Understanding pediatric long COVID using a tree-based scan statistic approach: An EHR-based cohort study from the RECOVER Program

STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSPost-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect signals associated with PASC. Materials and MethodsWe used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) (N=1250) to children with (N=6250) and without (N=6250) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. ResultsWe found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. DiscussionOur study addresses methodological limitations of prior studies that rely on pre-specified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. ConclusionWe identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation.

Associations between area-level health-related social factor indices and risk of acute COVID-19: An EHR-based cohort study from the RECOVER program

BackgroundResearch demonstrates that SARS-CoV-2 infection (COVID-19) among adults disproportionately impacts racial and ethnic minorities and those living in lower-income communities. Similar research in children is limited due, in part, to the relatively low COVID-19 incidence in children compared to adults. This analysis, conducted as part of the RECOVER Initiative, explores this question. MethodsElectronic health record (EHR) data from PEDSnet, a multi-institutional research network of pediatric healthcare organizations, were geocoded and linked to two indices of contextual social deprivation: the Area Deprivation Index and the Child Opportunity Index. Univariate statistics were employed to test the association between each index and COVID19 positivity among children ages 0-20 tested at one of six Childrens hospitals. Multivariate logistic regression was used to explore the relationship between these social context indices and racial disparities in positivity, controlling co-variates. ResultsBoth ADI and COI were significantly associated with COVID-19 positivity in univariate and adjusted models, particularly in the pre-delta and delta variant waves. ADI showed a stronger association. Higher rates of positivity were found for non-Hispanic Black, Hispanic, and multi-racial children compared to non-Hispanic White children. These racial disparities remained significant after control for either index and for other variables. ConclusionADI and COI are significantly associated with COVID-19 test positivity in a population of children and adolescents tested in childrens hospital settings. These social contextual variables do not fully explain racial disparities, arguing that racial disparities are not solely a reflection of socioeconomic status. Future disparities research should consider both race and social context.

Impact of SARS-CoV-2 infection on disease trajectory in youth with T1D: An EHR-based cohort study from the RECOVER program

BackgroundPost-acute sequelae of SARS-Co-V-2 infection (PASC) is associated with worsening diabetes trajectory. It is unknown whether PASC in children with type 1 diabetes (T1D) manifests as worsening diabetes trajectory. ObjectiveTo explore the association between SARS-CoV-2 infection (COVID-19) and T1D-related healthcare utilization (for diabetic ketoacidosis [DKA] or severe hypoglycemia [SH]) or Hemoglobin (Hb) A1c trajectory. MethodsWe included children <21 years with T1D and [≥]1 HbA1c prior to cohort entry, which was defined as COVID-19 (positive diagnostic test or diagnosis code for COVID-19, multisystem inflammatory syndrome in children, or PASC) or a randomly selected negative test for those who were negative throughout the study period (Broad Cohort). A subset with [≥]1 HbA1c value from 28-275 days after cohort entry (Narrow Cohort) was included in the trajectory analysis. Propensity score-based matched cohort design followed by weighted Cox regression was used to evaluate the association of COVID-19 with healthcare utilization [≥]28 days after cohort entry. Generalized estimating equation models were used to measure change in HbA1c in the Narrow cohort. ResultsFrom 03/01/2020-06/22/2022, 2,404 and 1,221 youth met entry criteria for the Broad and Narrow cohorts, respectively. The hazard ratio for utilization was (HR 1.45 [95%CI,0.97,2.16]). In the Narrow Cohort, the rate of change (slope) of HbA1c increased 91-180 days after cohort entry for those with COVID-19 (0.138 vs. -0.002, p=0.172). Beyond 180 days, greater declines in HbA1c were observed in the positive cohort (-0.104 vs. 0.008 per month, p=0.024). ConclusionWhile a trend towards worse outcomes following COVID-19 in T1D patients was observed, these findings were not statistically significant. Continued clinical monitoring of youth with T1D following COVID-19 is warranted. Authorship StatementAuthorship has been determined according to ICMJE recommendations DisclaimerThe content is solely the responsibility of the authors and does not necessarily represent the official views of the RECOVER Program, the NIH or other funders. Funding SourceThis research was funded by the National Institutes of Health (NIH) Agreement OT2HL161847-01 as part of the Researching COVID to Enhance Recovery (RECOVER) program of research.

Changes in Treatment and Severity of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program

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.

Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program

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.

Multisystem Inflammatory Syndrome in Children Managed in the Outpatient Setting: An EHR-based cohort study from the RECOVER program

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.

Healthcare utilization following SARS-CoV-2 infection in children and adolescents with chronic conditions: An EHR-based Cohort Study from the RECOVER Program

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.

Leveraging serology testing to identify children at risk for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the RECOVER program

The impact of post-acute sequelae of SARS-CoV-2 infection (PASC) in children is underrecognized. We developed an EHR-based algorithm across eight pediatric institutions to identify children with COVID-19 based on serology testing from 3/2020 through 4/2022 who had not been identified by PCR. Overall, serology tests were used 100-fold less than PCR. Seroprevalence of IgG anti-nucleocapsid antibodies remained stable, while rates of positive IgG anti-spike antibodies increased in teenagers after COVID-19 vaccine approval. Through data harmonization and after excluding 1,410 serology test results that may have been influenced by vaccines, we identified 2,714 children that were COVID-19 positive exclusively by serology. These patients were frequently tested as inpatients (24% vs. 2%), had chronic conditions more frequently (37% vs 24%), and a MIS-C diagnosis (23% vs. <1%) compared with PCR-positive children. Identification of children that could have been paucisymptomatic, not tested, or missed is critical to define the burden of PASC in children.

Clinical features and burden of post-acute sequelae of SARS-CoV-2 infection in children and adolescents: an exploratory EHR-based cohort study from the RECOVER program

ImportanceThe post-acute sequelae of SARS-CoV-2 (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. ObjectiveTo identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Design, Setting and ParticipantsRetrospective cohort study using electronic health records from 9 US childrens hospitals for individuals <21 years-old who underwent reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020 - October 31, 2021 and had at least 1 encounter in the 3 years before testing. ExposureSARS-CoV-2 PCR positivity. Main Outcomes and MeasuresWe identified syndromic (symptoms), systemic (conditions), and medication PASC features in the 28-179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting PCR-positive with PCR-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race/ethnicity, and time-period of cohort entrance. We estimated the incidence proportion for any syndromic, systemic or medication PASC feature in the two groups to obtain a burden of PASC estimate. ResultsAmong 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings. The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16-3.32), myocarditis (aHR 3.10 [95% CI 1.94-4.96]), and cough and cold preparations (aHR 1.52 [95% CI 1.18-1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 41.9% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.7% (95% CI 3.2-4.2%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. Conclusions and RelevanceIn this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children? FindingsIn this retrospective cohort study of 659,286 children tested for SARS-CoV-2 by polymerase chain reaction (PCR), the symptom, condition and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations. The incidence proportion of non-MIS-C related PASC in the PCR-positive group exceeded the PCR-negative group by 3.7% (95% CI 3.2-4.2), with increased rates associated with acute illness severity, young age, and medical complexity. MeaningPASC in children appears to be uncommon, with features that differ from adults.

Diagnostic Accuracy of Commercially Available Tests for Respiratory Syncytial Virus: A Scoping Literature Review in the COVID-19 Era

BackgroundNon-pharmaceutical interventions to prevent the spread of coronavirus disease 2019 also decreased the spread of respiratory syncytial virus (RSV) and influenza. Viral diagnostic testing in patients with respiratory tract infections (RTI) is a necessary tool for patient management; therefore, sensitive and specific tests are required. This scoping literature review evaluated the analytical validity of commercially available sample-to- answer RSV diagnostic tests in different contexts. ContentPubMed and Embase were queried for studies reporting on the analytical validity of tests for RSV in patients with RTI (published January 2005-January 2021). Sensitivity and specificity of RSV tests and information on study design, patient, and setting characteristics were extracted from 77 studies that met predefined inclusion criteria. A literature gap was identified for studies of RSV tests conducted in adult-only populations (5.3% of total sub- records), and in outpatient (7.5%) or household (0.8%) settings. Overall, RSV tests with analytical time >30 min had higher sensitivity (62.5-100%) versus RSV tests with analytical time [≤] 30 min (25.7-100%), this sensitivity range could be partially attributed to the different modalities (antigen versus molecular) used. Molecular-based rapid RSV tests had higher sensitivity (66.7-100%) and specificity (94.3-100%) than antigen-based RSV tests (25.7- 100%; 80.3-100%). SummaryMolecular-based RSV tests should be considered for first-line use when possible, given their high sensitivity and specificity and that adults with RTI typically have low viral load, necessitating a highly sensitive test. This review benefits healthcare professionals by summarizing the diagnostic accuracy data available for commercially available RSV tests. IMPACT STATEMENTViral diagnostic testing in patients with respiratory tract infection is a powerful tool for patient management. This scoping literature review included 77 studies reporting the analytical validity of commercially available respiratory syncytial virus (RSV) diagnostic tests (published January 2005-January 2021) and examined the characteristics of such studies. The data suggest that molecular-based RSV tests have higher sensitivity and specificity than antigen-based tests, thus should be considered for first-line use for timely diagnosis and to detect infections in adults with low level viral load. Future studies should investigate the diagnostic accuracy of RSV tests in adults and in outpatient/household settings.