Temporal Clusters of Kawasaki Disease Cases Share Distinct Phenotypes That Suggest Response to Diverse Triggers

Abstract

Objective: To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters.

Study design: We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-year period (2002-2019) from a single clinical site and compared the cluster characteristics with those of 2 control groups of synthetic Kawasaki disease clusters. We defined a "true" Kawasaki disease cluster as at least 5 patients within a 7-day moving window. The observed and synthetic Kawasaki disease clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis.

Results: In a univariate analysis, the median values for age, coronary artery z-score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true Kawasaki disease clusters exceeded the 95th percentile for the 2 synthetic clusters. REOF analyses revealed distinct patterns of demographic and clinical measures within clusters.

Conclusions: Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensities of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of Kawasaki disease.

Keywords: coronary artery aneurysm; epidemiology; pediatrics; vasculitis.

Figure 1

Study area and temporal clustering. A, Monthly distribution of 1332 cases and temporal trend in cases of Kawasaki disease seen at RCHSD between January 2002 and March 2019. B, Time series of daily cases (black dots) and clusters (blue lines), defined as 5 or more cases in 7 days. C, Distribution of case density for the study period; n = 5 is the 97.5th percentile density. D, Monte Carlo simulation drawing 100 time series of 1332 randomly selected dates with the same time trend and seasonality as the true data (blue squares). Comparing that with the true data (black dots) shows more clusters of 6 or 7 cases in the true data than would be expected from a random distribution of established trends and seasonality.

Figure 3

REOFs. A, The first 4 REOF modes, with their respective fraction of variance (% of total), showing combinations of patient demographic and clinical characteristics that were prevalent in the 47 Kawasaki disease clusters. Horizontal bars indicate, for a given REOF, the characteristics that associated positively (to the right) or negatively (to the left). Red bars designate characteristics for a given REOF that associate most strongly, with weights >1.1 SD. Orange bars indicate moderately strong associations, with weights between 0.9 and 1.1 SD. B, From the Monte Carlo trials, the fraction of REOFs from control clusters, shuffled clusters, and true clusters that exhibit the defining characteristics of the leading 4 REOFs from the true clusters shown in A.

Figure 2

Cluster-level averages of patient demographic and clinical characteristics (A-N). Observed cluster-level averages for 47 Kawasaki disease clusters (black squares) compared with 100 equal-size synthetic clusters created by (blue) randomly shuffling cluster membership of cluster cases of Kawasaki disease (shuffled clusters), and (red) randomly drawn noncluster cases of Kawasaki disease from the same season as the true cluster (control clusters). For both comparison groups, the dots show the mean value of 100 iterations, thick lines show the IQR (25th-75th percentiles), and thin lines show the inner 95th percentile of the distribution. Red and blue asterisks at the base of each figure indicate whether the true value for the given cluster lies outside the 95th percentile of either comparison distribution; these are totaled at the lower right of the figure to provide a summary of how many of the true clusters are extreme compared with the 2 comparison groups. s, shuffled; c, control. At the right of the individual clusters, the summary of both comparison sets and the true data (yellow circle) are presented.