Association of antibiotic exposure with Kawasaki disease

Abstract Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that primarily affects children under five years old. Emerging evidence suggests that gut microbiota alterations may contribute to KD pathogenesis. Because antibiotics modify intestinal microbial composition, their inappropriate or repeated use in early childhood may increase KD susceptibility. However, population-based evidence linking antibiotic exposure with KD onset remains limited, and the influence of antibiotic class, number of antibiotic prescriptions, and administration route has not been systematically evaluated. To examine the association between antibiotic type, number of antibiotic prescriptions, route of administration, and KD onset in a nationwide dataset. We conducted a matched case–control study using the JMDC database (2005–2024). Children aged 0–6 years were eligible. Newly diagnosed KD cases ( n = 17,410) and controls ( n = 68,621) were matched 1:4 by age, sex, and birth year. Antibiotic exposure from birth until one month before the index date was assessed by class (penicillins, cephalosporins, macrolides, quinolones, others), number of antibiotic prescriptions, and administration route (oral vs. intravenous). Multivariable conditional logistic regression estimated odds of KD onset adjusted for antiviral agent use, antifungal agent use, preterm birth, and low birth weight, with matching by age, sex, and birth year accounted for in the conditional analysis. Among 86,031 children, exposure to penicillins (OR, 1.27; 95% CI, 1.21–1.34), cephalosporins (OR, 1.16; 95% CI, 1.10–1.23), quinolones (OR, 1.48; 95% CI, 1.27–1.73), and macrolides (OR, 1.19; 95% CI, 1.09–1.31) was associated with increased KD risk. Higher odds of KD were observed with increasing numbers of antibiotic prescriptions (≥ 5 prescriptions: OR, 1.22; 95% CI, 1.16–1.28). Oral antibiotic use showed a significant association (OR, 1.22; 95% CI, 1.16–1.27), while intravenous use did not. Repeated antibiotic prescriptions, especially via oral administration, were associated with KD. These findings support an association between prior antibiotic exposure and KD, warranting further mechanistic investigation.