype-negative relatives in families with genotype-positive hypertrophic cardiomyopathy unless the disease- causing variant is downgraded to a variant of uncertain significance, likely benign, or benign variant during follow-up. D As per ESC 2014 guidelines, obtain clinical evaluation with ECG and echocardiography and long-term follow-up in first-degree relatives harboring the same definite disease-causing mutation as the proband. B Show 2 more Screening of family relatives, counseling: As per ACC/AHA 2020 guidelines, offer preconception and prenatal reproductive and genetic counseling in affected families with hypertrophic cardiomyopathy. B As per ESC 2014 guidelines, consider allowing sports activity in definite mutation carriers with no evidence of disease expression after taking into account the underlying mutation, the type of sports activity, and the results of regular and repeated cardiac examinations. C 2. Classification and risk stratification SCD risk assessment: As per ESC 2022 guidelines, assess the 5-year risk of sudden cardiac death at first evaluation and at 1-3-year intervals, or when there is a change in clinical status. B As per AHA 2018 guidelines, assess the sudden cardiac death risk at the time of initial evaluation and periodically thereafter in patients with hypertrophic cardiomyopathy. B As per ESC 2014 guidelines, use the HCM Risk-SCD score to estimate the risk of sudden death at 5 years in patients with hypertrophic cardiomyopathy aged 16 years, in the absence of a history of resuscitated VT/VF or spontaneous sustained VT causing syncope or hemodynamic compromise. B 3. Diagnostic investigations History and physical examination: elicit a complete medical and three-generation family history and perform a comprehensive physical examination as part of the initial diagnostic assessment in patients with suspected hypertrophic cardiomyopathy. B Show 2 more Electrocardiogram: As per AHA 2020 guidelines, obtain a 12-lead ECG as part of the initial evaluation of patients with hypertrophic cardiomyopathy. B https://web.pathway.md/diseases/recp2rCpGQe4lzw9C 3/4 6/24/23, 12:45 PM Hypertrophic cardiomyopathy Pathway As per ESC 2014 guidelines, obtain standard 12-lead ECG to aid diagnosis and provide clues to underlying etiology in patients with suspected hypertrophic cardiomyopathy. B Ambulatory ECG monitoring: As per AHA 2020 guidelines, obtain 24-48 hour ambulatory ECG monitoring during the initial evaluation to identify patients at risk for sudden cardiac death and to guide the management of arrhythmias. B Show 3 more As per AHA 2019 guidelines, consider obtaining prolonged ambulatory ECG monitoring in patients undergoing alcohol septal ablation and being at risk for developing late AV block. C As per ESC 2014 guidelines: Obtain 48-hour ambulatory ECG monitoring to detect atrial and ventricular arrhythmia in patients with newly diagnosed hypertrophic cardiomyopathy. B Obtain 48-hour ambulatory ECG monitoring in patients with frequent or sustained palpitations. B Implantable loop recorder: Consider placing an implantable loop recorder in patients with recurrent episodes of unexplained syncope at low risk of sudden cardiac death. C Consider placing an implantable loop recorder in patients with frequent palpitations with no identified cause after prolonged ECG monitoring. C Transthoracic echocardiogram: As per AHA 2020 guidelines, obtain a TTE in the initial evaluation of patients with suspected hypertrophic cardiomyopathy. B Show 4 more As per ESC 2014 guidelines, obtain a TTE (2D and Doppler) in all patients with hypertrophic cardiomyopathy at initial evaluation. B Show 5 more Transesophageal echocardiogram: As per AHA 2020 guidelines: Obtain an intraoperative TEE to assess mitral valve anatomy and function and adequacy of septal myectomy in patients with hypertrophic cardiomyopathy undergoing surgical septal myectomy. B Consider obtaining a TEE in patients with hypertrophic cardiomyopathy when the TTE is inconclusive in clinical decision-making regarding medical therapy, or for planning myectomy, excluding subaortic membrane or MR secondary to structural abnormalities of the mitral valve apparatus, or assessing the feasibility of alcohol septal ablation. C As per ESC 2014 guidelines: Obtain a TEE in patients undergoing septal myectomy, in order to confirm the mechanism of LV outflow tract obstruction, guide the surgical strategy, assess post-surgical complications, and detect residual LV outflow tract obstruction. B https://web.pathway.md/diseases/recp2rCpGQe4lzw9C 4/4

Guideline sources The following summarized guidelines for the evaluation and management of hypoglycemia are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the Endocrine Society (ES 2022; 2016; 2013; 2009), the American Heart Association (AHA/ASA 2022; 2019), the United Kingdom Kidney Association (UKKA 2020), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2020; 2013), the American Society of Anesthesiologists (ASA/ACE/OS/AACE/ASMBS/OMA 2020), the Dumping Syndrome Consensus Group (DS-CG 2020), the Japanese Society of Nephrology (JSN 2019), the Diabetes Canada Guidelines (Diabetes Canada 2018), the European Association for the Study of Obesity (EASO 2017), the American Society for Metabolic and Bariatric Surgery (ASMBS 2017), the Pediatric Endocrine Society (PES 2015), the The Scottish Intercollegiate Guidelines Network (SIGN 2015), and the Guidelines and Audit Implementation Network (GAIN 2014). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Guidelines https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 1/10 6/24/23, 12:47 PM Hypoglycemia Pathway 1. Diagnostic investigations Initial evaluation, patients with diabetes: As per ADA 2023 guidelines, review occurrence and risk for hypoglycemia at every encounter and investigate as indicated. Consider assessing for awareness of hypoglycemia using validated tools. B As per Diabetes Canada 2018 guidelines, review the patient's experience with hypoglycemia at each visit, including an estimate of cause, frequency, symptoms, recognition, severity, and treatment, as well as the risk of driving with hypoglycemia. B As per ES 2009 guidelines: Evaluate hypoglycemia only in patients presenting with Whipple's triad: symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised. A Assess conventional risk factors and those indicative of compromised defenses against hypoglycemia in patients with recurrent treatment-induced hypoglycemia. A Initial evaluation (patients without diabetes): Adopt the following strategy in patients with hypoglycemia without diabetes mellitus: review the history, physical findings, and all available laboratory data seeking clues to specific disorders (drugs, critical illnesses, hormone deficiencies, non-islet cell tumors) measure plasma glucose, insulin, C-peptide, proinsulin, -hydroxybutyrate, and insulin antibodies and screen for oral hypoglycemic agents during an episode of spontaneous hypoglycemia when the cause of the hypoglycemic disorder is not evident (seemingly well individual), and observe the plasma glucose response to IV injection of 1 mg glucagon recreate the circumstances in which symptomatic hypoglycemia is likely to occur (such as during a fast of up to 72 hours or after a mixed meal) when a spontaneous hypoglycemic episode cannot be observed document endogenous hyperinsulinism based on the findings of symptoms, signs, or both with plasma concentrations of glucose < 55 mg/dL (< 3 mmol/L), insulin 3 U/mL (18 pmol/L), C- peptide of 0.6 ng/mL ( 0.2 nmol/L), and proinsulin 5.0 pmol/L document hypoglycemia as induced by insulin (or insulin-like growth factor) based on the findings of symptoms, signs, or both with plasma concentrations of -hydroxybutyrate 2.7 mmol/L and glucose 25 mg/dL (1.4 mmol/L) after IV glucagon administration obtain diagnostic investigations, such as CT or MRI, transabdominal and EUS, and, if necessary, perform selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels, to localize an insulinoma in patients with documented fasting or postprandial endogenous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, and no circulating insulin antibodies tailor treatment to the specific hypoglycemic disorder taking into account the burden of hypoglycemia on patient wellbeing and patient preferences. B Screening for anxiety: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 2/10 6/24/23, 12:47 PM Hypoglycemia Pathway Consider screening patients with diabetes for symptoms or diabetes-related worries. Consider discussing diabetes-related worries and referring to a qualified mental health professional for further assessment and treatment if anxiety symptoms indicate interference with diabetes self- management behaviors or quality of life. C Refer patients with hypoglycemia unawareness, which can co-occur with fear of hypoglycemia, to a trained professional to receive evidence-based intervention to help re-establish awareness of symptoms of hypoglycemia and reduce fear of hypoglycemia. A Screening for cognitive impairment: Monitor cognitive capacity throughout the life span in all patients with diabetes, particularly in patients experiencing severe hypoglycemia episodes. B Consider obtaining an ongoing assessment of cognitive function with increased vigilance for hypoglycemia by the clinician, patient, and caregivers in patients with impaired or declining cognition. C 2. Medical management Oral carbohydrates: As per ADA 2023 guidelines: Administer glucose (approximately 15-20 g) as the preferred treatment in conscious patients with blood glucose < 70 mg/dL (3.9 mmol/L), although any form of carbohydrate-containing glucose may be used. Repeat treatment if blood glucose monitoring shows continued hypoglycemia 15 minutes after treatment. B Avoid using carbohydrate sources high in protein for the treatment or prevention of hypoglycemia as ingested protein appears to increase insulin response without increasing plasma glucose concentrations in patients with T2DM. D As per Diabetes Canada 2018 guidelines, administer oral carbohydrates (15 g; preferably as glucose or sucrose tablets or solution rather than orange juice or glucose gels) for the treatment of mild-to-moderate hypoglycemia in patients with diabetes. B Show 2 more As per ES 2009 guidelines, administer oral carbohydrates, if feasible, for urgent treatment of hypoglycemia. A IV carbohydrates and glucagon: As per ADA 2023 guidelines, prescribe glucagon in all patients at increased risk of level 2 or 3 hypoglycemia, so that it is available should it be needed. Ensure that caregivers, school personnel, or family members providing support to these patients know where it is and when and how to administer it as glucagon administration is not limited to healthcare professionals. B As per ES 2022 guidelines, use glucagon preparations not requiring reconstitution in outpatients with severe hypoglycemia. B As per Diabetes Canada 2018 guidelines: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 3/10 6/24/23, 12:47 PM Hypoglycemia Pathway Administer SC or intramuscularly glucagon (1 mg) for the treatment of severe hypoglycemia in unconscious patients with diabetes with no IV access. Administer IV glucose (10-25 g; 20-50 mL of 50% dextrose solution) over 1-3 minutes in patients with IV access. B Educate support persons of patients with diabetes at risk of severe hypoglycemia on glucagon administration techniques. B As per ES 2009 guidelines, administer parenteral glucagon or glucose for urgent treatment of hypoglycemia, if oral carbohydrate administration is not feasible. A 3. Specific circumstances Neonatal patients: consider evaluating neonates suspected to be at high risk of having a persistent hypoglycemia disorder when the infant is 48 hours of age so that the period of transitional glucose regulation has passed and persistent hypoglycemia may be excluded before discharge home. B Show 4 more Pediatric patients (evaluation): evaluate and manage pediatric patients able to communicate their symptoms only in the presence of Whipple's triad. A Show 2 more Pediatric patients (glycemic targets, T1DM): individualize Hgb A1C goals and reassess over time, recognizing that an Hgb A1C level of < 7% (53 mmol/mol) is appropriate for many pediatric and adolescent patients. B Show 3 more Pediatric patients (glycemic targets, T2DM): set < 7% (53 mmol/mol) as a reasonable Hgb A1C target in most pediatric and adolescent patients with T2DM. Consider setting more stringent Hgb A1C targets (such as < 6.5%; 48 mmol/mol) in selected patients (such as patients with a short duration of diabetes and lesser degrees of -cell dysfunction and patients treated with lifestyle or metformin only and achieved significant weight improvement) if they can be achieved without significant hypoglycemia or other adverse effects of treatment. B Show 2 more Pediatric patients (glucose monitoring, T1DM): advise all young patients with T1DM to monitor glucose levels multiple times daily (up to 6-10 times/day by blood glucose meter or continuous glucose monitoring), including before meals and snacks, at bedtime, and as needed for safety in specific situations, such as exercise, driving, or the presence of symptoms of hypoglycemia. B Show 6 more Pediatric patients (glucose monitoring, T2DM): Individualize blood glucose monitoring taking into consideration the pharmacologic treatment of the patient. B Obtain real-time continuous glucose monitoring or intermittently scanned continuous glucose monitoring for diabetes management in young patients with T2DM on multiple daily injections or continuous SC insulin infusion capable of using the device safely (either by themselves or with a https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 4/10 6/24/23, 12:47 PM Hypoglycemia Pathway caregiver). Decide on the choice of the device based on patient circumstances, desires, and needs. B Pregnant patients: As per ADA 2023 guidelines, obtain fasting and postprandial blood glucose monitoring in both gestational diabetes mellitus and preexisting diabetes in pregnancy, to achieve optimal glucose levels. Set the following glucose targets: fasting plasma glucose < 95 mg/dL (5.3 mmol/L) and either 1-hour postprandial glucose < 140 mg/dL (7.8 mmol/L) or 2-hour postprandial glucose < 120 mg/dL (6.7 mmol/L). Obtain blood glucose preprandially in some patients with preexisting diabetes. B Show 4 more As per ES 2013 guidelines, consider targeting blood glucose and Hgb A1C levels as close to normal as possible in female patients with diabetes seeking to conceive, without causing undue hypoglycemia. C Show 2 more Elderly patients: prefer medication classes with a low risk of hypoglycemia in older patients with T2DM at increased risk of hypoglycemia. B Show 8 more Patients with chronic kidney disease (glycemic targets): Do not treat to a target Hgb A1c of < 7.0% (< 53 mmol/mol) in patients at risk of hypoglycemia. D Consider setting a target Hgb A1c of > 7.0% (> 53 mmol/mol) in patients with comorbidities or limited life expectancy and risk of hypoglycemia. C Patients with chronic kidney disease (considerations for pharmacotherapy): Recognize that the risk of hypoglycemia is generally low with GLP-1 receptor agonists when used alone, but the risk is increased when GLP-1 receptor agonists are used concomitantly with other medications, such as sulfonylureas or insulin. Consider reducing the doses of sulfonylurea and/or insulin. B Consider discontinuing or reducing the dose of an antihyperglycemic drug other than metformin to facilitate the addition of an SGLT-2 inhibitor when additional glucose-lowering may increase the risk for hypoglycemia (such as treated with insulin or sulfonylureas and currently meeting glycemic targets). C Patients with chronic kidney disease (continuous glucose monitoring): Consider obtaining daily glycemic monitoring with continuous glucose monitoring or self- monitoring of blood glucose to help prevent hypoglycemia and improve glycemic control when antihyperglycemic therapies associated with the risk of hypoglycemia are used. C Prefer antihyperglycemic agents posing a lower risk of hypoglycemia and administer in doses appropriate for the level of estimated GFR in patients with T2DM and CKD refusing daily glycemic monitoring by continuous glucose monitoring or self-monitoring of blood glucose. B Patients with chronic kidney disease (elderly patients): consider deciding the target for glycemic control in 75 years old patients with CKD and diabetes mellitus individually depending https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 5/10 6/24/23, 12:47 PM Hypoglycemia Pathway on the patient's health condition (age, cognitive function, physical function, comorbidity, risk of hypoglycemia, and time to live) as they are at risk of severe hypoglycemia. C Patients with post-bariatric hypoglycemia, general principles: As per ADA 2023 guidelines: Exclude other potential disorders contributing to hypoglycemia in patients with suspected postbariatric hypoglycemia. Provide education, medical nutrition therapy with a dietitian experienced in postbariatric hypoglycemia, and medication treatment as needed for the management of patients with postbariatric hypoglycemia. A Consider obtaining continuous glucose monitoring as an important adjunct to improve safety by alerting patients to hypoglycemia, especially in patients with severe hypoglycemia or hypoglycemia unawareness. C As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines, discontinue all insulin secretagogues (sulfonylureas and meglitinides), SGLT-2 inhibitors, and thiazolidinediones and adjust insulin doses (due to low-calorie intake) to minimize the risk of hypoglycemia in the immediate postoperative period in patients with T2DM. B Show 3 more As per EASO 2017 guidelines, direct treatment in the first 7-10 days after surgery toward fasting glucose values and instruct patients to test blood glucose at least BID - fast in the morning (target values: 100-120 mg/dL) and during the day (< 180 mg/dL 2 hours after a meal). B Show 3 more Patients with post-bariatric hypoglycemia, postprandial hyperinsulinemic hypoglycemia: As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines: Evaluate patients undergone Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, or sleeve gastrectomy and presenting with postprandial hypoglycemic symptoms not responding to nutritional manipulation, to differentiate non-insulinoma pancreatogenous hypoglycemia syndrome from factitious or iatrogenic causes, dumping syndrome, and insulinoma. B Offer dietary changes (low-carbohydrate diet), octreotide, diazoxide, acarbose, calcium- channel antagonists, gastric restriction, and/or reversal procedures (with partial or total pancreatectomy reserved for the rare recalcitrant cases) in patients with non-insulinoma pancreatogenous hypoglycemia. B As per ASMBS 2017 guidelines, recognize that postprandial hyperinsulinemic hypoglycemia after bariatric surgery is rare and most commonly associated with Roux-en-Y gastric bypass. Screen for, educate, and counsel to recognize the signs and symptoms of hypoglycemia. E Show 5 more Patients with post-bariatric hypoglycemia (late dumping syndrome): recognize that hypoglycemia is the main symptom of late dumping syndrome and is driven by a hyperinsulinemic response and GLP-1 release. B Show 2 more Patients with acute stroke: https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 6/10 6/24/23, 12:47 PM Hypoglycemia Pathway As per ASA 2022 guidelines: Monitor serum glucose to reduce the risk of hyperglycemia and hypoglycemia in patients with spontaneous intracerebral hemorrhage. B Treat hypoglycemia (< 40-60 mg/dL; < 2.2-3.3 mmol/L) to reduce mortality in patients with spontaneous intracerebral hemorrhage. B As per AHA 2019 guidelines, assess blood glucose levels before administering IV alteplase since hypoglycemia may mimic acute stroke presentations. B Show 2 more Patients with hyperkalemia: As per UKKA 2020 guidelines, consider administering a preemptive infusion of 10% glucose at 50 mL/hour for 5 hours (25 g) following insulin/glucose treatment for hyperkalemia in patients with a pre-treatment blood glucose < 7.0 mmol/L, to avoid hypoglycemia (target blood glucose 4-7 mmol/L). C As per GAIN 2014 guidelines, monitor blood glucose 15 and 30 minutes after starting insulin/glucose infusion for hyperkalemia, and then hourly up to 6 hours after completion of the infusion, as delayed hypoglycemia is commonly reported when < 30 g of glucose is administered with insulin. E Patients with status epilepticus: administer IV glucose (50 mL of 50% solution) in patients with status epilepticus if there is any suggestion of hypoglycemia. B 4. Preventative measures General principles: As per ADA 2023 guidelines, assess the hypoglycemia risk, in addition to the assessments of overall health status, diabetes complications, and cardiovascular risk, to guide the ongoing management of diabetes. B Take the hypoglycemia risk into account to guide the choice of pharmacologic agents in patients with T2DM. B Show 2 more As per Diabetes Canada 2018 guidelines, counsel about the risk, prevention, recognition, and treatment of hypoglycemia in all patients with diabetes currently using or starting therapy with insulin or insulin secretagogues and their support persons. Identify and address risk factors for severe hypoglycemia. B Show 2 more Choice of insulin: As per ADA 2023 guidelines, prescribe multiple daily injections of prandial and basal insulin, or continuous SC insulin infusion in most patients with T1DM. A Show 4 more As per ES 2022 guidelines, consider prescribing long-acting insulin analogs rather than human NPH insulin in adult and pediatric outpatients on basal insulin therapy at high risk for hypoglycemia. C https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 7/10 6/24/23, 12:47 PM Hypoglycemia Pathway Show 2 more As per ES 2016 guidelines, prescribe continuous subcutaneous insulin infusion over analog- based basal-bolus multiple daily injections in patients with T1DM not achieved the Hgb A1C goal, B or achieved the Hgb A1C goal but continuing to experience severe hypoglycemia or high glucose variability, as long as the patient and caregivers are willing and able to use the device. B Show 3 more Continuous glucose monitoring: As per ES 2022 guidelines, obtain continuous glucose monitoring rather than self-monitoring of blood glucose by fingerstick in patients with T1DM receiving multiple daily injections. B Show 5 more As per ES 2022 guidelines, consider obtaining real-time continuous glucose monitoring with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing (in hospital settings where resources and training are available) in adult patients with insulin-treated diabetes at high risk of hypoglycemia hospitalized for a non-critical illness. C As per ES 2016 guidelines, obtain real-time continuous glucose monitoring in adult patients with T1DM with Hgb A1C levels above target, if they are willing and able to use continuous glucose monitoring devices on a nearly daily basis. A Show 3 more Counseling on alcohol use: Advise adult patients with diabetes drinking alcohol to do so in moderation ( 1 drink/day for adult females and 2 drinks/day for adult males). B Educate patients with diabetes about the signs, symptoms, and self-management of delayed hypoglycemia after drinking alcohol, especially when using insulin or insulin secretagogues. Emphasize the importance of glucose monitoring after drinking alcoholic beverages to reduce hypoglycemia risk. B 5. Follow-up and surveillance Post-hypoglycemia care: As per ADA 2023 guidelines, advise patients to consume a meal or snack once the blood glucose monitoring or glucose pattern is trending up, to prevent the recurrence of hypoglycemia. B As per Diabetes Canada 2018 guidelines, advise patients to have the usual meal or snack that is due at that time of the day, once the hypoglycemia has been reversed, to prevent repeated hypoglycemia. Advise having a snack (including 15 g carbohydrate and a protein source) if a meal is > 1 hour away. B As per ES 2009 guidelines, obtain a fundamental review of the treatment regimen and the glycemic goals after an episode of severe hypoglycemia, unless the cause is easily remediable. A https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 8/10 6/24/23, 12:47 PM Hypoglycemia Pathway References 1. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 2. Diabetes Canada Clinical Practice Guidelines Expert Committee, Jean-Fran ois Yale, Breay Paty et al. Hypoglycemia. Can J Diabetes. 2018 Apr;42 Suppl 1 S104 S108. Open 3. McVeigh G, Maxwell P, O'Donell S et al. Guidelines for the Treatment of Hyperkalaemia in Adults. GAIN Sub-Group on the Treatment of Hyperkalaemia in Adults. Open 4. William J Powers, Alejandro A Rabinstein, Teri Ackerson 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 Dec;50 12):e344-e418. Open 5. Busetto L, Dicker D, Azran C et al. Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obes Facts. 2017;10 6 597 632. Open 6. Annette Alfonzo, Alexander Harrison, Richard Baines et al. Clinical Practice Guidelines Treatment of Acute Hyperkalaemia in Adults. The Renal Association. 2020 Jun. Open 7. Kidney Disease: Improving Global Outcomes KDIGO Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020 Oct;98 4S S1 S115. Open 8. Anthony L McCall, David C Lieb, Roma Gianchandani et al. Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Dec 7;dgac596. Open 9. Anne L Peters, Andrew J Ahmann, Tadej Battelino et al. Diabetes Technology-Continuous Subcutaneous Insulin Infusion Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Nov;101 11 3922 3937. Open 10. Philip E Cryer, Lloyd Axelrod, Ashley B Grossman et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009 Mar;94 3 709 28. Open 11. KDIGO Executive Committee. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. KDIGO. 2013 Jan;3 1 . Open 12. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open 13. Jeffrey I Mechanick, Caroline Apovian, Stacy Brethauer et al. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity Silver Spring). 2020 Apr;28 4 O1 O58. Open https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 9/10 6/24/23, 12:47 PM Hypoglycemia Pathway 14. Steven M Greenberg, Wendy C Ziai, Charlotte Cordonnier et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2022 May 17;101161STR0000000000000407. Open 15. Paul S Thornton, Charles A Stanley, Diva D De Leon et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015 Aug;167 2 238 45. Open 16. Dan Eisenberg, Dan E Azagury, Saber Ghiassi et al. ASMBS Position Statement on Postprandial Hyperinsulinemic Hypoglycemia after Bariatric Surgery. Surg Obes Relat Dis. 2017 Mar;13 3 371 378. Open 17. Mary T Korytkowski, Ranganath Muniyappa, Kellie Antinori-Lent et al. Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Jun 12;dgac278. Open 18. SIGN. SIGN 143 Diagnosis and management of epilepsy in adults. SIGN, 2015. Open 19. Emidio Scarpellini, Joris Arts, George Karamanolis et al. International consensus on the diagnosis and management of dumping syndrome. Nat Rev Endocrinol. 2020 Aug;16 8 448 466. Open 20. Blumer I, Hadar E, Hadden DR et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013 Nov;98 11 4227 49. Open 21. Endocrine Society. Choosing Wisely ES recommendations. Choosing Wisely. 2013. Open 22. B P Kovatchev, D J Cox, L A Gonder-Frederick et al. Assessment of risk for severe hypoglycemia among adults with IDDM validation of the low blood glucose index. Diabetes Care. 1998 Nov;21 11 1870 5. Open 23. William G. Herrington, Andrew H. Frankel, Alexa Wonnacott et al. UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 SGLT 2 Inhibition in Adults with Kidney Disease. UKKA. 2021 Oct. Open https://web.pathway.md/diseases/recz7ExdKlJXV9SlO 10/10

Guideline sources The following summarized guidelines for the evaluation and management of hypokalemia are prepared by our editorial team based on guidelines from the American Association of Family Physicians (AAFP 2015) and the National Council on Potassium in Clinical Practice (NCPCP 2000). 1 2 2 2 2 2 2 Definition Hypokalemia refers to the presence of serum potassium levels < 3.6 mmol/L. 2 Epidemiology Potassium depletion occurs due to inadequate dietary intake, increased renal excretion (e.g. due to diuretic therapy), or increased gastrointestinal losses in the context of diarrhea. 2 Pathophysiology Hypokalemia is the most common electrolyte disorder encountered in clinical practice. 2 Disease course Manifestations of hypokalemia include muscle weakness, ileus, and cardiac arrhythmias. Typical electrocardiographic changes include flat or inverted T waves, ST-segment depression, and prominent U waves. 2 Prognosis and risk of recurrence https://web.pathway.md/diseases/recJkzF5VNUOm60du 1/3 6/24/23, 12:47 PM Hypokalemia Pathway Severe untreated hypokalemia can lead to rhabdomyolysis and malignant cardiac arrhythmias, such as VT and VF. 2 Guidelines 1. Diagnostic investigations Measurement of potassium levels: Use serum potassium as the most convenient laboratory test to establish the diagnosis if hypokalemia, recognizing that it is not always an accurate indicator of total body potassium. E Consider measurement of 24-hour urinary potassium excretion as a more appropriate indicator of total body potassium in patients who are at high risk of complications from hypokalemia, such as those with HF. E 2. Medical management General principles: Initiate potassium replacement in individuals who are subject to nausea, vomiting, diarrhea, bulimia, or diuretic/laxative abuse. E Administer potassium supplements are best administered PO in a moderate dosage over a period of days to weeks to achieve full repletion of potassium. E Electrocardiographic monitoring: consider electrocardiographic monitoring in patients with severe hypokalemia (serum potassium < 2.5 mmol/L). C Intravenous potassium replacement: Intravenous potassium should be reserved for patients with: serum potassium < 2.5 mmol/L hypokalemic ECG changes physical signs or symptoms of hypokalemia inability to tolerate the oral form. B Oral potassium replacement: Consider using a dosage of 20 mmol/day of potassium in oral form for the prevention of hypokalemia. E Consider using a dosage of 40 to 100 mmol/day of potassium in oralform for for the tratment of hypokalemia. E Optimization of patient adherence: Use the simplest regimen possible for potassium supplementation, in order to optimize long- term compliance. E Consider using compliance-enhancing regimens, such as microencapsulated potassium, in order to increase patient adherence to potassium supplementation. E https://web.pathway.md/diseases/recJkzF5VNUOm60du 2/3 6/24/23, 12:47 PM Hypokalemia Pathway 3. Nonpharmacologic interventions Dietary considerations: initiate potassium replacement therapy in combination with dietary consumption of potassium-rich foods. E 4. Specific circumstances Patients with hypertension: Initiate potassium supplementation in patients with drug-related hypokalemia (such as therapy with a non-potassium-sparing diuretic). E Maintain serum potassium levels 4.0 mmol/L patients with asymptomatic hypertension. Dietary consumption of potassium-rich foods and potassium supplementation should be instituted as necessary. E Patients with heart disease: As per AAFP 2015 guidelines, maintain serum potassium levels 4.0 mmol/L patients with a history of congestive HF or myocardial infarction. B As per NCPCP 2000 guidelines, consider potassium supplementation routinely in patients with HF, even if the initial potassium determination appears to be normal. E Patients with cardiac arrhythmias: maintain serum potassium levels 4.0 mmol/L patients with cardiac arrhythmias. E Patients at risk of stroke: consider maintaining optimal potassium levels in patients at high risk for stroke, including those with a history of atherosclerotic or hemorrhagic cerebral vascular accidents. E Patients with diabetes mellitus: monitor potassium levels closely monitored in patients with diabetes mellitus, and initiate potassium replacement therapy when appropriate. E References 1. J N Cohn, P R Kowey, P K Whelton et al. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000 Sep 11;160 16 2429 36. Open 2. Anthony J Viera, Noah Wouk. Potassium Disorders: Hypokalemia and Hyperkalemia. Am Fam Physician. 2015 Sep 15;92 6 487 95. Open 3. Ashish R Panchal, Jason A Bartos, Jos G Caba as et al. Part 3 Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142 16_suppl_2 S366 S468. Open https://web.pathway.md/diseases/recJkzF5VNUOm60du 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hyponatremia are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ASA 2023), the Korean Society of Nephrology (KSN/KSEBPR 2022), the American Association for the Study of Liver Diseases (AASLD 2021), the Wilderness Medical Society (WMS 2020), the European Association for the Study of the Liver (EASL 2018; 2010), and the European Society of Intensive Care Medicine (ESICM/ERA-EDTA/ESE 2014). 1 2 3 4 5 6 7 8 8 8 8 9 Definition Hyponatremia an electrolyte disorder characterized by low serum sodium concentration, and is typically defined as a serum sodium of less than 135 mEq/L. 8 Epidemiology Causes of hyponatremia include increased water intake (psychogenic polydipsia), low dietary solute intake (tea and toast diet), decreased water excretion secondary to elevated plasma ADH levels (volume depletion, SIADH secretion, severe hypothyroidism, adrenal insufficiency), and expansion of plasma volume in the context of edematous states. 8 Pathophysiology The prevalence of hyponatremia in the general population of the United States is 1.72%. 9 https://web.pathway.md/diseases/recBYiXbMCoztp9CG 1/7 6/24/23, 12:47 PM Hyponatremia Pathway Disease course Treatment of hyponatremia requires careful attention to avoid overly rapid correction of serum sodium, which can lead to osmotic demyelination syndrome, permanent neurological impairment, and death. 8 Prognosis and risk of recurrence Approximately 40% of patients with osmotic demyelination syndrome recover fully, whereas 25% have persistent neurological deficits. Mortality associated with osmotic demyelination syndrome is approximately 6%. 8 Guidelines 1. Classification and risk stratification Classification: Classify hyponatremia based on the documented duration: Situation Guidance < 48 hours Acute 48 hours Chronic If it cannot be classified unless there is clinical or anamnestic evidence of the contrary. Chronic (presumably) Severity grading (based on sodium concentration): Classify hyponatremia based on the serum sodium concentration: Situation Guidance 130-135 mmol/L Mild 125-129 mmol/L Moderate < 125 mmol/L. Profound Severity grading (based on symptoms): Classify hyponatremia based on the symptomatic presentation: moderate: any biochemical degree of hyponatremia in the presence of moderate symptoms (nausea without vomiting, confusion, or headache) severe: any biochemical degree of hyponatremia in the presence of severe symptoms (vomiting, altered level of consciousness, seizures, or cardiorespiratory distress). https://web.pathway.md/diseases/recBYiXbMCoztp9CG 2/7 6/24/23, 12:47 PM Hyponatremia Pathway Risk of osmotic demyelination: Recognize that the risk of osmotic demyelination syndrome depends on the following factors: biochemical degree and duration of hyponatremia at presentation speed of increase in serum sodium concentration history of alcohol abuse and/or liver disease use of thiazide or antidepressant medications. 2. Diagnostic investigations Urine sodium: measure urine sodium concentration on a spot urine sample (obtained and interpreted with concomitant serum sodium concentration) in patients with urine osmolality > 100 mOsm/kg. B Show 2 more Urine osmolality: Obtain and interpret urine osmolality on a spot urine sample as the initial step in the evaluation of patients with hypotonic hyponatremia. B Attribute hyponatremia to relative excess water intake in patients with a urine osmolality 100 mOsm/kg. B Serum osmolality: View hyponatremia as hypotonic hyponatremia in the absence of causes of non-hypotonic hyponatremia, such as: effective osmoles raising serum osmolality causing hyponatremia: isotonic or hypertonic glucose, mannitol, glycine, histidine-tryptophan-ketoglutarate, hyperosmolar radiocontrast media, maltose presence of endogenous solutes causing pseudohyponatremia (laboratory artifact): triglycerides, cholesterol, protein, IVIG, monoclonal gammopathies. Recognize that hyponatremia with a measured serum osmolality < 275 mOsm/kg reflects hypotonic hyponatremia. Serum glucose: measure serum glucose concentration to exclude hyperglycemic hyponatremia, and correct the measured serum sodium concentration for the serum glucose concentration if the latter is increased. B Fractional urinary excretion of uric acid: consider obtaining an additional measurement of fractional urinary excretion of uric acid in patients with hyponatremia to differentiate likely causes of hyponatremia, such as syndrome of inappropriate antidiuresis or diuretic-induced hyponatremia. E Copeptin-to-urinary sodium ratio: insufficient evidence to recommend obtaining copeptin-to- urinary sodium ratio to assess patient volume status. I Vasopressin levels: avoid measuring vasopressin as part of the diagnostic evaluation for the SIADH secretion. D https://web.pathway.md/diseases/recBYiXbMCoztp9CG 3/7 6/24/23, 12:47 PM Hyponatremia Pathway 3. Medical management Management of mildly symptomatic patients, acute setting: As per KSEBPR/KSN 2022 guidelines, obtain rigorous evaluation for the causes of mild hyponatremia and manage causative diseases to improve clinical outcomes. E As per ERA-EDTA/ESE/ESICM 2014 guidelines, obtain prompt diagnostic assessment in mildly symptomatic patients with hyponatremia. B Show 5 more Management of mildly symptomatic patients (chronic setting): discontinue non-essential fluids, medications, and other factors likely to contribute to or provoke hyponatremia. Show 4 more Management of moderately symptomatic patients: obtain prompt diagnostic assessment in moderately symptomatic patients with hyponatremia. B Show 8 more Management of severely symptomatic patients, initial management: As per KSEBPR/KSN 2022 guidelines, consider administering rapid intermittent boluses of hypertonic saline in patients with symptomatic severe hypotonic hyponatremia. C As per ERA-EDTA/ESE/ESICM 2014 guidelines, administer IV infusion of 3% hypertonic saline (150 mL IV, over 20 minutes) promptly in patients with severely symptomatic hyponatremia. B Show 3 more Management of severely symptomatic patients (adequate response to initial management): discontinue hypertonic saline infusion in patients with severely symptomatic hyponatremia displaying an adequate response to initial management. B Show 4 more Management of severely symptomatic patients (inadequate response to initial management): continue IV infusion of 3% hypertonic saline in patients with severely symptomatic hyponatremia displaying an inadequate response to initial treatment, aiming for an additional increase in serum sodium concentration by 1 mmol/L per hour. B Show 2 more Management of overly rapid correction: As per KSN 2022 guidelines, consider administering desmopressin individually according to risk factors affecting overcorrection, hypertonic saline therapeutic regimen, and whether to administer dextrose solution during overcorrection in patients with hyponatremia. C As per ESE 2014 guidelines, discontinue any ongoing treatments aimed at raising serum sodium in patients with overly rapid correction. B Show 3 more 4. Specific circumstances https://web.pathway.md/diseases/recBYiXbMCoztp9CG 4/7 6/24/23, 12:47 PM Hyponatremia Pathway Patients with hypovolemic hyponatremia: administer IV infusion of a crystalloid solution (0.9% saline or a balanced crystalloid, 0.5-1.0 mL/kg/hour) to restore extracellular volume in patients with hypovolemic hyponatremia. A Show 2 more Patients with hypervolemic hyponatremia: do not implement therapeutic measures aimed solely at increasing the serum sodium concentration in patients with mild or moderate hyponatremia. D Show 2 more Patients with SIADH: As per KSN 2022 guidelines, consider administering vaptans in patients with the syndrome of inappropriate antidiuresis and moderate-to-severe hyponatremia. C As per ESE 2014 guidelines, avoid measuring vasopressin as part of the diagnostic evaluation for the SIADH secretion. D Show 3 more Patients with exercise-associated hyponatremia (prevention): advise avoiding sustained overhydration during exercise, as it is the primary risk factor for development of all variants of exercise-associated hyponatremia. A Show 3 more Patients with exercise-associated hyponatremia (assessment): obtain point-of-care testing in at-risk symptomatic patients when available. Integrate all available clinical and historical information into an assessment of the patient's hydration status (history of fluid intake, food intake, presenting signs and symptoms, body weight if available, and urine output), if testing is unavailable. B Patients with exercise-associated hyponatremia (outpatient management): Advise restricting oral fluids if exercise-associated hyponatremia from fluid overload is associated with mild symptoms. Do not administer hypotonic fluids in patients with suspected exercise-associated hyponatremia. B Consider adding oral sodium in hypertonic solutions or advising foods with high sodium content (salty snacks) for increasing serum sodium levels and enhancing symptom relief (over fluid restriction) in patients with mild exercise-associated hyponatremia, if tolerated. C Patients with exercise-associated hyponatremia (inpatient management): inform receiving caregivers about the potential diagnosis of exercise-associated hyponatremia and appropriate fluid management (withhold hypotonic fluids) when transferring care. B Show 7 more Patients with exercise-associated hyponatremia (observation): observe patients for at least 60 minutes after exercise to ensure no decompensation from delayed symptomatic exercise- associated hyponatremia occurs after cessation of exercise. B Patients with heart failure: consider administering vaptans in patients with HF and hypervolemic hyponatremia in terms of rapid sodium correction. C Patients with liver disease: https://web.pathway.md/diseases/recBYiXbMCoztp9CG 5/7 6/24/23, 12:47 PM Hyponatremia Pathway As per KSN 2022 guidelines, insufficient evidence to support the use of vaptans in patients with liver cirrhosis and hypervolemic hyponatremia. I As per AASLD 2021 guidelines, obtain monitoring and advise water restriction in patients with mild hyponatremia (126-135 mEq/L) without symptoms. E Show 6 more As per EASL 2018 guidelines, recognize that the development of hyponatremia (serum sodium concentration < 130 mmol/L) in patients with cirrhosis carries an ominous prognosis, as it is associated with increased mortality and morbidity. Evaluate patients with hyponatremia for liver transplantation. B Show 5 more As per EASL 2010 guidelines, consider administering albumin in patients with hypervolemic hyponatremia in the setting of liver disease. C Show 3 more Patients with cerebral disease: As per AHA 2023 guidelines, consider administering mineralocorticoids for the treatment of natriuresis and hyponatremia in patients with aneurysmal subarachnoid hemorrhage. C As per KSN 2022 guidelines, individualize administration of hypertonic or isotonic saline infusion, oral sodium chloride, or fludrocortisone for the correction of hypoosmolar hyponatremia in patients with cerebral diseases. E 5. Preventative measures Primary prevention in hospitalized patients: Administer isotonic fluids as maintenance fluid therapy to prevent hyponatremia in hospitalized pediatric patients over 1 month and under 18 years of age. A Insufficient evidence to support administrating isotonic fluids as maintenance fluid therapy to prevent hyponatremia in neonates because of the risk of hypernatremia. I References 1. Spasovski G, Vanholder R, Allolio B et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014 Feb 25;170 3 G1 47. Open 2. Scott W Biggins, Paulo Angeli, Guadalupe Garcia-Tsao et al. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Aug;74 2 1014 1048. Open 3. Brad L Bennett, Tamara Hew-Butler, Mitchell H Rosner et al. Wilderness Medical Society Clinical Practice Guidelines for the Management of Exercise-Associated Hyponatremia: 2019 Update. Wilderness Environ Med. 2020 Mar;31 1 50 62. Open 4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open https://web.pathway.md/diseases/recBYiXbMCoztp9CG 6/7 6/24/23, 12:47 PM Hyponatremia Pathway 5. Yeonhee Lee, Kyung Don Yoo, Seon Ha Baek et al. Korean Society of Nephrology 2022 Recommendations on controversial issues in diagnosis and management of hyponatremia. Kidney Res Clin Pract. 2022 Jul;41 4 393 411. Open 6. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53 3 397 417. Open 7. Brian L Hoh, Nerissa U Ko, Sepideh Amin-Hanjani et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2023 May 22. Online ahead of print. Open 8. Rondon-Berrios H, Agaba EI, Tzamaloukas AH. Hyponatremia: pathophysiology, classification, manifestations and management. Int Urol Nephrol. 2014 Nov;46 11 2153 65. Open 9. Mohan S, Gu S, Parikh A et al. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med. 2013 Dec;126 12 1127 37. Open https://web.pathway.md/diseases/recBYiXbMCoztp9CG 7/7

Guideline sources The following summarized guidelines for the evaluation and management of hypoplastic left heart syndrome (HLHS) are prepared by our editorial team based on guidelines from the Association for European Paediatric and Congenital Cardiology (AEPC/EACTS 2020) and the American Heart Association (AHA 2018). 1 2 Calculator NYHA functional classification f Guidelines 1. Screening and diagnosis https://web.pathway.md/diseases/rec9a3ruUUM6kGOlZ 1/5 6/24/23, 12:47 PM Hypoplastic left heart syndrome Pathway Prenatal diagnosis: obtain an obstetrical fetal anomaly scan at 18-22 weeks of gestation. Include at minimum a four-chamber view, outflow tract views, and three-vessel tracheal view in the cardiac imaging during obstetrical fetal anomaly scan. B Show 4 more Postnatal diagnosis: Obtain TTE to rule out congenital heart disease, including HLHS, in undiagnosed neonates with persistent tachypnea or desaturation. B Assess global cardiac function, structures by four- chamber view, outflow tract views, aortic arch, coeliac trunk, and cerebral blood flow. B Confirm the diagnosis of HLHS by a pediatric cardiologist and provide counseling to the parents in conjunction with a pediatric cardiac surgeon. B 2. Diagnostic investigations Cardiac imaging: obtain echocardiographic evaluation of HLHS to define the HLHS type, including the situs and cardiac variants, and assess the left ventricle and its function, ventricular septal defect, atrial septum, pulmonary veins (anatomy and Doppler flow patterns), aortic arch including flow patterns (antegrade, retrograde), RV function, and tricuspid valve. Obtain cardiac MRI as the standard for measurement of right ventricle volume and function. B Electrocardiogram: obtain an ECG to exclude cardiac arrhythmias. B Chest X-ray: obtain CXR by clinical indication only. B Genetic testing: obtain testing for chromosomal abnormalities in patients with extracardiac abnormalities to provide additional information for postnatal counseling and prognosis. B 3. Medical management Setting of delivery: allow delivery of a fetus with HLHS, in the absence of risk factors, to occur spontaneously up to 40 weeks. Offer elective delivery planning (induction of labor or Cesarean delivery) no earlier than 39 weeks as long as there are no obstetrical risk factors. B Show 2 more Initial resuscitation: Perform resuscitation, including intubation and ventilation and placement of central and invasive monitoring lines, in unstable neonates. B Administer oxygen and perform intubation and ventilation only by strict indications. B Ensure minimal handling in a tranquil environment with HR, respiratory rate, SaO , and BP monitoring in stable neonates. B Prostaglandin E1: administer continuous, low-dose prostaglandin E1 infusion to preserve patency of the ductus arteriosus before stage I procedure. B Hemodynamic support: administer inodilators (milrinone) to support RV function before stage I procedure, if adequate coronary perfusion pressure is maintained. B https://web.pathway.md/diseases/rec9a3ruUUM6kGOlZ 2/5 6/24/23, 12:47 PM Hypoplastic left heart syndrome Pathway Show 3 more 4. Perioperative care Preoperative imaging: obtain TTE for planning initial surgery in patients with classical HLHS. Consider obtaining 3D echocardiography to assist in imaging the tricuspid valve to assess morphology and regurgitation. B Show 3 more Intraoperative imaging: obtain intraoperative transesophageal or epicardial echocardiography in conjunction with hemodynamic assessment during the Norwood procedure. Consider obtaining exit angiography or CT for clinical concerns, particularly for anatomy less accessible to echocardiography. B Postoperative imaging: obtain TTE as the initial imaging modality for postoperative assessment including all operated regions (atrial communication, neoaortic valve, aortic-pulmonary artery connection, coronary flow, arch reconstruction, source of pulmonary blood flow, and branch pulmonary arteries after after the Norwood procedure, and atrial communication, ductus arteriosus stent, aortic arch flow, bilateral pulmonary artery banding after the hybrid procedure). Consider obtaining angiography or CT for clinical concerns unanswered by echocardiography. B 5. Surgical interventions Prenatal interventions: Consider performing fetal intervention to augment the size of the atrial septal communication to improve perinatal and longer-term outcomes in the fetus with a restrictive foramen ovale. C Consider performing fetal intervention to improve antegrade flow across the aortic valve in an effort to achieve a biventricular outcome in fetuses with critical aortic stenosis and features of emerging HLHS. C Immediate postnatal interventions: consider performing immediate transcatheter or surgical intervention in neonates with HLHS and restrictive ductus arteriosus, restrictive foramen ovale, totally anomalous pulmonary venous drainage, pulmonary valve stenosis, or non-restrictive foramen ovale with high pulmonary blood flow. C Pre-stage 1 interventions: Perform balloon atrial septostomy to treat pulmonary congestion and to increase pulmonary blood flow in cases of insufficient inter-circulatory mixing. B Perform bilateral pulmonary banding for low cardiac output based on a high pulmonary blood flow and widely patent ductus arteriosus. B Norwood stage 1 palliation: Use the following techniques for the management of pulmonary arteries: patch reconstruction of the central pulmonary arteries B direct closure of the central pulmonary arteries B https://web.pathway.md/diseases/rec9a3ruUUM6kGOlZ 3/5 6/24/23, 12:47 PM Hypoplastic left heart syndrome Pathway division of the branch pulmonary arteries B ligature of the proximal ductus arteriosus, no patch. B Show 5 more Hybrid stage 1 palliation: perform hybrid stage 1 palliation electively in the first postnatal week. B Show 2 more Considerations for anesthesia: reduce systemic vascular resistance and prevent surges in afterload to improve systemic perfusion and maintain a balanced pulmonary blood flow/systemic blood flow. B Show 3 more 6. Specific circumstances Patients with tricuspid regurgitation: recognize that tricuspid regurgitation moderately increases mortality and morbidity rates and prevents completion of the single ventricle pathway. B Show 5 more Patients with restrictive atrial septal defect: recognize that intact atrial septum or restrictive foramen ovale are predictors of poor outcome in HLHS. B Show 4 more Patients with pulmonary vein anomalies: perform surgery as early as possible in patients with anomalies of pulmonary venous connection with obstruction. Repair the anomalous connection by anastomosis between the common pulmonary vein and the most convenient part of the common atrium. B Patients with coronary anomalies: Recognize that coronary anomalies can negatively impact survival after stage 1 palliation. Obtain preoperative echocardiographic evaluation if a coronary anomaly is suspected. B Use a particular strategy for stage 1 palliation in patients with aortic atresia/MS associated with a ventriculocoronary connection as it is associated with a higher mortality rate. B 7. Follow-up and surveillance Early postoperative care: ensure compliance with an operating room checklist and a rigorous handover to the ICU team based on an algorithm. A Show 8 more Interstage 1 monitoring: As per EACTS 2020 guidelines, include the following components in the interstage 1 monitoring programs: dedicated interstage 1 care team B https://web.pathway.md/diseases/rec9a3ruUUM6kGOlZ 4/5 6/24/23, 12:47 PM Hypoplastic left heart syndrome Pathway interstage 1 clinic B provision of red flag action plan B standardized discharge process including family education and rooming in B written communication with primary pediatrician and cardiologist B involvement of a registered dietitian B feeding/nutrition protocol including clear daily weight change goals B use of telehealth visits B use of tablet or mobile apps. B As per AHA 2018 guidelines, consider providing a home monitoring program including the following components for the interstage period to reduce interstage morbidity and mortality: daily oxygen saturations daily weights diet record close communication with discharging facility. C 8. Quality improvement Analysis of outcomes: Use the International Paediatric and Congenital Cardiac Code in all registries, databases, and research studies in pediatric and congenital cardiac care, including cases of HLHS. B Ensure that all pediatric and congenital cardiac teams routinely assess their data against national and international benchmarks using multi-institutional databases and registries. B References 1. Nelson Alphonso, Annalisa Angelini, David J Barron et al. Guidelines for the management of neonates and infants with hypoplastic left heart syndrome: The European Association for Cardio-Thoracic Surgery EACTS and the Association for European Paediatric and Congenital Cardiology AEPC Hypoplastic Left Heart Syndrome Guidelines Task Force. Eur J Cardiothorac Surg. 2020 Sep 1;58 3 416 499. Open 2. Bradley S Marino, Sarah Tabbutt, Graeme MacLaren et al. Cardiopulmonary Resuscitation in Infants and Children With Cardiac Disease: A Scientific Statement From the American Heart Association. Circulation. 2018 May 29;137 22):e691-e782. Open https://web.pathway.md/diseases/rec9a3ruUUM6kGOlZ 5/5

Guideline sources The following summarized guidelines for the evaluation and management of hypospadias are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022), the Canadian Urological Association (CUA 2017), and the American Urological Association (AUA 2014). 1 2 3 Guidelines 1. Diagnostic investigations Evaluation for disorders of sex development: As per EAU 2022 guidelines, differentiate isolated hypospadias from disorders of sex development at birth which are mostly associated with cryptorchidism or micropenis. A As per CUA 2017 guidelines, obtain karyotype testing in patients with at least one undescended testicle and proximal hypospadias, especially in the setting of non-palpable gonads. B As per AUA 2014 guidelines, assess for the possibility of a disorder of sex development in patients with cryptorchidism and severe hypospadias. B 2. Perioperative care https://web.pathway.md/diseases/reco5V5OeFHwoQ735 1/3 6/24/23, 12:47 PM Hypospadias Pathway Preoperative hormonal therapy: consider offering preoperative androgen stimulation therapy to increase penile length and glans circumference C in pediatric patients with proximal hypospadias and a small appearing penis, reduced glans circumference or reduced urethral plate. C Perioperative antibiotics: Consider administering intraoperative antibiotic prophylaxis during hypospadias repair. C Avoid administering postoperative antibiotic prophylaxis after hypospadias repair. D 3. Surgical interventions Surgical repair (timing): Consider performing primary hypospadias repair at age of 6-18/24 months. C Recognize that age at surgery is not a risk factor for complications in prepubertal patients undergoing tubularized incised plate urethroplasty repair. B Surgical repair (penile curvature correction and urethroplasty): correct the penile curvature and form a neo-urethra of adequate size with an opening on the glans with proper skin coverage of the penile shaft to achieve an overall acceptable functional and cosmetic outcome. B Show 14 more Surgical repair (dressing): consider placing a circular dressing with slight compression. C 4. Patient education General counseling: counsel caregivers on functional indications for surgery, esthetically feasible operative procedures (psychological, cosmetic indications) and possible complications. A 5. Follow-up and surveillance Postoperative follow-up: obtain long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, ejaculation disorder, and to evaluate patient's satisfaction. A Show 3 more References 1. Kolon TF, Herndon CD, Baker LA et al. Evaluation and treatment of cryptorchidism: AUA guideline. J Urol. 2014 Aug;192 2 337 45. Open 2. Lisette A 't Hoen, Guy Bogaert, Christian Radmayr et al. EAU guidelines on Paediatric Urology. EAU. 2022 Mar. Open https://web.pathway.md/diseases/reco5V5OeFHwoQ735 2/3 6/24/23, 12:47 PM Hypospadias Pathway 3. Luis H Braga, Armando J Lorenzo, Rodrigo L P Romao. Canadian Urological Association-Pediatric Urologists of Canada CUA PUC guideline for the diagnosis, management, and followup of cryptorchidism. Can Urol Assoc J. 2017 Jul;11 7 E251 E260. Open https://web.pathway.md/diseases/reco5V5OeFHwoQ735 3/3

Guideline sources The following summarized guidelines for the evaluation and management of hypothyroidism are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2020), the American Heart Association (AHA/HRS/ACC 2019), the American Thyroid Association (ATA 2017), and the American Thyroid Association (ATA/AACE 2012). 1 2 3 4 5 5 5 5 6 Definition Hypothyroidism is a chronic endocrine disease associated with deficiency of thyroxine (T4) and T3 (T3) thyroid hormones. 5 Epidemiology Hypothyroidism is most frequently caused by a failure of the thyroid gland to produce thyroid hormones (99%). Other causes include the underproduction of TSH by the pituitary gland and deficiency of the thyrotropin-releasing hormone. 5 Pathophysiology The prevalence of overt and subclinical hypothyroidism in the United States is estimated at 300 per 100,000 population and 4,300 per 100,000 population, respectively. Hypothyroidism is 2-8 times https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 1/6 6/24/23, 12:47 PM Hypothyroidism Pathway more prevalent in women than men, and it's prevalence increases with age. 5 Disease course Clinical manifestations include weight gain, fatigue, proximal weakness, decreased concentration, depression, diffuse muscle pain, menstrual irregularities, constipation, dry skin, hair loss, and sensory neuropathy. A severe form of hypothyroidism-myxedema coma- presents with altered mental status, hypothermia, hyponatremia and bradycardia. The disease decreases productivity and quality of life. 5 Prognosis and risk of recurrence Hypothyroidism is not associated with an increase in mortality. Treatment is well tolerated and results in improved quality of life in most patients. However, untreated hypothyroidism leads to disease progression and ultimately, coma and death. 6 Guidelines 1. Screening and diagnosis Clinical scoring systems: avoid using clinical scoring systems to diagnose hypothyroidism. D Indications for screening: consider obtaining screening for hypothyroidism in > 60 years old individuals. B Show 2 more Indications for testing (dyslipidemia): evaluate for and rule out hypothyroidism as the cause of hyperlipidemia before initiating lipid-lowering therapy in patients with hyperlipidemia. A Indications for testing (infertility): assess serum TSH concentration in all females seeking care for infertility. B 2. Diagnostic investigations Anti-TPO antibodies: measure anti-TPO antibodies in the evaluation of patients with subclinical hypothyroidism. B Show 3 more Thyroid hormone tests: measure serum free T4 (free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti-T4 antibodies) instead of total T4 in the evaluation of hypothyroidism. A Show 3 more Other diagnostic tests: avoid tests such as clinical assessment of reflex relaxation time, cholesterol, and muscle enzymes to diagnose hypothyroidism. D https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 2/6 6/24/23, 12:47 PM Hypothyroidism Pathway 3. Medical management Indications for L-thyroxine (abnormal TSH): Consider initiating levothyroxine in patients with serum TSH levels > 10 mIU/L, as these patients are at increased risk for HF and cardiovascular mortality. B Consider initiating treatment based on individual factors in patients with TSH levels between the upper limit of a given laboratory's reference range and 10 mIU/L, particularly if patients have symptoms suggestive of hypothyroidism, positive anti-TPO antibodies, or evidence of ASCVD, HF, or associated risk factors for these diseases. B Indications for L-thyroxine (normal TSH): Consider initiating L-thyroxine therapy in female patients of childbearing age with serum TSH levels within the reference range for the local laboratory if: serum TSH is > 2.5 mIU/L in patients planning a pregnancy in the immediate future (including assisted reproduction) serum TSH is > 2.5 mIU/L during the first trimester of pregnancy serum TSH is > 3.0 mIU/L during the second trimester of pregnancy serum TSH is > 3.5 mIU/L during the third trimester of pregnancy. C Show 6 more Choice of agent: treat patients with hypothyroidism with levothyroxine monotherapy. A Initial L-thyroxine dose: consider full replacement doses when initiating therapy in young healthy adults with overt hypothyroidism. C Treatment targets: Target the normal range of a third-generation TSH assay in nonpregnant patients with hypothyroidism. Consider targeting an ULN of 4.12 mIU/L in iodine-sufficient areas if an ULN for a third-generation TSH assay is not available, and a LLN of 0.45 mIU/L if a LLN is not available. B Assess serum free T4 to guide therapy in patients with central hypothyroidism, targeting to exceed the midnormal range value for the assay being used. B Management of dyslipidemia: avoid treating hyperlipidemia until the patient becomes euthyroid in order to more accurately assess the lipid profile in patients with overt hypothyroidism. D Show 2 more 4. Nonpharmacologic interventions Iodine supplementation: do not use iodine supplementation, including kelp or other iodine- containing functional foods, in the management of hypothyroidism in iodine-sufficient areas. D Selenium supplementation: do not use selenium for the prevention or treatment of hypothyroidism. D https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 3/6 6/24/23, 12:47 PM Hypothyroidism Pathway 5. Specific circumstances Pregnant patients: Obtain the measurement of total thyroxine or a free thyroxine index, in addition to TSH, to assess thyroid status in pregnancy. Because of the wide variation in the results of different free thyroxine assays, employ direct immunoassay measurement of free thyroxine only when method-specific and trimester-specific reference ranges for serum free thyroxine are available. B Base the target range for TSH in patients with hypothyroidism who are pregnant on trimester- specific ranges for that laboratory. If trimester-specific reference ranges are not available in the laboratory, follow the following upper-normal reference ranges: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; and third trimester, 3.5 mIU/L. B Patients with combined adrenal insufficiency: initiate corticosteroids before treatment with levothyroxine in patients with combined adrenal insufficiency and hypothyroidism. B Patients with conduction disorders: consider permanent cardiac pacing without further observation for reversibility in patients with symptomatic second-degree or third-degree AV block associated with thyroid function abnormalities but without clinical myxedema. C 6. Patient education Timing of L-thyroxine doses: advise levothyroxine to be taken with water consistently 30-60 minutes before breakfast, or at bedtime, 4 hours after the last meal. B Nutraceuticals for hypothyroidism: advise patients taking dietary supplements and nutraceuticals for hypothyroidism that commercially available thyroid-enhancing products are not a remedy for hypothyroidism and counsel about the potential side effects of various preparations particularly those containing iodine or sympathomimetic amines as well as those marked as "thyroid support" since they could be adulterated with levothyroxine or T3. B 7. Follow-up and surveillance Indications for specialist referral: Manage most patients with primary hypothyroidism by non- endocrinologist physicians familiar with the diagnosis and treatment of hypothyroidism. Refer patients with hypothyroidism meeting any of the following criteria for a consultation with an endocrinologist: infant and pediatric patients female patient planning conception pregnant patients patients difficult to render and maintain in a euthyroid state cardiac disease presence of goiter, nodule, or other structural changes in the thyroid gland https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 4/6 6/24/23, 12:47 PM Hypothyroidism Pathway presence of other endocrine diseases, such as adrenal or pituitary disorders unusual constellation of thyroid function test results unusual causes of hypothyroidism, such as induced by agents interfering with the absorption of levothyroxine, impacting thyroid gland hormone production or secretion, affecting the hypothalamic-pituitary-thyroid axis (directly or indirectly), increasing clearance, or peripherally impacting metabolism. B References 1. Garber JR, Cobin RH, Gharib H et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18 6 988 1028. Open 2. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 3. Fred M Kusumoto, Mark H Schoenfeld, Coletta Barrett 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. Circulation. 2019 Aug 20;140 8):e382-e482. Open 4. Erik K Alexander, Elizabeth N Pearce, Gregory A Brent et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27 3 315 389. Open 5. Luca Chiovato, Flavia Magri, Allan Carle. Hypothyroidism in Context: Where We've Been and Where We're Going. 2019 Sep;36 Suppl 2 47 58.2019 Sep;36 Suppl 2 47 58. Open 6. Neige M Y Journy, Marie-Odile Bernier, Michele M Doody et al. Hyperthyroidism, Hypothyroidism, and Cause-Specific Mortality in a Large Cohort of Women. Thyroid. 2017 Aug;27 8 1001 1010. Open 7. LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015 May 5;162 9 641 50. Open 8. Society for Maternal-Fetal Medicine. Choosing Wisely SMFM recommendations. Choosing Wisely. 2019. Open 9. Endocrine Society. Choosing Wisely ES recommendations. Choosing Wisely. 2017. Open 10. Luca Chiovato, Flavia Magri, Allan Carl . Hypothyroidism in Context: Where We've Been and Where We're Going. Adv Ther. 2019 Sep;36 Suppl 2 47 58. Open 11. Peter N Taylor, Diana Albrecht, Anna Scholz et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018 May;14 5 301 316. Open 12. Jeffrey R Garber, Rhoda H Cobin, Hossein Gharib et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012 Dec;22 12 1200 35. Open 13. Vivek Mathew, Raiz Ahmad Misgar, Sujoy Ghosh et al. Myxedema coma: a new look into an old crisis. J Thyroid Res. 2011;2011 493462. Open https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 5/6 6/24/23, 12:47 PM Hypothyroidism Pathway 14. Scott A Sullivan. Hypothyroidism in Pregnancy. Clin Obstet Gynecol. 2019 Jun;62 2 308 319. Open 15. Jacqueline Jonklaas, Antonio C Bianco, Andrew J Bauer et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24 12 1670 751. Open 16. Neige M Y Journy, Marie-Odile Bernier, Michele M Doody et al. Hyperthyroidism, Hypothyroidism, and Cause-Specific Mortality in a Large Cohort of Women. 2017 Aug;27 8 1001 1010.2017 Aug;27 8 1001 1010. Open 17. Jacqueline Jonklaas, Antonio C Bianco, Andrew J Bauer et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24 12 1670 751. Open https://web.pathway.md/diseases/reczsKmQVIbWTbsAr 6/6

Guideline sources The following summarized guidelines for the evaluation and management of ICU delirium are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2022; 2018; 2013). 1 2 4 Calculator Calculator Pathway AWOL score for delirium Confusion assessment method ICU deliriu Diagnosis a Guidelines 1. Screening and diagnosis Indications for screening: monitor critically ill adult patients regularly for delirium. E Risk factors: Preexisting dementia, history of hypertension and/or alcoholism, and a high severity of illness at admission are strongly associated with the development of delirium in the ICU. B https://web.pathway.md/diseases/reccEXtBzUpU4rERP 1/3 6/24/23, 2:27 PM ICU delirium Pathway Benzodiazepine use may be a risk factor for the development of delirium in adult ICU patients. B 2. Classification and risk stratification Risk stratification: Predictive models that include delirium risk factors at both the time of ICU admission and in the first 24 hours of ICU admission have been validated and shown to be capable of predicting delirium in critically ill adults. Positive delirium screening in critically ill adults is strongly associated with cognitive impairment at 3 and 12 months after ICU discharge and may be associated with a longer hospital stay. 3. Medical management General principles: use a multidisciplinary approach to facilitate the management of delirium in critically ill adult patients, including preprinted and/or computerized protocols and order forms, quality ICU rounds checklists, and provider education. B Pharmacologic therapy: consider not using haloperidol or an atypical antipsychotic to treat subsyndromal delirium in critically ill adults. D Show 2 more Management of sedation: Consider using light sedation rather than deep sedation in critically ill, mechanically ventilated adults. C Consider using either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults. C Management of sleep disturbance: consider using noise and light reduction strategies to improve sleep in critically ill adults. C Show 3 more 4. Specific circumstances Pediatric patients (management of delirium): use the preschool and pediatric Confusion Assessment Methods for the ICU or the Cornell Assessment for Pediatric Delirium as the most valid and reliable delirium monitoring tools in critically ill pediatric patients. A Show 8 more Pediatric patients (management of sedation): use the COMFORT-B scale or thr State Behavioral Scale to assess level of sedation in mechanically ventilated pediatric patients. B Show 11 more https://web.pathway.md/diseases/reccEXtBzUpU4rERP 2/3 6/24/23, 2:27 PM ICU delirium Pathway 5. Preventative measures Early mobilization: mobilize adult ICU patients as soon as safe and feasible, to reduce the incidence and duration of delirium. B Pharmacologic prophylaxis: consider avoiding the use of haloperidol, dexmedetomidine, statins, or ketamine to prevent delirium in critically ill adults. D Bright light therapy: consider avoiding the use of bright light therapy to reduce delirium in critically ill adults. D References 1. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41 1 263 306. Open 2. Devlin JW, Skrobik Y, G linas C et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46 9):e825-e873. Open 3. Federico Coccolini, Francesco Corradi, Massimo Sartelli et al. Postoperative pain management in non- traumatic emergency general surgery: WSES GAIS SIAARTI AAST guidelines. World J Emerg Surg. 2022 Sep 21;17 1 50. Open 4. Heidi A B Smith, James B Besunder, Kristina A Betters et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med. 2022 Feb 1;23 2):e74-e110. Open 5. Suresh Arumugam, Ayman El-Menyar, Ammar Al-Hassani et al. Delirium in the Intensive Care Unit. J Emerg Trauma Shock. Jan-Mar 2017;10 1 37 46. Open 6. Rodrigo Cavallazzi, Mohamed Saad, Paul E Marik. Delirium in the ICU an overview. Ann Intensive Care. 2012 Dec 27;2 1 49. Open 7. Jason W W Thomason, Ayumi Shintani, Josh F Peterson et al. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care. 2005 Aug;9 4 R375 81. Open 8. Koen S Simons, Robert J F Laheij, Mark van den Boogaard et al. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial. Lancet Respir Med. 2016 Mar;4 3 194 202. Open 9. Pratik P Pandharipande, Brenda T Pun, Daniel L Herr et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298 22 2644 53. Open 10. DAS Taskforce, Ralf Baron, Andreas Binder et al. Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 DAS Guideline 2015 short version. Ger Med Sci. 2015 Nov 12;13 Doc19. Open https://web.pathway.md/diseases/reccEXtBzUpU4rERP 3/3

Guideline sources The following summarized guidelines for the evaluation and management of ICU-acquired weakness are prepared by our editorial team based on guidelines from the American Association for Thoracic Surgery (AATS 2014). 1 Guidelines 1. Classification and risk stratification Risk factors for poor recovery: clinical research is required to determine the role of prior patient disability in the development of and recovery from ICU-acquired weakness. B 2. Nonpharmacologic interventions Physical rehabilitation: well-designed, adequately powered and executed RCTs are recommended to compare physical rehabilitation or other alternative treatments with usual care in patients with ICU-acquired weakness that measure and report patient-important outcomes. B 3. Patient education General counseling: clinical research is required to determine whether or not patients would want to know if they have ICU-acquired weakness, even though no specific therapy currently exists, https://web.pathway.md/diseases/recWpDfd4u1JnXtoH 1/2 6/24/23, 2:27 PM ICU-acquired weakness Pathway and how patient preferences influences medical decision making or the perception of prognosis. B References 1. Fan E, Cheek F, Chlan L et al. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014 Dec 15;190 12 1437 46. Open 2. Eddy Fan, Fern Cheek, Linda Chlan et al. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014 Dec 15;190 12 1437 46. Open 3. Naeem A Ali, James M O'Brien Jr, Stephen P Hoffmann et al. Acquired weakness, handgrip strength, and mortality in critically ill patients. Am J Respir Crit Care Med. 2008 Aug 1;178 3 261 8. Open 4. Sarah E Jolley, Aaron E Bunnell, Catherine L Hough. ICU Acquired Weakness. Chest. 2016 Nov;150 5 1129 1140. Open 5. Greet Hermans, Greet Van den Berghe. Clinical review: intensive care unit acquired weakness. Crit Care. 2015 Aug 5;19 1 274. Open https://web.pathway.md/diseases/recWpDfd4u1JnXtoH 2/2

Guideline sources The following summarized guidelines for the evaluation and management of ICU-associated pain are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2022; 2013). 1 2 Guidelines 1. Screening and diagnosis Monitoring for pain: monitor pain routinely in all adult patients hospitalized in the ICU. B 2. Medical management Analgesia prior to invasive procedures: consider preemptive analgesic therapy and/or nonpharmacologic interventions prior to performing invasive and potentially painful procedures in adult ICU patients. C Management of non-neuropathic pain: Use intravenous opioids as first-line therapy for the management of non-neuropathic pain in critically ill patients. B https://web.pathway.md/diseases/recAqwELYTyYCXXXK 1/2 6/24/23, 2:27 PM ICU-associated pain Pathway Consider using nonopioid analgesics to decrease the amount of opioids administered (or to eliminate the need for intracvenous opioids altogether) and to decrease opioid-related side effects. C Managagement of neuropathic pain: consider either enterally administered gabapentin or carbamazepine, in addition to intravenous opioids, for treatment of neuropathic pain. B 3. Therapeutic procedures Neuraxial analgesia: Consider thoracic epidural analgesia for postoperative pain relief in patients undergoing AAA surgery. B Consider thoracic epidural analgesia for patients with traumatic rib fractures. C 4. Specific circumstances Pediatric patients: consider obtaining routine pain assessment via self-report using the Visual Analog Scale, NRS, Oucher Scale, or Wong-Baker Faces pain scale in critically ill pediatric patients aged 6 years capable of communicating. C Show 10 more References 1. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41 1 263 306. Open 2. Heidi A B Smith, James B Besunder, Kristina A Betters et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med. 2022 Feb 1;23 2):e74-e110. Open 3. Christina J Hayhurst, Jim C Jackson, Kristin R Archer et al. Pain and Its Long-term Interference of Daily Life After Critical Illness. Anesth Analg. 2018 Sep;127 3 690 697. Open 4. Ayahiro Yamashita, Masaki Yamasaki, Hiroki Matsuyama et al. Risk factors and prognosis of pain events during mechanical ventilation: a retrospective study. J Intensive Care. 2017 Feb 8;5 17. Open https://web.pathway.md/diseases/recAqwELYTyYCXXXK 2/2