Objectives:Examine the bronchial epithelium-derived gene expression signature of bronchiectasis (BE) in nasal epithelium. Methods:We studied 220 participants from the Detection of Early Lung Cancer Among Military Personnel study with bulk RNA sequencing of nasal epithelium brushings. Gene set enrichment analysis (GSEA) examined whether genes previously identified as increased or decreased in the bronchial epithelium of individuals with radiologic BE are enriched among genes most altered in nasal epithelium. GSEA and cell-type specific signatures assessed changes in nasal epithelium cellular composition associated with radiologic BE. Results:No genes were significantly differentially expressed in nasal epithelium between participants with and participants without widespread radiologic BE. However, genes previously found altered in bronchial epithelium are concordantly enriched among genes most increased or decreased in nasal epithelium (p=3×10-7, increased; p=6×10-8, decreased). GSEA using cell-type signatures shows that BE in nasal epithelium is associated with increased multiciliated and deuterosomal cell-related gene expression and decreased basal cell-related gene expression, consistent with bronchial findings. Conclusion:This work validates our bronchial BE signature in an independent dataset and demonstrates that gene expression changes associated with radiologic BE in nasal epithelium are concordant but reduced in magnitude compared with bronchial epithelium. These findings support considering nasal brushings as a less invasive tool for BE screening and monitoring.

BACKGROUND:The relationship of social determinants of health (SDOH), environmental exposures and medical history to lung function trajectories is underexplored. A better understanding of these relationships could inform preventive strategies for lung health. METHODS:We analysed data from COPDGene, a US longitudinal, observational study. Participants were tobacco-exposed (≥10 pack-years of smoking) non-Hispanic Black and non-Hispanic White adults aged 45-80 years. We analysed 2990 males and 2945 females, using Bayesian trajectory modelling on post-bronchodilator forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). We applied multinomial logistic regression to assess the association of SDOH, environmental exposures and medical history with lung function trajectories. MEASUREMENTS AND MAIN RESULTS:Six trajectories were identified within each sex. Non-Hispanic Black race was more prevalent in trajectories characterised by lower FEV1 and FVC values (ie, lower lung function trajectories) compared with non-Hispanic White adults. In adjusted models, non-Hispanic Black race, residence in the Southeastern USA, lifetime asthma and a father with COPD were associated with significantly higher odds of the lowest trajectory (ie, trajectory six vs the reference trajectory) for both sexes. Higher income and private insurance showed inverse associations with lower lung function trajectories. The Social Vulnerability Index socioeconomic theme (based on census-level poverty, unemployment, income and educational attainment) was associated with the lowest trajectory in males. CONCLUSIONS:Significant disparities in lung function trajectories exist between non-Hispanic Black adults and non-Hispanic White adults. Individual- and community-level factors are associated with lower lung function trajectory in people exposed to tobacco.

BACKGROUND:Change in 6-min walk distance (6MWD) over time serves as a measure of change in functional exercise performance. We analysed a large cohort of current or former tobacco smokers over a 5-year period to identify correlates of 6MWD decline. METHODS:A total of 4734 participants with normal spirometry or spirometric evidence of chronic obstructive pulmonary disease (COPD) who completed a 5-year follow-up in the COPDGene study were included. Baseline and 5-year assessments included 6MWD, spirometry, St. George's Respiratory Questionnaire (SGRQ), gender, race and CT measures of emphysema, gas trapping and airway wall thickness. 6MWD decline correlates relative to baseline and 5-year changes were examined using univariate and multivariate linear regression. RESULTS:At baseline, 2573 had normal spirometry; 487 were classified as GOLD1, 1044 as GOLD2, 514 as GOLD3 and 116 as GOLD4. Average 5-year decline in 6MWD was 35.6±101.7 (SD) metres (p<0.001). COPD participants experienced greater 6MWD decline (44.1±101.9 m, p<0.001) compared with those with normal spirometry (28.5±101.0 m, p<0.001). Only baseline 6MWD and study site accounted for appreciable fractions of 6MWD decline variance (R2=12.1% and 9.1%, respectively). 5 year change in variables assessed (including FEV1 and SGRQ) explained only small fractions of 6MWD decline variance (each R2≤5%). CONCLUSION:6MWD declined significantly, but with high variability; spirometry, CT, health status, demographic and anthropometric measures accounted for only small portions of this variance. Our findings suggest that a meaningful decline in 6MWD observed over 5 years in COPD patients is in large part related to factors other than decline in pulmonary structure or function.

RATIONALE:In smokers with and without chronic obstructive pulmonary disease (COPD), the differential strengths of association between chest computed tomography (CT)-based metrics of pulmonary vascular disease and adverse outcomes are unknown. OBJECTIVES:We aimed to quantify the differential strengths of association of CT features, from the distal pulmonary arteries to the central great vessels and cardiac chambers, with acute respiratory exacerbations (AREs) and mortality in smokers with and without COPD. METHODS:Smokers with and without COPD with pulmonary vascular morphology and outcomes data were identified in COPDGene. Negative binominal and multivariable Cox proportional hazard models were used to investigate the association of CT features, including volume of the distal pulmonary arterial vasculature or pruning (<5 mm2 normalized to total arterial blood vessel volume [aBV5/aTBV]), preacinar vessels (5-20 mm2), and pulmonary artery to aorta (PA/Ao) and right to left ventricular epicardial volume (RV/LV) ratios, with outcomes. Kaplan-Meier curves were used to describe pruning risk on mortality. RESULTS:A total of 3169 smokers with COPD and 2530 smokers without COPD were analyzed. Among smokers with COPD, PA/Ao was the only imaging feature significantly associated with AREs (incidence rate ratio, 1.08 [95% CI, 1.04-1.12]), even after adjusting for aBV5/aTBV. Conversely, pruning demonstrated the strongest association with mortality, even in smokers without COPD (hazard ratio, 1.22 [95% CI, 1.14-1.30] and 1.26 [95% CI, 1.11-1.42], respectively). The association of preacinar vessels with mortality in smokers with COPD and in those without COPD, but with significant emphysema on imaging (≥5%), was novel. CONCLUSIONS:Pruning is significantly associated with mortality risk in smokers with and without COPD; however, PA/Ao selectively associates with AREs in COPD, even when accounting for distal vasculopathy.

RATIONALE:Mucus plug formation and chronic bronchitis are manifestations of mucus pathology in chronic obstructive pulmonary disease. Identifying gene expression changes related to mucus pathology could provide insight into its pathogenesis. OBJECTIVES:To investigate gene expression changes in individuals with mucus plugs, identify related biological pathways, and assess whether mucus plug-related gene expression associates with clinical features of other mucus pathologies. METHODS:We studied 290 participants from the Detection of Early Lung Cancer Among Military Personnel 2 study with mainstem bronchial brush bulk RNA-sequencing data (n = 204 discovery, n = 86 validation). We scored mucus plugging based on the number of lung segments with mucus plugs identified on chest computed tomography scans and used correlative analysis to identify differentially expressed genes and examine their association with chronic bronchitis symptoms. MEASUREMENTS AND MAIN RESULTS:Seventy-six participants (37%) in the discovery set had mucus plugs. Differentially expressed genes were broadly epithelial- or immune-related. Epithelial-related genes show decreased expression of genes involved in cilia maintenance and microtubule function and increased expression of genes related to epithelial maintenance and protection. Expression patterns of epithelial-related genes are associated with chronic bronchitis symptoms. Immune-related genes are enriched for innate and adaptive pathways. Expression of immune genes varies by lung function and was more weakly associated with mucus plugs than that of epithelial-related genes. Findings were replicated in an independent validation set. CONCLUSION:Several distinct gene expression patterns are linked to the presence of mucus plugs, highlighting biological -pathways involved in mucus pathophysiology. Variability in gene expression suggests a spectrum of mucus pathophysiology contributes to mucus plugs and chronic bronchitis symptoms.

Objective: To investigate associations between rheumatoid arthritis (RA), chronic lung diseases, and acute respiratory exacerbations.Methods: Using the multicenter prospective COPDGene cohort of current and former people who smoke, RA cases were identified using self-report and disease-modifying antirheumatic drug use. Interstitial lung abnormalities (ILA), bronchiectasis (BR), chronic obstructive pulmonary disease (COPD), and mucus plugging (MP) were identified via high-resolution computed tomography scans and spirometry and prevalences were compared among participants with and without RA. Risk of acute respiratory exacerbation over 10 years of follow-up was compared for those with and without RA and stratified by lung abnormality using multivariable Cox regression, accounting for competing mortality risk.Results: We analyzed 76 RA cases (mean age 64.0 years, 67.1% female) and 8,175 non-RA comparators (mean age 59.4 years, 46.2% female). RA cases vs non-RA comparators had higher prevalences of ILA (17.3% vs 7.1%, p=0.0002) and BR (35.5% vs 24.6%, p=0.027), but prevalences of COPD (46.1% vs 43.7%, p=0.69) and MP (36.8% vs 29.6%, p=0.17) were similar. RA was associated with higher risk of acute respiratory exacerbation than non-RA (adjusted HR 1.68, 95%CI 1.25 to 2.26), and those with RA and COPD had the highest risk (adjusted HR 3.57, 95%CI 2.15 to 5.94) compared to non-RA without COPD.Conclusion: In this large prospective study, people who smoke with RA were more likely to have ILA and BR than those without RA, but had similar prevalences of COPD and MP. Participants with RA, particularly those with COPD, had higher risk of acute respiratory exacerbation.

Background: Bronchiectasis is increasingly recognized on chest CT among tobacco-exposed individuals, yet its longitudinal changes and prognostic significance are poorly understood. We tested whether progression of CT-based bronchial dilation over time is associated with higher mortality among tobacco-exposed individuals. Methods: We conducted a longitudinal analysis of the prospective COPDGene Study. Participants were aged 45-80 years and had a smoking history of at least 10 pack-years. They were enrolled at 21 centers across the United States between November 2007 and April 2011 and were followed up through July 2023 The percentage of airways with an airway-to-artery diameter ratio (AAR)>1 was quantified on CT using a validated artificial intelligence–based tool. A higher percentage of AAR>1 indicates a greater extent of bronchial dilation. Progression of bronchial dilation was defined as an increase in percentage of AAR>1 from baseline to 5-yr follow-up CT scan. Multivariable proportional hazard models were used to assess the association between bronchial dilation and all-cause mortality. Findings: Among 4,282 participants with baseline and 5-yr imaging data, 3,508 (81.9%) demonstrated CT-based bronchial dilation progression. During a median follow-up of 10.7 years (IQR 5.4-13.0), 836 (19.5%) deaths occurred. Mortality rates were higher in participants with progression than in those without (20.8% vs 13.7%). Bronchial dilation progression was associated with increased all-cause mortality after adjustment (adjusted hazard ratio 1.48, 95% CI 1.18-1.87). Interpretation: In tobacco-exposed individuals, progression of CT-based bronchial dilation was prevalent and was associated with increased all-cause mortality.

Mucus plugs have been previously recognized as an important pathological feature in asthma and chronic obstructive pulmonary disease (COPD), but their clinical role in these diseases has not been explored in depth until recently. Mucus plug formation is driven by mucus hyperconcentration, changes in mucus viscoelastic properties, impaired clearance, and mucociliary collapse. Scoring systems, such as the bronchopulmonary segment mucus plug score, have been used to associate greater mucus plug burden with poor clinical outcomes. Additional scoring methods obtained through quantitative image processing are currently under development. Mucus plug burden has been associated with greater exacerbations and spirometric decline in both asthma and COPD, as well as greater mortality in COPD. Recently, mucus plug burden has been used as an endpoint in clinical trials to evaluate the effectiveness of biologic therapies in asthma; multiple biologic therapies demonstrated decreases in mucus plug burden and associated improvements in spirometry with treatment. Together, these data suggest that mucus plugs may be a treatable trait in asthma and COPD. Mucus plug burden has current clinical, phenotypic, and predictive utility and shows promise as a future biomarker. Increased incorporation into clinical trials, expanded evidence of treatment effect, and standardization of methodology and imaging protocols will be needed. Computed tomographic detection of mucus plug burden is ready for greater incorporation into both research outcomes and clinical care.

Airway-occluding mucus plugs (MPs)—as identified on CT scans—are frequent in patients with chronic obstructive pulmonary disease (COPD). Prior studies have shown that body mass index (BMI) tends to be lower among individuals with MPs. To further investigate this relationship, we assessed whether BMI is associated with MPs in two large, multicentre cohorts of tobacco-exposed participants with and without COPD. In multivariable models, lower BMI was associated with an increased prevalence of MPs in COPD and non-COPD groups. Future studies are warranted to elucidate the mechanisms underlying this association.

Rationale: Airway mucus plugs are prevalent in COPD patients and are associated with increased mortality and exacerbations. Despite their clear clinical relevance, subjective assessments are highly variable and not standard practice. Objective approaches to the detection and quantification of airway mucus plugs are needed. This study aims to compare an AI-based mucus plug detector with visual detection regarding their associations with all-cause mortality and exacerbation risk. Methods: We have developed and validated an AI mucus plug segmentation model using nnUnet trained with synthetic mucus plugs generated via cycleGAN. Mucus plugs were automatically segmented per lobe, and an AI Mucus Plug Score (AI-MP) was created, representing the average number of segments with mucus detection. The relationships between AI-MPs, visual MPs and outcomes, including mortality and acute exacerbations (AEs), were assessed using Cox proportional hazards regression and zero-inflated Poisson regression. Models were adjusted for covariates based on prior studies. Model comparison was performed using Likelihood Ratio (LR) Test and C-index. Results: In a cohort of 4,483 COPD participants, 4,369 were included in primary analyses, with complete mortality data available for 4,167 participants and AE data for 3,756 participants. AI-MP distribution scores were 1,133 (AI-MP=0), 1,978 (AI-MP 1-2), and 1,259 (AIMP ≥3) while the visual MP scores were distributed as 3,186, 363 and 806 respectively. Compared to AI-MP=0, participants with AI-MP scores of 1-2 and ≥3 segments showed adjusted hazard ratios for death of 1.19 (95% CI, 1.06-1.34) and 1.51 (95% CI, 1.30-1.75), respectively. In contrast, visual detection scores yielded hazard ratios of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41). The survival models comparing visual and AI scoring methods were statistically significant (LR=4.84, p=0.02) and the C-Index was slightly higher for the AI model (C-Index=0.717) than for the visual scoring model (C-Index=0.715). AI-MP scores of 1-2 and ≥3 segments were associated with increased risk of severe AEs during follow-up (adjusted rate ratio [aRR]=1.08 [95% CI, 1.04-1.12] and 1.15 [95% CI, 1.11-1.21]), compared to visual scores (aRR=1.05 [1.01-1.08] and 1.09 [1.02-1.18]). Conclusions: AI-detected mucus plugs were more highly prevalent than those detected visually, and their clinical prognostic value was stronger than visual data. AI-based detection of mucus plugs could facilitate the identification of individuals at increased risk of poor outcomes in COPD.