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Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19

Our take —

This case series of 1117 children and adolescents (<21 years) hospitalized with MIS-C (N=539) and severe acute COVID-19 (N=577) at 66 hospitals across 31 US states between March 15 and October 31, 2020 compared the clinical characteristics and outcomes of each condition. Compared to those with severe acute COVID-19, individuals with MIS-C were less likely to have an underlying condition, were more often aged 6-12 years than 0-5 or 13-20 years, were much more likely to have severe cardiovascular involvement, and more often admitted to the ICU, though risk of death was similar. Results should be interpreted with caution given reliance on electronic medical record data and possible detection bias, though they provide important insight about differentiating the presentation of MIS-C and COVID-19 in children.

Study design

Case Series

Study population and setting

This case series included 1116 children and adolescents (<21 years) who were hospitalized with COVID-19-related illnesses between March 15 and October 31, 2020 (with follow-up through January 5, 2021) from 66 hospitals across 31 states in the US. Patients were classified as being hospitalized due to multisystem inflammatory syndrome in children (MIS-C; N=539, median age 8.9 years, 58% male) or severe acute COVID-19 (N=577, median age 11.7 years, 53% male) based on adjudication by site and coordinating principal investigators. MIS-C was defined based on fever lasting more than 24 hours, laboratory evidence of inflammation, multisystem (≥2) organ involvement, no alternative plausible diagnosis, and a positive SARS-CoV-2 test based on RT-PCR, antibody, or antigen test (indicating recent or current infection). Before May 31, prior/recent SARS-CoV-2 infection criteria could also be met by exposure to a suspected or confirmed COVID-19 case in the previous 4 weeks. The case-definition for severe acute COVID-19 included: positive RT-PCR test during current illness, severe involvement of at least one organ system, and not meeting the definition for MIS-C. Demographic, clinical, and laboratory findings were abstracted from hospital medical records. Analyses compared sociodemographics, clinical presentation and outcomes (respiratory support, length of hospitalization, ICU admission, death) between patients with MIS-C and COVID-19 and evaluated cardiac dysfunction resolution over time for patients with MIS-C.

Summary of Main Findings

Overall, patients with MIS-C were younger (median age 8.9 vs. 11.7 years), more likely to be non-Hispanic Black (35% vs. 23%), and had fewer underlying medical conditions (presence of at least one underlying condition: 31% vs. 62%) than severe acute COVID-19 cases; these differences were significant in multivariable Poisson models adjusting for age, sex, race/ethnicity, presence of underlying medical conditions, and US Census region. Approximately 80% of both groups had respiratory involvement, but MIS-C cases more often had cardiovascular involvement (67% vs. 12%), asthma exacerbation (56% vs. 23%), hematologic involvement (48% vs. 22%), pleural effusion (32% vs. 15%), pericardial effusion (25% vs. 4%), coronary artery aneurysm (13% vs. 1%), or arrhythmia (8% vs. 1%). Comparing mutually-exclusive categories of severe organ impairment, most severe acute COVID-19 cases had severe respiratory involvement without cardiovascular involvement (71%), whereas MIS-C cases most often had severe cardiorespiratory involvement (56%), followed by severe respiratory without cardiovascular involvement (24%) and severe cardiovascular without respiratory involvement (11%). MIS-C cases were more likely to require vasopressor use (45% vs. 9%), ICU admission (74% vs. 44%), and had longer length of hospital stays (median 7 days vs. 3 days), but both groups had similar risk of death (1.9% vs. 1.4%). Among patients with MIS-C, 503 (93%) had left ventricular ejection fraction (LVEF) evaluated on at least one echocardiogram, and of those, 34% had depressed LVEF (majority of which were mildly depressed, 55%); almost all had returned to normal by 30 days (91%) and among the subset followed through 90 days, all but patient had normalized. Of 424 patients with coronary artery evaluation, 57 (13%) had coronary aneurysm (93% mild), but which had returned to normal in 79% by 30 days and 100% in the subset with follow-up through 90 days.

Study Strengths

The study was a relatively large, multi-site, case series differentiating MIS-C and severe acute COVID-19 in children and adolescents in the United States. Data included several important clinical and laboratory assessments, and applied standardized criteria for case, demographic, clinical, laboratory and outcome criteria.


Data originated from electronic medical records, which are subject to incomplete documentation and reporting, and missing data were excluded from analyses. Diagnostic or detection bias dependent on individual diagnosis is possible, resulting in potential over- or under-ascertainment of clinical phenotypes and laboratory testing. For example, few children with severe acute COVID-19 received cardiac assessment, whereas almost all patients with MIS-C did; this may have underestimated cardiac involvement in the latter group and overestimated the differences in cardiac manifestations between the two conditions. Diagnostic criteria for MIS-C and severe acute COVID-19 changed throughout the study period and may have resulted in some misclassification; of the patients with MIS-C, 31% were RT-PCR and antibody positive, 45% were only antibody positive, 5% were RT-PCR positive and antibody negative, and 19% did not have antibody testing performed.

Value added

The largest case series of MIS-C and severe acute COVID-19 to date, and first to directly compare the conditions.

This review was posted on: 12 March 2021