Decoding clinical heterogeneity and age-related coronary risk in incomplete Kawasaki disease: a multicenter cluster analysis and structural equation modeling study

Objectives To identify pretreatment clinical subphenotypes in incomplete Kawasaki disease (iKD) and examine their associations with post-IVIG coronary outcomes. Methods We retrospectively analyzed 1,619 iKD patients from six centers. Hierarchical clustering was performed using 11 pretreatment clinical and laboratory variables, with coronary measures excluded from cluster derivation. Post-IVIG coronary outcomes were subsequently compared across clusters. Logistic regression, exploratory structural equation modeling (SEM), and LOESS analyses were used to examine factors associated with coronary artery aneurysm (CAA). The same clustering framework was also applied to the entire KD cohort (n=6,264). Focused sensitivity analyses excluded patients whose retrospective iKD classification depended on coronary findings and separately evaluated pre-IVIG coronary abnormalities and newly developed or worsening abnormalities after IVIG. Results Four clinically distinct iKD clusters were identified. C1 showed greater systemic inflammation, C2 was characterized by younger age, longer pretreatment fever duration, and marked thrombocytosis, C3 by prominent hepatobiliary involvement, and C4 by a relatively low-inflammatory profile. C2 had the highest CAA prevalence (68.9%) and greatest coronary burden, whereas C3 had the highest IVIG-resistance rate (12.7%). Younger age, longer pretreatment fever duration, fewer clinical manifestations, lower albumin, lower hemoglobin Z-score, and lower neutrophil ratio remained independently associated with CAA. SEM showed a strong direct association of age with CAA and only a small indirect association through symptom count and pretreatment fever duration. In the whole-KD analysis, iKD was unevenly distributed across the independently derived clusters. The major cluster characteristics and the greater post-IVIG coronary burden of C2 remained evident after exclusion of patients whose iKD classification depended on coronary findings. Conclusions iKD comprises clinically heterogeneous pretreatment phenotypes associated with different coronary and treatment-response profiles. The coronary vulnerability of younger patients appears multifactorial rather than explained solely by longer pretreatment fever duration.