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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 = 0.98]. We further extended this methodology into a multiclass machine learning framework that achieved 80% 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., Competing Interests: Competing interests statement:C.J.L and I.D.V are inventors on submitted patents pertaining to cell-free nucleic acids (US patent applications 63/237,367 and 63/429,733). I.D.V. is listed as an inventor on submitted patents pertaining to cell-free nucleic acids (US patent applications 63/237,367, 63/056,249, 63/015,095, 16/500,929, 41614P-10551-01-US) and receives consulting fees from Eurofins Viracor. C.A.R. has received institutional support from ModernaTX, Inc., Pfizer Inc., BioFire Inc., GSK plc, MedImmune, Micron Technology Inc., Janssen Pharmaceuticals, Merck & Co., Inc., Novavax, PaxVax, Regeneron, and Sanofi Pasteur. She is co-inventor of patented RSV vaccine technology which has been licensed to Meissa Vaccines, Inc. C.Y.C. receives grant funding for research unrelated to this work from the Bay Area Lyme Disease Foundation, the Chan-Zuckerberg Biohub, and Abbott Laboratories, Inc.

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.

Background: About 10-20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features., Methods: Data were from two cohorts: a Korean cohort of 7101 KD patients from 2015 to 2017 and a cohort of 649 KD patients from San Diego enrolled from 1998 to 2021. Features included laboratory values, the worst Z-score from the initial echocardiogram or during hospitalization, and the five clinical KD signs at presentation., Results: Five machine learning models achieved a maximum median AUC of 0.711 [IQR: 0.706-0.72] in the Korean cohort and 0.696 [IQR: 0.609-0.722] in the San Diego cohort during stratified 10-fold cross-validation using significant laboratory features identified from univariate analysis. Adding the Z-score, KD clinical signs, or both did not considerably improve the median AUC in either cohort., Conclusions: Using commonly measured clinical laboratory data alone or in conjunction with echocardiographic findings and clinical features is not sufficient to predict IVIG resistance. Further attempts to predict IVIG resistance will need to incorporate additional data such as transcriptomics, proteomics, and genetics to achieve meaningful predictive utility., Impact: We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD). Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner. Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful., (© 2023. The Author(s).)

Background: Although Kawasaki disease is commonly regarded as a single disease entity, variability in clinical manifestations and disease outcome has been recognised. We aimed to use a data-driven approach to identify clinical subgroups., Methods: We analysed clinical data from patients with Kawasaki disease diagnosed at Rady Children's Hospital (San Diego, CA, USA) between Jan 1, 2002, and June 30, 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables, including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin infusion, and normalised echocardiographic measures of coronary artery diameters at diagnosis. We also analysed the seasonality and Kawasaki disease incidence from 2002 to 2019 by subgroup. To explore the biological underpinnings of identified subgroups, we did differential abundance analysis on proteomic data of 6481 proteins from 32 patients with Kawasaki disease and 24 healthy children, using linear regression models that controlled for age and sex., Findings: Among 1016 patients with complete data in the final analysis, four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase, and total bilirubin levels, lowest coronary artery aneurysm but highest intravenous immunoglobulin resistance rates (n=157); (2) highest band neutrophil count and Kawasaki disease shock rate (n=231); (3) cervical lymphadenopathy with high markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, white blood cell, and platelet counts) and lowest age-adjusted haemoglobin Z scores (n=315); and (4) young age at onset with highest coronary artery aneurysm but lowest intravenous immunoglobulin resistance rates (n=313). The subgroups had distinct seasonal and incidence trajectories. In addition, the subgroups shared 211 differential abundance proteins while many proteins were unique to a subgroup., Interpretation: Our data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation., Funding: US National Institutes of Health and the Irving and Francine Suknow Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Current treatments for patients with coronary aneurysms caused by Kawasaki disease (KD) are based primarily on aneurysm size. This ignores hemodynamic factors influencing myocardial ischemic risk. We performed patient-specific computational hemodynamics simulations for 15 KD patients, with parameters tuned to patients' arterial pressure and cardiac function. Ischemic risk was evaluated in 153 coronary arteries from simulated fractional flow reserve (FFR), wall shear stress, and residence time. FFR correlated weakly with aneurysm [Formula: see text]-scores (correlation coefficient, [Formula: see text]) but correlated better with the ratio of maximum-to-minimum aneurysmal lumen diameter ([Formula: see text]). FFR dropped more rapidly distal to aneurysms, and this correlated more with the lumen diameter ratio ([Formula: see text]) than [Formula: see text]-score ([Formula: see text]). Wall shear stress correlated better with the diameter ratio ([Formula: see text]), while residence time correlated more with [Formula: see text]-score ([Formula: see text]). Overall, the maximum-to-minimum diameter ratio predicted ischemic risk better than [Formula: see text]-score. Although FFR immediately distal to aneurysms was nonsignificant, its rapid rate of decrease suggests elevated risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Children with Kawasaki disease (KD) and an initial echocardiogram that demonstrates coronary artery aneurysms (CAAs, Z score ≥2.5) are at high risk for severe cardiovascular complications. We sought to determine if primary adjunctive infliximab treatment at a dose of either 5 or 10 mg/kg, compared with intravenous immunoglobulin (IVIG) alone, is associated with a greater likelihood of CAA regression in patients with KD with CAA at the time of diagnosis., Design and Setting: Single-centre observational study., Patients: Children with acute KD and Z score ≥2.5 at baseline., Interventions: Primary adjunctive infliximab (5 or 10 mg/kg) within 48 hours of initiating IVIG 2 g/kg., Main Outcome Measures: Incidence of CAA regression to Zmax <2 within 2 months of disease onset., Results: Of the 168 patients with KD, 111 received IVIG alone and 57 received primary adjunctive infliximab therapy: 39 received 5 mg/kg and 18 received 10 mg/kg. Incidence of CAA regression to Zmax <2 within 2 months was statistically significant at 52%, 62% and 83% in the IVIG alone, IVIG+infliximab 5 mg/kg and IVIG+infliximab 10 mg/kg, respectively. The multivariable logistic regression model adjusting for age, sex, baseline Zmax and bilateral CAA at baseline showed that IVIG plus 10 mg/kg infliximab was significantly associated with a greater likelihood of CAA regression (adjusted OR: 4.45, 95% CI 1.17 to 16.89, p=0.028) compared with IVIG alone. The difference between IVIG+infliximab 5 mg/kg and IVIG alone was not significant., Conclusions: Primary adjunctive high-dose 10 mg/kg infliximab treatment was associated with a greater likelihood of CAA regression in patients with CAA at the time of diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share some clinical manifestations, their cardiovascular outcomes are different, and this may be reflected at the level of the endothelial cell (EC). We performed RNA-seq on cultured ECs incubated with pre-treatment sera from KD ( n = 5), MIS-C ( n = 7), and healthy controls ( n = 3). We conducted a weighted gene co-expression network analysis (WGCNA) using 935 transcripts differentially expressed between MIS-C and KD using relaxed filtering (unadjusted p < 0.05, >1.1-fold difference). We found seven gene modules in MIS-C, annotated as an increased TNFα/NFκB pathway, decreased EC homeostasis, anti-inflammation and immune response, translation, and glucocorticoid responsive genes and endothelial-mesenchymal transition (EndoMT). To further understand the difference in the EC response between MIS-C and KD, stringent filtering was applied to identify 41 differentially expressed genes (DEGs) between MIS-C and KD (adjusted p < 0.05, >2-fold-difference). Again, in MIS-C, NFκB pathway genes, including nine pro-survival genes, were upregulated. The expression levels were higher in the genes influencing autophagy ( UBD , EBI3 , and SQSTM1 ). Other DEGs also supported the finding by WGCNA. Compared to KD, ECs in MIS-C had increased pro-survival transcripts but reduced transcripts related to EndoMT and EC homeostasis. These differences in the EC response may influence the different cardiovascular outcomes in these two diseases.

Kawasaki disease (KD) is a leading cause of acquired heart disease in children and is characterized by the presence of a combination of five clinical signs assessed during the physical examination. Timely treatment of intravenous immunoglobin is needed to prevent coronary artery aneurysm formation, but KD is usually diagnosed when pediatric patients are evaluated by a clinician in the emergency department days after onset. One or more of the five clinical signs usually manifests in pediatric patients prior to ED admission, presenting an opportunity for earlier intervention if families receive guidance to seek medical care as soon as clinical signs are observed along with a fever for at least five days. We present a deep learning framework for a novel screening tool to calculate the relative risk of KD by analyzing images of the five clinical signs. The framework consists of convolutional neural networks to separately calculate the risk for each clinical sign, and a new algorithm to determine what clinical sign is in an image. We achieved a mean accuracy of 90% during 10-fold cross-validation and 88% during external validation for the new algorithm. These results demonstrate the algorithms in the proposed screening tool can be utilized by families to determine if their child should be evaluated by a clinician based on the number of clinical signs consistent with KD.Clinical Relevance- This screening framework has the potential for earlier clinical evaluation and detection of KD to reduce the risk of coronary artery complications.

Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections., Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39)., Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV., Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Multisystem inflammatory syndrome in children (MIS-C) is a novel disease identified during the COVID-19 pandemic that may lead to cardiac dysfunction or death in pediatric patients. Early detection of MIS-C remains a challenge given the lack of a diagnostic test and its clinical similarities to Kawasaki disease (KD) and other acute childhood illnesses. We developed and validated the KawasakI Disease vs Multisystem InflAmmaTory syndrome in CHildren (KIDMATCH) clinical decision support tool for screening patients for MIS-C, KD, or other febrile illnesses. Here we describe the implementation and iterative refinement of KIDMATCH with provider feedback as a web calculator in the clinical workflow within Rady Children's Hospital. Our findings demonstrate KIDMATCH and its underlying artificial intelligence model have clinical utility in aiding clinicians at the time of initial evaluation within the hospital setting to distinguish patients who have MIS-C, KD, or other febrile illnesses., (©2022 AMIA - All rights reserved.)

Background: Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier., Methods: We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier., Results: The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections., Conclusion: We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory., Impact: A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory., (© 2022. The Author(s).)

The most significant sequelae of Kawasaki disease (KD) are coronary artery aneurysms, which can lead to risk of future myocardial ischemia. Exercise stress echocardiography allows for non-invasive assessment of myocardial dysfunction. We reviewed our single center experience with exercise stress echocardiography in patients with previous history of KD with coronary aneurysms. We reviewed the records of 53 KD patients who underwent exercise stress echocardiography from 2000 to 2020. Abnormal stress echocardiograms were defined as those showing no increase in biventricular systolic function post-exercise or regional wall motion abnormalities. Computed tomography angiography and cardiac magnetic resonance imaging were reviewed for patients with abnormal stress echocardiograms. Clinical data were reviewed and correlated with stress echocardiogram results. Of the 53 patients, three (5.7%) had an abnormal exercise stress echocardiogram. All three patients were classified as AHA Risk Level 4 or 5 by coronary Z-score (internal dimension normalized for body surface area) and were confirmed to have coronary aneurysms, stenosis, or myocardial tissue perfusion defects on advanced cardiac imaging that could account for the results seen on stress echocardiogram. Exercise stress echocardiography detected signs of myocardial ischemia in a subset of high-risk patients with Kawasaki disease and coronary aneurysms and may be considered as a useful screening tool for this complex patient cohort., (© 2022. The Author(s).)

Background: Kawasaki disease (KD) disproportionately affects children of Asian descent. San Diego is home to a large Vietnamese population but no previous study has addressed the outcome of KD in this group., Methods: We performed a retrospective review of Vietnamese patients seen at Rady Children's Hospital San Diego from 2001 to 2019. Non-Vietnamese Asian and non-Asian KD patients were matched (2:1) based on date of onset and age with Vietnamese patients. Demographic, clinical, and echocardiographic data were compared. Interviews with cardiologists at the Children's Hospital 1 in Ho Chi Minh City, Vietnam, explored local practices in the diagnosis and management of KD patients. KD publications in Vietnamese were translated and summarized., Results: Of 978 KD patients for whom both parents had the same ethnicity, 20 were Vietnamese (2.1%), 168 (17%) were non-Vietnamese Asian, and 789 (81%) were non-Asian. Vietnamese and non-Vietnamese Asians had an earlier median day of diagnosis at day 6 (interquartile range [IQR] 5-6) and 5.5 (IQR 4-6.75), respectively, compared with non-Asians (day 7, IQR 5-8.75, P = 0.02). Prominent cervical lymphadenopathy at diagnosis was more common in both Vietnamese and non-Vietnamese Asians (20% and 40%, respectively) compared with non-Asians (12.5%, P = 0.01). Importantly, Vietnamese KD patients had a higher rate of coronary artery aneurysms (60% vs. 27.5%) compared to non-Asians (P = 0.024). Vietnamese literature review and structured interviews suggested a high incidence and severity of KD in Vietnamese children., Conclusions: Physicians should be aware that Vietnamese children may be disproportionately affected by KD and have worse coronary artery outcomes., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Kawasaki disease (KD) is the leading cause of acquired heart disease in children. The major challenge in KD diagnosis is that it shares clinical signs with other childhood febrile control (FC) subjects. We sought to determine if our algorithmic approach applied to a Taiwan cohort., Methods: A single center (Chang Gung Memorial Hospital in Taiwan) cohort of patients suspected with acute KD were prospectively enrolled by local KD specialists for KD analysis. Our previously single-center developed computer-based two-step algorithm was further tested by a five-center validation in US. This first blinded multi-center trial validated our approach, with sufficient sensitivity and positive predictive value, to identify most patients with KD diagnosed at centers across the US. This study involved 418 KDs and 259 FCs from the Chang Gung Memorial Hospital in Taiwan., Findings: Our diagnostic algorithm retained sensitivity (379 of 418; 90.7%), specificity (223 of 259; 86.1%), PPV (379 of 409; 92.7%), and NPV (223 of 247; 90.3%) comparable to previous US 2016 single center and US 2020 fiver center results. Only 4.7% (15 of 418) of KD and 2.3% (6 of 259) of FC patients were identified as indeterminate. The algorithm identified 18 of 50 (36%) KD patients who presented 2 or 3 principal criteria. Of 418 KD patients, 157 were infants younger than one year and 89.2% (140 of 157) were classified correctly. Of the 44 patients with KD who had coronary artery abnormalities, our diagnostic algorithm correctly identified 43 (97.7%) including all patients with dilated coronary artery but one who found to resolve in 8 weeks., Interpretation: This work demonstrates the applicability of our algorithmic approach and diagnostic portability in Taiwan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuo, Hao, Jin, Chou, Han, Chang, Huang, Hwa, Whitin, Sylvester, Reddy, Chubb, Ceresnak, Kanegaye, Tremoulet, Burns, McElhinney, Cohen and Ling.)

Background: Multisystem inflammatory syndrome in children (MIS-C) is a novel disease that was identified during the COVID-19 pandemic and is characterised by systemic inflammation following SARS-CoV-2 infection. Early detection of MIS-C is a challenge given its clinical similarities to Kawasaki disease and other acute febrile childhood illnesses. We aimed to develop and validate an artificial intelligence algorithm that can distinguish among MIS-C, Kawasaki disease, and other similar febrile illnesses and aid in the diagnosis of patients in the emergency department and acute care setting., Methods: In this retrospective model development and validation study, we developed a deep-learning algorithm called KIDMATCH (Kawasaki Disease vs Multisystem Inflammatory Syndrome in Children) using patient age, the five classic clinical Kawasaki disease signs, and 17 laboratory measurements. All features were prospectively collected at the time of initial evaluation from patients diagnosed with Kawasaki disease or other febrile illness between Jan 1, 2009, and Dec 31, 2019, at Rady Children's Hospital in San Diego (CA, USA). For patients with MIS-C, the same data were collected from patients between May 7, 2020, and July 20, 2021, at Rady Children's Hospital, Connecticut Children's Medical Center in Hartford (CT, USA), and Children's Hospital Los Angeles (CA, USA). We trained a two-stage model consisting of feedforward neural networks to distinguish between patients with MIS-C and those without and then those with Kawasaki disease and other febrile illnesses. After internally validating the algorithm using stratified tenfold cross-validation, we incorporated a conformal prediction framework to tag patients with erroneous data or distribution shifts. We finally externally validated KIDMATCH on patients with MIS-C enrolled between April 22, 2020, and July 21, 2021, from Boston Children's Hospital (MA, USA), Children's National Hospital (Washington, DC, USA), and the CHARMS Study Group consortium of 14 US hospitals., Findings: 1517 patients diagnosed at Rady Children's Hospital between Jan 1, 2009, and June 7, 2021, with MIS-C (n=69), Kawasaki disease (n=775), or other febrile illnesses (n=673) were identified for internal validation, with an additional 16 patients with MIS-C included from Connecticut Children's Medical Center and 50 from Children's Hospital Los Angeles between May 7, 2020, and July 20, 2021. KIDMATCH achieved a median area under the receiver operating characteristic curve during internal validation of 98·8% (IQR 98·0-99·3) in the first stage and 96·0% (95·6-97·2) in the second stage. We externally validated KIDMATCH on 175 patients with MIS-C from Boston Children's Hospital (n=50), Children's National Hospital (n=42), and the CHARMS Study Group consortium of 14 US hospitals (n=83). External validation of KIDMATCH on patients with MIS-C correctly classified 76 of 81 patients (94% accuracy, two rejected by conformal prediction) from 14 hospitals in the CHARMS Study Group consortium, 47 of 49 patients (96% accuracy, one rejected by conformal prediction) from Boston Children's Hospital, and 36 of 40 patients (90% accuracy, two rejected by conformal prediction) from Children's National Hospital., Interpretation: KIDMATCH has the potential to aid front-line clinicians to distinguish between MIS-C, Kawasaki disease, and other similar febrile illnesses to allow prompt treatment and prevent severe complications., Funding: US Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Heart, Lung, and Blood Institute, US Patient-Centered Outcomes Research Institute, US National Library of Medicine, the McCance Foundation, and the Gordon and Marilyn Macklin Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background Damage to the coronary arteries during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myointimal proliferation, and endothelial cell (EC) dysfunction. To understand the response of ECs to KD treatment, we studied the genome-wide transcriptional changes in cultured ECs incubated with KD sera before and after treatment with or without atorvastatin. Methods and Results RNA sequencing of human umbilical vein ECs incubated with pooled sera from patients with acute KD before or after treatment with intravenous immunoglobulin and infliximab revealed differentially expressed genes in interleukin-1, tumor necrosis factor-α, and inflammatory cell recruitment pathways. Subacute sera pooled from patients treated with intravenous immunoglobulin, infliximab, and atorvastatin uniquely induced expression of NOS3 , Kruppel like factor ( KLF2 , and KLF4 (promotes EC homeostasis and angiogenesis) and ZFP36 ring finger protein (ZFP36) and suppressor of cytokine signaling 3 (SOCS3) (suppresses inflammation), and suppressed expression of TGFB2 and DKK1 (induces endothelial-mesenchymal transition) and sphingosine kinase 1 (SPHK1) and C-X-C motif chemokine ligand 8 (CXCL8) (induces inflammation). Conclusions These results suggest that atorvastatin treatment of patients with acute KD may improve EC health, reduce mediators of inflammation produced by ECs, and block KD-induced myofibroblast proliferation.

Intravenous immunoglobulin (IVIG) is used as an immunomodulatory agent in many inflammatory conditions including Multisystem Inflammatory Syndrome-Children (MIS-C) and Kawasaki disease (KD). However, the exact mechanisms underlying its anti-inflammatory action are incompletely characterized. Here, we show that in KD, a pediatric acute vasculitis that affects the coronary arteries, IVIG induces a repertoire of natural Treg that recognize immunodominant peptides in the Fc heavy chain constant region. To address which antigen-presenting cell (APC) populations present Fc peptides to Treg, we studied the uptake of IgG by innate cells in subacute KD patients 2 weeks after IVIG and in children 1.6-14 years after KD. Healthy adults served as controls. IgG at high concentrations was internalized predominantly by two myeloid dendritic cell (DC) lineages, CD14+ cDC2 and ILT-4+ CD4+ tmDC mostly through Fcγ receptor (R) II and to a lesser extent FcγRIII. Following IgG internalization, these two DC lineages secreted IL-10 and presented processed Fc peptides to Treg. The validation of IVIG function in expanding Fc-specific Treg presented by CD14+ cDC2 and ILT-4+ CD4+ tmDC was addressed in a small cohort of patients with MIS-C. Taken together, these results suggest a novel immune regulatory function of IgG in activating tolerogenic innate cells and expanding Treg, which reveals an important anti-inflammatory mechanism of action of IVIG., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Importance: Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology., Objectives: To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD., Design, Setting, and Participants: This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children's Hospital San Diego [RCHSD])., Main Outcomes and Measures: For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence., Results: A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates., Conclusions and Relevance: In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

Multisystem inflammatory syndrome in children (MIS-C) is an illness that emerged amidst the COVID-19 pandemic but shares many clinical features with the pre-pandemic syndrome of Kawasaki disease (KD). Here we compare the two syndromes using a computational toolbox of two gene signatures that were developed in the context of SARS-CoV-2 infection, i.e., the viral pandemic (ViP) and severe-ViP signatures and a 13-transcript signature previously demonstrated to be diagnostic for KD, and validated our findings in whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues. Results show that KD and MIS-C are on the same continuum of the host immune response as COVID-19. Both the pediatric syndromes converge upon an IL15/IL15RA-centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis; however, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures reveal unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity., (© 2022. The Author(s).)

Objectives: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA)., Study Design: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy., Results: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing., Conclusions: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The immunopathogenesis of multisystem inflammatory syndrome (MIS-C) in children that may follow exposure to SARS-CoV-2 is incompletely understood. Here, we studied SARS-CoV-2-specific T cells in MIS-C, Kawasaki disease (KD), and SARS-CoV-2 convalescent controls using peptide pools derived from SARS-CoV-2 spike or nonspike proteins, and common cold coronaviruses (CCC). Coordinated CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in five MIS-C subjects with cross-reactivity to CCC. CD4+ and CD8+ T-cell responses alone were documented in three and one subjects, respectively. T-cell specificities in MIS-C did not correlate with disease severity and were similar to SARS-CoV-2 convalescent controls. T-cell memory and cross-reactivity to CCC in MIS-C and SARS-CoV-2 convalescent controls were also similar. The chemokine receptor CCR6, but not CCR9, was highly expressed on SARS-CoV-2-specific CD4+ but not on CD8+ T cells. Only two of 10 KD subjects showed a T-cell response to CCC. Enumeration of myeloid APCs revealed low cell precursors in MIS-C subjects compared to KD. In summary, children with MIS-C mount a normal T-cell response to SARS-CoV-2 with no apparent relationship to antecedent CCC exposure. Low numbers of tolerogenic myeloid DCs may impair their anti-inflammatory response., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Background: Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease., Methods: In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244., Findings: Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only., Interpretation: Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion., Funding: Patient Centered Outcomes Research Institute., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13., (© 2021. The Author(s).)

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD., (© 2021. The Author(s).)

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient., Competing Interests: The authors have declared that no competing interests exist.

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host 'omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple 'omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of 'omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both 'omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both 'omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.

We present a case in which emergency medical services (EMS) intervened on a critically ill child with known giant coronary aneurysms as sequela to her severe complicated Kawasaki disease. This patient's severe shock ultimately ended in cardiac arrest and death. We discuss the keys to recognition, and critical importance to early intervention of pediatric shock in prehospital care. We also detail the cardiac ramifications of Kawasaki disease, steps for prompt identification of high risk complaints in these patients, and opportunities for treatment.

In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) for long-term management are defined by both maximal and current coronary artery (CA) dimensions normalized as z-scores. We sought to determine the degree to which current recommended practice differs from past actual practice, highlighting areas for knowledge translation efforts. The International KD Registry (IKDR) included 1651 patients with CA aneurysms (z-score > 2.5) from 1999 to 2016. Patients were classified by AHA RL using maximum CA z-score (RL 3 = small, RL 4 = medium, RL 5 = large/giant) and subcategorized based on decreases over time. Medical management provided was compared to recommendations. Low-dose acetylsalicylic acid (ASA) use ranged from 86 (RL 3.1) to 95% (RL 5.1) for RLs where use was "indicated." Dual antiplatelet therapy (ASA + clopidogrel) use ranged from 16% for RL 5.2 to 9% for RL 5.4. Recommended anticoagulation (warfarin or low molecular weight heparin) use was 65% for RL 5.1, while 12% were on triple therapy (anticoagulation + dual antiplatelet). Optional statin use ranged from 2 to 8% depending on RL. Optional beta-blocker use was 2-25% for RL 5, and 0-5% for RLs 3 and 4 where it is not recommended. Generally, past practice was consistent with the latest AHA guidelines, taking into account the flexible wording of recommendations based on the limited evidence, as well as unmeasured patient-specific factors. In addition to strengthening the overall evidence base, knowledge translation efforts may be needed to address variation in thromboprophylaxis management.

Objective: To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters., Study Design: We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-year period (2002-2019) from a single clinical site and compared the cluster characteristics with those of 2 control groups of synthetic Kawasaki disease clusters. We defined a "true" Kawasaki disease cluster as at least 5 patients within a 7-day moving window. The observed and synthetic Kawasaki disease clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis., Results: In a univariate analysis, the median values for age, coronary artery z-score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true Kawasaki disease clusters exceeded the 95th percentile for the 2 synthetic clusters. REOF analyses revealed distinct patterns of demographic and clinical measures within clusters., Conclusions: Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensities of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of Kawasaki disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical features of Kawasaki disease (KD) display overlap with common pediatric viral illnesses, leading some to hypothesize that a viral infection is the inciting event for KD. To investigate viral infection history in KD patients, we performed comprehensive serological profiling using a high-throughput phage immunoprecipitation sequencing assay covering the complete reference protein sequences of known viruses with human tropism. KD and matched febrile control sera did not demonstrate differences in antiviral antibody profiles. We conclude that in the acute and subacute phases of disease, KD patients do not exhibit serologic evidence of exposure to known viruses that differs from controls., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The clinical features of Kawasaki disease (KD) overlap with those of other paediatric febrile illnesses. A missed or delayed diagnosis increases the risk of coronary artery damage. Our computer algorithm for KD and febrile illness differentiation had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 94.8%, 70.8%, 93.7% and 98.3%, respectively, in a single-centre validation study. We sought to determine the performance of this algorithm with febrile children from multiple institutions across the USA., Methods: We used our previously published 18-variable panel that includes illness day, the five KD clinical criteria and readily available laboratory values. We applied this two-step algorithm using a linear discriminant analysis-based clinical model followed by a random forest-based algorithm to a cohort of 1059 acute KD and 282 febrile control patients from five children's hospitals across the USA., Results: The algorithm correctly classified 970 of 1059 patients with KD and 163 of 282 febrile controls resulting in a sensitivity of 91.6%, specificity of 57.8% and PPV and NPV of 95.4% and 93.1%, respectively. The algorithm also correctly identified 218 of the 232 KD patients (94.0%) with abnormal echocardiograms., Interpretation: The expectation is that the predictive accuracy of the algorithm will be reduced in a real-world setting in which patients with KD are rare and febrile controls are common. However, the results of the current analysis suggest that this algorithm warrants a prospective, multicentre study to evaluate its potential utility as a physician support tool., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Kawasaki disease (KD) is an inflammatory disorder of young children, associated with vasculitis of the coronary arteries with subsequent aneurysm formation in up to one-third of untreated patients. Those who develop aneurysms are at life-long risk of coronary thrombosis or the development of stenotic lesions, which may lead to myocardial ischaemia, infarction or death. The incidence of KD is increasing worldwide, and in more economically developed countries, KD is now the most common cause of acquired heart disease in children. However, many clinicians in the UK are unaware of the disorder and its long-term cardiac complications, potentially leading to late diagnosis, delayed treatment and poorer outcomes. Increasing numbers of patients who suffered KD in childhood are transitioning to the care of adult services where there is significantly less awareness and experience of the condition than in paediatric services. The aim of this document is to provide guidance on the long-term management of patients who have vascular complications of KD and guidance on the emergency management of acute coronary complications. Guidance on the management of acute KD is published elsewhere., Competing Interests: Competing interests: PB has received institutional grants from SOBI, Roche, Novartis and Novimmune and consultancy fees from SOBI, Novartis, Roche and UCB. RMRT has received grants and speaker fees from Actelion, Abbvie, GSK, Bayer, Pfizer, Jansen. Societi Foundation (RMcC) has received grants from SOBI and Roche., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Coronary artery aneurysms and myocarditis are well-recognized complications of Kawasaki disease (KD) but no systematic evaluation of the consequences of myocarditis has been performed in the subset presenting with low ejection fraction (EF). We postulated that more severe myocardial inflammation as evidenced by low EF during the acute phase could lead to late myocardial fibrosis. Methods and Results We measured the carboxyterminal propeptide of procollagen type I (PIPC), soluble suppressor of tumorigenicity 2, galectin-3 (Gal-3), growth-differentiation factor-15, and calprotectin by ELISA in late convalescent blood samples from 16 KD patients who had an EF ≤55% on their initial echocardiogram. Results were compared with samples from sex- and age-matched KD patients with initial EF >60%. In the univariate analysis, the median Gal-3 and PIPC levels in the low EF group were significantly higher than those in the normal EF group (Gal-3: low EF 6.216 versus normal EF 4.976 mg/dL P =0.038, PIPC: low EF 427.4 versus normal EF 265.2 mg/dL, P =0.01). In a multivariable analysis, there were significant differences for Gal-3 and PIPC levels between the low and normal EF groups, adjusting for age, sex, and worst z score. Conclusions Convalescent KD patients with a history of low EF during the acute illness had significantly elevated levels of Gal-3 and PIPC when compared with matched-control KD patients with normal EF. These findings raise concern for myocardial fibrosis as a potential late sequela of the more severe myocarditis experienced by a subset of KD patients during the acute phase.

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.

Objectives: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA)., Study Design: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment., Results: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls., Conclusions: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.)

Background Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction. Methods and Results A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8 weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer-Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8 weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age <6 months, Asian race, and C-reactive protein ≥13 mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low- (0-1), moderate- (2), and high- (3-5) risk groups. The odds of CAA s were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71-27.7 [ P<0.001]), and >40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8-180 [ P<0.001]). Conclusions Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing.

Background: Coronary artery aneurysms (CAA) are a serious complication of Kawasaki disease. Treatment with intravenous immunoglobulin (IVIg) within 10 days of fever onset reduces the risk of CAA from 25% to <5%. Corticosteroids and infliximab are often used in high-risk patients or those with CAA at diagnosis, but there are no data on their longer-term impact on CAA., Methods: Retrospective multicenter study including children who had CAA with a z score ≥2.5 and <10 at time of diagnosis and who received primary therapy with IVIg alone or in combination with either corticosteroids or infliximab within 10 days of onset of fever., Results: Of 121 children, with a median age of 2.8 (range 0.1-15.5) years, 30 (25%) received primary therapy with corticosteroids and IVIg, 58 (48%) received primary therapy with infliximab and IVIg, and 33 (27%) received primary therapy with IVIg only. Median coronary z scores at the time of diagnosis did not differ among treatment groups ( P = .39). Primary treatment intensification with either corticosteroids or infliximab were independent protective factors against progression of coronary size on follow-up (coefficient: -1.31 [95% confidence interval: -2.33 to -0.29]; coefficient: -1.07 [95% confidence interval: -1.95 to -0.19], respectively)., Conclusions: Among a high-risk group of patients with Kawasaki disease with CAA on baseline echocardiography, those treated with corticosteroids or infliximab in addition to IVIg had less progression in CAA size compared with those treated with IVIg alone. Prospective randomized trials are needed to determine the best adjunctive treatment of patients who present with CAA., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Friedman has served as a paid expert witness in cases of missed diagnosis of Kawasaki disease (unrelated to the current study); the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)