Outcomes Associated With Giant Coronary Artery Aneurysms After Kawasaki Disease: A Single-Center United States Experience.

OBJECTIVE: To determine the long-term outcomes among a cohort of patients with Kawasaki disease (KD) and a history of giant coronary artery aneurysms (CAA) at a single US center. RESULTS: There were 60 patients with KD and giant CAAs identified between 1989 and 2023. The majority of patients were male (71.7%) with median age at diagnosis of 0.9 years (0.2-13.3). Patients were followed for a median of 11 years, up to 34.5 years. MACE occurred in 13 (21.7%) patients at a median of 1.4 years (0.04-22.6) after KD diagnosis. The 10-, 20-, and 30-year MACE-free rates were 75%, 75%, and 60%. Patients with maximal CA z-scores ≥20 or bilateral CAA were more likely to have MACE. During follow-up, 26.7% of CAA regressed to normal luminal diameter at a median of 3.6 years (0.6-12.0). The 10-, 20- and 30-year likelihood of CA regression to normal luminal diameter was 36%, 46%, and 46%. CONCLUSIONS: Over 30 years, MACE occurred in nearly 22% of patients, more often in those with bilateral CAA or CA z-scores ≥20. Despite regression to normal luminal diameter in over 25% of CAA, patients with a history of KD-associated giant CAA require ongoing surveillance for cardiac complications, even years after the initial disease.

Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth. METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions. RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range [IQR], 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25). CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.

Physicians' Self-reported Exercise Testing and Physical Activity Recommendations in Kawasaki Patients.

Recommendations for management of patients with Kawasaki disease (KD) and coronary artery aneurysms (CAA) include physical activity (PA) promotion. This study aimed to characterize self-reported practices of KD providers to evaluate practice variation in use of cardiopulmonary exercise testing (CPET) and PA recommendations. We developed a REDCap survey with different clinical scenarios of KD patients. It was completed by members of the International Kawasaki Disease Registry (IKDR) and community pediatric cardiologists. Twenty-eight physicians responded; 63% practiced in the US, 63% practiced in an academic setting, 48% were general pediatric cardiologists, and 55% were IKDR members. Most respondents (69%) followed < 50 KD patients. The great majority (93%) agreed that patients with no CAA do not require CPET and could be cleared for all PA. For patients with small CAA, 43% of respondents recommended CPET and 75% cleared for all PA if CAAs regressed completely, but only 32% cleared if CAA persisted. For patients with medium CAA, 66% respondents cleared for PA if CAA regressed, and only 7% if CAA persisted; with 66% and 75% recommending CPET, respectively. For patients with large/giant CAA, 81% of respondents recommended CPET. No respondents felt comfortable clearing their patients with persistent large/giant CAA for PA and 19% would restrict from the entire physical education program. There is practice variation in use of CPET in KD patients with CAAs. Providers are hesitant to promote PA in KD patients with CAA despite known benefits and current guidelines.

Patients with Post-COVID-19 Vaccination Myocarditis Have More Favorable Strain in Cardiac Magnetic Resonance Than Those With Viral Myocarditis.

There have been reports of myocarditis following vaccination against COVID-19. We sought to describe cardiac magnetic resonance (CMR) findings among pediatric patients. Retrospective review at a large academic center of patients clinically diagnosed with post-vaccine myocarditis (PVM) undergoing CMR. Data collected included parametric mapping, ventricular function, and degree of late gadolinium enhancement (LGE). Post-processing strain analysis was performed using feature tracking. Strain values, T1/T2 values, and ventricular function were compared to age- and gender-matched controls with viral myocarditis using a Wilcoxon Signed Rank test. Among 12 patients with presumed PVM, 11 were male and 11 presented after the second vaccination dose, typically within 4 days. All presented with chest pain and elevated troponin. 10 met MRI criteria for acute myocarditis. All had LGE typically seen in the lateral and inferior walls; only five had prolonged T1 values. 10 met criteria for edema based on skeletal muscle to myocardium signal intensity ratio and only 5 had prolonged T2 mapping values. Patients with PVM had greater short-axis global circumferential and radial strain, right ventricle function, and cardiac output when compared to those with viral myocarditis. Patients with PVM have greater short-axis global circumferential and radial strains compared to those with viral myocarditis. LGE was universal in our cohort. Signal intensity ratios between skeletal muscle and myocardium may be more sensitive in identifying edema than T2 mapping. Overall, the impact on myocardial strain by CMR is less significant in PVM compared to more classic viral myocarditis.

The NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives.

BACKGROUND: The Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. METHODS: This multicenter observational cohort study will enroll at least 600 patients <21 years old who meet the Centers for Disease Control and Prevention case definition of MIS-C across multiple North American centers over 2 years. The study will collect detailed hospital and follow-up data for up to 5 years, and optional genetic testing. Cardiac imaging at specific time points includes standardized echocardiographic assessment (all participants) and cardiac magnetic resonance imaging (CMR) in those with left ventricular ejection fraction (LVEF) <45% during the acute illness. The primary outcomes are the worst LVEF and the highest coronary artery z-score of the left anterior descending or right coronary artery. Other outcomes include occurrence and course of non-cardiac organ dysfunction, inflammation, and major medical events. Independent adjudication of cases will classify participants as definite, possible, or not MIS-C. Analysis of the outcomes will include descriptive statistics and regression analysis with stratification by definite or possible MIS-C. The MUSIC study will provide phenotypic data to support basic and translational research studies. CONCLUSION: The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Assessing the utility of screening electrocardiograms in paediatric patients following COVID-19.

OBJECTIVE: To determine the utility of screening electrocardiograms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children in detecting myocarditis related to coronavirus disease 2019 (COVID-19). STUDY DESIGN: A retrospective chart review was performed at a large paediatric academic institution to identify patients with prior SARS-CoV-2 infection who received a screening electrocardiogram by their primary care providers and were subsequently referred for outpatient cardiology consultation due to an abnormal electrocardiogram. The outcomes were the results from their cardiology evaluations, including testing and final diagnoses. RESULTS: Among 46 patients, during their preceding COVID-19 illness, the majority had mild symptoms, 4 were asymptomatic, and 1 had moderate symptoms. The median length of time from positive SARS-CoV-2 test to screening electrocardiogram was 22 days, and many electrocardiogram findings that prompted cardiology consultation were normal variants in asymptomatic adolescent athletes. Patients underwent frequent additional testing at their cardiology appointments: repeat electrocardiogram (72%), echocardiogram (59%), Holter monitor (11%), exercise stress test (7%), and cardiac MRI (2%). Five patients were incidentally diagnosed with CHD or structural cardiac abnormalities, and three patients had conduction abnormalities (pre-mature atrial contractions, pre-mature ventricular contractions, borderline prolonged QTc), although potentially incidental to COVID-19. No patients were diagnosed with myocarditis or ventricular dysfunction. CONCLUSION: In a small cohort of children with prior COVID-19, who were primarily either asymptomatic or mildly symptomatic, subsequent screening electrocardiograms identified various potential abnormalities prompting cardiology consultation, but no patient was diagnosed with myocarditis. Larger multi-centre studies are necessary to confirm these results and to evaluate those with more severe disease.

Echocardiographic Assessment of Diastolic Function in Children with Incident Systemic Lupus Erythematosus.

The timing and etiology of diastolic impairment in pediatric-onset systemic lupus erythematosus (SLE) are poorly understood. We compared echocardiographic metrics of left ventricular diastolic function in children at SLE diagnosis to controls and identified factors associated with diastolic indices. Echocardiograms of children aged 5-18 years within 1 year of SLE diagnosis and age-/sex-matched controls were retrospectively read by blinded cardiologists. Clinical characteristics were abstracted separately. Z-scores for diastolic indices (E/A, e', E/e', and isovolumetric relaxation time (IVRT)) were calculated using published normative data and study controls, and compared using linear mixed-effects models adjusted for blood pressure. Pericardial effusions and valvular disease were also evaluated. Linear regression was used to identify factors associated with diastolic measures. 85 children with incident SLE had echocardiograms performed a median of 6 days after diagnosis (interquartile range (IQR) 1-70). Prior cumulative prednisone exposure was minimal (median 60 mg, IQR 0-1652). SLE cases had lower E/A, lower e', higher E/e', and longer IVRT compared to controls. Though none met criteria for Grade I diastolic dysfunction, Z-scores for e', E/e', and IVRT were abnormal in 30%, 25%, and 6% of SLE cases, respectively. Greater disease activity was associated with lower septal e' (p < 0.01), higher E/e' (p = 0.02), and longer IVRT (p < 0.01). Children with incident SLE have worse diastolic indices at diagnosis compared to peers without SLE, independent of blood pressure and prior to significant prednisone exposure. Longitudinal studies will determine whether diastolic dysfunction develops in this population over time.

Risk factors for mortality in paediatric cardiac ICU patients managed with extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation is frequently used in patients with cardiac disease. We evaluated short-term outcomes and identified factors associated with hospital mortality in cardiac patients supported with veno-arterial extracorporeal membrane oxygenation. METHODS: A retrospective review of patients supported with veno-arterial extracorporeal membrane oxygenation at a university-affiliated children's hospital was performed. RESULTS: A total of 253 patients with cardiac disease managed with extracorporeal membrane oxygenation were identified; survival to discharge was 48%, which significantly improved from 39% in an earlier era (1995-2001) (p=0.01). Patients were categorised into surgical versus non-surgical groups on the basis of whether they had undergone cardiac surgery before or not, respectively. The most common indication for extracorporeal membrane oxygenation was extracorporeal cardiopulmonary resuscitation: 96 (51%) in the surgical group and 45 (68%) in the non-surgical group. In a multiple covariate analysis, single-ventricle physiology (p=0.01), duration of extracorporeal membrane oxygenation (p<0.01), and length of hospital stay (p=0.03) were associated with hospital mortality. Weekend or night shift cannulation was associated with mortality in non-surgical patients (p=0.05). CONCLUSION: We report improvement in survival compared with an earlier era in cardiac patients supported with extracorporeal membrane oxygenation. Single-ventricle physiology continues to negatively impact survival, along with evidence of organ dysfunction during extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, and length of stay.

Long-Term Outcomes of Pediatric Cardiac Patients Supported by Extracorporeal Membrane Oxygenation.

OBJECTIVE: Extracorporeal membrane oxygenation is an important form of short-term mechanical support in children with cardiac disease, but information on long-term outcomes and quality of life is limited. The primary objective of this study was to determine the long-term outcomes of children previously supported by extracorporeal membrane oxygenation for cardiac etiologies. DESIGN: A retrospective analysis was performed on patients with cardiac disease managed with extracorporeal membrane oxygenation between January 1, 1995, and December 31, 2012, at the Children's Hospital of Philadelphia. Survivors completed patient- and parent-reported verbal and written surveys, and univariate analyses assessed risk factors for long-term outcomes. SETTING: Tertiary-care children's hospital. PATIENTS: Patients with cardiac disease managed with extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over 18 years, 396 patients were managed with extracorporeal membrane oxygenation with 43% survival to discharge. The median age at cannulation was 78 days. The majority had congenital heart disease (86%), surgery prior to extracorporeal membrane oxygenation (71%), and cardiopulmonary arrest as the primary extracorporeal membrane oxygenation indication (53%). With 6-year median follow-up, 66% are known to be deceased, including 38 deaths after hospital discharge. Among survivors at discharge, 65 (38%) completed the phone survey, and 33 (19%) completed the written survey. Negative clinical outcomes, defined as having at least significant physical limitations or "fair" or "poor" health, were present in 18% of patients. No patient- or extracorporeal membrane oxygenation-related variables were associated with negative outcomes in univariate analyses. There were significantly lower self-reported and parent-reported written Pediatric Quality of Life Inventory quality of life scores in children compared with healthy individual normative data but no differences in adolescents. CONCLUSIONS: In this series of pediatric cardiac patients supported by extracorporeal membrane oxygenation, mortality was 66% with 6-year median follow-up. The majority reported positive outcomes with respect to health and physical limitations, but children reported lower quality of life compared with healthy individuals.

Prevalence and Risk Factors for Pericardial Effusions Requiring Readmission After Pediatric Cardiac Surgery.

Pericardial effusion (PE) may require readmission after cardiac surgery and has been associated with postoperative morbidity and mortality. We sought to identify the prevalence and risk factors for postoperative PE requiring readmission in children. A retrospective analysis of the Pediatric Health Information System database was performed between January 1, 2003, and September 30, 2014. All patients ≤18 years old who underwent cardiac surgery were identified by ICD-9 codes. Those readmitted within 1 year with an ICD-9 code for PE were identified. Logistic regression analysis was performed to determine risk factors for PE readmissions. Of the 142,633 surgical admissions, 1535 (1.1%) were readmitted with PE. In multivariable analysis, older age at the initial surgical admission [odds ratio (OR) 1.17, p < 0.001], trisomy 21 (OR 1.24, p = 0.015), geographic region (OR 1.33-1.48, p ≤ 0.001), and specific surgical procedures [heart transplant (OR 1.82, p < 0.001), systemic-pulmonary artery shunt (OR 2.23, p < 0.001), and atrial septal defect surgical repair (OR 1.34, p < 0.001)] were independent risk factors for readmission with PE. Of readmitted patients, 44.2% underwent an interventional PE procedure. Factors associated with interventions included shorter length of stay (LOS) for the initial surgical admission (OR 0.85, p = 0.008), longer LOS for the readmission (OR 1.37, p < 0.001), and atrial septal defect surgery (OR 1.40, p = 0.005). In this administrative database of children undergoing cardiac surgery, readmissions for PE occurred after 1.1% of cardiac surgery admissions. The risk factors identified for readmissions and interventions may allow for improved risk stratification, family counseling, and earlier recognition of PE for children undergoing cardiac surgery.

Exercise restriction is not associated with increasing body mass index over time in patients with anomalous aortic origin of the coronary arteries.

Anomalous aortic origin of the coronary arteries is associated with exercise-induced ischaemia, leading some physicians to restrict exercise in patients with this condition. We sought to determine whether exercise restriction was associated with increasing body mass index over time. From 1998 to 2015, 440 patients ⩽30 years old were enrolled into an inception cohort. Exercise-restriction status was documented in 143 patients. Using linear mixed model repeated-measures regression, factors associated with increasing body mass index z-score over time, including exercise restriction and surgical intervention as time-varying covariates, were investigated. The 143 patients attended 558 clinic visits for which exercise-restriction status was recorded. The mean number of clinic visits per patient was 4, and the median duration of follow-up was 1.7 years (interquartile range (IQR) 0.5-4.4). The median age at first clinic visit was 10.3 years (IQR 7.1-13.9), and 71% (101/143) were males. All patients were alive at their most recent follow-up. At the first clinic visit, 54% (78/143) were exercise restricted, and restriction status changed in 34% (48/143) during follow-up. The median baseline body mass index z-score was 0.2 (IQR 0.3-0.9). In repeated-measures analysis, neither time-related exercise restriction nor its interaction with time was associated with increasing body mass index z-score. Surgical intervention and its interaction with time were associated with decreasing body mass index z-score. Although exercise restriction was not associated with increasing body mass index over time, surgical intervention was associated with decreasing body mass index z-score over time in patients with anomalous aortic origin of the coronary arteries.

Prevalence of electrocardiogram use in infants with apparent life-threatening events: a multicenter database study.

OBJECTIVE: An apparent life-threatening event (ALTE) is a common diagnosis in pediatrics, but there is no standardized method to evaluate these patients. We sought to determine the prevalence of electrocardiogram (ECG) use in patients presenting to children's hospitals with an ALTE. METHODS: The data from the Pediatric Health Information System database from 43 children's hospitals were collected during a 15-month period between October 2009 and December 2010. Patients were included if they were younger than 1 year at the time of presentation. Demographic data, including age, length of hospital stay, second ALTE, and survival, were recorded, along with the prevalence of ECGs and International Classification of Diseases, Ninth Revision, cardiac diagnoses. RESULTS: There were 2179 patients with an ALTE, with a mean age of 65.7 days old and length of stay of 3.4 days. A total of 947 (43%) of these patients received an ECG. The prevalence of ECG use and cardiac diagnoses were variable among the participating hospitals. Depending on the institution, 0% to 93% of patients had an ECG, and 4% to 39% of patients had an International Classification of Diseases, Ninth Revision, cardiac diagnosis. CONCLUSIONS: Electrocardiograms are performed in fewer than half of patients with ALTE presenting to children's hospitals. There is wide variation in the prevalence of ECG use as a diagnostic tool for infants presenting with an ALTE.

Acute disseminated encephalomyelitis following meningoencephalitis: case report and literature review.

Meningoencephalitis and acute disseminated encephalomyelitis (ADEM) are both neurological disease processes, but there have been few cases of meningoencephalitis progressing to ADEM in the pediatric population. A case of a 4-year-old girl with an initial diagnosis of meningoencephalitis is presented here, whose initial presentation was manifested by prolonged fever, gray matter signal abnormality on brain magnetic resonance imaging, cerebrospinal fluid pleocytosis, and a markedly irritable mental status. As her neurological examination changed with focal abnormalities, a repeat magnetic resonance imaging demonstrated new areas of both gray and white matter signal abnormality, consistent with ADEM. Her symptoms and imaging findings completely resolved with a course of methylprednisolone. Based on the literature and this current case, it is our recommendation to consider ADEM as a diagnosis if meningoencephalitis is not improving.

The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience.

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [- 3.86% (95% CI - 5.28-2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [- 3.46% (95% CI - 4.95-1.96)] and Pseudomonas aeruginosa [- 2.80%95% CI (- 4.26-1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (- 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

Correction: Adverse Events Reported From Hyaluronic Acid Dermal Filler Injections to the Facial Region: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.7759/cureus.38286.].

Adverse Events Reported From Hyaluronic Acid Dermal Filler Injections to the Facial Region: A Systematic Review and Meta-Analysis.

Dermal filler injections are one of the most popular cosmetic procedures in the United States. Of the many options available, hyaluronic acid (HA) dermal fillers like Juvederm or Restylane are often used. Despite their use and popularity, adverse events are known to occur from these procedures. Although most outcomes may be mild and resolve over time, rare instances of severe complications cannot be ignored, as these effects may be irreversible. Healthcare practitioners and patients must be aware of these risks, as these cosmetic procedures can affect the patient's quality of life. The aim of this study was to evaluate the incidence of adverse events (AEs) reported from the use of hyaluronic acid dermal fillers in the facial region. A systemized search of randomized controlled trials was conducted using Cochrane Central, Embase, Medical Literature Analysis and Retrieval System Online (MEDLINE), and the Web of Science databases. After screening for eligibility and conducting a critical appraisal of the articles, 19 studies were retained for the final review. The meta-analysis results included different side effects by facial location, i.e., nasolabial fold (NLF) vs. other (midface, perioral line, and lip region). The midface includes the anteromedial cheek region, the zygomaticomalar region, and the submalar region. The adverse events were swelling, pain, erythema, bruising, lumps and bumps, firmness, tenderness, itching, and skin discoloration. A significant difference was found in the proportion of individuals experiencing swelling, lumps or bumps, and firmness at the nasolabial fold site versus the midface, perioral line, and lip region. There was no significant difference in the proportion of individuals experiencing pain, erythema, bruising, tenderness, itching, or skin discoloration at the nasolabial fold site versus the other sites. The study highlights the prevalence of common AEs that can result from HA dermal fillers like Juvederm or Restylane, thus emphasizing the importance of healthcare professionals explaining the risk and benefits to patients.

Management of Multisystem Inflammatory Syndrome in Children: Decision-Making Regarding a New Condition in the Absence of Clinical Trial Data.

Multisystem inflammatory syndrome in children (MIS-C) is a new illness that evolved during the COVID-19 pandemic with initial reports of severe disease including use of extracorporeal membrane oxygenation and death. Institutions rapidly assembled task forces to develop treatment algorithms. At the national/international levels, collaboratives and associations assembled consensus writing groups to draft guidelines. These guidelines and algorithms were initially on the basis of expert opinion and small case series. Some groups used the Delphi approach, and the resultant guidelines often mimicked those for other conditions that resembled MIS-C, like Kawasaki disease (KD). For instance, intravenous immunoglobulin (IVIG), a known effective treatment for KD, was recommended for MIS-C. Early in the pandemic many favoured IVIG over steroids as first-line therapy. As evidence evolved so did some guidelines, which now endorse the dual use of IVIG with steroids as first-line therapy. In contrast, withholding immunotherapy became an option for some MIS-C patients with mild symptoms. Herein, we review guidelines and discuss the evidence informing early recommendations, how this has evolved, the role and limitations of expert opinion and observational data, and the importance of leveraging existing research infrastructures, such as the intensive care unit collaborative (Overcoming COVID-19 surveillance registry), and the International Kawasaki Disease Registry. Finally, we discuss strategies to rapidly develop, deploy, and adapt clinical trials evaluating the treatment of such rare conditions in children, which might include alternatives to conventional clinical trial design. The emergence of MIS-C during the COVID-19 pandemic has highlighted unmet needs regarding research of a new condition.

Emerging Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome Associated With COVID-19 in Children.

Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare delayed hyperinflammatory response to SARS-CoV-2 infection and causes severe morbidity in the pediatric age group. Although MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic, and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6 to12 years, and specific racial or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurologic complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein-as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens-are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C vs both acute SARS-CoV-2 infection and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine-associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.

Obesity and Outcomes of Kawasaki Disease and COVID-19-Related Multisystem Inflammatory Syndrome in Children.

Importance: Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Objective: To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C. Design, Setting, and Participants: In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with KD who had evidence of a recent COVID-19 infection or missing or unknown COVID-19 status were excluded. Main Outcomes and Measures: Patient demographic characteristics, clinical features, disease course, and outcome variables were collected from the IKDR data set. Using body mass index (BMI)/weight z score percentile equivalents, patient weight was categorized as normal weight (BMI <85th percentile), overweight (BMI ≥85th to <95th percentile), and obese (BMI ≥95th percentile). The association between adiposity category and clinical features and outcomes was determined separately for KD and MIS-C patient groups. Results: Of 1767 children, 338 with KD (median age, 2.5 [IQR, 1.2-5.0] years; 60.4% male) and 1429 with MIS-C (median age, 8.7 [IQR, 5.3-12.4] years; 61.4% male) were contemporaneously included in the study. For patients with MIS-C vs KD, the prevalence of overweight (17.1% vs 11.5%) and obesity (23.7% vs 11.5%) was significantly higher (P < .001), with significantly higher adiposity z scores, even after adjustment for age, sex, and race and ethnicity. For patients with KD, apart from intensive care unit admission rate, adiposity category was not associated with laboratory test features or outcomes. For patients with MIS-C, higher adiposity category was associated with worse laboratory test values and outcomes, including a greater likelihood of shock, intensive care unit admission and inotrope requirement, and increased inflammatory markers, creatinine levels, and alanine aminotransferase levels. Adiposity category was not associated with coronary artery abnormalities for either MIS-C or KD. Conclusions and Relevance: In this international cohort study, obesity was more prevalent for patients with MIS-C vs KD, and associated with more severe presentation, laboratory test features, and outcomes. These findings suggest that obesity as a comorbid factor should be considered at the clinical presentation in children with MIS-C.

Clinical phenotypes and outcomes in children with multisystem inflammatory syndrome across SARS-CoV-2 variant eras: a multinational study from the 4CE consortium.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES -1.18 years [95% CI -2.05, -0.32]), had fewer respiratory symptoms (RD -0.15 [95% CI -0.33, -0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD -0.35 [95% CI -0.64, -0.07]), lower lymphocyte count (ES -0.16 × 109/uL [95% CI -0.30, -0.01]), lower C-reactive protein (ES -28.5 mg/L [95% CI -46.3, -10.7]), and lower troponin (ES -0.14 ng/mL [95% CI -0.26, -0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES -1.6 years [95% CI -2.5, -0.8]), had less frequent SIRS (RD -0.18 [95% CI -0.30, -0.05]), lower lymphocyte count (ES -0.39 × 109/uL [95% CI -0.52, -0.25]), lower troponin (ES -0.16 ng/mL [95% CI -0.30, -0.01]) and less frequently received anticoagulation therapy (RD -0.19 [95% CI -0.37, -0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (-1.3 days [95% CI -2.3, -0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.