Researchers at the University of California at San Diego report that while Kawasaki disease (KD) occurs in groups, the traits and thus the triggers of inflammatory disease vary between groups. The findings are published in the September 2020 online issue of The Journal of Pediatrics.
“The importance of this work is that it will take Kawasaki disease research in a completely different direction. We now have strong evidence that there are different triggers for Kawasaki disease, which suggests slightly different genetic susceptibilities,” Jane said. C. Burns, MD, a pediatrician at Rady Children’s Hospital-San Diego and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine.
“In four decades of research, we have brought all of these patients together and looked for a single cause. Our team’s analysis now shows that we need to look for multiple causes of KD, not just one.”
The data suggest that either different triggers or different intensities of environmental exposures result in KD case clusters that share a similar response pattern. This observation resonates with current observations linking the SARS-CoV-2 virus to multisystem inflammatory syndrome (MIS-C), a disease that shares many clinical features with KD.
In both KD and MIS-C, babies are likely born with a genetic predisposition to react to something in their environment and develop severe inflammation. For MIS-C, we know the cause – it’s SARS-CoV-2. For KD, we’re now going to start analyzing our data in a whole new way, Burns said.
This was an unusually fertile interdisciplinary study. The results obtained could not have been achieved without intense collaboration between earth scientists, statisticians and pediatric doctors who care for patients with Kawasaki disease and MIS-C. “
Jen Burney, Associate Professor, University of California – San Diego School of Global Policy and Strategy
UC San Diego researchers enrolled 1,332 KD patients who met American Heart Association (AHA) guidelines for complete or incomplete KD and were diagnosed and treated at Rady Children’s Hospital-San Diego between January 2002 and March 2019.
Cases of KD within a cluster were found to be more similar in demographic and clinical characteristics and levels of inflammation than would be expected by chance.
For example, markers of systemic inflammation when elevated were more likely to be associated with low hemoglobin levels and vice versa (lower measures of inflammation associated with normal hemoglobin).
“While this makes biological sense, the important finding was that some clusters had this feature while other clusters did not,” Burns said. “With respect to clinical features, cases with ‘strawberry tongue’ or ‘first presentation of lymph nodes’ also pooled, as did cases without these clinical features.”
Important information about the different etiologies of KD can be obtained by focusing on patients who share the demographic and clinical phenotypes identified in our analysis, Burns said.
The presence or absence of clusters of these phenotypes in the KD patients differed significantly from the two control groups of synthetic clusters, which may indicate that the KD patients within these clusters were responding to different stimuli, resulting in in several clinical presentations.
Similarly, the laboratory evidence of inflammation was high or low in several groups, again suggesting a non-random distribution of these characteristics.
The indication that different KD clusters exhibit different physiological responses reinforces the team’s previous findings.
“Our focus on KD case clusters has been directed by our finding that clusters of these clusters are associated with distinct weather patterns,” said Dan Cayan, PhD, climate researcher with the Scripps Institution of Oceanography.
“These previous findings have led to the hypothesis that, rather than having a single causal mechanism, Kawasaki disease may have multiple environmental triggers. These triggers were highlighted by a combination of abnormal temperature, precipitation and wind patterns.”
Kawasaki disease is the most common acquired heart disease in children. Untreated, about a quarter of children with KD develop coronary artery aneurysms -; balloon-like swellings of the heart vessels -; which can eventually lead to heart attacks, congestive heart failure or sudden death.
Although KD is estimated to affect fewer than 6,000 children in the United States each year, the incidence rate is increasing in San Diego County. While the average incidence per 100,000 children under the age of 5 residing in San Diego County was about 10 during the 1990s, the estimated incidence rate from 2006 to 2015 was 25.5.
Incidence rates in the United States are approximately 19 to 25 cases per 100,000 children under 5 -; but they are higher in children of Asian descent. Predictive models estimate that by 2030, one in 1,600 American adults will have been affected by the disease.
This month, UC San Diego School of Medicine and Imperial College London announced a collaboration with SkylineDx to jointly develop a diagnostic test that will facilitate early detection of KD. The test is based on 13 genes that form a “genetic signature” in the blood of children with KD, which allows KD to be distinguished from other infectious and inflammatory diseases.
University of California – San Diego
Burns, JC, et al. (2020) Temporal clusters of Kawasaki disease cases share distinct phenotypes that suggest a response to different triggers. The Journal of Pediatrics. doi.org/10.1016/j.jpeds.2020.09.043.