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  • MIS-C (multisystem inflammatory syndrome in children) is a clinical syndrome thought to represent a postinfectious, dysregulated inflammatory response to a previous (nonacute) exposure or infection with SARS-CoV-2 in children and adolescents; syndrome is noted to have a strong temporal association with high local prevalence of COVID-19, occurring in clusters following a regional COVID-19 outbreak 1

  • MIS-C is a rare and novel disease; therefore, it is not yet possible to make firm evidence-based recommendations. Rigorous data to guide most diagnostic and management strategies are lacking and optimal treatment is unknown2, 1


DIAGNOSTIC PROCEDURES Primary diagnostic tools

  • There is no confirmatory diagnostic test; diagnosis is based on case definition by constellation of clinical, laboratory, echocardiographic, and epidemiologic factors. Most patients have laboratory evidence of SARS-CoV-2 (polymerase chain reaction, antigen, or antibody) 3, 4

  • WHO, CDC, and Royal College of Paediatrics and Child Health have published case definitions that are broadly similar 4, 3 -Available guidance is in agreement that laboratory evidence of current (positive SARS CoV-2 antigen or polymerase chain reaction) or suspected recent infection (positive SARS CoV-2 antibodies) is not necessary for meeting case definition for MIS-C -All available guidance strongly recommends for exclusion of alternate sources of infection and noninfectious conditions that can present similarly to MIS-C2

  • WHO definition applies to aged 0 to 19 years who meet all of the following criteria 5 ○

    • Fever for 3 days or longer 2 or more of the following:

    • Rash or bilateral conjunctivitis (nonpurulent) or mucocutaneous inflammation of mouth, hands, or feet

    • Hypotension or shock

    • Features of myocardial dysfunction, pericarditis, valvulitis, or coronary artery abnormalities (including echography findings or elevated levels of troponin or NT-proBNP [N-terminal–pro hormone brain natriuretic peptide])

    • Evidence of coagulopathy (eg, elevated D-dimer, prolonged prothrombin time, partial thromboplastin time)

    • Acute gastrointestinal symptoms (eg, vomiting, diarrhea, abdominal pain)

    • Elevated markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein, procalcitonin)

    • No obvious alternate microbial cause of inflammation (eg, bacterial sepsis, staphylococcal or streptococcal toxic shock syndrome)

    • Evidence of COVID-19 (positive reverse transcription polymerase chain reaction test result, detectable antigen, or antibody) or likely exposure to COVID-19

  • Suspect diagnosis when clinical presentation is concerning for diagnosis, particularly in the 2- to 6-week timeframe following COVID-19 community outbreak. Common presenting patterns include: 1, 6

    • Persistent, unexplained high fever in a child with laboratory evidence of marked inflammation

    • Presentation with, or rapid development of, shock or shocklike state secondary to significant cardiac dysfunction, multiorgan dysfunction, and/or cytokine release syndrome ("cytokine storm")

    • Patients require judicious fluid resuscitation and aggressive hemodynamic support; children under investigation for MIS-C with life-threatening manifestations may require immunomodulatory treatment for MIS-C before full diagnostic evaluation can be completed6, 2

    • Fever with significant gastrointestinal distress, mimicking acute abdomen, and/or concerning neurological manifestations (eg, meningismus, altered mental status, or lethargy)

    • Features of Kawasaki disease (eg, conjunctival and mucosal injection, rash, swelling of hands and feet, coronary artery dilation) or toxic shock syndrome (eg, erythroderma, hypotension, renal and multiorgan involvement)

    • Younger children tend to present with a Kawasaki disease-like phenotype and older children are more likely to develop myocarditis and shock 6 Note that manifestation may not appear simultaneously but evolve over days, constellation of presenting manifestations vary from patient to patient, and disease severity is variable

  • A tiered diagnostic testing approach may be utilized to assess children without life-threatening manifestations with suspicion for MIS-C based on clinical presentation; obtain full diagnostic evaluation for children with myocarditis and/or shock or shocklike state with an epidemiological link to COVID-191, 6 6

    • First tier testing involves initial screening laboratory tests and tests for inflammation, specific tests for SARS-CoV-2, and microbiologic evaluation for alternate infectious causes of presentation

    • Obtain general baseline tests including CBC with differential, electrolyte panel with renal function, urinalysis, and liver function testing 6, 7

    • Consistent findings include anemia, thrombocytopenia, neutrophilia, and lymphopenia; elevated creatinine, BUN, transaminases; proteinuria, hyponatremia, and hypoalbuminemia

    • Obtain inflammatory markers including erythrocyte sedimentation rate and C-reactive protein Inflammatory markers are often markedly elevated6, 1

    • Obtain specific testing for COVID-19 SARS-CoV-2 antibodies are often positive (up to 90%), while polymerase chain reaction or antigen test results are more often negative (up to 40%) 6

    • Focused microbiologic evaluation for alternate infectious causes as directed by clinical suspicion8, 9, 10

    • Evaluation may include studies such as nasopharyngeal swabs for common respiratory viruses, Epstein-Barr virus, enteroviruses, and blood, throat, urine, stool, and cerebrospinal fluid cultures as clinically indicated

    • Complete second tier (full diagnostic) evaluation in patients with initial findings consistent with significant inflammatory response and concerning for MIS-C1, 6 Often includes testing for laboratory evidence of evolving picture of cytokine release syndrome and coagulopathy, and assessment for myocarditis with troponin, NT-proBNP, ECG, chest radiograph, and emergent echocardiogram1, 6

    • Consistent laboratory findings often include elevated ferritin, cytokines (eg, interleukin-6, interleukin-10), lactate dehydrogenase, fibrinogen, D-dimer, triglycerides, lactate, creatine kinase, and prolonged prothrombin time and partial thromboplastin time 1

    • Elevation in cardiac biomarkers, troponin, and NT-proBNP is consistent with myocardial inflammation 9, 11, 12

    • ECG: findings may include heart block (first, second, or third degree), increased QT interval, ventricular arrhythmias, and ST segment changes 12, 8

    • Echocardiogram: consistent findings may include general features of myocarditis (left ventricular systolic dysfunction) and/or additional changes characteristic of pancarditis (coronary artery dilation, hyperechoic coronary arteries, valvulitis, pericardial effusion) 10, 13, 12

    • Chest radiograph: nonspecific patchy infiltrates are not unusual with MIS-C; evidence of pleural effusion and cardiomegaly may be visible 14, 13, 9

    • Comprehensive list of possible laboratory investigations 14 – is available

  • Obtain additional testing as directed by clinical presentation For example, abdominal ultrasonography may be necessary to assess for possible appendicitis; findings on abdominal ultrasonogram consistent with MIS-C include hepatosplenomegaly, lymphadenopathy, bowel wall edema, or ascites 4, 15

  • Diagnostic pathway developed by the American College of Rheumatology clinical guidance task force 6 and clinical pathway developed by Children's Hospital of Philadelphia based on CDC case definition16 are available



  • Admission criteria

○Admission is recommended for patients who meet MIS-C criteria, preferably to a facility with pediatric ICU capabilities when available; rapid deterioration requiring vasopressor and/or inotrope support has been noted in a significant number of patients 17

○Additional admission recommendations include patients who are under investigation for MIS-C (ie, do not yet meet full MIS-C criteria) and are ill appearing, have abnormal vital signs, have evidence of end organ dysfunction (eg, respiratory distress, neurologic changes, hepatic or renal dysfunction, abnormal ECG, or serum markers of cardiac injury), or have marked elevation of inflammatory markers (eg, C-reactive protein ≥ 10 mg/dL)

  • Recommendations for specialist referral

○Management in consultation with a multidisciplinary treatment team of specialists is preferred when possible 6, 7

-Consultants may include specialists in intensive care, rheumatology or immunology, infectious disease, cardiology, and hematology 6


  • General treatment overview18, 19, 9, 11, 13 • Select patients with mild manifestations can be managed conservatively with close outpatient follow-up and observation for progression of disease 1, 6

○IV immunoglobulin is current mainstay of first line treatment; corticosteroids may be added as a first line adjunct in patients with severe disease 6, 2 –IV immunoglobulin is indicated for hospitalized patients with diagnosis of MIS-C or patients presenting with severe disease who are under investigation for MIS-C, including those with myocarditis or who otherwise meet criteria for Kawasaki disease or toxic shock syndrome ○Corticosteroids and immune modulators may be used for severe or refractory disease 2 ○ –Follow local infection control precautions appropriate for patients under investigation for COVID-19; note however, that antiviral therapy is generally not indicated given that MIS-C appears to be a postinfectious inflammatory response to COVID-192, 14

  • Initial stabilization and urgent management priorities

○Provide airway, breathing, and circulatory support as indicated clinically; specific guidance for treatment of shock and hypoxia secondary to MIS-C is lacking – Address hypoxia with oxygen, secure airway, and provide mechanical ventilation when necessary – Treat shock with judicious fluid resuscitation, paying very close attention to responsiveness, and vasopressor support using appropriate shock protocols (eg, cardiogenic 20 versus distributive/vasodilatory 21) – Epinephrine, dopamine, dobutamine, or milrinone are reasonable medications to initiate during resuscitation of children with cardiogenic shock; epinephrine and norepinephrine are reasonable initial vasoactive medications to trial for patients with fluid resistant distributive forms of shock 22, 23

○Early initiation of IV immunoglobulin and methylprednisolone for patients presenting in shock under consideration for MIS-C is critical given that early treatment may be associated with rapid clinical improvement and improved overall outcome 6 ○Begin broad spectrum empiric antibiotics for ill appearing patients or in patients with any concerns for sepsis or serious bacterial infection until bacterial infection has been ruled out 7, 1, 14, 2

  • Anti-inflammatory and immunomodulatory treatment

○First line treatment recommended by most guidance documents is high-dose IV immunoglobulin with or without methylprednisolone 24

– Commonly used dose of IV immunoglobulin is 2 g/kg IV (max of 100 grams/day) 2 – □ Monitor fluid status and cardiac function with care during infusion; consider extremely slow administration of dose (1 g/kg each day for 2-day course) and/or administration in conjunction with furosemide in fluid sensitive patients 1

– Most experts recommend addition of low-dose methylprednisolone (1-2 mg/kg/day for about 5 days) to first line IV immunoglobulin treatment regimen for severely ill children with shock or organ threatening disease (eg, significant cardiac involvement) 7, 6, 25 – Data from a large observational study suggest that initial treatment with both IV immunoglobulin and corticosteroid therapy results in earlier resolution of fever than IV immunoglobulin alone 25

○ Corticosteroids are standard second line treatment for patients with suboptimal response (eg, persistent fever, lack of clinical improvement, lack of improvement in inflammatory markers) to first line treatment strategy – Some experts advocate use of low-dose methylprednisolone (1-2 mg/kg/day for about 5 days) in corticosteroid naïve patients 6 – Intensified course of high-dose pulse methylprednisolone for 3 days 25, 7 (20-30 mg/kg/day infused over 1-3 hours with a maximum daily dose of 1 g) 1 is suggested if standard methylprednisolone dose has already been administered with first line treatment regimen □ Add gastric protection (eg, omeprazole) for patients requiring high-dose corticosteroids 7 □ – Some experts recommend a second dose of IV immunoglobulin if patient can tolerate fluid load based on degree of cardiac decompensation; 7 other guidance documents do not recommend a second dose 6 ○ Third line treatment options include immunomodulatory medications – Some guidance documents lean toward the preference for use of anakinra (interleukin-1 receptor antagonist) at a dose of 2 to 10 mg/kg/day divided every 6 to 12 hours subcutaneously or intravenously 2 1, 6 – Other treatments variably recommended include infliximab (tumor necrosis factor inhibitor) and tocilizumab (interleukin-6 receptor antagonist) 24, 7 ○ Patients treated with corticosteroids or biologics often are discharged with a 3-week outpatient taper to avoid rebound inflammation2 ○ Note that it is not necessary to exclude serious bacterial infection before administration of corticosteroids in the setting of possible MIS-C; exclusion of occult infection that may be unmasked by biologics before starting immunomodulatory agents is ideal, but likely not feasible given time constraints of management decisions 7

  • Anticoagulation ○ MIS-C is typically associated with a hypercoagulable state Start all patients diagnosed with MIS-C without contraindications on course of low-dose aspirin (3-5 mg/kg/day PO with maximum dose of 81 mg/day) for thromboprophylaxis for at least 6 weeks and until platelet count normalizes and normal coronary arteries are confirmed10, 24 ○ Contraindications include active bleeding and/or platelet count less than 80 to 100,000/μL 6, 2 – ○ Use of compression stockings for thrombotic prophylaxis among hospitalized children older than 12 years with MIS-C is recommended by some authorities 7, 24 ○ Treat patients with coronary artery aneurysms characterized by a z score of 2.5 to 10 with low dose aspirin only. Therapeutic anticoagulation with enoxaparin (factor Xa level 0.5-1) or warfarin is indicated for patients with coronary artery aneurysms who have a z score of greater than or equal to 10, an ejection fraction of less than 35%, or documented intracardiac thrombosis 6

  • Extracorporeal membrane oxygenation has been used in some patients with severe disease refractory to other medical management

  • Management pathways

    ○ Management algorithm developed by the American College of Rheumatology clinical guidance task force and clinical pathway developed by Children's Hospital of Philadelphia 16 are available ○ Treat patients who meet criteria for Kawasaki disease in standard fashion based on regional guidelines (eg, supportive care, high-dose IV immunoglobulin, aspirin) ○ Treat patients who meet criteria for toxic shock syndrome in standard fashion based on regional guidelines (eg, supportive care, cephalosporin or vancomycin plus clindamycin, IV immunoglobulin)


  • Monitoring during acute disease

○ Monitor clinical assessments, with frequency guided by severity of disease, and close cardiorespiratory monitoring (with pulse oximetry, continuous respiratory and cardiac monitor, and frequent blood pressure measurements) 14

○ Frequent monitoring of laboratory markers of inflammation is important until values stabilize and improve 14

○ Serial ECGs (at least every 48 hours) and echocardiograms are appropriate 6

  • Discharge criteria from hospital include stable cardiac function, absence of fever for 24 hours, and otherwise well appearance with reassuring physical exam7

Complications and Prognosis


  • Most patients respond promptly to therapy with a favorable short-term outcome; however, long-term outcome data is lacking11, 9, 26, 18, 13

  • Major source of short-term morbidity and mortality in patients with MIS-C is myocardial dysfunction6

○ Long-term complications of myocardial inflammation are largely unknown

  • Coronary artery aneurysms may develop late in disease course or after apparent improvement; therefore, serial follow-up echocardiography is recommended at 2 and 6 weeks after presentation6, 18 and cardiology follow-up is recommended starting at 1 to 2 weeks following discharge 2

○Clinical significance and evolution of coronary artery dilatation noted during acute phase of illness has yet to be determined 1

  • Children with persistent left ventricular dysfunction and coronary artery aneurysms require vigilant and frequent cardiology and echocardiography follow-up



  • MIS-C is characterized by persistent fever, laboratory markers of inflammation, and evidence of single or multiorgan dysfunction, including myocarditis; severe abdominal pain and diarrhea are common presenting manifestations

  • May include features suggestive of Kawasaki syndrome or toxic shock syndrome; some present with cardiogenic shock Diagnosis is based on case definition comprised of a constellation of clinical, laboratory, echocardiographic, and epidemiologic factors; most patients have evidence of recent SARS-CoV-2 infection

  • Patients with mild manifestation of disease may be managed conservatively with close monitoring for progressive worsening of disease

  • First line treatment for patients fulfilling criteria for diagnosis of MIS-C is admission to hospital for high-dose immunoglobulin with or without methylprednisolone

  • Second line treatment usually involves addition of methylprednisolone course (if not already administered first line) or intensified course of pulse IV methylprednisolone (if corticosteroids were already administered first line); third line pharmacotherapy involves the addition of immunomodulatory medication

  • Thromboprophylaxis with low-dose aspirin is recommended for all patients with diagnosis of MIS-C


  • Patients with shock require immediate intervention beginning with fluid resuscitation; they may need oxygen supplementation (including mechanical ventilation), and many require hemodynamic support

  • Begin treatment with high-dose IV immunoglobulin and


  • Maintain a high degree of suspicion for MIS-C given that children with this illness can deteriorate rapidly if not expediently and appropriately managed; early recognition and management are important for optimal outcomes


  1. Berard RA et al: Practice Point: Paediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19. Canadian Paediatric Society website. Posted July 6, 2020. Updated May 3, 2021. Accessed May 11, 2021. https://www.cps.ca/en/documents/position/pims

  2. American Academy of Pediatrics: Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance. AAP website. Updated February 10, 2021. Accessed May 11, 2021. https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/multisystem-inflammatorysyndrome-in-children-mis-c-interim-guidance/

  3. CDC: Multisystem Inflammatory Syndrome (MIS-C): Information for Healthcare Providers About Multisystem Inflammatory Syndrome in Children (MIS-C). Case Definition for MIS-C. Reviewed Feb 17, 2021. Accessed May 11, 2021. https://www.cdc.gov/mis-c/hcp/

  4. Royal College of Paediatrics and Child Health: Guidance - Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19 (PIMS). RCPCH website. Published May 1, 2020. Accessed May 11, 2021. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatorysyndrome-temporally-associated-covid-19-pim

  5. WHO: Multisystem Inflammatory Syndrome in Children and Adolescents with COVID-19. Scientific Brief. WHO website. Published May 15, 2020. Accessed May 11, 2021. https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19

  6. Henderson LA 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 2. Arthritis Rheumatol. 73(4):e13-29, 2021

  7. Harwood R et al: A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health. 5(2):133-41, 2021

  8. Toubiana J et al: Kawasaki-like multisystem inflammatory syndrome in children during the COVID-19 pandemic in Paris, France: prospective observational study. BMJ. 369:m2094, 2020

  9. Chiotos K et al: Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series. J Pediatric Infect Dis Soc. ePub, 2020

  10. Carter MJ et al: Paediatric inflammatory multisystem syndrome temporally-associated with SARS-CoV-2 infection: an overview. Intensive Care Med. 47(1):90-3, 2021

  11. Riphagen S et al: Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. ePub, 2020

  12. Belhadjer Z et al: Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. ePub, 2020

  13. Verdoni L et al: An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. ePub, 2020

  14. Royal College of Paediatrics and Child Health: Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19 (PIMS) - Guidance for Clinicians. National Consensus Management Pathway. RCPCH website. Accessed May 11, 2021. https://www.rcpch.ac.uk/resources/paediatricmultisystem-inflammatory-syndrome-temporally-associated-covid-19-pims-guidance

  15. CDC Center for Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID19). CDC Clinician Outreach and Communication Activity (COCA) webinar. May 19, 2020. Accessed May 11, 2021. https://emergency.cdc.gov/coca/ppt/2020/COCA_Call_Slides_05_19_2020.pdf

  16. Chiotos K et al: Emergency Department, ICU and Inpatient Clinical Pathway for Evaluation of Possible Multisystem Inflammatory Syndrome (MIS-C). Children's Hospital of Philadelphia website. Revised March 20, 2021. Accessed May 11, 2021. https://www.chop.edu/clinical-pathway/multisysteminflammatory-syndrome-mis-c-clinical-pathway

  17. Belot A et al: SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020. Euro Surveill. 25(22), 2020

  18. Whittaker E et al: Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. ePub, 2020

  19. Cabrero-Hernández M et al: Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain. Pediatr Infect Dis J. ePub, 2020

  20. Brissaud O et al: Experts' recommendations for the management of cardiogenic shock in children. Ann Intensive Care. 6(1):14, 2016

  21. Weiss SL et al: Surviving Sepsis Campaign International guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 21(2):e52-106, 2020

  22. Annane D et al: A global perspective on vasoactive agents in shock. Intensive Care Med. 44(6):833-46, 2018 Published April 30, 2021; Updated May 19, 2021 Copyright © 2021 ElsevierMIS-C

  23. Topjian AA et al: Part 4: Pediatric basic and advanced life support 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics. 147(Suppl 1), 2021

  24. National COVID-19 Clinical Evidence Taskforce: Australian Guidelines for the Clinical Care of People with COVID-19: Paediatric Inflammatory Multisystem Syndrome (PIMS-TS). MAGIC Evidence Ecosystem Foundation. Updated April 1, 2021. Accessed May 11, 2021. https://app.magicapp.org/#/guideline/L4Q5An

  25. Ouldali N et al: Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA. 325(9):855-64, 2021

  26. McCrindle BW et al: Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 135(17):e927-99, 2017