Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication associated with COVID-19. Patients with MIS-C have presented with a persistent fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions and in severe cases, hypotension and shock. Patients have elevated inflammatory markers and, in a majority, laboratory markers of damage to the heart.
Not all children will have the same signs and symptoms, and some children may have symptoms not listed here. A child under investigation for MIS-C should also be evaluated for other infectious (e.g., septic shock) and non-infectious (e.g., malignancy) etiologies that may explain the clinical presentation.
MIS-C may begin weeks after a child is infected with SARS-CoV-2. The child may have been infected from an asymptomatic contact and, in some cases, the child and their caregivers may not even know they had been infected.
Most children diagnosed with MIS-C have had laboratory evidence of either past or current COVID-19 infection and the majority have had no documented underlying medical conditions. Receipt of 2 doses of Pfizer-BioNTech vaccine has been shown to be highly effective in preventing MIS-C in persons aged 12–18 years.
Information on laboratory evaluation, treatment, follow-up, and other clinical considerations for patients with suspected or diagnosed MIS-C have been provided by the CDC, American Academy of Pediatrics and a recently published guidance from the American College of Rheumatology which also compares and contrasts features of MIS-C and Kawasaki disease as well as providing guidance evaluation and treatment.
CDC Case Definition for MIS-C
- An individual aged <21 years presenting with feveri, and evidence of clinically severe illness requiring hospitalization or resulting in death; AND
- Absence of a more likely alternative diagnosis; AND
- C-reactive protein (CRP) ≥3.0mg/dL (30 mg/L); AND
- New onset manifestations in ≥2 of the following categories:
- Cardiac involvement indicated by left ventricular ejection fraction <55%, coronary artery dilatation, aneurysm, or ectasia, or troponin elevated above normal;
- Mucocutaneous involvement indicated by rash, inflammation of the oral mucosa, conjunctivitis or conjunctival injection, or extremity findings (erythema, edema);
- Gastrointestinal involvement indicated by abdominal pain, vomiting, or diarrhea;
- Hematologic involvement indicated by platelet count <150k/μL, or absolute lymphocyte count (ALC) <1,000 cells/μL; AND
- Detection of SARS-CoV-2 nucleic acid/antigen up to 60 days prior to or during hospitalization, or in a post-mortem specimen; OR
- Detection of SARS-CoV-2 specific antibodies associated with current illness; OR
- Close contact with a confirmed or probable case of COVID-19 illness in the 60 days prior to hospitalization; OR
- Death certificate lists MIS-C as an underlying cause of death or a significant condition contributing to death
iSubjective or documented fever (T≥38.0°C)
- If MIS-C is ruled out and an alternate diagnosis of Kawasaki disease is made, that illness no longer needs to be reported as possible MIS-C.
- Consider MIS-C in any pediatric death with evidence of SARS-CoV-2 infection
Consider testing any patient for whom MIS-C is a clinical consideration for acute COVID-19 infection (i.e. RT-PCR) and for prior COVID-19 infection (antibody testing).
Testing aimed at identifying laboratory evidence of inflammation as listed in the Case Definition section is warranted. Similarly, SARS-CoV-2 detection by RT-PCR is indicated.
Where feasible, SARS-CoV-2 serology testing is suggested, even in the presence of positive RT-PCR or antigen testing. Any serology testing should be performed prior to administering IVIG or any other exogenous antibody treatments.
Given the frequent association of MIS-C with cardiac involvement, many centers are performing cardiac testing including, but not limited to:
- cardiac enzyme or troponin testing (per the center’s testing standards); and
- B-type natriuretic peptide (BNP) or NT-proBNP.
Other testing to evaluate multisystem involvement should be directed by patient signs or symptoms. Additionally, testing to evaluate for other potential diagnoses should be directed by patient signs or symptoms.
Providers are advised to immediately refer patients with a picture of toxic shock or Kawasaki disease to a specialist in pediatric infectious disease, rheumatology, and/or critical care, as indicated. Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications. Providers are advised to immediately refer patients with a picture of toxic shock or Kawasaki Disease to a specialist in pediatric infectious disease, rheumatology, and/or critical care, as indicated. Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications.
According to guidelines from the American Academy of Pediatrics the following ICD-10-CM diagnosis codes should be used for a child admitted to the hospital due to documented MIS-C.
U07.1, COVID-19 (principal diagnosis) and M35.81, other specified systemic involvement of connective tissue (secondary diagnosis).
Report cases that meet the CDC definition of Multisystem Inflammatory Syndrome in Children (MIS-C) by phone within 1 working day. Note patients should be reported regardless of SARS-CoV-2 PCR test result.
- Los Angeles County DPH Acute Communicable Disease Control: Call 213-240-7941
- Long Beach Health and Human Services: Call 562-570-4302.
- Pasadena Public Health Department: Call 626-744-6089. Fax to 310-605-4274
- NEW CDC COCA Webinar: Updates on Multisystem Inflammatory Syndrome in Children (MIS-C): Epidemiology, Case Definition, and COVID-19 Vaccination: Slides | Recording
- CDPH MIS-C Communications Toolkit: Webpage
- CDC MIS-C Resources for Providers: Webpage
- CDPH Information Sheet for Parents "Don't MISS the Signs of MIS-C: Handout
- CDC Clinical Considerations for Use of COVID-19 Vaccines-COVID-19 vaccination and MIS-C and MIS-A.
- CDC COCA Webinar: What Clinicians Need to Know About Multisystem Inflammatory Syndrome in Children: Slides Recording 02-10-22.
- CDC Webpage for Providers: Webpage
- CDC webpage For Parents: Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19. Webpage
- Epidemiology of Exposures, Preceding Illness and Testing History in Children With Multisystem Inflammatory Syndrome in Children in the First 18 Months of the COVID-19 Pandemic, Los Angeles County, California. The Pediatric Infectious Disease Journal. 41(11):e453-e455, November 2022. doi: 10.1097/INF.0000000000003688
- Reported cases of multisystem inflammatory syndrome in children aged 12–20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation. Lancet Child Adolescent Health. 2022 May;6(5):303-312. doi: 10.1016/S2352-4642(22)00028-1.
- Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12–18 Years — United States, July–December 2021. MMWR (1-7-22) DOI: http://dx.doi.org/10.15585/mmwr.mm7102e1.
- Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic JAMA Pediatrics Published online April 6, 2021. doi:10.1001/jamapediatrics.2021.0630
- Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance. American Academy of Pediatrics Guidance
- Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 and Hyperinflammation in COVID-19. American College of Rheumatology Guidance
- Carlin RF et al. Discriminating MIS-C requiring treatment from common febrile conditions in outpatient settings. J Pediatr2020 Oct 13; [e-pub].https://doi.org/10.1016/j.jpeds.2020.10.013
- Hyperinflammatory shock in children during COVID-19 pandemic. Lancet (5-7-20) doi: 10.1016/S0140- 6736(20)31094
- COVID-19–Associated Multisystem Inflammatory Syndrome in Children — United States, March–July 2020. MMWR (8-14-20) doi: 10.15585/mmwr.mm6932e2