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.