COVID-19, Multisystem Inflammatory Syndrome (MIS-C, MIS-A)

by Andrew T. Pavia, M.D. last updated 2022-08-26 10:34:51.696095-04:00 © Antimicrobial Therapy, Inc.

Clinical Setting

  • Multisystem Inflammatory Syndrome (MIS-C, MIS-A) is a COVID-19 post infectious complication identified in children and adolescents under age 21 years. Median age 8.
  • Similar presentation has been occasionally identified in young adults, referred to as Multisystem Inflammatory Syndrome in adults (MIS-A ) MMWR 2020;69:1450.
  • Onset is usually 2-6 weeks after acute infection but acute infection is not always identified.
  • Multisystem Inflammatory Syndrome in Children (MIS-C) (CDC HAN No, 432, 05/14/20). Also called Pediatric Multisystem Inflammatory Syndrome. Temporally associated with SARS-CoV-2 (PMIS-TS)
    • CDC Case definition:
      • Age <21 years, fever, lab evidence of inflammation, hospitalized severe illness, multi-organ (≥2) involvement: cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological + no alternate diagnosis + current / recent positive test for SARS CoV-2 or COVID-19 exposure within 4 weeks of symptom onset.
      • See also WHO and Royal College of Physicians definitions Lancet ID 2020;20:e276.
    • Most common symptoms:
      • Shock, with cardiac involvement, gastrointestinal symptoms, and significantly elevated markers of inflammation and positive serology for SARS CoV-2. Similar to Kawasaki disease and toxic shock syndrome and can be difficult to distinguish. MMWR 7 Aug 2020 early release. N Engl J Med 2020;383:347; N Engl J Med 2020;383:334.
      • Fever, abdominal pain, vomiting, diarrhea.
      • Other symptoms include rash, conjuctivitis, headache, cervical adenopathy, lip swelling.
    • Most (60-80%) SARS-CoV-2 Ab positive, some (15-30%) PCR positive
    • Lab abnormaliites:
      • Lymphopenia, thrombocytopenia, elevated ferritin, d-dimer, CRP, ESR, soluble IL-2 receptor, transaminases
    • Many have cardiac involvement with elevated troponin, BNP, decreased function, conduction abnormalities.  Coronary artery dilation in a minority. Echocardiography  and EKG recommended.
    • Clinical phenotype likely broader including shock syndrome with cardiac involvement, Kawasaki-like picture, and persistent fever with inflammation and headache.
    • Alternative causes of symptoms must be excluded - many examples of cognitive bias with anchoring on a diagnosis of MIS-C when children present with unexplained fevers leading to delayed treatment.
    • Lancet. 2020 Jun 6 2020; JAMA June 8 2020
  • For general management and all other issues see COVID-19 and COVID-19 Vaccines
  • Important note re Delta variant (Aug 2021):
    • Key characteristics: hypertransmissibility and high peak viral loads.
    • Much of the knowledge of clinical, epidemiologic, therapeutic, and diagnostic aspects of infection and COVID-19 are based on studies done in the pre-Delta era and recommendations based on references that pre-date Delta should be interpreted in that context. Of course, we will continue to update COVID-19 information and recommendations based on new developments.
  • Important note re Omicron variant (Dec 2021):
    • Omicron is at least twice as transmissible as Delta. Early evidence suggests clinical disease is less severe than Delta, especially in "Fully Vaccinated" (meaning, those who have had 2 initial injections with an mRNA vaccine and boosted with a third shot); unclear regarding the virulence of Omicron among unvaccinated individuals.


  • SARS CoV-2

Primary Regimens

  • No definitive data or consensus on optimal therapy
  • IVIG 2 gm/kg and/or methylprednisolone 2 mg/kg first line therapy
  • In observational study use of IVIG with steroids associated with decreased treatment failure and shorter ICU stay than steroids alone JAMA 2021;325:855
  • A second large observational study using propensity scores found initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (N Engl J Med. 2021 Jul 1;385:23)
  • A third observational study did not find definitive evidence of superiority between approaches but secondary endpoints favored the use of glucocorticoids (N Engl J Med 2021; 385:11-22)
  • Refractory cases: Consider anakinra or infliximab
  • Low dose ASA for all patients. Consider anti-coagulation with severe cardiac involvement
  • Preliminary clinical guidance from American College of Rheumatology Arthritis Rheumatol. 2021 Apr;73(4):e13-e29

Alternative Regimens

  • Inotropic and vasopressor support up to and including ECMO may be needed


  • Prognosis is generally favorable.
  • Increased risk of thrombosis but optimal anticoagulation unclear Blood. 2021 Apr 25 (epub ahead of print)
  • Followup echocardiography indicated for those with cardiac involvement. Coronary aneurysms in < 10%
  • Studies of optimal treatment needed
  • Up to date review and recommendations in NIH Covid Treatment Guidelines