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Purpose of Review: Recent recognition of the importance of abnormal spirometry without obstruction has generated interest in its epidemiology, risk factors, longitudinal outcomes, and clinical implications., Recent Findings: Preserved ratio impaired spirometry (PRISm), defined as an forced expiratory volume in 1 s (FEV 1 )/ forced vital capacity (FVC) ≥0.7 with an FEV 1 <80% predicted, has a high prevalence globally (2.4-16.7%) and is more common in individuals with metabolic comorbidities, smoking history, female sex, and higher BMI. PRISm is associated with increased respiratory symptoms and poor clinical outcomes such as increased all-cause mortality and cardiovascular events compared to normal spirometry. Longitudinal studies show substantial subsets of individuals with PRISm will transition to other spirometric categories, including progression to obstruction. Individuals with PRISm are heterogeneous; recent investigations have focused on subtyping PRISm based on spirometric features or pathobiologically-based phenotypes., Summary: PRISm is a common spirometric abnormality which is robustly associated with negative outcomes. However, current knowledge gaps with respect to heterogeneity, specific etiologies, and longitudinal progression preclude the development of universal evidence-based diagnostic and management strategies. At present, clinicians are advised to focus on risk factor modification (e.g., diabetes, obesity) and the identification of actionable traits (e.g. emphysema, interstitial lung abnormalities) among patients with PRISm., (Copyright © Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown., Objective: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history., Methods: We analyzed data from COPDGene participants with ≥10 pack-years cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FEV 1 ≥LLN. We examined whether respiratory exacerbations occurring between Visits 1 and the 5-year follow-up visit (Visit 2) were associated with FEV 1 decline, and all-cause mortality., Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between visit 1 and 2 was associated with a 2.96 ml/year FEV 1 decline (95%CI 1.81 to 4.12; P<0.001) at Visit 2. Experiencing ≥1 severe exacerbation between Visits 1 and 2 was associated with 14.6 ml/year FEV 1 decline relative to those with no severe exacerbations (95% CI 8.56 to 20.6; P<0.001). Individuals with ≥1 severe exacerbation between Visits 1 and 2 had increased mortality compared to those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio 1.97;95% CI 1.40 to 2.77; P<0.001)., Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

Background: Post-9/11 veterans were exposed to environmental and occupational pollutants during deployment., Objective: Our aim was to determine associations between deployment-related exposures and sinusitis and rhinitis., Methods: Between April 2018 and March 2020, veterans with land-based deployment after 9/11 who were living within 25 miles of 6 Department of Veteran Affairs medical centers were randomly chosen by using a Defense Manpower Data Center roster. Participants completed interviewer-administered questionnaires, which included a 32-item deployment exposure battery and self-report of rhinitis and health professional-diagnosed sinusitis. Exposure categories included burn pit smoke, combustion engine exhaust/ground dust, other open combustion sources, toxicants, and military job-related VGDF. Each item was scored on the basis of frequency and duration of exposure; ordinal scores were summed and scaled to 100 within each category. Odds ratios (ORs) were estimated using logistic regression for sinusitis and rhinitis separately. ORs were scaled per 20-point exposure score., Results: Among the 1960 participants, the incidences of sinusitis and rhinitis with onset during deployment were 2.1% and 3.6%, respectively; the incidences of postdeployment onset were 5.1% and 5.6%, respectively. Toxicant exposure consisted mainly of "applying pesticide, insecticide, or repellent to your own skin or to your own clothing" and was associated with rhinitis with onset during deployment (OR = 1.50 [95% CI = 1.31-1.84]) and onset after deployment (OR = 1.21 [95% CI = 0.93-1.50]). There were no associations with burn pit smoke or other exposure categories., Conclusion: Veterans with deployment exposures to toxicants were at increased risk of rhinitis, particularly during deployment. The clinical evaluation of postdeployment veterans should address rhinitis as a deployment-related condition., Competing Interests: Supported by the VA Cooperative Studies Program 595: Pulmonary Health and Deployment to Southwest Asia and Afghanistan, also known as SHADE (Service and Health Among Deployed Veterans) from the US Department of Veterans Affairs, 10.13039/100006379Office of Research and Development, 10.13039/100015728Clinical Science Research and Development, Cooperative Studies Program. The contents do not represent the views of the US Department of Veterans Affairs or the US Government. Disclosure of potential conflict of interest: E. S. Wan has served on a scientific advisory board for Verona Pharma, outside the current work. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Introduction: The effects of smoking on lung function among post-9/11 Veterans deployed to environments with high levels of ambient particulate matter are incompletely understood., Materials and Methods: We analyzed interim data (04/2018-03/2020) from the Veterans Affairs (VA) Cooperative Studies Program #595, "Service and Health Among Deployed Veterans". Veterans with ≥1 land-based deployments enrolled at 1 of 6 regional Veterans Affairs sites completed questionnaires and spirometry. Multivariable linear regression models assessed associations between cigarette smoking (cumulative, deployment-related and non-deployment-related) with pulmonary function., Results: Among 1,836 participants (mean age 40.7 ± 9.6, 88.6% male), 44.8% (n = 822) were ever-smokers (mean age 39.5 ± 9.5; 91.2% male). Among ever-smokers, 86% (n = 710) initiated smoking before deployment, while 11% (n = 90) initiated smoking during deployment(s). Smoking intensity was 50% greater during deployment than other periods (0.75 versus 0.50 packs-per-day; P < .05), and those with multiple deployments (40.4%) were more likely to smoke during deployment relative to those with single deployments (82% versus 74%). Total cumulative pack-years (median [IQR] = 3.8 [1, 10]) was inversely associated with post-bronchodilator FEV1%-predicted (-0.82; [95% CI] = [-1.25, -0.50] %-predicted per 4 pack-years) and FEV1/FVC%-predicted (-0.54; [95% CI] = [-0.78, -0.43] %-predicted per 4 pack-years). Deployment-related pack-years demonstrated similar point estimates of associations with FEV1%-predicted (-0.61; [95% CI] = [-2.28, 1.09]) and FEV1/FVC%-predicted (-1.09; [95% CI] = [-2.52, 0.50]) as non-deployment-related pack-years (-0.83; [95% CI] = [-1.26, -0.50] for FEV1%-predicted; -0.52; [95% CI] = [-0.73, -0.36] for FEV1/FVC%-predicted)., Conclusions: Although cumulative pack-years smoking was modest in this cohort, an inverse association with pulmonary function was detectable. Deployment-related pack-years had a similar association with pulmonary function compared to non-deployment-related pack-years., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The relationships between physical activity (PA) and exercise performance and systemic biomarkers in persons with chronic obstructive pulmonary disease (COPD) have not been well characterized. The impact of PA promotion on biomarkers reflecting myocardial stress, systemic inflammation, and muscle injury is unclear., Methods: This secondary analysis used 3 previously published studies in persons with COPD (2 examined a PA intervention that promoted community-based walking for 3 months) to explore these relationships. PA (daily step counts) and exercise performance (6-minute walk test [6MWT]) were assessed. Serum N-terminal pro-β-type natriuretic peptide (NT-proBNP), the soluble receptor for advanced glycation end products (sRAGE), and muscle-type creatine kinase (CKMM) were assayed at baseline and 3 months. General linear models examined associations between PA/exercise performance and systemic biomarkers at baseline and the effect of the PA intervention on change in biomarkers., Results: Participants included 366 U.S. Veterans: 98% male, mean age 70±8 years, and forced expiratory volume in 1 second percentage predicted 59±21%. Lower baseline NT-proBNP, but not sRAGE or CKMM, was associated with higher daily step count (-0.95pg/ml per 1000 steps/day, p =.060) and higher 6MWT distance (-0.80pg/ml per 100 meters, p =.001). Change in daily step count, but not 6MWT, was significantly greater in the intervention (789±1864) compared to the control group (-174±1448; p =.002). The PA intervention had no significant impact on change in the systemic biomarkers., Interpretation: Exercise performance is associated with NT-proBNP in persons with COPD. A 3-month community-based walking intervention is not associated with myocardial stress or muscle injury as assessed by NT-proBNP and CKMM, respectively. Clinical Trial Registration: NCT01772082 and NCT02099799., (JCOPDF © 2024.)

Objectives: Characterise inhalational exposures during deployment to Afghanistan and Southwest Asia and associations with postdeployment respiratory symptoms., Methods: Participants (n=1960) in this cross-sectional study of US Veterans (Veterans Affairs Cooperative Study 'Service and Health Among Deployed Veterans') completed an interviewer-administered questionnaire regarding 32 deployment exposures, grouped a priori into six categories: burn pit smoke; other combustion sources; engine exhaust; mechanical and desert dusts; toxicants; and military job-related vapours gas, dusts or fumes (VGDF). Responses were scored ordinally (0, 1, 2) according to exposure frequency. Factor analysis supported item reduction and category consolidation yielding 28 exposure items in 5 categories. Generalised linear models with a logit link tested associations with symptoms (by respiratory health questionnaire) adjusting for other covariates. OR were scaled per 20-point score increment (normalised maximum=100)., Results: The cohort mean age was 40.7 years with a median deployment duration of 11.7 months. Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%). The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively. Burn pit smoke exposure was associated with dyspnoea (OR 1.22; 95% CI 1.06 to 1.47) and chronic bronchitis (OR 1.22; 95% CI 1.13 to 1.44). Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35)., Conclusion: Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Depression is known to limit physical activity (PA) among individuals with chronic obstructive pulmonary disease (COPD). However, whether and how depression influences the effectiveness of PA interventions is unknown., Purpose: The study examined the association between baseline depression symptoms and change in daily step count and whether group assignment to a web-based, pedometer-mediated PA intervention moderated the association between baseline depression symptoms and change in daily step count., Methods: Secondary analysis included two cohorts of U.S. Veterans with COPD (n = 212; 97% male; mean age 69 ± 8 years) assessed at baseline and 3 months. Cohorts 1 and 2 were randomly assigned to the same PA intervention (n = 111) or a control group (n = 101). Multivariate regressions tested the main effects of baseline depression symptoms (BDI-II total and cognitive-affective and somatic subscales) on change in daily steps, as well as the interaction between baseline BDI-II and subscales and group assignment on change in daily steps., Results: Greater BDI-II total score (B = -31.8, SE = 14.48, p = .030) and somatic subscale scores (B = -99.82, SE = 35.76, p = .006) were associated with less improvement in daily step count. There was a significant interaction between baseline cognitive-affective subscale and the intervention predicting change in daily step count (B = -88.56, SE = 42.31, p = .038). When cognitive-affective subscale scores were ≥1 SD above the mean, the intervention was no longer associated with an increase in daily step count (p = .585)., Conclusions: Depression should be routinely assessed and targeted as part of PA promotion efforts., (Published by Oxford University Press on behalf of the Society of Behavioral Medicine 2023.)

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822-1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EKS received grant support from GlaxoSmithKline and Bayer. ESW received honoraria from Pri-Med. JAK reports a grant from U.S. National Institutes of Health (NIH) paid to the institution during the conduct of the study. He also reports personal fees from GlaxoSmithKline consulting on antibodies for acute COVID-19; personal fees from AstraZeneca consulting on antibodies for severe asthma, paid to the institution; personal fees from CereVu Medical consultant for medical device for dyspnea, paid to the institution; and personal fees from BData consultant for severe asthma registry outside the submitted work. JLC reports grants from NIH/NHLBI and the COPD Foundation for the current work and paid to his institution; grants from NIH/NHLBI, the COPD Foundation, NIH/NIAID, and the Departments of Veterans Affairs and of Defense, outside the current work and paid to his institution; and consulting fees from CSL Behring, LLC, AstraZenca, and Novartis Corp., outside the current work and paid to his institution. MCN has received grant support from GlaxoSmithKline. MHC has received grant support from GlaxoSmithKline and Bayer, consulting fees from AstraZeneca, and speaking fees from Illumina. MK received consulting fees from Arrowhead pharmaceuticals and has a patent pending for mucin measurements in chronic bronchitis. MKH reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Amgen, UpToDate, Altesa Biopharma, Medscape, NACE, MDBriefcase, Integrity and Medwiz. She has received either in kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, Astrazeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. She has received stock options from Meissa Vaccines and Altesa Biopharma. MVDB reports research grants paid to their institution by GlaxoSmithKline, Novartis, AstraZeneca, Roche and Genentech. SAC received consulting fees from Sanofi/Regeneron, GlaxoSmithKline, AstraZeneca, Glenmark Pharmaceuticals, and Amgen; honoraria from Sanofi/Regeneron, MJH Holdings LLC: Physicians? Education Resource, Sunovion, UpToDate, and Wolters Kluwer Health; travel support from AstraZeneca and GlaxoSmithKline; and sits on the data safety board or advisory boards of Sanofi/Regeneron, and AstraZeneca, and GlaxoSmithKline. TL has stock options from Variant Bio. VEO is on the Data Safety Monitoring Board or Advisory Board for Sanofi and Regeneron. ATH, EVB, GR, HD, SG, SL, SK, SNPK, WKO, and YL have no competing interests to declare., (Copyright: © 2023 Buren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry., Methods: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD., Results: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated., Conclusions: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment., Competing Interests: Declaration of competing interest Alejandro Comellas has consulted for GSK and VIDA Diagnostics. Arianne K. Baldomero is supported by the NIHNational Center for Advancing Translational Sciences Grants KL2TR002492 and UL1TR002494. Jeffrey L. Curtis is supported by R01 HL144718, R01 HL144849, U01 HL137880, and I01 CX001969 and has consulted for AstraZeneca PLC, Novartis AG, and CSL Behring LLC. Richard Casaburi has received consultant fees or honoraria from Boehringer Ingelheim, Glaxo Smith Kline and Inogen. Victor Kim has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from American Board of Internal Medicine. Alejandro A. Diaz is supported by NIH grants R01-HL133137, R01-HL14986; has reported speaker fees from Boehringer Ingelheim, outside the submitted work. Edwin K. Silverman has received grant support from GlaxoSmithKline and Bayer. Surya P. Bhatt is supported by NIH Grants R01HL151421, R21EB027891, and UG3HL155806 and he has served on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. Spyridon Fortis has received grants from American Thoracic Society and Fisher &Paykel and served as a consultant for Genentech. The rest of the authors have no relevant conflicts to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (N cases  = 4,325; N controls  = 507,640; OR = 0.89 [0.82-0.97]; P  = 6.86 × 10 -3 ) and joint meta-analyses with the HGI (N cases  = 13,320; N controls  = 1,508,841; OR, 0.90 [0.86-0.95]; P  = 8.99 × 10 -5 ). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (N cases  = 19,168/N controls  = 492,854; OR, 0.98 [0.95-1.01]; P  = 0.06) but was nominally significant ( P  < 0.05) in the joint meta-analysis with the HGI (N cases  = 44,820; N controls  = 1,775,827; OR, 0.97 [0.95-1.00]; P  = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P  = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Rationale: Differences in body composition may contribute to variability in exercise capacity (EC) and physical activity (PA) in individuals with chronic obstructive pulmonary disease (COPD). Most studies have used bioimpedance-based surrogates of muscle (lean) mass; relatively few studies have included consideration of fat mass, and limited studies have been performed using dual X-ray absorptiometry (DXA) to assess body composition. Objectives: To determine whether DXA-assessed muscle (lean) and fat mass exhibit differential correlations with EC and PA in subjects with COPD. Methods: U.S. veterans with COPD (defined as forced expiratory volume in 1 second/forced vital capacity < 0.7 or emphysema on clinical chest computed tomography) had DXA-assessed body composition, EC (6-minute-walk distance), objective PA (average daily step counts), and self-reported PA measured at enrollment. Associations among EC, PA, and body composition were examined using Spearman correlations and multivariable models adjusted a priori for age, sex, race, and lung function. Results: Subjects ( n  = 98) were predominantly White (90%), obese (mean body mass index, 30.2 ± 6.2 kg/m 2 ), and male (96%), with a mean age of 69.8 ± 7.9 years and moderate airflow obstruction (mean forced expiratory volume in 1 second percentage predicted, 68 ± 20%). Modest inverse correlations of EC and PA with fat mass were observed (Spearman's rho range, -0.20 to -0.34), whereas measures of muscle (lean) mass were not significantly associated with EC or PA. The ratio of appendicular skeletal muscle mass (ASM) to weight, which considers both muscle (lean) and fat mass, was consistently associated with EC (8.4 [95% confidence interval, 2.9-13.8] meter increase in 6-minute walk distance per 1% increase in ASM-to-weight ratio), objective PA (194.8 [95% confidence interval, 15.2-374.4] steps per day per 1% increase in ASM-to-weight ratio), and self-reported PA in multivariable-adjusted models. Conclusions: DXA-assessed body composition measures that include consideration of both lean and fat mass are associated with cross-sectional EC and PA in COPD populations. Clinical trial registered with www.clinicaltrials.gov (NCT02099799).

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear., Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19., Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021., Exposures: The hemoglobin beta S (HbS) allele (rs334-T)., Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records., Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure., Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

The Veterans Health Administration (VHA) is the largest integrated healthcare system in the United States (US) providing healthcare to an increasing number of middle-aged and older adults who remain at greater risk for chronic obstructive pulmonary disease (COPD) compared to their civilian counterparts. The VHA has obligated research funds, drafted clinical guidelines, and built programmatic infrastructure to support the diagnosis, treatment, and care management of Veterans with COPD. Despite these efforts, COPD remains a leading cause of morbidity and mortality in Veterans. This paper provides a narrative review of research conducted with US Veteran samples targeting improvement in COPD outcomes. We review key physiological, physical, and psychological health outcomes and intervention research that included US Veteran samples. We conclude with a discussion of directions for future research to continue advancing the treatment of COPD in Veterans and inform advancements in COPD research within and outside the VHA., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Bamonti et al.)

Objective: To examine predictors of uptake (never start), adherence (drop out), and completion of pulmonary rehabilitation (PR), as well as PR treatment response based on minimal clinically important difference (MCID) on the 6-minute walk test (6MWT) distance and Chronic Respiratory Questionnaire-Self-Report (CRQ-SR)., Design: Retrospective, cohort study., Setting: Veterans Health Administration., Participants: U.S. veterans with chronic obstructive pulmonary disease (COPD) (N=253) referred to PR between 2010 and 2018., Interventions: Outpatient PR program., Main Outcome Measures: Participants completed baseline (time 1) measures of depression (Beck Depression Inventory-II), health-related quality of life (CRQ-SR), self-efficacy (Exercise Self-Regulatory Efficacy Scale [Ex-SRES]), and COPD knowledge. Exercise capacity was assessed with the 6MWT. Participants who completed all 18 sessions of PR repeated assessments (time 2). Logistic regression models examined predictors of uptake, adherence, and completion of PR as well as treatment response based on MCID., Results: Participants were referred to PR with 24.90% never starting, 28.90% dropping out, and 46.20% completing. No differences emerged between never starters and dropouts. Having a history of any cancer increased the likelihood of completing PR (vs never starting; odds ratio [OR], 3.18; P=.003). Greater CRQ-SR dyspnea score, indicating less dyspnea, was associated with increased likelihood of completing PR (OR, 1.12; P=.006). Past smoking compared with current smoking was associated with increased likelihood of completion (OR, 3.89; P≤.002). Those without a history of alcohol use disorder had increased likelihood of completing PR (OR, 2.23; P=.048). Greater baseline 6MWT distance was associated with lower likelihood of achieving MCID in 6MWT (OR, 0.99; P<.001). Greater Ex-SRES was associated with decreased likelihood of achieving 6MWT MCID (OR, 0.98; P=.023)., Conclusions: Findings suggest that early psychoeducation on dyspnea management and smoking and alcohol cessation may increase completion of PR., (Published by Elsevier Inc.)

Background: Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV 1 and FVC, is a heterogeneous population with frequent transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (eg, whether transitions merely reflect measurement variability or noise)., Research Question: Are individuals with PRISm enriched for transitions associated with substantial changes in lung function?, Study Design and Methods: Current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV 1  < 80% predicted with FEV 1 /FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV 1  ≥ 80% predicted and FEV 1 /FVC ≥ 0.7), and obstruction (FEV 1 /FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV 1 % predicted and/or FVC % predicted between consecutive visits. Ever-PRISm was present if a subject had PRISm at any visit. Logistic regression examined the association between significant transitions and ever-PRISm status, adjusted for age, sex, race, FEV 1 % predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response., Results: Among subjects with complete data (N = 1,775) over 10.1 ± 0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted OR, 14.9; 95% CI, 10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV 1 alone (regardless of change in FVC % predicted) was used to define significant transitions., Interpretation: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT000608764; URL: www., Clinicaltrials: gov., (Published by Elsevier Inc.)

We examined the performance of a commercially-available handheld bioimpedance (BIA) device relative to dual X-ray absorptiometry (DXA) to assess body composition differences among Veterans with chronic obstructive pulmonary disease (COPD). Body composition was measured using DXA and BIA (Omron HBF-306C) at a single time point. Correlations between BIA- and DXA-assessed percent fat, fat mass, and fat-free mass were analyzed using Spearman (ρ) and Lin Concordance Correlation Coefficients (ρ c ). Mean differences in fat mass were visualized using Bland-Altman plots. Subgroup analyses by obesity status (BMI < 30 versus ≥ 30) were performed. Among 50 participants (96% male; mean age: 69.5 ± 6.0 years), BIA-assessed fat mass was strongly correlated (ρ = 0.94) and demonstrate excellent concordance (ρ c  = 0.95, [95%CI: 0.93-0.98]) with DXA, with a mean difference of 2.7 ± 3.2 kg between BIA and DXA. Although Spearman correlations between BIA- and DXA-assessed percent fat and fat-free mass were strong (ρ = 0.8 and 0.91, respectively), concordance values were only moderate (ρ c  = 0.67 and 0.74, respectively). Significantly stronger correlations were observed for obese relative to non-obese subjects for total percent fat (ρ obese  = 0.85 versus ρ non-obese  = 0.5) and fat mass (ρ obese  = 0.96 versus ρ non-obese  = 0.84). A handheld BIA device demonstrated high concordance with DXA for fat mass and moderate concordance for total percent fat and fat-free mass.ClinicalTrials.gov: NCT02099799., (© 2022. The Author(s).)

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood., Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults., Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018)., Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted., Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities., Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42])., Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

Background: The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown., Methods: We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7)., Results: Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25-3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21-1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26-4.01)., Conclusions: In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

Electronic health records (EHR) provide an unprecedented opportunity to conduct large, cost-efficient, population-based studies. However, the studies of heterogeneous diseases, such as chronic obstructive pulmonary disease (COPD), often require labor-intensive clinical review and testing, limiting widespread use of these important resources. To develop a generalizable and efficient method for accurate identification of large COPD cohorts in EHRs, a COPD datamart was developed from 3420 participants meeting inclusion criteria in the Mass General Brigham Biobank. Training and test sets were selected and labeled with gold-standard COPD classifications obtained from chart review by pulmonologists. Multiple classes of algorithms were built utilizing both structured (e.g. ICD codes) and unstructured (e.g. medical notes) data via elastic net regression. Models explicitly including and excluding spirometry features were compared. External validation of the final algorithm was conducted in an independent biobank with a different EHR system. The final COPD classification model demonstrated excellent positive predictive value (PPV; 91.7%), sensitivity (71.7%), and specificity (94.4%). This algorithm performed well not only within the MGBB, but also demonstrated similar or improved classification performance in an independent biobank (PPV 93.5%, sensitivity 61.4%, specificity 90%). Ancillary comparisons showed that the classification model built including a binary feature for FEV1/FVC produced substantially higher sensitivity than those excluding. This study fills a gap in COPD research involving population-based EHRs, providing an important resource for the rapid, automated classification of COPD cases that is both cost-efficient and requires minimal information from unstructured medical records., (© 2021. The Author(s).)

Background: Exercise capacity (EC) and physical activity (PA) are independent, potentially modifiable predictors of clinical outcomes in COPD. Molecular measures of biological age may help characterize variability in EC and PA observed among COPD patients., Methods: Veterans with COPD (FEV 1 /FVC<0.7 or emphysema on chest computed tomography) enrolled in 2 cohorts at VA Boston completed questionnaires, a 6-min walk distance (6MWD) for EC, and blood collection at enrollment. PA data (average daily step count) was collected using an HJ-720 ITC pedometer over ≥5 days. A subset of subjects returned for repeat assessment after 12 weeks. DNA methylation data was generated using the HumanMethylationEPIC platform; epigenetic estimates of biological age and age acceleration were generated using established algorithms. Multivariable models examined the associations between biological age, 6MWD, PA and future acute exacerbations (AEs), adjusting for chronological age, sex, race, smoking status, pack-years, body mass index, cohort, and estimated cell counts., Results: Subjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV 1 % of 57.7 ± 21.1, 6MWD of 374.3 ± 93.5 m, and daily steps of 3043.4 ± 2374 at baseline. In adjusted models, multiple measures of baseline epigenetic age and age acceleration were inversely associated with 6MWD; only GrimAge was inversely associated with PA. Longitudinal change in Hannum-Age was inversely associated with change in EC at 12 weeks (n = 94). No measures of biological age were significantly associated with prospective AEs over 1.3 ± 0.3 years., Conclusions: Epigenetic measures of biological age are independent predictors of EC and PA, but not AEs, among individuals with COPD., (Published by Elsevier Ltd.)

Background: Pain is a common but underappreciated symptom experienced by people with Chronic Obstructive Pulmonary Disease (COPD). The relationships between pain and physical activity (PA) and exercise capacity are poorly understood., Methods: This retrospective secondary analysis includes three cohorts of Veterans with COPD who participated in longitudinal studies evaluating PA and exercise capacity with objective measures of daily step counts and 6-min walk test (6MWT) distance, respectively. Pain was assessed using the bodily pain domain of the Veterans RAND-36. In two cohorts, participants were randomly assigned to a web-based, pedometer-mediated PA intervention which has previously been demonstrated to improve PA., Results: Three-hundred and seventy-three (373) unique study participants were included in this analysis. Eighty-three percent (n = 311) of the population reported at least mild pain and/or at least a little bit of interference due to pain at baseline. Cross-sectionally, greater bodily pain was associated with lower 6MWT distance (β = 0.51; 95% CI 0.20, 0.82; p = 0.0013). Longitudinally, worsening bodily pain was associated with a decline in 6MWT distance (β = 0.30; 95% CI 0.03, 0.58; p = 0.0312). There was no association between baseline bodily pain and baseline daily step counts, baseline bodily pain and change in PA, or change in bodily pain and change in PA. Compared to usual care, our PA intervention improved bodily pain scores (β = 6.17; 95% CI 1.84, 10.45; p = 0.0054). Bodily pain scores did not affect the impact of the intervention on daily step counts., Conclusion: Pain is highly prevalent and significantly associated with lower exercise capacity among Veterans with COPD. Worsening pain co-occurred with decline in exercise capacity but not PA. Our intervention reduced pain, although pain did not affect the impact of the intervention on PA., (© 2021. The Author(s).)

We aimed to investigate the impact of mechanical cardiopulmonary resuscitation devices over manual cardiopulmonary resuscitation on outcomes from inhospital cardiac arrests., Design: Restrospective review., Setting: Single academic medical center., Participants: Data were collected on all patients who suffered cardiac arrest from December 2015 to November 2019., Main Outcomes and Measures: Primary end point was return of spontaneous circulation. Secondary end points included survival to discharge and survival to discharge with favorable neurologic outcomes., Results: About 104 patients were included in the study: 59 patients received mechanical cardiopulmonary resuscitation and 45 patients received manual cardiopulmonary resuscitation during the enrollment period. Return of spontaneous circulation rate was 83% in the mechanical cardiopulmonary resuscitation group versus 48.8% in the manual group ( p = 0.009). Survival-to-discharge rate was 32.2% in the mechanical cardiopulmonary resuscitation group versus 11.1% in those who received manual cardiopulmonary resuscitation ( p = 0.02). Of the patients who survived to discharge and received mechanical cardiopulmonary resuscitation, 100% ( n = 19) had a favorable neurologic outcome versus 40% (two out of five) of patients who survived and received manual cardiopulmonary resuscitation ( p = 0.005)., Conclusions: Our findings demonstrate a significant association of improved outcomes with mechanical cardiopulmonary resuscitation over manual cardiopulmonary resuscitation during inhospital cardiac arrests. Mechanical cardiopulmonary resuscitation may improve rates of return of spontaneous circulation, survival to discharge, and favorable neurologic outcomes., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Chronic obstructive pulmonary disease (COPD) is prevalent among older adults. Promoting physical activity and increasing exercise capacity are recommended for all individuals with COPD. Pulmonary rehabilitation is the standard of care to improve exercise capacity, although there are barriers that hinder accessibility. Technology has the potential to overcome some of these barriers, but it is unclear how aging adults with a chronic disease like COPD perceive technology-based platforms to support their disease self-management., Objective: Guided by the unified theory of acceptance and use of technology, the current retrospective secondary analysis explores if age moderates multiple factors that influence an individual with COPD's openness toward an internet-mediated, pedometer-based physical activity intervention., Methods: As part of an efficacy study, participants with COPD (N=59) were randomly assigned to use an internet-mediated, pedometer-based physical activity intervention for 12 weeks. At completion, they were asked about their experience with the intervention using a survey, including their performance expectancy and effort expectancy, facilitating conditions (ie, internet use frequency and ability), and use of the intervention technology. Logistic regression and general linear modeling examined the associations between age and these factors., Results: Participants ranged in age from 49 to 89 years (mean 68.66, SD 8.93). Disease severity was measured by forced expiratory volume in the first second percent predicted (mean 60.01, SD 20.86). Nearly all participants (54/59) believed the intervention was useful. Regarding effort expectancy, increasing age was associated with reporting that it was easy to find the time to engage in the intervention. Regarding facilitating conditions, approximately half of the participants believed the automated step count goals were too high (23/59) and many did not feel comfortable reaching their goals (22/59). The probability of these perceptions increased with age, even after accounting for disease severity. Age was not associated with other facilitating conditions or use of the technology., Conclusions: Age does not influence performance expectancy or use of technology with an internet-mediated, pedometer-based physical activity intervention. Age is associated with certain expectations of effort and facilitating conditions. Consideration of age of the user is needed when personalizing step count goals and time needed to log in to the website., Trial Registration: ClinicalTrials.gov NCT01772082; https://clinicaltrials.gov/ct2/show/NCT01772082., (©Stephanie A. Robinson, Emily S. Wan, Stephanie L. Shimada, Caroline R. Richardson, Marilyn L. Moy. Originally published in JMIR Aging (http://aging.jmir.org), 09.09.2020.)

One quarter of individuals with Preserved Ratio Impaired Spirometry (PRISm) will develop airflow obstruction, but there are no established methods to identify these individuals. We examined the utility of FVC/TLC in identifying features of obstructive lung disease. The ratio of post-bronchodilator FVC and TLC CT from chest CT (FVC/TLC CT ) among current and former smokers with PRISm (FEV 1 /FVC ≥ 0.7 and FEV1 < 80%) in COPDGene was used to stratify subjects into quartiles: very high, high, low, and very low. We examined the associations between FVC/TLC CT quartiles and (1) baseline characteristics, (2) respiratory exacerbations, (3) progression to COPD at 5 years, and (4) all-cause mortality. Among participants with PRISm at baseline (n = 1,131), the very low FVC/TLC CT quartile was associated with increased gas trapping and emphysema, and higher rates of progression to COPD at 5 years (36% versus 17%; p < 0.001) relative to the very high quartile. The very low FVC/TLC CT quartile was associated with increased total (IRR = 1.65; 95% CI [1.07-2.54]) and severe (IRR = 2.24; 95% CI [1.29-3.89]) respiratory exacerbations. Mortality was lower in the very high FVC/TLC CT quartile relative to the other quartiles combined. Reduced FVC/TLC CT ratio in PRISm is associated with increased symptoms, radiographic emphysema and gas trapping, exacerbations, and progression to COPD.

Background: Technology-based physical activity (PA) interventions have been shown to improve daily step counts and health-related quality of life, but their effect on long-term clinical outcomes like acute exacerbations (AEs) is unknown in persons with COPD., Methods: U.S. Veterans with stable COPD were randomized (1:1) to either pedometer alone (control) or pedometer plus a website with feedback, goal-setting, disease education, and a community forum (intervention) for 3 months. AEs were assessed every 3 months over a follow-up period of approximately 15 months. Pedometer-assessed daily step counts, health-related quality-of-life (HRQL), and self-efficacy were assessed at baseline, end-of-intervention at 3 months, and during follow-up approximately 6 and 12 months after enrollment. Zero-inflated Poisson models assessed the effect of the intervention on risk for AEs, compared to controls. Generalized linear mixed-effects models for repeated measures examined between-group and within-group changes in daily step count, HRQL, and self-efficacy., Results: There were no significant differences in age, FEV 1 % predicted, baseline daily step count, AEs the year prior to enrollment, or duration of follow-up between the intervention (n = 57) and control (n = 52) groups. The intervention group had a significantly reduced risk of AEs (rate ratio = 0.51, [95%CI 0.31-0.85]), compared to the control group. There were no significant between-group differences in change in average daily step count, HRQL, or self-efficacy at 6 and 12 months after enrollment., Conclusions: A 3-month internet-mediated, pedometer-based PA intervention was associated with reduced risk for AEs of COPD over 12-15 months of follow-up. ClinicalTrials.gov identifier: NCT01772082., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Moy reports receiving an honorarium for consulting from AstraZeneca, outside the submitted work. The remaining authors have no relevant conflicts to disclose., (Published by Elsevier Ltd.)

Background: Previous attempts to explore the heterogeneity of chronic obstructive pulmonary disease (COPD) clustered individual patients using clinical, demographic, and disease features. We developed continuous multidimensional disease axes based on radiographic and spirometric variables that split into an airway-predominant axis and an emphysema-predominant axis., Methods: The COPD Genetic Epidemiology study (COPDGene ® ) is a cohort of current and former smokers, > 45 years, with at least 10 pack years of smoking history. Spirometry measures, blood pressure and body mass were directly measured. Mortality was assessed through continuing longitudinal follow-up and cause of death was adjudicated. Among 8157 COPDGene ® participants with complete spirometry and computed tomography (CT) measures, the top 2 deciles of the airway-predominant and emphysema-predominant axes previously identified were used to categorize individuals into 3 groups having the highest risk for mortality using Cox proportional hazard ratios. These groups were also assessed for causal mortality. Biomarkers of COPD (fibrinogen, soluble receptor for advanced glycation end products [sRAGE], C-reactive protein [CRP], clara cell secretory protein [CC16], surfactant-D [SP-D]) were compared by group., Findings: High-risk subtype classification was defined for 2638 COPDGene ® participants who were in the highest 2 deciles of either the airway-predominant and/or emphysema-predominant axis (32% of the cohort). These high-risk participants fell into 3 groups: airway-predominant disease only (APD-only), emphysema-predominant disease only (EPD-only) and combined APD-EPD. There was 26% mortality for the APD-only group, 21% mortality for the EPD-only group, and 54% mortality for the combined APD-EPD group. The APD-only group (n=1007) was younger, had a lower forced expiratory volume in 1 second (FEV 1 ) percent (%) predicted and a strong association with the preserved ratio-impaired spirometry (PRISm) quadrant. The EPD-only group (n=1006) showed a relatively higher FEV 1 % predicted and included largely GOLD stage 0, 1 and 2 partipants. Individuals in each of the 3 high-risk groups were at greater risk for respiratory mortality, while those in the APD-only group were additionally at greater risk for cardiovascular mortality. Biomarker analysis demonstrated a significant association of the APD-only group with CRP, and sRAGE demonstrated greatest significance with both the EPD-only and the combined APD-EPD groups., Interpretation: Among current and former smokers, individuals in the highest 2 deciles for mortality risk on the airway-predominant axis and the emphysema-predominant axis have unique associations to spirometric patterns, different imaging characteristics, biomarkers and causal mortality., Competing Interests: MHC and EKS have received grant support from GlaxoSmithKline. RPB has received consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. All other authors declare they have no conflicting interests., (JCOPDF © 2019.)

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

Rationale: Shorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown., Methods: Data from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs., Results: A significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (β = 3x10-5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, β = -1.93, p = 0.04) and with prospective AEs (Cohort 3, β = -1.3388, p = 0.0003)., Conclusions: Among COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts., Competing Interests: Dr. Moy reports receiving an honorarium for consulting from AstraZeneca, outside the submitted work. This does not impact our compliance with PLOS ONE policies on sharing data and materials.

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., (Copyright © 2019. Published by Elsevier Inc.)

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lung Disease (GOLD)-unclassified spirometry, has expanded the body of knowledge on cross-sectional risk factors. However, longitudinal studies of PRISm remain limited., Objectives: To examine longitudinal patterns of change in lung function, radiographic characteristics, and mortality of current and former smokers with PRISm., Methods: Current and former smokers, aged 45 to 80 years, were enrolled in COPDGene (phase 1, 2008-2011) and returned for a 5-year follow-up (phase 2, 2012-2016). Subjects completed questionnaires, spirometry, chest computed tomography scans, and 6-minute-walk tests at both study visits. Baseline characteristics, longitudinal change in lung function, and mortality were assessed by post-bronchodilator lung function categories: PRISm (FEV 1 /FVC < 0.7 and FEV 1  < 80%), GOLD0 (FEV 1 /FVC > 0.7 and FEV 1  > 80%), and GOLD1-4 (FEV 1 /FVC < 0.7)., Measurements and Main Results: Although the prevalence of PRISm was consistent (12.4-12.5%) at phases 1 and 2, subjects with PRISm exhibited substantial rates of transition to and from other lung function categories. Among subjects with PRISm at phase 1, 22.2% transitioned to GOLD0 and 25.1% progressed to GOLD1-4 at phase 2. Subjects with PRISm at both phase 1 and phase 2 had reduced rates of FEV 1 decline (-27.3 ± 42.1 vs. -33.0 ± 41.7 ml/yr) and comparable proportions of normal computed tomography scans (51% vs. 52.7%) relative to subjects with stable GOLD0 spirometry. In contrast, incident PRISm exhibited accelerated rates of lung function decline. Subjects with PRISm at phase 1 had higher mortality rates relative to GOLD0 and lower rates relative to the GOLD1-4 group., Conclusions: PRISm is highly prevalent, is associated with increased mortality, and represents a transitional state for significant subgroups of subjects. Additional studies to characterize longitudinal progression in PRISm are warranted.

Determinants of change in physical activity and outcomes of physical activity promotion are unclear. In this secondary analysis of a randomised controlled trial of a physical activity intervention, we assess predictors of change in physical activity and the effects of increasing physical activity on chronic obstructive pulmonary disease (COPD) measures. Physical activity was promoted in 94 subjects with COPD using the Omron HJ-720ITC pedometer alone or the pedometer plus a website that provides goal setting, feedback, motivational and educational messages, and social support for 3 months. We assessed forced expiratory volume in 1 s (FEV 1 ), 6-min walk test (6MWT) distance, depression, social support and markers of systemic inflammation (C-reactive protein (CRP) and interleukin (IL)-6). Data from both groups were combined and subjects categorised as responders (increased steps per day) or nonresponders (decreased steps per day). Linear regression models explored predictors of change in physical activity and assessed the effect of response on changes in COPD measures. The cohort of responders (n=62) and nonresponders (n=32) had mean FEV 1 1.89±0.64 L (63±22% predicted). Baseline steps per day, diagnosis of depression, social support, oxygen use and season significantly predicted change in daily step count. Responders had increases in physical activity (2038 steps per day), FEV 1 (308 mL) and 6MWT distance (43.6 m), and decreases in CRP (7.84 mg·L -1 ) and IL-6 (2.73 ng·mL -1 ) compared with nonresponders (p<0.0001-0.009). History of depression, social support, oxygen use and season predict change in physical activity, and should be routinely assessed in exercise counselling. Increases in physical activity are associated with improvements in lung function, exercise capacity and systemic inflammation., Competing Interests: Conflict of interest: M.L. Moy reports personal fees (honorarium for consultancy) from AstraZeneca, outside the submitted work. She has also received a grant from the Dept of Veterans Affairs.

Background: Low physical activity (PA) is associated with adverse health outcomes independent of airflow limitation in COPD. Self-reported assessments are often limited to global estimates of PA and may not be directly translatable to patients' goals and motivations. We developed a task-oriented PA checklist and examined its performance relative to pedometer-assessed daily step count in two COPD cohorts., Methods: Task-oriented daily physical activity (DPA) was assessed in two COPD cohorts using either interviewer-administered recall questionnaire (DPA-R, Cohort 1, n = 109) or a self-administered diary-format daily checklist (DPA-C, Cohort 2, n = 175). Daily step count was measured in both cohorts using the Omron HJ-720 ITC pedometer. Univariate associations between individual DPA items and [a] cross-sectional and [b] longitudinal change (Cohort 1) in daily step count were assessed using a Pearson's correlation. Composite scores comprised of individual DPA items with univariate association p-values <0.1 were tested for association with daily step count using multivariate models., Results: Tasks associated with average daily step count in both cohorts included putting on shoes, showering, washing hair, walking for exercise, the frequency of walks >10 min, and walking on an incline (Pearson's rho range = 0.14-0.43). A composite score of these 6 DPA items demonstrated significant associations with baseline average daily step count in both cohorts (ρ = 0.5 & 0.47, Cohorts 1 & 2, respectively) and longitudinal change in daily step count (ρ = 0.46, Cohort 1)., Conclusions: Self-reported task-oriented assessments complement direct monitoring and have potential clinical utility in exercise counseling to increase PA among COPD patients., Trial Registration: ClinicalTrials.gov NCT01772082., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied., Methods: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) <50% predicted and FEV 1 /forced vital capacity <0.7. All subjects completed a detailed questionnaire and underwent standardized pre-bronchodilator and post-bronchodilator spirometry. Subjects with known tuberculosis (TB)-associated lung parenchymal destruction were excluded. Univariate and multivariate assessments of the impact of the country of origin on respiratory symptoms and respiratory illness were performed., Results: In both univariate and multivariate analyses, a history of TB (38.7%) and physician-diagnosed asthma (43.9%) were significantly more common in subjects with severe COPD from Korea than USA or Poland, while attacks of bronchitis (64.2%) were more common in subjects with severe COPD from Poland. COPD subjects from Poland had more severe dyspnea (modified Medical Research Council 3.3±1.0) and more frequently reported symptoms of chronic bronchitis (52.2%). A history of TB was also more common in Poland (10.8%) than in USA (0.3%) severe COPD patients., Conclusion: Respiratory symptoms and other respiratory illnesses associated with severe COPD differed widely among three continents., Competing Interests: Disclosure In the past 3 years, Edwin K Silverman received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria and travel support from Novartis. The other authors report no conflicts of interest in this work.

Rationale: Low physical activity is highly prevalent among COPD patients and is associated with increased healthcare utilization and mortality and reduced HRQL. The addition of a website to pedometer use is effective at increasing physical activity; however, the timeline of change and impact of environmental factors on efficacy is unknown., Methods: U.S. Veterans with COPD were randomized (1:1) to receive either (1) a pedometer and website which provided goal-setting, feedback, disease-specific education, and an online community forum or (2) pedometer alone for 3 months. Primary outcome was change in daily step count. Secondary outcomes included 6MWT distance, HRQL, dyspnea, depression, COPD knowledge, exercise self-efficacy, social support, motivation, and confidence to exercise. Generalized linear mixed-effects models evaluated the effect of the pedometer plus website compared to pedometer alone., Results: Data from 109 subjects (98.5% male, mean age 68.6 ± 8.3 years) were analyzed. At 13 weeks, subjects in the pedometer plus website group had significant increases daily step count from baseline relative to the pedometer alone group (804 ± 356.5 steps per day, p = 0.02). The pedometer plus website group had significant improvements in daily step count from baseline beginning in week 3 which were sustained until week 13. In subgroup analyses, the pedometer plus website attenuated declines in daily step count during the transition from summer to fall. No significant differences in secondary outcomes were noted between groups., Conclusions: A website added to pedometer use improves daily step counts, sustains walking over 3 months, and attenuates declines in physical activity due to season., (Published by Elsevier Ltd.)

Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip +/- heterozygotes and wild type (Hhip +/+ ) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change ≥2 and Student's t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip +/- heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip +/- but not in Hhip +/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states.

Background and Objective: The exacerbation-prone phenotype of COPD is particularly important, as exacerbations lead to poor quality of life and disease progression. We previously found that COPD patients who lack Siglec-14, a myeloid cell protein that recognizes bacteria and triggers inflammatory responses, are less prone to exacerbation. We hypothesized that the variations in other SIGLEC genes could also influence COPD exacerbation frequency, and investigated the association between SIGLEC9 polymorphisms and the exacerbation-prone phenotype of COPD., Methods: We examined whether SIGLEC9 polymorphisms affect the frequency of COPD exacerbation in 135 subjects within our study population, and also analysed the correlation between the genotypes and the severity of airflow obstruction and emphysema in 362 Japanese smokers including 244 COPD patients. The association between these single nucleotide polymorphisms (SNPs) and COPD phenotypes were also assessed in a Caucasian population of ECLIPSE study. The effects of these coding SNPs (cSNPs) on Siglec-9 protein functions were analysed using in vitro assays., Results: The G allele of rs2075803 and rs2075803 G/rs2258983 A(GA) haplotype in SIGLEC9 was associated with higher frequency of exacerbations and the extent of emphysema in COPD. These results did not replicate in the ECLIPSE study. A myeloid cell line expressing the Siglec-9 variant corresponding to GA haplotype produced more TNF-α than the one expressing the variant corresponding to the other major haplotype., Conclusion: The SIGLEC9 rs2075803 G/rs2258983 A haplotype, which corresponds to a Siglec-9 variant that is less effective at suppressing inflammatory response, may be a risk factor for the development of emphysema., (© 2016 Asian Pacific Society of Respirology.)

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10 -49 ), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown., Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up., Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events., Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline., Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Asthma is a complex disease well-suited to metabolomic profiling, both for the development of novel biomarkers and for the improved understanding of pathophysiology. In this review, we summarize the 21 existing metabolomic studies of asthma in humans, all of which reported significant findings and concluded that individual metabolites and metabolomic profiles measured in exhaled breath condensate, urine, plasma, and serum could identify people with asthma and asthma phenotypes with high discriminatory ability. There was considerable consistency across the studies in terms of the reported biomarkers, regardless of biospecimen, profiling technology, and population age. In particular, acetate, adenosine, alanine, hippurate, succinate, threonine, and trans-aconitate, and pathways relating to hypoxia response, oxidative stress, immunity, inflammation, lipid metabolism and the tricarboxylic acid cycle were all identified as significant in at least two studies. There were also a number of nonreplicated results; however, the literature is not yet sufficiently developed to determine whether these represent spurious findings or reflect the substantial heterogeneity and limited statistical power in the studies and their methods to date. This review highlights the need for additional asthma metabolomic studies to explore these issues, and, further, the need for standardized methods in the way these studies are conducted. We conclude by discussing the potential of translation of these metabolomic findings into clinically useful biomarkers and the crucial role that integrated omics is likely to play in this endeavor., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Preeclampsia is a leading cause of maternal and fetal mortality worldwide, yet its exact pathogenesis remains elusive., Objectives: This study, nested within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), aimed to develop integrated omics models of preeclampsia that have utility in both prediction and in the elucidation of underlying biological mechanisms., Methods: Metabolomic profiling was performed on first trimester plasma samples of 47 pregnant women from VDAART who subsequently developed preeclampsia and 62 controls with healthy pregnancies, using liquid-chromatography tandem mass-spectrometry. Metabolomic profiles were generated based on logistic regression models and assessed using Received Operator Characteristic Curve analysis. These profiles were compared to profiles from generated using third trimester samples. The first trimester metabolite profile was then integrated with a pre-existing transcriptomic profile using network methods., Results: In total, 72 (0.9%) metabolite features were associated (p<0.01) with preeclampsia after adjustment for maternal age, race, and gestational age. These features had moderate to good discriminatory ability; in ROC curve analyses a summary score based on these features displayed an area under the curve (AUC) of 0.794 (95%CI 0.700, 0.888). This profile retained the ability to distinguish preeclamptic from healthy pregnancies in the third trimester (AUC:0.762 (95% CI 0.663, 0.860)). Additionally, metabolite set enrichment analysis identified common pathways, including glycerophospholipid metabolism, at the two time-points. Integration with the transcriptomic signature refined these results suggesting a particular role for lipid imbalance, immune function and the circulatory system., Conclusions: These findings suggest it is possible to develop a predictive metabolomic profile of preeclampsia. This profile is characterized by changes in lipid and amino acid metabolism and dysregulation of immune response and can be refined through interaction with transcriptomic data. However validation in larger and more diverse populations is required., Competing Interests: Conflict of Interest: All authors declare that they have no conflicts of interest.

Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development., Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline., Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping., Measurements and Main Results: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively., Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).