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Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Objective: This study describes the burden of prematurity-associated wheezing in black infants with respect to caregiver missed work. Study Design: We analyzed data from the D-Wheeze trial (ClinicalTrials.gov identifier NCT01601847). Black infants between 28-0/7 to 36-6/7 weeks’ gestational age at birth receiving

Caregivers frequently report poor quality of life (QOL) in children with sleep-disordered breathing (SDB). Our objective is to assess the correlation between caregiver- and child-reported QOL in children with mild SDB and identify factors associated with differences between caregiver and child report.Analysis of baseline data from a multi-institutional randomized trial.Pediatric Adenotonsillectomy Trial for Snoring, where children with mild SDB (obstructive apnea-hypopnea index3) were randomized to observation or adenotonsillectomy.The Pediatric Quality of Life Inventory (PedsQL) assessed baseline global QOL in participating children 5 to 12 years old and their caregivers. Caregiver and child scores were compared. Multivariable regression assessed whether clinical factors were associated with differences between caregiver and child report.PedsQL scores were available for 309 families (mean child age, 7.0 years). The mean caregiver-reported PedsQL score was higher at 75.2 (indicating better QOL) than the mean child-reported score of 67.9 (Caregiver- and child-reported global QOL in children with SDB was weakly correlated, more so for young children. In pediatric SDB, child-perceived QOL may be poorer than that reported by caregivers. Further research is needed to assess whether similar trends exist for disease-specific QOL metrics.

At the start of the Coronavirus Disease of 2019 (COVID-19) pandemic, the risk of cases in childcare programs was unknown. Thus, a rapid-response research approach was launched in Ohio childcare settings. Passive surveillance data from a state-operated incident reporting system were evaluated to estimate the number of COVID-19 cases from 15 August 2020 to 1 January 2021. Additionally, active surveillance with self-administered reverse transcriptase–polymerase chain reaction (RT-PCR) tests were conducted among staff at 46 childcare programs. Finally, six zoom-based focus groups with program administrators were used to gain feedback. Staff and children in childcare settings contributed 0.38% and 0.15% of the COVID-19 cases in Ohio during this timeframe, respectively. RT-PCR testing identified 3 unrecognized cases (0.88% of tests), and all occurred when the statewide positivity rate was >5%. Focus groups revealed that access to affordable cleaning supplies, masks, and reliable staffing were critical. Perhaps most importantly, we conclude that expanding the incident reporting system to include a childcare census would allow for the tracking of future health problems with highly valuable incidence rate estimations.

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Study Objectives Obstructive sleep apnea is associated with neurobehavioral dysfunction, but the relationship between disease severity as measured by the apnea-hypopnea index and neurobehavioral morbidity is unclear. The objective of our study is to compare the neurobehavioral morbidity of mild sleep-disordered breathing versus obstructive sleep apnea. Methods Children 3–12 years old recruited for mild sleep-disordered breathing (snoring with obstructive apnea-hypopnea index < 3) into the Pediatric Adenotonsillectomy Trial for Snoring were compared to children 5–9 years old recruited for obstructive sleep apnea (obstructive apnea-hypopnea 2–30) into the Childhood Adenotonsillectomy Trial. Baseline demographic, polysomnographic, and neurobehavioral outcomes were compared using univariable and multivariable analysis. Results The sample included 453 participants with obstructive sleep apnea (median obstructive apnea-hypopnea index 5.7) and 459 participants with mild sleep-disordered breathing (median obstructive apnea-hypopnea index 0.5). By polysomnography, participants with obstructive sleep apnea had poorer sleep efficiency and more arousals. Children with mild sleep-disordered breathing had more abnormal executive function scores (adjusted odds ratio 1.96, 95% CI 1.30–2.94) compared to children with obstructive sleep apnea. There were also elevated Conners scores for inattention (adjusted odds ratio 3.16, CI 1.98–5.02) and hyperactivity (adjusted odds ratio 2.82, CI 1.83–4.34) in children recruited for mild sleep-disordered breathing. Conclusions Abnormal executive function, inattention, and hyperactivity were more common in symptomatic children recruited into a trial for mild sleep-disordered breathing compared to children recruited into a trial for obstructive sleep apnea. Young, snoring children with only minimally elevated apnea-hypopnea levels may still be at risk for deficits in executive function and attention. Trial Registration Pediatric Adenotonsillectomy for Snoring (PATS), NCT02562040; Childhood Adenotonsillectomy Trial (CHAT), NCT00560859

Introduction Among individuals with severe asthma, FEV1 is low in individuals with low dehydroepiandrosterone (DHEA) sulfate (DHEAS) levels. In the Severe Asthma Research Program (SARP), no women with DHEAS > 200 μg/dL had an FEV1 1 in asthmatic women with low DHEAS. Methods Premenopausal, nonsmoking, otherwise healthy women, 18-50 years old, with mild or moderate asthma and baseline FEV1 > 60% predicted received 100 mg DHEA orally every 12 h for 2 weeks. Spirometry and DHEAS were measured at the initial visit and 2 weeks later, after completion of DHEA treatment. Based on our previous work, the primary outcome variable for this pilot study was post-albuterol spirometry in the low-DHEAS group. Subjects also continued their other routine asthma management. Results Serum DHEAS increased with DHEA treatment in women with starting DHEAS n = 10; p = 0.0001). The increase in the high-DHEAS group was smaller. Post-albuterol FEV1 increased by 51 mL, from 3.026 ± 0.5 to 3.077 ± 0.49 L (n = 10; p = 0.034 by paired t test, significant after Bonferroni), in women with low DHEAS. In the high-DHEAS group (baseline DHEAS ≥ 200 µg/dl), post-albuterol FEV1 did not change significantly (n = 3, p = NS). Three subjects were excluded: one had comorbid COPD, one could not perform spirometry, and one did not take the DHEA. There were no adverse effects of DHEA treatment in this trial. Conclusions Endocrine treatments (corticosteroids) are a mainstay of anti-inflammatory management for moderate and severe asthma. Their use has improved asthma outcomes. Androgens also reduce airway inflammation and promote airway smooth muscle relaxation, but are rarely used clinically for asthma treatment. Our results suggest that the over-the-counter steroid DHEA may improve lung function in asthma outcomes among women with DHEAS

BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (

BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of two common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus (Der p), and IgE to Blattella germanica (Bla g) were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma study (VDKA), a multicenter, double-blind, randomized placebo-controlled trial of vitamin D(3) supplementation (4,000 IU/day) to prevent severe exacerbations in children with persistent asthma and vitamin D levels

Over 25% of U.S. children are witness to traumatic intrafamilial or community violence each year, and sleep medicine and developmental research jointly suggest that trauma-exposed youth experience more sleep disturbance than their non-exposed counterparts. Sleep medicine literature emphasizes physical and social environmental factors affecting sleep, and trauma literature underscores children’s seeking out physically and emotionally safe and predictable environments during trauma recovery. This study employed a hermeneutic phenomenological framing to explore the lived experiences of 65 violence-exposed children and families, and to examine how youths’ social and physical sleep environments facilitated or impeded sleep in the aftermath of trauma. Children’s sleep experiences following violence exposure shared two primary essences of experience: a) navigating external threats that agitated sleep after trauma; and b) exercising agency over sleep and related environments to restabilize emotional security. Clinicians and social services coordinators working with children and families are uniquely positioned to indicate sleep assessments as part of treatment following trauma, and to also facilitate identification of tangible, sleep-supportive and changeable factors in sleep environments.

Vitamin D supplementation, compared with placebo, had no significant effect on percent predicted lung function measures (FEV1, FVC, or FEV1/FVC), asthma control, or asthma-related quality of life in children with asthma and low vitamin D levels. Observational studies have shown that low vitamin D levels are linked to worse lung function and poor asthma control in children with asthma. We hypothesized that vitamin D supplementation would improve function, disease control, and quality of life in children with asthma (ages 6–16 years) and vitamin D levels below 30 ng·mL−1. We tested this hypothesis in a secondary analysis of data from the Vitamin D Kids Asthma Study (VDKA), a randomized, double-blind, parallel, placebo-controlled clinical trial. Each participant in the VDKA was randomly assigned to either daily placebo capsules or daily vitamin D3 (4000 IU) plus low-dose inhaled fluticasone propionate. Of the 192 randomized participants, 176 were included in the analysis of change in percent predicted lung function measures (FEV1, FVC, and FEV1/FVC) and asthma control scores. Of these 176 participants, 94 were also included in the analysis of change in asthma-related quality of life scores, as they were 10 years and older. Linear regression was used for the multivariable analysis of vitamin D supplementation and each outcome, which was adjusted for study site, race, sex, and time in the study. In this analysis, vitamin D supplementation was not significantly associated with change in any outcome (lung function measures, asthma control, or asthma-related quality of life) between the randomization and exit visits. Our results do not support recommending vitamin D supplementation to improve lung function, asthma control, or asthma-related quality of life in children with asthma and vitamin D levels below 30 ng·mL−1. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Han has nothing to disclose. Conflict of interest: Dr. Forno has nothing to disclose. Conflict of interest: Dr. Bacharier has nothing to disclose. Conflict of interest: Dr. Phipatanakul reports personal fees from GSK, Genentech, Novartis, Regeneron, Sanofi, and Teva, grants from Genentech, Novartis, Regeneron, Sanofia, Circassia, Monaghen, Thermo Fisher, Alk Abello, Lincoln Diagnostics, GSK, Kaleo, and Merck, grants from Genentech, Regeneron, Novartis, and the US NIH, outside the submitted work; . Conflict of interest: Dr. Guilbert reports personal fees from American Board of Pediatrics (Pediatric Pulmonary Sub-board), GSK, TEVA, and Sanofi/Regeneron, grants from Astra-Zeneca, Novartis, and Sanofi/Regeneron, non-financial support from Up To Date, outside the submitted work; . Conflict of interest: Dr. Cabana reports other from United States Preventive Services Task Force (USPSTF), outside the submitted work; . Conflict of interest: Dr. Ross has nothing to disclose. Conflict of interest: Dr. Blatter has nothing to disclose. Conflict of interest: Dr. Rosser has nothing to disclose. Conflict of interest: Dr. Durrani has nothing to disclose. Conflict of interest: Dr. Luther has nothing to disclose. Conflict of interest: Dr. Wisniewski has nothing to disclose. Conflict of interest: Dr. Celedon reports non-financial support from Pharmavite and GSK, during the conduct of the study; non-financial support from Merck, outside the submitted work.Dr. Celedon reports non-financial support from Pharmavite and GSK, during the conduct of the study; non-financial support from Merck, outside the submitted work; .

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. Alarge proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients’ biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Coronavirus Disease 2019 (COVID-19) has been an unprecedented and continuously evolving healthcare crisis. SARS-CoV-2 spread rapidly and initially little was known about the virus or the clinical course for infected children. In the United States of America, the medical response has been regionalized, based on variation in community transmission of the virus and localized outbreaks. Pediatric pulmonary and sleep divisions evolved in response to the administrative and clinical challenges. As the workforce transitioned to working remotely, video conferencing technology and multicenter collaborative efforts were implemented to create clinical protocols. The COVID-19 pandemic challenges the framework of current medical practice but also highlights the dynamic and cooperative nature of pediatric pulmonology and sleep medicine. Our response to this pandemic has laid the groundwork for future challenges. This article is protected by copyright. All rights reserved.

Importance Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3supplementation reduces severe childhood asthma exacerbations is unclear. Objective To determine whether vitamin D3supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old). Main Outcomes and Measures The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3group vs 253 days in the placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85];P = .63). Vitamin D3supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3group, n = 11; placebo group, n = 9). Conclusions and Relevance Among children with persistent asthma and low vitamin D levels, vitamin D3supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02687815

Objective To test the effects of inhaled ipratropium on clinical outcomes of critical asthma in the first randomized trial of this adjunctive therapy in critically ill children. Design Pilot, placebo-controlled, double-blinded, and randomized-controlled trial PATIENTS: Thirty children (15 per group) with critical asthma receiving high-intensity albuterol per a standardized pathway utilizing objective assessments to wean patients to less frequent albuterol administration. Interventions Subjects were randomized to receive either nebulized ipratropium bromide (500 µg in 0.9% saline per dose) or an equivalent volume of nebulized 0.9% saline every 6 h until the patient was successfully weaned to albuterol doses every 2 h ("q2 albuterol"). Measurements and main results Demographics, initial clinical severity score, and asthma histories were similar between groups. There was no significant difference in the median duration of high-intensity albuterol between the treatment group (17.5 [10.3-22.1] h) and placebo group (14.6 [12.7-24.5] days; p = .56). Similarly, there was no significant difference in pediatric intensive care unit length of stay (22.6 [21.1-33.6] vs. 21.4 [16.1-35.8] h; p = .74) or hospital length of stay (48.0 [41.8-59.8] vs. 47.3 [37.2-63.1] h; p = .67). In multivariate linear regression adjusting for identified confounders, treatment with ipratropium was not significantly associated with any of the three outcomes. Side effects were rare and occurred with equally between both groups CONCLUSIONS: Adjunctive therapy with ipratropium was not associated with decreased duration of high-intensity albuterol or shortened length of stay when compared to placebo. A larger, multicenter trial is warranted to confirm that ipratropium does not improve clinical outcomes.

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers. Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers. Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers. Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV(1) and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number. Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.

Unprecedented opportunities and daunting difficulties are anticipated in the future of pediatric pulmonary medicine. To address these issues and optimize pediatric pulmonary training, a group of faculty from various institutions met in 2019 and proposed specific, long-term solutions to the emerging problems in the field. Input on these ideas was then solicited more broadly from faculty with relevant expertise and from recent trainees. This proposal is a synthesis of these ideas. Pediatric pulmonology was among the first pediatric specialties to be grounded deliberately in science, requiring its fellows to demonstrate expertise in scientific inquiry (1). In the future, we will need more training in science, not less. Specifically, the scope of scientific inquiry will need to be broader. The proposal outlined below is designed to help optimize the practices of current providers and to prepare the next generation to be leaders in pediatric care in the future. We are optimistic that this can be accomplished. Our broad objectives are (a) to meet the pediatric subspecialty workforce demand by increasing interest and participation in pediatric pulmonary training; (b) to modernize training to ensure that future pediatric pulmonologists will be prepared clinically and scientifically for the future of the field; (c) to train pediatric pulmonologists who will add value in the future of pediatric healthcare, complemented by advanced practice providers and artificial intelligence systems that are well-informed to optimize quality healthcare delivery; and (d) to decrease the cost and improve the quality of care provided to children with respiratory diseases.

BACKGROUND: Oxygen exposure has been associated with increased wheezing and respiratory morbidity after discharge in extremely preterm infants and those with bronchopulmonary dysplasia. More mature preterm infants with less severe disease are also at risk for pulmonary complications, including rehospitalization for respiratory illnesses and wheezing disorders. Our aim was to evaluate associations between respiratory support and morbidity in preterm infants without bronchopulmonary dysplasia. METHODS: A secondary analysis was performed on 300 infants born at 28–34 weeks gestation without bronchopulmonary dysplasia. Exposure included oxygen or positive pressure, (continuous positive airway pressure or mechanical ventilation). The primary outcome was recurrent wheezing. Secondary outcomes were respiratory medications, emergency room visits, and hospitalizations. RESULTS: 50% of infants who received oxygen experienced recurrent wheezing compared to 42.4% of infants who did not (OR 1.15 CI 0.72–1.85 adjusted OR 1.15 CI 0.67–1.98). 51.1% of infants who received positive pressure experienced recurrent wheezing compared to 38.1% who did not (OR 1.57 CI 0.97–2.53 adjusted OR 1.58 CI 0.90–2.77). There were no significant associations between oxygen and positive pressure exposure and any primary or secondary outcomes in the adjusted analyses. CONCLUSIONS: After adjustment for known risk factors the analyses showed no significant associations between oxygen and positive pressure with respiratory morbidity in this population. Further study of infants with mild disease is needed.

Background Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. Methods To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6–18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. Results From pre−/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. Conclusions These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. Trial registration ClinicalTrials.gov registration number: NCT01748175. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

OBJECTIVES: To identify associations between use of ipratropium and/or intravenous magnesium and outcomes of children hospitalized with acute asthma exacerbations and treated with continuous albuterol. METHODS: Secondary analysis of data from children prospectively enrolled in the multicenter Ohio Pediatric Asthma Repository restricted to only children who were treated with continuous albuterol in their initial inpatient location. Children were treated with adjunctive therapies per the clinical team. RESULTS: Among 242 children who received continuous albuterol, 94 (39%) received ipratropium only, 13 (5%) received magnesium alone, 42 (17%) received both, and 93 (38%) received neither. The median duration of continuous albuterol was 7.0 (interquartile range [IQR]: 2.8–12.0) hours. Ipratropium use was associated with a shorter duration of continuous albuterol (4.9 [IQR: 2.0–10.0] hours) compared with dual therapy (11.0 [IQR: 5.6–28.6] hours; P = .001), but magnesium use was not (7.5 [IQR: 2.5–16.0] hours; P = .542). In Cox proportional models (adjusted for hospital, demographics, treatment location, and respiratory failure), magnesium was associated with longer durations of continuous albuterol (hazard ratio, 0.54 [95% confidence interval: 0.37–0.77]; P < .001) and hospitalization (hazard ratio, 0.41 [95% confidence interval: 0.28–0.60]; P < .001), but ipratropium was not. CONCLUSIONS: Ipratropium and magnesium were both often used in children with severe asthma hospitalizations that required continuous albuterol therapy. Magnesium use was associated with unfavorable outcomes, possibly reflecting preferential treatment to patients with more severe cases and differing practices between centers. Given the high prevalence of asthma, wide variations in practice, and the potential to improve outcomes and costs, prospective trials of these adjunctive therapies are needed.

BackgroundExposure to violence has been associated with lower lung function in cross-sectional studies.MethodsWe examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9–16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)).ResultsIn a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI −6.44– −0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI −4.86– −0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI −0.50– −0.10 points; p1 and FVC were obtained in the prospective study of Puerto Rican youth.ConclusionsOur findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

Severe acute exacerbations are common in children with asthma. They are troublesome to patients and caregivers, can result in long-term morbidity, and are costly. While severe (requiring emergency room and hospital-based care) and life-threatening (with impending or established respiratory failure requiring intensive care unit-based care) exacerbations can occur in any child with asthma, children with more severe chronic asthma and those with a recent exacerbation are at highest risk. Systemic corticosteroids and beta2-agonists are the primary treatments used, with many adjunctive therapies available although less well studied.

Objective: Little is known about weight status and its effects on clinical course during hospitalization for asthma exacerbation. We sought to evaluate associations between weight status, specifica...

Severe asthma is broadly defined as asthma requiring a high level of therapy, usually high doses of inhaled corticosteroids, to bring under control. Children who remain symptomatic despite such treatment are a heterogeneous population, and bear a high burden of disease and require high resource utilization. Children with severe asthma require a comprehensive evaluation, careful consideration of alternative diagnoses and comorbid conditions, assessment of medication adherence and environmental conditions, and frequent disease monitoring.

Asthma is a heterogeneous developmental disorder influenced by complex interactions between genetic susceptibility and exposures. Wheezing in infancy and early childhood is highly prevalent, with a substantial minority of children progressing to established asthma by school age, most of whom are atopic. Adolescence is a time of remission of symptoms with persistent lung function deficits. The transition to asthma in adulthood is not well understood.

Background Tools for quantification of asthma severity are limited. Objective We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Methods Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. Results ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. Conclusions The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

Adherence to positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) remains a challenge in children. We hypothesized that the presence of another family member on PAP therapy (parent, sibling, other family member) would be associated with better adherence in the child.We conducted a retrospective chart review to identify children18 years of age who had a new diagnosis of OSA between Jan 2011 and May 2013. Outcomes were objective PAP adherence at 1 week, 1 month, and 3 months. Potential predictors included family member on PAP therapy, patient demographics, and clinical characteristics. Group differences between children with and without a family member on PAP therapy were determined using χ(2) test and Wilcoxon two-sample test. PAP adherence measures at each time point and patterns of change across time between the two groups were examined using mixed-effects models.The final analytic sample included 56 children: age 13.2 ± 3.7 years, 60% male, 67% African American, 65% obese, and 32% with developmental disabilities. The mean obstructive apnea-hypopnea index was 25.2 ± 28.7, and 19 (33%) had a family member on PAP therapy. Overall PAP adherence was 2.8 ± 2.4 h/night at 3 months. At month 3, the group with a family member on PAP therapy had significantly greater average nightly PAP use on all nights (3.6 ± 0.6 vs. 2.3 ± 0.39) and on nights used (4.8 ± 0.6 vs. 3.8 ± 0.40); (p value = 0.04).Overall PAP adherence was low, but having a family member on PAP therapy as a "role model" was associated with better adherence.A commentary on this article appears in this issue on page 941.

Objectives To determine differences in the incidence of respiratory morbidity during the first year of life among infants born 32 0/7 -34 6/7 weeks' gestational age (GA) before and after the administration policy for palivizumab, as written by the American Academy of Pediatrics, was updated in 2009. Study design Secondary analysis of the dataset collected for the Gastrointestinal Risk Factors for Wheezing in Premature Infants study, which enrolled preterm infants without bronchopulmonary dysplasia and followed them by parental questionnaires at 3, 6, 9, and 12 months adjusted age for prematurity. Participants were included if they were enrolled in Gastrointestinal Risk Factors for Wheezing in Premature Infants, born 32 0/7 -34 6/7 weeks' GA, and completed the 12-month questionnaire. We compared rates of recurrent wheezing, respiratory medication use, and health care use before (Epoch 1) and after (Epoch 2) the 2009 administration policy change. Results A total of 165 infants met inclusion criteria. There was a significant increase in recurrent wheezing in Epoch 2 (46.2%) vs Epoch 1 (28.8%) (OR 2.22 [95% CI 1.08-4.53], P = .03). There was a nonsignificant increase in visits to the emergency department in Epoch 2 (27.4%) vs Epoch 1 (15.3%) (OR 2.12 [95% CI 0.91-4.96], P = .08). There were no differences in hospital admissions or respiratory medication use. Conclusions Infants born 32 0/7 -34 6/7 weeks' GA treated after the American Academy of Pediatrics administration policy change in 2009 had a greater incidence of recurrent wheezing than those treated according to the previous policy. It will be important to track rates of recurrent wheezing after the 2014 administration policy, because it may be an important factor in future cost-effectiveness analyses.

Restoration of vitamin D sufficiency may reduce asthma exacerbations, events that are often associated with respiratory tract infections and cold symptoms.To determine whether vitamin D supplementation reduces cold symptom occurrence and severity in adults with mild to moderate asthma and vitamin D insufficiency.Colds were assessed in the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial, in which 408 adult patients were randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy. The primary outcome was cold symptom severity, which was assessed using daily scores on the 21-item Wisconsin Upper Respiratory Symptom Survey.A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1-43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1-68.9; placebo] and 58.7 [95% CI, 52.4-65.0; vitamin D]; P = 0.39). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9-1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1-2.7; P = 0.02). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1-1.7; P = 0.009).Our findings in patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction do not support the use of vitamin D supplementation for the purpose of reducing cold severity or frequency.

IntroductionMild obstructive sleep-disordered breathing (oSDB), characterised by habitual snoring without frequent apnoeas and hypopnoeas on polysomnography, is prevalent in children and commonly treated with adenotonsillectomy (AT). However, the absence of high-level evidence addressing the role of AT in improving health and behavioural outcomes has contributed to significant geographical variations in care and potential for surgery to be both overused and underused.Methods and analysisThe Pediatric Adenotonsillectomy Trial for Snoring (PATS) is a single-blinded, multicentre randomised controlled trial designed to evaluate the effect of AT in treating mild oSDB. Four hundred sixty eligible children, aged 3.0–12.9 years old, will be randomised to either early adenotonsillectomy or to watchful waiting with supportive care (WWSC) with a 1:1 ratio. The study’s coprimary endpoints are (1) change from baseline in executive behaviour relating to self-regulation and organisation skills as measured by the Behavioural Rating Inventory of Executive Function (BRIEF) Global Composite Score (GEC); and (2) change from baseline in vigilance as measured on the Go-No-Go (GNG) signal detection parameter (d-prime). A mixed effects model will be used to compare changes in the BRIEF GEC score and GNG score at 6 and 12 months from baseline between the AT arm and the WWSC arm.Ethics and disseminationThe study protocol was approved by the institutional review board (IRB) at Children’s Hospital of Philadelphia (CHOP) on 3 October 2014 (14–0 11 214). The approval of CHOP as the central IRB of record was granted on 29 February 2016. The results will be published in peer-reviewed journals and presented at academic conferences. The data collected from the PATS study will be deposited in a repository (National Sleep Research Resource, sleepdata.org) after completion of the study to maximise use by the scientific community.Trial registration numberNCT02562040; Pre-results.

Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma.We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence.Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually.At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/μL.In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.

Background: The programming of sleep architecture begins in pregnancy and depends upon optimal in utero formation and maturation of the neural connectivity of the brain. Particulate air pollution exposure can disrupt fetal brain development but associations between fine particulate matter (PM2.5) exposure during pregnancy and child sleep outcomes have not been previously explored. Methods: Analyses included 397 mother-child pairs enrolled in a pregnancy cohort in Mexico City. Daily ambient prenatal PM2.5 exposure was estimated using a validated satellite-based spatio-temporally resolved prediction model. Child sleep periods were estimated objectively using wrist-worn, continuous actigraphy over a 1-week period at age 4–5 years. Data-driven advanced statistical methods (distributed lag models (DLMs)) were employed to identify sensitive windows whereby PM2.5 exposure during gestation was significantly associated with changes in sleep duration or efficiency. Models were adjusted for maternal education, season, child's age, sex, and BMI z-score. Results: Mother's average age was 27.7 years, with 59% having at least a high school education. Children slept an average of 7.7 h at night, with mean 80.1% efficiency. The adjusted DLM identified windows of PM2.5 exposure between 31 and 35 weeks gestation that were significantly associated with decreased sleep duration in children. In addition, increased PM2.5 during weeks 1–8 was associated with decreased sleep efficiency. In other exposure windows (weeks 39–40), PM2.5 was associated with increased sleep duration. Conclusion: Prenatal PM2.5 exposure is associated with altered sleep in preschool-aged children in Mexico City. Pollutant exposure during sensitive windows of pregnancy may have critical influence upon sleep programming. Keywords: Particulate matter, Air pollution, Prenatal, Sleep, Child, Preschool-aged

BACKGROUND: Large-scale, multisite studies in which researchers evaluate patient- and systems-level factors associated with pediatric asthma exacerbation outcomes are lacking. We sought to investigate patient-level risks and system-level practices related to physiologic readiness for discharge (PRD) in the prospective Ohio Pediatric Asthma Repository. METHODS: Participants were children ages 2 to 17 years admitted to an Ohio Pediatric Asthma Repository hospital for asthma exacerbation. Demographics, disease characteristics, and individual hospital practices were collected. The primary outcome was PRD timing (hours from admission or emergency department [ED] presentation until the first 4-hour albuterol spacing). RESULTS: Data for 1005 participants were available (865 ED presentations). Several nonstandard care practices were associated with time to PRD (P < .001). Continuous pulse oximetry was associated with increased time to PRD (P = .004). ED dexamethasone administration was associated with decreased time to PRD (P < .001) and less ICU admittance and intravenous steroid use (P < .0001). Earlier receipt of chest radiograph, antibiotics, and intravenous steroids was associated with shorter time to PRD (P < .05). Care practices associated with shorter time to PRD varied markedly by hospital. CONCLUSIONS: Substantial variation in care practices for inpatient asthma treatment exists among children’s hospital systems in Ohio. We found several modifiable, system-level factors and therapies that contribute to PRD that warrant further investigation to identify the best and safest care practices. We also found that there was no standardized measure of exacerbation severity used across the hospitals. The development of such a tool is a critical gap in current practice and is needed to enable definitive comparative effectiveness studies of the management of acute asthma exacerbation.

Emergence of sleep states and maturation of control of breathing during sleep and wake are critical developmental milestones. These important developmental trajectories may be adversely affected by the direct impact of premature birth, by comorbid conditions, by neonatal treatments, and by environmental and treatment-related exposures in the perinatal period. Disorders of respiratory control, including sudden infant death syndrome and obstructive sleep apnea syndrome, are more common in infants and children born prematurely. The effects of prematurity on disordered breathing during sleep are most apparent in young children, while effects on circadian rhythm persist into adulthood.