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.

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.

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.

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.

BackgroundPost-COVID condition (PCC) in children and young people (PCCcyp) remains a significant health burden. Early identification of patients at risk for severe disease, including myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), is crucial to provide timely and adequate care. MethodsThis monocentric, observational registry study was performed at a tertiary pediatric hospital in Germany. Children and young people aged 7-25 years with post-COVID condition (PCC), according to the WHO, were included at the time of diagnosis. Standardized clinical assessment tools and patient-reported outcome measures were applied, including the novel Munich Long COVID Symptom Questionnaire (MLCSQ). Severe PCC was defined by clustered chronic symptom burden, fatigue severity scale (FSS), Total Composite Autonomic Symptom Score-31 (COMPASS-31), SF-36 composite scores, Bell Score, and confirmed ME/CFS diagnosis. FindingsOf 120 participants, severe PCCcyp was associated with a higher number of acute symptoms (adjusted OR 1{middle dot}22), acute orthostatic intolerance (adjusted OR 9{middle dot}87), acute trouble concentrating (adjusted OR 11{middle dot}8), and female sex (OR 3{middle dot}31). Categorising acute symptoms at a threshold of [&ge;]12 yielded the best model performance (AUC 0{middle dot}857; sensitivity 65{middle dot}6%; specificity 90{middle dot}2%). ME/CFS was diagnosed in 24% participants, all within the severe PCC cluster, and was characterised by greater acute symptom complexity, more fatigue, more autonomic symptoms, and poorer physical function. InterpretationThe number of acute symptoms and/or individual symptoms during the acute phase of the SARS-CoV-2 infection serve as early and specific predictors for severe PCCcyp. In particular, patients with [&ge;]12 acute symptoms should be closely monitored to enable early diagnosis of severe PCC and potentially ME/CFS. A distinct cluster of severely affected patients - frequently with ME/CFS diagnosis - was identified. FundingThis study was funded by the Bavarian State Ministry of Health and Care, and the German Center for Infection Research. Research in context Evidence before this studyPost-COVID condition (PCC) in children and young people (CYP) has been increasingly recognized, but robust evidence on predictors of severe disease has remained scarce. Previous reports in adult patients documented a wide spectrum of persistent symptoms, frequently including fatigue, neurocognitive complaints, and autonomic dysfunction, yet no study systematically investigated acute-phase predictors for severe PCCcyp. Added value of this studyIn this monocentric observational registry study on 120 CYP aged 7-25 years with PCC, we identified acute-phase risk factors for severe pediatric PCC. We show that a high number of acute symptoms ([&ge;]12 symptoms), female sex, acute orthostatic intolerance, and/or acute trouble concentrating strongly predicted a severe PCCcyp cluster. Importantly, 24% of patients fulfilled ME/CFS diagnostic criteria, and all clustered within the severe PCC group, underscoring the clinical overlap between severe pediatric PCC and ME/CFS. Implications of all the available evidenceThese findings provide a framework for early risk stratification in pediatric PCC. Recognising acute predictors is crucial to provide timely and adequate care, particularly to those with 12 or more acute symptoms and/or specific symptoms during the acute SARS-CoV-2 infection. The identification of a clinically relevant ME/CFS subgroup underscores the need to integrate ME/CFS expertise into pediatric PCC care pathways. Together, this evidence can inform clinical management, healthcare planning, and the design of interventional trials targeting the most vulnerable CYP with PCC.

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.

ImportanceMultisystem inflammatory syndrome in children (MIS-C) is an uncommon but severe hyperinflammatory illness occurring 2-6 weeks after SARS-CoV-2 infection. Presentation overlaps with other conditions, and risk factors for severe clinical outcomes differ by patient. Characterizing patterns of MIS-C presentation can guide efforts to reduce misclassification, categorize phenotypes, and identify patients at risk for severe outcomes. ObjectiveTo characterize phenotypic clusters of MIS-C and identify clusters with increased clinical severity. DesignWe describe MIS-C phenotypic clusters inferred using latent class analysis (LCA) applied to the largest cohort to date of cases from U.S. national surveillance. Illness onset ranged from February 2020 through December 2022. SettingNational surveillance comprising data from 55 U.S. public health jurisdictions. ParticipantsWe analyzed 9,333 MIS-C cases. Twenty-nine clinical signs and symptoms were selected for clustering after excluding variables with [&ge;]20% missingness and [&le;]10% or [&ge;]90% prevalence. We excluded 389 cases missing [&ge;]10 variables and conducted multiple imputation on the remaining 8,944 (96%) cases. Main Outcomes and MeasuresDifferences by cluster in prevalence of each clinical sign and symptom, percentage of cases admitted to the intensive care unit (ICU), length of hospital and ICU stay, mortality, and relative frequency over time. ResultsLCA identified three clusters characterized by 1) frequent respiratory findings primarily affecting older children (n = 713; 8.0% of cases; median age: 12.7 years); 2) frequent cardiac complications and shock (n = 3,359; 37.6%; 10.8 years); and 3) remaining cases (n = 4,872; 54.5%; 6.8 years). Mean duration of hospitalization and proportion of cases resulting in ICU admission or death were higher in the respiratory (7.9 days; 49.5%; 4.6%; respectively) and shock/cardiac clusters (8.7 days; 82.3%; 1.0%; respectively) compared with other cases (5.3 days; 33.0%; 0.06%; respectively). The proportion of cases in the respiratory and shock/cardiac clusters decreased after emergence of the Omicron variant in the United States. Conclusions and RelevanceMIS-C cases clustered into three subgroups with distinct clinical phenotypes, illness severity, and distribution over time. Use of clusters in future studies may support efforts to evaluate surveillance case definitions and help identify groups at highest risk for severe outcomes. Key pointsO_ST_ABSQuestionC_ST_ABSCan phenotypic clusters of multisystem inflammatory syndrome in children (MIS-C) be identified, and are some clusters associated with increased severity? FindingsWe describe clusters inferred using latent class analysis (LCA) on 9,333 MIS-C cases from U.S. national surveillance 2020-2022. LCA identified three clusters characterized by frequent respiratory symptoms, frequent cardiac complications and shock, and remaining clinically milder cases. Mortality and ICU admission were highest in the respiratory and shock/cardiac clusters; prevalence of these two clusters decreased over time. MeaningMIS-C clusters had distinct presentation, illness severity, and distribution over time, highlighting the importance of recognizing the varied presentation of MIS-C.

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.

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.

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.

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.

IntroductionPediatric gastrointestinal (GI) infections are a major cause of emergency department (ED) visits, yet the epidemiology of severe cases requiring hospitalization or intensive care remains poorly characterized. This study assessed the incidence, predictors, and temporal patterns of severe pediatric GI infections using national surveillance data. MethodsWe analyzed 7,326,429 records from the National Electronic Injury Surveillance System (NEISS) for patients [&le;] 18 years with narrative descriptions (n=2,876,152). GI infections were identified using keywords including vomiting, diarrhea, nausea, food poisoning, and pathogens such as Salmonella, E. coli, norovirus, Giardia, Campylobacter, and Shigella. Severe cases were defined by hospitalization, ICU admission, intravenous fluid administration, or hospital transfer. Weighted incidence rates were calculated per 100,000 ED visits. Multivariable logistic regression adjusting for year, age, sex, and month evaluated associations with severe outcomes. Seasonal and yearly trends were also examined. ResultsAmong pediatric ED visits, 438,354 weighted cases (0.50%) involved GI infections. Severe outcomes occurred in 0.82% of GI infection cases versus 0.21% in non-GI visits, equating to 8,179 versus 2,068 severe cases per 100,000 ED visits. GI infection was strongly associated with severe outcomes (adjusted OR=3.95, 95% CI: 3.82-4.09, p<0.001). Younger age (OR=0.99 per year, p<0.001) and male sex were also significant predictors. Seasonal peaks were observed in March, with troughs in May and December. ConclusionsPediatric GI infections carry nearly four-fold increased odds of severe outcomes, highlighting a substantial burden. Seasonal variability underscores the need for preventive measures, food safety initiatives, and targeted public health interventions to reduce severe pediatric GI infections.

BackgroundThe impact of the COVID-19 pandemic on medically fragile populations, who are at higher risk of severe illness and sequelae, has not been well characterized. Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD), and the COVID-19 pandemic represents an opportunity to study this vulnerable population. MethodsA convenience sampling cross-sectional serology study was conducted (October 2020 to June 2021) in households (N = 20) containing a child with MtD (N = 22). Samples (N = 83) were collected in the home using a microsampling apparatus and shipped to investigators. Antibodies against SARS-CoV-2 nucleocapsid (IgG), spike protein (IgG, IgM, IgA), and receptor binding domain (IgG, IgM, IgA) were determined by enzyme linked immunosorbent assay. ResultsWhile only 4.8% of participants were clinically diagnosed for SARS-CoV-2 infection, 75.9% of study participants were seropositive for SARS-CoV-2 antibodies. Most samples were IgM positive for spike or RBD (70%), indicating that infection was recent. This translated to all 20 families showing evidence of infection in at least one household member. For the children with MtD, 91% had antibodies against SARS-CoV-2 and had not experienced any adverse outcomes at the time of assessment. For children with recent infections (IgM+ only), serologic data suggest household members as a source. ConclusionsCOVID-19 was highly prevalent and undiagnosed in households with a child with MtD through the 2020-2021 winter wave of the pandemic. In this first major wave, children with MtD tolerated SARS-CoV-2 infection well, potentially due to household adherence to CDC recommendations for risk mitigation. FundingThis study was funded by the Intramural Research Program of the National Institutes of Health (HG200381-03). Clinical trial numberNCT04419870

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.

ImportanceOtologic disease is common among people with primary ciliary dyskinesia, yet little is known about its spectrum and severity. ObjectiveWe characterized otologic disease among participants with primary ciliary dyskinesia using data from the Ear-Nose-Throat Prospective International Cohort of PCD patients (EPIC-PCD). DesignCross-sectional analysis of baseline cohort data. SettingTwelve specialized primary ciliary dyskinesia centers in 10 countries. ParticipantsWe prospectively included children and adults with primary ciliary dyskinesia diagnoses, routine ENT examinations, and completed symptom questionnaires at the same visit or within 2 weeks. ExposuresPotential risk factors associated with increased risk of ear disease. Main outcomes and measuresWe describe the prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations; we identify potential factors associated with increased risk of ear inflammation and hearing impairment. ResultsWe included 397 (211 males) participants with median age 15 (range 0-73). A total of 204 (51%) reported ear pain, 110 (28%) ear discharge, and 183 (46%) hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion--usually bilateral--from otoscopy was most common among 121 (32%) of 384 participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed on 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed on 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems related to ear inflammation (autumn compared with spring odds ratio, 95% confidence interval: 2.4, 1.5-3.8) and age 30 and older of hearing impairment (age 41-50 compared with age 10 years and younger odds ratio, 95% confidence interval: 3.3, 1.1-9.9). Conclusion and relevanceMany people with primary ciliary dyskinesia suffer from ear problems yet frequency varies, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. We recommend multidisciplinary primary ciliary dyskinesia management includes regular otologic assessments for all ages even without specific complaints. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the characteristics of otologic disease among patients with primary ciliary dyskinesia (PCD)? FindingsBaseline data from a large multicenter cohort of patients with PCD showed frequent reports of ear pain and reduced hearing with age as the main factor associated with hearing impairment. Otitis media with effusion was the most common otoscopic finding; adults often presented with tympanic sclerosis following history of previous ear infections. MeaningSince otologic disease is an important yet underreported part of PCDs clinical expression, we recommend otologic assessments for all age groups as part of regular clinical follow-up.

Background and ObjectivesRecurrent acute otitis media (rAOM; defined as [&ge;]3 AOM episodes in 6 months or [&ge;]4 episodes in 12 months) affects 10-15% of children in the United States and is a leading cause of healthcare utilization and antibiotic prescriptions. Prospective identification of children at risk of rAOM could help target interventions and identify new risk factors to guide preventive approaches. We therefore sought to develop predictive models to identify children at risk of rAOM using electronic health records (EHR) data. MethodsWe extracted retrospective EHR data for children who were born at Duke University Health System (DUHS) hospitals between January 1, 2014, and June 30, 2022, and who had at least one AOM episode during the study period. We used LASSO to build predictive models for development of rAOM at each episode and identified factors associated with rAOM. ResultsWe identified 6,566 children who met the study criteria, including 1,634 (24.8%) who met criteria for rAOM. A model using only data available at the first AOM episode had an area under the curve (AUC) of 0.75 (0.73, 0.77) and an Area Under the Precision Recall Curve (AUPRC) of 0.41 (95% CI 0.37, 0.46), indicating moderate discriminative ability. At the time of the first AOM episode, features associated with subsequent rAOM development included age, number of prior antibiotic prescriptions, and diagnosis of gastroesophageal reflux disease (GERD). Further, children who developed rAOM were more likely to experience treatment failure than children who did not meet rAOM criteria across all episodes. ConclusionsOur findings indicate that clinical exposures and patient characteristics documented in the EHR distinguish children who are at risk of developing rAOM. Such models could be deployed within EHR systems to identify children who would benefit from early evaluation by an otolaryngologist and audiologist.

Direct comparisons of pediatric hospitalizations for acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. While there were more hospitalizations and deaths from acute COVID-19 amongst Canadian children between March 2020-May 2021, MIS-C cases were more severe, requiring more intensive care and vasopressor support.

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.