An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease

Multisystem inflammatory syndrome in children (MIS-C) emerged during the COVID-19 pandemic and shares many clinical features with the pre-pandemic syndrome of Kawasaki disease (KD). Using two SARS-CoV-2-related host-response gene signatures—the 166-gene viral pandemic (ViP) and 20-gene severe-ViP (sViP) signatures—together with a 13-transcript KD diagnostic signature, we compared MIS-C and KD across whole blood RNA sequencing, serum cytokines, and formalin-fixed heart tissues. KD and MIS-C lie on the same continuum of the host immune response as COVID-19 and converge on an IL15/IL15RA-centric cytokine storm, indicating shared proximal immunopathogenesis. However, they diverge in laboratory parameters and cardiac phenotypes. ViP signatures identify targetable cytokine pathways in MIS-C, position MIS-C farther along a severity spectrum than KD, and highlight key clinical and laboratory parameters—reduced cardiac function, thrombocytopenia, and eosinopenia—to monitor disease severity.

Pradipta Ghosh, Gajanan D. Katkar, Chisato Shimizu, Jihoon Kim, Soni Khandelwal, Adriana H. Tremoulet, John T. Kanegaye, Joseph Bocchini, Soumita Das, Jane C. Burns, Debashis Sahoo