Kawasaki disease From single disease entity to clinical hyperinflammatory spectrum

Kawasaki disease (KD) is a severe pediatric vasculitis, with a risk of coronary artery aneurysms (CAA). This thesis aimed to improve understanding of the clinical, immunological, and genetic heterogeneity of KD.
Part I describes the clinical spectrum of KD and MIS-C. Analysis of >1000 KD patients demonstrated substantial changes in disease presentation over time, and a clinical overlap between KD and MIS-C, which suggests a shared underlying pathophysiology.
Part II investigates immunological features of KD and MIS-C. Despite some distinct severity markers, largely overlapping inflammatory profiles were identified. T-cell receptor Vβ21.3+ expansions, considered characteristic of MIS-C, were also observed in patients with KD shock syndrome, suggesting that this response is not specific to SARS-CoV-2. A case of severe KD treated with targeted IL-1 blockade further illustrated the complexity of KD inflammation and the limitations of targeting a single pathway.
Part III focuses on determinants of cardiac outcomes. In contrast to KD, about half of MIS-C patients had transient cardiac dysfunction. Genetic analyses found no association between Fcγ receptor polymorphisms and IVIG resistance or CAA. Instead, specific TLR7/8 polymorphisms may be associated with larger aneurysms and reduced CAA normalization, potentially contributing to the male predominance of giant CAA. Functional differences were not demonstrated, highlighting the need for further investigation of local coronary immune mechanisms.
Overall, this thesis supports KD as a heterogeneous syndrome within a broader spectrum of pediatric hyperinflammatory disorders. Improved understanding of this heterogeneity may enable more accurate diagnosis, risk stratification, and targeted treatment to reduce long-term cardiovascular morbidity.