Guideline sources The following summarized guidelines for the evaluation and management of multisystem inflammatory syndrome (MIS-C) are prepared by our editorial team based on guidelines from the World Health Organization (WHO 2023), the American College of Rheumatology (ACR 2022), and the Center for Disease Control (CDC 2021; 2020). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Epidemiology: Recognize that the vast majority of pediatric patients with COVID-19 present with mild symptoms and have excellent outcomes, and the MIS-C in children remains a rare complication of SARS-CoV-2 infections. A Recognize that MIS-C in children is tempPO associated with SARS-CoV-2 infections. Use the prevalence of the virus in a given geographic location, which may change over time, to inform management decisions. B Definitions: https://web.pathway.md/diseases/recTB5IUPG45qWFjB 1/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway As per CDC 2021 guidelines, diagnose MIS-C in adults in 21 years old patients hospitalized for 24 hours (or with an illness resulting in death) meeting the following clinical and laboratory criteria, in the absence of a more likely alternative diagnosis for the illness (such as bacterial sepsis, exacerbation of a chronic medical condition): subjective or documented fever ( 38.0 C) for 24 hours before hospitalization or within the first 3 days of hospitalization and at least 3 of the following clinical criteria occurring prior to hospitalization or within the first 3 days of hospitalization (at least 1 must be a primary clinical criterion): Situation Guidance Severe cardiac illness (myocarditis, pericarditis, coronary artery dilatation/aneurysm, new-onset right or LV dysfunction (LVEF < 50%), second- or third- degree AV block, or VT) Primary clinical criteria Rash and non-purulent conjunctivitis New-onset neurologic signs and symptoms (encephalopathy in a patient without prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy including Guillain-Barr syndrome) Secondary clinical criteria Shock or hypotension not attributable to medical therapy (such as sedation, RRT) Abdominal pain, vomiting, or diarrhea Thrombocytopenia (platelet count < 150, 000/ L) Elevated levels of at least 2 of the following E Laboratory evidence As per CDC 2020 guidelines, diagnose MIS-C in children if all of the following criteria are met: patient aged < 21 years presenting with fever (> 38.0 C for 24 hours, or report of subjective fever lasting 24 hours), laboratory evidence of inflammation (iIncluding, but not limited to, 1 of the following: elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (> 2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological) no alternative plausible diagnoses positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test, or COVID-19 exposure within the 4 weeks before the onset of symptoms. E https://web.pathway.md/diseases/recTB5IUPG45qWFjB 2/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway Differential diagnosis: do not use seropositivity to SARS-CoV-2 (nucleocapsid or spike protein) to adequately distinguish between MIS-C in children and other overlapping syndromes, given the high prevalence of COVID-19 in certain communities. Suspect alternative diagnoses in case of a negative finding on antibody test. D Show 3 more 2. Diagnostic investigations Initial evaluation: As per ACR 2022 guidelines, obtain diagnostic evaluation for MIS-C in children in patients under investigation without life-threatening manifestations before initiating immunomodulatory treatment. B Show 3 more As per CDC 2021 guidelines, obtain the following laboratory tests aimed at identifying laboratory evidence of inflammation for the evaluation of MIS-C in children: CBC CRP ESR fibrinogen procalcitonin D-dimer ferritin LDH IL-6albumin. E Show 3 more Diagnostic imaging: evaluate ventricular/valvular function, pericardial effusion, and coronary artery dimensions with measurements indexed to BSA using Z-scores during echocardiography obtained at diagnosis. A Show 2 more Evaluation for other causes: As per ACR 2022 guidelines: Evaluate patients under investigation for MIS-C in children also for other possible infections and non-infection-related conditions (such as malignancy) likely to explain the clinical presentation. A Obtain diagnostic evaluation in patients without life-threatening manifestations before initiating immunomodulatory treatment. B As per CDC 2021 guidelines, evaluate for other potential diagnoses directed by patient signs or symptoms. E https://web.pathway.md/diseases/recTB5IUPG45qWFjB 3/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway 3. Diagnostic procedures Lumbar puncture: consider performing lumbar puncture in patients under investigation for MIS-C in children. B 4. Medical management General principles: consider offering close monitoring only without immunomodulatory therapy in some patients with mild symptoms, after evaluation by specialists with expertise in MIS-C in children. C Show 3 more Setting of care: consider obtaining evaluation for MIS-C in children in an outpatient setting in well-appearing patients with stable vital signs and for ensuring that physical examinations provide close clinical follow-up. C Show 2 more Intravenous immunoglobulin: initiate IVIG in hospitalized patients with MIS-C in children patients and/or patients fulfilling Kawasaki disease criteria. A Show 6 more Corticosteroids: As per WHO 2023 guidelines: Consider initiating corticosteroids in addition to supportive care (rather than either IVIG plus supportive care, or supportive care alone) in hospitalized pediatric patients aged 0-18 years meeting a standard case definition for MIS-C in children. C Consider initiating corticosteroids in addition to standard of care for Kawasaki disease in hospitalized pediatric patients aged 0-18 years meeting both a standard case definition for MIS-C in children and diagnostic criteria for Kawasaki disease. C As per ACR 2022 guidelines: Initiate low-to-moderate-dose corticosteroids (1-2 mg/kg/day; methylprednisolone or another corticosteroid at equivalent dosing) with IVIG as dual therapy for the treatment hospitalized patients with MIS-C in children. B Consider administering high-dose, IV pulse corticosteroids (10-30 mg/kg/day) in patients not responding to IVIG and low-to-moderate-dose corticosteroids, especially in patients requiring high-dose or multiple inotropes and/or vasopressors. C Biologics: Consider initiating high-dose anakinra (> 4 mg/kg/day IV or SC) for the treatment of patients with MIS-C in children refractory to IVIG and corticosteroids and features of macrophage activation syndrome or in patients with contraindications to long-term use of corticosteroids. C Consider initiating infliximab (5-10 mg/kg/day IV 1 dose) as an alternative biologic agent to anakinra for the treatment of patients with MIS-C in children refractory to IVIG and corticosteroids, or in patients with contraindications to long-term use of corticosteroids. Do not https://web.pathway.md/diseases/recTB5IUPG45qWFjB 4/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway use infliximab for the treatment of patients with MIS-C in children and features of macrophage activation syndrome. C Antiplatelet and anticoagulant therapy: initiate low-dose aspirin (3-5 mg/kg/day; maximum 81 mg/day) in patients with MIS-C in children and continue until the platelet count is normalized and normal coronary arteries are confirmed at 4 weeks after diagnosis. Avoid aspirin therapy in patients with active bleeding, significant bleeding risk, and/or a platelet count of 80, 000/ L. B Show 5 more 5. Specific circumstances Patients with hyperinflammation syndrome: recognize that pediatric patients, particularly infants, with medical complexity including T1DM, complex congenital heart disease, neurologic conditions, obesity, or asthma and patients receiving immunosuppressive medications may be at higher risk for severe COVID-19. Recognize that racial and ethnic minorities may also be at higher risk. B Show 12 more 6. Follow-up and surveillance Serial cardiac monitoring: monitor BNP and/or troponin T levels until normalization in patients with MIS-C in children with abnormalities of these laboratory parameters at diagnosis. A Show 5 more Clinical findings Symptoms Past medical history Abdominal pain AKI Confusion Coronary artery aneurysm Cracked lips Covid-19 infection Diarrhea Neurological exam Fever Foot swelling Altered mental status Hand swelling Coma Irritability Encephalopathy Muscle pains Focal neurologic deficits Seizure Meningismus Shortness of breath Head and neck exam Skin rash Throat pain Oral mucosal erythema Vomiting Strawberry tongue https://web.pathway.md/diseases/recTB5IUPG45qWFjB 5/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway Vital signs Lymphatic exam Signs of shock Lymphadenopathy Tachypnea Lab findings Ocular exam Hyperkalemia Conjunctivitis Hypoalbuminemia Papilledema ESR blood B-type natriuretic peptide Abdominal exam serum ALP Ascites serum ALT Hepatomegaly serum AST serum CRP Integument exam serum D-dimer Erythema of lips serum IL-6 Maculopapular rash serum LDH Petechiae serum NT-proB-type natriuretic peptide Hematological findings serum TBIL serum creatinine Anemia serum ferritin Coagulopathy serum fibrinogen blood neutrophil count serum procalcitonin blood lymphocyte count serum triglycerides blood platelet count serum troponin T serum urea serum sodium Imaging findings Atelectasis Coronary artery dilation Ground-glass opacities MR Patchy pulmonary infiltrates Pericardial effusion Pleural effusion LVEF References 1. No authors listed. Living guidance for clinical management of COVID 19. WHO living guidance. 2023 Jan 13. Open https://web.pathway.md/diseases/recTB5IUPG45qWFjB 6/7 6/30/23, 1:06 AM Multisystem inflammatory syndrome Pathway 2. Lauren A Henderson, Scott W Canna, Kevin G Friedman et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS CoV 2 and Hyperinflammation in Pediatric COVID 19 Version 3. Arthritis Rheumatol. 2022 Feb 3. Open 3. Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome in Adults MIS A Case Definition Information for Healthcare Providers. CDC. 2021 Oct 7. Open 4. Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome in Children MIS C Associated with Coronavirus Disease 2019 COVID 19 . CDC. 2020 Mar 27. Open 5. Centers for Disease Control and Prevention. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children MIS C . CDC. 2021 May 20. Open https://web.pathway.md/diseases/recTB5IUPG45qWFjB 7/7