Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019

Abstract

Background The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs. COVID-19 are poorly understood. Methods We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the CDC case definition for MIS-C (n=118), acute COVID-19 (n=88), or contemporaneous healthy controls (n=24). We measured SARS-CoV-2 spike receptor binding domain (RBD) 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<0.001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median 2783 vs. 1135, P=0.010) in contrast to patients with COVID-19 (146 vs. 4795, P<0.001). MIS-C was characterized by transient acute pro-inflammatory hypercytokinemia, including elevated levels of IL-6, IL-10, IL-17A, and IFN-γ. Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (PR 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.

IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a South African cohort

“…Notably, IL6 expression was not increased in this South African cohort compared to healthy controls, despite several prior studies demonstrating elevation of this cytokine in MIS-C (10,17,19,(55)(56)(57)(58)(59)(60)(61) or its association with MIS-C severity (62-66). In fact, although not statistically significant, IL6 expression clustered into clade 1 (Figure 2): genes that appeared downregulated in our cohort compared to healthy controls.…”

Age-Associated Weaker Immunity to Coronaviruses is Characteristic of Children that Develop Multisystem Inflammatory Syndrome following SARS-CoV-2 Infection

“…The striking, but steady decline in the incidence of MIS-C with each wave of variants over the past two years, may indicate that new viral epitopes are less likely than previous homologs to trigger the delayed and complex repertoire of humoral and cellular responses we now recognize in children 4-6 weeks after each spike in SARS-CoV-2 (Holm et al, 2022;Levy et al, 2022;Yuen et al, 2020). Alternatively, the drop in MIS-C cases over time may have resulted from the accumulation of pediatric SARS-CoV-2 infections during this period, which provided prior immunity that blocked the development of MIS-C. Our results largely agree with and add to previous studies of the immune profile of MIS-C (Anderson et al, 2021); (Lapp et al, 2022); (Ramaswamy et al, 2021;Thiriard et al, 2023: Gruber et al, 2020Consiglio et al, 2020). Our study, however, used more MIS-C patients than all but one of these studies and investigated more cytokines and more coronavirus proteins than any previous study.…”

Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children

“…3c ). Interestingly, the MIS-C immune profile, particularly Fc effector responses, diminish at follow-up, likely due to the delayed onset of symptoms in acute illness, a compensation for dramatic acute responses as well as anti-inflammatory treatments during illness 15 , 16 (Fig. 3c ).…”