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

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or Long COVID) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIHs REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

The hypercoagulable state in Kawasaki disease (KD) may lead to complex cardiovascular sequelae. We present the case of a 2-month-old infant with complete KD complicated by giant coronary artery aneurysms, coronary sinus thrombosis, and post-myocardial infarction syndrome (Dressler syndrome), resulting in 2 distinct episodes of pericardial effusion. (Level of Difficulty: Intermediate.).

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 Childrens 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.

ObjectiveChildren 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 settingSingle-centre observational study.PatientsChildren with acute KD and Z score ≥2.5 at baseline.InterventionsPrimary adjunctive infliximab (5 or 10 mg/kg) within 48 hours of initiating IVIG 2 g/kg.Main outcome measuresIncidence of CAA regression to Zmax

We present a 22-week fetus with isolated absent aortic valve and inverse circular shunt. The pregnancy was interrupted. Here, echocardiography and pathology images demonstrate this rare entity. Whole genome sequencing revealed a potentially disease-causing variant in the APC gene. Whole genome sequencing should be considered in severe and rare fetal diseases. (Level of Difficulty: Advanced.).

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.

Our study demonstrates that children who developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination-induced myocarditis and may not receive another vaccination, could be susceptible to infection with Omicron and emerging variants. We observed higher neutralizing antibody titers in myocarditis patients vs. healthy vaccinated children, but significantly lower neutralization titers against Omicron in both groups.

We studied SARS-CoV-2-specific T cell responses in 22 subacute MIS-C children enrolled in 2021 and 2022 using peptide pools derived from SARS-CoV-2 spike or nonspike proteins. CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in 5 subjects, CD4+ T helper (Th) responses alone were detected in 12 subjects, and CD8+ cytotoxic T cell (CTL) responses alone were documented in 1 subject. Notably, a sizeable subpopulation of CD4- CD8- double-negative (DN) T cells out of total CD3+ T cells was observed in MIS-C (median: 14.5%; IQR 8.65-25.3) and recognized SARS-CoV-2 peptides. T cells bearing the Vβ21.3 T cell receptor (TcRs), previously reported as pathogenic in the context of MIS-C, were detected in high frequencies, namely, in 2.8% and 3.9% of the CD4+ and CD8+ T cells, respectively. However, Vβ21.3 CD8+ T cells that responded to SARS-CoV-2 peptides were detected in only a single subject, suggesting recognition of nonviral antigens in the majority of subjects. Subjects studied 6-14 months after MIS-C showed T cell epitope spreading, meaning the activation of T cells that recognize more SARS-CoV-2 peptides following the initial expansion of T cells that see immunodominant epitopes. For example, subjects that did not recognize nonspike proteins in the subacute phase of MIS-C showed good Th response to nonspike peptides, and/or CD8+ T cell responses not appreciable before arose over time and could be detected in the 6-14 months' follow-up. The magnitude of the Th and CTL responses also increased over time. In summary, patients with MIS-C associated with acute lymphopenia, a classical feature of MIS-C, showed a physiological response to the virus with a prominent role for virus-specific DN T cells.

Importance: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children., Objective: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis., Design, Setting, and Participants: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023., Main Outcomes and Measures: IgG, IgM and IgA antibody binding to cardiac tissue., Results: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditis or cardiomyopathy had positive IgG staining with raised fluorescence intensity (median [IQR] intensity, 11 060 [10 223-11 858] AU). There were no significant differences in median fluorescence intensity in all other patient cohorts compared with controls for IgG (MIS-C, 6033 [5834-6756] AU; vaccine myocarditis, 6392 [5710-6836] AU; adult myocarditis or inflammatory cardiomyopathy, 5688 [5277-5990] AU; healthy pediatric controls, 6235 [5924-6708] AU; healthy vaccinated adults, 7000 [6423-7739] AU), IgM (MIS-C, 3354 [3110-4043] AU; vaccine myocarditis, 3843 [3288-4748] AU; healthy pediatric controls, 3436 [3313-4237] AU; healthy vaccinated adults, 3543 [2997-4607] AU) and IgA (MIS-C, 3559 [2788-4466] AU; vaccine myocarditis, 4389 [2393-4780] AU; healthy pediatric controls, 3436 [2425-4077] AU; healthy vaccinated adults, 4561 [3164-6309] AU)., Conclusions and Relevance: This etiological diagnostic study found no evidence of antibodies from MIS-C and COVID-19 vaccine myocarditis serum binding cardiac tissue, suggesting that the cardiac pathology in both conditions is unlikely to be driven by direct anticardiac antibody-mediated mechanisms.