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A primary sink of air pollutants and their precursors is dry deposition. Dry deposition estimates differ across chemical transport models, yet an understanding of the model spread is incomplete. Here, we introduce Activity 2 of the Air Quality Model Evaluation International Initiative Phase 4 (AQMEII4). We examine 18 dry deposition schemes from regional and global chemical transport models as well as standalone models used for impact assessments or process understanding. We configure the schemes as single-point models at eight Northern Hemisphere locations with observed ozone fluxes. Single-point models are driven by a common set of site-specific meteorological and environmental conditions. Five of eight sites have at least 3 years and up to 12 years of ozone fluxes. The interquartile range across models in multiyear mean ozone deposition velocities ranges from a factor of 1.2 to 1.9 annually across sites and tends to be highest during winter compared with summer. No model is within 50 % of observed multiyear averages across all sites and seasons, but some models perform well for some sites and seasons. For the first time, we demonstrate how contributions from depositional pathways vary across models. Models can disagree with respect to relative contributions from the pathways, even when they predict similar deposition velocities, or agree with respect to the relative contributions but predict different deposition velocities. Both stomatal and nonstomatal uptake contribute to the large model spread across sites. Our findings are the beginning of results from AQMEII4 Activity 2, which brings scientists who model air quality and dry deposition together with scientists who measure ozone fluxes to evaluate and improve dry deposition schemes in the chemical transport models used for research, planning, and regulatory purposes.

Monocyte-derived alveolar macrophages drive lung injury and fibrosis in murine models and are associated with pulmonary fibrosis in humans. Monocyte-derived alveolar macrophages have been suggested to develop a phenotype that promotes lung repair as injury resolves. We compared single-cell and cytokine profiling of the alveolar space in a cohort of 35 patients with post-acute sequelae of COVID-19 who had persistent respiratory symptoms and abnormalities on a computed tomography scan of the chest that subsequently improved or progressed. The abundance of monocyte-derived alveolar macrophages, their gene expression programs, and the level of the monocyte chemokine CCL2 in bronchoalveolar lavage fluid positively associated with the severity of radiographic fibrosis. Monocyte-derived alveolar macrophages from patients with resolving or progressive fibrosis expressed the same set of profibrotic genes. Our findings argue against a distinct reparative phenotype in monocyte-derived alveolar macrophages, highlighting their utility as a biomarker of failed lung repair and a potential target for therapy., (© 2024. The Author(s).)

Rationale Emphysema progression is heterogeneous. Predicting temporal changes in lung density and detecting rapid progressors may facilitate selection of individuals for targeted therapies. Objective To test whether computed tomography (CT) radiomics can be used to predict changes in lung density and detect rapid progressors. Methods We extracted radiomics features from inspiratory chest CT in 4,575 subjects with and without airflow obstruction at enrollment, who completed a follow-up visit at approximately 5 years. We quantified emphysema using adjusted lung density (ALD) and estimated emphysema progression as the annualized change in ALD (∆ALD/year) between visits. We categorized participants into rapid progressors (>1% ∆ALD/year) and stable disease (≤1% ∆ALD/year). A gradient boosting model was used (1) to predict ALD at 5-years and (2) to identify rapid progressors. Four models using demographics (base clinical model); CT density; radiomics; and combined features (clinical, radiomics, and CT density) were evaluated and tested. Results There were 1,773 (38.8%) rapid progressors. For predicting ALD at 5-years in the 20% held-out data, the base model explained 31% of the variance (adjusted R2 = 0.31) whereas R2 was 0.74 for the CT density model, 0.66 for the radiomics-only model, and 0.77 for the combined features model. For detecting rapid progressors, the base model (AUC = 0.57, 95%CI 0.53-0.61) was outperformed by the radiomics-only model (AUC = 0.73, 95%CI 0.69-0.76, ∆ =0.0003, p < 0.001) and the combined model (AUC = 0.74, 95%CI 0.71-0.77, ∆ = 0.0003, p < 0.001). Conclusions Parenchymal and airway radiomics features derived from inspiratory scans can be used to predict temporal changes in lung density and help identify rapid progressors.

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 (FEV 1 %) 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 (FEV 1 /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 FEV 1 % decline (β=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV 1 % decline than non-RA comparators (β=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (β=1.12, p=0.01). Results were similar for FEV 1 /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 FEV 1 % and FEV 1 /FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV 1 % decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA., Competing Interests: Competing interests: PAJ reports grant funding and other support from Novartis, Galapagos and Boehringer Ingelheim, unrelated to this work. MM reports institutional grant support from Bayer and Honoraria from Chickasaw Nation. MHC has received grant funding from Bayer, unrelated to this work. TJD received support from Bayer and has been part of a clinical trial funded by Genentech, unrelated to this study. PFD reports grant funding from Bristol Myers Squibb. ZW has received grant funding from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, Nkarta, Inc, Adicet Bio, and Therapeutic’s and participation in data safety monitoring board or advisory board for Sanofi, Horizon, Novartis, Visterra/Otsuka and Shionogi, unrelated to this work. GMH reports consulting fees from Boehringer-Ingelheim, and the Gerson Lehrman Group, unrelated to this work. EKS has received grant support from Bayer and Northpond Laboratories, unrelated to this work. SYA reports consulting fees from Verona Pharmaceuticals and Vertex Pharmaceuticals and is cofounder and co-owner of Quantitative Imaging Solutions. RSJE reports contracts from Lung Biotechnology and Insmed, received a grant support from Boehringer Ingelheim and is cofounder and an equity holder of Quantitative Imaging Solutions. GRW reports grants from Boehringer Ingelheim, consultancy for Pulmonx, Janssen Pharmaceuticals, Novartis, and Vertex, and is founder and co-owner of Quantitative Imaging Solutions. JS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, unrelated to this work. Other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: SA reports equity/dividends from Quantitative Imaging Solutions and consulting for Vertex Pharmaceuticals, Verona Pharmaceuticals and Triangulate Knowledge, all unrelated to the current work. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech, unrelated to the current work. BC reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. RuSJE reports consulting fees from Quantitative Imaging Solutions, unrelated to the current work. VC reports no competing interests. NE reports no competing interests. RK reports grants and personal fees from AstraZeneca, personal fees from CVS Caremark, personal fees from Aptus Health, grants and personal fees from GlaxoSmithKline, personal fees from Boston Scientific, personal fees from Boston Consulting Group, all outside the submitted work. GL reports no competing interests. RB reports no competing interests. DOW reports advisory board membership and shareholder of Online Disruptive Technologies, unrelated to the current work. RaSJE reports equity/dividends from Quantitative Imaging Solutions, unrelated to the current work. IOR reports no competing interests. GRW reports grants from Boehringer Ingelheim, BTG Interventional Medicine and Janssen Pharmaceuticals; consultancies/advisory board participation for Boehringer Ingelheim, Janssen Pharmaceuticals, Pulmonx, Novartis, Philips, CSL Behring and Vertex; and equity/dividends from Quantitative Imaging Solutions, unrelated to the current work, all outside the submitted work. GRW’s wife works for Biogen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

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.

Objective: To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators., Methods: We analysed associations between ILAs, RA, and mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression., Results: We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA [odds ratio 4.76 (95% CI 2.54, 8.92)]. RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs [hazard ratio (HR) 3.16 (95% CI 2.11, 4.74)] and RA cases without ILA [HR 3.02 (95% CI 1.36, 6.75)]., Conclusions: In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Visually normal areas of the lung with high attenuation on computed tomography (CT) imaging, termed CT lung injury, may represent injured but not yet remodelled lung parenchyma. This prospective cohort study examined if CT lung injury is associated with future interstitial features on CT and restrictive spirometry abnormality among participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study., Methods: CARDIA is a population-based cohort study. CT scans obtained at two time points were assessed objectively for amount of lung tissue characterised as CT lung injury and interstitial features. Restrictive spirometry was defined as having a forced vital capacity (FVC) <80% predicted with forced expiratory volume in 1 s/FVC ratio >70%., Results: Among 2213 participants, the median percentage of lung tissue characterised as CT lung injury at a mean age of 40 years was 3.4% (interquartile range 0.8-18.0%). After adjustment for covariates, a 10% higher amount of CT lung injury at mean age 40 years was associated with a 4.37% (95% CI 3.99-4.74%) higher amount of lung tissue characterised as interstitial features at mean age 50 years. Compared to those with the lowest quartile of CT lung injury at mean age 40 years, there were higher odds of incident restrictive spirometry at mean age 55 years in quartile 2 (OR 2.05, 95% CI 1.20-3.48), quartile 3 (OR 2.80, 95% CI 1.66-4.72) and quartile 4 (OR 3.77, 95% CI 2.24-6.33)., Conclusions: CT lung injury is an early objective measure that indicates risk of future lung impairment., Competing Interests: Conflict of interest: G.Y. Liu has no conflicts of interest or financial disclosures. Conflict of interest: L.A. Colangelo has no conflicts of interest or financial disclosures. Conflict of interest: S.Y. Ash reports equity/dividends from Quantitative Imaging Solutions, unrelated to the current work. Conflict of interest: R. San Jose Estepar is co-founder and stockholder of Quantitative Imaging Solutions, unrelated to the current work. Conflict of interest: D.R. Jacobs Jr. has no conflicts of interest or financial disclosures. Conflict of interest: B. Thyagarajan has no conflicts of interest or financial disclosures. Conflict of interest: J.M. Wells has no conflicts of interest or financial disclosures. Conflict of interest: R.K. Putman has no conflicts of interest or financial disclosures. Conflict of interest: B. Choi receives consulting fees from Quantitative Imaging Solutions, unrelated to the current work. Conflict of interest: C.S. Stevenson is employed by Johnson & Johnson, Inc. Conflict of interest: M.R. Carnethon has no conflicts of interest or financial disclosures. Conflict of interest: G.R. Washko reports grants from Boehringer Ingelheim, BTG Interventional Medicine and Janssen Pharmaceuticals; and consultancies/advisory board participation for Boehringer Ingelheim, Janssen Pharmaceuticals, Pulmonx, Novartis, Philips, CSL Behring and Vertex, all outside the submitted work. He is a cofounder and equity share holder of Quantitative Imaging Solutions, unrelated too this work; and his wife works for Biogen. Conflict of interest: R. Kalhan receives grants and personal fees from AstraZeneca and GlaxoSmithKline, and personal fees from CVS Caremark, Aptus Health, Boston Scientific and Boston Consulting Group, all outside the submitted work., (Copyright ©The authors 2023.)

Background: Cardiorespiratory fitness is not limited by pulmonary mechanical reasons in the majority of adults. However, the degree to which lung function contributes to exercise response patterns among ostensibly healthy individuals remains unclear., Methods: We examined 2314 Framingham Heart Study participants who underwent cardiopulmonary exercise testing (CPET) and pulmonary function testing. We investigated the association of forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC and diffusing capacity of the lung for carbon monoxide ( D LCO ) with the primary outcome of peak oxygen uptake ( V ' O 2 ) along with other CPET parameters using multivariable linear regression. Finally, we investigated the association of total and peripheral pulmonary blood vessel volume with peak V ' O 2 ., Results: We found lower FEV 1 , FVC and D LCO were associated with lower peak V ' O 2 . For example, a 1 L lower FEV 1 and FVC was associated with a 7.1% (95% CI 5.1-9.1%) and 6.0% (95% CI 4.3-7.7%) lower peak V ' O 2 , respectively. By contrast, FEV 1 /FVC was not associated with peak V ' O 2 . Lower lung function was associated with lower oxygen uptake efficiency slope, oxygen pulse slope, V ' O 2 at anaerobic threshold (AT), minute ventilation ( V ' E ) at AT and breathing reserve. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V ' O 2 ., Conclusions: In a large, community-based cohort of adults, we found lower FEV 1 , FVC and D LCO were associated with lower exercise capacity, as well as oxygen uptake efficiency slope and ventilatory efficiency. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V ' O 2 . These findings underscore the importance of lung function and blood vessel volume as contributors to overall exercise capacity., Competing Interests: Conflict of interest: J. McNeill has nothing to disclose. Conflict of interest: A. Chernofsky has nothing to disclose. Conflict of interest: M. Nayor reports grants from the NIH, during the conduct of the study. Conflict of interest: F.N. Rahaghi has nothing to disclose. Conflict of interest: R. San Jose Estepar has contracts with Lung Biotechnology, Insmed and Boehringer Ingelheim, receives consulting fees from Leuko Labs, and has stock options in Quantitative Imaging Solutions. Conflict of interest: G. Washko reports grants from the NIH, DoD, Boehringer Ingelheim, Janssen Pharmaceuticals, BTG Therapeutics, Pulmonx, Lung Biotechnology and Insmed; participation in advisory boards and consultancies for Boehringer Ingelheim, CSL Behring, Novartis, Phillips and Vertex Pharmaceuticals; is a co-founder and equity shareholder in Quantitative Imaging Solutions, a company that provides consulting services for image and data analytics; finally, the author's spouse works for Biogen. Conflict of interest: A. Synn reports grants from the American Lung Association and NHLBI, outside the submitted work. Conflict of interest: R.S. Vasan has nothing to disclose. Conflict of interest: G. O'Connor has nothing to disclose. Conflict of interest: M.G. Larson has nothing to disclose. Conflict of interest: J.E. Ho reports grants from the NIH/NHLBI, during the conduct of the study; research support from Gilead Sciences and Bayer AG, and research supplies from EcoNugenics, outside the submitted work. Conflict of interest: G.D. Lewis reports grants from Amgen, Cytokinetics, AstraZeneca, Applied Therapeutics and Sonivie, personal fees and other for advisory board work from American Regent, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Body composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined., Research Question: Is the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?, Study Design and Methods: Participants with complete data for at least one visit in the COPDGene study (n = 9,268) and the ECLIPSE study (n = 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation., Results: Both cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm 2 PMA loss, mortality increased 3.1% (95% CI, 2.4%-3.7%; P < .001) in COPDGene, and 2.4% (95% CI, 0.9%-4.0%; P < .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA., Interpretation: Longitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Background: Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV 1 and FVC, is a heterogeneous population with frequent transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (eg, whether transitions merely reflect measurement variability or noise)., Research Question: Are individuals with PRISm enriched for transitions associated with substantial changes in lung function?, Study Design and Methods: Current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV 1  < 80% predicted with FEV 1 /FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV 1  ≥ 80% predicted and FEV 1 /FVC ≥ 0.7), and obstruction (FEV 1 /FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV 1 % predicted and/or FVC % predicted between consecutive visits. Ever-PRISm was present if a subject had PRISm at any visit. Logistic regression examined the association between significant transitions and ever-PRISm status, adjusted for age, sex, race, FEV 1 % predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response., Results: Among subjects with complete data (N = 1,775) over 10.1 ± 0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted OR, 14.9; 95% CI, 10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV 1 alone (regardless of change in FVC % predicted) was used to define significant transitions., Interpretation: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT000608764; URL: www., Clinicaltrials: gov., (Published by Elsevier Inc.)