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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.

Importance: The etiology of Kawasaki disease (KD) remains elusive, with immunologic and epidemiologic data suggesting different triggers in individuals who are genetically susceptible. KD remains the most common cause of acquired heart disease in pediatric patients, and Japan is the country of highest incidence, with an increasing number of cases., Objective: To investigate whether an analysis of the epidemiologic KD record in Japan stratified by age and prefecture (subregion) may yield new clues regarding mechanisms of exposure to etiologic agents associated with KD., Design, Setting, and Participants: This cross-sectional study was conducted using a dataset of patients with KD with detailed information on location and age at onset created through nationwide surveys of hospitals caring for pediatric patients with KD throughout Japan. Pediatric patients hospitalized in Japan for KD from 1970 to 2020 were included. Data were analyzed from January 2022 to January 2024., Exposure: Pediatric patients with KD., Main Outcomes and Measures: The KD dataset was analyzed by patient age (infants [aged <6 months], toddlers [aged 6 to <24 months], children aged 2 years [aged 24 to <36 months], and children and adolescents aged 3 years or older [aged ≥36 months]), with investigations of seasonal cycles, interannual variations, and correlations across regions., Results: Among 422 528 pediatric patients (243 803 males [57.7%] and 178 732 females [42.3%]; median [IQR] age, 23.69 [11.96-42.65] months), infants, toddlers, and patients aged 3 years or older exhibited different rates of increase in KD incidence, seasonality, and degrees of coherence of seasonality across prefectures. Although the mean (SD) incidence of KD among infants remained relatively stable over the past 30 years compared with older patients (1.00 [0.07] in 1987-1992 to 2.05 [0.11] in 2011-2016), the mean (SD) incidence rate for children and adolescents aged 3 years or older increased 5.2-fold, from 1.00 (0.08) in 1987 to 1992 to 5.17 (0.46) in 2014 to 2019. Patients aged 3 years or older saw a reduction in mean (SD) incidence, from peaks of 5.71 (0.01) in October 2014 through June 2015 and July 2018 through March 2019 to 4.69 (0.11) in 2016 to 2017 (17.8% reduction) not seen in younger children. The seasonal cycle varied by age group; for example, mean (SD) incidence peaked in July and August (5.63 [0.07] cases/100 000 individuals) for infants and in December and January (4.67 [0.13] cases/100 000 individuals) for toddlers. Mean (SD) incidence changed dramatically for toddlers beginning in the early 2010s; for example, the normalized mean (SD) incidence among toddlers for October was 0.74 (0.03) in 1992 to 1995 and 1.10 (0.01) in 2016 to 2019. Across Japan, the seasonal cycle of KD incidence of older children and adolescents exhibited mean (SD) correlation coefficients between prefectures as high as 0.78 (0.14) for prefecture 14 among patients aged 3 years or older, while that of infants was much less (highest mean [SD] correlation coefficient, 0.43 [0.23])., Conclusions and Relevance: This study found distinct temporal signatures and changing spatial consistency of KD incidence across age groups, suggesting different age-related mechanisms of exposure. Some results suggested that social factors may modulate exposure to etiologic agents of KD; however, the increase in KD incidence in older children coupled with the correlation across prefectures of KD incidence suggest that the intensity of an environmental exposure that triggers KD in this age group may have increased over time.

Recent advances on the environmental determinants of Kawasaki Disease have pointed to the important role of the atmospheric transport of a still unknown agent potentially triggering the disease. The hypothesis arose from an innovative methodology combining expertise in climate dynamics, the analysis of ocean and atmosphere data, the use of dispersion models and the search for biological agents in air samples. The approach offered a new perspective to reveal the identity of the potential trigger, but at the same time, it increased the level of complexity, which could potentially lead to the misinterpretation of the mechanisms. Some years after it was originally formulated, we here provide a brief clarification on the approach and limits of the methodology in order to prevent an eventual misuse of our research ideas and theory, so that further research can better focus on the knowledge gaps that still remain open., Competing Interests: The authors have declared that no competing interests exist.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children., (Copyright © 2019. Published by Elsevier Inc.)

Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987-2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (<24 h) from exposure, thus making an infectious agent unlikely. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols compared with ground aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, consistent with the Candida animal model for KD, provide support for the concept and feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD, consistent with an agricultural source, a short incubation time and synchronized outbreaks. Our study suggests that the causative agent of KD is a preformed toxin or environmental agent rather than an organism requiring replication. We propose a new paradigm whereby an idiosyncratic immune response, influenced by host genetics triggered by an environmental exposure carried on winds, results in the clinical syndrome known as acute KD.

The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. The number of cases continues to rise in many parts of the world and KD is the most common cause of acquired heart disease in childhood in developed countries. Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.

Kawasaki syndrome (KS) is the most common cause of acquired pediatric heart disease in the developed world. There have been 2 distinctive patterns for the emergence of KS that are likely related to several factors including exposure to the causative agent(s) and host genetics. In Europe and North America where we presume the genetic susceptibility seems to be low, KS has existed in the pediatric population for more than a century and is associated with relatively low incidence. In Japan where genetic susceptibility is presumed to be high, KS seems not to have existed before the early 1950s. This relatively recent exposure has resulted in 3 nationwide epidemics and a high current endemic rate of 200 per 100,000 in children less than 5 years. If our history of alternative patterns of the emergence of KS is valid, it may prove useful as a predictive tool for countries including India, where clusters of KS cases have been recently reported. This article examines the historical evidence in support of a 2-tiered emergence of KS in Euro-America and Japan and then returns briefly to discuss its implications for the pediatric populations of India and the health care delivery systems in the developing world.

Clinical similarities and shared seasonality suggested a relationship between adenovirus infection and Kawasaki disease. We performed adenovirus serology and quantitative polymerase chain reaction for both adenovirus and adeno-associated virus in patients with acute Kawasaki disease. No evidence was found to suggest a link between either virus and Kawasaki disease.

Background: The distribution of a syndrome in space and time may suggest clues to its etiology. The cause of Kawasaki syndrome, a systemic vasculitis of infants and children, is unknown, but an infectious etiology is suspected., Methods: Seasonality and clustering of Kawasaki syndrome cases were studied in Japanese children with Kawasaki syndrome reported in nationwide surveys in Japan. Excluding the years that contained the 3 major nationwide epidemics, 84,829 cases during a 14-year period (1987-2000) were analyzed. To assess seasonality, we calculated mean monthly incidence during the study period for eastern and western Japan and for each of the 47 prefectures. To assess clustering, we compared the number of cases per day (daily incidence) with a simulated distribution (Monte Carlo analysis)., Results: Marked spatial and temporal patterns were noted in both the seasonality and deviations from the average number of Kawasaki syndrome cases in Japan. Seasonality was bimodal with peaks in January and June/July and a nadir in October. This pattern was consistent throughout Japan and during the entire 14-year period. Some years produced very high or low numbers of cases, but the overall variability was consistent throughout the entire country. Temporal clustering of Kawasaki syndrome cases was detected with nationwide outbreaks., Conclusions: Kawasaki syndrome has a pronounced seasonality in Japan that is consistent throughout the length of the Japanese archipelago. Temporal clustering of cases combined with marked seasonality suggests an environmental trigger for this clinical syndrome.

Kawasaki disease is a rash/fever illness of early childhood in which coronary artery aneurysms (CAA), sometimes fatal, may develop in up to 25 percent of untreated children. Because its etiology and pathophysiology are unknown and no diagnostic laboratory test exists, diagnosis is made via a list of clinical signs; however, a significant number of children fail to meet the clinical criteria and go on to develop CAA. We suspected a connection between these missed cases and the continuing difficulty in identifying the etiological agent(s) and mechanisms for CAA. In search of that connection, we launched a historical investigation into the institutionalization of the clinical criteria, and explored how this process influenced the framing of research questions. Our findings suggest that the canonization of the Kawasaki disease case definition was as much due to the enshrinement of the historical narrative as to compelling scientific findings. The Kawasaki disease narrative encompasses interrelated issues of definition, discovery, and naming; these, in turn, have profoundly influenced diagnosis, treatment, and research. "Atypical" cases, despite being at risk for CAA, often fail to receive prompt diagnosis and treatment; consequently, research has been limited to the population that meets the diagnostic criteria for Kawasaki disease, rather than including those who are at risk of CAA. Although clinical concerns prompted this investigation, it nevertheless has important implications for the history of medicine: it provides an illustration of how a historical interrogation of a syndrome's construction can free medical researchers to pursue novel approaches. Equally important, it demonstrates how historians can make unique contributions as collaborators in clinical care and medical research.

This paper describes the historical evolution of the Kawasaki disease (KD) case definition and its limitations for identification and treatment of children at risk for coronary artery aneurysms (CAA). The dominant view of pathogenesis is that an unknown agent infects infants and children, who then develop the signs of KD. Some of the infected infants and children then develop CAA, and a few die from myocardial infarction. Because the etiologic agent remains unknown, diagnosis of KD relies on observation and recognition of the clinical signs that comprise the KD case definition criteria. This approach has been successful in identifying and treating many children at risk for CAA. Unfortunately, however, it has delayed the effective treatment of children who fail to meet the KD case definition criteria but who, nevertheless, develop CAA. The original case definition was developed before the general acceptance of CAA as sequelae of KD, the availability of the echocardiogram, and effective treatment with intravenous immunoglobulin. Despite an evolution in awareness, detection, and treatment of possible CAA sequela, the case definition has not been altered so as to incorporate this knowledge. Our investigation explores the transformation of the case definition from an epidemiological instrument to a diagnostic tool. We urge the construction of a more sensitive KD case definition that includes signs and laboratory findings associated with CAA.

Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan. Although an infectious agent is suspected, the cause remains unknown. However, significant progress has been made toward understanding the natural history of the disease and therapeutic interventions have been developed that halt the immune-mediated destruction of the arterial wall. We present a brief history of KD, review progress in research on the disease, and suggest avenues for future study. Kawasaki saw his first case of KD in January 1961 and published his first report in Japanese in 1967. Whether cases existed in Japan before that time is currently under study. The most significant controversy in the 1960s in Japan was whether the rash and fever sign/symptom complex described by Kawasaki was connected to subsequent cardiac complications in a number of cases. Pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that KD was a self-limited illness with no sequelae. This controversy was resolved in 1970 when the first Japanese nationwide survey of KD documented 10 autopsy cases of sudden cardiac death after KD. By the time of the first English-language publication by Kawasaki in 1974, the link between KD and coronary artery vasculitis was well-established. KD was independently recognized as a new and distinct condition in the early 1970s by pediatricians Marian Melish and Raquel Hicks at the University of Hawaii. In 1973, at the same Hawaiian hospital, pathologist Eunice Larson, in consultation with Benjamin Landing at Los Angeles Children's Hospital, retrospectively diagnosed a 1971 autopsy case as KD. The similarity between KD and infantile periarteritis nodosa (IPN) was apparent to these pathologists, as it had been to Tanaka earlier. What remains unknown is the reason for the simultaneous recognition of this disease around the world in the 1960s and 1970s. There are several possible explanations. KD may have been a new disease that emerged in Japan and emanated to the Western World through Hawaii, where the disease is prevalent among Asian children. Alternatively, KD and IPN may be part of the spectrum of the same disease and clinically mild KD masqueraded as other diseases, such as scarlet fever in the preantibiotic era. Case reports of IPN from Western Europe extend back to at least the 19th century, but, thus far, cases of IPN have not been discovered in Japan before World War II. Perhaps the factors responsible for KD were introduced into Japan after the World War II and then reemerged in a more virulent form that subsequently spread through the industrialized Western world. It is also possible that improvements in health care and, in particular, the use of antibiotics to treat infections caused by organisms including toxin-producing bacteria reduced the burden of rash/fever illness and allowed KD to be recognized as a distinct clinical entity. Itsuzo Shigematsu, Hiroshi Yanagawa, and colleagues have conducted 14 nationwide surveys in Japan. These have indicated that: 1) KD occurred initially in nationwide epidemics but now occurs in regional outbreaks; 2) there are approximately 5,000 to 6,000 new cases each year; 3) current estimates of incidence rates are 120 to 150 cases per 100,000 children <5 years old; 4) KD is 1.5 times more common in males and 85% of cases occur in children <5 years old; and 5) the recurrence rate is low (4%). In 1978, David Morens at the Centers for Disease Control and Prevention published a case definition based on Kawasaki's original criteria. The Centers for Disease Control and Prevention developed a computerized database in 1984, and a passive reporting system currently exists in 22 states. Regional investigations and national surveys suggest an annual incidence of 4 to 15 cases per 100 000 children <5 years o