Predictors of Progression in Pre-COPD: The 3P Study Rationale and Design

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Concerns about PRISm

Spirometric Transition of at Risk Individuals and Risks for Progression to Chronic Obstructive Pulmonary Disease in General Population

Background: Preserved ratio impaired spirometry (PRISm) is defined as a FEV₁ of less than 80% predicted and a FEV₁/forced vital capacity (FVC) ratio of 0·70 or higher. Previous research has indicated that PRISm is associated with respiratory symptoms and is a precursor of chronic obstructive pulmonary disease (COPD). However, these findings are based on relatively small selective cohorts with short follow-up. We aimed to determine the prevalence, risk factors, clinical implications, and mortality of PRISm in a large adult general population. Methods: For this cohort analysis, we used data from the UKBiobank to assess PRISm prevalence, risk factors and associated symptoms, and associated comorbidities in a large adult population. Participants with spirometry deemed acceptable by an investigator (best measure FEV₁ and FVC values) at baseline were included. Participants were excluded if they did not have acceptable spirometry or were missing data on body-mass index or smoking status. Control spirometry was defined as a FEV₁ of 80% or more predicted and a FEV₁/FVC ratio of 0·70 or higher. Airflow obstruction was defined as a FEV₁/FVC ratio of less than 0·70. We used multivariable regression to determine risk factors for PRISm and associated comorbidities. Individuals who lived within close proximity to an assessment centre were invited for follow-up, with repeat spirometry. Only participants who had been included at baseline were examined in follow-up. This allowed for a longitudinal analysis of PRISm over time and risk factors for transition to airflow obstruction. We also did the survival analysis for a 12-year period. Findings: Participants were recruited by UK Biobank between Dec 19, 2006, and Oct 10, 2010. We included 351 874 UK Biobank participants (189 247 women and 162 627 men) in our study, with a median follow-up of 9·0 years (IQR 8·0–10·0). 38 639 (11·0%) of 351 874 participants had PRISm at baseline. After adjustment, PRISm was strongly associated with obesity (odds ratio [OR] 2·40 [2·26–2·55], p < 0·0001), current smoking (1·48 [1·36–1·62], p < 0·0001), and patient reported doctor-diagnosed asthma (1·76 [1·66–1·88], p < 0·0001). Other risk factors identified included female sex, being overweight, trunk fat mass, and trunk fat percentage. PRISm was strongly associated with symptoms and comorbidity including increased risk of breathlessness (adjusted OR 2·0 [95% CI 1·91–2·14], p < 0·0001) and cardiovascular disease (adjusted OR 1·71 [1·64–1·83], p < 0·0001 for heart attack). Longitudinal analysis showed that 241 (12·2%) of 1973 participants who had PRISm at baseline had transitioned to airflow obstruction consistent with COPD. PRISm was associated with increased all-cause mortality (adjusted hazard ratio 1·61 [95% CI 1·53–1·69], p < 0·0001) versus control participants. Interpretation: PRISm was associated with breathlessness, multimorbidity, and increased risk of death, which does not seem to be explained by smoking, obesity, or existing lung disease. Although for many patients PRISm is transient, it is important to understand which individuals are at risk of progressive lung function abnormalities. Further research into the genetic, structural and functional pathophysiology of PRISm is warranted. Funding: UK Medical Research Council and University of Bristol.

Trajectory and mortality of preserved ratio impaired spirometry: the Rotterdam Study.

Prevalence, risk factors, and clinical implications of preserved ratio impaired spirometry: a UK Biobank cohort analysis

BackgroundPersistent chronic airway inflammation and progressive airflow limitation are typical features of chronic obstructive pulmonary disease (COPD). Emerging evidence indicates that small airway dysfunction (SAD) plays a critical role in driving the sustained pathological progression of COPD. Preserved ratio impaired spirometry (PRISm) represents a spirometric pattern characterized by a reduced forced expiratory volume in 1 second (FEV₁) despite a preserved ratio. Current evidence inadequately elucidates the pathophysiological role of SAD and its intricate interplay with PRISm and COPD progression. On the other hand, impulse oscillometry (IOS) can be used as a complementary tool to spirometry to detect SAD. Detection of SAD in patients with chronic respiratory symptoms could help in the diagnosis of PRISm and COPD when spirometry is not achievable.ObjectiveTo investigate the diagnostic value of IOS for identifying SAD in patients with chronic respiratory symptoms, PRISm and COPD.MethodsBetween September 2021 and July 2023, 552 symptomatic patients without known structural lung disease who underwent both spirometry and IOS on the same day in the outpatient clinic were evaluated. The correlations between spirometry and the IOS parameters, and the ROC curves of the IOS parameters for SAD patients and COPD patients were analyzed.ResultsAmong the 552 patients included in the study, 96 patients had COPD, 39 patients had PRISm, and 417 patients had chronic cough. Among 456 chronic cough patients with preserved ratio spirometry, the incidence of PRISm was 8.55%. Based on spirometry-defined SAD, the incidence of SAD in the PRISm population was 71.8%, which was significantly higher than the 9.35% of the non-PRISm population. With increasing COPD GOLD stage, the IOS parameters R5-R20, R5, Fres, and Ax increased, whereas the traditional lung function parameters and X5 decreased. R5-R20, X5, Fres, and AX of COPD GOLD stage 1 patients were not substantially different from those of PRISm patients. In PRISm patients, R5-R20, R5 and Fres were strongly correlated with FEF25%-75%. R5-R20, R5, X5, Fres and AX were significantly associated with FEV1, FEV1/FVC, FEV1% predicted, FEF50%, FEF75% and FEF25%-75% in COPD patients. Through ROC curve analysis, the cutoffs for identifying SAD in patients with chronic respiratory symptoms and PRISm patients were obtained, with R5-R20 values of 0.075 and 0.105 kPa/L/s, respectively. The values of R5 were 0.365 and 0.375 kPa/L/s, respectively. The Fres values are 16.31 Hz and 17.11 Hz, respectively. The cutoff for detecting COPD in all patients was 0.485 kPa/L/s for R5, 0.125 kPa/L/s for R5-R20, -0.155 kPa/L/s for X5, and 17.98 Hz for Fres. Fres had the highest AUC value for both SAD and COPD detection, and it detected COPD the most in all patients, with a prevalence of 24.1%. R5 detected SAD the most in patients with chronic respiratory symptoms, with a prevalence of 47.5%. With a prevalence of 71.8%, spirometry identified SAD in patients with PRISm the most frequently.ConclusionAlmost all IOS parameters Linked to the small airways were significantly different in the PRISm population compared with patients with chronic respiratory symptoms. SAD severity in PRISm patients is similar to that in GOLD stage 2 COPD patients. The IOS can assess the disease severity of COPD.

Pulmonary diseases, especially pneumonia, have been among the most frequent complications of HIV since early in the AIDS epidemic [1–3]. In parallel with other complications of HIV, the spectrum of pulmonary diseases currently reflects a substantial burden of non-AIDS-defining chronic diseases as HIV-infected patients are aging on antiretroviral therapy (ART) [4–9]. A leading cause of global mortality [10,11], chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease diagnosed in HIV-infected patients, encountered in approximately 20% of patients in different cohorts [4,6,8,9,12]. However, our understanding of the impact of chronic HIV infection on lung health over time remains incomplete. Does HIV cause a unique impairment in lung health, or is HIV a 'second hit' to accelerate the toxic effects of other exposures such as cigarette smoking to cause typical diseases like COPD? Or, is the increased burden of lung diseases in HIV merely explained by a greater prevalence of smoking, drug use, respiratory infections, and other exposures that are common in many HIV-infected populations? To date, whether HIV infection is an independent risk factor for chronic lung diseases, particularly COPD, remains uncertain. Cross-sectional studies in HIV-infected and uninfected persons comparing the prevalence of COPD, defined by the presence of fixed airflow obstruction on spirometry, have had somewhat conflicting results [6,8]. Disentangling the effects of numerous behavioral, environmental, and occupational exposures, and the contribution of comorbid conditions from those of HIV infection on lung health is challenging, particularly in cross-sectional analyses. The current work by Drummond et al. [13] in this month's issue of AIDS expands our knowledge of the effects of HIV infection on lung health with one of the first longitudinal studies of lung function decline in HIV-infected compared to demographically and behaviorally similar HIV-uninfected persons in the combination ART era. They examined the effect of HIV infection, specifically HIV viral load and CD4 cell count, on lung function decline in a cohort of injection drug users, the AIDS Linked to the IntraVenous Experience (ALIVE) study. Several findings from the study will be important both to clinicians caring for HIV-infected patients and to researchers trying to understand the causes of HIV-associated lung disease. First, absolute values of airflow, namely, the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC), were significantly lower in HIV-infected compared with uninfected participants in analyses adjusted for demographic, behavioral, and clinical factors; whether this is because of a prior period of accelerated decline in lung function such as from earlier episodes of pneumonia, or due to a lower attainment of overall lung function such as from earlier initiation of smoking or childhood illness, or for other reasons, is not known. Second, the rate of decline in lung function, as measured by the change in FEV1 and the FVC, was similar in HIV-infected and uninfected drug users overall. The decrease in FEV1 was nonsignificantly higher, and the decrease in FVC was greater, but of borderline significance in HIV-infected individuals (P = 0.05). Given the nearly universal smoking history and high rate of current drug use, the decrements in lung function over time are overall surprisingly small. There may have also been differences in prescription of bronchodilators that had an unmeasured effect on the results, and bronchodilator testing was not administered during spirometry. The most intriguing finding is that despite the lack of difference in lung function decline in the overall HIV-infected population compared to HIV-uninfected, when stratified by HIV disease severity, a higher HIV viral load (defined as >75 000 copies/ml) and a lower CD4 cell count (considering absolute values as well as CD4%) were associated with a greater rate of decline in both FEV1 and FVC over time. HIV-infected participants with CD4 cell counts of 200 cells/μl and below were significantly more likely to have a greater decline in FEV1 and FVC over time compared to HIV-uninfected individuals. In contrast, decline in lung function was similar in HIV-infected persons with CD4 cell count above 200 cells/μl and those without HIV. These data raise the possibility that ART and better control of HIV may ameliorate the decline in lung function in HIV, although previous studies have found an association of ART with worse airway obstruction [9,14] and time-updated ART use was not significantly associated with change in lung function in the current analyses. Residual confounding in human studies always remains as a potential explanation for these findings. However, Drummond et al. assessed other risk factors in a rigorous fashion and utilized time-updated covariates to account for factors such as current smoking status, recent HIV disease severity, and intercurrent respiratory infection [13]. In particular, increased risk for pneumonia in patients with poorly controlled HIV could certainly mediate rate of decline in lung function. Notably, the incidence of pneumonia was low, especially in those with CD4 cell counts below 100. However, assuming that capture of pneumonia events was complete, these data support that the association of HIV viremia and/or immunodeficiency with greater lung function decline is independent of pneumonia and other major confounders. These findings raise a number of intriguing questions. Why is uncontrolled HIV disease associated with a greater risk of decline in lung function? Is the association with higher HIV viral load due to effects of the virus itself, accompanying inflammation, and/or immune activation? Does poorly controlled HIV increase the risk for colonization with microorganisms that may play a role in COPD pathogenesis (such as with Pneumocystis[15])? Furthermore, is the effect of HIV viremia or immunodeficiency more important, and is there an independent effect of ART initiation? In analyses grouped by combined CD4 and viral load levels, decline in FEV1 appeared more strongly associated with HIV RNA greater than 75 000 copies/ml, whereas decline in FVC appeared more strongly associated with CD4 cell counts below 100 cells/μl. Taken together, these data suggest that HIV viremia and immunodeficiency may contribute to different lung diseases. Although the predominant effect seems to be an increase in airflow obstruction over time, not all disease in HIV-infected individuals may represent COPD. Additional studies are needed with evaluation of full pulmonary function inclusive of bronchodilator testing, lung volumes, and diffusing capacity paired with chest computed tomography scans to better understand the physiology and disease processes driving the decrease in airflow (i.e., FEV1, FVC). Furthermore, whether similar declines in FEV1 and FVC will be seen in HIV-infected cohorts with a lower prevalence of injection drug use requires investigation. A final important finding of this study to highlight is the documented increase in individuals with airflow obstruction in the cohort over time. At baseline, 16% of the cohort met spirometric criteria for airflow obstruction (defined as an FEV1/FVC<70%). During follow-up, the proportion of individuals with airflow obstruction increased to 23% at last visit. Although markers of HIV disease control were associated with more rapid decline in FEV1 and FVC, the magnitude of decrement in FEV1 decline was greater. Overall, these data confirm that the burden of chronic lung disease, particularly obstructive disease, in HIV-infected populations is increasing over time. What are the implications for clinical care? The management of chronic lung diseases such as COPD in HIV-infected populations has not been well defined as there have been no large-scale trials of COPD therapies in HIV-infected individuals. COPD is a major cause of morbidity in HIV-infected patients: it is a strong risk factor for hospitalization [16], a leading cause of respiratory failure in critically ill HIV-infected patients [17], and is associated with significantly worse health-related quality of life [18]. Whether current guidelines for management of COPD and other chronic lung diseases in HIV-uninfected patients can be applied to those with HIV infection is uncertain and requires further study. Two conclusions, however, are clear: given that approximately 40–50% of HIV-infected patients smoke compared to 20% in the general population [19], smoking-related comorbidities with a long latency of onset such as COPD will become increasingly common as HIV-infected patients are aging; and increased efforts to improve smoking cessation in HIV-infected populations are urgently needed. The study by Drummond et al. [13] underscores the importance of COPD in HIV and the need for increased awareness and understanding of obstructive lung diseases in this population. Acknowledgements Conflicts of interest There are no conflicts of interest.

Background CT is used to quantify abnormal changes in the lung parenchyma of smokers that might overlap chronic obstructive pulmonary disease (COPD), but studies on the progression of expiratory air trapping in smokers are scarce. Purpose To evaluate the relationship between longitudinal changes in forced expiratory volume in 1 second (FEV1) and CT-quantified emphysema and air trapping in smokers. Materials and Methods Cigarette smokers with and those without COPD participating in the multicenter observational COPDGene study were evaluated. Subjects underwent inspiratory and expiratory chest CT and spirometry at baseline and 5-year follow-up. Emphysema was quantified by using adjusted lung density (ALD). Air trapping was quantified by using mean lung density at expiratory CT and CT-measured functional residual capacity-to-total lung volume ratio. Linear models were used to regress quantitative CT measurements taken 5 years apart, and models were fit with and without adding FEV1 as a predictor. Analyses were stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (GOLD 0, no COPD; GOLD 1, mild COPD; GOLD 2, moderate COPD; GOLD 3, severe COPD; GOLD 4, very severe COPD). Subjects with preserved FEV1-to-forced vital capacity ratio and reduced FEV1 percentage predicted were categorized as having preserved ratio impaired spirometry (PRISm). Results A total of 4211 subjects (503 with PRISm; 2034 with GOLD 0, 388 with GOLD 1, 816 with GOLD 2, 381 with GOLD 3, 89 with GOLD 4) were evaluated. ALD decreased by 1.7 g/L (95% confidence interval [CI]: -2.5, -0.9) in subjects with GOLD 0 at baseline and by 5.3 g/L (95% CI: -6.2, -4.4) in those with GOLD 1-4 (P < .001 for both). When adjusted for changes in FEV1, corresponding numbers were -2.2 (95% CI: -3.0, -1.3) and -4.6 g/L (95% CI: -5.6, -3.4) (P < .001 for both). Progression in air trapping was identified only in GOLD stage 2-4. Approximately 33%-50% of changes in air trapping in GOLD stages 2-4 were accounted for by changes in FEV1. Conclusion CT measures of emphysema and air trapping increased over 5 years in smokers. Forced expiratory volume in one second accounted for less than 10% of emphysema progression and less than 50% of air trapping progression detected at CT. © RSNA, 2020 Online supplemental material is available for this article.

In the general population, chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) have been shown to increase mortality risk. While increased respiratory disease risk has been observed in type 1 diabetes (T1D), data on PRISm and COPD, especially in middle-age, are scarce in T1D. We thus assessed correlates of COPD and PRISm among individuals with childhood-onset T1D. Data were from the 30-year visit of the EDC study (n=162, median age/T1D duration, 56/47 years). Pulmonary function was assessed with the NDD EasyOne™ Spirometer using NHANES reference values for the predicted values. COPD was defined as Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity (FVC)<0.7. PRISm was defined as FEV1% predicted<80% and FEV1/FVC≥0.7. The majority of participants were classified as having COPD (43.2%) or PRISm (25.9%), with only 30.9% having normal pulmonary function. Univariate differences by pulmonary disease status are shown in the Table. Multinomial logistic regression models were constructed to assess independent correlates of COPD and PRISm. High ABI (>1.3) was associated with greater odds of COPD (OR=4.64, 95% CI: 1.42-15.13, p=0.01) and BMI with PRISm (OR=1.10, 95% CI: 1.01-1.21, p=0.03). No other risk factor was associated with COPD or PRISm.In conclusion, high ABI and BMI appear to be independently associated with greater odds of COPD and PRISm, respectively, in T1D.View largeDownload slideView largeDownload slide DisclosureJ. Ju: None. G. L. Kinney: None. R. G. Miller: None. T. J. Orchard: None. T. Costacou: None.FundingNational Institutes of Health (DK34818)

RATIONALE: Preserved Ratio Impaired Spirometry (PRISm) is a heterogeneous condition linked to increased respiratory symptoms and elevated all-cause mortality. PRISm is characterized by a preserved FEV1/FVC ratio (≥70%) alongside a reduced FEV1 (&amp;lt;80% predicted), and its course is unstable, with some individuals reverting to normal lung function while others progress to chronic obstructive pulmonary disease (COPD). The long-term trajectory over decades and impact of PRISm have not been thoroughly assessed in the UK. Using data from a birth cohort study, we evaluated PRISm trajectories in ever-smokers over two decades and investigated its association with mortality. METHODS: We conducted a cohort analysis using data from the Medical Research Council National Survey of Health &amp; Development, a birth cohort initiated in 1946. Participants underwent regular clinical assessments, including pulmonary function tests (PFTs) at ages 43, 53, and 63. Associations with mortality were assessed using multivariable Cox proportional hazards models, adjusted for sex, smoking history (pack years), asthma diagnosis, and severity of airflow obstruction (classified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria). Mortality data were obtained through linked national death registries as of May 2024. RESULTS: 2,238 ever-smokers underwent PFTs at age 43 (47% female): 75% had normal spirometry, 16% had PRISm, and 9% exhibited COPD. At age 53, 1,877 ever-smokers were tested (48% female): 72% had normal spirometry, 18% had PRISm, and 10% had COPD. PRISm at age 43 was associated with increased all-cause mortality (Hazard Ratio (HR) = 1.31, 95%CI = 1.04-1.6, p = 0.020) and respiratory-specific mortality (HR = 2.5, 95%CI = 1.32-4.7, p = 0.005). PRISm at age 53 also predicted higher all-cause mortality (HR = 1.45, 95%CI = 1.11-1.89, p = 0.006). PRISm was unstable over time; of 196 participants with PRISm at age 43 who underwent repeat testing at ages 53 and 63, PRISm persisted in 72 (37%) at age 53, while 18 (9%) progressed to COPD and 106 (54%) reverted to normal spirometry. By age 63, of the 72 with persistent PRISm at age 53, 56 (78%) remained in the PRISm group, 5 (7%) developed COPD, and 11 (15%) reverted to normal spirometry. CONCLUSIONS: PRISm is an unstable condition over time, with a significant proportion of individuals reverting to normal lung function over a 10-20 year period. However, PRISm is linked to increased mortality as early as 43 years of age, highlighting its prognostic importance in high-risk populations.

BackgroundAirway obstruction is a characteristic spirometric finding in asthma but the clinical significance of other abnormal spirometric patterns is less well described. We aimed to explore pre- and post-bronchodilator (BD) prevalences and clinical characteristics of preserved ratio impaired spirometry (PRISm), dysanapsis and airflow obstruction with low forced expiratory volume in 1 s (FEV1) in children diagnosed with asthma.MethodsWe extracted specialist care data (clinical and spirometry) from the Swedish National Airway Register (n=3301, age 5–17 years). Normal spirometry was defined as FEV1≥ lower limit of normal (LLN) and FEV1/forced vital capacity (FVC)≥LLN. PRISm was defined as forced FEV1< LLN and FEV1/FVC≥LLN, dysanapsis as FEV1/FVC<LLN and FEV1≥LLN, and airflow obstruction with reduced FEV1 as FEV1/FVC<LLN and FEV1<LLN. The BD response (BDR) was calculated as ((post-BD(L)−pre-BD(L))/predicted (L))×100. Values >10% were considered positive (BDRpos). Groups were compared using parametric tests and associations were explored using logistic regression analysis.ResultsPre-/post-BD PRISm, dysanapsis and obstruction with low FEV1 were identified in 9%/7%, 10%/4% and 8%/2%, respectively. Compared with normal spirometry, all three groups were associated with older age and BDRpos in pre-BD analyses. Furthermore, dysanapsis was associated with overweight/obesity and obstruction with low FEV1 with uncontrolled asthma and more treatment.InterpretationIn this paediatric asthma cohort, PRISm and dysanapsis were associated with BDRpos and they were at least as common as airflow obstruction with reduced FEV1. These spirometric phenotypes should be addressed in the management of childhood asthma and testing of BDR should be considered also in children with PRISm and dysanapsis.

Preserved ratio impaired spirometry (PRISm), defined as a forced expiratory volume in 1s (FEV1) to forced vital capacity (FVC) ratio ≥0.70 and a predicted FEV1 <80%, is associated with increased morbidity and mortality. However, determinants of PRISm, particularly in younger populations, remain poorly characterised. We aimed to address this knowledge gap. We conducted a cross-sectional analysis of 12,350 participants from a Japanese community-based cohort using data from the Tohoku Medical Megabank Project. Participants underwent spirometry, blood pressure measurement, laboratory testing, and completed standardised questionnaires. Multivariate logistic regression was used to identify factors associated with PRISm across three age groups: 20-39, 40-59, and ≥60 years. Interactions between age groups and other explanatory variables were assessed. In the 20-39-year group, PRISm was independently associated with being men, diabetes mellitus, hypothyroidism, and low body mass index (BMI <18.5kg/m2), and inversely associated with age. Among participants aged ≥60 years, PRISm was significantly associated with increasing age, overweight status (BMI ≥25.0-<30.0kg/m2), being men, current smoking, hypertension, diabetes mellitus, bronchial asthma, elevated eosinophil counts (≥300cells/μL), and birth weight ≥2000-<2500g. Significant interactions were observed between age and BMI, bronchial asthma, and thyroid dysfunction. Our findings indicate that PRISm in younger adults is associated with hypothyroidism and underweight status, whereas in older adults, it is more closely related to constitutional and lifestyle-related factors. These results highlight the heterogeneity of PRISm and indicate that its pathophysiology and optimal management may vary by age group.

Rationale: Preserved Ratio Impaired Spirometry (PRISm) is a condition defined by an FEV1 &amp;lt; 80% predicted and FEV1/FVC ratio ≥ 0.7. While specific driver mutations, such as EGFR and ALK1,2, are well-documented in lung adenocarcinoma patients with chronic obstructive pulmonary disease (COPD), the mutation profile in PRISm patients remains underexplored in current medical literature. This study aimed to investigate the distribution and clinical implications of driver mutations in lung adenocarcinoma patients across different lung function groups, including PRISm, COPD, and normal lung function. Methods: A retrospective analysis was conducted of 147 adenocarcinoma patients treated in the Mount Sinai Health System from January 2018 to May 2024. Patients were categorized by lung function (normal, COPD, PRISm). We compared the prevalence of driver mutations (ALK, BRAF, EGFR, HER2, MET, KRAS, NRAS, PIK3C, RET, ROS1, TP53), emphysema, PD-L1 levels, ECOG performance, cancer stage, and metastases in patients with normal lung function, PRISm and COPD. Statistical analyses used Kruskal-Wallis and Chi-Square tests, with significance at p &amp;lt; 0.05. Results: COPD patients had a significantly higher prevalence of emphysema (p = 0.0005) and lower ECOG scores, indicating poorer functional status compared to PRISm and normal groups (p = 0.015). Cancer stages III and IV were more common in PRISm and COPD groups than in the normal group (p = 0.023). PRISm patients had a significantly higher metastatic burden (p = 0.036). PD-L1 expression was not statistically significant across groups, and no significant differences were found for driver mutations between patients with normal lung function, PRISm and COPD. Discussion: The findings reveal distinct profiles for lung adenocarcinoma patients based on lung function. PRISm and COPD patients had higher metastatic burden and more advanced cancer stages than patients with normal lung function, suggesting a more aggressive disease course. Higher emphysema prevalence and lower ECOG scores in COPD demonstrate how COPD phenotype can affect functional status. Although driver mutations did not vary significantly between patients with normal lung function, PRISm and COPD, lung function stratification may be valuable in guiding treatment. Conclusion: PRISm and COPD adenocarcinoma patients have a more aggressive disease profile compared to those with normal lung function, marked by greater metastatic burden and advanced stage of lung cancer. Lung cancer screening should be therefore emphasized in PRISm patients who meet lung canceer screening eligibility. Increased emphysema prevalence in lung cancer and its effect on ECOG performance may effect patient outcomes.

Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric chronic obstructive pulmonary disease (COPD) and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. To establish how lung volumes change with the development of spirometric COPD, we examined lung volumes from the pulmonary function data (seated posture) available in the U.S. Department of Veterans Affairs electronic health records (n=71,356) and lung volumes measured by computed tomography (supine posture) available from the COPD Genetic Epidemiology (COPDGene®) study (n=7969) and the SubPopulations and InterMediate Outcome Measures In COPD Study (SPIROMICS) (n=2552) cohorts, and studied their cross-sectional distributions and longitudinal changes across the airflow obstruction spectrum. Patients with preserved ratio-impaired spirometry (PRISm) were excluded from this analysis. Lung volumes from all 3 cohorts showed similar patterns of distributions and longitudinal changes with worsening airflow obstruction. The distributions for total lung capacity (TLC), vital capacity (VC), and inspiratory capacity (IC) and their patterns of change were nonlinear and included different phases. When stratified by airflow obstruction using Global initiative for chronic Obstructive Lung Disease (GOLD) stages, patients with GOLD 1 (mild) COPD had larger lung volumes (TLC, VC, IC) compared to patients with GOLD 0 (smokers with preserved spirometry) or GOLD 2 (moderate) disease. In longitudinal follow-up of baseline GOLD 0 patients who progressed to spirometric COPD, those with an initially higher TLC and VC developed mild obstruction (GOLD 1) while those with an initially lower TLC and VC developed moderate obstruction (GOLD 2). In COPD, TLC, and VC have biphasic distributions, change in nonlinear fashions as obstruction worsens, and could differentiate those GOLD 0 patients at risk for more rapid spirometric disease progression.