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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

Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...

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.

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.Author SummaryChronic obstructive pulmonary disease (COPD) is characterized by presence of emphysema and/or chronic bronchitis. Excessive mucus production is a defining phenotype of chronic bronchitis, and is associated with several important features of COPD, including exacerbations and loss of lung function. Recent studies have demonstrated that the amount of mucus produced in COPD patients is an important marker of disease state. We investigated whether common genetic variants are associated with the concentration of two key proteins in mucus, MUC5AC and MUC5B, and whether the variants we identified are also associated with COPD outcomes. We identified multiple genetic variants that were associated with MUC5AC or MUC5B concentration. The strongest association we detected, for MUC5B on chromosome 11, was also associated with features of COPD, including chronic bronchitis and acute exacerbations, in one COPD study population but not another. Results from a much larger study, the UK Biobank, indicate that this variant is associated with chronic mucus production and chronic cough, which are key features of chronic bronchitis. Thus, we conclude that the concentration of key proteins in mucus are influenced by genetic variation, and that a variant on chromosome 11 that affects MUC5B may in turn alter COPD outcomes.

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.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

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 (FEV(1):FVC) greater than or equal to 0.70 and FEV(1) less than 80% predicted; obstructive spirometry FEV(1):FVC ratio of less than 0.70; and normal spirometry FEV(1):FVC ratio greater than or equal to 0.7 and FEV(1) 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.

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

RationaleA commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.ConclusionsTheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.

BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

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

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.

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

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

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...

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.

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 included three cohorts of Veterans with COPD and objective measures of PA (daily step counts) and exercise capacity (6-minute walk test [6MWT] distance) who participated in longitudinal studies evaluating PA. Pain was assessed using the Bodily Pain (BP) 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 BP was associated with lower 6MWT distance (β=0.51; 95% CI 0.20, 0.82; p=0.0013). Longitudinally, worsening BP 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 BP and baseline daily step counts, baseline BP and change in PA, or change in BP and change in PA. Compared to usual care, our PA intervention improved BP scores (β=6.17; 95% CI 1.84, 10.45; p=0.0054). BP 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.

BACKGROUND: The objective of our study was to identify variables associated with inhaled medication use in smokers with normal spirometry (GOLD-0) and to examine the association of inhaled medication use with development of exacerbations and obstructive spirometry in the future. METHODS: We performed a retrospective multivariable analysis of GOLD-0 subjects identified in data from the COPDGene study to examine factors associated with medication use. Five categories were identified: (1) no medications, (2) short-acting bronchodilator, (3) long-acting bronchodilator; long-acting muscarinic antagonists and/or long-acting β agonist, (4) inhaled corticosteroids (ICS) with or without long-acting bronchodilator, and (5) dual bronchodilator with ICS. Sensitivity analysis was performed excluding subjects with history of asthma. We also evaluated whether long-acting inhaled medication use was associated with exacerbations and obstructive spirometry at the follow-up visit 5 y after enrollment. RESULTS: Of 4,303 GOLD-0 subjects within the analysis, 541 of them (12.6%) received inhaled medications. Of these, 259 (6%) were using long-acting inhaled medications and 282 (6.6%) were taking short-acting bronchodilator. Female sex (odds ratio [OR] 1.47, P = .003), numerous medical comorbidities, radiographic emphysema (OR 2.22, P = .02), chronic bronchitis (OR 1.77, P < .001), dyspnea (OR 2.24, P < .001), asthma history (OR 15.56, P < .001), prior exacerbation (OR 8.45, P < .001), and 6-min walk distance (OR 0.9, P < .001) were associated with medication use. Minimal changes were noted in a sensitivity analysis. Additionally, inhaled medications were associated with increased total (incidence rate ratio 2.83, P < .001) and severe respiratory exacerbations (incidence rate ratio 3.64, P < .001) and presence of obstructive spirometry (OR 2.83, P = .002) at follow-up. CONCLUSIONS: Respiratory symptoms, history of asthma, and radiographic emphysema were associated with inhaled medication use in smokers with normal spirometry. These individuals were more likely to develop obstructive spirometry, which suggests that health care providers may be able to identify obstructive lung disease prior to meeting the current criteria for COPD.

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

BackgroundChronic 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.ObjectiveGuided 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.MethodsAs 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.ResultsParticipants 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.ConclusionsAge 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 RegistrationClinicalTrials.gov NCT01772082; https://clinicaltrials.gov/ct2/show/NCT01772082

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. CLINICALTRIAL ClinicalTrials.gov NCT01772082; https://clinicaltrials.gov/ct2/show/NCT01772082

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 TLCCT from chest CT (FVC/TLCCT) among current and former smokers with PRISm (FEV1/FVC ≥ 0.7 and FEV1 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/TLCCT quartile was associated with increased gas trapping and emphysema, and higher rates of progression to COPD at 5 years (36% versus 17%; p 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/TLCCT quartile relative to the other quartiles combined. Reduced FVC/TLCCT 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, FEV1% 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.

Contains fulltext : 220761.pdf (Publisher’s version ) (Open Access) Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue-->Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway-->Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P < 0.001] in the Tissue-->Airway group; r = -0.14 [P = 0.011] in the Airway-->Tissue group). SuStaIn placed 30% of smokers with normal lung function at elevated stages, suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up.Conclusions: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One third of healthy smokers have detectable imaging changes, suggesting a new biomarker of "early COPD."

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Background Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions. Methods Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at Results Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans. Conclusions Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period. Trial Registry ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov.

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.

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 (FEV1/FVC Results Subjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV1% 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.

Woo Jin Kim,1 Jae-Joon Yim,2 Deog Kyeom Kim,3 Myung Goo Lee,4 Anne L Fuhlbrigge,5 Pawel Sliwinski,6 Iwona Hawrylkiewicz,6 Emily S Wan,7,8 Michael H Cho,7,8 Edwin K Silverman7,8 1Department of Internal Medicine and Environmental Health Center, Kangwon National University Hospital, Chuncheon, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, 3Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, 4Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Korea; 5Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 62nd Department of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 7Channing Division of Network Medicine, 8Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA 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 (FEV1)

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.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.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.A website added to pedometer use improves daily step counts, sustains walking over 3 months, and attenuates declines in physical activity due to season.