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Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM 2.5 ), nitrogen oxides (NO x ), nitrogen dioxide (NO 2 ), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B -promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism ( P value interaction term for NO x  = 0.04 and PM 2.5  = 0.05) and smoking status ( P value interaction term for NO x  = 0.05; NO 2  = 0.01; and ozone = 0.05). With higher exposure to NO x and PM 2.5 , MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NO x , 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 μg ⋅ m -3 PM 2.5 , 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO 2 , former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Rationale: The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. Objectives: To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). Methods: Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. Measurements and Main Results: Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations ( P  < 0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included Alloprevotella , Oribacterium , and Veillonella species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of Streptococcus , Actinobacillus , Actinomyces , and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV 1 regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in Prevotella , Leptotrichia , and Neisseria species. In contrast, the rapid decline group (FEV 1 slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in Streptococcus species. Conclusions: In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation rates before and during this pandemic., Methods: Exacerbation patterns were analysed using electronic medical records or claims data of patients with COPD before (2017-2019) and during the COVID-19 pandemic (2020 through early 2022) in France, Germany, Italy, the United Kingdom and the United States. Data from each country were analysed separately. The proportions of patients with COPD receiving maintenance treatment were also estimated., Results: The proportion of patients with exacerbations fell 45-78% across five countries in 2020 versus 2019. Exacerbation rates in most countries were reduced by >50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53-22.13% in 2019 to 9.94-34.17% in 2021., Conclusion: Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation., Competing Interests: F.J. Martinez reports support for the present manuscript from Chiesi Farmaceutici S.p.A.; reports grants or contracts from AstraZeneca, Chiesi Farmaceutici S.p.A., GSK and Sanofi/Regeneron; reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., CSL Behring, GSK, Novartis, Polarean, Pulmatrix, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and UpToDate®; reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca and GSK; and reports participation on a Data Safety Monitoring Board or advisory board for GSK and Medtronic. A. Papi reports study support from Chiesi Farmaceutici S.p.A.; reports grants or contracts from Agenzia Italiana del Farmaco (AIFA), AstraZeneca, Chiesi Farmaceutici S.p.A., GSK and Sanofi; reports consulting fees from AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Elpen Pharmaceuticals, GSK, Novartis, Roche and Sanofi; reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Edmond Pharma, Elpen Pharmaceuticals, GSK, IQVIA, Menarini, Mundipharma, Novartis, Sanofi and Zambon; and reports advisory board membership for AstraZeneca, Avillion, Chiesi Farmaceutici S.p.A., Elpen Pharmaceuticals, GSK, IQVIA, MSD, Novartis, Regeneron and Sanofi. T. Welte reports all support for the present manuscript from Chiesi Farmaceutici S.p.A.; reports consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A. and GSK; and reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A. and GSK. He also reports a grant paid to his institution from the German Ministry of Research and Education. D. Singh reports consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., Cipla, CSL Behring, EpiEndo, Genentech, GSK, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance Biopharma and Verona Pharma. D. Singh is also supported by the National Institute for Health Research Manchester Biomedical Research Centre. D.V. Galkin is an employee of Chiesi Farmaceutici S.p.A.; reports support for this manuscript from Chiesi Farmaceutici S.p.A.; and holds stock or stock options with GSK. A. Guasconi is an employee of Chiesi Farmaceutici S.p.A. S. Pirondi is an employee of Chiesi Farmaceutici S.p.A. and is on SiMEF Società Italiana di Medicina Farmaceutica Working Group on Observational Studies. G. Georges is an employee of Chiesi Farmaceutici S.p.A. J. Imperato and R. Hermans are employees of IQVIA and were on the consulting team that led the analysis of the real-world data for this manuscript. The authors report no other conflicts of interest in this work., (© 2024 Martinez et al.)

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts. Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. We measured QIAs using a local density histogram method. We assessed the associations between proteomic biomarker concentrations and QIAs using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, and study center (Benjamini-Hochberg false discovery rate-corrected P  ⩽ 0.05). Measurements and Main Results: In total, 852 proteins were significantly associated with QIAs in COPDGene and 185 in CARDIA. Of the 144 proteins that overlapped between COPDGene and CARDIA, all but one shared directionalities and magnitudes. These proteins were enriched for 49 Gene Ontology pathways, including biological processes in inflammatory response, cell adhesion, immune response, ERK1/2 regulation, and signaling; cellular components in extracellular regions; and molecular functions including calcium ion and heparin binding. Conclusions: We identified the proteomic biomarkers of QIAs in an older, smoking population with a higher prevalence of pulmonary disease and in a younger, healthier community cohort. These proteomics features may be markers of early precursors of advanced lung diseases.

Rationale: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among individuals with chronic obstructive pulmonary disease (COPD). Black women with COPD are at elevated risk of CVD-related mortality compared with White women. CVD risk factors are undertreated in Black men and women. However, barriers to CVD prevention from the perspective of Black individuals living with COPD have not been previously identified. Objectives: To identify barriers and facilitators for CVD prevention among Black individuals living with COPD. Methods: We conducted semistructured interviews with Black participants living with COPD and attending clinics at two urban hospitals. Participants were included if they had physician-confirmed COPD diagnoses and presence of CVD or CVD risk factors. Interviews were conducted until thematic saturation was reached, with additional interviews conducted to confirm saturation. Data were analyzed using thematic analysis, iteratively revising and updating the codebook by consensus of the study team. Codes were grouped into categories, subthemes, and themes. Themes were organized using the social ecological framework into individual, interpersonal, health system, and societal levels. Results: We interviewed 30 participants of mean age 67.8 ± 8.3 years; 17 (57%) were Black women and 13 (43%) were Black men. Individual-level themes were that living with COPD and resultant multimorbidity affects CVD prevention (theme 1) and that self-efficacy and advocacy affect care received (theme 2). At the interpersonal level, supportive relationships facilitate improved access to CVD prevention (theme 3). System-level themes were that health systems are not designed to support patients with COPD and CVD (theme 4) and that health systems do not deliver effective patient education (theme 5). At the societal level, structural barriers and racism prevent access to care and adoption of a healthy lifestyle (theme 6). Conclusions: We identified barriers to CVD prevention at all levels of the socioecological framework for Black individuals living with COPD. To maximize their impact, future interventions to prevent CVD among individuals with COPD can use these findings to target barriers at multiple levels.

Background: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline., Methods: PRM metrics of normal lung (PRM Norm ) and functional SAD (PRM fSAD ) were generated from CT scans collected as part of the COPDGene study (n = 8956). Volume density (V) and Euler-Poincaré Characteristic (χ) image maps, measures of the extent and coalescence of pocket formations (i.e., topologies), respectively, were determined for both PRM Norm and PRM fSAD . Association with COPD severity, emphysema, and spirometric measures were assessed via multivariable regression models. Readouts were evaluated as inputs for predicting FEV 1 decline using a machine learning model., Results: Multivariable cross-sectional analysis of COPD subjects showed that V and χ measures for PRM fSAD and PRM Norm were independently associated with the amount of emphysema. Readouts χ fSAD (β of 0.106, p < 0.001) and V fSAD (β of 0.065, p = 0.004) were also independently associated with FEV 1 % predicted. The machine learning model using PRM topologies as inputs predicted FEV 1 decline over five years with an AUC of 0.69., Conclusions: We demonstrated that V and χ of fSAD and Norm have independent value when associated with lung function and emphysema. In addition, we demonstrated that these readouts are predictive of spirometric decline when used as inputs in a ML model. Our topological PRM approach using PRM fSAD and PRM Norm may show promise as an early indicator of emphysema onset and COPD progression., (© 2024. The Author(s).)

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO 2 ) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO 2 , using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV 1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV 1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV 1 decline differed by smoking status. Among former smokers, every 10 μg/m 3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV 1 ( P  = 0.044). Among current smokers, FEV 1 decline did not differ by indoor PM. The results of indoor NO 2 suggest trends similar to those for PM ⩽2.5 μm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.

Background: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations., Methods: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined., Results: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1 , which is implicated in mucin hypersecretion (p=1.1 ×10 -8 ). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome., Conclusion: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD., Competing Interests: Competing interests: EDA, PPB, AM, YS, WS, JHMA, MHC, DC, EH, DRJ, SK, JDK, TL, JL, ECO, WP, MRP, SSR, EKS, KEW and AFL reports receiving grants from the National Institutes of Health (NIH). JY performed the work at Columbia University but is now an employee of Google. EAH reports receiving grants from the NIH; being a founder and shareholder of VIDA Diagnostics; and holding patents for an apparatus for analysing CT images to determine the presence of pulmonary tissue pathology, an apparatus for image display and analysis, and a method for multiscale meshing of branching biological structures. EBA reports receiving grants from the American Heart Association and the NIH. CBC reports receiving personal fees from GlaxoSmithKline. MTD reports receiving a grant from the NHLBI and personal fees from AstraZeneca, GlaxoSmithKline, Pulmonx, PneumRx/BTG and Quark. MKH reports consulting for GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim receiving research support from Novartis and Sunovion. NNH reports receiving grants from the NIH, Boehringer Ingelheim, and the COPD Foundation. JDK reports receiving grants from US Environmental Protection Agency and the NIH. FJM reports serving on COPD advisory boards for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Sunovion and Teva; serving as a consultant for ProterixBio and Verona; serving on the steering committees of studies sponsored by the NHLBI, AstraZeneca, and GlaxoSmithKline; having served on data safety and monitoring boards of COPD studies supported by Genentech and GlaxoSmithKline. BMS reports receiving grants from the NIH, Canadian Institutes of Health Research (CIHR), Fonds de la recherche en santé du Québec (FRQS), the Research Institute of the McGill University Health Centre, the Quebec Lung Association and AstraZeneca. PGW reports receiving personal fees for consultancy from Theravance, AstraZeneca, Regeneron, Sanofi, Genentech, Roche and Janssen. RGB reports receiving grants from the COPD Foundation, the US Environmental Protection Agency (EPA), the American Lung Association and the NIH., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In 2008, a dedicated American Thoracic Society/European Respiratory Society task force published a paper on the possible use and limitations of clinical outcomes and biomarkers to evaluate the impact of pharmacological therapy in patients with chronic obstructive pulmonary disease. Since then, our scientific understanding of chronic obstructive pulmonary disease has increased considerably; there has been a progressive shift from a one-size-fits-all diagnostic and therapeutic approach to a personalized approach; and many new treatments currently in development will require new endpoints to evaluate their efficacy adequately. Objectives: The emergence of several new relevant outcome measures motivated the authors to review advances in the field and highlight the need to update the content of the original report. Methods: The authors separately created search strategies for the literature, primarily based on their opinions and assessments supported by carefully chosen references. No centralized examination of the literature or uniform criteria for including or excluding evidence were used. Measurements and Main Results: Endpoints, outcomes, and biomarkers have been revisited. The limitations of some of those reported in the American Thoracic Society/European Respiratory Society task force document have been highlighted. In addition, new tools that may be useful, especially in evaluating personalized therapy, have been described. Conclusions: Because the "label-free" treatable traits approach is becoming an important step toward precision medicine, future clinical trials should focus on highly prevalent treatable traits, and this will influence the choice of outcomes and markers to be considered. The use of the new tools, particularly combination endpoints, could help better identify the right patients to be treated with the new drugs.

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

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, progressive inflammatory airway disease associated with a significant impact on patients' lives, including morbidity and mortality, and significant healthcare costs. Current pharmacologic strategies, including first- and second-line therapies such as long-acting β 2 -agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD. However, many patients remain symptomatic, with persistent symptoms and/or acute exacerbations and progressive lung function loss. Although neutrophilic inflammation is the most common type of inflammation in COPD, 20-40% of patients with COPD exhibit type 2 inflammation, with roles for CD4 + (cluster of differentiation 4) T-helper cell type 1 cells, type 2 innate lymphoid cells, eosinophils, and alternatively activated macrophages. On the basis of the current limitations of available therapies, a significant unmet need exists in COPD management, including the need for targeted therapies to address the underlying pathophysiology leading to disease progression, such as type 2 inflammation, as well as biomarkers to help select the patients who would most benefit from the new therapies. Significant progress is being made, with evolving understanding of the pathobiology of COPD leading to novel therapeutic targets including epithelial alarmins. In this review, we describe the current therapeutic landscape in COPD, discuss unmet treatment needs, review the current knowledge of type 2 inflammation and epithelial alarmins in COPD, explore potential biomarkers of type 2 inflammation in COPD, and finally provide a rationale for incorporating therapies targeting type 2 inflammation and epithelial alarmins in COPD. Video Abstract available online at www.atsjournals.org.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV 1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV 1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV 1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV 1 , E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV 1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV 1 ; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV 1 ) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV 1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD., (© 2023. The Author(s).)

Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world., Competing Interests: Conflict of interest: There was no external funding for the submitted work. D.D. Sin reports receipt of honorarium from AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim for giving talks on COPD, and participation on an advisory board for an NHLBI-sponsored trial. A. Agusti reports grants from AstraZeneca, GlaxoSmithKline, Menarini, Sanofi and Chiesi, and receipt of consulting fees and honoraria for presentations from AstraZeneca, GlaxoSmithKline, Chiesi, Menarini, Sanofi and Zambon. F.J. Martinez reports grants from AstraZeneca, Chiesi, GlaxoSmithKline and Sanofi/Regeneron, receipt of consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Bering, GlaxoSmithKline, Novartis, Polarean, Pulmonx, Sanofi, Regeneron, Sunovion, Teva, Theravance and UptoDate, honoraria for presentations from AstraZeneca and GlaxoSmithKline, and advisory board participation with MedTronic and GlaxoSmithKline. A. Anzueto reports receipt of consulting fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Viatix/Theravance. B.R. Celli reports receipt of consulting fees from GlaxoSmithKline, AstraZeneca, Axios, Menarini and Sanofi, honoraria for presentations from GlaxoSmithKline, AstraZeneca, Menarini, Chiesi and Regeneron, travel support from GlaxoSmithKline and Sanofi, and advisory board participation for AstraZeneca Therapeutics, Sanofi Aventis and Vertx. D. Halpin reports receipt of honoraria for presentations from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, Sanofi, Berlin-Chemie and Menarini, travel support from Menarini, and advisory board participation with Chiesi, GlaxoSmithKline and Inogen. M.K. Han reports grants from the NIH, Sanofi, Novartis, Nuvaira, Sunovion, Gala Therapeutics, COPD Foundation, AstraZeneca, American Lung Association, Boehringer Ingelheim and Biodesix, consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pulmonox, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, United Therapeutics, Regeneron, Altesa Biopharma and Amgen, honoraria for presentations from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medscape, Integrity and NACE, royalties from UptoDate, Norton Publishing and Penguin Random House, advisory board membership for Novartis and Medtronic, leadership roles with the COPD Foundation (board), COPD Foundation (scientific advisory committee), ALA (advisory committee), American Thoracic Society (journal editor), ALA (volunteer spokesperson), GOLD (scientific committee) and Emerson School Board, Ann Arbor, MI, stock or stock options from Meissa Vaccines and Altesa BioPharma, writing support from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca and Novartis, and other personal fees from Medscape and Integrity. A. Papi reports grants from Chiesi, AstraZeneca, GlaxoSmithKline, Sanofi and Agenzia Italiana del Farmaco (AIFA), receipt of consulting fees from Chiesi, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Avillion and Elpen Pharmaceuticals, honoraria for presentations from Chiesi, AstraZeneca, GlaxoSmithKline, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion and Elpen Pharmaceuticals, and advisory board participation for Chiesi, AstraZeneca, GlaxoSmithKline, MSD, Novartis, Sanofi, Iqvia, Avillion and Elpen Pharmaceuticals. I. Pavord reports grants from Chiesi, receipt of consulting fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi, Teva, Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, RespiVert and Schering-Plough, and honoraria for presentations from Aerocrine BB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva. N. Roche reports grants from Boehringer Ingelheim, Novartis, GlaxoSmithKline and Pfizer, receipt of consulting fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva and Bayer, and honoraria for presentations from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Sanofi, Chiesi, Pfizer, Novartis, Teva, Zambon and MSD. D. Singh reports receipt of consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Bering, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona, outside of the submitted work. R. Stockley reports receipt of consulting fees from Vertex, CSL Bering and Mereo Biopharma, and data safety monitoring board participation with Syneos. J. Wedzicha reports grants from AstraZeneca, Boehringer, Chiesi, GlaxoSmithKline, Novartis, Genentech and 37Clinical, receipt of consulting fees from AstraZeneca, Epiendo, GlaxoSmithKline, Gilead, Novartis, Pieris and Pulmatrix, honoraria for presentations from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Recipharm and Novartis, and data safety monitoring board participation with Virtus. C. Vogelmeier reports grants from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols and, Novartis, and personal fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, MedUpdate, Aerogen, Roche, Sanofi and Insmed, outside of the submitted work. J. Bourbeau reports grants from the Canadian Institute of Heath Research (CIHR), Réseau en santé respiratoire du FRQS, McGill University, McGill University Health Centre Foundation, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Grifols, Novartis, Sanofi and Trudell Canada Ltd, and receipt of honoraria from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Trudell and COVIS Pharma for presentations, outside of the submitted work. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air-liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal-distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2 + SFTPB + terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8 + T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ. Conclusions: Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.

Background: Inhaled corticosteroids (ICSs) combined with bronchodilators have been identified to improve outcomes in COPD but also to be associated with certain adverse effects., Objective: We performed a systematic review and meta-analysis to compile and summarize data on the efficacy and safety of dosing levels (high versus medium/low) of ICS alongside ancillary bronchodilators following PRISMA guidelines., Data Sources: Medline and Embase were systematically searched until December 2021. Randomized, clinical trials (RCTs) that met predefined inclusion criteria were included., Data Extraction: Risk ratios (RRs) with 95% confidence intervals (CI) were extracted. Any acute exacerbation of COPD (AECOPD) risk was chosen as the primary efficacy outcome, mortality rate as the primary safety outcome, moderate/severe AECOPD risk as the secondary efficacy outcome and pneumonia risk as the secondary safety outcome. Subgroup analyses of individual ICS agents, of patients with baseline moderate/severe/very severe COPD and of patients with recent COPD exacerbation history were also performed. A random-effects model was used., Results: We included 13 RCTs in our study. No data on low doses were included in the analysis. High dose ICS was not associated with a statistically significant difference in any AECOPD risk (RR: 0.98, 95% CI: 0.91-1.05, I 2 : 41.3%), mortality rate (RR: 0.99, 95% CI: 0.75-1.32, I 2 : 0.0%), moderate/severe AECOPD risk (RR: 1.01, 95% CI: 0.96-1.06, I 2 : 0.0%) or pneumonia risk (RR: 1.07, 95% CI: 0.86 -1.33, I 2 : 9.3%) compared to medium dose ICS. The same trend was identified with the several subgroup analyses., Conclusion: Our study collected RCTs investigating the optimal dosing level of ICS prescribed alongside ancillary bronchodilators to patients with COPD. We identified that the high ICS dose neither reduces AECOPD risk and mortality rates nor increases pneumonia risk relative to the medium dose., Competing Interests: 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. He is also a part of the event adjudication committee for Medtronic. SF has received grants from American Thoracic Society and Fisher & Paykel; personal fees from Hospital Medicine (SHM) and has consulted Genentech. The authors report no other conflicts of interest in this work., (© 2023 Archontakis Barakakis et al.)

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC ≤100 ) in people with COPD to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC ≤100 phenotype is inadequately characterized, especially in advanced COPD., Research Question: Are there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes?, Study Design and Methods: We used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC ≤100 vs BEC > 100 (BEC 100+ ) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS., Results: We identified n = 485 with BEC ≤100 (n = 61 GOLD group D) and n = 929 people with BEC 100+ (n = 124 GOLD group D). BEC ≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC 100+ , BEC ≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC ≤100 vs BEC 100+ , -50 vs -39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC ≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of -68 mL/y vs -23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029)., Interpretation: In non-ICS-treated GOLD group D COPD, people with BEC ≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov., (Copyright © 2023. Published by Elsevier Inc.)

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.)

Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care., Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD., Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice-based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected., Exposure: Undiagnosed COPD., Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months., Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85)., Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes.

Background: Quantitative CT is becoming increasingly common for the characterisation of lung disease; however, its added potential as a clinical tool for predicting severe exacerbations remains understudied. We aimed to develop and validate quantitative CT-based models for predicting severe chronic obstructive pulmonary disease (COPD) exacerbations., Methods: We analysed the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort, a multicentre study done at 12 clinical sites across the USA, of individuals aged 40-80 years from four strata: individuals who never smoked, individuals who smoked but had normal spirometry, individuals who smoked and had mild to moderate COPD, and individuals who smoked and had severe COPD. We used 3-year follow-up data to develop logistic regression classifiers for predicting severe exacerbations. Predictors included age, sex, race, BMI, pulmonary function, exacerbation history, smoking status, respiratory quality of life, and CT-based measures of density gradient texture and airway structure. We externally validated our models in a subset from the Genetic Epidemiology of COPD (COPDGene) cohort. Discriminative model performance was assessed using the area under the receiver operating characteristic curve (AUC), which was also compared with other predictors, including exacerbation history and the BMI, airflow obstruction, dyspnoea, and exercise capacity (BODE) index. We evaluated model calibration using calibration plots and Brier scores., Findings: Participants in SPIROMICS were enrolled between Nov 12, 2010, and July 31, 2015. Participants in COPDGene were enrolled between Jan 10, 2008, and April 15, 2011. We included 1956 participants from the SPIROMICS cohort who had complete 3-year follow-up data: the mean age of the cohort was 63·1 years (SD 9·2) and 1017 (52%) were men and 939 (48%) were women. Among the 1956 participants, 434 (22%) had a history of at least one severe exacerbation. For the CT-based models, the AUC was 0·854 (95% CI 0·852-0·855) for at least one severe exacerbation within 3 years and 0·931 (0·930-0·933) for consistent exacerbations (defined as ≥1 acute episode in each of the 3 years). Models were well calibrated with low Brier scores (0·121 for at least one severe exacerbation; 0·039 for consistent exacerbations). For the prediction of at least one severe event during 3-year follow-up, AUCs were significantly higher with CT biomarkers (0·854 [0·852-0·855]) than exacerbation history (0·823 [0·822-0·825]) and BODE index 0·812 [0·811-0·814]). 6965 participants were included in the external validation cohort, with a mean age of 60·5 years (SD 8·9). In this cohort, AUC for at least one severe exacerbation was 0·768 (0·767-0·769; Brier score 0·088)., Interpretation: CT-based prediction models can be used for identification of patients with COPD who are at high risk of severe exacerbations. The newly identified CT biomarkers could potentially enable investigation into underlying disease mechanisms responsible for exacerbations., Funding: National Institutes of Health and the National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests EAH has received grants from the National Institutes of Health (NIH) and American Lung Association (ALA); has received royalties from VIDA Diagnostics; is a participant on Siemens photon counting CT advisory board; and is founder and shareholder of VIDA Diagnostics. JG has received grants from NIH and is a shareholder of VIDA Diagnostics. APC has received grants from NIH and is a paid consultant for GlaxoSmithKline and AstraZeneca. JDN has received grants from NIH and VIDA Diagnostics; has received royalties from Elsevier; and has received consulting fees, honoraria for lectures, travel expenses, fees for leadership roles, is also shareholder for, shares multiple patents with, and has received computer equipment from VIDA Diagnostics. PN has received grants from the NIH and honoraria from the GE Medical–University of Washington Imaging Symposium. SF has received grants from the American Thoracic Society, Fisher, and Paykel; and has served as a consultant for Genentech. GEC has received grants from the NIH; royalties from VIDA Diagnostics; fees for consultancy work from PowerPollen; and holds stocks or stock options in PowerPollen. FA has received grants from the NIH. IZB has received grants from Theravance & Viatris; fees for consultancy work from Theravance & Viatris, GlaxoSmithKline, AstraZeneca, and GE Healthcare; payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from Theravance & Viatris, AstraZeneca, and Grifols; is a participant on a data safety monitoring board for Theravance & Viatris, GlaxoSmithKline, and AstraZeneca; and is a member of the American Thoracic Society pulmonary function test committee. RGB has received grants from the NIH, the National Heart, Lung, and Blood Institute (NHLBI), The COPD Foundation, ALA, and the Foundation for the NIH; has received travel expenses from The COPD Foundation for an NIH-funded study; and has served The COPD Foundation in an unpaid leadership or fiduciary role. SPB has received grants from NIH; royalties from Springer Humana; fees for consultancy work from Boehringer Ingelheim, Sanofi/Regeneron, Sunovion, and GlaxoSmithKline; and holds stock options for Vigor Medical Systems. CBC has received grants from the NIH, The COPD Foundation, and the Foundation for the NIH; royalties from the Cambridge University Press; fees for consultancy work from Nuvaira and MGC Diagnostics; and personal fees from GlaxoSmithKline, and medicolegal personal fees from various law firms. MKH has received grants from the NHLBI, Sanofi, Novartis, Nuvaira, Sunovion; royalties from UpToDate and Norton Publishing; fees for consultancy work from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pulmonx, Teva, Verona, Merck, Sanofi, DevPro, Aerogen, and United Therapeutics; payments or honoraria from Cipla, Chiesi, Astra Zeneca, Boehringer Ingelheim, and GlaxoSmithKline; has participated on a data safety monitoring board or advisory board for Novartis and MedTronic; and is a member of The COPD Foundation Board, The COPD Foundation Scientific Advisory Committee, and ALA advisory committee. FJM has received grants from NHLBI, AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi/Regeneron; fees for consultancy work from Astra Zeneca, Boehringer Ingelheim, Chiesi, CsL Behring, Gala, GlaxoSmithKline, Novartis, Polarean, PulmonX, Sanofi/Regeneron, Sunovion, Teva, Theravance & Viatris, and Virona; payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from UpToDate; and is a member of the data safety monitoring board of MedTronic. MGM has received grants from the NIH and NHLBI. VEO is member of an independent data safety monitoring board for Sanofi and Regeneron. RP has received grants from NHLBI, The COPD Foundation, and Department of Veteran Affairs; and has received fees for consultancy work from Partner Therapeutics. PGW has received grants from The COPD Foundation, and Genentech; fees for consultancy work from Glenmark Pharmaceuticals, the University of Wisconsin, NGM Pharma, GlaxoSmithKline, Theravance, Sanofi, and AstraZeneca; and honoraria from the Western Society of Allergy, Asthma and Immunology. JMR has received grants from the NHLBI, and The Roy J Carver Charitable Trust; royalties from VIDA Diagnostics; personal fees from Boehringer Ingelheim; payment for expert testimony from Desmarais LLP; and is a shareholder of VIDA Diagnostics. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized., Research Questions: What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression?, Study Design and Methods: Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality., Results: Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P < .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P < .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001)., Interpretation: The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count., Methods: Patients (40-80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 µg, BGF 160/14.4/10 µg, GFF 14.4/10 µg, or BFF 320/10 µg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (<100, ≥100, ≥100-<300, ≥300 cells/mm 3 ), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety., Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥100 cells/mm 3 . BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥100, ≥100-<300, and ≥300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George's Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the <100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups., Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥100 cells/mm³., Competing Interests: MB reports grants from AstraZeneca, and honoraria from AstraZeneca, Chiesi, and GlaxoSmithKline; and is on the scientific advisory board for Albus Health and ProAxsis. KFR reports grants and personal fees from AstraZeneca and Boehringer Ingelheim; and personal fees from Berlin Chemie, Chiesi Pharmaceuticals, GlaxoSmithKline, Novartis, Regeneron, Roche, and Sanofi, outside the submitted work. FJM reports grants, personal fees, and non-financial support from AstraZeneca during the conduct of the study; grants, personal fees, and non-financial support from AstraZeneca, Boehringer Ingelheim, Bioscale/Proterrix Bio, Chiesi, CSL Behring, Gala, GlaxoSmithKline, Metronic, Novartis, Polarean, Pulmatrix, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris, and Verona; grants and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, and Sanofi/Regeneron. He is also a COPD teleconsultant for Bayer. DS reports personal fees from AstraZeneca during the conduct of the study; and personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona, outside the submitted work. PDa, MJ, MA, and MP are employees of AstraZeneca and hold stock and/or stock options in the company. PDo is a former employee of AstraZeneca and previously held stock and/or stock options in the company. The authors report no other conflicts of interest in this work., (© 2022 Bafadhel et al.)

Background and Objective: Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT., Methods: Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg, FF/VI 100/25 μg or UMEC/VI 62.5/25 μg and designated CMH+ if they scored 1/2 in St George's Respiratory Questionnaire (SGRQ) questions 1 and 2. Endpoints assessed by baseline CMH status included on-treatment exacerbation rates, change from baseline in trough forced expiratory volume in 1 second, SGRQ total score, COPD Assessment Test (CAT) score, proportion of SGRQ and CAT responders at Week 52 and safety., Results: Of 10,355 patients in the intent-to-treat population, 10,250 reported baseline SGRQ data (CMH+: 62% [n = 6383]). FF/UMEC/VI significantly (p < 0.001) reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in CMH+ (rate ratio: 0.87 and 0.72) and CMH- patients (0.82 and 0.80). FF/UMEC/VI significantly (p < 0.05) reduced on-treatment severe exacerbation rates versus UMEC/VI in CMH+ (0.62) and CMH- (0.74) subgroups. Similar improvements in health status and lung function with FF/UMEC/VI were observed, regardless of CMH status. In CMH+ patients, FF/VI significantly (p < 0.001) reduced on-treatment moderate/severe and severe exacerbation rates versus UMEC/VI (0.83 and 0.70)., Conclusion: FF/UMEC/VI had a favourable benefit: risk profile versus dual therapies irrespective of CMH status. The presence of CMH did not influence treatment response or exacerbations, lung function and/or health status. However, CMH did generate differences when dual therapies were compared and the impact of CMH should be considered in future trial design., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status., Methods: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed., Results: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers., Conclusions: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers., Clinical Trial Registration: GSK (CTT116855/NCT02164513)., Competing Interests: Declaration of competing interest DM and DAL are GSK employees and hold GSK stocks/shares. SB is a former GSK employee and holds GSK stocks/shares. GJC has received personal fees from Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, Chiesi, CSA Medical, Eolo, Gala Therapeutics, GSK, Helios Medical, HGE Technologies, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Nuvaira, Olympus, Philips, Pulmonx, Respironics, Respivant Sciences, The Implementation Group and Verona. DMGH has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer and Sanofi, and non-financial support from Boehringer Ingelheim and GSK. MKH reports personal fees from Medscape and Integrity, as well as consulting fees from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Altesa Biopharma and United Therapeutics. She has received royalties from UpToDate, WW Norton and Penguin Random House. She has received payment or honoraria for consultancy from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GSK, Medscape and Integrity. She has served roles on boards or scientific committees for COPD foundation, ALA, Emerson School and GOLD, and has been a volunteer spokesperson for ALA and deputy editor of the ATS journal. She has received either in-kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. She holds stock options from Meissa Vaccines and Altesa Biopharma. NAH is the Editor-in-Chief for Respiratory Medicine and was an investigator on the IMPACT study. He reports receiving personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Sanofi Genzyme, Novartis, Regeneron, Genentech, Sunovion, and Mylan for serving as an advisor or consultant. He also received research support from GSK, Boehringer Ingelheim and AstraZeneca. DH has received personal fees from GSK, Boehringer Ingelheim, AstraZeneca, Mylan, Novartis, and Sunovion. Research support from GSK, Boehringer Ingelheim and Mylan. He is a National Board of Directors member for the American Lung Association. PL has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi and GSK. FJM has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, GSK, Novartis, Polarean, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and Verona; grant support from AstraZeneca, Chiesi, GSK and Sanofi/Regeneron; payment or honoraria from UpToDate for participation in COPD CME activities; and participated in an event adjudication committee for MedTronic. FJM states that AstraZeneca, Boehringer Ingelheim and GSK are partners of the SPIROMICS program and partners in the NHLBI CAPTURE validation study; Novartis, Sanofi/Regeneron, Sunovion and Teva are partners of the SPIROMICS program; Theravance/Viatris are partners in the NHLBI CAPTURE validation study. TMS has received research grants from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Compleware, Evidera (PPD), Forest Research Institute (now AstraZeneca), GSK, Novartis, Pearl Therapeutics, Proterix BioPharma, Oncocyte, Sanofi, Seer, Sunovion, Teva, Theravance BioPharma, Vapotherm, Verona Pharma, Restorbio and Westward, and personal fees from GSK, Sunovion, Theravance Biopharma and Vapotherm. DS has received consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GSK, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona. RAW has received personal fees from AstraZeneca, Boehringer Ingelheim, Contrafect, Roche-Genentech, Bristol Myers Squibb, Merck, Verona, Theravance, AbbVie, GSK, Chemerx, Kiniksa, Savara, Galderma, Kamada, Pulmonx, Kinevant, Vaxart, Polarean, Chiesi, 4D Pharma, Puretech, and grant support from AstraZeneca, Sanofi, Verona, Genentech, Boehringer Ingelheim and 4DX imaging. He has received payment for expert testimony from the United States Government and Genentech; and support for attending meetings and/or travel from AstraZeneca. Additionally, he has received editorial support from GSK, AstraZeneca, Boehringer Ingelheim and Merck Foundation; and has served on the Board of Directors/Medical and Scientific Advisory Committee for the COPD Foundation, and on a Scientific Advisory Board for the American Lung Association. RNvZS was an investigator on the IMPACT study and reports receiving personal fees from Aspen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, MSD, Pfizer, Sanofi, Novartis and Roche. NB was an investigator on the IMPACT study and reports receiving consulting fees and serving as a participant in advisory boards for Kamada, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi Genzyme and Novartis, as well as serving as a participant in advisory boards for Teva. He has also received lecture fees for Kamada, AstraZeneca, Boehringer Ingelheim, GSK and Sanofi Genzyme., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Airway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM 2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown., Methods: We analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (<$35,000, $35,000~$74,999, ≥$75,000, decline to answer), BMI, and use of long-acting beta-agonist/long-acting muscarinic antagonists, with sensitivity analysis performed with inclusion of urinary cotinine and lung function as covariates., Results: Of 324 participants, 143 were current smokers and 201 had spirometric-confirmed COPD. Modeled indoor fine (< 2.5 μm in aerodynamic diameter) particulate matter (PM 2.5 ) and urinary cotinine were associated with higher AM BC. Other assessed indoor and ambient pollutant exposures were not associated with higher AM BC. Higher AM BC was associated with worse lung function and odds of severe exacerbation, as well as worse functional status, respiratory symptoms and quality of life., Conclusion: Indoor PM 2.5 and cigarette smoke exposure may lead to increased AM BC deposition. Black carbon content in AMs is associated with worse COPD morbidity in current and former smokers, which remained after sensitivity analysis adjusting for cigarette smoke burden. Airway macrophage BC, which may alter macrophage function, could serve as a predictor of experiencing worse respiratory symptoms and impaired lung function., (© 2022. The Author(s).)

Rationale: Despite differences in chronic obstructive pulmonary disease (COPD) comorbidities, race- and sex-based differences in all-cause mortality and cause-specific mortality are not well described. Objectives: To examine mortality differences in COPD by race-sex and underlying mechanisms. Methods: Medicare claims were used to identify COPD among REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort participants. Mortality rates were calculated using adjudicated causes of death. Hazard ratios (HRs) for mortality comparing race-sex groups were modeled with Cox proportional hazards regression. Results: In the 2,148-member COPD subcohort, 49% were women, and 34% were Black individuals; 1,326 deaths occurred over a median 7.5 years (interquartile range, 3.9-10.5 yr) follow-up. All-cause mortality per 1,000 person-years comparing Black versus White men was 101.1 (95% confidence interval [CI], 88.3-115.8) versus 93.9 (95% CI, 86.3-102.3; P  = 0.99); comparing Black versus White women, all-cause mortality per 1,000 person-years was 74.2 (95% CI, 65.0-84.8) versus 70.6 (95% CI, 63.5-78.5; P  = 0.99). Cardiovascular disease (CVD) was the leading cause-specific mortality among all race-sex groups. HR for CVD and chronic lung disease mortality were nonsignificant comparing Black versus White men. HR for CVD death was higher in Black compared with White women (HR, 1.44; 95% CI, 1.06-1.95), whereas chronic lung disease death was lower (HR, 0.44; 95% CI, 0.25-0.77). These differences were attributable to higher CVD risk factor burden among Black women. Conclusions: In the REGARDS COPD cohort, there were no race-sex differences in all-cause mortality. CVD was the most common cause of death for all race-sex groups with COPD. Black women with COPD had a higher risk of CVD-related mortality than White women. CVD comorbidity management, especially among Black individuals, may improve mortality outcomes.

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 The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08-3.32]) or severe (HR, 21.84 [95% CI, 17.71-26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28-2.08]; severe: HR, 1.75 [95% CI, 0.99-3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53-3.97]; severe: HR, 41.29 [95% CI, 30.43-56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02164513; Unique identifier: NCT02164513.

Rationale: Chronic obstructive pulmonary disease (COPD) is defined by fixed spirometric ratio, FEV 1 /FVC < 0.70 after inhaled bronchodilators. However, the implications of variable obstruction (VO), in which the prebronchodilator FEV 1 /FVC ratio is less than 0.70 but increases to 0.70 or more after inhaled bronchodilators, have not been determined. Objectives: We explored differences in physiology, exacerbations, and health status in participants with VO compared with reference participants without obstruction. Methods: Data from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort were obtained. Participants with VO were compared with reference participants without obstruction. Measurements and Main Results: We assessed differences in baseline radiographic emphysema and small airway disease at study entry, baseline, and change in lung function by spirometry, functional capacity by 6-minute walk, health status using standard questionnaires, exacerbation rates, and progression to COPD between the two groups. All models were adjusted for participant characteristics, asthma history, and tobacco exposure. We assessed 175 participants with VO and 603 reference participants without obstruction. Participants with VO had 6.2 times the hazard of future development of COPD controlling for other factors (95% confidence interval, 4.6-8.3; P  < 0.001). Compared with reference participants, the VO group had significantly lower baseline pre- and post-bronchodilator (BD) FEV 1 , and greater decline over time in post-BD FEV 1 , and pre- and post-BD FVC. There were no significant differences in exacerbations between groups. Conclusions: Significant risk for future COPD development exists for those with pre- but not post-BD airflow obstruction. These findings support consideration of expanding spirometric criteria defining COPD to include pre-BD obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: Chronic obstructive pulmonary disease (COPD) is variable in its development. Lung microbiota and metabolites collectively may impact COPD pathophysiology, but relationships to clinical outcomes in milder disease are unclear. Objectives: Identify components of the lung microbiome and metabolome collectively associated with clinical markers in milder stage COPD. Methods: We analyzed paired microbiome and metabolomic data previously characterized from bronchoalveolar lavage fluid in 137 participants in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), or (GOLD [Global Initiative for Chronic Obstructive Lung Disease Stage 0-2). Datasets used included 1 ) bacterial 16S rRNA gene sequencing; 2 ) untargeted metabolomics of the hydrophobic fraction, largely comprising lipids; and 3 ) targeted metabolomics for a panel of hydrophilic compounds previously implicated in mucoinflammation. We applied an integrative approach to select features and model 14 individual clinical variables representative of known associations with COPD trajectory (lung function, symptoms, and exacerbations). Measurements and Main Results: The majority of clinical measures associated with the lung microbiome and metabolome collectively in overall models (classification accuracies, >50%, P  < 0.05 vs. chance). Lower lung function, COPD diagnosis, and greater symptoms associated positively with Streptococcus , Neisseria , and Veillonella , together with compounds from several classes (glycosphingolipids, glycerophospholipids, polyamines and xanthine, an adenosine metabolite). In contrast, several Prevotella members, together with adenosine, 5'-methylthioadenosine, sialic acid, tyrosine, and glutathione, associated with better lung function, absence of COPD, or less symptoms. Significant correlations were observed between specific metabolites and bacteria ( P adj  < 0.05). Conclusions: Components of the lung microbiome and metabolome in combination relate to outcome measures in milder COPD, highlighting their potential collaborative roles in disease pathogenesis.

Study Objectives: Sleep is an important dimension in the care of chronic obstructive pulmonary disease (COPD), but its relevance to exacerbations is unclear. We wanted to assess whether sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) is associated with an increased risk of COPD exacerbations and does this differ by socio-environmental exposures., Methods: We included 1647 current and former smokers with spirometrically confirmed COPD from the SPIROMICS cohort. We assessed incidence rate ratios for exacerbation using zero-inflated negative binomial regression adjusting for demographics, medical comorbidities, and multiple metrics of disease severity, including respiratory medications, airflow obstruction, and symptom burden. Our final model adjusted for socio-environmental exposures using the Area Deprivation Index, a composite measure of contemporary neighborhood quality, and Adversity-Opportunity Index, a composite measure of individual-level historic and current socioeconomic indicators. We used a pre-determined threshold of 20% missingness to undertake multiple imputation by chained equations. As sensitivity analyses, we repeated models in those with complete data and after controlling for prior exacerbations. As an exploratory analysis, we considered an interaction between socio-environmental condition and sleep quality., Results: After adjustment for all co-variates, increasing PSQI scores (range 0-21) were associated with a 5% increased risk for exacerbation per point (p = .001) in the imputed dataset. Sensitivity analyses using complete cases and after controlling for prior exacerbation history were similar. Exploratory analysis suggested less effect among those who lived in poor-quality neighborhoods (p-for-interaction = .035)., Conclusions: Poor sleep quality may contribute to future exacerbations among patients with COPD. This represents one target for improving disease control., Clinical Trial Registration: Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). ClinicalTrials.gov Identifier# NCT01969344. Registry URL: https://clinicaltrials.gov/ct2/show/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting., Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs., Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals., Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI., Competing Interests: Dr Gabrio has nothing to disclose. Dr Gunsoy reports personal fees from AbbVie (current employee, and owns stock), and GlaxoSmithKline (former employee). Dr Baio has nothing to disclose. Dr A. Martin is an employee of GlaxoSmithKline. At the time of the study, Dr Paly was an employee of ICON. Dr Risebrough reports grants from GlaxoSmithKline. Dr Halpin reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, and Sanofi. Dr Singh reports personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, personal fees from Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Sanofi, personal fees from Synairgen, personal fees from Teva, Theravance, and Verona. Dr Wise reports research grants from AstraZeneca, 4D Pharma, Chiesi, Savara, Vaxart, Polarean, Boehringer Ingelheim, GlaxoSmithKline, MedImmune, Pearl, and Sanofi-Aventis; is a consultant for AstraZeneca, Circassia, Galderma, MedImmune, Mylan/Theravance, Pearl, Pneuma, Propeller Health, and Verona; is on an advisory board for GlaxoSmithKline; data monitoring committee for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ChemRx, GlaxoSmithKline, Kamada, Kinevant, MedImmune, Merck, Pearl, Pulmonx, PureTech, and Roche-Genentech; steering committee for Boehringer Ingelheim, and GlaxoSmithKline; and clinical endpoint committee for Contrafect, GlaxoSmithKline, and Kiniksa. Dr Han reports analytic and publication support for this research from GlaxoSmithKline. She also reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Pulmonx, Teva, Verona, Merck, Sanofi, DevPro, Aerogen, Polarian, Regeneron, United Therapeutics, Cipla and Chiesi. She has received stock options from Meissa Vaccines. She has received either in kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. Dr Martinez reports receiving honoraria and travel support from AstraZeneca, Boehringer Ingelheim, Canadian Respiratory Society, CME Outfitters, CSL Behring, Genentech, GlaxoSmithKline, Inova Fairfax, MDMagazine, Miller Communications, National Association for Continuing Education/Integritas, Novartis, NYP Methodist Hospital Brooklyn, Patara/Respivant, Peer View, Rare Diseases Healthcare Communications, Sanofi/Regeneron, Sunovion, Teva, University of Birmingham Alabama, and WebMD/MedScape; honoraria from Dartmouth University, New York University, Pearl, Physicians Education Resource, Rockpointe Communications, Theravance/Viatris, Medtronic, UpToDate, and Vindico; travel support from Chiesi and Zambon; research support from ProTerrix Bio and Zambon; publication support from Boehringer Ingelheim; is on an advisory board for AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, Genentech, GlaxoSmithKline, Pearl, Sanofi/Regeneron, Sunovion, Teva, Zambon, and Verona; steering committee for AstraZeneca, AbbVie, Afferent/Merck, Bayer, Biogen, Boehringer Ingelheim, GlaxoSmithKline, Nitto, Patara/Respivant, ProMedior, Shionogi, United Therapeutics, and Veracyte; data monitoring committee for Biogen, Boehringer Ingelheim, Genentech Asthma, and GlaxoSmithKline; is a consultant for AbbVie, IQVIA, ProTerrix Bio, and Raziel; continuing medical education/study presentations for Boehringer Ingelheim, Canadian Respiratory Society, Dartmouth University, France Foundation, Inova Fairfax, National Association for Continuing Education/Integritas, New York University, Novartis, NYP Methodist Hospital Brooklyn, Peer View, Physicians Education Resource, Rare Diseases Healthcare Communications, Rockpointe Communications, University of Birmingham Alabama, Vindico, and WebMD/MedScape; and teleconference without compensation for Bristol Myers Squibb and twoXAR. Dr Criner reports consulting fees from Amgen, AstraZeneca, Auris Health, Boehringer Ingelheim, Broncus, BTG, Chiesi, CSA Medical, EOLO, Fisher Paykel, Gilead, GlaxoSmithKline, Intuitive Surgical Inc, Lungpacer, Medtronic Vascular, Mereo, NGM, Novartis Pharma AG, Nuvaira, Olympus, Pneumrx, Pulmonx, Regeneron Healthcare Solutions Inc, ResMed, Respironics, Sanofi, and Verona; and ownership interest in HGE Health Care Solutions LLC. At the time of the study, Dr N. Martin was an employee of GlaxoSmithKline. Dr Lipson is an employee of and owns stocks/shares in GlaxoSmithKline. Dr Ismaila is an employee of and owns stocks/shares in GlaxoSmithKline; and is an unpaid part-time Professor at McMaster University, Canada. The authors report no other conflicts of interest in this work., (© 2022 Gabrio et al.)

Background: Neighborhood poverty has been associated with poor health outcomes. Previous studies have also identified adverse respiratory effects of long-term ambient ozone. Factors associated with neighborhood poverty may accentuate the adverse impact of ozone on respiratory health., Objectives: To evaluate whether neighborhood poverty modifies the association between ambient ozone exposure and respiratory morbidity including symptoms, exacerbation risk, and radiologic parameters, among participants of the SPIROMICS AIR cohort study., Methods: Spatiotemporal models incorporating cohort-specific monitoring estimated 10-year average outdoor ozone concentrations at participants' homes. Adjusted regression models were used to determine the association of ozone exposure with respiratory outcomes, accounting for demographic factors, education, individual income, body mass index (BMI), and study site. Neighborhood poverty rate was defined by percentage of families living below federal poverty level per census tract. Interaction terms for neighborhood poverty rate with ozone were included in covariate-adjusted models to evaluate for effect modification., Results: 1874 participants were included in the analysis, with mean (± SD) age 64 (± 8.8) years and FEV 1 (forced expiratory volume in one second) 74.7% (±25.8) predicted. Participants resided in neighborhoods with mean poverty rate of 9.9% (±10.3) of families below the federal poverty level and mean 10-year ambient ozone concentration of 24.7 (±5.2) ppb. There was an interaction between neighborhood poverty rate and ozone concentration for numerous respiratory outcomes, including COPD Assessment Test score, modified Medical Research Council Dyspnea Scale, six-minute walk test, and odds of COPD exacerbation in the year prior to enrollment, such that adverse effects of ozone were greater among participants in higher poverty neighborhoods., Conclusion: Individuals with COPD in high poverty neighborhoods have higher susceptibility to adverse respiratory effects of ambient ozone exposure, after adjusting for individual factors. These findings highlight the interaction between exposures associated with poverty and their effect on respiratory health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Belz reports grant support from NIH/NHLBI. Mark Dransfield reports grant support from NIH, DOD, and the American Lung Association; consulting from AstraZeneca, GlaxoSmithKline, Pulmonx, Teva; and contracted clinical trials through Boerhinger Ingelheim, Gala, and Pulmonx. MeiLan Han reports consulting for Novartis, Sunovion, Cipla, Chiesi, Teva, Verona, Merck, Mylan, Sanofi, GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca as well as research support from Novartis and Sunovion. Jerry Krishnan reports research grants from NIH, PCORI, and Sergey Brin Family Foundation as well as consulting fees from GlaxoSmithKline for monoclonal antibody against SARS-CoV-2. Nadia Hansel reports grants from NIH, grants from COPD Foundation, grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, personal fees from Mylan during the conduct of the study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

Background: In the Phase III ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid (ICS) doses reduced moderate/severe exacerbation rates and improved symptoms, health-related quality of life (HRQoL), and lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) dual therapy in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Here, we assessed whether the benefit for BGF versus GFF was driven by patients who received ICS before randomization to GFF., Methods: ETHOS was a 52-week, randomized, double-blind, multicenter, parallel-group study in symptomatic patients with COPD and ≥1 moderate/severe exacerbation in the previous year. Patients received BGF 320/14.4/10 μg, BGF 160/14.4/10 μg, GFF 14.4/10 μg, or BFF 320/10 μg twice daily via a single metered dose Aerosphere™ inhaler. In these subgroup analyses, efficacy and safety were assessed in patients with or without prior ICS use in the 30 days before screening., Results: The modified intent-to-treat population comprised 8509 patients (prior ICS use, n = 6810 [80%]; no prior ICS use, n = 1699 [20%]). Moderate/severe exacerbation rates were reduced by 24% and 23% in patients with and without prior ICS use, respectively, with BGF 320 versus GFF. Benefits of BGF 320 versus GFF were also similar in patients with and without prior ICS use across other endpoints relating to exacerbations, symptoms, HRQoL, lung function, and safety. Trends were similar for BGF 160 versus GFF., Conclusion: Benefits on exacerbations, symptoms, HRQoL, and lung function with BGF versus GFF were observed, irrespective of prior ICS use in the 30 days before screening., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF., Methods: We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets., Results: We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts., Conclusions: We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF., (© 2022. The Author(s).)

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.)

Chronic obstructive pulmonary disease (COPD) manifests with a variety of clinical presentations, reflecting its complex pathology. Currently, care focuses on symptom amelioration and prevention of complications and thus is generally tailored to disease severity rather than targeting specific pathophysiologic mechanisms. Chronic inflammation and mucus hypersecretion are key features of COPD. Epithelial ion channel dysfunction may be important, as it results in airway dehydration and defective host defense, contributing to chronic airway inflammation. Recent evidence suggests considerable similarities between COPD and cystic fibrosis (CF), a disease in which chloride ion channel dysfunction has been extensively studied (in particular CFTR [CF transmembrane conductance regulator]). Understanding commonalities between CF and COPD, and the role of CFTR in CF, may help in designing strategies targeting ion channel dysfunction and lead to new treatments with potential to alter the natural history of disease progression. Here, we review the roles of airway mucus and CFTR in normal lung function, the previously underestimated contribution of mucus stasis to the development of COPD, and the evidence for targeting CFTR to counteract mucus accumulation.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives: Examine the impact of depressive symptoms compared with FEV 1 % on COPD morbidity. Methods: Using longitudinal data from individuals with COPD in the Subpopulations and Intermediate Outcome Measures in COPD Study, longitudinal growth analysis was performed to assess COPD morbidity by assessing differences in baseline 6-minute walk distance and patient reported outcomes (PROs) and their rate of change over time explained by depressive symptoms or lung function, as measured by Hospital Anxiety and Depression Scale or FEV 1 % respectively. PROs consisted of in-person completion of St. George's Respiratory Questionnaire, COPD Assessment Test, Functional Assessment of Chronic Illness Therapy Fatigue, and Modified Medical Research Council Dyspnea Scale measures. Results: Of the individuals analyzed ( n  = 1,830), 43% were female, 81% Caucasian with mean ± SD age of 65.1 ± 8.1, and 52.7 ± 27.5 pack-years smoking. Mean ± SD FEV 1 % was 60.9 ± 23.0% and 20% had clinically significant depressive symptoms. Adjusted models showed higher Hospital Anxiety and Depression Scale scores and lower FEV 1 % each were associated with worse PROs at baseline ( P  ⩽ 0.001). Depression accounted for more baseline variance in St. George's Respiratory Questionnaire, COPD Assessment Test, and Functional Assessment of Chronic Illness Therapy Fatigue than FEV 1 %, explaining 30-67% of heterogeneity. FEV 1 % accounted for more baseline variance in Modified Medical Research Council Dyspnea Scale and 6-minute walk distance than depression, explaining 16-32% of heterogeneity. Depressive symptoms accounted for 3-17% variance in change over time in PROs. In contrast, FEV 1 % accounted for 1-4% variance over time in PROs. Conclusions: Depression is more strongly associated with many PROs at baseline and their change over time compared with FEV 1 %. Recognizing and incorporating the impact of depressive symptoms into individualized care may improve COPD outcomes.

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 <-950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF (placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions: Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.