Deep immune profiling uncovers novel associations with clinical phenotypes of Multisystem Inflammatory Syndrome in Children (MIS-C)

Abstract

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic inflammatory condition that follows SARS-CoV2 infection or exposure in children. Clinical presentations are highly variable and include fever, gastrointestinal (GI) disease, shock, and Kawasaki Disease-like illness (MIS-C/KD). Compared to patients with acute COVID, patients with MIS-C have a distinct immune signature and expansion of TRVB11 expressing T cells. However, the relationship between immunological and clinical phenotypes of MIS-C is unknown. Here, we measured serum biomarkers, TCR repertoire, and SARS-CoV2-specific T cell responses in a cohort of 76 MIS-C patients. Serum biomarkers associated with macrophage and Th1 activation were elevated in patients with shock, consistent with previous reports. Significantly increased SARS-CoV-2-induced IFN-γ, IL-2, and TNF-α production were seen in CD4 ⁺ T cells from patients with neurologic involvement and respiratory failure. Diarrhea was associated with a significant reduction in shock-associated serum biomarkers, suggesting a protective effect. TRVB11 usage was highly associated with MIS-C/KD and coronary aneurysms, suggesting a potential biomarker for these manifestations in MIS-C patients. By identifying novel immunologic associations with the different clinical phenotypes of MIS-C, this study provides insights into the clinical heterogeneity of MIS-C. These unique immunophenotypic associations could provide biomarkers to identify patients at risk for severe complications of MIS-C, including shock and MIS-C/KD.

Figure 1:. Clinical associations with immunological phenotypes in MIS-C.

A. Serum biomarkers significantly associated with clinical phenotypes in MIS-C. Biomarkers are grouped by clinical associations. Heatmap (purple) displays significance of clinical association. Heatmap (red) displays average expression level of each biomarker for the clinical group, normalized by row. B,C. Bar graphs display CD4⁺CD45RO⁺ (memory) T cell responses to SARS-CoV2 peptides in patients with oxygen requirement (B) or neurological involvement (C). PBMC were stimulated for 6h in the presence of CD28/CD49d alone or in combination with spike, membrane, or nucleocapsid peptide pools. Cytokine expression was measured using intracellular staining and flow cytometry, and the difference was calculated between CD28/CD49d + peptide-treated and CD28/CD49d-treated cells. Responses were compared in subjects with vs. without clinical symptoms. D. Bar graphs display TRVB11 usage in MIS-C patients with vs. without Kawasaki Disease-like phenotype (MIS-C/KD), and in MIS-C/KD patients with vs. without coronary artery aneurysms. *FDR<0.05, **FDR<0.01, Mann-Whitney with multiple comparison adjustment.