Search

Rationale: Early in life, lung growth can occur by alveolarization, an increase in the number of alveoli, as well as expansion. We hypothesized that if lung growth early in life occurred primarily by alveolarization, then the ratio of pulmonary diffusion capacity of carbon monoxide (Dl(CO)) to alveolar volume (V(A)) would remain constant; however, if lung growth occurred primarily by alveolar expansion, then Dl(CO)/V(A) would decline with increasing age, as observed in older children and adolescents.Objectives: To evaluate the relationship between alveolar volume and pulmonary diffusion capacity early in life.Methods: In 50 sleeping infants and toddlers, with equal number of males and females between the ages of 3 and 23 months, we measured Dl(CO) and V(A) using single breath-hold maneuvers at elevated lung volumes.Measurements and Main Results: Dl(CO) and V(A) increased with increasing age and body length. Males had higher Dl(CO) and V(A) when adjusted for age, but not when adjusted for length. Dl(CO) increased with V(A); there was no gender difference when Dl(CO) was adjusted for V(A). The ratio of Dl(CO)/V(A) remained constant with age and body length.Conclusions: Our results suggest that surface area for diffusion increases proportionally with alveolar volume in the first 2 years of life. Larger Dl(CO) and V(A) for males than females when adjusted for age, but not when adjusted for length, is primarily related to greater body length in boys. The constant ratio for Dl(CO)/V(A) in infants and toddlers is consistent with lung growth in this age occurring primarily by the addition of alveoli rather than the expansion of alveoli. [ABSTRACT FROM AUTHOR]

Rationale: The development of early lung disease in patients with cystic fibrosis (CF) remains poorly defined. Objective: Determine whether asymptomatic infants with CF have evidence for changes in airway structure when assessed by high-resolution computed tomography, and whether airway structure correlates with airway function in this age group. Methods: Thirteen infants with CF (8-33 mo) and 13 control infants (7-25 mo) were evaluated. Airway wall and lumen areas were measured from three 1-mm-thick cross-sectional images obtained from upper, middle, and lower lobes during a respiratory pause with the lungs inflated to an airway pressure of 20 cm H2O. Lung tissue density was measured from images obtained during a respiratory pause at FRC. Forced expiratory flows were measured by the rapid thoracic compression technique in 11 infants with CF. Results: Airway wall area increased more per unit increase in airway size, whereas airway lumen area increased less per unit increase in airway size in the CF than in the control group. Among infants with CF, a greater ratio of wall to lumen area correlated with lower airway function. In addition, lung density at relaxed (passive) FRC was lower for infants with CF than for control infants (0.38 vs. 0.43 g/ml; p < 0.02). Conclusions: Our results indicate that infants with CF have thickened airway walls, narrowed airway lumens, and air trapping, when assessed by high-resolution computed tomography, and measurements of airway structure correlated with airway function. [ABSTRACT FROM AUTHOR]

Parental tobacco smoking is associated with lower airway function and an increased incidence of wheezy respiratory illnesses in infants. We evaluated in 76 healthy infants whether exposure to parental tobacco smoking was associated with airway hyperreactivity, which could contribute to lower airway function and the increased wheezy illnesses. Airway function was measured using the raised-volume rapid thoracic compression technique, and airway reactivity was assessed by methacholine challenge (0.015-10 mg/ml), which was stopped for a more than 30% decrease in forced expiratory flow (FEF)75 or the final dose with a less than 30% decrease. Parental tobacco smoking was associated with lower baseline airway function (FEF[50], 600 vs. 676 ml/second, p < 0.04; FEF[25-75], 531 vs. 597 ml/second, p < 0.05). Infants exposed to tobacco smoking were approximately half as likely to develop a more than 30% decline in FEF[75] at any given methacholine dose (hazard ratio = 0.4, p = 0.001). In addition, a history of asthma in an extended family member increased the likelihood that an infant would develop a more than 30% decline in FEF[75] (hazard ratio = 1.7, p = 0.04). We conclude that exposure to parental smoking is associated with lower airway function but not increased airway reactivity; however, family history of asthma is associated with heightened airway reactivity. [ABSTRACT FROM AUTHOR]

Respiratory system compliance (Crs) in infants with cystic fibrosis (CF) has been reported as decreased or not different compared with healthy control subjects; however, the reported measurements of Crs were 'quasi-static' or by the single-breath occlusion technique, with all measurements limited to tidal lung volume, as well as using inspiratory rather than expiratory pressures. We compared the passive elastic properties of the respiratory system of sleeping infants with CF (n = 10) and healthy control subjects (n = 34) by measuring static deflation pressure--volume (PV) curves from a lung volume at 30 cm H(2)O (V(30)) to FRC. There was no significant difference between the groups for Crs, which was measured as the slope between airway relaxation pressures of 5 and 15 cm H(2)O, the linear portion of the deflation PV curve. In addition, when PV curves were normalized to V(30), there were no differences between the infants with CF and healthy control subjects in the fractional volumes at any airway pressure. The infants with CF had significantly lower forced expiratory flows; however, lower flows did not correlate with fractional volumes measured from the PV curve. Our findings indicate that infants with CF have normal elastic properties of the respiratory system. [ABSTRACT FROM AUTHOR]

Background: Spirometry is the gold standard for assessing airway function for clinical studies; however, obtaining high-quality data in young children remains challenging. Since the forced oscillation technique (FOT) requires less subject cooperations, there has been increasing interest in FOT, particularly in young children. We evaluated whether spirometry and FOT in young children provides comparable ability to detect a treatment effect., Methods: We recently reported in a randomized controlled trial that vitamin C compared to placebo treatment of mothers who smoked during pregnancy (MSDP) results in the offspring having significantly higher forced expiratory flows (FEFs) at 5-years of age, as well as significantly less wheeze at 4-6 years of age. In these same offspring, we also measured respiratory impedance using FOT at 8-Hz impedance at 3, 4, and 5 years of age., Results: Although spirometry demonstrated significantly increased FEFs in vitamin C compared to placebo-treatment group at 5 years of age (p < 0.001), we were not able to detect a similar treatment effect using FOT impedance., Conclusions: It may be challenging to obtain technically successful spirometry in preschool children; however, FEFs may provide a better outcome than single-frequency FOT impedance to assess improvements in airway function in these young subjects., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health., (© 2024. The Author(s).)

Background: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy., Methods: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed., Results: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001)., Conclusion: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers., Impact Statement: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaptation to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild-type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 wk of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (V a ), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. Although no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2, or apelin. Sexual dimorphisms were noted in PA wall thickness and PA lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling. NEW & NOTEWORTHY By exposing novel loss-of-function estrogen receptor alpha (Erα) mutant rats to a novel model of human high-altitude exposure, we demonstrate that ERα has subtle but inconsistent effects on endpoints relevant to cardiopulmonary adaptation to chronic hypoxia. Given that we observed some histologic, sex, and genotype differences, further research into cell-specific effects of ERα during hypoxia-induced cardiopulmonary adaptation is warranted.

Background: Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established., Objective: Our aim was to develop biomarkers of MSDP using DNAm measured in placentas ( N = 96 ), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost., Methods: We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, N = 426 ; and the Rhode Island Children's Health Study, N = 237 ., Results: Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only ( n = 72 ) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array ( R 2 = 0.98 )., Discussion: To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

Background: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze., Methods: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF 25-75 ), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF 25-75 . We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age., Results: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF 25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment., Conclusions: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci. Clinical trial registration ClinicalTrials.gov, NCT01723696 and NCT03203603., (© 2024. The Author(s).)

Populations that are born and raised at high altitude develop under conditions of chronic developmental hypoxia (CDH), which results in pulmonary adaptations of increased lung volume and diffusion capacity to increase gas exchange. It is not clear how CDH may alter allergic inflammation in the lung. In this study, we sought to characterize the impact of CDH on immune cell populations in the rat lung during a murine model of asthma. Rats were bred and raised in either hypoxic (15% oxygen, CDH) or normobaric room air (20% oxygen). At 3-weeks of age, animals were sensitized to ovalbumin (OVA) or physiologic saline (phosphate-buffered saline [PBS]) as a control, followed by three consecutive days of intra-nasal OVA or PBS at 6-weeks of age. We then assessed airway reactivity and allergic-associated cytokine levels. This was followed by single-cell transcriptomic profiling of lung cell populations. In scRNA-seq analysis, we assessed differentially expressed genes, differentially enriched functional pathways, immune cell exhaustion/activation markers, and immune cell secretory products. Our results show that while OVA heightened airway reactivity, CDH suppressed airway reactivity in OVA-challenged and control animals. Through scRNA-seq analysis, we further demonstrate that CDH alters the transcriptional landscape in the lung and alters transcriptional programs in immune cells. These data define CDH-dependent changes in the lung that impact airway reactivity., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Antenatal corticosteroids improve neonatal outcomes when administered to infants who are at risk of preterm delivery. Many women who receive antenatal corticosteroids for threatened preterm labor proceed to deliver at term. Thus, long-term outcomes should be evaluated for term-born infants who were exposed to antenatal corticosteroids in utero., Objective: This study aimed to compare long-term outcomes between term-born children aged ≥5 years who were born to women who received antenatal corticosteroids for threatened preterm labor and children whose mothers were also evaluated for threatened preterm labor but did not receive antenatal corticosteroids., Study Design: We performed a retrospective cohort study of children born at ≥37 weeks' gestation, aged ≥5 years, and born to mothers diagnosed with threatened preterm labor during pregnancy. The primary exposure of interest was receiving antenatal corticosteroids. Among the collected childhood medical conditions, the primary outcome of interest was a diagnosis of asthma., Results: Of the 3556 term-born children aged ≥5 years, 629 (17.6%) were exposed to antenatal corticosteroids (all betamethasone), and 2927 (82.3%) were controls whose mothers were evaluated for threatened preterm birth but did not get antenatal corticosteroid injections. Women receiving antenatal corticosteroids had higher rates of maternal comorbidities (diabetes mellitus, hypertension; P≤.01). Antenatal corticosteroid-exposed children had no difference in diagnosis of asthma (12.6% vs 11.6%), attention deficit disorder, or developmental delay (P=.47, .54, and .10, respectively). Controlling for maternal and neonatal characteristics, asthma was not different between those exposed to antenatal corticosteroids and controls (odds ratio, 1.05; 95% confidence interval, 0.79-1.39). The odds of the child's weight percentile being <10% were increased for antenatal corticosteroid-exposed children born at term (odds ratio, 2.00; 95% confidence interval, 1.22-3.25)., Conclusion: Children born at term who were exposed to antenatal corticosteroids may have increased odds of being in a lower growth percentile than those not exposed. However, rates of diagnoses such as asthma, developmental delay, and attention deficit disorders were not different., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed., Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze., Design, Setting, and Participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021., Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment., Main Outcomes and Measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze., Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003)., Conclusions and Relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health., Trial Registration: ClinicalTrials.gov Identifier: NCT03203603.

Rationale: Animal models suggest pre-eclampsia (Pre-E) affects alveolar development, but data from humans are lacking., Objective: Assess the impact of Pre-E on airway function, diffusion capacity, and respiratory morbidity in preterm and term infants born from mothers with Pre-E., Methods: Infants born from mothers with and without Pre-E were recruited for this study; term and preterm infants were included in both cohorts. Respiratory morbidity in the first 12 months of life was assessed through monthly phone surveys. Raised volume rapid thoracoabdominal compression and measurement of diffusion capacity of the lung to carbon monoxide (DLCO) were performed at 6 months corrected age., Measurements and Main Results: There were 146 infants in the Pre-E cohort and 143 in the control cohort. The Pre-E cohort was further divided into nonsevere (N = 41) and severe (N = 105) groups. There was no significant difference in DLCO and DLCO/alveolar volume among the three groups. Forced vital capacity was similar among the three groups, but the nonsevere Pre-E group had significantly higher forced expiratory flows than the other two groups. After adjusting for multiple covariates including prematurity, the severe Pre-E group had a lower risk for wheezing in the first year of life compared to the other two groups., Conclusions: Pre-E is not associated with reduced DLCO, lower forced expiratory flows, or increased wheezing in the first year of life. These results differ from animal models and highlight the complex relationships between Pre-E and lung function and respiratory morbidity in human infants., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c + and CD11c - interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1 + lung macrophages but not Arg1 - lung macrophages promoted allergic inflammation that Il9r -/- mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.

The pathogenesis of atopic dermatitis (AD) results from complex interactions between environmental factors, barrier defects, and immune dysregulation resulting in systemic inflammation. Therefore, we sought to characterize circulating inflammatory profiles in pediatric AD patients and identify potential signaling nodes which drive disease heterogeneity and progression. We analyzed a sample set of 87 infants that were at high risk for atopic disease based on atopic dermatitis diagnoses. Clinical parameters, serum, and peripheral blood mononuclear cells (PBMCs) were collected upon entry, and at one and four years later. Within patient serum, 126 unique analytes were measured using a combination of multiplex platforms and ultrasensitive immunoassays. We assessed the correlation of inflammatory analytes with AD severity (SCORAD). Key biomarkers, such as IL-13 (rmcorr=0.47) and TARC/CCL17 (rmcorr=0.37), among other inflammatory signals, significantly correlated with SCORAD across all timepoints in the study. Flow cytometry and pathway analysis of these analytes implies that CD4 T cell involvement in type 2 immune responses were enhanced at the earliest time point (year 1) relative to the end of study collection (year 5). Importantly, forward selection modeling identified 18 analytes in infant serum at study entry which could be used to predict change in SCORAD four years later. We have identified a pediatric AD biomarker signature linked to disease severity which will have predictive value in determining AD persistence in youth and provide utility in defining core systemic inflammatory signals linked to pathogenesis of atopic disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: Antenatal corticosteroids improve newborn outcomes for preterm infants. However, predicting which women presenting for threatened preterm labor will have preterm infants is inaccurate, and many women receive antenatal corticosteroids but then go on to deliver at term., Objective: This study aimed to compare the short-term outcomes of infants born at term to women who received betamethasone for threatened preterm labor with infants who were not exposed to betamethasone in utero., Study Design: We performed a retrospective cohort study of infants born at or after 37 weeks' gestational age to mothers diagnosed as having threatened preterm labor during pregnancy. The primary neonatal outcomes of interest included transient tachypnea of the newborn, neonatal intensive care unit admission, and small for gestational age and were evaluated for their association with betamethasone exposure while adjusting for covariates using multiple logistic regression., Results: Of 5330 women, 1459 women (27.5%) received betamethasone at a mean gestational age of 32.2±3.3 weeks. The mean age of women was 27±5.9 years and the mean gestational age at delivery was 38.9±1.1 weeks. Women receiving betamethasone had higher rates of maternal comorbidities (P<.001 for diabetes mellitus, asthma, and hypertensive disorder) and were more likely to self-identify as White (P=.022). Betamethasone-exposed neonates had increased rates of transient tachypnea of the newborn, neonatal intensive care unit admission, small for gestational age, hyperbilirubinemia, and hypoglycemia (all, P<.05). Controlling for maternal characteristics and gestational age at delivery, betamethasone exposure was not associated with a diagnosis of transient tachypnea of the newborn (adjusted odds ratio, 1.10; 95% confidence interval, 0.80-1.51), although it was associated with more neonatal intensive care unit admissions (adjusted odds ratio, 1.49; 95% confidence interval, 1.19-1.86) and higher odds of the baby being small for gestational age (adjusted odds ratio, 1.78; 95% confidence interval, 1.48-2.14)., Conclusion: Compared with women evaluated for preterm labor who did not receive betamethasone, women receiving betamethasone had infants with higher rates of neonatal intensive care unit admission and small for gestational age. Although the benefits of betamethasone to infants born preterm are clear, there may be negative impacts for infants delivered at term., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There are no widely accepted prognostic tools for childhood asthma; this is in part due to the multifactorial and time-dependent nature of mechanisms and risk factors that contribute to asthma development. Our study objective was to develop and evaluate the prognostic performance of conditional inference decision tree-based rules using the Pediatric Asthma Risk Score (PARS) predictors as an alternative to the existing logistic regression-based risk score for childhood asthma prediction at 7 years in a high-risk population., Methods: The Canadian Asthma Primary Prevention Study data were used to develop, compare, and contrast the prognostic performance (area under the curve [AUC], sensitivity, and specificity) of conditional inference tree-based decision rules to the pediatric asthma risk score for the prediction of childhood asthma at 7 years., Results: Conditional inference decision tree-based rules have higher prognostic performance (AUC: 0.85; 95% CI: 0.81, 0.88; sensitivity = 47%; specificity = 93%) than the pediatric asthma risk score at an optimal cutoff of ≥6 (AUC: 0.71; 95% CI: 0.67, 0.76; sensitivity = 60%; specificity = 74%). Moreover, the pediatric asthma risk score is not linearly related to asthma risk, and at any given pediatric asthma risk score value, different combinations of its pediatric asthma risk score clinical variables differentially predict asthma risk., Conclusion: Conditional inference tree-based decision rules could be a useful childhood asthma prognostic tool, providing an alternative way to identify unique subgroups of at-risk children, and insights into associations and effect mechanisms that are suggestive of appropriate tailored preventive interventions. However, the feasibility and effectiveness of such decision rules in clinical practice is warranted., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes., Results: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers., Conclusions: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 ., (© 2021. The Author(s).)

Antenatal corticosteroids (ACS) administration to pregnant women for threatened preterm labor is standard obstetric care to reduce neonatal respiratory distress syndrome and the associated respiratory morbidity. While ACS stimulates surfactant production in the fetal lung, the effects of ACS upon the subsequent growth and development of the lung are unclear. Follow-up studies outside of the neonatal period have been primarily limited to spirometry, and most subjects evaluated were born prematurely. To our knowledge, no study has assessed both airway and parenchymal function in infants or adults following ACS exposure. We hypothesized that ACS impairs lung growth and performed infant pulmonary function testing, which included spirometry, alveolar volume (V A ) and lung diffusion (D L ). As a pilot study, we limited our assessment to infants whose mothers received ACS for threatened preterm labor, but then proceeded to full term delivery. This approach evaluated a more homogenous population and eliminated the confounding effects of preterm birth. We evaluated 36 full-term infants between 4 to 12 months of age; 17 infants had ACS exposure and 19 infants had no ACS exposure. Infants exposed to ACS had a significantly lower forced vital capacity compared with non-ACS exposed infants (250 vs 313 mL; P = .0075). FEV 0.5 tended to be lower for the ACS exposed group (205 vs 237 mL; P = .075). V A and D L did not differ between the two groups. These findings suggest that ACS may impair subsequent growth of the lung parenchyma., (© 2020 Wiley Periodicals LLC.)

T helper cell differentiation requires lineage-defining transcription factors and factors that have shared expression among multiple subsets. BATF is required for development of multiple Th subsets but functions in a lineage-specific manner. BATF is required for IL-9 production in Th9 cells but in contrast to its function as a pioneer factor in Th17 cells, BATF is neither sufficient nor required for accessibility at the Il9 locus. Here we show that STAT5 is the earliest factor binding and remodeling the Il9 locus to allow BATF binding in both mouse and human Th9 cultures. The ability of STAT5 to mediate accessibility for BATF is observed in other Th lineages and allows acquisition of the IL-9-secreting phenotype. STAT5 and BATF convert Th17 cells into cells that mediate IL-9-dependent effects in allergic airway inflammation and anti-tumor immunity. Thus, BATF requires the STAT5 signal to mediate plasticity at the Il9 locus.

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

Background: Vitamin C (500 mg·day -1 ) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported., Objective: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age., Methods: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day -1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance., Results: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec -1 for FEF 75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec -1 for FEF 50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec -1 for FEF 25-75 (95% CI, 9.7 to 100.5; p=0.013)., Conclusions: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway., (Copyright ©ERS 2020.)

Rationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF 75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF 50 and FEF 25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C ( n  = 113) had the following FEFs at 3 months of age compared with those randomized to placebo ( n  =  109) as measured by FEF 75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P  = 0.10), FEF 50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P  = 0.02), and FEF 25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P  = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF 75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF 50 and FEF 25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF 50 and FEF 25-75 ) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

The role of perinatal insults in the development of adult onset pulmonary hypertension (PH) is unclear. We surveyed patients with and without PH for a history of early life risk factors, and identified prematurity, oxygen use, and respiratory illness each as risk predictors for development of adult PH.

Background and Objective: Asthma is characterized by airway hyperreactivity and airway inflammation. We previously demonstrated that adults with mild well-controlled asthma exhibited a marked decrease in airway reactivity (PC20 increased >2-fold) after using nocturnal continuous positive airway pressure (CPAP) for 1 week. If CPAP produces a similar suppression of airway reactivity in children with moderate-severe asthma, who require chronic use of corticosteroids, then this non-pharmacological therapy might provide a beneficial alternative or supplemental therapy in these subjects., Methods: Children aged 8-17 years with moderate-severe asthma were treated with 4 weeks of nocturnal CPAP (8-10 cm H 2 O) or sham CPAP (<2 cm H 2 O). Adherence was monitored with a modem installed in the equipment or by memory cards. Airway reactivity, assessed by methacholine bronchial challenge, was measured prior to and following treatment., Results: The percentage of subjects adherent to treatment was similar in both groups (19/27 CPAP vs 19/28 sham, ~70%). There was a tendency for PC20 to increase with treatment in both groups (3.0-5.3 mg/mL CPAP vs 3.2 to 4.3 mg/mL sham, P = 0.083); however, the change did not differ significantly between groups (P = 0.569)., Conclusion: We found that the 4-week treatment with nocturnal CPAP did not produce a twofold suppression of airway reactivity in children with moderate-severe asthma., (© 2018 Asian Pacific Society of Respirology.)

Background: Lung diffusion assessed by the uptake of carbon monoxide (DL CO ) and alveolar volume (V A ) by inert gas dilution are readily assessed in cooperative older subjects; however, obtaining these measurements in infants has been much more difficult. Our laboratory has measured DL CO and V A in sleeping infants using a mass spectrometer, which continuously measures gas concentrations, and demonstrated that infants with bronchopulmonary dysplasia (BPD) have lower DL CO , but no difference in V A compared to full-term controls. The mass spectrometer is expensive and lacks portability; therefore, we evaluated whether measurement of end-expiratory alveolar gas concentrations using a gas chromatograph would provide an alternative approach., Methods: (1) Using our previously digitized data for infants with BPD and full-term controls, DL CO and V A were calculated at end-expiration rather than between 60 and 80% of expired volume, as previously reported. (2) In a new group of infants, DL CO and V A were measured using gas concentrations obtained at end-expiration with a mass spectrometer and a gas chromatograph., Results: (1) Using end-expiratory concentrations, infants with BPD (n = 49) had significantly lower DL CO , but similar V A compared to healthy controls (n = 34) (DL CO : 4.2 vs 4.6 mL/min/mmHg, P = 0.047; V A : 614 vs 608 mL, P = 0.772). (2) Among newly evaluated infants (n = 28), DL CO and V A obtained with a mass spectrometer and a gas chromatograph were highly correlated (R 2  = 0.94 and 0.99, respectively), and were not significantly different for the two analyzers., Conclusion: Measuring DL CO and V A at end-expiration using a gas chromatograph can provide an effective assessment of gas exchange in sleeping infants., (© 2017 Wiley Periodicals, Inc.)

Despite strong anti-smoking efforts, at least 12% of American women cannot quit smoking when pregnant resulting in >450,000 smoke-exposed infants born yearly. Smoking during pregnancy is the largest preventable cause of childhood respiratory illness including wheezing and asthma. Recent studies have shown a protective effect of vitamin C supplementation on the lung function of offspring exposed to in utero smoke in a non-human primate model and an initial human trial. Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) is a randomized, double-blind, placebo-controlled trial to evaluate pulmonary function at 3months of age in infants delivered to pregnant smokers randomized to 500mg/day of vitamin C versus placebo during pregnancy. Secondary aims evaluate the incidence of wheezing through 12months and pulmonary function testing at 12months of age. Women are randomized between 13 and 23weeks gestation from clinical sites in Portland, Oregon at Oregon Health & Science University and PeaceHealth Southwest Medical Center and in Indianapolis, Indiana at Indiana University and Wishard Hospital. Vitamin C supplementation occurs from randomization to delivery. Monthly contact with participants and monitoring of medical records is performed to document medication adherence, changes in smoking and medical history, and adverse events. Pulmonary function testing of offspring occurs at 3 and 12months of age and incidence of wheezing and respiratory illness through 12months is captured via at least quarterly questionnaires. Ancillary studies are investigating the impact of vitamin C on placental blood flow and DNA methylation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Bronchopulmonary dysplasia (BPD) results from alveolar simplification and abnormal development of alveolar and capillary structure. Survivors of BPD display persistent deficits in airflow and membrane and vascular components of alveolar gas diffusion. Despite being the defining feature of BPD, various neonatal hyperoxia models of BPD have not routinely assessed pulmonary gas diffusion., Methods: To simulate the most commonly-utilized neonatal hyperoxia models, we exposed neonatal mice to room air or ≥90% hyperoxia during key stages of distal lung development: through the first 4 (saccular), 7 (early alveolar), or 14 (bulk alveolar) postnatal days, followed by a period of recovery in room air until 8 weeks of age when alveolar septation is essentially complete. We systematically assessed and correlated the effects of neonatal hyperoxia on the degree of alveolar-capillary structural and functional impairment. We hypothesized that the degree of alveolar-capillary simplification would correlate strongly with worsening diffusion impairment., Results: Neonatal hyperoxia exposure, of any duration, resulted in alveolar simplification and impaired pulmonary gas diffusion. Mean Linear Intercept increased in proportion to the length of hyperoxia exposure while alveolar and total lung volume increased markedly only with prolonged exposure. Surprisingly, despite having a similar effect on alveolar surface area, only prolonged hyperoxia for 14 days resulted in reduced pulmonary microvascular volume. Estimates of alveolar and capillary structure, in general, correlated poorly with assessment of gas diffusion., Conclusion: Our results help define the physiological and structural consequences of commonly-employed neonatal hyperoxia models of BPD and inform their clinical utility. Pediatr Pulmonol. 2017;52:616-624. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Rationale: Studies have demonstrated that application of stress suppresses airway smooth muscle contractility. In animal models of asthma, continuous positive airway pressure (CPAP) reduced airway reactivity. Short-term studies of CPAP in patients with asthma showed reductions in airway reactivity., Objectives: To evaluate whether nocturnal CPAP decreased the provocative concentration of methacholine to reduce FEV 1 by 20% (PC 20 )., Methods: One hundred ninety-four individuals with asthma were randomized (1:1:1) to use CPAP with warmed, filtered, humidified air at night at pressures either less than 1 cm H 2 O (sham) or at 5 cm H 2 O or 10 cm H 2 O. The primary outcome was change in PC 20 after 12 weeks., Measurements and Main Results: Adherence to CPAP was low in all groups. Regardless, all groups had a significant improvement in PC 20 , with 12 weeks/baseline PC 20 ratios of 2.12, 1.73, and 1.78 for the sham, 5 cm H 2 O, and 10 cm H 2 O groups, respectively, and no significant differences between the active and sham groups. Changes in FEV 1 and exhaled nitric oxide were minimal in all groups. The sham group had larger improvements in most patient-reported outcomes measuring asthma symptoms and quality of life, as well as sinus symptoms, than the 5 cm H 2 O group. The 10 cm H 2 O group showed similar but less consistent improvements in scores, which were not different from improvements in the sham group., Conclusions: Adherence to nocturnal CPAP was low. There was no evidence to support positive pressure as being effective for reducing airway reactivity in people with well-controlled asthma. Regardless, airway reactivity was improved in all groups, which may represent an effect of participating in a study and/or an effect of warm, humid, filtered air on airway reactivity. Clinical trial registered with www.clinicaltrials.gov (NCT01629823).

Rationale: Adults born and raised at high altitudes have larger lung volumes and greater pulmonary diffusion capacity compared with adults at low altitude; however, it remains unclear whether the air and tissue volumes have comparable increases and whether there is a difference in airway size., Objectives: To assess the effect of chronic hypoxia on lung growth using in vivo high-resolution computed tomography measurements., Methods: Healthy adults born and raised at moderate altitude (2,000 m above sea level; n = 19) and at low altitude (400 m above sea level; n = 23) underwent high-resolution computed tomography. Differences in total lung, air, and tissue volume, mean lung density, as well as airway lumen and wall areas in anatomically matched airways were compared between groups., Measurements and Main Results: No significant differences for age, sex, weight, or height were found between the two groups (P > 0.05). In a multivariate regression model, altitude was a significant contributor for total lung volume (P = 0.02), air volume (P = 0.03), and tissue volume (P = 0.03), whereby the volumes were greater for the moderate- versus the low-altitude group. However, altitude was not a significant contributor for mean lung density (P = 0.35) or lumen and wall areas in anatomically matched segmental, subsegmental, and subsubsegmental airways., Conclusions: Our findings suggest that the adult lung did not increase lung volume later in life by expansion of an existing number of alveoli, but rather from increased alveolarization early in life. In addition, chronic hypoxia accentuates dysanaptic lung growth by increasing the lung parenchyma but not the airways.

Rationale: Asthma is prevalent in children with eosinophilic esophagitis (EoE) estimated at 24-42% in prior studies versus 9% for the general population. However, pulmonary function and airway hyperresponsiveness (AHR) in children with EoE have not been previously defined., Methods: A cross-sectional prospective study was conducted of children ages 7-18 years with EoE and healthy controls. Methacholine bronchial challenge and exhaled nitric oxide were assessed. As measures of atopy and immune activation, peripheral blood was analyzed for total IgE, specific IgE to selected aeroallergens, eosinophil count, and serum cytokines including eotaxin., Results: EoE subjects (n = 33) and healthy controls (n = 37) demonstrated similar, normal baseline spirometry. AHR occurred in 33% of children with EoE and 11% of healthy controls (P = 0.04; 95% confidence intervals [19%, 52%] and [4%, 26%], respectively). The majority of EoE subjects with AHR had no prior diagnosis of asthma. Overall, 69.7% of EoE subjects had either asthma or AHR. For EoE subjects, total serum IgE was the only biomarker associated with a greater risk of AHR (OR = 9.643, 95%CI 1.633, 56.925). EoE subjects with and without asthma were similar to healthy controls in mean levels of serum cytokines (IL-5, IL-9, EGF, FGF-2, eotaxin). In exploratory analyses, the subgroup with EoE and asthma without asthma controller therapy had higher mean FGF-2 than EoE subjects without asthma (110 pg/ml vs. 65 pg/ml, P = 0.0426)., Conclusions: Asthma and AHR may be more prevalent than previous estimates in children with EoE. For subjects with EoE, elevation in serum IgE was associated with a greater risk of AHR., (© 2015 Wiley Periodicals, Inc.)

Rationale: Autopsied lungs of infants with bronchopulmonary dysplasia (BPD) demonstrate impaired alveolar development with larger and fewer alveoli, which is consistent with our previous physiologic findings of lower pulmonary diffusing capacity of the lung for carbon monoxide (DL(CO)) in infants and toddlers with BPD compared with healthy controls born at full term (FT). However, it is not known whether the decreased DL(CO) in infants with BPD results from a reduction in both components of DL(CO): pulmonary membrane diffusing capacity (D(M)) and Vc., Objectives: We hypothesized that impairment of alveolar development in BPD results in a decrease in both D(M) and Vc components of DlCO but that the D(M)/Vc ratio would not differ between the BPD and FT groups., Methods: DL(CO) was measured under conditions of room air and high inspired oxygen (90%), which enabled D(M) and Vc to be calculated., Measurements and Main Results: D(M) and Vc increased with increasing body length; however, infants with BPD had significantly lower D(M) and Vc than FT subjects after adjustment for race, sex, body length, and corrected age. In contrast to D(M) and Vc, the D(M)/Vc ratio remained constant with increasing body length and did not differ for infants with BPD and FT subjects., Conclusions: Our findings are consistent with infants with BPD having impaired alveolar development with fewer but larger alveoli, as well as a reduced Vc.

Previous studies of pulmonary diffusing capacity in healthy children primarily focused upon Caucasian (C) subjects. Since lung volumes in African-Americans (AA) are smaller than lung volumes in C subjects of the same height, diffusing capacity values in AA children might be interpreted as low or abnormal using currently available equations without adjusting for race. Healthy AA (N = 151) and C (N = 301) children between 5 and 18 years of age performed acceptable measurements of single breath pulmonary diffusing capacity for carbon monoxide (DLCO ) and alveolar volume (VA ) according to current ATS/ERS guidelines. The natural log of DLCO and VA were associated with height, gender, age, and race; AA children had lower DLCO and VA compared to C children. Adjustment of DLCO for Hemoglobin (Hgb) resulted in no significant difference in DLCO among these healthy subjects with normal Hgb. In summary, we report prediction equations for DLCO and VA that include adjustment for race (C; AA) demonstrating that AA have lower DLCO and VA compared to C children for the same height, gender, and age., (© 2015 Wiley Periodicals, Inc.)

Rationale: While infants who are born extremely premature and develop bronchopulmonary dysplasia (BPD) have impaired alveolar development and decreased pulmonary diffusion (DLCO), it remains unclear whether infants born less premature and do not develop BPD, healthy premature (HP), have impaired parenchymal development. In addition, there is increasing evidence that pro-angiogenic cells are important for vascular development; however, there is little information on the relationship of pro-angiogenic cells to lung growth and development in infants., Objective: and Methods Determine among healthy premature (HP) and fullterm (FT) infants, whether DLCO and alveolar volume (VA) are related to gestational age at birth (GA), respiratory support during the neonatal period (mechanical ventilation [MV], supplemental oxygen [O2], continuous positive airway pressure [CPAP]), and pro-angiogenic circulating hematopoietic stem/progenitor cells (CHSPCs). We measured DLCO, VA, and CHSPCs in infants between 3-33 months corrected-ages; HP (mean GA = 31.7 wks; N = 48,) and FT (mean GA = 39.3 wks; N =88)., Result: DLCO was significantly higher in HP than FT subjects, while there was no difference in VA , after adjusting for body length, gender, and race. DLCO and VA were not associated with GA, MV and O2; however, higher values were associated with higher CHSPCs, as well as treatment with CPAP., Conclusion: Our findings suggest that in the absence of extreme premature birth, as well as BPD, prematurity per se, does not impair lung parenchymal development., (© 2014 Wiley Periodicals, Inc.)