Association between maternal heavy metal exposure and Kawasaki Disease, the Japan Environment and Children's Study (JECS).

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting young children, with an unclear etiology. We investigated the link between maternal heavy metal exposure and KD incidence in children using the Japan Environment and Children's Study, a large-scale nationwide prospective cohort with approximately 100,000 mother-child pairs. Maternal blood samples collected during the second/third trimester were analyzed for heavy metals [mercury (Hg), cadmium (Cd), lead (Pb), selenium (Se), manganese (Mn)], divided into four quartiles based on concentration levels. KD incidence within the first year of life was tracked via questionnaire. Among 85,378 mother-child pairs, 316 children (0.37%) under one year were diagnosed with KD. Compared with the lowest concentration group (Q1), the highest (Q4) showed odds ratios (95% confidence interval) for Hg, 1.29 (0.82-2.03); Cd, 0.99 (0.63-1.58); Pb, 0.84 (0.52-1.34); Se, 1.17 (0.70-1.94); Mn, 0.70 (0.44-1.11), indicating no concentration-dependent increase. Sensitivity analyses with logarithmic transformation and extended outcomes up to age 3 yielded similar results. No significant association was found between maternal heavy metal levels and KD incidence, suggesting that heavy metal exposure does not increase KD risk.

[Recent research on platelet-leukocyte aggregates and their role in the pathogenesis of Kawasaki disease]. / 血小板-ç™½ç»†èƒžèšé›†ä½“åŠå ¶åœ¨å·å´Žç— å‘ç— ä¸­çš„ç ”ç©¶è¿›å±•.

Activated platelets may interact with various types of leukocytes such as monocytes, neutrophils, dendritic cells, and lymphocytes, trigger intercellular signal transduction, and thus lead to thrombosis and synthesis of massive inflammatory mediators. Elevated levels of circulating platelet-leukocyte aggregates have been found in patients with thrombotic or inflammatory diseases. This article reviews the latest research on the formation, function, and detection methods of platelet-leukocyte aggregates and their role in the onset of Kawasaki disease, so as to provide new ideas for studying the pathogenesis of Kawasaki disease.

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

Recent research on platelet-leukocyte aggregates and their role in the pathogenesis of Kawasaki disease / 中国当代儿科杂志

Activated platelets may interact with various types of leukocytes such as monocytes, neutrophils, dendritic cells, and lymphocytes, trigger intercellular signal transduction, and thus lead to thrombosis and synthesis of massive inflammatory mediators. Elevated levels of circulating platelet-leukocyte aggregates have been found in patients with thrombotic or inflammatory diseases. This article reviews the latest research on the formation, function, and detection methods of platelet-leukocyte aggregates and their role in the onset of Kawasaki disease, so as to provide new ideas for studying the pathogenesis of Kawasaki disease.

Kawasaki disease and the environment: an enigmatic interplay.

Kawasaki disease (KD) is a common systemic vasculitis of childhood. Although it has been almost 6 decades since Dr. Tomisaku Kawasaki reported the first case series of KD, the underlying cause remains a mystery. KD is a self-limiting disease. However, a dreaded complication is development of coronary artery abnormalities (CAAs). KD is the most common cause of acquired heart disease in children in the developed world and is being increasingly reported from developing countries too. Over the years, significant observations have been made about epidemiology of KD. It usually affects children below 5, has male preponderance and has significantly higher incidence in North East Asian countries. While several hypotheses have been proffered for etiology of KD, none have been conclusive. These include associations of KD epidemics in Japan and the United Stated with changes in tropospheric wind patterns suggesting wind-borne agents, global studies showing peaks of incidence related to season, and increased rates in populations with a higher socioeconomic profile related to hygiene hypothesis and vaccination. Furthermore, the self-limiting, febrile nature of KD suggests an infectious etiology, more so with sudden decline noted in cases in Japan with onset of COVID-19 mitigation measures. Finally, single nucleotide polymorphisms have been identified as possible risk alleles in patients with KD and their significance in the pathogenesis of this disease are also being defined. The purpose of this review is to elucidate the puzzling associations of KD with different environmental factors. Looking at patterns associated with KD may help us better predict and understand this disease.

Características clínicas, tratamiento y evolución de una serie de niños con síndrome inflamatorio multisistémico asociado a SARS-CoV-2 hospitalizados en dos centros de salud / Clinical characteristics, treatment and evolution of a series of children with multisystemic inflammatory syndrome associated with SARS-CoV-2 hospitalized in two health centers / Características clínicas, tratamento e evolução de uma série de crianças com síndrome inflamatória multissistêmica associada ao SARS-CoV-2 internadas em dois centros de saúde

Introducción: en marzo del 2021 se registró el pico de incidencia de COVID-19 en Uruguay y un aumento de la infección en pediatría. Objetivo: describir las características clínicas, el tratamiento y la evolución de una serie de menores de 15 años con SIM-Ped S hospitalizados en dos centros de salud. Metodología: estudio descriptivo, retrospectivo, de los niños hospitalizados entre el 1/3 y el 31/6 de 2021 que cumplieron los criterios diagnósticos de SIM-Ped de la OMS. Se analizan variables clínicas, paraclínicas, tratamiento y evolución. Resultados: se incluyeron 12 niños, mediana de edad 7 años (22 meses-10 años). Se presentaron complicación posinfecciosas en 8 y en el curso de la infección en 4. Las manifestaciones fueron: fiebre (media 6 días, rango 3-10), digestivas 10 y mucocutáneas 7. Se presentaron como enfermedad Kawasaki símil 5 y como shock 2. La infección por SARS CoV-2 se confirmó por PCR en 6, serología 4 y test antigénico 2. Recibieron tratamiento en cuidados moderados 8 e intensivos 4: inmunoglobulina 9, corticoides 11, heparina 7 y ácido acetilsalicílico 7. Presentaron dilatación de arterias coronarias 2, alteraciones valvulares 2, disminución de la FEVI 2 y derrame pericárdico 2. Todos evolucionaron favorablemente. Conclusiones: en estos centros, los primeros casos de SIMS-Ped S coincidieron con el pico de incidencia de COVID-19 en el país. Predominaron las formas postinfecciosas en escolares con manifestaciones digestivas. Este estudio puede contribuir al reconocimiento de esta entidad y adecuar los algoritmos nacionales de manejo.

Introduction: in March 2021, there was a peak incidence of COVID-19 and an increase in pediatric infections in Uruguay. Objective: describe the clinical characteristics, treatment and evolution of a group of children under 15 years of age with SIM-Ped S hospitalized in two health centers. Methodology: descriptive, retrospective study of children hospitalized between 3/1 and 6/31 of 2021 who met the WHO diagnostic criteria for SIM-Ped. Clinical and paraclinical variables, as well as treatment and evolution were analyzed. Results: 12 children were included, median age 7 years (22 months-10 years). Eight of them showed post-infectious complications and 4 of them had complications during the course of the infection. The manifestations were: fever (mean 6 days, range 3-10), digestive symptoms 10 and mucocutaneous 7. Five of them presented a Kawasaki-like disease and 2 of them shock. SARS CoV-2 infection was confirmed by PCR in 6 cases, serology in 4 and antigenic test in 2. Eight of them received treatment in moderate care and 4 of them in intensive care: immunoglobulin 9, corticosteroids 11, heparin 7 and acetylsalicylic acid 7. Two of them presented dilated arteries coronary , valvular alterations 2, decreased LVEF 2 and pericardial effusion 2. All progressed favorably. Conclusions: in these centers, the first cases of SIMS-Ped S coincided with the peak incidence of COVID-19 in the country. Post-infectious forms predominated in schoolchildren who showed digestive manifestations. This study may contribute to the recognition of this entity and to the adaptation of national management algorithms.

Introdução: em março de 2021, foi registrado no Uruguai um pico de incidência da COVID-19 e um aumento dos casos da infecção pediátrica. Objetivo: descrever as características clínicas, tratamento e evolução de uma série de crianças menores de 15 anos com SIM-Ped S internadas em dois centros de saúde. Metodologia: estudo descritivo, retrospectivo, de crianças internadas entre 1/3 e 31/6 de 2021 que preencheram os critérios diagnósticos da OMS para o SIM-Ped. Foram analisadas variáveis clínicas e para-clinicas, tratamento e evolução. Resultados: foram incluídas 12 crianças, com idade média de 7 anos (22 meses-10 anos). Oito delas apresentaram complicações pós-infecciosas e 4 delas durante o curso da infecção. As manifestações foram: febre (média de 6 dias, intervalo 3-10), digestivas 10 e mucocutânea 7. Cinco delas apresentaram doença de Kawasaki-like e 2 delas sofreram Shock. A infecção por SARS CoV-2 foi confirmada por PCR em 6, sorologia em 4 e teste antigênico em 2. Oito delas receberam tratamento em cuidados moderados e 4 delas em cuidados intensivos: imunoglobulina 9, corticosteroides 11, heparina 7 e ácido acetilsalicílico 7. Duas delas apresentaram artérias coronárias dilatadas 2, alterações valvares 2, diminuição da FEVE 2 e derrame pericárdico 2. Todas evoluíram favoravelmente. Conclusões: nesses centros, os primeiros casos de SIMS-Ped S coincidiram com um pico de incidência de COVID-19 no país. As formas pós-infecciosas predominaram em escolares com manifestações digestivas. Este estudo pode contribuir para o reconhecimento desta entidade e adaptar algoritmos nacionais de gestão.

Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines.

BACKGROUND: Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. METHODS: We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. RESULTS: During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. CONCLUSIONS: PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.

Regional Differences in Kawasaki Disease Incidence Reduction Before and After the Onset of the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: To assess regional differences in reduction of the incidence of Kawasaki disease during the mitigation period for the coronavirus disease 2019 pandemic, with a hypothesis that more sparsely populated regions have fewer opportunities for human-to-human contact, resulting in a greater reduction in the incidence of Kawasaki disease. STUDY DESIGN: A retrospective ecological study was conducted using data from patients hospitalized for Kawasaki disease as well as infectious diseases surveillance reports in Shiga Prefecture, Japan, during 2015-2020. We defined the periods before and after the onset of pandemic as January 2015-March 2020 and as April 2020-December 2020, respectively. We compared the reductions in the incidence of Kawasaki disease among 6 administrative regions in the prefecture according to the density of the populations. RESULTS: A total of 1290 patients with Kawasaki disease were identified. The incidence of Kawasaki disease (per 100 000 person-years) was significantly reduced after the coronavirus disease 2019 pandemic onset (period before pandemic onset, 105.6 [95% CI 99.8-111.8]; period after pandemic onset, 68.6 [95% CI 56.7-83.0]). During the period after pandemic onset, the incidence of Kawasaki disease was significantly reduced in May, compared with the corresponding period in previous years. The number of patients aged 2-4 years was significantly reduced after the pandemic onset. Notably, greater reductions in the incidence of Kawasaki disease were found in regions with lower population densities. CONCLUSIONS: Assuming that there were fewer opportunities for human-to-human contact in more sparsely populated regions during the pandemic mitigation period, our findings support the hypothesis that human-to-human contact may be associated with development of Kawasaki disease.

Ambient Air Pollution and Kawasaki Disease in Korean Children: A Study of the National Health Insurance Claim Data.

Background Kawasaki disease (KD) is a systemic vasculitis of unknown etiology that primarily affects children under 5 years of age. Some researchers suggested a potential triggering effect of air pollution on KD, but the findings are inconsistent and limited by small sample size. We investigated the association between ambient air pollution and KD among the population of South Korea younger than 5 years using the National Health Insurance claim data between 2007 and 2019. Methods and Results We obtained the data regarding particulate matter ≤10 or 2.5 µm in diameter, nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone from 235 regulatory monitoring stations. Using a time-stratified case-crossover design, we performed conditional logistic regression to estimate odds ratios (OR) of KD according to interquartile range increases in each air pollutant concentration on the day of fever onset after adjusting for temperature and relative humidity. We identified 51 486 children treated for KD during the study period. An interquartile range increase (14.67 µg/m3) of particulate matter ≤2.5 µm was positively associated with KD at lag 1 (OR, 1.016; 95% CI, 1.004-1.029). An interquartile range increase (2.79 ppb) of sulfur dioxide concentration was associated with KD at all lag days (OR, 1.018; 95% CI, 1.002-1.034 at lag 0; OR, 1.022; 95% CI, 1.005-1.038 at lag 1; OR, 1.017; 95% CI, 1.001-1.033 at lag 2). Results were qualitatively similar in the second scenario of different fever onset, 2-pollutant model and sensitivity analyses. Conclusions In a KD-focused national cohort of children, exposure to particulate matter ≤2.5 µm and sulfur dioxide was positively associated with the risk of KD. This finding supports the triggering role of ambient air pollution in the development of KD.

Prenatal and early life exposure to air pollution and the incidence of Kawasaki disease.

Kawasaki disease (KD) is the most common form of acquired pediatric cardiac disease in the developed world. However, its etiology is still unclear. Epidemiological studies have shown that air pollution is a plausible risk factor in stimulating oxidative stress, inducing inflammation and causing autoimmune diseases. This study aims to assess the connections between prenatal and early life air pollution exposure to the incidence of KD. The main data source of this nationwide longitudinal study was the National Health Insurance Research Database (NHIRD) of Taiwan. NHIRD was linked with Taiwan Maternal and Child Health Database to establish the link between mothers and children. In total, 4192 KD cases involving children under 6 years of age were identified between January 2004 and December 2010. Children in the control group were randomly selected at a 1:4 ratio and matched using their age and index year. Integrated data for the air pollutants were obtained from 71 Environmental Protection Agency monitoring stations across Taiwan. Patients who had main admission diagnosis of KD and subsequently received intravenous immunoglobulin treatment were defined as incidence cases. Ambient exposure, including pollutant standards index (PSI), carbon monoxide (CO), nitric oxide (NO), nitric dioxide (NO2), and nitrogen oxide (NOx) during pregnancy were all positively associated with KD incidence. Conversely, ozone (O3) exposure had a negative correlation. Exposure to CO, NO, NO2, and NOx after childbirth remained consistent with regards to having a positive association with KD incidence. Exposure to PSI and O3 after delivery displayed no significant association with KD. Both prenatal and postnatal cumulative CO, NO, NO2, and NOx exposure had a dose dependent effect towards increasing KD incidence. Certain prenatal and early life air pollutant exposure may increase the incidence of KD.

Kawasaki Disease and Atopic Diseases: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: The etiology of Kawasaki disease (KD), an inflammatory and cardiovascular disorder, remains largely unexplained after more than 50 years of intensive research. In recent years, the association between KD and atopic diseases had been explored by some observational studies. We systematically reviewed and summarized the literature on the relationship between KD and atopic diseases. METHODS: MEDLINE and EMBASE were searched to identify observational studies on the association between KD and atopic diseases from inception to May 2021. Odds ratio (OR) was pooled using random-effects models. Heterogeneity was assessed using the I2 and Cochran Q statistics. Primary outcomes were to compare the prevalence of KD among individuals with atopic diseases to nonatopic disease controls and the prevalence of atopic diseases among individuals with KD to non-KD controls. RESULTS: Thirteen studies, including 12,651 cases and 170,708 controls, were included in this meta-analysis. In cross-sectional studies, KD was associated with allergic rhinitis (n = 6; OR, 1.69; 95% CI, 1.52-1.87), asthma (n = 3; OR, 1.72; 95% CI, 1.38-2.14), allergic conjunctivitis (n = 2; OR, 1.95; 95% CI, 1.68-2.27), and atopic dermatitis (n = 3; OR, 1.35; 95% CI, 1.22-1.49). In case-control and cohort studies, KD was associated with allergic rhinitis (n = 3; OR, 1.35; 95% CI, 1.28-1.43), asthma (n = 8; OR, 1.40; 95% CI, 1.19-1.65), allergic conjunctivitis (n = 1; OR, 1.74; 95% CI, 1.45-2.09), and atopic dermatitis (n = 3; OR, 1.39; 95% CI, 1.26-1.53). CONCLUSION: KD diagnosed was associated with four common atopic diseases. Among the four allergic diseases, allergic conjunctivitis and asthma have the highest correlation with KD, which may provide a direction for exploring the etiology of KD.

MicroRNA-197-3p mediates damage to human coronary artery endothelial cells via targeting TIMP3 in Kawasaki disease.

Kawasaki disease (KD) causes cardiovascular system injury in children. However, the pathogenic mechanisms of KD have not been well defined. Recently, strong correlation between aberrant microRNAs and KD nosogenesis has been revealed. A role of microRNA-197-3p (miR-197-3p) in the pathogenesis of KD is identified in the present study. Cell proliferation assay showed human coronary artery endothelial cells (HCAECs) were suppressed by serum from KD patients, which was correlated with high levels of miR-197-3p in both KD serum and HCAECs cultured with KD serum. The inhibition of HCAECs by miR-197-3p was confirmed by cells expressing miR-197-3p mimic and miR-197-3p inhibitor. Comparative proteomics analysis and Ingenuity Pathway Analysis (IPA) revealed TIMP3 as a potential target of miR-197-3p, which was demonstrated by western blot and dual-luciferase reporter assays. Subsequently, by detecting the endothelium damage markers THBS1, VWF, and HSPG2, the role of miR-197-3p/TIMP3 in KD-induced damage to HCAECs was confirmed, which was further validated by a KD mouse model in vivo. The expressions of miR-197-3p and its target, TIMP3, are dramatically variational in KD serum and HCAECs cultured with KD serum. Increased miR-197-3p induces HCAECs abnormal by restraining TIMP3 expression directly. Hence, dysregulation of miR-197-3p/TIMP3 expression in HCAECs may be an important mechanism in cardiovascular endothelium injury in KD patients, which offers a feasible therapeutic target for KD treatment.

Identifying Circulating MicroRNA in Kawasaki Disease by Next-Generation Sequencing Approach.

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs; therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes >2 and <0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-ß, epithelial-mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p < 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.

Associations between the spatiotemporal distribution of Kawasaki disease and environmental factors: evidence supporting a multifactorial etiologic model.

The etiology of Kawasaki Disease (KD), the most common cause of acquired heart disease in children in developed countries, remains elusive, but could be multifactorial in nature as suggested by the numerous environmental and infectious exposures that have previously been linked to its epidemiology. There is still a lack of a comprehensive model describing these complex associations. We present a Bayesian disease model that provides insight in the spatiotemporal distribution of KD in Canada from 2004 to 2017. The disease model including environmental factors had improved Watanabe-Akaike information criterion (WAIC) compared to the base model which included only spatiotemporal and demographic effects and had excellent performance in recapitulating the spatiotemporal distribution of KD in Canada (98% and 86% spatial and temporal correlations, respectively). The model suggests an association between the distribution of KD and population composition, weather-related factors, aeroallergen exposure, pollution, atmospheric concentration of spores and algae, and the incidence of healthcare encounters for bacterial pneumonia or viral intestinal infections. This model could be the basis of a hypothetical data-driven framework for the spatiotemporal distribution of KD. It also generates novel hypotheses about the etiology of KD, and provides a basis for the future development of a predictive and surveillance model.

Exposures associated with the onset of Kawasaki disease in infancy from the Japan Environment and Children's Study.

Kawasaki disease (KD) is an acute systemic vasculitis that mainly affects infants and young children. The etiology of KD has been discussed for several decades; however, no reproducible risk factors have yet been proven. We used the Japan Environment and Children's Study data to explore the association between the causal effects of exposure during the fetal and neonatal periods and KD onset. The Japan Environment and Children's Study, a nationwide birth cohort study, has followed approximately 100,000 children since 2011. We obtained data on exposures and outcomes from the first trimester to 12 months after birth. Finally, we included 90,486 children who were followed for 12 months. Among them, 343 children developed KD. Multivariate logistic regression revealed that insufficient intake of folic acid during pregnancy (odds ratio [OR], 1.37; 95% CI 1.08-1.74), maternal thyroid disease during pregnancy (OR, 2.03; 95% CI 1.04-3.94), and presence of siblings (OR, 1.33; 95% CI 1.06-1.67) were associated with KD onset in infancy. In this study, we identified three exposures as risk factors for KD. Further well-designed studies are needed to confirm a causal relationship between these exposures and KD onset.

A case report of atypical Kawasaki disease presented with severe elevated transaminases and literature review.

BACKGROUND: Kawasaki disease (KD) is the most common cause of acquired heart disease among children in developed countries, in which the resulting coronary artery (CA) abnormalities cause myocardial ischemia, infarction, and death. Prompt diagnosis was essential, and supplemental information should be used to assist the diagnosis when classical clinical criteria are incomplete. The elevated levels of serum transaminases in most KD patients are mild. Herein, a case of atypical KD child with severely elevated transaminase was reported. CASE PRESENTATION: A child with clinical manifestations of fever, high C-reactive protein (CRP) and severely elevated transaminases was reported. The treatment effect of antibiotic and liver-protecting drugs was not satisfactory. A bilateral diffuse dilation of the CA was detected on echocardiography on day 5 of the illness; thus, atypical KD was diagnosed. Elevated transaminases declined rapidly to normal after the treatment of intravenous immunoglobulin (IVIG). A 1-month follow-up revealed that CA returned to normal, and 2-month, 6-months, and 1-year follow-up revealed the child was in good general health. CONCLUSIONS: This case highlighted that atypical KD clinical symptoms were diverse, and severely elevated transaminases might provide a clue to healthcare providers for the diagnosis and management of atypical KD.

Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis.

Objective: Kawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD. Methods: Vasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development. Results: STAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development. Conclusion: Proteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.

Children with Kawasaki disease or Kawasaki-like syndrome (MIS-C/PIMS) at the time of COVID-19: are they all the same? Case series and literature review.

Since the coronavirus disease 2019 (COVID-19) outbreak started, children have been considered marginally involved compared to adults, with a quite significant percentage of asymptomatic carriers. Very recently, an overwhelming inflammatory activation, which shares clinical similarities with Kawasaki disease (KD), has been described in children exposed to COVID-19. We report three KD-like cases that occurred during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a highly affected area of Northern Italy. The clinical presentation was characterized by the presence of unremitting fever, diarrhea and elevated inflammatory markers. Case #1 and Case #2 occurred one week apart and shared other clinical features: laboratory tests confirmed COVID-19 exposure and high inflammatory activation with myocardial involvement. Case #3 followed a more typical pattern for KD. Interestingly, this patient showed lower levels of procalcitonin, C-reactive protein, D-dimers, and ferritin compared to the other two cases, whereas platelet count was higher. We hypothesize that SARS-CoV-2 might act in children as a trigger, either inducing a classical KD phenotype or causing a systemic inflammatory response leading to a severe KD-like phenotype, eventually characterized by myocardial impairment. We think that bringing these cases and their differences to the attention of the rheumatology community during the COVID-19 pandemic will be beneficial in order to highlight the importance of early diagnosis and to increase awareness of this new phenomenon.

SARS-CoV-2 infection triggering recurrence of Kawasaki disease in a 10-year-old child.

SARS-CoV-2 infection has recently been related to a spectrum of hyper-inflammatory states in children. There is a striking similarity between these hyper-inflammatory states and Kawasaki disease (KD). We present an interesting case of KD recurrence in a 10-year-old child, who had previously developed KD at 4 years of age. His symptoms included fever, maculopapular rash and altered sensorium. Investigations showed noticeably elevated inflammatory markers, and an echocardiography revealed dilated coronary arteries. SARS-CoV-2 IgG antibodies were positive. The child responded dramatically to intravenous immunoglobulin and intravenous methylprednisolone. It is possible that SARS-CoV-2 infection triggered the recurrence of KD in this child who might have been genetically predisposed to KD.