The etiologies of Kawasaki disease.

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.

SARS-CoV-2 variants are associated with different clinical courses in children with MIS-C.

BACKGROUND: Recent infection with SARS­CoV­2 in children has been associated with multisystem inflammatory syndrome in children (MIS-C). SARS­CoV­2 has undergone different mutations. Few publications exist about specific variants and their correlation with the severity of MIS-C. METHODS: This was a single-center, retrospective study including all patients admitted with MIS-C at Rady Children's Hospital-San Diego between May 2020 and March 2022. Local epidemiologic data, including viral genomic information, were obtained from public records. Demographics, clinical presentation, laboratory values, and outcomes were obtained from electronic medical records. RESULTS: The analysis included 104 pediatric patients. Four MIS-C waves were identified. Circulating variants in San Diego during the first wave included clades 20A to C. During the second wave, there were variants from clades 20A to C, 20G, 21C (Epsilon), 20I (Alpha), and 20J (Gamma). The third wave had Delta strains (clades 21A, 21I, and 21J), and the fourth had Omicron variants (clades 21K, 21L, and 22C). MIS-C presented with similar symptoms and laboratory findings across all waves. More patients were admitted to the pediatric intensive care unit (PICU) (74%) and required inotropic support (63%) during the second wave. None of the patients required mechanical circulatory support, and only two required invasive ventilatory support. There was no mortality. CONCLUSIONS: The various strains of SARS-CoV-2 triggered MIS-C with differing severities, with the second wave having a more severe clinical course. Whether the differences in disease severity across variants were due to changes in the virus or other factors remains unknown.

Age-Dependent Variations in Kawasaki Disease Incidence in Japan.

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.

Plasma Cell-free RNA Signatures of Inflammatory Syndromes in Children.

Inflammatory syndromes, including those caused by infection, are a major cause of hospital admissions among children and are often misdiagnosed because of a lack of advanced molecular diagnostic tools. In this study, we explored the utility of circulating cell-free RNA (cfRNA) in plasma as an analyte for the differential diagnosis and characterization of pediatric inflammatory syndromes. We profiled cfRNA in 370 plasma samples from pediatric patients with a range of inflammatory conditions, including Kawasaki disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), viral infections and bacterial infections. We developed machine learning models based on these cfRNA profiles, which effectively differentiated KD from MIS-C - two conditions presenting with overlapping symptoms - with high performance (Test Area Under the Curve (AUC) = 0.97). We further extended this methodology into a multiclass machine learning framework that achieved 81% accuracy in distinguishing among KD, MIS-C, viral, and bacterial infections. We further demonstrated that cfRNA profiles can be used to quantify injury to specific tissues and organs, including the liver, heart, endothelium, nervous system, and the upper respiratory tract. Overall, this study identified cfRNA as a versatile analyte for the differential diagnosis and characterization of a wide range of pediatric inflammatory syndromes.