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Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not. Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.

Abstract Background Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. Purpose To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. Methods The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. Results Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. Conclusions Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the child’s care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth. Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34± 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth.

Emerging evidence suggests that adverse early life events can affect long-term health trajectories throughout life. Preterm birth, in particular, is a significant early life event that affects approximately 10% of live births. Worldwide, prematurity is the number one cause of death in children less than 5 years of age and has been shown to disrupt normal lung development with lasting effects into adult life. Along with impaired lung development, interventions used to support gas exchange and other sequelae of prematurity can lead to the development of bronchopulmonary dysplasia (BPD). BPD is a chronic respiratory disease of infancy characterized by alveolar simplification, small airways disease, and pulmonary vascular changes. Although many survivors of BPD improve with age, survivors of BPD often have chronic lung disease characterized by airflow obstruction and intermittent pulmonary exacerbations. Long-term lung function trajectories as measured by FEV1 can be lower in children and adults with a history BPD. In this review, we discuss the epidemiology and manifestations of BPD and its long-term consequences throughout childhood and into adulthood. Available evidence suggests that disrupted lung development, genetic susceptibility and subsequent environment and infectious events that occur in prenatal and postnatal life likely increase the predisposition of children with BPD to develop early onset chronic obstructive pulmonary disease (COPD). The reviews of this paper are available via the supplemental material section.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability globally. While genetic and environmental risk factors are known, these insights have not yet resulted in individualized prevention strategies. Polygenic scores (PS) have enhanced our understanding of genetic risk and early-life lung function differences, but their applicability across diverse populations remains unclear. As such, we aimed evaluate whether a COPD PS captures population-wide risk or disproportionately affects sub-populations defined by ancestry or sex. This observational study assessed the association between a previously validated COPD PS and lung function in children with asthma, using spirometry results from children with asthma in the Center of Applied Genomics biorepository. Mixed-effects linear regression models were used to examine the relationship between PS and spirometry measures (FEV1 and FEV1/FVC), with stratified analyses by sex and ancestry. 25,477 spirometry results from 6336 patients were included. Population-wide, children in the high PS group had significantly lower FEV1/FVC z-scores compared to the low PS group ( P  = 0.0037, beta =  − 0.11, 95% confidence interval [CI] − 0.18 to − 0.036). When stratified by sex, high PS was associated with lower FEV1/FVC z-scores in males ( P  = 0.0088, beta =  − 0.14, 95% CI − 0.24 to − 0.035), but no significant effect was found in females. Ancestry-specific analysis revealed that males of European (EUR) ancestry with high PS had significantly lower FEV1 ( P  = 0.0035, beta =  − 0.37, 95% CI − 0.63 to − 0.12) and FEV1/FVC z-scores ( P  = 0.00076, beta =  − 0.35, 95% CI − 0.55 to − 0.15). No significant associations were observed in females with EUR ancestry or in African ancestry groups. Logistic regression analysis showed that high PS in males of EUR ancestry increased the odds of having an FEV1/FVC ratio below 0.7, a marker for COPD ( P  = 0.0074, OR = 2.01, 95% CI 1.19 to 3.31). This study demonstrates sex-specific effects of a COPD PS in pediatric asthma patients, with males of EUR ancestry at highest risk. The findings underscore the need to include diverse populations in genomic studies to improve the generalizability of PS for COPD prevention.

Lung function is complex trait with both genetic and environmental factors contributing to variation. It is unknown how geographic factors such as climate affect population respiratory health. To determine whether ambient air temperature is associated with lung function (FEV1) in the general population. Associations between spirometry data from two National Health and Nutrition Examination Survey (NHANES) periods representative of the U.S. non-institutionalized population and mean annual ambient temperature were assessed using survey-weighted multivariate regression. The NHANES III (1988-94) cohort included 14,088 individuals (55.6% female) and the NHANES 2007-12 cohort included 14,036 individuals (52.3% female), with mean ages of 37.4±23.4 and 34.4±21.8 years old and FEV1 percent predicted values of 99.8±15.8% and 99.2±14.5%, respectively. After adjustment for confounders, warmer ambient temperatures were associated with lower lung function in both cohorts (NHANES III p = 0.020; NHANES 2007-2012 p = 0.014). The effect was similar in both cohorts with a 0.71% and 0.59% predicted FEV1 decrease for every 10°F increase in mean temperature in the NHANES III and NHANES 2007-2012 cohorts, respectively. This corresponds to ~2 percent predicted difference in FEV1 between the warmest and coldest regions in the continental United States. In the general U.S. population, residing in regions with warmer ambient air temperatures was associated with lower lung function with an effect size similar to that of traffic pollution. Rising temperatures associated with climate change could have effects on pulmonary function in the general population.

Progressive lung disease accounts for the majority of morbidity and mortality observed in cystic fibrosis (CF). Beyond secondhand smoke exposure and socio-economic status, the effect of specific environmental factors on CF lung function is largely unknown. Multivariate regression was used to assess correlation between specific environmental factors, the presence of pulmonary pathogens, and variation in lung function using subjects enrolled in the U.S. CF Twin and Sibling Study (CFTSS: n = 1378). Significant associations were tested for replication in the U.S. CF Foundation Patient Registry (CFF: n = 16439), the Australian CF Data Registry (ACFDR: n = 1801), and prospectively ascertained subjects from Australia/New Zealand (ACFBAL: n = 167). In CFTSS subjects, the presence of Pseudomonas aeruginosa (OR = 1.06 per °F; p<0.001) was associated with warmer annual ambient temperatures. This finding was independently replicated in the CFF (1.02; p<0.001), ACFDR (1.05; p = 0.002), and ACFBAL (1.09; p = 0.003) subjects. Warmer temperatures (-0.34 points per °F; p = 0.005) and public insurance (-6.43 points; p<0.001) were associated with lower lung function in the CFTSS subjects. These findings were replicated in the CFF subjects (temperature: -0.31; p<0.001; insurance: -9.11; p<0.001) and similar in the ACFDR subjects (temperature: -0.23; p = 0.057). The association between temperature and lung function was minimally influenced by P. aeruginosa. Similarly, the association between temperature and P. aeruginosa was largely independent of lung function. Ambient temperature is associated with prevalence of P. aeruginosa and lung function in four independent samples of CF patients from two continents.

Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T. PBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status. RNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4-6 year period. RNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4-6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.

Pulmonary hypertension (PH) is a significant cause of morbidity in preterm infants, but no screening guidelines exist. We sought to identify risk factors and clinical outcomes associated with PH in preterm infants to develop a PH risk score. Retrospective analysis of two separate populations of preterm infants (NICU cohort n = 230; Clinic registry n = 580). 8.3% of the NICU cohort had PH after 4 weeks of age, while 14.8% of the clinic registry had PH after 2 months of age. Lower birth weights and longer initial hospitalizations were associated with PH in both populations (p<0.001 for all tests). Using adjusted logistic regression, patent ductus arteriosus (PDA) requiring ligation was associated with PH in both the NICU cohort (OR: 3.19; p = 0.024) and the clinic registry (OR: 2.67; p<0.001). Risk factors (birth weight ≤780 grams, home supplemental oxygen use, and PDA ligation) identified in the clinic registry (training dataset) were validated in the NICU cohort with 0-1 factors present were associated with ≤1.5% probability of having PH, any 2 factors with a 25% probability, and all 3 factors with a 40% probability. Lower birth weight, PDA ligation, and respiratory support were associated with PH in both populations. A PH risk score based on clinical indicators from the training dataset predicted PH in the validation set. This risk score could help focus resources to preterm infants at higher risk for PH. Further work is needed to determine whether earlier or more aggressive management of ductal lesions could alter PH outcomes.

Ongoing advancements in neonatal care since the late 1980s have led to increased numbers of premature infants surviving well beyond the neonatal period. As a result of increased survival, many individuals born preterm manifest chronic respiratory symptoms throughout infancy, childhood, and adult life. The archetypical respiratory disease of prematurity, bronchopulmonary dysplasia, is the second most common chronic pediatric respiratory disease after asthma. However, there are several commonly held misconceptions. These misconceptions include that bronchopulmonary dysplasia is rare, that bronchopulmonary dysplasia resolves within the first few years of life, and that bronchopulmonary dysplasia does not impact respiratory health in adult life. This focused review describes a spectrum of respiratory conditions that individuals born prematurely may experience throughout their lifespan. Specifically, this review provides quantitative estimates of the number of individuals with alveolar, airway, and vascular phenotypes associated with bronchopulmonary dysplasia, as well as non-bronchopulmonary dysplasia respiratory phenotypes such as airway malacia, obstructive sleep apnea, and control of breathing issues. Furthermore, this review illustrates what is known about the potential for progression and/or lack of resolution of these respiratory phenotypes in childhood and adult life. Recognizing the spectrum of respiratory phenotypes associated with individuals born preterm and providing comprehensive and personalized care to these individuals may help to modulate adverse respiratory outcomes in later life.