Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19

Sacco, K.; Castagnoli, R.; Vakkilainen, S.; Liu, C.; Delmonte, O. M.; Oguz, C.; Kaplan, I. M.; Alehashemi, S.; Burbelo, P. D.; Bhuyan, F.; de Jesus, A. A.; Dobbs, K.; Rosen, L. B.; Cheng, A.; Shaw, E.; Vakkilainen, M. S.; Pala, F.; Lack, J.; Zhang, Y.; Fink, D.; Oikonomou, V.; Snow, A. L.; Dalgard, C. L.; Chen, J.; Sellers, B. A.; Montealegre Sanchez, G. A.; Barron, K.; Rey, E.; Vial, M. C.; Poli, M. C.; Licari, A.; Montagna, D.; Marseglia, G. L.; Licciardi, F.; Ramenghi, U.; Discepolo, V.; Lo Vecchio, A.; Guarino, A.; Eisenstein, E. M.; Imberti, L.; Sottini, A.; Biondi, A.; Mato, S.; Gerstbac,

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-{kappa}B dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.