BACKGROUND: Clinical management of multisystem inflammatory syndrome in children (MIS-C) has varied over time and by medical institution. METHODS: Data on patients with MIS-C were collected from 4 children's hospitals between March 16, 2020 and March 10, 2021. Relationships between MIS-C treatments and patient demographics, clinical characteristics, and outcomes were described. Propensity score matching was utilized to assess the relative risk of outcomes dependent on early treatment with intravenous immunoglobulin (IVIG) or low-dose steroids, controlling for potential confounding variables. RESULTS: Of 233 patients diagnosed with MIS-C, the most commonly administered treatments were steroids (88.4%), aspirin (81.1%), IVIG (77.7%) and anticoagulants (71.2%). Compared with those patients without respiratory features, patients with respiratory features were less likely to receive IVIG and steroids on the same day (combination treatment) (44.1%). Controlling for confounding variables, patients receiving IVIG within 1 day of hospitalization were less likely to have hospital length of stay ≥8 days (RR = 0.53, 95% CI: 0.31-0.88). Patients receiving low-dose steroids within 1 day of hospitalization were less likely to develop ventricular dysfunction (RR = 0.45, 95% CI: 0.26-0.77), have increasingly elevated troponin levels (RR = 0.55, 95% CI: 0.40-0.75) or have hospital length of stay ≥8 days (RR = 0.46, 95% CI: 0.29-0.74). CONCLUSION: Treatments for MIS-C differed by hospital, patient characteristics and illness severity. When IVIG and low-dose steroids were administered in combination or low-dose steroids were administered alone within 1 day of hospitalization, the risk of subsequent severe outcomes was decreased.

BACKGROUND: The long-term effects of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) or acute COVID-19 are not well known. Our objective was to determine long-term outcomes. METHODS: Children hospitalized with MIS-C or COVID-19 at 3 US hospitals from March 2020, through February 2021 were followed to assess health through 2 years post-hospitalization using medical records and patient surveys. RESULTS: Medical record abstraction was performed for 183 patients hospitalized with MIS-C, 53 of whom participated in surveys, and 97 patients hospitalized with COVID-19, 35 of whom participated in surveys. Patients with MIS-C were younger (median, 9 vs. 14 years of age for COVID-19 patients; P = 0.004), more frequently male (62% vs. 39%; P < 0.001) and had more cardiac (14% vs. 2%; P = 0.001) and neurologic sequelae (8% vs. 1%; P = 0.023). Children with COVID-19 more often had other comorbidities (59% vs. 19%; P < 0.001). Full mental recovery at the time of survey 2 (median, 16 months post-hospitalization for patients with MIS-C and 20 months for patients with COVID-19) was 85% and 88%, respectively; full physical recovery was 87% and 81%, respectively; and nearly all had resumption of normal activities. Patients with MIS-C reported more frequent headache at 1 month (45% vs. 20%; P = 0.037). Patients with COVID-19 were more likely to report cough at 1 month (37% vs. 17%; P = 0.045). Fatigue persisted >1 year in 15%-20% of patients in both groups. CONCLUSIONS: Approximately 20% of children with MIS-C and COVID-19 continued to have symptoms including fatigue and headache >1 year after hospital discharge. The duration of these findings emphasizes the importance of providers following patients until sequelae have resolved.

Understanding the serological responses to COVID-19 vaccination in children with history of MIS-C could inform vaccination recommendations. We prospectively enrolled five children hospitalized with MIS-C and measured SARS-CoV-2 binding IgG antibodies to spike protein variants longitudinally pre- and post-Pfizer-BioNTech BNT162b2 primary series COVID-19 vaccination. We found that SARS-CoV-2 variant cross-reactive IgG antibodies waned following acute MIS-C, but were significantly boosted with vaccination and maintained for at least 3 months. We then compared post-vaccination binding, pseudovirus neutralizing, and functional antibody-dependent cell-mediated cytotoxicity (ADCC) titers to the reference strain (Wuhan-hu-1) and Omicron variant (B.1.1.529) among previously healthy children (n=6) and children with history of MIS-C (n=5) or COVID-19 (n=5). Despite the breadth of binding antibodies elicited by vaccination in all three groups, pseudovirus neutralizing and ADCC titers were reduced to the Omicron variant. Vaccination after MIS-C or COVID-19 (hybrid immunity) conferred advantage in generating pseudovirus neutralizing and functional ADCC antibodies to Omicron. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

Understanding the serological responses to COVID-19 vaccination in children with history of MIS-C could inform vaccination recommendations. We prospectively enrolled seven children hospitalized with MIS-C and measured SARS-CoV-2 binding IgG antibodies to spike protein variants longitudinally pre- and post-Pfizer-BioNTech BNT162b2 primary series COVID-19 vaccination. We found that SARS-CoV-2 variant cross-reactive IgG antibodies variably waned following acute MIS-C, but were significantly boosted with vaccination and maintained for up to 3 months. We then compared post-vaccination binding, pseudovirus neutralizing, and functional antibody-dependent cell-mediated cytotoxicity (ADCC) titers to the reference strain (Wuhan-hu-1) and Omicron variant (B.1.1.529) among previously healthy children (n = 16) and children with history of MIS-C (n = 7) or COVID-19 (n = 8). Despite the breadth of binding antibodies elicited by vaccination in all three groups, pseudovirus neutralizing and ADCC titers were significantly reduced to the Omicron variant.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a multiorgan hyperinflammatory condition following SARS-CoV-2 infection. Data on COVID-19 vaccine adverse events and vaccine attitudes in children with prior MIS-C are limited. We described characteristics associated with COVID-19 vaccination, vaccine adverse events and vaccine attitudes in children with a history of MIS-C or COVID-19 and their parents/guardians. METHODS: We enrolled children previously hospitalized for MIS-C or COVID-19 from 3 academic institutions. We abstracted charts and interviewed children and parents/guardians regarding vaccine adverse events and acceptability. RESULTS: Of 163 vaccine-eligible children enrolled with a history of MIS-C and 70 with history of COVID-19, 51 (31%) and 34 (49%), respectively, received mRNA COVID-19 vaccine a median of 10 (Interquartile Range 6-13) months after hospital discharge. Among 20 children with MIS-C and parents/guardians who provided interviews, local injection site reaction of brief duration (mean 1.8 days) was most commonly reported; no children required medical care within 2 weeks postvaccination. Vaccine survey results of interviewed, vaccinated children and their parents/guardians: of 20 children with MIS-C and 15 children with COVID-19, 17 (85%) and 13 (87%), respectively, listed doctors in the top 3 most trusted sources for vaccine information; 13 (65%) and 9 (60%) discussed vaccination with their doctor. CONCLUSIONS: COVID-19 vaccination was well tolerated in children with prior MIS-C or COVID-19 participating in our investigation. Parents/guardians regarded their children's doctors as a trusted source of information for COVID-19 vaccines, and most vaccinated children's parents/guardians had discussed COVID-19 vaccination for their child with their doctor.

BACKGROUND: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood. METHODS: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients. RESULTS: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P < .001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P = .010) in contrast to patients with COVID-19 (median, 146 vs 4795; P < .001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]). CONCLUSIONS: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ.

BACKGROUND: Distinguishing multisystem inflammatory syndrome in children (MIS-C) from coronavirus disease 2019 (COVID-19), Kawasaki disease (KD), and toxic shock syndrome (TSS) can be challenging. Because clinical management of these conditions can vary, timely and accurate diagnosis is essential. METHODS: Data were collected from patients <21 years of age hospitalized with MIS-C, COVID-19, KD, and TSS in 4 major health care institutions. Patient demographics and clinical and laboratory data were compared among the 4 conditions, and a diagnostic scoring tool was developed to assist in clinical diagnosis. RESULTS: A total of 233 patients with MIS-C, 102 with COVID-19, 101 with KD, and 76 with TSS were included in the analysis. Patients with MIS-C had the highest prevalence of decreased cardiac function (38.6%), myocarditis (34.3%), pericardial effusion (38.2%), mitral regurgitation (31.8%) and pleural effusion (34.8%) compared with patients with the other conditions. Patients with MIS-C had increased peak levels of C-reactive protein and decreased platelets and lymphocyte nadir counts compared with patients with COVID-19 and KD and elevated levels of troponin, brain natriuretic peptide and pro-brain natriuretic peptide compared with COVID-19. Diagnostic scores utilizing clinical findings effectively distinguished MIS-C from COVID-19, KD, and TSS, with internal validation showing area under the curve ranging from 0.87 to 0.97. CONCLUSIONS: Compared with COVID-19, KD, and TSS, patients with MIS-C had significantly higher prevalence of cardiac complications, elevated markers of inflammation and cardiac damage, thrombocytopenia, and lymphopenia. Diagnostic scores can be a useful tool for distinguishing MIS-C from COVID-19, KD, and TSS.