MIS-C Overlap, Not Prior COVID-19 Itself, Drives Treatment Escalation in Kawasaki Disease: A Nationwide Cohort Study

Background: Whether prior coronavirus disease 2019 (COVID-19) independently influences treatment response in children with Kawasaki disease (KD) is unclear, as prior reports may have been confounded by overlap with multisystem inflammatory syndrome in children (MIS-C). We investigated this in a nationwide cohort, accounting for these factors. Methods: We conducted a retrospective cohort study using the Korean National Health Insurance Service database. Children diagnosed with KD on or after January 1, 2020 who received IVIG within 7 days were included. Prior COVID-19 was defined as documented infection within 3 months before KD diagnosis. The primary outcome was second-line treatment within 7 days after initial IVIG (composite of second IVIG or additional steroid). 1:1 propensity score matching was performed using age, sex, MIS-C status, and steroid use with initial IVIG. Results: Among 6572 eligible children, 512 had prior COVID-19; 431 patients were matched per group. Second-line treatment occurred in 32/431 (7.4%) versus 23/431 (5.3%) (p = 0.265). Prior COVID-19 was not independently associated with second-line treatment (adjusted HR 1.42; 95% CI 0.83–2.43). In subgroup analysis, elevated risk was confined to children with concurrent MIS-C (HR 3.01; 95% CI 1.34–6.74); prior COVID-19 without MIS-C showed no increase (HR 1.18; 95% CI 0.66–2.11). Sensitivity analyses excluding MIS-C and restricted to 2022 onward were consistent. Conclusions: Prior COVID-19 alone was not independently associated with second-line treatment once MIS-C overlap and concurrent steroid use were accounted for. The elevated treatment escalation rate appeared driven primarily by MIS-C, highlighting the importance of distinguishing MIS-C from classic KD.