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Background: Bronchopulmonary dysplasia, a sequela of preterm birth, is the most common chronic respiratory disorder in infancy, and the second most common in children. Despite this, clinical care remains highly variable with guidelines supported by limited evidence, and do not provide specific guidance for timing of clinical follow-up, echocardiography, modalities of pulmonary function testing, etc. OBJECTIVE/METHODS: To further our understanding of care delivery for BPD, we sought to describe outpatient care patterns at tertiary care centers through survey data from 27 well-established BPD programs., Results: We observed variability in referral patterns to outpatient BPD clinics, ancillary services provided, indications for follow-up echocardiograms, availability of lung function testing, and criteria for discharge from care., Conclusion: More comprehensive and detailed clinical guidelines similar to other pulmonary diseases such as asthma and cystic fibrosis should be developed to help standardize care and may improve long term outcomes., (© 2024 Wiley Periodicals LLC.)

Objective: To determine the association between indoor air pollution and respiratory morbidities in children with bronchopulmonary dysplasia (BPD) recruited from the multicenter BPD Collaborative., Study Design: A cross-sectional study was performed among participants <3 years old in the BPD Collaborative Outpatient Registry. Indoor air pollution was defined as any reported exposure to tobacco or marijuana smoke, electronic cigarette emissions, gas stoves, and/or wood stoves. Clinical data included acute care use and chronic respiratory symptoms in the past 4 weeks., Results: A total of 1011 participants born at a mean gestational age of 26.4 ± 2.2 weeks were included. Most (66.6%) had severe BPD. More than 40% of participants were exposed to ≥1 source of indoor air pollution. The odds of reporting an emergency department visit (OR, 1.7; 95% CI, 1.18-2.45), antibiotic use (OR, 1.9; 95% CI, 1.12-3.21), or a systemic steroid course (OR, 2.18; 95% CI, 1.24-3.84) were significantly higher in participants reporting exposure to secondhand smoke (SHS) compared with those without SHS exposure. Participants reporting exposure to air pollution (not including SHS) also had a significantly greater odds (OR, 1.48; 95% CI, 1.08-2.03) of antibiotic use as well. Indoor air pollution exposure (including SHS) was not associated with chronic respiratory symptoms or rescue medication use., Conclusions: Exposure to indoor air pollution, especially SHS, was associated with acute respiratory morbidities, including emergency department visits, antibiotics for respiratory illnesses, and systemic steroid use., Competing Interests: Declaration of Competing Interest Supported by the NIH (JLR: K23ES029985). All authors disclose that they have no financial interests in the subject of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To characterize a cohort of ventilator-dependent infants and children with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) and to describe their cardiorespiratory outcomes., Methods: Subjects with BPD on chronic home ventilation were recruited from outpatient clinics. PH was defined by its presence on ≥1 cardiac catheterization or echocardiogram on or after 36 weeks post-menstrual age. Kaplan-Meier analysis was used to compare the timing of key events., Results: Of the 154 subjects, 93 (60.4%) had PH and of those, 52 (55.9%) required PH-specific medications. The ages at tracheostomy, transition to home ventilator, and hospital discharge were older in those with PH. Most subjects were weaned off oxygen and liberated from the ventilator by 5 years of age, which did not occur later in subjects with PH. The mortality rate after initial discharge was 2.6%., Conclusions: The majority of infants with BPD-PH receiving chronic invasive ventilation at home survived after initial discharge. Subjects with BPD-PH improved over time as evidenced by weaning off oxygen and PH medications, ventilator liberation, and tracheostomy decannulation. While the presence of PH was not associated with later ventilator liberation or decannulation, the use of PH medications may be a marker of a more protracted disease trajectory., Impact Statement: There is limited data on long-term outcomes of children with bronchopulmonary dysplasia (BPD) who receive chronic invasive ventilation at home, and no data on those with the comorbidity of pulmonary hypertension (PH). Almost all subjects with BPD-PH who were on chronic invasive ventilation at home survived after their initial hospital discharge. Subjects with BPD-PH improved over time as evidenced by weaning off oxygen, PH medications, liberation from the ventilator, and tracheostomy decannulation. The presence of PH did not result in later ventilator liberation or decannulation; however, the use of outpatient PH medications was associated with later ventilation liberation and decannulation., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To identify factors associated with the timing of ventilator liberation and tracheostomy decannulation among infants with severe bronchopulmonary dysplasia (sBPD) who required chronic outpatient invasive ventilation., Study Design: Multicenter retrospective study of 154 infants with sBPD on outpatient ventilators. Factors associated with ventilator liberation and decannulation were identified using Cox regression models and multilevel survival models., Results: Ventilation liberation and decannulation occurred at median ages of 27 and 49 months, respectively. Older age at transition to a portable ventilator and at discharge, higher positive end expiratory pressure, and multiple respiratory readmissions were associated with delayed ventilator liberation. Surgical management of gastroesophageal reflux was associated with later decannulation., Conclusions: Ventilator liberation timing was impacted by longer initial admissions and higher ventilator pressure support needs, whereas decannulation timing was associated with more aggressive reflux management. Variation in the timing of events was primarily due to individual-level factors, rather than center-level factors., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: Our objective was to compare rates of hospitalizations for respiratory illnesses in preterm and full-term (FT) children for 4 years before and after the 2014 update to the American Academy of Pediatrics (AAP) respiratory syncytial virus (RSV) immunoprophylaxis guidance, which restricted eligibility among infants born at 29 to 34 weeks in the first winter and all preterm infants in the second winter after neonatal discharge., Study Design: We conducted pre-post and interrupted time series analyses on claims data from a commercial national managed care plan. We compared the number of RSV and all respiratory hospital admissions in the first and second RSV seasons after neonatal discharge among a cohort of preterm children, regardless of palivizumab status, in the 4 years before and after the implementation of the 2014 palivizumab eligibility change. A FT group was included for reference., Results: The cohort included 821 early preterm (EP, <29 weeks), 4,790 moderate preterm (MP, 29-34 weeks), and 130,782 FT children. Palivizumab use after the policy update decreased among MP children in the first and second RSV seasons after neonatal discharge, without any change in the odds of hospitalization with RSV or respiratory illness. For the EP group, there was no change in the rate of palivizumab or the odds of hospitalization with RSV or respiratory illness after the policy update. For the FT group, there was a slight decrease in odds of hospitalization post-2014 after the policy update. The interrupted time series did not reveal any secular trends over time in hospitalization rates among preterm children. Following the policy change, there were cost savings for MP children in the first and second RSV seasons, when accounting for the cost of hospitalizations and the cost of palivizumab., Conclusion: Hospitalizations for RSV or respiratory illness did not increase, and cost savings were obtained after the implementation of the 2014 AAP palivizumab prophylaxis policy., Key Points: · Palivizumab use decreased among children born moderate preterm (29 to34 weeks) after the 2014 palivizuamb policy update.. · There was no change in odds of hospitalization with respiratory syncitial virus or respiratory illness among preterm infants after the policy update when compared to before.. · There were cost savings, when accounting for the cost of hospitalizations and the cost of palivizumab, after the policy update among children born moderate preterm.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers., Study Design: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains., Results: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge., Conclusion: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD., Key Points: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Bronchopulmonary dysplasia (BPD), a common complication of prematurity, is associated with outpatient morbidities, including respiratory exacerbations. Daycare attendance is associated with increased rates of acute and chronic morbidities in children with BPD. We sought to determine if additional children in the household conferred similar risks for children with BPD., Methods: The number of children in the household and clinical outcomes were obtained via validated instruments for 933 subjects recruited from 13 BPD specialty clinics in the United States. Clustered logistic regression models were used to test for associations., Results: The mean gestational age of the study population was 26.5 ± 2.2 weeks and most subjects (69.1%) had severe BPD. The mean number of children in households (including the subject) was 2.1 ± 1.3 children. Each additional child in the household was associated with a 13% increased risk for hospital admission, 13% increased risk for antibiotic use for respiratory illnesses, 10% increased risk for coughing/wheezing/shortness of breath, 14% increased risk for nighttime symptoms, and 18% increased risk for rescue medication use. Additional analyses found that the increased risks were most prominent when there were three or more other children in the household., Conclusions: We observed that additional children in the household were a risk factor for adverse respiratory outcomes. We speculate that secondary person-to-person transmission of respiratory viral infections drives this finding. While this risk factor is not easily modified, measures do exist to mitigate this disease burden. Further studies are needed to define best practices for mitigating this risk associated with household viral transmission., (© 2023 Wiley Periodicals LLC.)

Objective: To estimate the association of transpyloric feeding (TPF) with the composite outcome of tracheostomy or death for patients with severe bronchopulmonary dysplasia (sBPD)., Study Design: Retrospective multi-center cohort study of preterm infants <32 weeks with sBPD receiving enteral feedings. We compared infants who received TPF at 36, 44, or 50 weeks post-menstrual age to those who did not receive TPF at any of those timepoints. Odds ratios were adjusted for gestational age, small for gestational age, male sex, and invasive ventilation and FiO 2 at 36 weeks., Results: Among 1039 patients, 129 (12%) received TPF. TPF was associated with an increased odds of tracheostomy or death (aOR 3.5, 95% CI 2.0-6.1) and prolonged length of stay or death (aOR 3.1, 95% CI 1.9-5.2)., Conclusions: Use of TPF in sBPD after 36 weeks was infrequent and associated with worse in-hospital outcomes, even after adjusting for respiratory severity at 36 weeks., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features., Objective: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRS Asthma ) and spirometry (FEV 1 and FEV 1 /forced vital capacity; PRS spiro ) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO)., Methods: We developed and tested 2 asthma PRSs and applied the higher performing PRS Asthma and a previously published PRS spiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry., Results: In meta-analyses of 102,477 participants, the PRS Asthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRS spiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRS spiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRS spiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRS Asthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRS spiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRS Asthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRS spiro was associated with asthma exacerbations in White, LatinX, and East Asian participants., Conclusions: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts., (Published by Elsevier Inc.)

Introduction: Data on the use of remote spirometry are limited in the pediatric population. We sought to assess the feasibility and accuracy of a digital turbine spirometer, Medical International Research (MIR) Spirobank Smart (MIR, New Berlin, WI, USA), compared with a pneumotachography spirometer, Pneumotrac (Vitalograph Inc., Lenexa, KS, USA), in field-based clinical research. Methods: This is a cross-sectional study of a subgroup of school-aged participants enrolled in the Air quality, Environment, and Respiratory Outcomes in Bronchopulmonary Dysplasia (BPD) study, who performed same-day paired coached baseline spirometry measurements from the Pneumotrac and MIR devices. Proportion of successful tests was estimated for each device and compared using McNemar's test. Correlation between devices forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) was analyzed by Lin's concordance correlation, and Bland-Altman plots were generated. Results: Twenty-one participants with history of BPD completed home spirometry maneuvers on both devices. The mean age of participants was 8.7 years. The mean FEV 1 and FVC measurement was 81% predicted and 90.4% predicted, respectively. The proportion of acceptable tests appeared higher using Pneumotrac (81%) than when using MIR (67%), although without evidence of discordance ( P  = 0.317). Among subjects with successful tests on both devices, Lin's concordance correlation demonstrated moderate agreement (FEV 1 r  = 0.955, 95% confidence interval [CI]: 0.87-0.98; FVC r  = 0.971, CI: 0.91-0.99). The mean difference in FEV 1 between Pneumotrac and MIR was 0.079 L (95% limits of agreement were -0.141 to 0.298 L) and FVC was 0.075 L (95% limits of agreement were -0.171 to 0.322 L). These were relatively small and without evidence of systematic or volume-dependent bias. Conclusions: Utilizing turbine spirometers may be a promising and feasible way to perform pulmonary function testing for field research in children.

Objective (s): Children with bronchopulmonary dysplasia (BPD) are at higher risk of respiratory insufficiency during respiratory illness. We aimed to investigate whether obstructive sleep apnea (OSA) is associated with increased morbidity among children with BPD hospitalized with acute respiratory illnesses., Study Design: Hospital discharge records were obtained from the Kid's Inpatient Database for children <21 years of age with BPD hospitalized for acute respiratory illness between 1997 and 2012. Acute respiratory illnesses included bacterial and/or viral pneumonia, bronchiolitis, acute upper respiratory tract infections, aspiration pneumonia, or asthma exacerbation. The primary exposure was OSA. The primary outcome was invasive mechanical ventilation (IMV), and secondary outcomes were noninvasive mechanical ventilation (NIMV), length of hospital stay (LOS), and inflation-adjusted cost of hospitalization (IACH). Multivariable regression was conducted to ascertain the associations between OSA and primary and secondary outcomes accounting for BPD-associated comorbidities., Results: Among 33,640 hospitalizations of children with BPD for acute respiratory illness, there were 607 (1.8%) cases with comorbid OSA vs. 33,033 (98.2%) controls without OSA. Patients with OSA were more likely to have aspiration pneumonia, central sleep apnea, obesity, laryngeal stenosis, congenital airway, and skull/face/jaw anomalies. Multivariable regression showed that OSA was associated with IMV (OR 1.45, 95% CI 1.09-1.94, p = 0.012) and NIMV (OR 2.61, 95% CI 1.71-3.98, p < 0.001), but not LOS or IACH., Conclusions: In BPD patients hospitalized with acute respiratory illness, having OSA is associated with increased risks for respiratory insufficiency requiring noninvasive or invasive mechanical ventilation. Clinicians should consider OSA, along with other BPD-associated comorbidities, in the management of this population., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objectives: Former premature infants with bronchopulmonary dysplasia (BPD) are at risk for hypoxemia during air travel, but it is unclear until what age. We aimed to determine pass rates for high altitude simulation testing (HAST) by age in children with BPD and identify risks for failure., Methods: Retrospective, observational analysis of HAST in children with BPD at Boston Children's Hospital, using interval censoring to estimate the time-to-event curve of first pass. Curves were stratified by neonatal risk factors. Pass was considered lowest Spo2 ≥ 90%, or ≥94% for subjects with ongoing pulmonary hypertension (PH)., Results: Ninety four HAST studies were analyzed from 63 BPD subjects; 59 studies (63%) were passed. At 3 months corrected gestational age (CGA), 50% of subjects had passed; at 6 months CGA, 67% has passed; at 12 and 18 months CGA, 72% had passed; and at 24 months CGA, 85% had passed. Neonatal factors associated with delayed time-to-pass included postnatal corticosteroid use, respiratory support at NICU discharge, and tracheostomy. BPD infants who did not require respiratory support at 36 weeks were likely to pass (91%) at 6 months CGA. At 24 months, children least likely to pass included those with a history of PH (63%) and those discharged from the NICU with oxygen or respiratory support (71%)., Conclusions: Children with BPD on respiratory support at 36 weeks should be considered for preflight hypoxemia challenges through at least 24 months CGA, and longer if they had PH or went home from NICU on respiratory support., (Copyright © 2023 by the American Academy of Pediatrics.)

Objectives: To describe outpatient respiratory outcomes and center-level variability among children with severe bronchopulmonary dysplasia (BPD) who require tracheostomy and long-term mechanical ventilation., Methods: Retrospective cohort of subjects with severe BPD, born between 2016 and 2021, who received tracheostomy and were discharged on home ventilator support from 12 tertiary care centers participating in the BPD Collaborative Outpatient Registry. Timing of key respiratory events including time to tracheostomy placement, initial hospital discharge, first outpatient clinic visit, liberation from the ventilator, and decannulation were assessed using Kaplan-Meier analysis. Differences between centers for the timing of events were assessed via log-rank tests., Results: There were 155 patients who met inclusion criteria. Median age at the time of the study was 32 months. The median age of tracheostomy placement was 5 months (48 weeks' postmenstrual age). The median ages of hospital discharge and first respiratory clinic visit were 10 months and 11 months of age, respectively. During the study period, 64% of the subjects were liberated from the ventilator at a median age of 27 months and 32% were decannulated at a median age of 49 months. The median ages for all key events differed significantly by center (P ≤ .001 for all events)., Conclusions: There is wide variability in the outpatient respiratory outcomes of ventilator-dependent infants and children with severe BPD. Further studies are needed to identify the factors that contribute to variability in practice among the different BPD outpatient centers, which may include inpatient practices., (Copyright © 2023 by the American Academy of Pediatrics.)

Introduction: Despite bronchopulmonary dysplasia (BPD) being a common morbidity of preterm birth, there is no validated objective tool to assess outpatient respiratory symptom control for clinical and research purposes., Methods: Data were obtained from 1049 preterm infants and children seen in outpatient BPD clinics of 13 US tertiary care centers from 2018 to 2022. A new standardized instrument was modified from an asthma control test questionnaire and administered at the time of clinic visits. External measures of acute care use were also collected. The questionnaire for BPD control was validated in the entire population and selected subgroups using standard methodology for internal reliability, construct validity, and discriminative properties., Results: Based on the scores from BPD control questionnaire, the majority of caregivers (86.2%) felt their child's symptoms were under control, which did not differ by BPD severity (p = 0.30) or a history of pulmonary hypertension (p = 0.42). Across the entire population and selected subgroups, the BPD control questionnaire was internally reliable, suggestive of construct validity (albeit correlation coefficients were -0.2 to -0.4.), and discriminated control well. Control categories (controlled, partially controlled, and uncontrolled) were also predictive of sick visits, emergency department visits, and hospital readmissions., Conclusion: Our study provides a tool for assessing respiratory control in children with BPD for clinical care and research studies. Further work is needed to identify modifiable predictors of disease control and link scores from the BPD control questionnaire to other measures of respiratory health such as lung function testing., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations., Methods: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses., Results: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV 1 /FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10 -08 ), with suggestive evidence of association with FEV 1 ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10 -07 ). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions., Conclusions: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease., (© 2023. The Author(s).)

Objective: To establish consensus practices among a panel of national experts for the discharge of premature infants with bronchopulmonary dysplasia (BPD) from the hospital to home., Study Design: We conducted a Delphi study that included US neonatologists and pediatric pulmonologists from the Bronchopulmonary Dysplasia Collaborative to establish consensus practices-defined as recommendations with at least 80% agreement-for infants with BPD being discharged from the hospital. Specifically, we evaluated recommendations for diagnostic tests to be completed around discharge, follow-up respiratory care, and family education., Results: Thirty-one expert participants completed 3 rounds of surveys, with a 99% response rate (92 of 93). Consensus was established that infants with moderate-severe BPD (ie, those who remain on respiratory support at 36 weeks) and those discharged on oxygen should be targeted for in-person pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal follow-up is an alternative for infants with mild BPD. Infants with moderate or severe BPD should have an echocardiogram performed after 36 weeks to screen for pulmonary hypertension. Infants with BPD warrant additional evaluations if they have growth restriction or poor growth, pulmonary hypertension, or tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral feeds., Conclusions: This Delphi survey establishes expert consensus around best practices for follow-up respiratory management and routine evaluation for infants with BPD surrounding neonatal discharge. Areas of disagreement for which consensus was not established are discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To test the hypothesis that daycare attendance among children with bronchopulmonary dysplasia (BPD) is associated with increased chronic respiratory symptoms and/or greater health care use for respiratory illnesses during the first 3 years of life., Study Design: Daycare attendance and clinical outcomes were obtained via standardized instruments for 341 subjects recruited from 9 BPD specialty clinics in the US. All subjects were former infants born preterm (<34 weeks) with BPD (71% severe) requiring outpatient follow-up between 0 and 3 years of age. Mixed logistic regression models were used to test for associations., Results: Children with BPD attending daycare were more likely to have emergency department visits and systemic steroid usage. Children in daycare up to 3 years of age also were more likely to report trouble breathing, having activity limitations, and using rescue medications when compared with children not in daycare. More severe manifestations were found in children attending daycare between 6 and 12 months of chronological age., Conclusions: In this study, children born preterm with BPD who attend daycare were more likely to visit the emergency department, use systemic steroids, and have chronic respiratory symptoms compared with children not in daycare, indicating that daycare may be a potential modifiable risk factor to minimize respiratory morbidities in children with BPD during the preschool years., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Preterm infants and young children with bronchopulmonary dysplasia (BPD) are at increased risk for acute care utilization and chronic respiratory symptoms during early life. Identifying risk factors for respiratory morbidities in the outpatient setting could decrease the burden of care. We hypothesized that public insurance coverage was associated with higher acute care usage and respiratory symptoms in preterm infants and children with BPD after initial neonatal intensive care unit (NICU) discharge., Methods: Subjects were recruited from BPD clinics at 10 tertiary care centers in the United States between 2018 and 2021. Demographics and clinical characteristics were obtained through chart review. Surveys for clinical outcomes were administered to caregivers., Results: Of the 470 subjects included in this study, 249 (53.0%) received employer-based insurance coverage and 221 (47.0%) received Medicaid as sole coverage at least once between 0 and 3 years of age. The Medicaid group was twice as likely to have sick visits (adjusted odd ratio [OR]: 2.06; p = 0.009) and emergency department visits (aOR: 2.09; p = 0.028), and three times more likely to be admitted for respiratory reasons (aOR: 3.04; p = 0.001) than those in the employer-based group. Additionally, those in the Medicaid group were more likely to have nighttime respiratory symptoms (aOR: 2.62; p = 0.004)., Conclusions: Children with BPD who received Medicaid coverage were more likely to utilize acute care and have nighttime respiratory symptoms during the first 3 years of life. More comprehensive studies are needed to determine whether the use of Medicaid represents a barrier to accessing care, lower socioeconomic status, and/or a proxy for detrimental environmental exposures., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone., Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?, Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10 -6 ) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2)., Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10 -8 ) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent., Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The long-term morbidity among children with severe bronchopulmonary dysplasia who require tracheostomy (tBPD) relative to those without tracheostomy (sBPD) is not well characterized. We compared childhood lung function and neurodevelopmental outcomes in tBPD and sBPD., Study Design: Retrospective case-control study of N = 49 tBPD and N = 280 sBPD subjects in Boston Children's Hospital Preterm Lung Patient Registry and medical record. We compared NICU course, childhood spirometry, and neurodevelopmental testing., Result: tBPD subjects were more likely than sBPD to be Black, have pulmonary hypertension, and have subglottic stenosis. tBPD subjects had lower maximal childhood FEV 1 % predicted (β = -0.14) and FEV 1 /FVC (β = -0.08); spirometry curves were more likely to suggest fixed extrathoracic obstruction. tBPD subjects had greater cognitive and motor delays <24 months, and greater cognitive delays >24 months., Conclusion: Compared to subjects with sBPD who did not require tracheostomy, tBPD subjects suffer from increased long-term impairment in respiratory function and neurodevelopment., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Bronchopulmonary dysplasia (BPD) is a common respiratory sequelae of preterm birth, for which longitudinal outpatient data are limited. Our objective was to describe a geographically diverse outpatient cohort of former preterm infants followed in BPD-disease specific clinics., Methods: Seven BPD specialty clinics contributed data using standardized instruments to this retrospective cohort study. Inclusion criteria included preterm birth (<37 weeks) and respiratory symptoms or needs requiring outpatient follow-up., Results: A total of 413 preterm infants and children were recruited (mean age: 2.4 ± 2.7 years) with a mean gestational age of 27.0 ± 2.8 weeks and a mean birthweight of 951 ± 429 grams of whom 63.7% had severe BPD. Total, 51.1% of subjects were nonwhite. Severe BPD was not associated with greater utilization of acute care/therapies compared to non-severe counterparts. Of children with severe BPD, differences in percentage of those on any home respiratory support (p = .001), home positive pressure ventilation (p = .003), diuretics (p < .001), inhaled corticosteroids (p < .001), and pulmonary vasodilators (p < .001) were found between centers, however no differences in acute care use were observed., Discussion: This examination of a multicenter collaborative registry of children born prematurely with respiratory disease demonstrates a diversity of management strategies among geographically distinct tertiary care BPD centers in the United States. This study reveals that the majority of children followed in these clinics were nonwhite and that neither variation in management nor severity of BPD at 36 weeks influenced outpatient acute care utilization. These findings suggest that post-neonatal intensive care unit factors and follow-up may modify respiratory outcomes in BPD, possibly independently of severity., (© 2021 Wiley Periodicals LLC.)

Introduction: Almost half of all school-age children with bronchopulmonary dysplasia (BPD) have asthma-like symptoms and more suffer from lung function deficits. While air pollution and indoor respiratory irritants are known to affect high-risk populations of children, few studies have objectively evaluated environmental contributions to long-term respiratory morbidity in this population. This study aimed to examine the role of indoor environmental exposures on respiratory morbidity in children with BPD., Methods and Analysis: The Air quality, Environment and Respiratory Ouctomes in BPD (AERO-BPD) study is a prospective, single-centre observational study that will enrol a unique cohort of 240 children with BPD and carefully characterise participants and their indoor home environmental exposures. Measures of indoor air quality constituents will assess the relationship of nitrogen dioxide (NO 2 ), particulate matter (PM 2.5 ), nitric oxide (NO), temperature and humidity, as well as dust concentrations of allergens, with concurrently measured respiratory symptoms and lung function.Adaptations to the research protocol due to the SARS-CoV-2 pandemic included remote home environment and participant assessments., Ethics and Dissemination: Study protocol was approved by the Boston Children's Hospital Committee on Clinical Investigation. Dissemination will be in the form of peer-reviewed publications and participant information products., Trial Registration Number: NCT04107701., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Survivors of prematurity are at risk for abnormal childhood lung function. Few studies have addressed trajectories of lung function and risk factors for abnormal growth in childhood. This study aims to describe changes in lung function in a contemporary cohort of children born preterm followed longitudinally in pulmonary clinic for post-prematurity respiratory disease and to assess maternal and neonatal risk factors associated with decreased lung function trajectories., Methods: Observational cohort of 164 children born preterm ≤ 32 weeks gestation followed in pulmonary clinic at Boston Children's Hospital with pulmonary function testing. We collected demographics and neonatal history. We used multivariable linear regression to identify the impact of neonatal and maternal risk factors on lung function trajectories in childhood., Results: We identified 264 studies from 82 subjects with acceptable longitudinal FEV 1 data and 138 studies from 47 subjects with acceptable longitudinal FVC and FEV 1 /FVC data. FEV 1 % predicted and FEV 1 /FVC were reduced compared to childhood norms. Growth in FVC outpaced FEV 1 , resulting in an FEV 1 /FVC that declined over time. In multivariable analyses, longer duration of mechanical ventilation was associated with a lower rate of rise in FEV 1 % predicted and greater decline in FEV 1 /FVC, and postnatal steroid exposure in the NICU was associated with a lower rate of rise in FEV 1 and FVC % predicted. Maternal atopy and asthma were associated with a lower rate of rise in FEV 1 % predicted., Conclusions: Children with post-prematurity respiratory disease demonstrate worsening obstruction in lung function throughout childhood. Neonatal risk factors including exposure to mechanical ventilation and postnatal steroids, as well as maternal atopy and asthma, were associated with diminished rate of rise in lung function. These results may have implications for lung function trajectories into adulthood.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers., Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene ® ) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model., Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women., Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at jcopdf@copdfoundation.org., (JCOPDF © 2020.)

Background: Previous studies have established a higher prevalence of vitamin D deficiency in patients with COPD, but the relationship between vitamin D levels and COPD exacerbations remains controversial. In addition, the effect of vitamin D levels on imaging characteristics remains mostly unexplored. Using cross-sectional and longitudinal follow up data from the COPDGene Study, we assessed the association between vitamin D levels on respiratory symptoms, exacerbations, and imaging characteristics. We hypothesized that vitamin D deficiency will be associated with worse respiratory-related outcomes., Methods: Current and former smokers between ages 45-80 were enrolled the COPDGene Study. Subjects completed questionnaires, spirometry, six-minute walk test, and chest computed tomography scans. A subset of subjects had measurement of serum concentration of 25-hydroxyvitamin D (25(OH)D). Vitamin D deficiency was defined as serum concentration less than 20 ng/mL. Longitudinal follow up was conducted via a web-based or telephone questionnaire., Results: Vitamin D levels were measured on 1544 current and former smokers, of which 981 subjects had sufficient vitamin D levels and 563 subjects had vitamin D deficiency. Subjects with vitamin D deficiency were younger with increased likelihood of being African American, being current smokers, having a lower percent predicted FEV 1 , and having COPD. Vitamin D deficiency was associated with worse quality of life, increased dyspnea, decreased exercise tolerance, and increased frequency of severe exacerbations. Vitamin D deficiency was also associated with increased segmental airway wall thickness on chest CT scans., Conclusion: Vitamin D deficiency was associated with increased respiratory symptoms, decreased functional status, increased frequency of severe exacerbations, as well as airway wall thickening on chest CT scans. Further research is needed to determine the potential impact of vitamin D supplementation to improve disease outcomes.

Asthma-COPD overlap (ACO) is a common clinical syndrome, yet there is no single objective definition. We hypothesized that immunoglobulin E (IgE) measurements could be used to refine the definition of ACO. In baseline plasma samples from 2870 participants in the COPD Genetic Epidemiology (COPDGene®) study, we measured total IgE levels and specific IgE levels to 6 common allergens. Compared to usual chronic obstructive pulmonary disease (COPD), participants with ACO (based on self-report of asthma) had higher total IgE levels (median 67.0 versus 42.2 IU/ml) and more frequently had at least one positive specific IgE (43.5% versus 24.5%). We previously used a strict definition of ACO in participants with COPD, based on self-report of a doctor's diagnosis of asthma before age 40. This strict ACO definition was refined by the presence of atopy, determined by total IgE > 100 IU/ml or at least one positive specific IgE, as was the broader definition of ACO based on self-reported asthma history. Participants with all 3 ACO definitions were younger (mean age 60.0-61.3 years), were more commonly African American (36.8%-44.2%), had a higher exacerbation frequency (1.0-1.2 in the past year), and had more airway wall thickening on quantitative analysis of chest computed tomography (CT) scans. Among participants with ACO, 37%-46% did not have atopy; these individuals had more emphysema on chest CT scan. Based on associations with exacerbations and CT airway disease, IgE did not clearly improve the clinical definition of ACO. However, IgE measurements could be used to subdivide individuals with atopic and non-atopic ACO, who might have different biologic mechanisms and potential treatments., Competing Interests: Dr. Hersh reports grant support from the National Institutes of Health and Novartis for this study. He reports grant support from Boehringer-Ingelheim and personal fees from AstraZeneca and 23andMe outside of this study. None of the other authors report any disclosures related to this study., (JCOPDF © 2020.)

Objective: To analyze longitudinal trends of pulmonary function testing in patients with congenital diaphragmatic hernia (CDH) followed in our multidisciplinary clinic., Study Design: This was a retrospective cohort study of CDH patients born between 1991 and 2013. A linear mixed effects model was fitted to estimate the trends of percent predicted forced expiratory volume in 1 second (FEV 1 pp), percent predicted forced vital capacity (FVCpp), and FEV 1 /FVC over time., Results: Of 268 patients with CDH who survived to discharge, 119 had at least 1 pulmonary function test study. The FEV 1 pp (P < .001), FVCpp (P = .017), and FEV 1 /FVC (P = .001) decreased with age. Compared with defect size A/B, those with defect size C/D had lower FEV 1 pp by an average of 11.5% (95% CI, 2.9%-20.1%; P = .010). A history of oxygen use at initial hospital discharge also correlated with decreased FEV 1 pp by an average of 8.0% (95% CI, 1.2%-15.0%; P = .023)., Conclusions: In a select cohort of CDH survivors, average pulmonary function declines with age relative to expected population normative values. Those with severe CDH represent a population at risk for worsening pulmonary function test measurements who may benefit from recognition and monitoring for complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene ® ), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality., Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene ® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV 1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined., Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene ® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics., Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at COPDC@njhealth.org., (JCOPDF © 2019.)

Background: Childhood asthma is strongly influenced by genetics and is a risk factor for reduced lung function and chronic obstructive pulmonary disease (COPD) in adults. This study investigates self-reported childhood asthma in adult smokers from the COPDGene Study. We hypothesize that childhood asthma is associated with decreased lung function, increased risk for COPD, and that a genome-wide association study (GWAS) will show association with established asthma variants., Methods: We evaluated current and former smokers ages 45-80 of non-Hispanic white (NHW) or African American (AA) race. Childhood asthma was defined by self-report of asthma, diagnosed by a medical professional, with onset at < 16 years or during childhood. Subjects with a history of childhood asthma were compared to those who never had asthma based on lung function, development of COPD, and genetic variation. GWAS was performed in NHW and AA populations, and combined in meta-analysis. Two sets of established asthma SNPs from published literature were examined for association with childhood asthma., Results: Among 10,199 adult smokers, 730 (7%) reported childhood asthma and 7493 (73%) reported no history of asthma. Childhood asthmatics had reduced lung function and increased risk for COPD (OR 3.42, 95% CI 2.81-4.18). Genotype data was assessed for 8031 subjects. Among NHWs, 391(7%) had childhood asthma, and GWAS identified one genome-wide significant association in KIAA1958 (rs59289606, p = 4.82 × 10 - 8 ). Among AAs, 339 (12%) had childhood asthma. No SNPs reached genome-wide significance in the AAs or in the meta-analysis combining NHW and AA subjects; however, potential regions of interest were identified. Established asthma SNPs were examined, seven from the NHGRI-EBI database and five with genome-wide significance in the largest pediatric asthma GWAS. Associations were found in the current childhood asthma GWAS with known asthma loci in IL1RL1, IL13, LINC01149, near GSDMB, and in the C11orf30-LRRC32 region (Bonferroni adjusted p < 0.05 for all comparisons)., Conclusions: Childhood asthmatics are at increased risk for COPD. Defining asthma by self-report is valid in populations at risk for COPD, identifying subjects with clinical and genetic characteristics known to associate with childhood asthma. This has potential to improve clinical understanding of asthma-COPD overlap (ACO) and enhance future research into ACO-specific treatment regimens., Trial Registration: ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008).

Background: Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions., Methods: Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at < 16 years. Childhood asthma was defined as self-reported asthma diagnosed by a health professional at < 16 years. ACO was defined as subjects with COPD who self-reported asthma diagnosed by a health-professional at ≤ 40 years. Smokers with and those without these early-life respiratory diseases were compared on measures of disease progression., Results: Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P < .001; ACO, P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans., Conclusions: Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period., Trial Registry: ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Previous studies have indicated that in adult smokers, a history of childhood pneumonia is associated with reduced lung function and chronic obstructive pulmonary disease. There have been few previous investigations using genome-wide association studies to investigate genetic predisposition to pneumonia. This study aims to identify the genetic variants associated with the development of pneumonia during childhood and over the course of the lifetime. Study subjects included current and former smokers with and without chronic obstructive pulmonary disease participating in the COPDGene Study. Pneumonia was defined by subject self-report, with childhood pneumonia categorized as having the first episode at <16 years. Genome-wide association studies for childhood pneumonia (843 cases, 9,091 control subjects) and lifetime pneumonia (3,766 cases, 5,659 control subjects) were performed separately in non-Hispanic whites and African Americans. Non-Hispanic white and African American populations were combined in the meta-analysis. Top genetic variants from childhood pneumonia were assessed in network analysis. No single-nucleotide polymorphisms reached genome-wide significance, although we identified potential regions of interest. In the childhood pneumonia analysis, this included variants in NGR1 (P = 6.3 × 10 -8 ), PAK6 (P = 3.3 × 10 -7 ), and near MATN1 (P = 2.8 × 10 -7 ). In the lifetime pneumonia analysis, this included variants in LOC339862 (P = 8.7 × 10 -7 ), RAPGEF2 (P = 8.4 × 10 -7 ), PHACTR1 (P = 6.1 × 10 -7 ), near PRR27 (P = 4.3 × 10 -7 ), and near MCPH1 (P = 2.7 × 10 -7 ). Network analysis of the genes associated with childhood pneumonia included top networks related to development, blood vessel morphogenesis, muscle contraction, WNT signaling, DNA damage, apoptosis, inflammation, and immune response (P ≤ 0.05). We have identified genes potentially associated with the risk of pneumonia. Further research will be required to confirm these associations and to determine biological mechanisms., Clinical Trial Registration: NCT00608764.

Background: Development of adult respiratory disease is influenced by events in childhood. The impact of childhood pneumonia on chronic obstructive pulmonary disease (COPD) is not well defined. We hypothesize that childhood pneumonia is a risk factor for reduced lung function and COPD in adult smokers., Methods: COPD cases and control smokers between 45-80 years old from the United States COPDGene Study were included. Childhood pneumonia was defined by self-report of pneumonia at <16 years. Subjects with lung disease other than COPD or asthma were excluded. Smokers with and without childhood pneumonia were compared on measures of respiratory disease, lung function, and quantitative analysis of chest CT scans., Results: Of 10,192 adult smokers, 854 (8.4%) reported pneumonia in childhood. Childhood pneumonia was associated with COPD (OR 1.40; 95% CI 1.17-1.66), chronic bronchitis, increased COPD exacerbations, and lower lung function: post-bronchodilator FEV1 (69.1 vs. 77.1% predicted), FVC (82.7 vs. 87.4% predicted), FEV1/FVC ratio (0.63 vs. 0.67; p < 0.001 for all comparisons). Childhood pneumonia was associated with increased airway wall thickness on CT, without significant difference in emphysema. Having both pneumonia and asthma in childhood further increased the risk of developing COPD (OR 1.85; 95% CI 1.10-3.18)., Conclusions: Children with pneumonia are at increased risk for future smoking-related lung disease including COPD and decreased lung function. This association is supported by airway changes on chest CT scans. Childhood pneumonia may be an important factor in the early origins of COPD, and the combination of pneumonia and asthma in childhood may pose the greatest risk., Clinical Trials Registration: ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008).

Lung function tracks from the earliest age that it can be reliably measured. Genome wide association studies suggest that most variants identified for common complex traits are regulatory in function and active during fetal development. Fetal programming of gene expression during development is critical to the formation of a normal lung. An understanding of how fetal developmental genes related to diseases of the lungs and airways is a critical area for research. This review article considers the developmental origins hypothesis, the stages of normal lung development and a variety of environmental exposures that might influence the developmental process: in utero cigarette smoke exposure, vitamin D and folate. We conclude with some information on developmental genes and asthma.