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.

Rationale: In predominantly White populations, early chronic obstructive pulmonary disease (COPD) (i.e., COPD in people aged <50 yr) has been linked to higher hospitalization rates and mortality; however, the prevalence, risk factors, and population attributable risk (PAR) of early COPD remain to be determined in non-White populations. Objectives: We aimed to examine the prevalence, risk factors, and PARs of early COPD among Hispanic/Latino individuals, the largest U.S. minority group. Methods: We used baseline data from the Hispanic Community Health Study/Study of Latinos, a population-based probability sample of 16,415 Hispanic/Latino individuals aged 18-74 years. Participants aged <50 years were included (N = 7,323). Early COPD was defined as a forced expiratory volume in 1 second to forced vital capacity ratio less than the lower limit of normal. We used survey logistic regression analysis to identify risk factors and estimate the prevalence of early COPD. PARs of the risk factors identified were estimated. Results: A total of 524 participants met the criteria for early COPD, yielding a sex- and age-adjusted prevalence of 7.6% (95% confidence interval [CI], 6.8-8.6). Asthma (odds ratio [OR], 3.37; 95% CI, 2.57-4.41), smoking status (ever vs. never; OR, 1.65; 95% CI, 1.24-2.20), and chronic sinusitis (OR, 1.71; 95% CI, 1.09-2.66) were associated with increased odds of early COPD. Immigrants versus U.S.-born individuals have lower odds of early COPD (age at immigration <15 yr and living in the United States <10 yr; OR, 0.94; 95% CI, 0.39-2.27; age at immigration <15 yr and living in the United States ⩾10 yr; OR, 0.55; 95% CI, 0.37-0.84; age at immigration ⩾15 yr and living in the United States <10 yr; OR, 0.86; 95% CI, 0.57-1.30; and age at immigration ⩾15 yr and living in the United States ⩾10 yr; OR, 0.63; 95% CI, 0.42-0.95). Among smokers, pack-years was not associated with early COPD (5-9.9 vs. <5 pack-years; OR, 1.04; 95% CI, 0.59-1.82; ⩾10 vs. <5 pack-years; OR, 1.20; 95% CI, 0.74-1.94). The mean PAR for asthma, smoking status, and chronic sinusitis was 26.3% (95% CI, 22.1-30.3), 22.4% (95% CI, 17.4-27.1), and 6.9% (95% CI, 4.3-9.4), respectively. Conclusions: Among U.S. Hispanic/Latino individuals, asthma is one of the most important risk factors for early COPD, followed by smoking and chronic sinusitis. Immigrants appear to have a lower risk of early COPD than U.S.-born Hispanic/Latino individuals.

INTRODUCTION: Loss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesise that CFTR variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. METHODS: Whole-genome sequencing was performed through the National Heart, Lung, and Blood Institute TOPMed (TransOmics in Precision Medicine) programme in 8597 subjects from the COPDGene (Genetic Epidemiology of COPD) study, an observational study of current and former smokers. We extracted clinically annotated CFTR variants and performed single-variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2118 subjects from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. RESULTS: We identified 301 coding variants within the CFTR gene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF-causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one-sided p=0.0025; OR 1.53) and in meta-analysis of COPDGene and ECLIPSE (one-sided p=0.0060; OR 1.52). Single-variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one-sided p=0.015; OR 1.47). In addition, we identified 32 subjects with two or more CFTR variants on separate alleles and these subjects were enriched for COPD cases (p=0.010). CONCLUSIONS: Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.

Background Pulmonary and cardiac functions decline with age, but the associations of pulmonary dysfunction with cardiac function and heart failure (HF) risk in late life is not known. We aimed to determine the associations of percent predicted forced vital capacity (ppFVC) and the ratio of forced expired volume in 1 second (FEV1) to forced vital capacity (FVC; FEV1/FVC) with cardiac function and incident HF with preserved or reduced ejection fraction in late life. Methods and Results Among 3854 HF-free participants in the ARIC (Atherosclerosis Risk in Communities) cohort study who underwent echocardiography and spirometry at the fifth study visit (2011-2013), associations of FEV1/FVC and ppFVC with echocardiographic measures, cardiac biomarkers, and risk of HF, HF with preserved ejection fraction, and HF with reduced ejection fraction were assessed. Multivariable linear and Cox regression models adjusted for demographics, body mass index, coronary disease, atrial fibrillation, hypertension, and diabetes. Mean age was 75±5 years, 40% were men, 19% were Black, and 61% were ever smokers. Mean FEV1/FVC was 72±8%, and ppFVC was 98±17%. In adjusted analyses, lower FEV1/FVC and ppFVC were associated with higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; both P<0.001) and pulmonary artery pressure (P<0.004). Lower ppFVC was also associated with higher left ventricular mass, left ventricular filling pressure, and high-sensitivity C-reactive protein (all P<0.01). Lower FEV1/FVC was associated with a trend toward higher risk of incident HF with preserved ejection fraction (hazard ratio [HR] per 10-point decrease, 1.31; 95% CI, 0.98-1.74; P=0.07) and HF with reduced ejection fraction (HR per 10-point decrease, 1.24; 95% CI, 0.91-1.70; P=0.18), but these associations did not reach statistical significance. Lower ppFVC was associated with incident HF with preserved ejection fraction (HR per 10-unit decrease, 1.21; 95% CI, 1.04-1.41; P=0.013) but not with HF with reduced ejection fraction (HR per 10-unit decrease, 0.90; 95% CI, 0.76-1.07; P=0.24). Conclusions Subclinical reductions in FEV1/FVC and ppFVC differentially associate with cardiac function and HF risk in late life.

BACKGROUND: Computed tomography (CT) imaging complements spirometry and may provide insight into racial disparities in respiratory health. OBJECTIVE: To determine the difference in emphysema prevalence between Black and White adults with different measures of normal spirometry results. DESIGN: Observational study using clinical data and spirometry from the CARDIA (Coronary Artery Risk Development in Young Adults) study obtained in 2015 to 2016 and CT scans done in 2010 to 2011. SETTING: 4 U.S. centers. PARTICIPANTS: Population-based sample of Black and White adults. MEASUREMENTS: Self-identified race and visually identified emphysema on CT in participants with different measures of "normal" spirometry results, calculated using standard race-specific and race-neutral reference equations. RESULTS: A total of 2674 participants (485 Black men, 762 Black women, 659 White men, and 768 White women) had both a CT scan and spirometry available for analysis. Among participants with a race-specific FEV1 between 80% and 99% of predicted, 6.5% had emphysema. In this group, emphysema prevalence was 3.9-fold (95% CI, 2.1- to 7.1-fold; 15.5% vs. 4.0%) higher among Black men than White men and 1.9-fold (CI, 1.0- to 3.8-fold; 6.6% vs. 3.4%) higher among Black women than White women. Among participants with a race-specific FEV1 between 100% and 120% of predicted, 4.0% had emphysema. In this category, Black men had a 6.4-fold (CI, 2.2- to 18.7-fold; 13.9% vs. 2.2%) higher prevalence of emphysema than White men, whereas Black and White women had a similar prevalence of emphysema (2.6% and 2.0%, respectively). The use of race-neutral equations to identify participants with an FEV1 percent predicted between 80% and 120% attenuated racial differences in emphysema prevalence among men and eliminated racial differences among women. LIMITATION: No CT scans were obtained during the most recent study visit (2015 to 2016) when spirometry was done. CONCLUSION: Emphysema is often present before spirometry findings become abnormal, particularly among Black men. Reliance on spirometry alone to differentiate lung health from lung disease may result in the underrecognition of impaired respiratory health and exacerbate racial disparities. PRIMARY FUNDING SOURCE: National Institutes of Health.

BACKGROUND: Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. RESEARCH QUESTION: Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? STUDY DESIGN AND METHODS: Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. RESULTS: Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System "S-modifier" [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. INTERPRETATION: Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA.

BACKGROUND: There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease. STUDY QUESTION: Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function? STUDY DESIGN AND METHODS: Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits. RESULTS: Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function. INTERPRETATION: sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.

BACKGROUND: Most pulmonary conditions reduce FVC, but studies of patients with combined pulmonary fibrosis and emphysema demonstrate that reductions in FVC are less than expected when these two conditions coexist clinically. RESEARCH QUESTION: Do interstitial lung abnormalities (ILAs), chest CT imaging findings that may suggest an early stage of pulmonary fibrosis in individuals with undiagnosed disease, affect the association between emphysema and FVC? STUDY DESIGN AND METHODS: Measures of ILA and emphysema were available for 9,579 and 5,277 participants from phases 1 (2007-2011) and 2 (2012-2016) of the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study (COPDGene), respectively. ILA were defined by Fleischner Society guidelines. Adjusted linear regression models were used to assess the associations and interactions among ILA, emphysema, measures of spirometry, and lung function. RESULTS: ILA were present in 528 (6%) and 580 (11%) of participants in phases 1 and 2 of COPDGene, respectively. ILA modified the association between emphysema and FVC (P < .0001 for interaction) in both phases. In phase 1, in those without ILA, a 5% increase in emphysema was associated with a reduction in FVC (-110 mL; 95% CI, -121 to -100 mL; P < .0001); however, in those with ILA, it was not (-11 mL; 95% CI, -53 to 31; P = .59). In contrast, no interaction was found between ILA and emphysema on total lung capacity or on diffusing capacity of carbon monoxide. INTERPRETATION: The presence of ILA attenuates the reduction in FVC associated with emphysema.