Pediatrics

BackgroundHypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are connective tissue disorders marked by chronic pain, joint instability, and extensive multisystem involvement. Despite affecting an estimated 1 in 500 individuals, these conditions remain poorly understood, and current diagnostic categories lack clarity and consistency. This study aimed to characterize the clinical presentation, comorbidities, and healthcare burden of individuals with hEDS and HSD through a large-scale international survey. Methods and FindingsA cross-sectional, anonymous online survey was distributed globally between September 2023 and March 2024. Of 9,258 responses, 3,906 participants met inclusion criteria and were included in analysis. The 418-item questionnaire covered symptom domains, diagnoses, healthcare access, and quality of life. Responses were statistically analyzed using chi-square and Mann-Whitney U tests with Bonferroni correction and compared to the All of Us dataset (n=354,400). Participants reported high rates of gastrointestinal disorders (84.3% hEDS, 69.0% HSD), with 21.2% of hEDS participants diagnosed with gastroparesis and 7.1% requiring feeding devices. Dysautonomia was common, affecting 71.4% of those with hEDS and 40.3% with HSD (p<0.0001), with postural orthostatic tachycardia syndrome (POTS) as the most frequently reported subtype. Neurological complications were also prevalent, with hEDS participants reporting significantly higher rates of tethered cord syndrome (4.6%, 0.9%), Chiari malformation (6.3%, 0.9%), and small fiber neuropathy (10.0%, 4.4%) compared to those with HSD. Chronic pain was nearly universal (98.8% hEDS, 92.7% HSD). On average, hEDS participants reported 24 comorbid diagnoses and HSD participants 17, with diagnostic delays averaging over 20 years. Notably, 50% of those reporting HSD met hEDS criteria, while 26% of those reporting hEDS did not meet full criteria, underscoring persistent diagnostic uncertainty. ConclusionsThis global survey underscores the profound multisystemic burden, diagnostic ambiguity, and unmet clinical needs faced by individuals with hEDS and HSD. The high prevalence of immune-mediated, neurological, gastrointestinal, and autonomic dysfunctions, alongside the frequent identification of triggering events such as infections and hormonal transitions, challenges the conventional framework that defines these disorders as purely connective tissue in origin. Instead, our findings support the hypothesis that hEDS and/or HSD may represent complex syndromes in which connective tissue fragility may be a downstream consequence rather than the primary cause. This reframing has critical implications for diagnosis, pathophysiology, and therapeutic development, and highlights the need for mechanistic studies that explore distinct etiologies beyond the connective tissue paradigm.

ObjectivesWe aimed to measure SARS-CoV-2 serologic responses in children hospitalized with multisystem inflammatory syndrome (MIS-C) compared to COVID-19, Kawasaki Disease (KD) and other hospitalized pediatric controls. MethodsFrom March 17, 2020 - May 26, 2020, we prospectively identified hospitalized children at Childrens Healthcare of Atlanta with MIS-C (n=10), symptomatic PCR-confirmed COVID-19 (n=10), KD (n=5), and hospitalized controls (n=4). With IRB approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike (S) receptor binding domain (RBD) IgM and IgG binding antibodies by quantitative ELISA and SARS-CoV-2 neutralizing antibodies by live-virus focus reduction neutralization assay. We statistically compared the log-transformed antibody titers among groups and performed correlation analyses using linear regression. ResultsAll children with MIS-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated strongly with neutralizing antibodies (R2=0.667, P<0.001). Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer [GMT] 6800, 95%CI 3495-13231) than children with COVID-19 (GMT 626, 95%CI 251-1563, P<0.001), children with KD (GMT 124, 95%CI 91-170, P<0.001) and other hospitalized pediatric controls (GMT 85 [all below assay limit of detection], P<0.001). All children with MIS-C also had detectable RBD IgM antibodies, indicating recent SARS-CoV-2 infection. RBD IgG titers correlated with erythrocyte sedimentation rate (ESR) (R2=0.512, P<0.046) and with hospital and ICU lengths of stay (R2=0.590, P=0.010). ConclusionQuantitative SARS-CoV-2 RBD antibody titers may have a role in establishing the diagnosis of MIS-C, distinguishing it from other similar clinical entities, and stratifying risk for adverse outcomes. Table of Contents SummaryChildren with MIS-C have high antibody titers to the SARS-CoV-2 spike protein receptor binding domain, which correlate with neutralization, systemic inflammation, and clinical outcomes. Whats Known on This SubjectAlthough the clinical features of a multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been recently described, the serologic features of MIS-C are unknown. What This Study AddsIn this case series, all hospitalized children with MIS-C had significantly higher SARS-CoV-2 binding and neutralizing antibodies than children with COVID-19 or Kawasaki Disease. SARS-CoV-2 antibodies correlated with metrics of systemic inflammation and clinical outcomes, suggesting diagnostic and prognostic value.

BackgroundMulti-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. MethodsWe conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. FindingsWe identified 1186 children hospitalized with MIS-C. The highest proportion of children (44{middle dot}4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40{middle dot}2%). Most (67{middle dot}8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72{middle dot}5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51{middle dot}1% of children early in the pandemic, which decreased to 33{middle dot}9% from the pre-delta period to the omicron period. InterpretationMIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms "multi-system inflammatory syndrome in children" or "pediatric inflammatory multisystem syndrome" and "phenotypes". Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this studyPEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidenceThese results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment.

ObjectivesThe purpose of this study was to examine how the treatment and severity of multisystem inflammatory syndrome in children (MIS-C) has changed over more than two years of the COVID-19 pandemic in the United States. MethodsElectronic health record data were retrieved from the PEDSnet network as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative. The study included data for children ages 0 to 20 years hospitalized for MIS-C from March 1, 2020 through July 20, 2022. Descriptive statistics for MIS-C treatments and laboratory results were computed for three time periods of interest: March 1, 2020 - May 31, 2021 (pre-Delta); June 1 - December 31, 2021 (primarily Delta); January 1 - July 20, 2022 (primarily Omicron). Standardized differences measured the effect size of the difference between Omicron and pre-Omicron cohorts. ResultsThe study included 946 children with a diagnosis of MIS-C. The largest differences in the Omicron period compared to prior years were decreases in the percentage of children with abnormal troponin (effect size = 0.40), abnormal lymphocytes (effect size = 0.33), and intensive care unit (ICU) visits (effect size = 0.34). There were small decreases in the Omicron period for the majority of treatments and abnormal laboratory measurements examined, including infliximab, anticoagulants, furosemide, aspirin, IVIG without steroids, echocardiograms, mechanical ventilation, platelets, ferritin, and sodium. ConclusionsThis study provides the first evidence that the severity of MIS-C declined in the first half of the year 2022 relative to prior years of the COVID-19 pandemic in the United States. Article SummaryUsing electronic health record data for 946 children, we found evidence that the severity of MIS-C declined during the first half of the year 2022. Whats Known on This SubjectThe clinical management of multisystem inflammatory syndrome in children (MIS-C) has commonly included intravenous immune globulin, steroids, and non-steroidal anti-inflammatory agents. Many children with MIS-C have required intravenous fluids, inotropes and vasopressors, and in some cases, mechanical ventilation. What This Study AddsRecent decreases in the percentage of children with MIS-C that have abnormal troponin, abnormal lymphocytes, or intensive care unit visits provide evidence that the severity of MIS-C has declined in the first half of the year 2022.

BackgroundIn the absence of evidence-based therapies for Multisystem Inflammatory Syndrome in Children (MIS-C), we aimed to describe the similarities and differences in the evaluation and treatment of MIS-C at hospitals in the United States. MethodsWe conducted a cross-sectional survey from June 16 to July 16, 2020 of U.S. childrens hospitals regarding protocols for patients with MIS-C. Elements included hospital characteristics, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers that had treated >5 patients vs. those that had treated [&le;]5 patients. ResultsForty centers of varying size and experience with MIS-C participated. About half (21/40) of centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely used medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols for primarily the moderate or severe cases. Aspirin was commonly used including for mild cases, whereas heparin or low molecular weight heparin were used primarily in severe cases. In severe cases, anakinra and vasopressors were frequently recommended. Nearly all centers (39/40) recommended follow up with cardiology. There were similar findings between centers that had treated >5 patients vs. those that had treated [&le;]5 patients. A supplement containing hospital protocols is provided. ConclusionThere are many similarities yet some key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C patients. Article SummaryThis survey of U.S. hospitals highlights the interhospital similarities and differences in management of Multisystem Inflammatory Syndrome in Children. Whats Known on This SubjectMIS-C is a novel and life-threatening disease in children associated with COVID-19. Early cases were treated with immunomodulatory agents similar to current guidelines for Kawasaki disease. There are currently no evidence-based guidelines for treatment of MIS-C. What This Study AddsThis study describes the protocolized evaluation and treatment of children with MIS-C at 40 hospitals in the U.S. These findings can help other hospitals create protocols to care for these children at their centers.

BackgroundEarly in the pandemic, COVID-19 was found to infect adults at higher rates than children, leaving limited data on disease presentation in children. Further understanding of the epidemiology of COVID-19 symptoms among children is needed. Our aim was to explore how symptoms vary between children testing positive for COVID-19 infection versus children testing negative. MethodsData analysis of symptom prevalence among pediatric patients presenting to emergency departments (ED) in the Johns Hopkins Health System (JHHS) with concern for COVID-19 who subsequently received COVID-19 testing. Inclusion criteria included patients 0-17 years-of-age, ED evaluation between March 15th, 2020 - May 11th, 2020, and those who were ordered for COVID-19 testing. Chart review was performed to document symptoms using ED provider notes. Comparisons were made using chi-squared t-tests and Students t-tests. ResultsFever (62.6%) and cough (47.9%) were the most prevalent symptoms among children with suspected COVID-19 infection. Compared to children with a negative COVID-19 test, children who tested positive had higher prevalence of myalgia (21.7% vs 6.0%) and loss of taste/smell (15.2% vs 0.9%). Over half of the children who tested positive for COVID-19 had public insurance (52.2%) and 58.7% of the positive tests occurred among children with Hispanic ethnicity. ConclusionsMyalgia and loss of taste/smell were found to be significantly more prevalent among COVID-19 positive children compared to children testing negative. Additionally, children with public insurance and those with Hispanic ethnicity were more likely to test positive, emphasizing the importance of social factors in the screening and decision-making process.

BackgroundChronic medical conditions are a risk factor for moderate or severe COVID-19 in children, but little is known about post-acute sequelae of SARS-CoV-2 infection (PASC) in children with chronic medical conditions (CMCs). To understand whether SARS-CoV-2 infection led to potential exacerbation of underlying chronic disease in children, we explored whether children with CMCs had increased healthcare utilization in the post-acute (28 days after infection) period compared to children with CMCs without SARS-CoV-2 infection. MethodsWe conducted a retrospective, matched-cohort study using electronic health record data collected from 8 pediatric health care systems participating in the PEDSnet network. We included children <21 years of age with a wide array of chronic conditions, defined by the presence of diagnostic codes, who were diagnosed with COVID-19 between March 1, 2020 and February 28, 2022. Cohort entry was defined by presence of a positive SARS-CoV-2 PCR test (polymerase chain reaction or antigen) or diagnostic codes for COVID-19, PASC or MIS-C. A comparison cohort of patients testing negative or without these conditions was matched using a stratified propensity score model and exact matching on age group, race/ethnicity, institution, test location, and month of cohort entry. A negative binomial model was used to examine our primary outcome: composite and setting-specific (inpatient, outpatient, ED) utilization rate ratios between the positive and comparison cohorts. Secondary outcomes included time to first utilization in the post-acute period, and utilization stratified by severity at cohort entry. ResultsWe identified 748,692 patients with at least one chronic condition, 78,744 of whom met inclusion criteria for the COVID-19 cohort. 96% of patients from the positive cohort were matched. Cohorts were well-balanced for chronic condition clusters, total number of conditions, time since first diagnosis, baseline utilization, cohort entry period, age, sex, race/ethnicity and test location. We found that among children with chronic medical conditions, those with COVID-19 had higher healthcare utilization than those with no recorded COVID-19 diagnosis or positive test, with utilization rate ratio of 1.21 (95% CI: 1.18-1.24). The utilization was highest for inpatient care with utilization rate ratio of 2.03 (95% CI: 1.85-2.23) but the utilization was increased across all settings. Hazard ratios estimated in time-to-first-utilization analysis mirrored these results. Patients with severe or moderate acute COVID-19 illness had greater increases in utilization in all settings than those with mild or asymptomatic disease. ConclusionsWe found that care utilization in all settings was increased following COVID-19 in children with chronic medical conditions in the post-acute period, particularly in the inpatient setting. Increased utilization was correlated with more severe COVID-19. Additional research is needed to better understand the reasons for higher care utilization by studying condition-specific outcomes in children with chronic disease.

ImportanceMultisystem inflammatory syndrome in children (MIS-C) is the most severe life-threatening clinical entity associated with pediatric SARS-CoV-2 infection. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. ObjectiveTo assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Design, Setting, and ParticipantsPost-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12- 17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Each case was assessed for WHO MIS-C criteria. Causality assessment followed 2019 WHO recommendations. ExposureCOVID-19 mRNA vaccine. Main Outcome and MeasuresThe main outcome was the reporting rate of post-vaccine hyper-inflammatory syndrome per 1,000,000 COVID-19 mRNA vaccine doses in 12-17-year-old children. This reporting rate was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Secondary outcomes included the comparison of clinical features between post-vaccine hyper-inflammatory syndrome and post SARS-CoV-2 MIS-C. ResultsFrom June 2021 to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 9 presented a multisystemic hyper-inflammatory syndrome. All cases fulfilled MIS-C WHO criteria. Main clinical features included male predominance (8/9, 89%), cardiac involvement (8/9, 89%), digestive symptoms (7/9, 78%), coagulopathy (5/9, 54%), cytolytic hepatitis (4/9, 46%), and shock (3/9, 33%). 3/9 (33%) required intensive care unit transfer, and 2/9 (22%) hemodynamic support. All cases recovered. Only three cases had evidence of previous SARS-CoV-2 infection. The reporting rate was 1.1 (95%CI [0.5; 2.1]) per 1,000,000 doses injected. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Clinical features (inflammatory parameters, cytopenia) slightly differed from post-SARS-CoV-2 MIS-C, along with short-term outcomes (less PICU transfer than MIS-C). Conclusion and RelevanceVery few cases of hyper-inflammatory syndromes with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of MIS-C among same age children infected by SARS-CoV-2, supports the benefit of SARS-CoV-2 vaccination in children. Further studies are required to explore specific pathways of this entity compared to post-SARS-CoV-2 MIS-C. Key pointsO_ST_ABSQuestionC_ST_ABSIs COVID-19 mRNA vaccine in 12-17-year-old children associated with subsequent multisystemic hyper-inflammatory syndrome? FindingsThe French national pharmacovigilance system identified 9 children with a hyper-inflammatory syndrome with multi-organ involvement following COVID-19 mRNA vaccination (reporting rate 1.1 [0.5; 2.1] per 1,000,000 doses), of which only three had evidence of previous SARS-CoV-2 infection. All cases fulfilled WHO definition for MIS-C, but clinical and immunological features, along with short-term outcomes, slightly differed from classical post SARS-CoV-2 MIS-C. MeaningVery rare cases of hyper-inflammatory syndrome can occur following COVID-19 mRNA vaccine in 12-17-year-old children. The very low rate of this entity, compared to classical post-SARS-CoV-2 MIS-C, supports the benefit of SARS-CoV-2 vaccination in children.

ObjectivesTo understand the international epidemiology of critical pediatric COVID-19 and compare presentation, treatments, and outcomes of younger (<2 years) and older (>2 years) children. DesignProspective, observational study from April 1 to December 31, 2020 SettingInternational multicenter study from 55 sites from North America, Latin America, and Europe. ParticipantsPatients <19 years old hospitalized with critical COVID-19 Interventionsnone Main outcomes measuredClinical course, treatments, and outcomes were compared between younger and older children. Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) for hospital mortality. Results557 subjects (median age, 8 years; 24% <2 years) were enrolled from 55 sites (63% Latin American). Half had comorbidities. Younger children had more respiratory findings (56% vs 44%), viral pneumonia (45% vs 29%), and treatment with invasive ventilation (50% vs 37). Gastrointestinal (28% vs 69%) or mucocutaneous (16% vs 44%) findings, vasopressor requirement (44% vs 60%), and MIS-C (15% vs 40%) were less common in younger children. Hospital mortality was 10% overall but 15% in younger children (odds ratio 1.89 [95%CI 1.05-3.39]). When adjusted for age, sex, region, and illness severity, mortality-associated factors included cardiac (aOR 2.6; 95%CI 1.07-6.31) or pulmonary comorbidities (aOR 4.4; 95%CI 1.68-11.5), admission hypoxemia (aOR 2.33; 95%CI 1.24-4.37), and lower respiratory symptoms (aOR 2.83; 95%CI 1.49-5.39). Gastrointestinal (aOR 0.49; 95%CI 0.26-0.92) or mucocutaneous symptoms (aOR 0.31; 95%CI 0.15-0.64), treatment with intravenous immune globulin (aOR 0.33; 95%CI 0.17-0.65), and MIS-C (aOR 0.26; 95%CI 0.11-0.64) were associated with lower mortality. ConclusionsWe identified age-related differences in presentation and mortality for critical pediatric COVID-19 that should prompt more attention to improving management in younger children, especially in developing countries. Table of Contents SummaryThis is a multinational study describing critical pediatric COVID-19 clinical spectrum and related mortality in high and low-middle income countries during 2020. Whats known on this subjectPediatric critical illness due to COVID-19 is uncommon and have lower mortality compared to adults when hospitalized. While larger cohorts are from high-income countries (HICs), studies including data from low-middle-income countries (LMICs) remain scarce. What this study addsIn our multinational cohort of critical pediatric COVID-19, we identified higher mortality than previously reported and age-related disease patterns. Children <2 years old had more respiratory disease and higher mortality, and older children had more non-pulmonary disease and better outcomes.

ObjectiveTo develop a comprehensive checklist, define critical actions, and establish a minimal passing standard for adult and pediatric critical care clinicians as well as other providers to facilitate formative and summative assessment of brain death/death by neurologic criteria (BD/DNC) determination Design: A pre-specified three round modified Delphi consensus process to define checklist items followed by a modified Angoff standard setting process to determine critical actions and item average ratings. SettingElectronic surveys. SubjectsSelected authors of the 2023 Pediatric and Adult Brain Death/Death by Neurologic Criteria Consensus Practice Guideline, World Brain Death Project, and experts recommended by these authors (n=16) participated in the Delphi panel. Neurocritical care United Council for Neurologic Subspecialties and Accreditation Council for Graduate Medical Education examination committee members (n= 13) participated in Angoff standard setting. InterventionsNone. Measurements and Main ResultsA total of 98 unique checklist items related to assessment of prerequisites (23 items), performance of the clinical examination (28 items), apnea testing (36 items), and ancillary testing (11 items) were retained by the Delphi panel. Seven items were designated as critical actions based upon Angoff panelist consensus. The remaining 91 items were assigned item average ratings. The minimum passing score for an assessment including all items was set at 89%. ConclusionsThese guideline-concordant consensus checklist items, including critical actions and non-critical actions with their assigned item average ratings, may be applied selectively to simulated cases of BD/DNC determination for adults and children to determine a minimum passing score and readiness for independent practice, mitigating risk of inaccurate BD/DNC determination among critical care clinicians. Our process for systematically defining critical actions on a behavior checklist may be replicated for simulation-based summative assessment of learners in other critical care scenarios. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat behaviors should be included in a checklist for assessment of brain death/death by neurologic criteria (BD/DNC) determination and what level of performance is consistent with readiness for independent practice? FindingsA modified Delphi panel identified 98 checklist items which may be applied selectively to simulated cases of BD/DNC. An Angoff panel identified 7 critical actions and set average ratings for all other items. MeaningThese guideline-concordant consensus checklist items and their average ratings may be applied to assessments of simulated or real cases of BD/DNC, including those intended for summative assessment, to determine learner readiness for independent determination.

ObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). DesignProspective observational cohort study with rapid data gathering and near real time analysis. Setting260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome MeasuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. ResultsMedian age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p<0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p<0.001), myalgia (39% (11/28) vs 7% (12/170), p<0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). ConclusionsOur data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registrationISRCTN66726260

BackgroundPaediatric inflammatory multisystem syndrome (PIMS) is a rare but serious condition temporally associated with SARS-CoV-2 infection. Using the Canadian Paediatric Surveillance Program (CPSP), a national surveillance system, we aimed to 1) study the impact of SARS-CoV-2 linkage on clinical and laboratory characteristics, and outcomes in hospitalized children with PIMS across Canada 2) identify risk factors for ICU admission, and 3) establish the minimum national incidence of hospitalizations due to PIMS and compare it to acute COVID-19. MethodsWeekly online case reporting was distributed to the CPSP network of more than 2800 pediatricians, from March 2020 to May 2021. Comparisons were made between cases with respect to SARS-CoV-2 linkage. Multivariable modified Poisson regression was used to identify risk factors for ICU admission and Minimum incidence proportions were calculated. FindingsIn total, 406 PIMS cases were analyzed, of whom 202 (49{middle dot} 8%) had a positive SARS-CoV-2 linkage, 106 (26{middle dot} 1%) had a negative linkage, and 98 (24{middle dot} 1%) had an unknown linkage. The median age was 5{middle dot} 4 years (IQR 2{middle dot} 5-9{middle dot} 8), 60% were male, and 83% had no identified comorbidities. Compared to cases with a negative SARS-CoV-2 linkage, children with a positive SARS-CoV-2 linkage were older (8{middle dot} 1 years [IQR 4{middle dot} 2-11{middle dot} 9] vs. 4{middle dot} 1 years [IQR 1{middle dot} 7-7{middle dot} 7]; p<0{middle dot} 001), had more cardiac involvement (58{middle dot} 8% vs. 37{middle dot} 4%; p<0{middle dot} 001), gastrointestinal symptoms (88{middle dot} 6% vs. 63{middle dot} 2%; p<0{middle dot} 001), and shock (60{middle dot} 9% vs. 16{middle dot} 0%; p<0{middle dot} 001). At-risk groups for ICU admission include children [&ge;] 6 years and those with a positive SARS-CoV-2 linkage. No deaths were reported. The minimum incidence of PIMS hospitalizations during the study period was 5{middle dot} 6 hospitalizations per 100,000 population <18 years. InterpretationWhile PIMS is rare, almost 1 in 3 hospitalized children required ICU admission and respiratory/hemodynamic support, particularly those [&ge;] 6 years and with a positive SARS-CoV-2 linkage. FundingFinancial support for the CPSP was received from the Public Health Agency of Canada.

BACKGROUND AND OBJECTIVESex chromosome trisomies (SCT), including XXY, XYY, and XXX syndromes, have been historically underdiagnosed. Noninvasive prenatal cell-free DNA screening has significantly increased identification of these conditions, leading to a need for pediatric care for a growing population of newborns with SCT. Our goal was to analyze and compare perinatal features, medical diagnoses, and physical features in infants with prenatal identification of SCT conditions through the first year of life. METHODSThe eXtraordinarY Babies Study is an ongoing, prospective natural history study of prenatally identified children with SCT conducted by interdisciplinary teams in Colorado and Delaware. Participants were enrolled prior to 12 months of age and had pregnancy, birth, medical histories, and physical exams completed by board-certified pediatricians at 2, 6, and/or 12-month visits. Descriptive statistics were followed by comparisons between SCT groups using t-tests or ANOVA, Fisher exact, and correlations between medical features with alpha of 0.05. Relative risks were calculated compared to general population rates. RESULTS327 infants were included in the analysis (XXY=195, XXX=79, XYY=53). Major congenital anomalies were rare (1.7%). Relative risk compared to general population was elevated for breastfeeding difficulties (51.7%;RR 2.7), positional torticollis (28.2%;RR 7.2), eczema (48.0%;RR 3.5), food allergies (19.3%;RR 2.4), constipation requiring intervention (33.9%;RR 7.6), small cardiac septal defects (7.7%;RR 17.2), and structural renal abnormalities (4.4%;RR 9.7). Inpatient hospitalization was required for 12.4%, with 59.5% of hospitalizations attributable to respiratory infections. DISCUSSIONThese findings of medical conditions with a higher prevalence can inform anticipatory guidance and medical management for pediatricians caring for infants with SCT. Article SummaryMedical findings in largest cohort of prenatally identified infants with XXY, Trisomy X, and XYY from birth to 12 months and implications for pediatric care. Whats Known on This SubjectOne in [~]500 individuals have an extra X or Y chromosome, or sex chromosome trisomy (SCT). Prenatal screening is now routinely identifying SCT, however there are few studies to guide perinatal and infant care for these individuals. What This Study AddsThis prospective observational study presents medical features for 327 infants with prenatally identified SCT from birth through the first year of life. Results identify where proactive screenings and/or interventions may be warranted for infants with SCT.

Using electronic health record data combined with primary chart review, we identified 7 children across 8 pediatric medical centers with a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) who were managed as outpatients. These findings should prompt a discussion about modifying the case definition to allow for such a possibility.

BackgroundThere is growing evidence of Multisystem Inflammatory Syndrome in Children (MIS-C) resembling Kawasaki disease in children infected with SARS-CoV-2. The review was undertaken to evaluate the case definition, the spectrum of clinical presentations and current management practices in children with COVID-19 presenting with or without MIS-C. MethodsThe individual patient data from 119 studies accounting for 333 children were analyzed. We devised a scoring system as per WHO criteria to classify the patients as MIS-C or without MIS-C. A score of 3 was given for the presence of fever (>24h) and a score of 1 for lab-confirmed diagnosis of SARS-CoV-2. Additionally, a score of 1 was given for a) rash or conjunctivitis or muco-cutaneous inflammation signs, b) hypotension or shock, c) diarrhea, vomiting or abdominal pain, d) features of myocardial dysfunction as determined by abnormal eco-cardiography or elevated Troponin or N-terminal pro B-type Natriuretic Peptide (NT-proBNP), e) evidence of coagulopathy as evidenced by elevated levels of prothrombin time PT, partial thromboplastin time PTT or D-dimer, f) laboratory evidence of inflammation as determined by elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) or procalcitonin. A negative score of (-3) was given when there was a diagnosis of sepsis, staphylococcal or streptococcal shock syndrome. Based on these criteria, a minimum score of 6 was essential to classify the child as MIS-C. ResultsBased on this score, 18% (52/289) of cases were identified to be MIS-C. A greater proportion of children with MIS-C had cardiac involvement (MIS-C 80% vs Non-MIS-C 20%) and gastrointestinal involvement (MIS-C 71% vs Non-MIS-C 12%). Lymphopenia was commonly reported in MIS-C (MIS-C 54.2% vs Non-MIS-C 29.7%). In addition to routine inflammatory markers, significantly greater proportion of children with MIS-C had elevated Ferritin, LDH, Fibrinogen and IL-6. Children with MIS-C were less likely to have respiratory symptoms like cough (MIS-C 25% vs Non-MIS-C 75%) and rhinorrhea (MIS-C 4% vs Non-MIS-C 22.8%). A greater proportion of children with MIS-C required intensive care and aggressive treatment; and mortality rates were also higher in MIS-C group (MIS-C 10% vs Non-MIS-C 1%). ConclusionThe children with COVID-19 having cardiac and/or gastrointestinal involvement are more likely to develop MIS-C. The children with MIS-C have higher mortality rates. The scoring system developed herein will aid clinicians in patient diagnosis and timely management.

ImportanceIn April 2020, multiple reports of an association between a hyperinflammatory, Kawasaki-like condition and SARS-CoV-2 were published and termed as pediatric inflammatory multisystem syndrome (PIMS) or multisystem inflammatory syndrome (MIS). A thorough characterization of this syndrome (demographics, presentation, diagnosis, and outcome) is currently lacking. ObjectiveWe aimed to perform a systematic review of published cases of this novel multisystem inflammatory syndrome in children associated with COVID-19. Evidence reviewA literature search of Pubmed, Embase, BioRxiv, MedRxiv and COVID-19 specific research repositories (Cochrane COVID-19 Study Register and the World Health Organization (WHO) COVID-19 Global Research Database) was conducted from December 30th, 2019 to June 30th, 2020. Publications describing inflammatory syndromes associated with COVID-19 were included. Of 333 unique publications, 229 records were excluded based on title and abstract. After screening the full text, 40 observational studies and case reports were included, comprising 687 cases (published between May 9th, 2020 and June 30th, 2020). FindingsIn contrast to classic Kawasaki disease, epidemiological enrichment for adolescents (median age 9 [6.0-12.3]) and ethnic minorities (35.8% black and 24.5% Hispanic/Latino) was observed. There was a male predominance (59.1%). Apart from obesity (24.4%), pre-existing conditions were infrequent. The majority suffered from gastrointestinal (87.2%) and cardiocirculatory (79.2%) manifestations. Respiratory symptoms (51.2%) were less frequent. Over half of patients (56.3%) presented with hemodynamic shock, and critical care interventions were often necessary (inotropics (56.5%), mechanical ventilation (22.9%), non-invasive ventilation (30.6%), extracorporal membrane oxygenation (ECMO;4.5%)). Anti-SARS-CoV-2 IgG and RT-PCR were positive in respectively 69.4% and 36.7%. Eleven deaths were reported (1.6%). The RCPCH case definition proved to be most comprehensive comprising all single cases. In contrast, WHO and CDC MIS definitions are more stringent, with the CDC case definition often missing severe cases requiring intensive care (n = 33 out of 95 cases). Conclusions and RelevanceThis novel pediatric multisystem hyperinflammatory condition, associated with COVID-19, is characterized by a severe and heterogeneous disease spectrum. Despite frequent intensive care interventions, mortality rate was low and short-term outcome favorable. Long-term follow-up of possible chronic complications and additional clinical research, to elucidate the underlying immunological pathogenesis and possible genetic predisposition is crucial. Key pointsO_ST_ABSQuestionC_ST_ABSHow is the novel pediatric multisystem inflammatory condition associated with coronavirus disease 2019 (COVID-19) characterized? FindingsThis systematic review of 40 studies, comprising 687 cases, represents the heterogeneous spectrum of this novel pediatric disease related to COVID-19, including contrasting features with previously-described hyperinflammatory conditions. Adolescents and particular racial/ethnic minorities are affected more. Gastrointestinal and cardiocirculatory manifestations are often found, along with critical care interventions. Nevertheless, only 11 deaths are reported. MeaningThis novel condition has variable severity but good short-term outcome. Uniform case definitions are required to guide future (preferably controlled) research on epidemiological clustering, immunopathology, and long-term prognosis.

ObjectiveLong COVID, marked by persistent, recurring, or new symptoms post-COVID-19 infection, impacts childrens well-being yet lacks a unified clinical definition. This study evaluates the performance of an empirically derived Long COVID case identification algorithm, or computable phenotype, with manual chart review in a pediatric sample. This approach aims to facilitate large-scale research efforts to understand this condition better. MethodsThe algorithm, composed of diagnostic codes empirically associated with Long COVID, was applied to a cohort of pediatric patients with SARS-CoV-2 infection in the RECOVER PCORnet EHR database. The algorithm classified 31,781 patients with conclusive, probable, or possible Long COVID and 307,686 patients without evidence of Long COVID. A chart review was performed on a subset of patients (n=651) to determine the overlap between the two methods. Instances of discordance were reviewed to understand the reasons for differences. ResultsThe sample comprised 651 pediatric patients (339 females, Mage = 10.10 years) across 16 hospital systems. Results showed moderate overlap between phenotype and chart review Long COVID identification (accuracy = 0.62, PPV = 0.49, NPV = 0.75); however, there were also numerous cases of disagreement. No notable differences were found when the analyses were stratified by age at infection or era of infection. Further examination of the discordant cases revealed that the most common cause of disagreement was the clinician reviewers tendency to attribute Long COVID-like symptoms to prior medical conditions. The performance of the phenotype improved when prior medical conditions were considered (accuracy = 0.71, PPV = 0.65, NPV = 0.74). ConclusionsAlthough there was moderate overlap between the two methods, the discrepancies between the two sources are likely attributed to the lack of consensus on a Long COVID clinical definition. It is essential to consider the strengths and limitations of each method when developing Long COVID classification algorithms.

Background & ObjectiveCOVID-19 has caused significant shifts in healthcare utilization, including pediatric emergency departments (EDs). We describe variations in visits made to two large pediatric EDs during the first three months of the COVID-19 pandemic, compared to a historical control period. MethodsWe performed a retrospective cohort study of children presenting to two academic pediatric EDs in Quebec, Canada. We compared the number of ED visits during the first wave of COVID-19 pandemic (March-May 2020) to historical controls (March-May 2015-2019), using Poisson regression, adjusting for site and the underlying baseline trend. Secondary analyses examined variations in ED visits by acuity, disposition, and disease categories. ResultsFrom 2015 to 2019, the two EDs had a median of 1,632 visits per week [interquartile range (IQR) 1,548; 1,703]; in 2020, this number decreased to 536 visits per week [IQR 446; 744]. In multivariable analyses, this represent a 53.3% (95%CI: 52.1, 54.4) reduction in the number of ED visits. The reduction was larger among visits triage categories 4 and 5 (lower acuity) than categories 1, 2 and 3 (higher acuity): -54.2% vs. -42.0% (p<0.001). A greater proportion of children presenting to these sites were hospitalized during the COVID period than in pre-COVID period: 11.8% vs. 5.5% (p<0.001). ConclusionsDuring the early stages of the COVID-19 pandemic, there was a large decrease in visits to pediatric EDs. Patients presented with higher acuity at triage and the proportion of patients requiring hospitalization increased.

Case-based tracking of COVID-19 in children and adolescents may underestimate infection, and compared with adults there is little pediatric SARS-CoV-2 seroprevalence data. To assess evidence of previous SARS-CoV-2 infections among children and adolescents in Mississippi, serologic testing for antibodies to SARS-CoV-2 was conducted on a convenience sample of residual serum specimens collected for routine laboratory testing by an academic medical center laboratory during May 17 through September 19, 2020. Seroprevalence by calendar month was standardized to the state population by race/ethnicity; cumulative numbers of infections were estimated by extrapolating seroprevalence to all those aged <18 years in Mississippi. Serum specimens from 1,603 individuals were tested; 175 (10.9%) were positive for SARS-CoV-2 antibodies. Among 1,579 (98.5%) individuals for whom race/ethnicity was known, the number testing positive was 16 (23.2%) of 69 Hispanic individuals, 117 (13.0%) of 901 non-Hispanic Black individuals and 30 (5.3%) of 565 non-Hispanic White individuals. Population-weighted seroprevalence estimates among those aged <18 years increased from 2.6% in May to 16.9% in September 2020. Cumulative numbers of infections extrapolated from seroprevalence data, however, were estimated at 117,805 (95% confidence interval [CI] = 68,771-168,708), suggesting that cases in children and adolescents are much higher than what was reported to the Mississippi State Department of Health (9,044 cases during this period). Further data to appreciate the burden of pediatric disease to inform public health policy is urgently needed.

BackgroundWith the rise of the COVID-19 pandemic, a new severe life-threatening inflammatory syndrome has been reported in some pediatric populations. Global attention was shifted towards the syndrome termed multisystem inflammatory syndrome in children (MIS-C), with new case reports flooding in. ObjectivesThe aim of this scoping review is to summarize the existing reports on MIS-C and focus on the demographics, diagnosis, clinical presentation, laboratory investigations, imaging studies, treatment, and patient outcomes. MethodsWe conducted a systemic search using LitCovid and MEDLINE electronic databases. We screened citations, titles and abstracts, then reviewed potentially relevant articles in full. After data extraction, we reported our final data under subheadings of demographics, diagnosis, clinical presentation, laboratory investigations, imaging studies, treatment, and patient outcomes. ResultsOur search strategy yielded 42 original studies reporting 674 pediatric patients fitting the case definition of MIS-C. The studies included 21 case reports, 16 case series and 5 cohort studies. The most common reported symptom of MIS-C was fever (98%). Gastrointestinal symptoms were common (N=557, 83%). Interleukin-6 (IL-6) levels were measured in 125 patients and was elevated in 94 % (N=117). Echocardiography detected coronary artery lesions in 100 patients. Prophylactic and/or therapeutic heparin was required in 34% (N=227) of patients. The most commonly administered treatment modality targeting MIS-C was intravenous immunoglobulin (IVIG) (N=490). Corticosteroids (N=347) and aspirin (N=112) were also integral parts of the treatment regimens. Biologic therapy was integrated into the treatment regimen for 116 patients. Intensive care unit (ICU) admission was alarming (N=478, 71%). 9 fatalities were recorded due to MIS-C ConclusionsWe believe MIS-C bears pathophysiological resemblance to the well-known Kawasaki disease but with some key differences highlighted. Understanding those differences will aid our management plan for such patients.