The etiologies of Kawasaki disease

Abstract

Kawasaki disease (KD) is a systemic vasculitis that affects young children and can result in coronary artery aneurysms. The etiology is currently unknown, but new clues from the epidemiology of KD in Japan, the country of highest incidence, are beginning to shed light on what may trigger this acute inflammatory condition. Additional clues from the global changes in KD incidence during the COVID-19 pandemic, coupled with a new birth cohort study from Japan, point to the potential role of person-to-person transmission of an infectious agent. However, the rising incidence of KD in Japan, with coherent waves across the entire country, points to an increasing intensity of exposure that cannot be explained by person-to-person spread. This Review discusses new and historical observations that guide us toward a better understanding of KD etiology and explores hypotheses and interpretations that can provide direction for future investigations. Once the etiology of KD is determined, accurate diagnostic tests will become available, and new, less expensive, and more effective targeted therapies will likely be possible. Clearly, solving the mystery of the etiologies of KD remains a priority for pediatric research.

Figure 1. Coronary artery damage from KD.

Illustrations represent giant aneurysms of the right and left anterior descending coronary arteries. IVIG therapy can reduce the prevalence of coronary artery aneurysm following acute KD from 25% to 5%, highlighting the need for accurate diagnostic tests and timely treatment.

Figure 2. Epidemiologic clues from Japan and the United States.

(A) Interpretation of epidemiologic clues from Japan’s unparalleled historical record of KD. Left: The first record of KD-like cases in Japan appeared in the 1950s, following large influxes of people from other regions, including repatriation of Japanese individuals from China and Korea as well as US military occupation following WWII and the Korean War. The subsequent 3 epidemics of KD in 1979, 1982, and 1986 are consistent with the introduction of a causative agent into a highly genetically susceptible population. The plateau period from 1988 to 1992 suggests a steady-state exposure to the KD trigger. Right: The 4.5-fold increase in cases in older children occurring from the mid-1990s to 2019 suggests increasing exposure of large populations to an environmental trigger, possibly a wind-borne aerosol. Post-WWII development or increasing intensity of some human activities could create an aerosol that might amplify this exposure, consistent with the rise in KD cases. Incidence in infants remained essentially unchanged over three decades, suggesting a different mode of exposure to the KD trigger in this youngest age group. In 2020, reduced exposure due to isolation measures taken during the COVID-19 pandemic resulted in a decrease in KD incidence that was mirrored by other countries around the globe. (B) Correlation of the seasonal pattern of KD across prefectures in Japan, 1988–2019. For infants less than 6 months of age (left) there is little coherence in seasonal patterns across Japan, in contrast to children 3 years and older (right), for whom there is striking synchrony of KD seasonal patterns across all of Japan. KD incidence and correlation data were adapted with permission from JAMA Network (16).

Figure 3. Pathways and genes influencing KD susceptibility and outcome.

Figure concept and design are courtesy of Chisato Shimizu.

Figure 4. Suggested research initiatives to shed light on KD etiology.

The figure also depicts the clinical signs of KD.