Kawasaki disease: a new understanding of the clinical spectrum

Kawasaki disease is an acute febrile vasculitis that usually affects children aged 6 months to 5 years.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar Without treatment, Kawasaki disease is complicated by coronary artery abnormalities in more than 20% of patients and is the leading cause of acquired heart disease in high-income countries.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar The diagnosis mainly relies on clinical criteria outlined more than 50 years ago, combining persistent fever for more than 5 days with at least four of the following five criteria: non-purulent conjunctivitis, cervical lymphadenopathy, skin rash, erythematous and cracked lips, and inflammation of the hands and feet.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar However, incomplete forms and numerous other symptoms have been described, making the diagnosis of Kawasaki disease still challenging.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar, 2de Graeff N Groot N Ozen S et al.European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease—the SHARE initiative.Rheumatology (Oxford). 2019; 58: 672-682Crossref PubMed Scopus (88) Google Scholar The pathophysiology of Kawasaki disease is poorly understood. Infectious agents might trigger Kawasaki disease, and genetic factors of the patient might also be involved.3Galeotti C Kaveri SV Cimaz R Koné-Paut I Bayry J Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease.Drug Discov Today. 2016; 21: 1850-1857Crossref PubMed Scopus (42) Google Scholar In a large single-centre cohort in the USA of 1016 patients recruited from 2002 to 2022, Hao Wang and colleagues4Wang H Shimizu C Bainto E et al.Subgroups of children with Kawasaki disease: a data-driven cluster analysis.Lancet Child Adolesc Health. 2023; (published online Aug 17.)https://doi.org/10.1016/S2352-4642(23)00166-9Summary Full Text Full Text PDF Google Scholar described four clusters of patients with distinct clinical and biological features, outcomes, and seasonal and incidence trajectories. These four clusters were named the liver subgroup, which includes patients with hepatobiliary involvement and older age; the band subgroup, which includes patients with a high band neutrophil count and Kawasaki disease shock rate; the node subgroup, which includes patients with the highest rate of cervical lymphadenopathy and inflammation; and the young subgroup, which includes patients with the youngest age at Kawasaki disease onset. Moreover, in a selected sample of the study cohort, specific cluster-related proteome profiles were identified. This study might be a turning point in the description of Kawasaki disease for several reasons. First, the methodological approach used to define the clusters is particularly interesting. To date, assessment of the phenotypic heterogeneity of Kawasaki disease through an objective data-driven point of view has not been done. Large clinical datasets have been used to build prediction models of Kawasaki disease through machine learning rather than to quantify the clustering tendency of phenotypic data.5Tsai CM Lin CR Kuo HC et al.Use of machine learning to differentiate children with Kawasaki disease from other febrile children in a pediatric emergency department.JAMA Netw Open. 2023; 6e237489Crossref Scopus (4) Google Scholar This approach is a promising application of artificial intelligence that could aid in better characterisation of complex multifactorial diseases. It also shows that beyond the increasingly developed multiomic approaches in inflammatory diseases, clinical and basic biological findings are still important, even in established diseases such as Kawasaki disease. Second, in this large cohort study, the young cluster was associated with a higher risk of coronary artery aneurysm and the liver cluster was associated with intravenous immunoglobulin resistance. The median age of onset of 1·2 years in the young cluster reinforces that young age should be recognised as an independent risk factor of coronary artery aneurysm as previously described.6Iio K Morikawa Y Miyata K et al.Risk factors of coronary artery aneurysms in Kawasaki disease with a low risk of intravenous immunoglobulin resistance: an analysis of post RAISE.J Pediatr. 2022; 240: 158-163.e4Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar It also suggests that the first-line intravenous immunoglobulin treatment should be intensified with corticosteroids in infants younger than 12 months, which has been increasingly recommended.2de Graeff N Groot N Ozen S et al.European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease—the SHARE initiative.Rheumatology (Oxford). 2019; 58: 672-682Crossref PubMed Scopus (88) Google Scholar, 7Scherler L Haas NA Tengler A Pattathu J Mandilaras G Jakob A Acute phase of Kawasaki disease: a review of national guideline recommendations.Eur J Pediatr. 2022; 181: 2563-2573Crossref PubMed Scopus (7) Google Scholar Moreover, this study shows that liver involvement is associated with intravenous immunoglobulin resistance but surprisingly not with coronary artery aneurysm, although the first classically predicts the second.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar Even if coronary artery aneurysm is observed in patients in the liver cluster, this might suggest a hepatic vasculitis-specific pattern of Kawasaki disease with its own pathophysiology. This hypothesis might be supported by the distance in the hierarchical tree between the liver and young clusters, the lack of seasonality of the liver cluster compared with the others, and the hepatic-specific proteome profile. Third, the identification of four distinct clusters clearly shows that Kawasaki disease is a syndrome rather than a homogeneous disease, and has various pathophysiological patterns that should be explored to improve its diagnosis and management. Thus, the clustering described by Wang and colleagues4Wang H Shimizu C Bainto E et al.Subgroups of children with Kawasaki disease: a data-driven cluster analysis.Lancet Child Adolesc Health. 2023; (published online Aug 17.)https://doi.org/10.1016/S2352-4642(23)00166-9Summary Full Text Full Text PDF Google Scholar has particular importance for cluster-adapted therapeutic studies and outcome assessments in the future. However, one of the major limitations of the generalisability of these findings is the monocentric nature of the study with very few children of African ancestry. The genetic basis of susceptibility to Kawasaki disease has been established for many years, initially recognised due to the higher incidence of Kawasaki disease in the Asian population compared with the European population.1McCrindle BW Rowley AH Newburger JW et al.Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association.Circulation. 2017; 135: e927-e999Crossref PubMed Scopus (2074) Google Scholar Extensive ethnic variation and linkage disequilibrium have also been observed in the locus of a gene encoding Fc-gamma receptors, a key effector in Kawasaki disease pathophysiology.8Nagelkerke SQ Tacke CE Breunis WB et al.Extensive ethnic variation and linkage disequilibrium at the FCGR2/3 locus: different genetic associations revealed in Kawasaki disease.Front Immunol. 2019; 10: 185Crossref PubMed Scopus (35) Google Scholar Moreover, there is high variability in the sensitivities and specificities of various severity scores among populations of various ethnic origins.9Ouldali N Dellepiane RM Torreggiani S et al.Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: a multicentre retrospective cohort study.Lancet Reg Health Eur. 2022; 22100481Google Scholar Thus, this study should be confirmed in populations including children of various origins, particularly children of African ancestry. In summary, through an original clinical data-based approach reinforced by epidemiological and proteomic data, this study highlights a clustered pattern of Kawasaki disease with specific short-term outcomes for the young and liver clusters. Although this cluster pattern needs to be confirmed in other multiethnic cohorts, these findings should prompt a new approach in further Kawasaki disease studies. I declare no competing interests. Subgroups of children with Kawasaki disease: a data-driven cluster analysisOur data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation. Full-Text PDF Open Access