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Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation ( n  = 1,367) versus above 4,000 ft (1,219 m) elevation ( n  = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV 1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: Research studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency., Objective: Determine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation., Methods: We administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years)., Results: Overall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohen's Kappa = 0.47 ± 0.07; P < 0.001). Nevertheless, self-reported and EHR-identified m/s-AECOPD events were both associated with higher BAL neutrophils (ß ± SEM: 3.0 ± 1.1 and 1.3 ± 0.5 per 10% neutrophil increase; P ≤ 0.018) and lymphocytes (0.9 ± 0.4 and 0.7 ± 0.3 per 10% lymphocyte increase; P ≤ 0.041). Exacerbation by either measure combined was associated with a larger estimated effect (3.7 ± 1.2 and 1.0 ± 0.5 per 10% increase in neutrophils and lymphocytes, respectively) but was not statistically significantly different compared to the self-report only approach. Among the 184 TEPS participants, there were fewer moderate to very severe respiratory exacerbations by self-report (n = 15 or 8%) or EHR-documentation (n = 9 or 5%), but a similar level of agreement as those with COPD was observed (Cohen's Kappa = 0.38 ± 0.07; P < 0.001)., Discussion: While there is modest agreement between self-reported and EHR-identified m/s-AECOPD, events are missed by relying on either method alone. However, m/s-AECOPD quantified by self-report or health records is associated with BAL neutrophilia and lymphocytosis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping., Methods: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO 2 ) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed., Results: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV 1 ] = 103 ± 16% predicted; FEV 1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO 2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity., Conclusions: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features., Research Question: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?, Study Design and Methods: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV 1 (FEV 1 -BDR), change in FVC (FVC-BDR), and change in in FEV 1 , FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV 1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV 1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD)., Results: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV 1 -BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV 1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group., Interpretation: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease., (Published by Elsevier Inc.)

Background: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking., Methods: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV 1 ] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent)., Results: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV 1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo., Conclusions: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease., Research Question: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV 3 /FEV 6 ) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?, Study Design and Methods: The study included 832 current and former smokers with post-bronchodilator FEV 1 /FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV 3 /FEV 6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV 3 and FEV 6 . Regression modeling was used to evaluate the relationship between baseline FEV 3 /FEV 6 and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD., Results: FEV 3 /FEV 6 less than the LLN at baseline, defined as reduced compared with FEV 3 /FEV 6 at or above the LLN, was associated with lower FEV 1 , poorer health status (St. George's Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV 3 and FEV 6 showed excellent agreement between repeat measurements. A reduced FEV 3 /FEV 6 was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV 3 /FEV 6 was also associated with development of COPD according to spirometry results (post-bronchodilator FEV 1 /FVC < 0.7) during study follow-up., Interpretation: FEV 3 /FEV 6 is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV 3 /FEV 6 can identify those at risk for future development of COPD and respiratory exacerbations., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov: ClinicalTrials.gov., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) poses a large burden on health care. Severe COPD exacerbations require emergency department visits or inpatient stays, often cause an irreversible decline in lung function and health status, and account for 90.3% of the total medical cost related to COPD. Many severe COPD exacerbations are deemed preventable with appropriate outpatient care. Current models for predicting severe COPD exacerbations lack accuracy, making it difficult to effectively target patients at high risk for preventive care management to reduce severe COPD exacerbations and improve outcomes., Objective: The aim of this study is to develop a more accurate model to predict severe COPD exacerbations., Methods: We examined all patients with COPD who visited the University of Washington Medicine facilities between 2011 and 2019 and identified 278 candidate features. By performing secondary analysis on 43,576 University of Washington Medicine data instances from 2011 to 2019, we created a machine learning model to predict severe COPD exacerbations in the next year for patients with COPD., Results: The final model had an area under the receiver operating characteristic curve of 0.866. When using the top 9.99% (752/7529) of the patients with the largest predicted risk to set the cutoff threshold for binary classification, the model gained an accuracy of 90.33% (6801/7529), a sensitivity of 56.6% (103/182), and a specificity of 91.17% (6698/7347)., Conclusions: Our model provided a more accurate prediction of severe COPD exacerbations in the next year compared with prior published models. After further improvement of its performance measures (eg, by adding features extracted from clinical notes), our model could be used in a decision support tool to guide the identification of patients with COPD and at high risk for care management to improve outcomes., International Registered Report Identifier (irrid): RR2-10.2196/13783., (©Siyang Zeng, Mehrdad Arjomandi, Yao Tong, Zachary C Liao, Gang Luo. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.01.2022.)

Background: Actigraphy can provide useful patient-centered outcomes for quantification of physical activity in the "real-world" setting., Methods: To characterize the relationship of actigraphy outputs with "in-laboratory" measures of cardiopulmonary function and respiratory symptoms in pre-COPD, we obtained actigraphy data for 8 h/day for 5 consecutive days a week before in-laboratory administration of respiratory questionnaires, PFT, and CPET to a subgroup of subjects participating in the larger study of the health effects of exposure to secondhand tobacco smoke who had air trapping but no spirometric obstruction (pre-COPD). Using machine learning approaches, we identified the most relevant actigraphy predictors and examined their associations with symptoms, lung function, and exercise outcomes., Results: Sixty-one subjects (age = 66±7 years; BMI = 24±3 kg/m 2 ; FEV 1 /FVC = 0.75 ± 0.05; FEV 1  = 103 ± 17 %predicted) completed the nested study. In the hierarchical cluster analysis, the activity, distance, and energy domains of actigraphy, including moderate to vigorous physical activity, were closely correlated with each other, but were only loosely associated with spirometric and peak exercise measures of oxygen consumption, ventilation, oxygen-pulse, and anaerobic threshold (VO 2AT ), and were divergent from symptom measures. Conversely, the sedentary domain clustered with respiratory symptoms, air trapping, airflow indices, and ventilatory efficiency. In Regression modeling, sedentary domain was inversely associated with baseline lung volumes and tidal breathing at peak exercise, while the activity domains were associated with VO 2AT . Respiratory symptoms and PFT data were not associated with actigraphy outcomes., Discussion: Outpatient actigraphy can provide information for "real-world" patient-centered outcomes that are not captured by standardized respiratory questionnaires, lung function, or exercise testing. Actigraphy activity and sedentary domains inform of distinct outcomes., (Published by Elsevier Ltd.)

Background: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV 1 /FVC., Research Question: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease?, Study Design and Methods: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV 1 /FVC ≥ 0.7 and FEV 1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV 1 /FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV 1 /SVC of ≥ 0.7 and 120 with postbronchodilator FEV 1 /SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV 1 /SVC < 0.7 with those characteristics and outcomes., Results: Participants with FEV 1 /SVC < 0.7 were older and had lower FEV 1 and more emphysema than those with FEV 1 /SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV 1 /SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV 1 /SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV 1 /SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV 1 /SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV 1 /SVC < 0.7 or FEV 1 /SVC less than the lower limit of normal with chest CT scan features and progression to COPD., Interpretation: Low FEV 1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future., Trial Registry: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov., (Published by Elsevier Inc.)

Lung myeloid cells are important in pulmonary immune homeostasis and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Multiparameter immunophenotypic characterization of these cells is challenging because of their autofluorescence and diversity. We evaluated the immunophenotypic landscape of airway myeloid cells in COPD using time of flight mass cytometry. Cells from BAL, which were obtained from never-smokers ( n  = 8) and smokers with ( n  = 20) and without ( n  = 4) spirometric COPD, were examined using a 44-parameter time of flight mass cytometry panel. Unsupervised cluster analysis was used to identify cellular subtypes that were confirmed by manual gating. We identified major populations of CD68 + and CD68 - cells with 22 distinct phenotypic clusters, of which 18 were myeloid cells. We found a higher abundance of putative recruited myeloid cells (CD68 + classical monocytes) in BAL from patients with COPD. CD68 + classical monocyte population had distinct responses to smoking and COPD that were potentially related to their recruitment from the interstitium and vasculature. We demonstrate that BAL cells from smokers and subjects with COPD have lower AXL expression. Also, among subjects with COPD, we report significant differences in the abundance of PDL1 high and PDL2 high clusters and in the expression of PDL1 and PDL2 across several macrophage subtypes suggesting modulation of inflammatory responses. In addition, several phenotypic differences in BAL cells from subjects with history of COPD exacerbation were identified that could inform potential disease mechanisms. Overall, we report several changes to the immunophenotypic landscape that occur with smoking, COPD, and past exacerbations that are consistent with decreased regulation and increased activation of inflammatory pathways.

Background: The Laboratory-based Intermountain Validated Exacerbation (LIVE) Score is associated with mortality and chronic obstructive pulmonary disease (COPD) exacerbation risk across multiple health systems. However, whether the LIVE Score and its associated risk is a stable patient characteristic is unknown., Methods: We validated the LIVE Score in a fourth health system. Then we determined the LIVE Score stability in a retrospective cohort of 98 766 patients with COPD in four health systems where it was previously validated. We assessed whether LIVE Scores changed or remained the same over time. Stability was defined as a majority of surviving patients having the same LIVE Score 4 years later., Results: The LIVE Score separated patients into three LIVE Score risk groups of low, medium, and high mortality and LIVE Score stability. Mortality ranged from 6.2% for low-risk LIVE to 45.8% for high-risk LIVE (p<0.001). We found that low-risk LIVE groups were stable and high-risk LIVE groups were unstable. Low-risk LIVE group patients remained low risk, but few high-risk LIVE group patients remained high risk (79.0% high vs 48.1% medium vs 8.8% low, p<0.001 for all pairwise comparisons)., Conclusion: The LIVE Score identifies three major clinically actionable cohorts: a stable low-risk LIVE group, an unstable high-risk LIVE group with high mortality rates, and a medium-risk LIVE group. These observations further our understanding of how existing data used to calculate the LIVE Score may target interventions across risk cohorts of patients with COPD in a health system., Competing Interests: Competing interests: DPB has participated in sponsored research, which has yielded publications in various forms at Intermountain Healthcare with the following companies: AstraZeneca, GlaxoSmithKline, Zebra Medical, and Prolung. VP has consulted for Edifices/Round Glass related to the need for and methods to address respiratory inhaler technique training, contributes to an asthma quality of care study funded by Novartis, is a subject matter expert for Vizient, and is currently supported on an NIH NHLBI R03 award (R03HL144883). MA receives salary support from the Department of Veterans Affairs. RM and the analytic group at Kaiser Permanente Center for Health Research had financial support in part from the Intermountain Foundation for data acquisition and analysis but otherwise no conflict relevant to this manuscript. RM has participated in sponsored research in COPD funded by GlaxoSmithKline, Spiration Inc, and Novartis. He has funding from PCORI as co-PI to lead the COPD Foundation Patient-Powered Research Network (PPRN)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV 1 (BDR FEV1 ) as a measure reflecting the change in flow and in FVC (BDR FVC ) reflecting the change in volume., Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models., Results: A majority of COPD participants exhibited BDR (52.7%). BDR FEV1 occurred more often in earlier stages of COPD, while BDR FVC occurred more frequently in more advanced disease. When defined by increases in either FEV 1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDR FVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDR FVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV 1 ., Conclusion: With advanced airflow obstruction in COPD, BDR FVC is more prevalent in comparison to BDR FEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV 1 , BDR FVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD., Clinical Trials Registration: ClinicalTrials.gov: NCT01969344T4., Competing Interests: IB has received research grants from AMGEN and GE Healthcare; and reports personal fees from Astra Zeneca, GSK, Boehringer Ingelheim, GE Healthcare, Theravance, Mylan, GRIFOLS, CSL Behring, Verona Pharma and Fisher & Pykel Healthcare. SPB is supported by NIH Grant K23HL133438 and he has served on an advisory board for Sunovion and reports grants from NIH, personal fees from Sunovion, personal fees from GlaxoSmithKline, outside the submitted work. JLC is supported by Merit Review award I01 CX000911 from the Department of Veterans Affairs, and reports grants the Department of Defense, the National Institutes of Health, and from MedImmune Corporation, Ltd., and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NIAID, grants from Department of Veterans Affairs, grants from Department of Defense, outside the submitted work. MKH has consulted for GSK, Boehringer Ingelheim and AstraZeneca, has received research support from Novartis and Sunovion and reports grants from NIH, during the conduct of the study; and Consulting for GSK, BI, Mylan and AstraZeneca, research support from Sunovion and Novartis. FJM reports grants from NHLBI, National Institutes of Health, personal fees from Continuing Education, personal fees from Forest Laboratories, Janssen, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, Puerto Rico Thoracic Society, outside the submitted work, and reports personal fees from Afferent/Merck, personal fees from American Thoracic Society, grants, personal fees, non-financial support from AstraZeneca, personal fees from Bayer, non-financial support from Boehringer Ingelehim, personal fees from ProTerrix Bio, personal fees from Bridge Biotherapeutics, personal fees, non-financial support from Chiesi, personal fees from Gala, personal fees, non-financial support, personal fees from Genentech, grants, personal fees, non-financial support from GlaxoSmithKline, grants, personal fees from Nitto, personal fees from ProMedior, personal fees from ProMetic, personal fees from Patara/Respivant, personal fees from Biogen, personal fees, non-financial support from Sunovion, personal fees, non-financial support from Teva, personal fees from Veracyte, during the conduct of the study. NH reports grants and personal fees from AstraZeneca, GSK, Boehringer Ingelheim, grants from NIH, COPD Foundation, outside the submitted work. GB has grants from the NIH, Foundation for the NIH, COPD Foundation and Alpha-1 Foundation, and reports grants, personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. JMW has received grant support from the NIH, contracts to conduct research from GSK, Bayer, MereoBioPharma,Quintiles, and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from Bayer, grants, personal fees from GSK, personal fees from Boehringer Ingelheim, grants, personal fees from Mereo BioPharma, personal fees from Quintiles, outside the submitted work. EAH a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, and reports personal fees from VIDA Diagnostics, during the conduct of the study. VK has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from ABIM, and reports personal fees from Medscape, personal fees from Gala Therapeutics, personal fees from ABIM Critical Care Testwriting Committee, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, outside the submitted work. MTD reports receiving grants from the NIH, the Department of Defense, and the American Heart Association; consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Astra Zeneca, Yungjin, PneumRx/BTG, Pulmonx, Genentech, Boston Scientific, Quark Pharmaceuticals, Mereo and received grants from American Lung Association and NIH, and reports grants from NIH, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Boston Scientific, grants from American Lung Association, grants from Department of Defense, grants from Department of Veterans Affairs, personal fees from Mereo, personal fees from Quark, outside the submitted work. MBD has received research grants from the NIH and reports personal fees from Boehringer-Ingelheim, GlaxoSmithKline, AstraZeneca, and Mylan-Theravance, outside the submitted work, and reports grants from NIH-NHLBI, during the conduct of the study; grants, personal fees from Boehringer-Ingelheim, personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Mylan-Theravance, grants from Department of Defense, personal fees from Novavax, personal fees from Parion, personal fees from Midmark, personal fees from Philips, outside the submitted work. SAC reports personal fees from AstraZeneca, GSK, Amgen, Glenmark, Sunovion, UpToDate, and received personal fees and non-financial support from Genentech, grants from MedImmune, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Glenmark, personal fees from Sunovion, personal fees from Genentech, non-financial support from Medimmune, outside the submitted work. JAK has received research grants from NIH and the Patient Centered Outcomes Research Institute. DPT reports personal fees from Boehringer-Ingelheim, AstraZeneca, Sunovion, Theravance/Innoviva, Mylan, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from Sunovion, during the conduct of the study; personal fees from AstraZeneca, personal fees from Sunovion, personal fees from Boehringer-Ingelheim, personal fees from Mylan, outside the submitted work. CBC has consulted with PulmonX, has received research funding from Equinox Fitness Clubs, Amgen and is employed part-time by the GlaxoSmithKline Global Respiratory Franchise, and reports personal fees from GlaxoSmithKline, outside the submitted work. DC has grants from the NIH, reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study and no other conflicts. RB served on the advisory boards (GlaxoSmithKline, Boehringer Ingelheim, and Mylan Pharmaceuticals) and received research grants from GlaxoSmithKline and Boehringer Ingelheim, and reports personal fees from GlaxoSmithKline, personal fees from Boehringer Ingelheim, personal fees from Mylan Pharmaceuticals, grants from GlaxoSmithKline, grants from Boehringer Ingelheim, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, NHLBI and Department of Veterans Affairs, outside the submitted work. RGB received personal fees from GlaxoSmithKline, grants from NIH/National Center for Advancing Translational Sciences, grants from NIH/NHLBI, and reports grants from NIH/NCATS, during the conduct of the study; personal fees from GlaxoSmithKline, grants from NIH/NHLBI, outside the submitted work; and Dr. Buhr is employed part-time by the Veterans Health Administration; the content of this manuscript does not necessarily reflect the views of the US Department of Veterans Affairs. RJK received grants and personal fees from Genentech, Boehringer Ingelheim, Medimmune/Astra Zeneca, and Gilead and reports grants from NIH, during the conduct of the study; grants, personal fees from Boehringer Ingelheim, grants, personal fees from Roche/Genentech, outside the submitted work. GC reports grants from Boehringer- Ingelheim, Novartis, Astra Zeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, Pulmonx, personal fees from HGE Health Care Solutions, Inc, Amirall, Boehringer- Ingelheim, Holaira. NB reports grants from NIH, outside the submitted work. PW reports personal fees from Glenmark Pharmaceuticals, personal fees from GSK, personal fees from NGM Pharma, personal fees from Amgen, nothing from Regeneron, nothing from 23andMe, nothing from Theravance, nothing from AstraZeneca, outside the submitted work. CMD reports grants from NIH, during the conduct of the study. SP reports grants from MIH, HNLBI, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2019 Barjaktarevic et al.)

The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV 1 ) to forced vital capacity (FVC) ratio, CT-measured residual volume (RV CT ) to total lung capacity (TLC CT ) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RV CT /TLC CT had a greater differential rate of decline in FEV 1 /FVC; those in the upper RV CT /TLC CT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RV CT /TLC CT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RV CT /TLC CT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RV CT /TLC CT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction., Competing Interests: Conflict of interest: S. Zeng reports salary support from United States Department of Veterans Affairs, during the conduct of the study. Conflict of interest: I. Barjaktarevic reports grants from AMGEN, grants and personal fees from GE Healthcare, personal fees from Grifols, AstraZeneca, CSL Behring, Boehringer Ingelheim, Verona Pharma and Fisher and Pykel Healthcare, outside the submitted work. Conflict of interest: R.G. Barr reports grants from NIH, Foundation for the NIH and COPD Foundation, during the conduct of the study; grants from Alpha1 Foundation, personal fees (royalties) from UpToDate, outside the submitted work. Conflict of interest: E.R. Bleecker reports grants from SARP, AsthmaNET, SPIROMICS, Pharmacogenetics and Foundation NIH, involvement in clinical trials administered through Wake Forest School of Medicine for Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Janssen/Johnson & Johnson, Novartis, Pfizer, Sanofi-Regeneron and Teva, personal fees for consultancy from Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Knopp, Novartis and Sanofi/Regeneron, outside the submitted work. Conflict of interest: R.P. Bowler reports having served on advistory boards for Boehringer-Ingelheim and Abbott Nutrition, outside the submitted work. Conflict of interest: R.G. Buhr reports personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: G.J. Criner has nothing to disclose. Conflict of interest: A.P. Comellas reports grants from NIH, during the conduct of the study; non-financial support for consultancy from VIDA Diagnostics, outside the submitted work. Conflict of interest: C.B. Cooper has nothing to disclose. Conflict of interest: D.J. Couper reports grants from NHLBI (NIH) and COPD Foundation, during the conduct of the study; grants from NHLBI (NIH), outside the submitted work. Conflict of interest: J.L. Curtis reports grants from NIH/NHLBI (U01HL137880), during the conduct of the study; and grants from Department of Veterans Affairs (I01 CX000911), NIH/NIAID (R01 AI120526, R21 AI 117371), Department of Defense (W81XWH-15-1-0705, PR150432) and MedImmune, Corp. Ltd, outside the submitted work. Conflict of interest: M.T. Dransfield reports grants from NIH, during the conduct of the study; grants from Department of Defense, NIH and the American Lung Association, personal fees for consultancy and involvement with contracted clinical trials for Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, PneumRx/BTG and Boston Scientific, involvement with contracted clinical trials for Novartis, Yungjin and Pulmonx, personal fees for consultancy from Genentech, Quark Pharmaceuticals and Mereo, outside the submitted work. Conflict of interest: M.K. Han reports personal fees from GSK, BI and AZ, non-financial support from Novartis and Sunovion, outside the submitted work. Conflict of interest: N.N. Hansel reports grants and personal fees for consultancy from AstraZeneca and GSK, grants from Boehringer Ingelheim, NIH and COPD Foundation, personal fees for consultancy from Mylan, outside the submitted work. Conflict of interest: E.A. Hoffman reports grants from NIH, during the conduct of the study; and is a founder and shareholder of VIDA Diagnostics, a company commercialising lung image analysis software developed, in part, at the University of Iowa. Conflict of interest: R.J. Kaner reports personal fees from Boehringer Ingelheim, Roche/Genentech, Medimmune/AstraZeneca, Gilead, Celgene and Janssen, outside the submitted work. Conflict of interest: R.E. Kanner has nothing to disclose. Conflict of interest: J.A. Krishnan has nothing to disclose. Conflict of interest: R. Paine III reports grants from NHLBI and COPD Foundation, during the conduct of the study; grants from Department of Veterans Affairs, outside the submitted work. Conflict of interest: S.P. Peters, reports grants from NIH, NHLBI as the PI of the Wake Forest Clinical Site for the SPIROMICS COPD Program, during the conduct of the study. Conflict of interest: S.I. Rennard is employed by AstraZeneca, Cambridge, UK and also retains Professorship and a part-time appointment at the the University of Nebraska Medical Center, Omaha, NE, USA. Conflict of interest: P.G. Woodruff reports personal fees for consultancy from Theravance, AstraZeneca, Regeneron, Sanofi, Genentech, Roche and Janssen, outside the submitted work. Conflict of interest: M. Arjomandi reports salary support from United States Department of Veterans Affairs, grants and salary support from United States National Institute of Health, during the conduct of the study., (Copyright ©ERS 2019.)

Background: Abnormal lung volumes that reflect air trapping are common in COPD. However, their significance in smokers with preserved spirometry (normal FEV 1 to FVC ratio) is unclear., Methods: Using the Veterans Administration Informatics and Computing Infrastructure database, we identified 7479 patients at risk for COPD (ever smokers >40 years of age without restrictive lung disease) who had preserved spirometry and concomitant lung volume measurements, and examined their subsequent health records for clinical diagnoses of COPD, healthcare utilisation, follow-up spirometry and mortality., Results: Air trapping was prevalent, with 31% of patients having residual volume to total lung capacity ratio (RV:TLC) greater than the upper limit of normal (ULN). RV:TLC varied widely from 14% to 77% (51% to 204% of predicted) across the normal ranges of FEV 1 :FVC and FEV 1 . Patients with RV:TLC greater than the ULN were more likely to receive subsequent clinical diagnoses of COPD (HR (95% CI)=1.55 (1.42 to 1.70), p<0.001) and had higher all-cause mortality (HR (95% CI)=1.41 (1.29 to 1.54), p<0.001). They had higher rates of respiratory medication prescriptions and hospital and intensive care unit admissions. Other air trapping and static hyperinflation indices showed similar associations with health outcomes. Additionally, high-normal RV:TLC was associated with intermediate adverse health outcomes compared with low-normal and abnormal RV:TLC. Abnormal RV:TLC predicted higher likelihood of progression to spirometric COPD (OR (95% CI)=1.30 (1.03 to 1.65), p=0.027)., Conclusion: In this study of the Veterans Affairs electronic health records, air trapping was common in smokers with preserved spirometry and predicted adverse respiratory outcomes and progression to overt COPD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early diagnosis and treatment of chronic obstructive pulmonary disease (COPD) can slow disease progression. The Department of Veterans Affairs (VA)/Department of Defense Clinical Practice Guidelines (CPG), established to improve patient outcomes, recommend the use of spirometry in the COPD diagnostic process. The aims of this study were to assess VA health care providers' performance related to CPG-recommended spirometry administration in the evaluation of newly diagnosed COPD among veterans, determine the patient characteristics that may influence the adherence rate, and compare VA concordance rates to those of other health plans., Methods: Administrative health care data related to Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) veterans was used to identify newly diagnosed COPD cases and the proportion of cases receiving spirometry. Cases were defined as veterans who had their first medical encounter with a coded diagnosis of COPD ≥ 6 months after their initial VA health care evaluation. The relationship between prediagnostic and comorbid conditions and the administration of CPG-concordant spirometry was examined using regression analyses., Findings: Among the 923,646 OEF/OIF/OND veterans receiving VA health care between January 2002 and December 2014, 32,076 (3%) had a coded diagnosis of COPD. Among those, 22,156 (69%) were identified as newly diagnosed COPD cases; only 6,827 (31%) had CPG-concordant spirometry. Concordant spirometry was more likely to occur in veterans aged ≥40. A pre-existing tobacco use disorder marginally changed the concordance rate., Discussion: VA provider adherence to CPG-concordant spirometry would decrease the prevalence of false-positive COPD cases and lead to more targeted disease treatment. Future research should focus on such cases by assessing the association between COPD diagnosis and bronchodilator responsiveness., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Background: Exposure to secondhand tobacco smoke (SHS) can be a risk factor for chronic obstructive pulmonary disease (COPD), but its role among relatively heavy smokers with potential co-exposure to workplace vapors, gas, dust, and fumes (VGDF) has not been studied., Methods: To estimate the contribution of SHS exposure to COPD risk, taking into account smoking effects and work-related exposures to VGDF, we quantified SHS based on survey responses for 1400 ever-employed subjects enrolled in the COPDGene study, all current or former smokers with or without COPD. Occupational exposures to VGDF were quantified based on a job exposure matrix. The associations between SHS and COPD were tested in multivariate logistic regression analyses adjusted for age, sex, VGDF exposure, and cumulative smoking., Results and Discussion: Exposures to SHS at work and at home during adulthood were associated with increased COPD risk: odds ratio (OR) = 1.12 (95% confidence interval [CI]: 1.02-1.23; p = 0.01) and OR = 1.09 (95%CI: 1.00-1.18; p = 0.04) per 10 years of exposure adjusted for smoking and other covariates, respectively. In addition, subjects with employment histories likely to entail exposure to VGDF were more likely to have COPD: OR = 1.52 (95%CI: 1.16-1.98; p < 0.01) (adjusted for other covariates). While adult home SHS COPD risk was attenuated among the heaviest smokers within the cohort, workplace SHS and job VGDF risks persisted in that stratum., Conclusion: Among smokers all with at least 10 pack-years, adult home and work SHS exposures and occupational VGDF exposure are all associated with COPD.