Retrospective Multicenter Cohort Study on Safety and Electroencephalographic Response to Lacosamide for Neonatal Seizures.

BACKGROUND: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates. METHODS: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days. RESULTS: Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates. CONCLUSIONS: The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results.

Postacute Sequelae of SARS-CoV-2 in Children.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.

Development and validation of a federated learning framework for detection of subphenotypes of multisystem inflammatory syndrome in children.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection. The highly diverse clinical features of MIS-C necessities characterizing its features by subphenotypes for improved recognition and treatment. However, jointly identifying subphenotypes in multi-site settings can be challenging. We propose a distributed multi-site latent class analysis (dMLCA) approach to jointly learn MIS-C subphenotypes using data across multiple institutions. Methods: We used data from the electronic health records (EHR) systems across nine U.S. children's hospitals. Among the 3,549,894 patients, we extracted 864 patients < 21 years of age who had received a diagnosis of MIS-C during an inpatient stay or up to one day before admission. Using MIS-C conditions, laboratory results, and procedure information as input features for the patients, we applied our dMLCA algorithm and identified three MIS-C subphenotypes. As validation, we characterized and compared more granular features across subphenotypes. To evaluate the specificity of the identified subphenotypes, we further compared them with the general subphenotypes identified in the COVID-19 infected patients. Findings: Subphenotype 1 (46.1%) represents patients with a mild manifestation of MIS-C not requiring intensive care, with minimal cardiac involvement. Subphenotype 2 (25.3%) is associated with a high risk of shock, cardiac and renal involvement, and an intermediate risk of respiratory symptoms. Subphenotype 3 (28.6%) represents patients requiring intensive care, with a high risk of shock and cardiac involvement, accompanied by a high risk of >4 organ system being impacted. Importantly, for hospital-specific clinical decision-making, our algorithm also revealed a substantial heterogeneity in relative proportions of these three subtypes across hospitals. Properly accounting for such heterogeneity can lead to accurate characterization of the subphenotypes at the patient-level. Interpretation: Our identified three MIS-C subphenotypes have profound implications for personalized treatment strategies, potentially influencing clinical outcomes. Further, the proposed algorithm facilitates federated subphenotyping while accounting for the heterogeneity across hospitals.

Vaccine Effectiveness Against Long COVID in Children.

OBJECTIVES: Vaccination reduces the risk of acute coronavirus disease 2019 (COVID-19) in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. METHODS: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record program for visits after vaccine availability. We examined both probable (symptom-based) and diagnosed long COVID after vaccination. RESULTS: The vaccination rate was 67% in the cohort of 1 037 936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, whereas diagnosed long COVID was 0.8%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5-44.7) against probable long COVID and 41.7% (15.0-60.0) against diagnosed long COVID. VE was higher for adolescents (50.3% [36.6-61.0]) than children aged 5 to 11 (23.8% [4.9-39.0]). VE was higher at 6 months (61.4% [51.0-69.6]) but decreased to 10.6% (-26.8% to 37.0%) at 18-months. CONCLUSIONS: This large retrospective study shows moderate protective effect of severe acute respiratory coronavirus 2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including electronic health record sources and prospective data.

Spectrum of severity of multisystem inflammatory syndrome in children: an EHR-based cohort study from the RECOVER program.

Multi-system inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection in children, and there is a critical need to unfold its highly heterogeneous disease patterns. Our objective was to characterize the illness spectrum of MIS-C for improved recognition and management. We conducted a retrospective cohort study using data from March 1, 2020-September 30, 2022, in 8 pediatric medical centers from PEDSnet. We included 1139 children hospitalized with MIS-C and used their demographics, symptoms, conditions, laboratory values, and medications for analyses. We applied heterogeneity-adaptive latent class analyses and identified three latent classes. We further characterized the sociodemographic and clinical characteristics of the latent classes and evaluated their temporal patterns. Class 1 (47.9%) represented children with the most severe presentation, with more admission to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 (23.3%) represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 (28.8%) represented a mild presentation. Our results indicated that MIS-C has a spectrum of clinical severity ranging from mild to severe and the proportion of severe or critical MIS-C decreased over time.

Vaccine Effectiveness Against Long COVID in Children: A Report from the RECOVER EHR Cohort.

Objective: Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5-17 years. Methods: This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits between vaccine availability, and October 29, 2022. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5-11, 12-17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination. Results: The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 - 44.5) against probable long COVID and 41.7% (15.0 - 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 - 61.0]) than children aged 5-11 (23.8% [4.9 - 39.0]). VE was higher at 6 months (61.4% [51.0 - 69.6]) but decreased to 10.6% (-26.8 - 37.0%) at 18-months. Discussion: This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. Article Summary: Vaccination against COVID-19 has a protective effect against long COVID in children and adolescents. The effect wanes over time but remains significant at 12 months. What's Known on This Subject: Vaccines reduce the risk and severity of COVID-19 in children. There is evidence for reduced long COVID risk in adults who are vaccinated, but little information about similar effects for children and adolescents, who have distinct forms of long COVID. What This Study Adds: Using electronic health records from US health systems, we examined large cohorts of vaccinated and unvaccinated patients <18 years old and show that vaccination against COVID-19 is associated with reduced risk of long COVID for at least 12 months. Contributors' Statement: Drs. Hanieh Razzaghi and Charles Bailey conceptualized and designed the study, supervised analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.Drs. Christopher Forrest and Yong Chen designed the study and critically reviewed and revised the manuscript.Ms. Kathryn Hirabayashi, Ms. Andrea Allen, and Dr. Qiong Wu conducted analyses, and critically reviewed and revised the manuscript.Drs. Suchitra Rao, H Timothy Bunnell, Elizabeth A. Chrischilles, Lindsay G. Cowell, Mollie R. Cummins, David A. Hanauer, Benjamin D. Horne, Carol R. Horowitz, Ravi Jhaveri, Susan Kim, Aaron Mishkin, Jennifer A. Muszynski, Susanna Nagie, Nathan M. Pajor, Anuradha Paranjape, Hayden T. Schwenk, Marion R. Sills, Yacob G. Tedla, David A. Williams, and Ms. Miranda Higginbotham critically reviewed and revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Authorship statement: Authorship has been determined according to ICMJE recommendations.

Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health record-based analysis from the RECOVER initiative.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC). METHODS: We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities. RESULTS: Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis. CONCLUSIONS: Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

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

Objectives: Post-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 conditions and symptoms associated with pediatric PASC. Materials and Methods: We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) (N = 1309) to children with (N = 6545) and without (N = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. Results: We 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. Discussion: Our study addresses methodological limitations of prior studies that rely on prespecified 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. Conclusion: We 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.

Leveraging Serologic Testing to Identify Children at Risk For Post-Acute Sequelae of SARS-CoV-2 Infection: An Electronic Health Record-Based Cohort Study from the RECOVER Program.

Using an electronic health record-based algorithm, we identified children with Coronavirus disease 2019 (COVID-19) based exclusively on serologic testing between March 2020 and April 2022. Compared with the 131 537 polymerase chain reaction-positive children, the 2714 serology-positive children were more likely to be inpatients (24% vs 2%), to have a chronic condition (37% vs 24%), and to have a diagnosis of multisystem inflammatory syndrome in children (23% vs <1%). Identification of children who could have been asymptomatic or paucisymptomatic and not tested is critical to define the burden of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection in children.

Pediatric and Congenital Cardiovascular Disease Research Challenges and Opportunities: JACC Review Topic of the Week.

The National Heart, Lung, and Blood Institute convened a workshop in August 2021 to identify opportunities in pediatric and congenital cardiovascular research that would improve outcomes for individuals with congenital heart disease across the lifespan. A subsidiary goal was to provide feedback on and visions for the Pediatric Heart Network. This paper summarizes several key research opportunities identified in the areas of: data quality, access, and sharing; aligning cardiovascular research with patient priorities (eg, neurodevelopmental and psychological impacts); integrating research within clinical care and supporting implementation into practice; leveraging creative study designs; and proactively enriching diversity of investigators, participants, and perspectives throughout the research process.

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

Background: Multi-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. Methods: We 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. Findings: We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44·4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40·2%). Most (67·8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72·5% 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 51·1% of children early in the pandemic, which decreased to 33·9% from the pre-delta period to the omicron period. Interpretation: MIS-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 context: Evidence before this study: We 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 study: PEDSnet 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 evidence: These 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.

Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents.

Importance: The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. Objective: To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children. Design, Setting and Participants: This retrospective cohort study used electronic health records from 9 US children's hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing. Exposures: SARS-CoV-2 positivity by viral test (antigen or RT-PCR). Main Outcomes and Measures: Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test-positive groups with viral test-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate. Results: Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). 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), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test-positive children vs 38.2% (95% CI, 38.1-38.4) among viral test-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 intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions. Conclusions and Relevance: In 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.

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.

Importance: The 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. Objective: To identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Design Setting and Participants: Retrospective cohort study using electronic health records from 9 US children's 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. Exposure: SARS-CoV-2 PCR positivity. Main Outcomes and Measures: We 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. Results: Among 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 Relevance: In 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 Points: Question: What are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children?Findings: In 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.Meaning: PASC in children appears to be uncommon, with features that differ from adults.

Improving Home Ventilator Alarm Use Among Children Requiring Chronic Mechanical Ventilation.

BACKGROUND AND OBJECTIVES: Children requiring long-term mechanical ventilation are at high risk of mortality. Setting ventilator alarms may improve safety, but best practices for setting ventilator alarms have not been established. Our objective was to increase the mean proportion of critical ventilator alarms set for those children requiring chronic mechanical ventilation followed in our pulmonary clinic from 63% to >90%. METHODS: Using the Institute for Healthcare Improvement Model for Improvement, we developed, tested, and implemented a series of interventions using Plan-Do-Study-Act cycles. We followed our progress using statistical process control methods. Our primary interventions were: (1) standardization of the clinic workflow, (2) development of an algorithm to guide physicians in selecting and setting ventilator alarms, (3) updating that algorithm based on review of failures and inpatient testing, and (4) enhancing staff engagement to change the culture surrounding ventilator alarms. RESULTS: We collected baseline data from May 1 to July 13, 2017 on 130 consecutive patients seen in the pulmonary medicine clinic. We found that 63% of critical ventilator alarms were set. Observation of the process, standardization of workflow, and adaptation of an alarm algorithm led to an increase to 85.7% of critical alarms set. Through revising our algorithm to include an apnea alarm, and maximizing provider engagement, more than 95% of critical ventilator alarms were set, exceeding our goal. We sustained this improvement through January 2021. CONCLUSIONS: Our stepwise approach, including process standardization, staff engagement, and integration of an alarm algorithm, improved the use of ventilator alarms in chronically ventilated pediatric patients.

Severity of Acute COVID-19 in Children <18 Years Old March 2020 to December 2021.

This national study evaluated trends in illness severity among 82 798 children with coronavirus disease 2019 from March 1, 2020, to December 30, 2021.

Pediatric Nirmatrelvir/Ritonavir Prescribing Patterns During the COVID-19 Pandemic.

Objective: This study was conducted to identify rates of pediatric nirmatrelvir/ritonavir (Paxlovid) prescriptions overall and by patient characteristics. Methods: Patients up to 23 years old with a clinical encounter and a nirmatrelvir/ritonavir (Paxlovid, n/r) prescription in a PEDSnet-affiliated institution between December 1, 2021 and September 14, 2022 were identified using electronic health record (EHR) data. Results: Of the 1,496,621 patients with clinical encounters during the study period, 920 received a nirmatrelvir/ritonavir prescription (mean age 17.2 years; SD 2.76 years). 40% (367/920) of prescriptions were provided to individuals aged 18-23, and 91% (838/920) of prescriptions occurred after April 1, 2022. The majority of patients (70%; 648/920) had received at least one COVID-19 vaccine dose at least 28 days before nirmatrelvir/ritonavir prescription. Only 40% (371/920) of individuals had documented COVID-19 within the 0 to 6 days prior to receiving a nirmatrelvir/ritonavir prescription. 53% (485/920) had no documented COVID-19 infection in the EHR. Among nirmatrelvir/ritonavir prescription recipients, 64% (586/920) had chronic or complex chronic disease and 9% (80/920) had malignant disease. 38/920 (4.5%) were hospitalized within 30 days of receiving nirmatrelvir/ritonavir. Conclusion: Clinicians prescribe nirmatrelvir/ritonavir infrequently to children. While individuals receiving nirmatrelvir/ritonavir generally have significant chronic disease burden, a majority are receiving nirmatrelvir/ritonavir prescriptions without an EHR-recorded COVID-19 positive test or diagnosis. Development and implementation of concerted pediatric nirmatrelvir/ritonavir prescribing workflows can help better capture COVID-19 presentation, response, and adverse events at the population level.

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study.

OBJECTIVE: To evaluate the odds of a behavioral health diagnosis among youth with differences of sex development (DSD) or congenital adrenal hyperplasia (CAH) compared with matched controls in the PEDSnet database. STUDY DESIGN: All youth with a diagnosis of DSD (n = 1216) or CAH (n = 1647) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) with controls (n = 4864 and 6588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. RESULTS: Youth with DSD had higher odds of a behavioral health diagnosis (OR, 1.7; 95% CI, 1.4-2.1; P < .0001) and neurodevelopmental diagnosis (OR, 1.7; 95% CI, 1.4, 2.0; P < .0001) compared with matched controls. Youth with CAH did not have an increased odds of a behavioral health diagnosis (OR, 1.0; 95% CI, 0.9, 1.1; P = .9) compared with matched controls but did have higher odds of developmental delay (OR, 1.8; 95% CI, 1.4, 2.4; P < .0001). CONCLUSIONS: Youth with DSD diagnosis have higher odds of a behavioral health or neurodevelopmental diagnosis compared with matched controls. Youth with CAH have higher odds of developmental delay, highlighting the need for screening in both groups.

Assessment of 135 794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States.

Importance: There is limited information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing and infection among pediatric patients across the United States. Objective: To describe testing for SARS-CoV-2 and the epidemiology of infected patients. Design, Setting, and Participants: A retrospective cohort study was conducted using electronic health record data from 135 794 patients younger than 25 years who were tested for SARS-CoV-2 from January 1 through September 8, 2020. Data were from PEDSnet, a network of 7 US pediatric health systems, comprising 6.5 million patients primarily from 11 states. Data analysis was performed from September 8 to 24, 2020. Exposure: Testing for SARS-CoV-2. Main Outcomes and Measures: SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) illness. Results: A total of 135 794 pediatric patients (53% male; mean [SD] age, 8.8 [6.7] years; 3% Asian patients, 15% Black patients, 11% Hispanic patients, and 59% White patients; 290 per 10 000 population [range, 155-395 per 10 000 population across health systems]) were tested for SARS-CoV-2, and 5374 (4%) were infected with the virus (12 per 10 000 population [range, 7-16 per 10 000 population]). Compared with White patients, those of Black, Hispanic, and Asian race/ethnicity had lower rates of testing (Black: odds ratio [OR], 0.70 [95% CI, 0.68-0.72]; Hispanic: OR, 0.65 [95% CI, 0.63-0.67]; Asian: OR, 0.60 [95% CI, 0.57-0.63]); however, they were significantly more likely to have positive test results (Black: OR, 2.66 [95% CI, 2.43-2.90]; Hispanic: OR, 3.75 [95% CI, 3.39-4.15]; Asian: OR, 2.04 [95% CI, 1.69-2.48]). Older age (5-11 years: OR, 1.25 [95% CI, 1.13-1.38]; 12-17 years: OR, 1.92 [95% CI, 1.73-2.12]; 18-24 years: OR, 3.51 [95% CI, 3.11-3.97]), public payer (OR, 1.43 [95% CI, 1.31-1.57]), outpatient testing (OR, 2.13 [1.86-2.44]), and emergency department testing (OR, 3.16 [95% CI, 2.72-3.67]) were also associated with increased risk of infection. In univariate analyses, nonmalignant chronic disease was associated with lower likelihood of testing, and preexisting respiratory conditions were associated with lower risk of positive test results (standardized ratio [SR], 0.78 [95% CI, 0.73-0.84]). However, several other diagnosis groups were associated with a higher risk of positive test results: malignant disorders (SR, 1.54 [95% CI, 1.19-1.93]), cardiac disorders (SR, 1.18 [95% CI, 1.05-1.32]), endocrinologic disorders (SR, 1.52 [95% CI, 1.31-1.75]), gastrointestinal disorders (SR, 2.00 [95% CI, 1.04-1.38]), genetic disorders (SR, 1.19 [95% CI, 1.00-1.40]), hematologic disorders (SR, 1.26 [95% CI, 1.06-1.47]), musculoskeletal disorders (SR, 1.18 [95% CI, 1.07-1.30]), mental health disorders (SR, 1.20 [95% CI, 1.10-1.30]), and metabolic disorders (SR, 1.42 [95% CI, 1.24-1.61]). Among the 5374 patients with positive test results, 359 (7%) were hospitalized for respiratory, hypotensive, or COVID-19-specific illness. Of these, 99 (28%) required intensive care unit services, and 33 (9%) required mechanical ventilation. The case fatality rate was 0.2% (8 of 5374). The number of patients with a diagnosis of Kawasaki disease in early 2020 was 40% lower (259 vs 433 and 430) than in 2018 or 2019. Conclusions and Relevance: In this large cohort study of US pediatric patients, SARS-CoV-2 infection rates were low, and clinical manifestations were typically mild. Black, Hispanic, and Asian race/ethnicity; adolescence and young adulthood; and nonrespiratory chronic medical conditions were associated with identified infection. Kawasaki disease diagnosis is not an effective proxy for multisystem inflammatory syndrome of childhood.

Personalized Medicine and Pediatric Asthma.

Asthma is a heterogeneous disorder described by a large number of clinical features. A growing body of literature on more specific asthma phenotypes provides evidence for a phenotype-based approach to management in which specific therapies are recommended based on patient and disease characteristics. This understanding, coupled with an increase in the number of available therapies for children with asthma, as well as emerging therapies and phenotypic markers, will allow for improved asthma management in the future.

Neonatal Lung Disease Associated with TBX4 Mutations.

Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.