IU Indianapolis ScholarWorks :: Browsing by Subject "Lung function"

Browsing by Subject "Lung function"

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Assessment of inhibited alveolar-capillary membrane structural development and function in bronchopulmonary dysplasia
(Wiley, 2014-03) Ahlfeld, Shawn K.; Conway, Simon J.; Department of Medicine, IU School of Medicine
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of extreme prematurity and is defined clinically by dependence on supplemental oxygen due to impaired gas exchange. Optimal gas exchange is dependent on the development of a sufficient surface area for diffusion. In the mammalian lung, rapid acquisition of distal lung surface area is accomplished in neonatal and early adult life by means of vascularization and secondary septation of distal lung airspaces. Extreme preterm birth interrupts secondary septation and pulmonary capillary development and ultimately reduces the efficiency of the alveolar-capillary membrane. Although pulmonary health in BPD infants rapidly improves over the first few years, persistent alveolar-capillary membrane dysfunction continues into adolescence and adulthood. Preventative therapies have been largely ineffective, and therapies aimed at promoting normal development of the air-blood barrier in infants with established BPD remain largely unexplored. The purpose of this review will be: (1) to summarize the histological evidence of aberrant alveolar-capillary membrane development associated with extreme preterm birth and BPD, (2) to review the clinical evidence assessing the long-term impact of BPD on alveolar-capillary membrane function, and (3) to discuss the need to develop and incorporate direct measurements of functional gas exchange into clinically relevant animal models of inhibited alveolar development.
Associations of alpha and gamma-tocopherol during early life with lung function in childhood
(Elsevier, 2020) Kumar, Rajesh; Ferrie, Ryan; Balmert, Lauren; Kienzi, Matthew; Rifas-Shiman, Sheryl L.; Gold, Diane R.; Sordillo, Joanne E.; Kleinman, Ken; Camargo, Carlos A., Jr.; Litonjua, Augusto A.; Oken, Emily; Cook-Mills, Joan; Pediatrics, School of Medicine
Background: Tocopherol isoforms may regulate child lung growth and spirometric measures. Objective: Our aim was to determine the extent to which plasma a-tocopherol (a-T) or g-tocopherol (g-T) isoform levels in early childhood or in utero are associated with childhood lung function. Methods: We included 622 participants in the Project Viva cohort who had lung function at a mid-childhood visit (age 6-10 years). Maternal and child tocopherol isoform levels were measured by HPLC at the second trimester and 3 years of age, respectively. Multivariable linear regression models (adjusted for mid-childhood body mass index z scores, maternal education, smoking in pregnancy, and prenatal particulate matter with diameter of <2.5 micrometers (PM2.5) particulate exposure) stratified by tertiles of child g-T level were used to assess the association of a-T levels with FEV1 and forced vital capacity (FVC) percent predicted. Similarly, models stratified by child a-T tertile evaluated associations of g-T levels with lung function. We performed similar analyses with maternal second trimester tocopherol isoform levels. Results: The median maternal second trimester a-T level was 63 mM (interquartile range 5 47-82). The median early-childhood level was 25 mM (interquartile range 5 20-33 mM). In the lowest tertile of early-childhood g-T, children with a higher a-T level (per 10 mM) had a higher mid-childhood FEV1 percent predicted (b 5 3.09; 95% CI 5 0.58-5.59 and a higher FVC percent predicted (b 5 2.77; 95% CI 5 0.47-5.06). This protective association of a-T was lost at higher g-T levels. We did not see any consistent associations of second trimester levels of either a-T or g-T with mid-childhood FEV1 or FVC. Conclusion: When g-T levels were in the lowest tertile, a higher early-childhood a-T level was associated with better lung function at mid-childhood. Second trimester maternal plasma a-T concentration was 3-fold higher than in the adult nonpregnant female population.
Correction: Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age
(Springer Nature, 2024-04-25) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of Medicine
Correction to: Clinical Epigenetics (2024) 16:35 10.1186/s13148-024-01644-8 Following publication of the original article [1], the authors noticed that the NCBI Gene Expression Omnibus (GEO) accession series has been incorrectly listed as GSE253158 within the “Availability of data and materials section”. The correct GEO series for this work is GSE252169.
Determinants of Lung Function Across Childhood in the Severe Asthma Research Program (SARP) 3
(Elsevier, 2023) Gaffin, Jonathan M.; Petty, Carter R.; Sorkness, Ronald L.; Denlinger, Loren C.; Phillips, Brenda R.; Ly, Ngoc P.; Gaston, Benjamin; Ross, Kristie; Fitzpatrick, Anne; Bacharier, Leonard B.; DeBoer, Mark D.; Teague, W. Gerald; Wenzel, Sally E.; Ramratnam, Sima; Israel, Elliot; Mauger, David T.; Phipatanakul, Wanda; National Heart, Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators; Pediatrics, School of Medicine
Background: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. Objective: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. Methods: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. Results: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. Conclusions: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.
Effect of CPAP on airway reactivity and airway inflammation in children with moderate-severe asthma
(Wiley, 2019-04) Praca, Eduardo; Jalou, Hasnaa; Krupp, Nadia; Delecaris, Angela; Hatch, Joseph; Slaven, James; Gunst, Susan J.; Tepper, Robert S.; Biostatistics, School of Public Health
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 H2 O) or sham CPAP (<2 cm H2 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.
Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age
(Springer Nature, 2024-02-27) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of Medicine
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 (FEF25-75), 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 FEF25-75. 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. FEF25-75 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.
Nutritional Status and Lung Function in Children with Pancreatic-Sufficient Cystic Fibrosis
(Elsevier, 2022) Madde, Ankitha; Okoniewski, Will; Sanders, Don B.; Ren, Clement L.; Weiner, Daniel J.; Forno, Erick; Pediatrics, School of Medicine
Background: There is a strong association between nutrition and long-term FEV1 in cystic fibrosis (CF), but studies have been driven by data from subjects with pancreatic insufficiency (PI-CF). We thus evaluated the association between body mass index (BMI) and FEV1 percent-predicted (FEV1pp) in children with pancreatic sufficiency (PS-CF) and contrasted it with the association in PI-CF. Methods: We utilized data from the CF Foundation Patient Registry. The cohort included children born 1995-2010, diagnosed <2 years of age, and who had annualized data on BMI percentile and FEV1pp at ages 6-16 years. Pancreatic status was defined based on pancreatic enzyme replacement therapy. The association between BMI and FEV1 was evaluated using linear and mixed-effects longitudinal regression. Results: There were 424 children with PS-CF and 7,849 with PI-CF. The association between BMI and FEV1 differed significantly by pancreatic status: each 10-pct higher BMI was associated with 2% [95%CI = 1.9-2.1] higher FEV1pp in PI-CF, compared to just 0.9% [0.5-1.3] in PS-CF (PINTERACTION < 0.001). Within the at-risk nutritional category (BMI <25pct), each 10-pct higher BMI was associated with 5% higher FEV1pp in PI-CF, but no significant increase in PS-CF. Moreover, in PS-CF, overweight/obesity (BMI ≥85pct) was associated with decreasing FEV1pp. In addition, FEV1pp decline through age 20 years in youth with PS-CF was modest (-0.6% per year) and independent of BMI (BMI*age PINTERACTION = 0.37). Conclusions: In children with PS-CF, BMI remains an important determinant of lung function. However, it may be less critical to attain a BMI >50th percentile; and BMI ≥85th percentile may be detrimental.
Progression of Lung Disease in Preschool Patients with Cystic Fibrosis
(American Thoracic Society, 2017-05-01) Stanojevic, Sanja; Davis, Stephanie D.; Retsch-Bogart, George t; Webster, Hailey; Davis, Miriam; Johnson, Robin C.; Jensen, Renee; Pizarro, Maria Ester; Kane, Mica; Clem, Charles C.; Schornick, Leah; Subbarao, Padmaja; Ratjen, Felix A.; Pediatrics, School of Medicine
RATIONALE: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. OBJECTIVES: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. METHODS: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. MEASUREMENTS AND MAIN RESULTS: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. CONCLUSIONS: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.
Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma
(American Thoracic Society, 2021) Denlinger, Loren C.; Phillips, Brenda R.; Sorkness, Ronald L.; Bleecker, Eugene R.; Castro, Mario; DeBoer, Mark D.; Fitzpatrick, Anne M.; Hastie, Annette T.; Gaffin, Jonathan M.; Moore, Wendy C.; Peters, Michael C.; Peters, Stephen P.; Phipatanakul, Wanda; Cardet, Juan Carlos; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin; Levy, Bruce D.; Meyers, Deborah A.; Ross, Kristie; Teague, W. Gerald; Wenzel, Sally E.; Woodruff, Prescott G.; Zein, Joe; Jarjour, Nizar N.; Mauger, David T.; Israel, Elliot; Pediatrics, School of Medicine
Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function. Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline. Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant’s post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5–2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline. Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3–1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index. Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.
Serum α-Klotho level, lung function, airflow obstruction and inflammatory markers in US adults
(European Respiratory Society, 2023-11-06) Han, Yueh-Ying; Celedón, Juan C.; Forno, Erick; Pediatrics, School of Medicine
Background: α-Klotho is a pleiotropic protein that may have anti-oxidative and anti-inflammatory properties in the lung, but its role in airflow obstruction or lung function is largely unknown. Methods: This was a cross-sectional study of 6046 adults aged 40-79 years in the US National Health and Nutrition Examination Survey (NHANES) 2007-2012. We used multivariable logistic or linear regression to examine the relation between serum α-Klotho level and airflow obstruction, defined as forced expiratory volume in 1 s (FEV1) <80% of predicted and FEV1/forced vital capacity (FVC) ratio <0.70; FEV1, FVC and FEV1/FVC as percentage of predicted; and inflammatory markers in blood (white blood cell count, eosinophils, neutrophils and C-reactive protein (CRP)). Results: α-Klotho levels in the second to fourth quartiles (Q2-Q4) were associated with significantly decreased odds of airflow obstruction (adjusted OR for Q2-Q4 versus lowest quartile (Q1) 0.54 (95% CI 0.35-0.81)) in never-smokers and ex-smokers with <10 pack-years of smoking, but not in current smokers or ex-smokers with ≥10 pack-years of smoking. In all participants, each unit increment in log10-transformed α-Klotho level was significantly associated with 5.0% higher FEV1 % pred and 3.7% higher FVC % pred. Higher α-Klotho was also associated with lower eosinophils, neutrophils and CRP in participants both with and without airflow obstruction. Conclusions: Higher serum α-Klotho is associated with lower inflammatory markers and higher lung function in adults with and without airflow obstruction, and with decreased odds of airflow obstruction in never-smokers and ex-smokers with <10 pack-years of smoking. Further studies are warranted to replicate our findings and evaluate underlying mechanisms.

Browsing by Subject "Lung function"

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