Proteomic Risk Score of Increased Respiratory Susceptibility: A Multi-Cohort Study.

RATIONALE: Accelerated decline in lung function is associated with incident COPD, hospitalizations and death. However, identifying this trajectory with longitudinal spirometry measurements is challenging in clinical practice. OBJECTIVE: To determine whether a proteomic risk score trained on accelerated decline in lung function can assess risk of future respiratory disease and mortality. METHODS: In CARDIA, a population-based cohort starting in young adulthood, longitudinal measurements of FEV1 percent predicted (up to six timepoints over 30 years) were used to identify accelerated and normal decline trajectories. Protein aptamers associated with an accelerated decline trajectory were identified with multivariable logistic regression followed by LASSO regression. The proteomic respiratory susceptibility score was derived based on these circulating proteins and applied to the UK Biobank and COPDGene studies to examine associations with future respiratory morbidity and mortality. MEASUREMENTS AND RESULTS: Higher susceptibility score was independently associated with all-cause mortality (UKBB: HR 1.56, 95%CI 1.50-1.61; COPDGene: HR 1.75, 95%CI 1.63-1.88), respiratory mortality (UKBB: HR 2.39, 95% CI 2.16-2.64; COPDGene: HR 1.83, 95%CI 1.33-2.51), incident COPD (UKBB: HR 1.84, 95%CI 1.71-1.98), incident respiratory exacerbation (COPDGene: OR 1.11, 95%CI 1.03-1.20), and incident exacerbation requiring hospitalization (COPDGene: OR 1.18, 95%CI 1.08-1.28). CONCLUSIONS: A proteomic signature of increased respiratory susceptibility identifies people at risk of respiratory death, incident COPD, and respiratory exacerbations. This susceptibility score is comprised of proteins with well-known and novel associations with lung health and holds promise for the early detection of lung disease without requiring years of spirometry measurements.

Prognostic importance of ischemic heart disease for patients with atrial fibrillation undergoing catheter ablation.

BACKGROUND: Ischemic heart disease (IHD) has been linked to an increased risk of atrial fibrillation (AF). However, data are sparse regarding the role of IHD in AF recurrence after catheter ablation. OBJECTIVE: We sought to investigate whether preexisting or new-onset IHD is associated with a greater risk of AF recurrence after ablation. METHODS: With use of Danish nationwide registries, all patients undergoing first-time AF ablation in Denmark from 2010 to 2020 were identified. The primary outcome was AF recurrence defined by AF-related hospital admission or antiarrhythmic drug use within 1 year after ablation excluding a 3-month blanking period. IHD was defined as an International Classification of Diseases, Tenth Revision diagnosis of IHD or prior coronary revascularization. RESULTS: Of 12,162 patients undergoing first-time ablation for AF (mean age, 62 years; 30% female), 20% had preexisting IHD. Preexisting IHD was associated with an increased risk of AF recurrence in univariable log-binomial logistic regression (relative risk, 1.09; 95% CI, 1.04-1.14; P < .001). However, after multivariable adjustment including procedural year, preexisting IHD was no longer associated with an increased risk of AF recurrence (relative risk, 1.02; 95% CI, 0.97-1.06; P = .42). In a nested case-control study of those without preexisting IHD before ablation (n = 9778), newly diagnosed IHD after ablation was associated with an increased risk of AF recurrence in multivariable analysis (hazard ratio, 3.03; 95% CI, 1.84-4.99; P < .001). CONCLUSION: The presence of IHD does not appear to reduce the effectiveness of AF ablation procedures. However, the emergence of IHD after AF ablation may serve as a trigger for AF that is insufficiently suppressed by prior ablation.

Development, Progression, and Mortality of Suspected Interstitial Lung Disease in COPDGene.

RATIONALE: Some with interstitial lung abnormalities (ILA) have suspected interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown. OBJECTIVES: To determine rates of development and progression of suspected ILD and assess effects of individual ILD and progression criteria on mortality. METHODS: Participants from COPDGene were included. ILD was defined as ILA and fibrosis and/or FVC <80% predicted. Prevalent ILD was assessed at enrollment, incident ILD and progression at 5-year follow-up. CT progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and ILD groups. RESULTS: Of 9,588 participants at enrollment, 267 (2.8%) had prevalent ILD. Those with prevalent ILD had 52% mortality after median 10.6 years, which was higher than ILA (33%; HR=2.0; p<0.001). The subgroup of prevalent ILD with fibrosis only had worse mortality (59%) than ILA (HR=2.2; p<0.001). 97 participants with prevalent ILD completed 5-year follow-up: 32% had stable CT and relative FVC decline <10%, 6% FVC decline ≥10% only, 39% CT progression only, and 22% both CT progression and FVC decline ≥10%. Mortality rates were 32%, 50%, 45%, and 46% respectively; those with CT progression only had worse mortality than ILA (HR=2.6; p=0.005). At 5-year follow-up, incident ILD occurred in 168/4,843 participants without prevalent ILD and had worse mortality than ILA (HR=2.5; p<0.001). CONCLUSION: Rates of mortality and progression are high among those with suspected ILD in COPDGene; fibrosis and radiologic progression are important predictors of mortality.

Rheumatoid arthritis and changes on spirometry by smoking status in two prospective longitudinal cohorts.

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.

Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in COPDGene.

RATIONALE: Quantitative interstitial abnormalities (QIA) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIA and its role in the QIA-outcome relationship is unknown. OBJECTIVES: To quantify radiographic pulmonary vasculopathy in quantitative interstitial abnormalities (QIA) and determine if this vasculopathy mediates the QIA-outcome relationship. METHODS: Ever-smokers with QIA, outcome, and pulmonary vascular mediator data were identified from the COPDGene cohort. CT-based vascular mediators were: right ventricle-to-left ventricle ratio (RV/LV), pulmonary artery-to-aorta ratio (PA/Ao), and pre-acinar intraparenchymal arterial dilation (PA volume 5-20mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were: six-minute walk distance (6MWD) and modified Medical Council Research Council (mMRC) Dyspnea score ≥2. Adjusted causal mediation analyses were used to determine if the pulmonary vasculature mediated the QIA effect on outcomes. Associations of pre-acinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. MAIN RESULTS: Among 8,200 participants, QIA burden correlated positively with vascular damage measures including pre-acinar arterial dilation. Pre-acinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6MWD (56.2-100%, p<0.001). PA/Ao was a weak mediator and RV/LV was a suppressor. Similar results were observed in the QIA-mMRC relationship. Pre-acinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels including angiopoietin-2 and NT-proBNP. CONCLUSIONS: Parenchymal quantitative interstitial abnormalities (QIA) deleteriously impact outcomes primarily through pulmonary vasculopathy. Pre-acinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIA.

Association of Acute Respiratory Disease Events with Quantitative Interstitial Abnormality Progression at CT in Individuals with a History of Smoking.

Background Acute respiratory disease (ARD) events are often thought to be airway-disease related, but some may be related to quantitative interstitial abnormalities (QIAs), which are subtle parenchymal abnormalities on CT scans associated with morbidity and mortality in individuals with a smoking history. Purpose To determine whether QIA progression at CT is associated with ARD and severe ARD events in individuals with a history of smoking. Materials and Methods This secondary analysis of a prospective study included individuals with a 10 pack-years or greater smoking history recruited from multiple centers between November 2007 and July 2017. QIA progression was assessed between baseline (visit 1) and 5-year follow-up (visit 2) chest CT scans. Episodes of ARD were defined as increased cough or dyspnea lasting 48 hours and requiring antibiotics or corticosteroids, whereas severe ARD episodes were those requiring an emergency room visit or hospitalization. Episodes were recorded via questionnaires completed every 3 to 6 months. Multivariable logistic regression and zero-inflated negative binomial regression models adjusted for comorbidities (eg, emphysema, small airway disease) were used to assess the association between QIA progression and episodes between visits 1 and 2 (intercurrent) and after visit 2 (subsequent). Results A total of 3972 participants (mean age at baseline, 60.7 years ± 8.6 [SD]; 2120 [53.4%] women) were included. Annual percentage QIA progression was associated with increased odds of one or more intercurrent (odds ratio [OR] = 1.29 [95% CI: 1.06, 1.56]; P = .01) and subsequent (OR = 1.26 [95% CI: 1.05, 1.52]; P = .02) severe ARD events. Participants in the highest quartile of QIA progression (≥1.2%) had more frequent intercurrent ARD (incidence rate ratio [IRR] = 1.46 [95% CI: 1.14, 1.86]; P = .003) and severe ARD (IRR = 1.79 [95% CI: 1.18, 2.73]; P = .006) events than those in the lowest quartile (≤-1.7%). Conclusion QIA progression was independently associated with higher odds of severe ARD events during and after radiographic progression, with higher frequency of intercurrent severe events in those with faster progression. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Little in this issue.

Utility of peripheral protein biomarkers for the prediction of incident interstitial features: a multicentre retrospective cohort study.

INTRODUCTION/RATIONALE: Protein biomarkers may help enable the prediction of incident interstitial features on chest CT. METHODS: We identified which protein biomarkers in a cohort of smokers (COPDGene) differed between those with and without objectively measured interstitial features at baseline using a univariate screen (t-test false discovery rate, FDR p<0.001), and which of those were associated with interstitial features longitudinally (multivariable mixed effects model FDR p<0.05). To predict incident interstitial features, we trained four random forest classifiers in a two-thirds random subset of COPDGene: (1) imaging and demographic information, (2) univariate screen biomarkers, (3) multivariable confirmation biomarkers and (4) multivariable confirmation biomarkers available in a separate testing cohort (Pittsburgh Lung Screening Study (PLuSS)). We evaluated classifier performance in the remaining one-third of COPDGene, and, for the final model, also in PLuSS. RESULTS: In COPDGene, 1305 biomarkers were available and 20 differed between those with and without interstitial features at baseline. Of these, 11 were associated with feature progression over a mean of 5.5 years of follow-up, and of these 4 were available in PLuSS, (angiopoietin-2, matrix metalloproteinase 7, macrophage inflammatory protein 1 alpha) over a mean of 8.8 years of follow-up. The area under the curve (AUC) of classifiers using demographics and imaging features in COPDGene and PLuSS were 0.69 and 0.59, respectively. In COPDGene, the AUC of the univariate screen classifier was 0.78 and of the multivariable confirmation classifier was 0.76. The AUC of the final classifier in COPDGene was 0.75 and in PLuSS was 0.76. The outcome for all of the models was the development of incident interstitial features. CONCLUSIONS: Multiple novel and previously identified proteomic biomarkers are associated with interstitial features on chest CT and may enable the prediction of incident interstitial diseases such as idiopathic pulmonary fibrosis.

Cluster Analysis of World Trade Center Related Lower Airway Diseases.

ABSTRACT: Introduction: Cluster analysis can classify without a priori assumptions the heterogeneous chronic lower airway diseases found in former workers at the World Trade Center (WTC) disaster site. Methods: We selected the first available chest computed tomography scan with quantitative computed tomography measurements on 311 former WTC workers with complete clinical, and spirometric data from their closest surveillance visit. We performed a nonhierarchical iterative algorithm K-prototype cluster analysis, using gap measure. Results: A five-cluster solution was most satisfactory. Cluster 5 had the healthiest individuals. In cluster 4, smoking was most prevalent and intense but there was scant evidence of respiratory disease. Cluster 3 had symptomatic subjects with reduced forced vital capacity impairment (low FVC). Clusters 1 and 2 had less dyspneic subjects, but more functional and quantitative computed tomography evidence of chronic obstructive pulmonary disease (COPD) in cluster 1, or low FVC in cluster 2. Clusters 1 and 4 had the highest proportion of rapid first-second forced expiratory volume decliners. Conclusions: Cluster analysis confirms low FVC and COPD/pre-COPD as distinctive chronic lower airway disease phenotypes on long-term surveillance of the WTC workers.

Quantification of Emphysema Progression at CT Using Simultaneous Volume, Noise, and Bias Lung Density Correction.

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study.

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.

Dysanapsis is differentially related to lung function trajectories with distinct structural and functional patterns in COPD and variable risk for adverse outcomes.

Background: Abnormal lung function trajectories are associated with increased risk of chronic obstructive pulmonary disease (COPD) and premature mortality; several risk factors for following these trajectories have been identified. Airway under-sizing dysanapsis (small airway lumens relative to lung size), is associated with an increased risk for COPD. The relationship between dysanapsis and lung function trajectories at risk for adverse outcomes of COPD is largely unexplored. We test the hypothesis that dysanapsis differentially affects distinct lung function trajectories associated with adverse outcomes of COPD. Methods: To identify lung function trajectories, we applied Bayesian trajectory analysis to longitudinal FEV1 and FVC Z-scores in the COPDGene Study, an ongoing longitudinal study that collected baseline data from 2007 to 2012. To ensure clinical relevance, we selected trajectories based on risk stratification for all-cause mortality and prospective exacerbations of COPD (ECOPD). Dysanapsis was measured in baseline COPDGene CT scans as the airway lumen-to-lung volume (a/l) ratio. We compared a/l ratios between trajectories and evaluated their association with trajectory assignment, controlling for previously identified risk factors. We also assigned COPDGene participants for whom only baseline data is available to their most likely trajectory and repeated our analysis to further evaluate the relationship between trajectory assignment and a/l ratio measures. Findings: We identified seven trajectories: supranormal, reference, and five trajectories at increased risk for mortality and exacerbations. Three at-risk trajectories are characterized by varying degrees of concomitant FEV1 and FVC impairments and exhibit airway predominant COPD patterns as assessed by quantitative CT imaging. These trajectories have lower a/l ratio values and increased risk for mortality and ECOPD compared to the reference trajectory. Two at-risk trajectories are characterized by disparate levels of FEV1 and FVC impairment and exhibit mixed airway and emphysema COPD patterns on quantitative CT imaging. These trajectories have markedly lower a/l ratio values compared to both the reference trajectory and airway-predominant trajectories and are at greater risk for mortality and ECOPD compared to the airway-predominant trajectories. These findings were observed among the participants with baseline-only data as well. Interpretation: The degree of dysanapsis appears to portend patterns of progression leading to COPD. Assignment of individuals-including those without spirometric obstruction-to distinct trajectories is possible in a clinical setting and may influence management strategies. Strategies that combine CT-assessed dysanapsis together with spirometric measures of lung function and smoke exposure assessment are likely to further improve trajectory assignment accuracy, thereby improving early detection of those most at risk for adverse outcomes. Funding: United States National Institute of Health, COPD Foundation, and Brigham and Women's Hospital.

Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease.

Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from ever-smokers and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell marker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs (q-value = 2.56E-111). LFs from patients with GOLD 1-2 COPD with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from patients with GOLD 1-2 COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Spatial Transcriptomics Resolve an Emphysema-specific Lymphoid Follicle B Cell Signature in COPD.

RATIONALE: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. OBJECTIVE: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and COPD patients with varying degrees of emphysema. METHODS: Lung sections from 40 COPD patients and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin and OCT-fixed lung samples obtained from biopsies or lung explants, were assessed for LF presence. Emphysema measurements were obtained from clinical chest CT scans. High confidence transcriptional (HCT) target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. MEASUREMENTS AND MAIN RESULTS: Overall, 115 LFs from ever-smokers and GOLD 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell markers genes in subjects with severe emphysema. HCT analysis revealed activation of abnormal B cell activity signature in LFs (q-value: 2.56E-111). LFs from GOLD 1-2 COPD patients with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from GOLD 1-2 COPD patients without emphysema showed an anti-inflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed towards chronic B cell activation. CONCLUSIONS: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Plasma metabolomics and quantitative interstitial abnormalities in ever-smokers.

BACKGROUND: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality. METHODS: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography-mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini-Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst. RESULTS: We found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways. CONCLUSIONS: Metabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers.

Suspected Bronchiectasis and Mortality in Adults With a History of Smoking Who Have Normal and Impaired Lung Function : A Cohort Study.

BACKGROUND: Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation-is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown. OBJECTIVE: To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry. DESIGN: Prospective, observational cohort. SETTING: The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. PARTICIPANTS: 7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry (n = 3277), PRISm (n = 986), and obstructive spirometry (n = 3399). MEASUREMENTS: Bronchiectasis identified by CT was ascertained using artificial intelligence-based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of "suspected bronchiectasis" was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations. RESULTS: Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, -0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, -0.001 to 0.08]). LIMITATIONS: Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific. CONCLUSION: Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.