Subgroups of Kawasaki Disease Patients: A Data-Driven Cluster Analysis

Background: Although Kawasaki disease (KD) is commonly regarded as a single disease, variability in clinical manifestations and disease outcome has been recognized. This study used a data-driven approach to identify clinical subgroups.Methods: We analyzed clinical data from 1,016 KD patients diagnosed at Rady Children’s Hospital-San Diego between 2002 and 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin (IVIG) infusion and normalized echocardiographic measures of coronary artery diameters at diagnosis. To explore the biological underpinnings of identified subgroups, we performed differential abundance (DA) analysis on proteomic data of 6,481 proteins from 32 KD patients and 24 healthy children, using linear regression models that controlled for age and sex. We also analyzed the seasonality and KD incidence from 2002-2019 by subgroup.Findings: Four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase and total bilirubin levels, lowest coronary artery aneurysm (CAA) but highest IVIG-resistance rates; (2) highest band neutrophil count and KD shock rate; (3) cervical lymphadenopathy with high markers of inflammation (ESR, CRP, white blood cell and platelet counts) and lowest age-adjusted hemoglobin Z-scores; and (4) young age at onset with highest CAA but lowest IVIG-resistance rates. The subgroups shared 211 DA proteins while many proteins (135, 264, 613 and 46) were unique to a subgroup. The subgroups had distinct seasonal and incidence trajectories.Interpretation: Our data-driven analysis provides insight into the heterogeneity of KD, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation.Funding: This study was funded by the National Institutes of Health PreVAIL grant (R61HD105590) and the Irving and Francine Suknow Foundation.Declaration of Interest: All authors declare no competing interests.Ethical Approval: arents and patients signed informed consent or assent as appropriate for this study approved by the UCSD Institutional Review Board (#140220).