Background Long-term studies of chronic obstructive pulmonary disease (COPD) can evaluate emphysema progression. Adjustment for differences in equipment and scanning protocols of individual CT examinations have not been studied extensively. Purpose To evaluate emphysema progression in current and former smokers in the COPDGene cohort over three imaging points obtained at 5-year intervals accounting for individual CT parameters. Materials and Methods Current and former cigarette smokers enrolled between 2008 and 2011 from the COPDGene study were prospectively followed for 10 years between 2008 and 2020. Extent of emphysema as adjusted lung density (ALD) from quantitative CT was measured at baseline and at 5- and 10-year follow-up. Linear mixed models adjusted for CT technical characteristics were constructed to evaluate emphysema progression. Mean annual changes in ALD over consecutive 5-year study periods were estimated by smoking status and baseline emphysema. Results Of 8431 participants at baseline (mean age, 60 years ± 9 [SD]; 3905 female participants), 4913 were at 5-year follow-up and 1544 participants were at 10-year follow-up. There were 4134 (49%) participants who were current smokers, and 4449 (53%) participants had more than trace emphysema at baseline. Current smokers with more than trace emphysema showed the largest decline in ALD, with mean annual decreases of 1.4 g/L (95% CI: 1.2, 1.5) in the first 5 years and 0.9 g/L (95% CI: 0.7, 1.2) in the second 5 years. Accounting for CT noise, field of view, and scanner model improved model fit for estimation of emphysema progression (P < .001 by likelihood ratio test). Conclusion Evaluation at CT of emphysema progression in the COPDGene study showed that, during the span of 10 years, participants with pre-existing emphysema who continued smoking had the largest decline in ALD. Adjusting for CT equipment and protocol factors improved these longitudinal estimates. Clinical trial registration no. NCT00608764 © RSNA, 2023 Supplemental material is available for this article. See the editorial by Parraga and Kirby in this issue.

INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

INTRODUCTION: Smokers with chronic obstructive pulmonary disease (COPD) are at increased risk of muscle weakness. There are limited data describing weakness in smokers with normal spirometry and preserved ratio-impaired spirometry (PRISm), 2 subgroups at risk of respiratory symptom burden and activity limitations. In this study, we evaluated the associations of 2 weakness measures, sit-to-stand (STS) and handgrip strength (HGS), with clinical outcomes in smokers with COPD, normal spirometry, and PRISm. METHODS: We evaluated 1972 current and former smokers from the COPD Genetic Epidemiology (COPDGene®) cohort with STS and HGS measurements at their 10-year study visit. Multivariable regression modeling was used to assess associations between weakness measures and the 6-minute walk distance (6MWD) test, the St George's Respiratory Questionnaire (SGRQ), the Short-Form-36 (SF-36), severe exacerbations, and prospective mortality, reported as standardized coefficients (β), odds ratios (ORs), or hazard ratios (HRs). RESULTS: Compared with HGS, STS was more strongly associated with the 6MWD (β=0.45, p<0.001 versus. β=0.25, p<0.001), SGRQ (β=-0.24, p<0.001 versus β=-0.18, p<0.001), SF-36 Physical Functioning (β=0.36, p<0.001 versus β=0.25, p<0.001), severe exacerbations (OR 0.95, p=0.04 versus OR 0.97, p=0.01), and prospective mortality (HR 0.83, p=0.001 versus HR 0.94, p=0.03). Correlations remained after stratification by spirometric subgroups. Compared with males, females had larger magnitude effect sizes between STS and clinical outcomes. CONCLUSIONS: STS and HGS are easy to perform weakness measures that provide important information about functional performance, health-related quality of life, severe exacerbations, and survival in smokers, regardless of spirometric subgroup. This iterates the importance of screening current and former smokers for weakness in the outpatient setting.

OBJECTIVES: Discovering airway gene expression alterations associated with radiological bronchiectasis may improve the understanding of the pathobiology of early-stage bronchiectasis. METHODS: Presence of radiological bronchiectasis in 173 individuals without a clinical diagnosis of bronchiectasis was evaluated. Bronchial brushings from these individuals were transcriptomically profiled and analysed. Single-cell deconvolution was performed to estimate changes in cellular landscape that may be associated with early disease progression. RESULTS: 20 participants have widespread radiological bronchiectasis (three or more lobes). Transcriptomic analysis reflects biological processes associated with bronchiectasis including decreased expression of genes involved in cell adhesion and increased expression of genes involved in inflammatory pathways (655 genes, false discovery rate <0.1, log2 fold-change >0.25). Deconvolution analysis suggests that radiological bronchiectasis is associated with an increased proportion of ciliated and deuterosomal cells, and a decreased proportion of basal cells. Gene expression patterns separated participants into three clusters: normal, intermediate and bronchiectatic. The bronchiectatic cluster was enriched by participants with more lobes of radiological bronchiectasis (p<0.0001), more symptoms (p=0.002), higher SERPINA1 mutation rates (p=0.03) and higher computed tomography derived bronchiectasis scores (p<0.0001). CONCLUSIONS: Genes involved in cell adhesion, Wnt signalling, ciliogenesis and interferon-γ pathways had altered expression in the bronchus of participants with widespread radiological bronchiectasis, possibly associated with decreased basal and increased ciliated cells. This gene expression pattern is not only highly enriched among individuals with radiological bronchiectasis, but also associated with airway-related symptoms in those without discernible radiological bronchiectasis, suggesting that it reflects a bronchiectasis-associated, but non-bronchiectasis-specific lung pathophysiological process.

BACKGROUND: Interest in lifetime lung function trajectories has increased in the context of emerging evidence that chronic obstructive pulmonary disease (COPD) can arise from multiple disadvantaged lung function pathways, including those that stem from poor lung function in childhood. To our knowledge, no previous study has investigated both obstructive and restrictive lifetime patterns concurrently, while accounting for potential overlaps between them. We aimed to investigate lifetime trajectories of the FEV1/forced vital capacity (FVC) ratio, FVC, and their combinations, relate these combined trajectory groups to static lung volume and gas transfer measurements, and investigate both risk factors for and consequences of these combined trajectory groups. METHODS: Using z scores from spirometry measured at ages 7, 13, 18, 45, 50, and 53 years in the Tasmanian Longitudinal Health Study (n=2422), we identified six FEV1/FVC ratio trajectories and five FVC trajectories via group-based trajectory modelling. Based on whether trajectories of the FEV1/FVC ratio and FVC were low (ie, low from childhood or adulthood) or normal, four patterns of lifetime spirometry obstruction or restriction were identified and compared against static lung volumes and gas transfer. Childhood and adulthood characteristics and morbidities of these patterns were investigated. FINDINGS: The prevalence of the four lifetime spirometry patterns was as follows: low FEV1/FVC ratio only, labelled as obstructive-only, 25·8%; low FVC only, labelled as restrictive-only, 10·5%; both low FEV1/FVC ratio and low FVC, labelled as mixed, 3·5%; and neither low FEV1/FVC ratio nor low FVC, labelled as reference, 60·2%. The prevalence of COPD at age 53 years was highest in the mixed pattern (31 [37%] of 84 individuals) followed by the obstructive-only pattern (135 [22%] of 626 individuals). Individuals with the mixed pattern also had the highest prevalence of parental asthma, childhood respiratory illnesses, adult asthma, and depression. Individuals with the restrictive-only pattern had lower total lung capacity and residual volume, and had the highest prevalence of childhood underweight, adult obesity, diabetes, cardiovascular conditions, hypertension, and obstructive sleep apnoea. INTERPRETATION: To our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEV1/FVC ratio and FVC from childhood to middle age. Mixed and obstructive-only patterns indicate those who might benefit from early COPD interventions. Those with the restrictive-only pattern had evidence of true lung restriction and were at increased risk of multimorbidity by middle age. FUNDING: National Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.

Rationale: Although interstitial lung abnormalities (ILA), specific patterns of incidentally-detected abnormal density on computed tomography, have been associated with abnormal lung function and increased mortality, it is unclear if a subset with incidental interstitial lung disease (ILD) accounts for these adverse consequences. Objectives: To define the prevalence and risk factors of suspected ILD and assess outcomes. Methods: Suspected ILD was evaluated in the COPDGene (Chronic Obstructive Pulmonary Disease Genetic Epidemiology) study, defined as ILA and at least one additional criterion: definite fibrosis on computed tomography, FVC less than 80% predicted, or DLCO less than 70% predicted. Multivariable linear, longitudinal, and Cox proportional hazards regression models were used to assess associations with St. George's Respiratory Questionnaire, 6-minute-walk test, supplemental oxygen use, respiratory exacerbations, and mortality. Measurements and Main Results: Of 4,361 participants with available data, 239 (5%) had evidence for suspected ILD, whereas 204 (5%) had ILA without suspected ILD. In multivariable analyses, suspected ILD was associated with increased St. George's Respiratory Questionnaire score (mean difference [MD], 3.9 points; 95% confidence interval [CI], 0.6-7.1; P = 0.02), reduced 6-minute-walk test (MD, -35 m; 95% CI, -56 m to -13 m; P = 0.002), greater supplemental oxygen use (odds ratio [OR], 2.3; 95% CI, 1.1-5.1; P = 0.03) and severe respiratory exacerbations (OR, 2.9; 95% CI, 1.1-7.5; P = 0.03), and higher mortality (hazard ratio, 2.4; 95% CI, 1.2-4.6; P = 0.01) compared with ILA without suspected ILD. Risk factors associated with suspected ILD included self-identified Black race (OR, 2.0; 95% CI, 1.1-3.3; P = 0.01) and pack-years smoking history (OR, 1.2; 95% CI, 1.1-1.3; P = 0.0005). Conclusions: Suspected ILD is present in half of those with ILA in COPDGene and is associated with exercise decrements and increased symptoms, supplemental oxygen use, severe respiratory exacerbations, and mortality.

Background CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans. Purpose To determine the extent of AARs using an artificial intelligence-based chest CT and assess the association of AARs with exacerbations over time. Materials and Methods In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of airway dilatation) in each participant on chest CT scans was determined. Pulmonary exacerbations were prospectively determined through biannual follow-up (from July 2009 to September 2021). Multivariable zero-inflated regression models were used to assess the association between the percentage of airways with AAR greater than 1 and the total number of pulmonary exacerbations over follow-up. Covariates included demographics, lung function, and conventional CT parameters. Results Among 4192 participants (median age, 59 years; IQR, 52-67 years; 1878 men [45%]), 1834 had chronic obstructive pulmonary disease (COPD). During a 10-year follow-up and in adjusted models, the percentage of airways with AARs greater than 1 (quartile 4 vs 1) was associated with a higher total number of exacerbations (risk ratio [RR], 1.08; 95% CI: 1.02, 1.15; P = .01). In participants meeting clinical and imaging criteria of bronchiectasis (ie, clinical manifestations with ≥3% of AARs >1) versus those who did not, the RR was 1.37 (95% CI: 1.31, 1.43; P < .001). Among participants with COPD, the corresponding RRs were 1.10 (95% CI: 1.02, 1.18; P = .02) and 1.32 (95% CI: 1.26, 1.39; P < .001), respectively. Conclusion In ever-smokers with chronic obstructive pulmonary disease, artificial intelligence-based CT measures of bronchiectasis were associated with more exacerbations over time. Clinical trial registration no. NCT00608764 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Schiebler and Seo in this issue.

BACKGROUND: Chest computed tomography (CT) enables characterization of pulmonary diseases by producing high-resolution and high-contrast images of the intricate lung structures. Deformable image registration is used to align chest CT scans at different lung volumes, yielding estimates of local tissue expansion and contraction. PURPOSE: We investigated the utility of deep generative models for directly predicting local tissue volume change from lung CT images, bypassing computationally expensive iterative image registration and providing a method that can be utilized in scenarios where either one or two CT scans are available. METHODS: A residual regression convolutional neural network, called Reg3DNet+, is proposed for directly regressing high-resolution images of local tissue volume change (i.e., Jacobian) from CT images. Image registration was performed between lung volumes at total lung capacity (TLC) and functional residual capacity (FRC) using a tissue mass- and structure-preserving registration algorithm. The Jacobian image was calculated from the registration-derived displacement field and used as the ground truth for local tissue volume change. Four separate Reg3DNet+ models were trained to predict Jacobian images using a multifactorial study design to compare the effects of network input (i.e., single image vs. paired images) and output space (i.e., FRC vs. TLC). The models were trained and evaluated on image datasets from the COPDGene study. Models were evaluated against the registration-derived Jacobian images using local, regional, and global evaluation metrics. RESULTS: Statistical analysis revealed that both factors - network input and output space - were significant determinants for change in evaluation metrics. Paired-input models performed better than single-input models, and model performance was better in the output space of FRC rather than TLC. Mean structural similarity index for paired-input models was 0.959 and 0.956 for FRC and TLC output spaces, respectively, and for single-input models was 0.951 and 0.937. Global evaluation metrics demonstrated correlation between registration-derived Jacobian mean and predicted Jacobian mean: coefficient of determination (r2 ) for paired-input models was 0.974 and 0.938 for FRC and TLC output spaces, respectively, and for single-input models was 0.598 and 0.346. After correcting for effort, registration-derived lobar volume change was strongly correlated with the predicted lobar volume change: for paired-input models r2 was 0.899 for both FRC and TLC output spaces, and for single-input models r2 was 0.803 and 0.862, respectively. CONCLUSIONS: Convolutional neural networks can be used to directly predict local tissue mechanics, eliminating the need for computationally expensive image registration. Networks that use paired CT images acquired at TLC and FRC allow for more accurate prediction of local tissue expansion compared to networks that use a single image. Networks that only require a single input image still show promising results, particularly after correcting for effort, and allow for local tissue expansion estimation in cases where multiple CT scans are not available. For single-input networks, the FRC image is more predictive of local tissue volume change compared to the TLC image.

BACKGROUND: Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. METHODS: To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome-wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non-Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity-associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. RESULTS: Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non-coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (β = 0.151, SE = 0.021, P = 1.40 × 10-12 for UK Biobank |β= 0.220, SE = 0.041, P = 9.99 × 10-8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (β = 0.129, SE = 0.024, P = 4.64 × 10-8 for UK Biobank |β = 0.203, SE = 0.045, P = 6.38 × 10-6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence-associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. CONCLUSIONS: Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.

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.