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 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.

Keywords: COVID-19; MIS-C; PIMS; SARS-CoV-2; children; cytokines; serology.

Figure 1.

A, Severe acute respiratory syndrome coronavirus 2 immunoglobulin G (IgG) antibody profiles of patients with acute multisystem inflammatory syndrome in children (MIS-C), acute coronavirus disease 2019 (COVID-19), convalescent MIS-C, convalescent COVID-19, and healthy pediatric controls. P values represent comparisons between each group and acute MIS-C. B, Associations between receptor-binding domain (RBD) and nucleocapsid protein IgG antibody titers for patients with MIS-C (red) and COVID-19 (blue). C, Paired acute vs convalescent RBD IgG antibody titers among a subset of patients with MIS-C and COVID-19. D, Acute RBD IgG endpoint titers vs days from symptom onset among patients with MIS-C (red) and COVID-19 (blue). Associations between continuous variables are shown as Pearson correlations with log-transformed titer values. Abbreviations: Conv., convalescent; COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; MIS-C, multisystem inflammatory syndrome in children; RBD, receptor-binding domain.

Figure 2.

Cytokine profiles of patients with acute and convalescent multisystem inflammatory syndrome in children (MIS-C) and coronavirus disease 2019 (COVID-19) and healthy pediatric controls. Units = pg/mL. Data represent patients with acute MIS-C (n = 117), acute COVID-19 (n = 88), convalescent MIS-C (n = 13), convalescent COVID-19 (n = 13), and healthy controls (n = 24). Statistical comparisons of log-transformed cytokine concentrations were made using Mann-Whitney U tests. P values represent comparisons between each group and acute MIS-C. Abbreviations: COVID, coronavirus disease 2019; IFN-γ, interferon gamma; IL, interleukin; MIS-C, multisystem inflammatory syndrome in children; TNF-α, tumor necrosis factor alpha.

Figure 3.

Cytokine signatures associated with multisystem inflammatory syndrome in children (MIS-C). Each column in the table shows a combination of cytokine levels (pg/mL), describing which cytokine thresholds are met; the bars above each table column shows the proportion of patients with MIS-C (blue) or coronavirus disease 2019 (COVID-19) (orange) with that combination of cytokine levels. For example, in the leftmost table column, all 4 of the cytokine levels have elevated = TRUE; this combination is seen in 32% of MIS-C patients and 0% of COVID-19 patients. Abbreviations: COVID-19, coronavirus disease 2019; IFN-γ, interferon gamma; IL, interleukin; MIS-C, multisystem inflammatory syndrome in children.