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

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

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

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

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap., (Copyright © 2019. Published by Elsevier Inc.)

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

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

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

Background: Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1)., Methods: Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects., Results: K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects., Conclusions: Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Acute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among individuals with COPD, some patients suffer an inordinate number of exacerbations while others remain relatively protected. We undertook a study to determine the clinical factors associated with "frequent exacerbator" status within a population of subjects with severe COPD., Methods: Case-control cohort recruited from two Boston-area practices. All subjects had GOLD stage 3 or 4 (FEV(1) ≤ 50% predicted) COPD. "Frequent exacerbators" (n = 192) had an average of ≥2 moderate-to-severe exacerbations per year while "non-exacerbators" (n = 153) had no exacerbations in the preceding 12 months. Multivariate logistic regression was performed to determine the significant clinical predictors of "frequent exacerbator" status., Results: Physician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF (25-75%) predicted were also significant clinical predictors of frequent exacerbator status (p < 0.05). Differences in exacerbation frequency were not found to be due to increased current tobacco use or decreased rates of maintenance medication use., Conclusions: Within our severe COPD cohort, a history of physician-diagnosed asthma was found to be a significant clinical predictor of frequent exacerbations. Although traditional risk factors such as decreased FEV(1)% predicted were not significantly associated with frequent exacerbator status, lower mid-expiratory flow rates, as assessed by FEF (25-75%) predicted, were significantly associated with frequent exacerbations in a subset of our cohort., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

COPD is a highly prevalent disorder that results from the interplay of genetic susceptibility and environmental exposures. Over the past 2 decades, significant technological advances have been made in genetic investigations of complex diseases, yet limited progress has been made in the identification of additional COPD susceptibility genes. Genetic and phenotypic heterogeneity, limited power due to modest study population sizes, and significant modification of genetic effects by environmental factors pose significant challenges in COPD and emphysema genetic studies. More refined characterization of the emphysema and airway components of COPD can now be obtained through the systematic use of CT scans. These improved phenotypes can be applied in genome-wide association studies and will likely lead to the discovery of additional susceptibility loci and therapeutic targets.