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1. Differentially co‐expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease

Author

Joe W. Chiles III, Ava C. Wilson, Rachel Tindal, Kaleen Lavin, Samuel Windham, Harry B. Rossiter, Richard Casaburi, Anna Thalacker‐Mercer, Thomas W. Buford, Rakesh Patel, J. Michael Wells, Marcas M. Bamman, Beatriz Y. Hanaoka, Mark Dransfield, and Merry‐Lynn N. McDonald

Subjects
COPD, fibre‐type shift, myofibre proportions, sex differences, skeletal muscle, transcriptomics, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. Methods Forty‐six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre‐type distribution and cross‐sectional area via immunofluorescence microscopy and RNA‐sequenced to generate transcriptome‐wide gene expression data. Sex‐stratified k‐means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co‐expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. Results Abnormal myofibre proportion was defined in males with COPD (n = 29) as 22% type IIx/IIax fibres and in females with COPD (n = 17) as 12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6‐min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s‐to‐forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty‐nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co‐expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co‐expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. Conclusions Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co‐expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Published
2024
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2. A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD

Author

Katarina M. DiLillo, Katy C. Norman, Christine M. Freeman, Stephanie A. Christenson, Neil E. Alexis, Wayne H. Anderson, Igor Z. Barjaktarevic, R. Graham Barr, Alejandro P. Comellas, Eugene R. Bleecker, Richard C. Boucher, David J. Couper, Gerard J. Criner, Claire M. Doerschuk, J. Michael Wells, MeiLan K. Han, Eric A. Hoffman, Nadia N. Hansel, Annette T. Hastie, Robert J. Kaner, Jerry A. Krishnan, Wassim W. Labaki, Fernando J. Martinez, Deborah A. Meyers, Wanda K. O’Neal, Victor E. Ortega, Robert Paine, Stephen P. Peters, Prescott G. Woodruff, Christopher B. Cooper, Russell P. Bowler, Jeffrey L. Curtis, Kelly B. Arnold, and SPIROMICS investigators

Subjects
Medicine, Science
Abstract

Abstract Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.

Published
2023
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3. Clinical risk factors for admission with Pseudomonas and multidrug-resistant Pseudomonas community-acquired pneumonia

Author

Adeniyi J. Idigo, J. Michael Wells, Matthew L. Brown, Howard W. Wiener, Russell L. Griffin, Gary Cutter, Sadeep Shrestha, and Rachael A. Lee

Subjects
Community-acquired pneumonia, Pseudomonas, Multidrug-resistant Pseudomonas, Chronic obstructive pulmonary disease, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship. Objectives To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD. Methods We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013–12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP. Results Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48–68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP. Conclusion Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.

Published
2022
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4. Computed tomography measure of lung injury and future interstitial features: the CARDIA Lung Study

Author

Gabrielle Y. Liu, Laura A. Colangelo, Samuel Y. Ash, Raul San Jose Estepar, David R. Jacobs, Bharat Thyagarajan, J. Michael Wells, Rachel K. Putman, Bina Choi, Christopher S. Stevenson, Mercedes Carnethon, George R. Washko, and Ravi Kalhan

Subjects
Medicine
Abstract

Introduction Visually normal areas of the lung with high attenuation on computed tomography (CT) imaging, termed CT lung injury, may represent injured but not yet remodelled lung parenchyma. This prospective cohort study examined if CT lung injury is associated with future interstitial features on CT and restrictive spirometry abnormality among participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Methods CARDIA is a population-based cohort study. CT scans obtained at two time points were assessed objectively for amount of lung tissue characterised as CT lung injury and interstitial features. Restrictive spirometry was defined as having a forced vital capacity (FVC) 70%. Results Among 2213 participants, the median percentage of lung tissue characterised as CT lung injury at a mean age of 40 years was 3.4% (interquartile range 0.8–18.0%). After adjustment for covariates, a 10% higher amount of CT lung injury at mean age 40 years was associated with a 4.37% (95% CI 3.99–4.74%) higher amount of lung tissue characterised as interstitial features at mean age 50 years. Compared to those with the lowest quartile of CT lung injury at mean age 40 years, there were higher odds of incident restrictive spirometry at mean age 55 years in quartile 2 (OR 2.05, 95% CI 1.20–3.48), quartile 3 (OR 2.80, 95% CI 1.66–4.72) and quartile 4 (OR 3.77, 95% CI 2.24–6.33). Conclusions CT lung injury is an early objective measure that indicates risk of future lung impairment.

Published
2023
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5. Spatial transcriptomic profiling of coronary endothelial cells in SARS-CoV-2 myocarditis

Author

Camilla Margaroli, Paul Benson, Maria G. Gastanadui, Chunyan Song, Liliana Viera, Dongqi Xing, J. Michael Wells, Rakesh Patel, Amit Gaggar, and Gregory A. Payne

Subjects
spatial transcriptomic, severe acute respiratory syndrome coronavirus-2, myocarditis, endothelium, cell programming, Medicine (General), R5-920
Abstract

ObjectivesOur objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 utilizing digital spatial transcriptomics.BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has well-established links to thrombotic and cardiovascular events. Endothelial cell infection was initially proposed to initiate vascular events; however, this paradigm has sparked growing controversy. The significance of myocardial infection also remains unclear.MethodsAutopsy-derived cardiac tissue from control (n = 4) and COVID-19 (n = 8) patients underwent spatial transcriptomic profiling to assess differential expression patterns in myocardial and coronary vascular tissue. Our approach enabled transcriptional profiling in situ with preserved anatomy and unaltered local SARS-CoV-2 expression. In so doing, we examined the paracrine effect of SARS-CoV-2 infection in cardiac tissue.ResultsWe observed heterogeneous myocardial infection that tended to colocalize with CD31 positive cells within coronary capillaries. Despite these differences, COVID-19 patients displayed a uniform and unique myocardial transcriptional profile independent of local viral burden. Segmentation of tissues directly infected with SARS-CoV-2 showed unique, pro-inflammatory expression profiles including upregulated mediators of viral antigen presentation and immune regulation. Infected cell types appeared to primarily be capillary endothelial cells as differentially expressed genes included endothelial cell markers. However, there was limited differential expression within the endothelium of larger coronary vessels.ConclusionOur results highlight altered myocardial programming during severe COVID-19 that may in part be associated with capillary endothelial cells. However, similar patterns were not observed in larger vessels, diminishing endotheliitis, and endothelial activation as key drivers of cardiovascular events during COVID-19.

Published
2023
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6. Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease

Author

Preeti Lakshman Kumar, Ava C. Wilson, Alison Rocco, Michael H. Cho, Emily Wan, Brian D. Hobbs, George R. Washko, Victor E. Ortega, Stephanie A. Christenson, Xingnan Li, J. Michael Wells, Surya P. Bhatt, Dawn L. DeMeo, Sharon M. Lutz, Harry Rossiter, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Wassim W. Labaki, Ruth Tal‐Singer, Russel P. Bowler, Craig P. Hersh, Hemant K. Tiwari, Mark Dransfield, Anna Thalacker‐Mercer, Deborah A. Meyers, Edwin K. Silverman, Merry‐Lynn N. McDonald, and COPDGene, ECLIPSE and SPIROMICS investigators

Subjects
GWAS, Cachexia, Weight loss, COPD, Genetics, Biomarkers, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome‐wide association study approach. Methods Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self‐reported unintentional weight loss > 5% in the past year or low BMI (BMI

Published
2021
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7. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors

Author

Jingzhou Zhang, Dawn L. DeMeo, Edwin K. Silverman, Barry J. Make, R. Chad Wade, J. Michael Wells, Michael H. Cho, and Brian D. Hobbs

Subjects
COPD, DLCO, Hypoxemia, Oxygen therapy, Polycythemia, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied. Methods We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy. Results In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41–8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09–1.49), male sex (OR 3.60, CI 2.20–5.90), non-Hispanic white race (OR 3.33, CI 1.71–6.50), current smoking (OR 2.55, CI 1.49–4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38–8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05–0.35) and nocturnal (OR 0.46, CI 0.21–0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center. Conclusions In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.

Published
2021
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8. Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort

Author

William Z. Zhang, Katherine L. Hoffman, Kristen T. Schiffer, Clara Oromendia, Michelle C. Rice, Igor Barjaktarevic, Stephen P. Peters, Nirupama Putcha, Russell P. Bowler, J. Michael Wells, David J. Couper, Wassim W. Labaki, Jeffrey L. Curtis, Meilan K. Han, Robert Paine, Prescott G. Woodruff, Gerard J. Criner, Nadia N. Hansel, Ivan Diaz, Karla V. Ballman, Kiichi Nakahira, Mary E. Choi, Fernando J. Martinez, Augustine M. K. Choi, and Suzanne M. Cloonan

Subjects
COPD, Mitochondrial dysfunction, mtDNA, SPIROMICS, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. Methods P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. Results P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. Conclusion In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. Trial Registration: ClinicalTrials.gov NCT01969344 (SPIROMICS)

Published
2021
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9. Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort

Author

Kristopher Opron, Lesa A. Begley, John R. Erb-Downward, Christine Freeman, Siddharth Madapoosi, Neil E. Alexis, Igor Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Russell P. Bowler, Stephanie A. Christenson, Alejandro P. Comellas, Christopher B. Cooper, David J. Couper, Claire M. Doerschuk, Mark T. Dransfield, MeiLan K. Han, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Robert J. Kaner, Jerry Krishnan, Wanda K. O’Neal, Victor E. Ortega, Robert Paine, Stephen P. Peters, J. Michael Wells, Prescott G. Woodruff, Fernando J. Martinez, Jeffrey L. Curtis, Gary B. Huffnagle, and Yvonne J. Huang

Subjects
Microbial ecology, QR100-130
Abstract

Abstract Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25–75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

Published
2021
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10. Heme metabolism genes Downregulated in COPD Cachexia

Author

Ava C. Wilson, Preeti L. Kumar, Sool Lee, Margaret M. Parker, Itika Arora, Jarrett D. Morrow, Emiel F. M. Wouters, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Alvar Agusti, Ruth Tal-Singer, Mark T. Dransfield, J. Michael Wells, Surya P. Bhatt, George Washko, Victor J. Thannickal, Hemant K. Tiwari, Craig P. Hersh, Peter J. Castaldi, Edwin K. Silverman, and Merry-Lynn N. McDonald

Subjects
Chronic obstructive pulmonary disease, Diseases of the respiratory system, RC705-779
Abstract

Abstract Introduction Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers. Methods We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) ( 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB. Results The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR

Published
2020
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11. The matrikine acetyl-proline-glycine-proline and clinical features of COPD: findings from SPIROMICS

Author

J. Michael Wells, Dongqi Xing, Liliana Viera, Robert M. Burkes, Yixin Wu, Surya P. Bhatt, Mark T. Dransfield, David J. Couper, Wanda O’Neal, Eric A. Hoffman, Amit Gaggar, Igor Barjaktarevic, Jeffrey L. Curtis, Wassim W. Labaki, Mei Lan K. Han, Christine M. Freeman, Nirupama Putcha, Thomas Schlange, J. Edwin Blalock, and for the SPIROMICS Investigators,

Subjects
COPD, Acetyl proline-glycine-proline (AcPGP), Sputum, Matrikine, Inflammation, Biomarker, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. Methods Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. Results The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. Conclusions In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. Trial registration ClinicalTrials.gov: NCT01969344 (SPIROMICS).

Published
2019
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12. A Metabolomic Severity Score for Airflow Obstruction and Emphysema

Author

Suneeta Godbole, Wassim W. Labaki, Katherine A. Pratte, Andrew Hill, Matthew Moll, Annette T. Hastie, Stephen P. Peters, Andrew Gregory, Victor E. Ortega, Dawn DeMeo, Michael H. Cho, Surya P. Bhatt, J. Michael Wells, Igor Barjaktarevic, Kathleen A. Stringer, Alejandro Comellas, Wanda O’Neal, Katerina Kechris, and Russell P. Bowler

Subjects
metabolomics, COPD, lung density, adaptive LASSO, Microbiology, QR1-502
Abstract

Chronic obstructive pulmonary disease (COPD) is a disease with marked metabolic disturbance. Previous studies have shown the association between single metabolites and lung function for COPD, but whether a combination of metabolites could predict phenotype is unknown. We developed metabolomic severity scores using plasma metabolomics from the Metabolon platform from two US cohorts of ever-smokers: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) (n = 648; training/testing cohort; 72% non-Hispanic, white; average age 63 years) and the COPDGene Study (n = 1120; validation cohort; 92% non-Hispanic, white; average age 67 years). Separate adaptive LASSO (adaLASSO) models were used to model forced expiratory volume at one second (FEV1) and MESA-adjusted lung density using 762 metabolites common between studies. Metabolite coefficients selected by the adaLASSO procedure were used to create a metabolomic severity score (metSS) for each outcome. A total of 132 metabolites were selected to create a metSS for FEV1. The metSS-only models explained 64.8% and 31.7% of the variability in FEV1 in the training and validation cohorts, respectively. For MESA-adjusted lung density, 129 metabolites were selected, and metSS-only models explained 59.0% of the variability in the training cohort and 17.4% in the validation cohort. Regression models including both clinical covariates and the metSS explained more variability than either the clinical covariate or metSS-only models (53.4% vs. 46.4% and 31.6%) in the validation dataset. The metabolomic pathways for arginine biosynthesis; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine pathway were enriched by adaLASSO metabolites for FEV1. This is the first demonstration of a respiratory metabolomic severity score, which shows how a metSS can add explanation of variance to clinical predictors of FEV1 and MESA-adjusted lung density. The advantage of a comprehensive metSS is that it explains more disease than individual metabolites and can account for substantial collinearity among classes of metabolites. Future studies should be performed to determine whether metSSs are similar in younger, and more racially and ethnically diverse populations as well as whether a metabolomic severity score can predict disease development in individuals who do not yet have COPD.

Published
2022
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13. Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort

Author

Surya P. Bhatt, Hrudaya P. Nath, Young-il Kim, Rekha Ramachandran, Jubal R. Watts, Nina L. J. Terry, Sushil Sonavane, Swati P. Deshmane, Prescott G. Woodruff, Elizabeth C. Oelsner, Sandeep Bodduluri, MeiLan K. Han, Wassim W. Labaki, J. Michael Wells, Fernando J. Martinez, R. Graham Barr, Mark T. Dransfield, and for the SPIROMICS investigators

Subjects
Emphysema, COPD, Coronary artery calcification, Cardiovascular disease, Mediators, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. Methods We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. Results FEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. Conclusions The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. Trial Registration ClinicalTrials.gov: Identifier: NCT01969344.

Published
2018
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14. Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection

Author

Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Dongqi Xing, Melanie Bosley, Xin Xu, J. Michael Wells, James F. George, Jose Tallaj, Massoud Leesar, J. Edwin Blalock, and Amit Gaggar

Subjects
Cardiology, Transplantation, Medicine
Abstract

Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil proinflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced proinflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within 2 independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provide a link between neutrophilic inflammation and cardiovascular injury, represent a potential target to reduce allogenic immune responses, and uncover a mechanism of cardiovascular disease that has been previously unrecognized to our knowledge.

Published
2021
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15. Supportive care of right ventricular failure due to fat embolism syndrome

Author

Kevin T. Schwalbach, R. Chad Wade, Takudzwa Mkorombindo, Sam K. McElwee, J. Michael Wells, and Keith M. Wille

Subjects
Fat embolism, Right ventricle, Pulmonary hypertension, Hypoxemia, Diseases of the respiratory system, RC705-779
Abstract

Pulmonary fat embolism is a common phenomenon in cases of traumatic long bone fractures, with only a minority developing the more catastrophic Fat Embolism Syndrome (FES). Diagnosis is clinical and requires a high index of suspicion. Treatment remains under-investigated, with common interventions having low quality level-of-evidence and no mortality benefit. In severe cases, focus should be on supporting the failing right ventricle through use of inotropes, pulmonary vasodilators, and mechanical circulatory support. This requires a thorough understanding of the unique physiology through the pulmonary circulation.

Published
2021
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16. The Matrikine Acetylated Proline-Glycine-Proline Couples Vascular Inflammation and Acute Cardiac Rejection

Author

Gregory A. Payne, Jindong Li, Xin Xu, Patricia Jackson, Hongwei Qin, David M. Pollock, J. Michael Wells, Suzanne Oparil, Massoud Leesar, Rakesh P. Patel, J. Edwin Blalock, and Amit Gaggar

Subjects
Medicine, Science
Abstract

Abstract The extracellular matrix (ECM) is a dynamic, bioactive structure critical to organ development, structure and function. Excessive remodeling of the ECM is a hallmark of a variety of inflammatory conditions including vascular disease. Endothelin-1 (ET1) synthesis is understood to promote cardiovascular diseases including acute cardiac transplant rejection; however, the contribution of ECM-derived chemokines (matrikines) to vascular inflammation remains poorly understood. Herein we report that the matrikine acetylated Pro-Gly-Pro (PGP) stimulates vascular inflammation through activation of endothelial CXC Chemokine Receptor 2 (CXCR2) and production of endothelin-1 both in vitro and in vivo. As a proof of hypothesis, we demonstrate that coronary PGP levels associate with both circulating endothelin-1 and acute rejection in cardiac transplant patients (sensitivity of 100% and specificity of 86%). These findings establish PGP as a novel mediator in cardiovascular disease, and implicate bioactive matrix fragments as underappreciated agents potentially active in numerous conditions propagated by progressive vascular inflammation.

Published
2017
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17. Fibroblast Growth Factor 23 is Associated with a Frequent Exacerbator Phenotype in COPD: A Cross-Sectional Pilot Study

Author

Swati Gulati, J. Michael Wells, Gisel P. Urdaneta, Kira Balestrini, Isabel Vital, Katherine Tovar, Jarrod W. Barnes, Surya P. Bhatt, Michael Campos, and Stefanie Krick

Subjects
FGF23, COPD, inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease punctuated by exacerbations (AECOPD). Subjects with frequent AECOPD, defined by having at least two exacerbations per year, experience accelerated loss of lung function, deterioration in quality of life and increase in mortality. Fibroblast growth factor (FGF)23, a hormone associated with systemic inflammation and altered metabolism is elevated in COPD. However, associations between FGF23 and AECOPD are unknown. In this cross-sectional study, individuals with COPD were enrolled between June 2016 and December 2016. Plasma samples were analyzed for intact FGF23 levels. Logistic regression analyses were used to measure associations between clinical variables, FGF23, and the frequent exacerbator phenotype. Our results showed that FGF23 levels were higher in frequent exacerbators as compared to patients without frequent exacerbations. FGF23 was also independently associated with frequent exacerbations (OR 1.02; 95%CI 1.004−1.04; p = 0.017), after adjusting for age, lung function, smoking, and oxygen use. In summary, FGF23 was associated with the frequent exacerbator phenotype and correlated with number of exacerbations recorded retrospectively and prospectively. Further studies are needed to explore the role of FGF 23 as a possible biomarker for AECOPD to better understand the pathobiology of COPD and to help develop therapeutic targets.

Published
2019
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18. Bronchodilator Responsiveness in Tobacco-Exposed People With or Without COPD

Author

Spyridon Fortis, Pedro M. Quibrera, Alejandro P. Comellas, Surya P. Bhatt, Donald P. Tashkin, Eric A. Hoffman, Gerard J. Criner, MeiLan K. Han, R. Graham Barr, Mehrdad Arjomandi, Mark B. Dransfield, Stephen P. Peters, Brett A. Dolezal, Victor Kim, Nirupama Putcha, Stephen I. Rennard, Robert Paine, Richard E. Kanner, Jeffrey L. Curtis, Russell P. Bowler, Fernando J. Martinez, Nadia N. Hansel, Jerry A. Krishnan, Prescott G. Woodruff, Igor Z. Barjaktarevic, David Couper, Wayne H. Anderson, Christopher B. Cooper, Neil E. Alexis, Igor Barjaktarevic, Patricia Basta, Lori A. Bateman, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, David J. Couper, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Annette T. Hastie, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, J. Michael Wells, and Robert A. Wise

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Abstract

Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Published
2023

19. Clinical Markers Associated With Risk of Suicide or Drug Overdose Among Individuals With Smoking Exposure

Author

Brigid A. Adviento, Elizabeth A. Regan, Barry J. Make, MeiLan K. Han, Marilyn G. Foreman, Anand S. Iyer, Surya P. Bhatt, Victor Kim, Jessica Bon, Xavier Soler, Gregory L. Kinney, Nicola A. Hanania, Katherine E. Lowe, Kristen E. Holm, Abebaw M. Yohannes, Gen Shinozaki, Karin F. Hoth, Jess G. Fiedorowicz, James D. Crapo, Edwin K. Silverman, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel El Boueiz, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Emily S. Wan, Jeong Yun, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Matthew Strand, Jim Crooks, Katherine Pratte, Aastha Khatiwada, Erin Austin, Gregory Kinney, Kendra A. Young, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2023

20. Prolonged, physiologically relevant nicotine concentrations in the airways of smokers

Author

Charles R, Esther, Wanda K, O'Neal, Neil E, Alexis, Abigail L, Koch, Christopher B, Cooper, Igor, Barjaktarevic, Laura M, Raffield, Russel P, Bowler, Alejandro P, Comellas, Stephen P, Peters, Annette T, Hastie, Jeffrey L, Curtis, Bonnie, Ronish, Victor E, Ortega, J Michael, Wells, Eitan, Halper-Stromberg, Stephen I, Rennard, and Richard C, Boucher

Subjects
Pulmonary and Respiratory Medicine, Nicotine, Pulmonary Disease, Chronic Obstructive, Smokers, Physiology, Physiology (medical), Respiratory System, Humans, Cell Biology, Cotinine, Biomarkers
Abstract

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8–10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70–850 ng/mL (∼0.5–5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

Published
2023

21. Reversible Airflow Obstruction Predicts Future Chronic Obstructive Pulmonary Disease Development in the SPIROMICS Cohort: An Observational Cohort Study

Author

Russell G. Buhr, Igor Z. Barjaktarevic, P. Miguel Quibrera, Lori A. Bateman, Eugene R. Bleecker, David J. Couper, Jeffrey L. Curtis, Brett A. Dolezal, MeiLan K. Han, Nadia N. Hansel, Jerry A. Krishnan, Fernando J. Martinez, William McKleroy, Robert Paine, Stephen I. Rennard, Donald P. Tashkin, Prescott G. Woodruff, Richard E. Kanner, Christopher B. Cooper, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, R. Graham Barr, Surya P. Bhatt, Richard C. Boucher, Russell P. Bowler, Stephanie A. Christenson, Alejandro P. Comellas, Gerard J. Criner, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Annette T. Hastie, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Stephen P. Peters, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, J. Michael Wells, and Robert A. Wise

Subjects
Airway Obstruction, Cohort Studies, Pulmonary and Respiratory Medicine, Pulmonary Disease, Chronic Obstructive, Spirometry, Forced Expiratory Volume, Vital Capacity, Humans, Critical Care and Intensive Care Medicine, Asthma, Bronchodilator Agents
Published
2022

22. Lung Microbiota and Metabolites Collectively Associate with Clinical Outcomes in Milder Stage Chronic Obstructive Pulmonary Disease

Author

Siddharth S. Madapoosi, Charmion Cruickshank-Quinn, Kristopher Opron, John R. Erb-Downward, Lesa A. Begley, Gen Li, Igor Barjaktarevic, R. Graham Barr, Alejandro P. Comellas, David J. Couper, Christopher B. Cooper, Christine M. Freeman, MeiLan K. Han, Robert J. Kaner, Wassim Labaki, Fernando J. Martinez, Victor E. Ortega, Stephen P. Peters, Robert Paine, Prescott Woodruff, Jeffrey L. Curtis, Gary B. Huffnagle, Kathleen A. Stringer, Russell P. Bowler, Charles R. Esther, Nichole Reisdorph, Yvonne J. Huang, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Gerard J. Criner, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Craig Galban, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Richard E. Kanner, Eric C. Kleerup, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J. Michael Wells, and Robert A. Wise

Subjects
Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published
2022

23. Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment

Author

Wassim W Labaki, Tian Gu, Susan Murray, Jeffrey L Curtis, J Michael Wells, Surya P Bhatt, Jessica Bon, Alejandro A Diaz, Craig P. Hersh, Emily S Wan, Victor Kim, Terri H Beaty, John E Hokanson, Russell P Bowler, Douglas A Arenberg, Ella A Kazerooni, Fernando J. Martinez, Edwin K. Silverman, James D Crapo, Barry J. Make, Elizabeth A Regan, and MeiLan K. Han

Subjects
Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published
2023

24. Identification of Sputum Biomarkers Predictive of Pulmonary Exacerbations in COPD

Author

Charles R. Esther, Wanda K. O’Neal, Wayne H. Anderson, Mehmet Kesimer, Agathe Ceppe, Claire M. Doerschuk, Neil E. Alexis, Annette T. Hastie, R. Graham Barr, Russell P. Bowler, J. Michael Wells, Elizabeth C. Oelsner, Alejandro P. Comellas, Yohannes Tesfaigzi, Victor Kim, Laura M. Paulin, Christopher B. Cooper, MeiLan K. Han, Yvonne J. Huang, Wassim W. Labaki, Jeffrey L. Curtis, Richard C. Boucher, Mehrdad Arjomandi, Igor Barjaktarevic, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Stephanie A. Christenson, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Nadia N. Hansel, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Richard E. Kanner, Eric C. Kleerup, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Fernando J. Martinez, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Robert Paine, Laura Paulin, Stephen P. Peters, Cheryl Pirozzi, Nirupama Putcha, Victor E. Ortega, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, Robert A. Wise, and Prescott G. Woodruff

Subjects
Pulmonary and Respiratory Medicine, Spirometry, Subpopulations and Intermediate Outcome Measures in COPD Study, Chronic Obstructive, Exacerbation, Chronic Obstructive Pulmonary Disease, Clinical Sciences, Respiratory System, Critical Care and Intensive Care Medicine, Cystic fibrosis, COPD: Original Research, Pulmonary Disease, Pulmonary Disease, Chronic Obstructive, mucus, Clinical Research, medicine, Humans, glutathione, Lung, COPD, medicine.diagnostic_test, business.industry, methionine salvage, Sputum, Area under the curve, medicine.disease, metabolomics, N-Acetylneuraminic Acid, Pathophysiology, respiratory tract diseases, Good Health and Well Being, adenosine, inflammation, Hypoxanthines, Immunology, Respiratory, Biomarker (medicine), medicine.symptom, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Published
2022

26. Comparative Impact of Depressive Symptoms and FEV1% on Chronic Obstructive Pulmonary Disease

Author

Jacqueline O’Toole, Han Woo, Nirupama Putcha, Christopher B. Cooper, Prescott Woodruff, Richard E. Kanner, Robert Paine, Russell P. Bowler, Alejandro Comellas, Karin F. Hoth, Jerry A. Krishnan, Meilan Han, Mark Dransfield, Anand S. Iyer, David Couper, Stephen P. Peters, Gerard Criner, Victor Kim, R. Graham Barr, Fernando J. Martinez, Nadia N. Hansel, Michelle N. Eakin, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Igor Barjaktarevic, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Alejandro P. Comellas, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Jeffrey L. Curtis, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, MeiLan K. Han, Annette T. Hastie, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J Michael Wells, Robert A. Wise, and Prescott G. Woodruff

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, COPD, business.industry, Internal medicine, medicine, Pulmonary disease, medicine.disease, business, Depressive symptoms, Depression (differential diagnoses), respiratory tract diseases
Abstract

Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...

Published
2022

27. Clinically Significant and Comorbid Anxiety and Depression Symptoms Predict Severe Respiratory Exacerbations in Smokers: A Post Hoc Analysis of the COPDGene and SPIROMICS Cohorts

Author

Anand S. Iyer, Trisha M. Parekh, Jacqueline O’Toole, Surya P. Bhatt, Michelle N. Eakin, Jerry A. Krishnan, Abebaw M. Yohannes, Prescott G. Woodruff, Christopher B. Cooper, Richard E. Kanner, Nicola A. Hanania, Mark T. Dransfield, Elizabeth A. Regan, Karin F. Hoth, Victor Kim, James D. Crapo, Edwin K. Silverman, Barry J. Make, Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Huries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San José Estépar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Los Angeles, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Comorbid anxiety, business.industry, Internal medicine, Post-hoc analysis, Medicine, Respiratory system, business, Depressive symptoms
Published
2022

28. Mortality Risk and Serious Cardiopulmonary Events in Moderate-to-Severe COPD: Post Hoc Analysis of the IMPACT Trial

Author

J. Michael Wells, Gerard J. Criner, David M.G. Halpin, MeiLan K. Han, Renu Jain, Peter Lange, David A. Lipson, Fernando J. Martinez, Dawn Midwinter, Dave Singh, and Robert A. Wise

Subjects
Pulmonary and Respiratory Medicine, Origianl Research
Abstract

Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1–90 and 91–365 days post moderate or severe exacerbation and time-to-first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49–64.15]; p

Published
2022

29. Outcome expectancies and resistance self-efficacy mediate the relationship between asthma diagnosis and e-cigarette use among youth and young adults

Author

Abdullah M. M. Alanazi, Mohammed M. Alqahtani, J. Michael Wells, Donald H. Lein, and Peter S. Hendricks

Subjects
Pulmonary and Respiratory Medicine, Pediatrics, Perinatology and Child Health, Immunology and Allergy
Abstract

The use of electronic cigarettes (e-cigarettes) may exacerbate pulmonary complications in youth and young adults with asthma. We sought to identify the cognitive mechanisms that might explain e-cigarette use in this population. We hypothesized that e-cigarette outcome expectancies and e-cigarette resistance self-efficacy would mediate the relationship between asthma diagnosis and e-cigarette use in youth and young adults.We enrolled youth and young adults (15-25 years old) in Alabama with a clinical diagnosis of asthma (The frequency of the susceptibility to e-cigarette use and current e-cigarette use was lower among those with clinically diagnosed asthma than among those without asthma (35.8% vs. 59.8% for susceptibility and 6.0% vs. 18.2% for current use). Individuals with asthma reported weaker expectancies that e-cigarettes would make them feel relaxed which, in turn, was a significant predictor of lower susceptibility to e-cigarette use and current e-cigarette use, suggesting mediation. Finally, individuals with asthma demonstrated greater e-cigarette resistance self-efficacy in the context of social opportunities and friends' influence to use e-cigarettes. This self-efficacy was associated with lower susceptibility to e-cigarette use as well as current e-cigarette use.Although longitudinal studies are needed to determine relationships prospectively, targeted interventions that reduce outcome expectancies and increase resistance self-efficacy to e-cigarette use may further reduce e-cigarette use among youth and young adults with asthma.

Published
2022

30. The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers

Author

Divay Chandra, Aman Gupta, Gregory L. Kinney, Carl R. Fuhrman, Joseph K. Leader, Alejandro A. Diaz, Jessica Bon, R. Graham Barr, George Washko, Matthew Budoff, John Hokanson, Frank C. Sciurba, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Adel R. Boueiz, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Carla G. Wilson, Robert Jensen, Jim Crooks, Douglas Everett, Camille Moore, null Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Carlos Martinez, Susan Murray, Xavier Soler, Farnoush Banaei-Kashani, Russell P. Bowler, Katerina Kechris, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Michael E. DeBakey, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya P. Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Carlos H. Martinez, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronary Artery Disease, Critical Care and Intensive Care Medicine, COPD: Original Research, Coronary artery disease, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Functional residual capacity, Risk Factors, Internal medicine, medicine, Humans, Lung volumes, 030212 general & internal medicine, Myocardial infarction, Lung, Subclinical infection, COPD, business.industry, Smoking, Organ Size, Middle Aged, respiratory system, medicine.disease, Coronary Vessels, United States, Respiratory Function Tests, respiratory tract diseases, Airway Obstruction, Plethysmography, Biological Variation, Population, Pulmonary Emphysema, 030228 respiratory system, Asymptomatic Diseases, Cohort, Cardiology, Airway Remodeling, Female, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business
Abstract

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Published
2021

31. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors

Author

Dawn L. DeMeo, Edwin K. Silverman, Brian D. Hobbs, Jingzhou Zhang, Michael H. Cho, R. Chad Wade, J. Michael Wells, and Barry J. Make

Subjects
Male, Secondary Polycythemia, medicine.medical_treatment, Severity of Illness Index, Hypoxemia, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, DLCO, Risk Factors, Diffusing capacity, Oxygen therapy, hemic and lymphatic diseases, Prevalence, Medicine, 030212 general & internal medicine, Prospective Studies, Hypoxia, Aged, 80 and over, COPD, Carbon Monoxide, medicine.diagnostic_test, Middle Aged, Pulmonary Emphysema, Female, medicine.symptom, Research Article, Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Polycythemia, Lower risk, Cigarette Smoking, 03 medical and health sciences, Diseases of the respiratory system, Sex Factors, Internal medicine, Humans, Aged, RC705-779, business.industry, Oxygen Inhalation Therapy, medicine.disease, United States, Cross-Sectional Studies, Logistic Models, 030228 respiratory system, business, Tomography, X-Ray Computed
Abstract

Background Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied. Methods We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy. Results In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41–8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09–1.49), male sex (OR 3.60, CI 2.20–5.90), non-Hispanic white race (OR 3.33, CI 1.71–6.50), current smoking (OR 2.55, CI 1.49–4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38–8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05–0.35) and nocturnal (OR 0.46, CI 0.21–0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center. Conclusions In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.

Published
2021

32. Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease

Author

Thuonghien V. Tran, Gregory L. Kinney, Alejandro Comellas, Karin F. Hoth, Arianne K. Baldomero, A. James Mamary, Jeffrey L. Curtis, Nicola Hanania, Richard Casaburi, Kendra A. Young, Victor Kim, Barry Make, Emily S. Wan, Alejandro A. Diaz, John Hokanson, James D. Crapo, Edwin K. Silverman, Surya P. Bhatt, Elizabeth Regan, Spyridon Fortis, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel El Boueiz, Marilyn G. Foreman, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Jeong Yun, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Jessica Bon, Susan Murray, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush BanaeiKashani, Perry G. Pernicano, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D'Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh

Subjects
Pulmonary and Respiratory Medicine
Published
2023

33. Clinical Phenotypes of Atopy and Asthma in COPD

Author

Russell P. Bowler, R. Graham Barr, Nirupama Putcha, Eric A. Hoffman, Gregory B. Diette, Craig P. Hersh, Alejandro P. Comellas, Elizabeth C. Matsui, Jerry A. Krishnan, Laura M. Paulin, Victor E. Ortega, Ashraf Fawzy, Prescott G. Woodruff, Li Gao, J. Michael Wells, Fernando J. Martinez, Mark T. Dransfield, MeiLan K. Han, C. Conover Talbot, Njira L Lugogo, Mark C. Liu, Wanda K. O'Neal, Richard E. Kanner, Gerard J. Criner, Robert A. Wise, Christopher B. Cooper, Nadia N. Hansel, and M. Bradley Drummond

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, COPD, Exacerbation, business.industry, medicine.drug_class, Concordance, Critical Care and Intensive Care Medicine, Rate ratio, medicine.disease, respiratory tract diseases, Atopy, Internal medicine, Meta-analysis, Bronchodilator, medicine, Cardiology and Cardiovascular Medicine, business, Asthma
Abstract

Background Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies. Research Question What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)? Study Design and Methods Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis. Results The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes. Interpretation Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

Published
2020

34. Current smoking with or without chronic bronchitis is independently associated with goblet cell hyperplasia in healthy smokers and COPD subjects

Author

Russell P. Bowler, Stephanie Jeong, Victor Kim, Fernando J. Martinez, Richard C. Boucher, Robert Paine, Mark T. Dransfield, MeiLan K. Han, Igor Barjaktarevic, J. Michael Wells, Stephen I. Rennard, Mehmet Kesimer, Wanda K. O'Neal, Jeffrey L. Curtis, Huaqing Zhao, Robert J. Kaner, Sarah L. O’Beirne, Christopher B. Cooper, Stephanie A. Christenson, and Prescott G. Woodruff

Subjects
Male, Chronic bronchitis, medicine.medical_specialty, Goblet cell hyperplasia, lcsh:Medicine, Sputum Production, Gastroenterology, Article, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, lcsh:Science, Lung function, Aged, COPD, Goblet cell, Hyperplasia, Smokers, Multidisciplinary, business.industry, Chronic obstructive pulmonary disease, Smoking, lcsh:R, Middle Aged, Translational research, Former Smoker, medicine.disease, respiratory tract diseases, Bronchitis, Chronic, Chronic cough, Logistic Models, medicine.anatomical_structure, 030228 respiratory system, Female, lcsh:Q, Goblet Cells, medicine.symptom, business
Abstract

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log10 transformed values. Log10GCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log10 GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high log10GCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.

Published
2020

35. Associations Among 25-Hydroxyvitamin D Levels, Lung Function, and Exacerbation Outcomes in COPD

Author

Robert M. Burkes, Agathe S. Ceppe, Claire M. Doerschuk, David Couper, Eric A. Hoffman, Alejandro P. Comellas, R. Graham Barr, Jerry A. Krishnan, Christopher Cooper, Wassim W. Labaki, Victor E. Ortega, J. Michael Wells, Gerard J. Criner, Prescott G. Woodruff, Russell P. Bowler, Cheryl S. Pirozzi, Nadia N. Hansel, Robert A. Wise, Todd T. Brown, M. Bradley Drummond, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Igor Barjaktarevic, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Christopher B. Cooper, David J. Couper, Ronald G. Crystal, Jeffrey L. Curtis, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, MeiLan K. Han, Annette T. Hastie, Yvonne Huang, Robert J. Kaner, Richard E. Kanner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Fernando J. Martinez, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Robert Paine, Laura Paulin, Stephen P. Peters, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, Lisa Postow, and Lisa Viviano

Subjects
Pulmonary and Respiratory Medicine, COPD, medicine.medical_specialty, Exacerbation, business.industry, Intermediate outcome, Critical Care and Intensive Care Medicine, medicine.disease, vitamin D deficiency, respiratory tract diseases, Odds, Internal medicine, Cohort, medicine, Vitamin D and neurology, Cardiology and Cardiovascular Medicine, business, Lung function
Abstract

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Published
2020

36. The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS

Author

Victor E. Ortega, Xingnan Li, Wanda K. O’Neal, Lela Lackey, Elizabeth Ampleford, Gregory A. Hawkins, Philip J. Grayeski, Alain Laederach, Igor Barjaktarevic, R. Graham Barr, Christopher Cooper, David Couper, MeiLan K. Han, Richard E. Kanner, Eric C. Kleerup, Fernando J. Martinez, Robert Paine, Stephen P. Peters, Cheryl Pirozzi, Stephen I. Rennard, Prescott G. Woodruff, Eric A. Hoffman, Deborah A. Meyers, Eugene R. Bleecker, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Lori A. Bateman, Surya P. Bhatt, Richard C. Boucher, Russell P. Bowler, Stephanie A. Christenson, Alejandro P. Comellas, Gerard J. Criner, Ronald G. Crystal, Jeffrey L. Curtis, Claire M. Doerschuk, Mark T. Dransfield, Christine M. Freeman, Craig Galban, Nadia N. Hansel, Annette T. Hastie, Yvonne Huang, Robert J. Kaner, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Wendy C. Moore, Laura Paulin, Nirupama Putcha, Elizabeth C. Oelsner, Sanjeev Raman, Donald P. Tashkin, J. Michael Wells, and Robert A. Wise

Subjects
Pulmonary and Respiratory Medicine, business.industry, Heterozygote advantage, Serpin, Critical Care and Intensive Care Medicine, Molecular biology, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Genotype, Pi, Medicine, 030212 general & internal medicine, business, Clade, Gene, Lung function
Abstract

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, me...

Published
2020

37. Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts

Author

Jason D. Keene, Sean Jacobson, Katerina Kechris, Gregory L. Kinney, Marilyn G. Foreman, Claire M. Doerschuk, Barry J. Make, Jeffrey L. Curtis, Stephen I. Rennard, R. Graham Barr, Eugene R. Bleecker, Richard E. Kanner, Eric C. Kleerup, Nadia N. Hansel, Prescott G. Woodruff, MeiLan K. Han, Robert Paine, Fernando J. Martinez, Russell P. Bowler, Wanda K. O’Neal, Neil E. Alexis, Wayne H. Anderson, Richard C. Boucher, Elizabeth E. Carretta, Stephanie A. Christenson, Alejandro P. Comellas, Christopher B. Cooper, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Mark T. Dransfield, Christine M. Freeman, Annette T. Hastie, Eric A. Hoffman, Robert J. Kaner, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, John D. Newell, Elizabeth C. Oelsner, Nirupama Putcha, Donald P. Tashkin, Mary Beth Scholand, J. Michael Wells, and Robert A. Wise

Subjects
Pulmonary and Respiratory Medicine, Critical Care and Intensive Care Medicine
Published
2020

38. Velocity Transfer Function In The Right Pulmonary Artery And Impaired Cardiopulmonary Reserve In COPD

Author

Mark T. Dransfield, Swati Gulati, J. Michael Wells, Steven G. Lloyd, Oleg F. Sharifov, Gregory A. Payne, Thomas S. Denney, and Himanshu Gupta

Subjects
medicine.medical_specialty, COPD, medicine.diagnostic_test, business.industry, Pulsatile flow, Hemodynamics, Magnetic resonance imaging, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Right pulmonary artery, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, medicine.anatomical_structure, 030228 respiratory system, Internal medicine, Predictive value of tests, medicine, Cardiology, Vascular resistance, business
Published
2019

39. Proline-Glycine-Proline Peptides Are Critical in the Development of Smoke-induced Emphysema

Author

Xin Xu, Gert Folkerts, Liliana Viera, Mariam Sadik, George M. Solomon, Preston E. Bratcher, Tomasz Szul, J. Edwin Blalock, Amit Gaggar, J. Michael Wells, Mojtaba Abdul Roda, Tarek Abdalla, Carmel M. McNicholas, and Frank A. Redegeld

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Clinical Biochemistry, Inflammation, Stimulation, 03 medical and health sciences, 0302 clinical medicine, Right ventricular hypertrophy, Internal medicine, medicine, Macrophage, CXC chemokine receptors, Molecular Biology, Smoke, COPD, Lung, business.industry, Cell Biology, respiratory system, medicine.disease, respiratory tract diseases, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, medicine.symptom, business
Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide and is characterized by an excessive airway neutrophilic response. The neutrophil chemoattractant proline-glycine-proline (PGP) and its more potent acetylated form (acPGP) have been found to be elevated in patients with COPD and act via CXCR2. Here, we investigated the impact of neutralizing PGP peptides in a murine model for emphysema. The PGP-neutralizing peptide l-arginine-threonine-arginine (RTR) was used first in a 6-week model of cigarette smoke exposure, where it attenuated lung inflammation. Then, in a model of chronic smoke exposure, mice were exposed to cigarette smoke and RTR treatment was initiated after 10 weeks of smoke exposure. This treatment was continued together with smoke exposure for another 13 weeks, for a total of 23 weeks of smoke exposure. RTR significantly inhibited neutrophil and macrophage influx into the lungs in the 6-week model of exposure. RTR also attenuated the development of emphysema, normalized lung volumes, and reduced right ventricular hypertrophy in the chronic exposure model. Murine epithelia expressed CXCR2, and this expression was increased after smoke exposure. In vitro, human bronchial epithelial cells also demonstrated robust expression of CXCR2, and stimulation of primary human bronchial epithelial cells with acPGP led to increased release of MMP-9 and IL-8. Overall, these results provide evidence that acPGP plays a critical role during the development of emphysema in cigarette smoke-induced injury, and highlight a new epithelial mechanism by which acPGP augments neutrophilic inflammation.

Published
2019

40. Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease

Author

Auyon J. Ghosh, Brian D. Hobbs, Matthew Moll, Aabida Saferali, Adel Boueiz, Jeong H. Yun, Frank Sciurba, Lucas Barwick, Andrew H. Limper, Kevin Flaherty, Gerard Criner, Kevin K. Brown, Robert Wise, Fernando J. Martinez, David Lomas, Peter J. Castaldi, Vincent J. Carey, Dawn L. DeMeo, Michael H. Cho, Edwin K. Silverman, Craig P. Hersh, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Adel El-Boueiz, Marilyn G. Foreman, Lystra P. Hayden, Jacqueline Hetmanski, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Jarrett Morrow, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Richard Rosiello, David Pace, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh

Subjects
Male, Endotype, Respiratory System, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Gastroenterology, Loss of heterozygosity, Pulmonary Disease, Chronic Obstructive, Genotype, 80 and over, 2.1 Biological and endogenous factors, Medicine, Longitudinal Studies, Aetiology, Lung, Aged, 80 and over, COPD, RNA sequencing, Middle Aged, Respiratory Function Tests, medicine.anatomical_structure, Phenotype, Meta-analysis, Respiratory, Female, alpha-1 antitrypsin, Genetic Markers, Adult, Pulmonary and Respiratory Medicine, Chronic Obstructive, Heterozygote, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, Pulmonary disease, Pulmonary Disease, Clinical Research, Internal medicine, alpha 1-Antitrypsin Deficiency, Humans, Allele, Aged, Emphysema, COPDGene Investigators, Whole Genome Sequencing, business.industry, Original Articles, medicine.disease, Survival Analysis, respiratory tract diseases, meta-analysis, alpha 1-Antitrypsin, Case-Control Studies, business
Abstract

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

Published
2021

41. Small Airway Disease and Emphysema Are Associated with Future Exacerbations in Smokers with CT-derived Bronchiectasis and COPD: Results from the COPDGene Cohort

Author

Alejandro A. Diaz, Timothy R. Aksamit, Gregory L. Kinney, David A. Lynch, Ashwin Basavaraj, J. Michael Wells, Raúl San José Estépar, Yuka Okajima, Wei Wang, Marcos I. Restrepo, Wojciech R Dolliver, Diego J. Maselli, Christina Mercugliano, Stefano Aliberti, Andrew Yen, Kendra A. Young, and Antonio Anzueto

Subjects
Male, medicine.medical_specialty, Exacerbation, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Interquartile range, Risk Factors, Internal medicine, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Original Research, Aged, COPD, Bronchiectasis, Smokers, business.industry, Middle Aged, medicine.disease, Symptom Flare Up, respiratory tract diseases, Clinical trial, 030220 oncology & carcinogenesis, Relative risk, Cohort, Female, business, Tomography, X-Ray Computed, Body mass index
Abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. PURPOSE: To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. MATERIALS AND METHODS: SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. RESULTS: Of 737 participants, 387 (median age, 64 years [interquartile range, 58–71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV(1), and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). CONCLUSION: In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021

Published
2021

42. Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease

Author

Stephen I. Rennard, Harry B. Rossiter, Emily S. Wan, Deborah A. Meyers, Brian D. Hobbs, R.P. Bowler, David A. Lomas, Dawn L. DeMeo, Eclipse COPDGene, Richard Casaburi, Craig P. Hersh, George R. Washko, J. Michael Wells, Mark T. Dransfield, Ruth Tal-Singer, Spiromics Investigators, Ava C. Wilson, Merry-Lynn McDonald, Edwin K. Silverman, Michael H. Cho, Alison Rocco, Wassim W. Labaki, Sharon M. Lutz, Xingnan Li, Stephanie A. Christenson, Anna E. Thalacker-Mercer, Surya P. Bhatt, Preeti Lakshman Kumar, Hemant K. Tiwari, and Victor E. Ortega

Subjects
Oncology, Linkage disequilibrium, Weight loss, Cachexia, Physiology, Genome-wide association study, Diseases of the musculoskeletal system, Pulmonary Disease, Chronic Obstructive, Skeletal muscle regeneration, 2.1 Biological and endogenous factors, GWAS, Orthopedics and Sports Medicine, Aetiology, Lung, Tissue homeostasis, Tissue remodelling, COPD, Skeletal, Respiratory, Muscle, ECLIPSE and SPIROMICS investigators, Original Article, medicine.symptom, Adult, Chronic Obstructive, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, 1.1 Normal biological development and functioning, Clinical Sciences, Nerve Tissue Proteins, Pulmonary Disease, COPDGene, Clinical Research, Underpinning research, Physiology (medical), Internal medicine, medicine, Genetics, Humans, Regeneration, Muscle, Skeletal, Nutrition, Genetic association, business.industry, Prevention, QM1-695, Human Genome, Genetic Variation, Bayes Theorem, Human Movement and Sports Sciences, Original Articles, medicine.disease, RC925-935, Human anatomy, business, Body mass index, Biomarkers, Genome-Wide Association Study
Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.MethodsParticipants with COPD (N=4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss>5% in the past year or low BMI (BMI&nbsp

Published
2021

43. POINT: Are Eosinophils Useful for the Management of COPD? Yes

Author

J. Michael Wells and R. Chad Wade

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, COPD, Point (typography), business.industry, MEDLINE, Pulmonary disease, Critical Care and Intensive Care Medicine, medicine.disease, Eosinophils, Pulmonary Disease, Chronic Obstructive, Eosinophilia, Humans, Medicine, Cardiology and Cardiovascular Medicine, business, Intensive care medicine, Biomarkers
Published
2020

44. Arterial Vascular Pruning, Right Ventricular Size, and Clinical Outcomes in Chronic Obstructive Pulmonary Disease. A Longitudinal Observational Study

Author

Farbod N. Rahaghi, Wassim W. Labaki, Michael J. Cuttica, Amil M. Shah, Gonzalo Vegas Sanchez-Ferrero, Carolyn E. Come, Raúl San José Estépar, Pietro Nardelli, J. Michael Wells, Gregory L. Kinney, George R. Washko, Alejandro A. Diaz, Kendra A. Young, James C. Ross, John E. Hokanson, Mark T. Dransfield, Alvar Agusti, Gabriela Querejeta Roca, Samuel Y. Ash, Carrie P. Aaron, Ravi Kalhan, MeiLan K. Han, and Surya P. Bhatt

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Hypertension, Pulmonary, Heart Ventricles, Pulmonary disease, Walk Test, Computed tomography, Pulmonary Artery, Vascular Remodeling, Critical Care and Intensive Care Medicine, Severity of Illness Index, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, Pulmonary Heart Disease, Internal medicine, medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Mortality, Aged, Proportional Hazards Models, COPD, Exercise Tolerance, Ventricular size, medicine.diagnostic_test, business.industry, Editorials, food and beverages, Original Articles, Organ Size, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Phenotype, Pulmonary Emphysema, 030228 respiratory system, Multivariate Analysis, Linear Models, cardiovascular system, Cardiology, Female, Observational study, Tomography, X-Ray Computed, business
Abstract

Rationale: Cor pulmonale (right ventricular [RV] dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes. Objectives: To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study. Methods: Epicardial (myocardium and chamber) RV volume (RV(EV)), distal pulmonary arterial blood vessel volume (arterial BV5: vessels

Published
2019

45. Clinical Epidemiology of COPD

Author

Marilyn G. Foreman, Russell P. Bowler, Nirupama Putcha, Craig P. Hersh, Barry J. Make, Edwin K. Silverman, J. Michael Wells, Antonio Anzueto, Ashraf Fawzy, MeiLan K. Han, Alejandro A. Diaz, Mark T. Dransfield, Victor Kim, Dawn L. DeMeo, Kendra A. Young, Nicola A. Hanania, Diego J. Maselli, Gregory L. Kinney, Gloria Westney, Emily S. Wan, and Surya P. Bhatt

Subjects
Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Chronic bronchitis, COPD, medicine.diagnostic_test, business.industry, Genome-wide association study, Critical Care and Intensive Care Medicine, medicine.disease, Comorbidity, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Genetic epidemiology, Internal medicine, Epidemiology, medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Asthma
Abstract

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap.

Published
2019

46. Aspirin Use and Respiratory Morbidity in COPD

Author

Ashraf Fawzy, Nirupama Putcha, Carrie P. Aaron, Russell P. Bowler, Alejandro P. Comellas, Christopher B. Cooper, Mark T. Dransfield, MeiLan K. Han, Eric A. Hoffman, Richard E. Kanner, Jerry A. Krishnan, Wassim W. Labaki, Robert Paine, Laura M. Paulin, Stephen P. Peters, Robert Wise, R. Graham Barr, Nadia N. Hansel, Neil E. Alexis, Wayne H. Anderson, Igor Barjaktarevic, Eugene R. Bleecker, Richard C. Boucher, Elizabeth E. Carretta, Stephanie A. Christenson, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Jeffrey L. Curtis, Claire M. Doerschuk, Christine M. Freeman, Annette T. Hastie, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Fernando J. Martinez, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Stephen Peters, Cheryl Pirozzi, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J. Michael Wells, Robert A. Wise, and Prescott G. Woodruff

Subjects
Pulmonary and Respiratory Medicine, COPD, medicine.medical_specialty, Aspirin, business.industry, Confounding, Odds ratio, Critical Care and Intensive Care Medicine, medicine.disease, Rate ratio, law.invention, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Randomized controlled trial, Quality of life, law, Internal medicine, Propensity score matching, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. Methods Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC Results Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, –2.2; 95% CI, –4.1 to –0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, –1.1; 95% CI, –1.9 to –0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, –14.3 to 15.6). Conclusions Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. Trial Registry ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Published
2019

47. Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction and Radiographic Bronchiectasis in Current and Former Smokers: A Cross-Sectional Study

Author

J. Michael Wells, Melis Atalar Aksit, Garry R. Cutting, S. Vamsee Raju, Karen S. Raraigh, Steven M. Rowe, Lawrence Rasmussen, Surya P. Bhatt, P. Hrudaya Nath, Mark T. Dransfield, Krittika Teerapuncharoen, and George M. Solomon

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Cystic Fibrosis, Cross-sectional study, Radiography, Cystic Fibrosis Transmembrane Conductance Regulator, Gastroenterology, Pulmonary Disease, Chronic Obstructive, Internal medicine, Humans, Medicine, Letters, Aged, Bronchiectasis, biology, business.industry, Smoking, Middle Aged, Former Smoker, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Cross-Sectional Studies, biology.protein, Female, Tomography, X-Ray Computed, business
Published
2019

48. Longitudinal Phenotypes and Mortality in Preserved Ratio Impaired Spirometry in the COPDGene Study

Author

Emily S. Wan, Spyridon Fortis, Elizabeth A. Regan, John Hokanson, MeiLan K. Han, Richard Casaburi, Barry J. Make, James D. Crapo, Dawn L. DeMeo, Edwin K. Silverman, Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dandi Qiao, Sungho Won, Phuwanat Sakornsakolpat, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Jessica Bon, Barry Make, Carlos Martinez, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Mustafa Atik, Venkata Bandi, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Arun Nachiappan, Amit Parulekar, Craig Hersh, R. Graham Barr, John Austin, Belinda D’Souza, Gregory D. N. Pearson, Anna Rozenshtein, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Follow up studies, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, Cardiology, medicine, 030212 general & internal medicine, Prism, business
Abstract

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

Published
2018

49. Binge Drinking Moderates the Association Between Chronic Lung Disease and E-Cigarette Use

Author

Peter S. Hendricks, Abdullah Alanazi, Gregory Pavela, Donald H. Lein, J. Michael Wells, Mark T. Dransfield, and Mohammed Alqahtani

Subjects
Pulmonary and Respiratory Medicine, Adult, Lung Diseases, Alcohol Drinking, Population, Binge drinking, Electronic Nicotine Delivery Systems, Critical Care and Intensive Care Medicine, Logistic regression, Binge Drinking, Behavioral Risk Factor Surveillance System, Environmental health, medicine, Prevalence, Humans, education, Association (psychology), Asthma, education.field_of_study, COPD, business.industry, Vaping, General Medicine, medicine.disease, Moderation, business
Abstract

BACKGROUND: There is a paucity of research on e-cigarette use among adults with chronic lung disease. Accordingly, little is known about the factors that may contribute to e-cigarette use in this population. The purpose of this study was to evaluate the relationship between chronic lung disease and e-cigarette use and to determine whether binge drinking moderates this relationship. METHODS: Data were derived from the 2018 Behavioral Risk Factor Surveillance System (BRFSS). Logistic regression was used to test the association between chronic lung disease status and e-cigarette use, controlling for demographic variables and chronic health conditions. We conducted moderation analyses to test the hypothesis that the association between chronic lung disease and lifetime e-cigarette use would be modified by binge drinking. RESULTS: The prevalence of lifetime e-cigarette use was higher among adults with chronic lung disease than among those without, and more frequent binge drinking was associated with an increased likelihood of lifetime e-cigarette use independent of chronic lung disease status. Binge drinking moderated the relationship between chronic lung disease and lifetime use of e-cigarettes such that the association between chronic lung disease and e-cigarette use was weaker among those who engaged in more episodes of binge drinking in the past 30 d. Among those without chronic lung disease, binge drinking was associated with an increased likelihood of e-cigarette use. CONCLUSIONS: E-cigarette use appears to be more common among adults with chronic lung disease. Although binge drinking was positively associated with e-cigarette use, more frequent binge drinking weakened the relationship between chronic lung disease and e-cigarette use. Though future studies are needed to determine precisely how binge drinking affects this association, it is possible that individuals with chronic lung disease who binge drink more frequently use e-cigarettes less frequently, despite an increased likelihood of having ever used an e-cigarette. (ClinicalTrials.gov registration NCT04135404.)

Published
2021

50. Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort

Author

Robert Paine, Eric A. Hoffman, Robert J. Kaner, Eugene R. Bleecker, Russell P. Bowler, John R. Erb-Downward, Wanda K. O'Neal, Gary B. Huffnagle, Prescott G. Woodruff, Jerry A. Krishnan, Neil E. Alexis, Igor Barjaktarevic, R. Graham Barr, Yvonne J. Huang, MeiLan K. Han, Christopher B. Cooper, Siddharth Madapoosi, Stephanie A. Christenson, David Couper, Nadia N. Hansel, Kristopher Opron, Stephen P. Peters, Christine M. Freeman, Victor E. Ortega, Claire M. Doerschuk, Jeffrey L. Curtis, Alejandro P. Comellas, Annette T. Hastie, Fernando J. Martinez, J. Michael Wells, Lesa Begley, and Mark T. Dransfield

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Lung microbiome, medicine.drug_class, Disease, Applied Microbiology and Biotechnology, Microbiology, Article, Microbial ecology, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Forced Expiratory Volume, RNA, Ribosomal, 16S, Internal medicine, Bronchodilator, medicine, Humans, Lung, Aged, COPD, Bacteria, medicine.diagnostic_test, Sequence Analysis, RNA, business.industry, QR100-130, Health care, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, 030104 developmental biology, Bronchoalveolar lavage, medicine.anatomical_structure, 030228 respiratory system, Spirometry, Cohort, Female, Microbiome, business, Bronchoalveolar Lavage Fluid, Biotechnology
Abstract

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25–75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

Published
2021

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