BACKGROUNDAsthma, chronic obstructive pulmonary disease (COPD) and chronic cough (CC) significantly burden the Canadian healthcare system. Despite therapeutic advances, many patients remain symptomatic, and symptom-based management strategies have modest effects. Airway mucus may contribute to disease severity and outcomes; however, its role remains underexplored.OBJECTIVEThe primary objective of the Canadian Consortium (CanMuc) is to measure airway mucus, rheology and inflammation and uncover relationships of the imaging and physico-biological characteristics of airway occlusions in asthma, COPD and CC compared with healthy controls. Secondary objectives include assessing biomarkers leading to persistent mucus.METHODSIn this 24-month, longitudinal, multi-center, observational study, 240 participants with pulmonary disease (100 moderate-to-severe asthma, 80 COPD, 60 CC) and 100 healthy volunteers (>= 18 years) will be recruited across 6 Canadian tertiary-care sites. Participants will undergo chest CT, blood and sputum collection, rheology, spirometry, oscillometry, cough monitoring, validated respiratory questionnaires and cough severity assessments. At 3 sites hyperpolarized 129Xe MRI will be performed. Quarterly telemonitoring will document exacerbations, hospitalizations, and symptoms or treatment changes. CT mucus burden (score, count, volume, radiodensity), mucus rheology (viscosity, elasticity, viscoelasticity) and inflammatory pathways will be analyzed. Participants will be classified into 4 phenotypes at end-of-study: mucus-free, persistent, resolved and new-onset. Secondary outcomes include evaluating clinical, physiological and molecular markers predicting airway mucus occlusions.CONCLUSIONSThe CanMuc study will evaluate the contribution of airway mucus occlusions to the severity and worsening of chronic airways diseases using imaging, immunologic, molecular and rheological characterization. Findings will provide multi-center evidence and validate airway occlusions as a potential treatable trait. CONTEXTEL'asthme, la maladie pulmonaire obstructive chronique (MPOC) et la toux chronique repr & eacute;sentent un fardeau consid & eacute;rable pour le syst & egrave;me de sant & eacute; canadien. Malgr & eacute; les progr & egrave;s th & eacute;rapeutiques, de nombreux patients restent symptomatiques et les strat & eacute;gies de prise en charge ax & eacute;es sur les sympt & ocirc;mes ont des effets modestes. Le mucus des voies respiratoires peut contribuer & agrave; la gravit & eacute; et aux issues de la maladie; toutefois, son r & ocirc;le reste sous-explor & eacute;.OBJECTIFL'objectif principal du Consortium canadien (CanMuc) est de mesurer le mucus des voies respiratoires, la rh & eacute;ologie et l'inflammation. Il vise & eacute;galement & agrave; mettre en & eacute;vidence les relations entre l'imagerie et les caract & eacute;ristiques physico-biologiques des occlusions des voies respiratoires chez les patients atteints d'asthme, de MPOC et de toux chronique, comparativement & agrave; des t & eacute;moins sains. Les objectifs secondaires comprennent l'& eacute;valuation des biomarqueurs conduisant & agrave; un mucus persistant.M & Eacute;THODESDans cette & eacute;tude observationnelle longitudinale multicentrique de 24 mois, 240 participants atteints d'une maladie pulmonaire (100 atteints d'asthme mod & eacute;r & eacute; & agrave; s & eacute;v & egrave;re, 80 atteints de MPOC et 60 atteints de toux chronique) ainsi que 100 volontaires en bonne sant & eacute; (>= 18 ans) seront recrut & eacute;s dans six centres de soins tertiaires canadiens. Les participants subiront une tomodensitom & eacute;trie thoracique, des pr & eacute;l & egrave;vements de sang et d'expectorations, une analyse rh & eacute;ologique, une spirom & eacute;trie, une oscillom & eacute;trie, une surveillance de la toux, des questionnaires respiratoires valid & eacute;s et des & eacute;valuations de la gravit & eacute; de la toux. Une IRM 129Xe hyperpolaris & eacute;e sera r & eacute;alis & eacute;e sur trois sites. Les exacerbations, les hospitalisations et les sympt & ocirc;mes, de m & ecirc;me que les changements de traitement, seront document & eacute;s par un t & eacute;l & eacute;suivi trimestriel. La charge de mucus & agrave; la tomodensitom & eacute;trie (score, num & eacute;ration, volume, radiodensit & eacute;), la rh & eacute;ologie du mucus (viscosit & eacute;, & eacute;lasticit & eacute;, visco & eacute;lasticit & eacute;) et les voies inflammatoires seront analys & eacute;es. Les participants seront class & eacute;s en quatre ph & eacute;notypes & agrave; la fin de l'& eacute;tude : sans mucus, mucus persistant, mucus r & eacute;solu et mucus nouveau. Les r & eacute;sultats secondaires comprennent l'& eacute;valuation des marqueurs cliniques, physiologiques et mol & eacute;culaires pr & eacute;disant les occlusions des voies respiratoires par le mucus.CONCLUSIONS & Agrave; l'aide de l'imagerie et de la caract & eacute;risation immunologique, mol & eacute;culaire et rh & eacute;ologique, l'& eacute;tude CanMuc & eacute;valuera la contribution des occlusions des voies respiratoires par le mucus & agrave; la gravit & eacute; et & agrave; l'aggravation des maladies chroniques des voies respiratoires. Les r & eacute;sultats fourniront des donn & eacute;es probantes multicentriques et valideront les occlusions des voies respiratoires comme trait potentiellement traitable.

Abstract Background Lung cancer resection is curative but associated with postoperative morbidity and mortality. This study evaluated whether elevated blood eosinophil count (BEC) was associated with postoperative outcomes in early-stage lung cancer. Methods This was a retrospective cohort study of consecutive adult patients undergoing lung resection for stage I and II non-small cell lung cancer in a large tertiary referral center from September 2017 to June 2021. Data were drawn from the institution’s Data Warehouse. The primary outcome was 90-day healthcare utilization defined as emergency department visit or hospital readmission. Secondary outcomes were postoperative complications, index hospitalization length of stay, and 1-year survival. Preoperative 90-day BEC was categorized by a threshold of 200 cells/µL. Covariates were age, sex, smoking status, Charlson Comorbidity Index, chronic obstructive pulmonary disease (COPD), asthma, tumor size, nodal status, surgical approach, and blood results (white blood cells, hemoglobin, and creatinine). The main analyses were validated by a second international cohort. Log-Poisson with robust variance estimation and Cox proportional hazards regression models were fit for primary and secondary outcomes. Analyses were replicated for BEC thresholds of 150 and 300 cells/µL. Results Among 715 patients undergoing lung resection (median age = 69 years, 42% male, 29% with COPD), 146 patients (20%) had high preoperative BEC ≥ 200 cells/µL. BEC ≥ 200 cells/µL was associated with a higher rate of 90-day healthcare utilization:19% vs. 14% for BEC < 200 cells/µL. This association remained after adjustment (Risk Ratio [RR], 1.52; 95% Confidence Interval [CI], 1.02–2.25) and the validation cohort (RR, 2.23; 95% CI, 1.06–4.69). BEC as a continuous measure was also associated with the primary outcome in both cohorts: RR, 2.15 (95% CI, 1.49–3.12) and RR, 1.42 (95% CI, 1.10–1.94), respectively. BEC ≥ 200 cells/µL was associated with higher probability of death 1 year post-surgery (adjusted Hazard Ratio, 2.41; 95% CI, 1.08–5.35). There was no difference in the risk of postoperative pulmonary complications between high and low BEC (RR, 0.86; 95% CI, 0.58–1.27). Conclusions Elevated preoperative BEC was associated with higher risk of postoperative healthcare utilization and lower 1-year survival after lung cancer resection among patients with or without respiratory disease.

BACKGROUND:CT imaging with machine learning can predict incident and prevalent COPD; however, it is unknown if sex-specific models improve performance. RESEARCH QUESTION:Do sex-specific machine learning models using CT imaging-derived disease features improve prediction of incident and prevalent COPD and identify sex-specific predictors? STUDY DESIGN AND METHODS:Canadian Cohort Obstructive Lung Disease (CanCOLD) study participants underwent baseline CT imaging and spirometry at baseline and follow-up. Models predicted incident and prevalent COPD using demographics and CT imaging features (lung density, texture, and shape and airway shape) for the combined-sex, male-only, and female-only data sets and externally tested in the Subpopulations and Intermediate Outcome Measures in COPD (SPIROMICS) study. Performance was evaluated using area under the receiver operating characteristic curve (AUC). RESULTS:The study included 1,283 participants from the CanCOLD study and 1,840 participants from the SPIROMICS study. For incident COPD, the female-only model outperformed the male-only and combined-sex models in internal tests (AUC, 0.86 vs 0.76 and 0.78; P < .05) and external tests (AUC, 0.83 vs 0.71 and 0.77; P < .05). For prevalent COPD, the female-only model again outperformed the male-only and combined-sex models in internal tests (AUC, 0.84 vs 0.78 and 0.78; P < .01) and external tests (AUC, 0.84 vs 0.70 and 0.73; P < .05). Female-only models selected parenchymal texture and lung shape features not selected in combined-sex models, whereas male-only models selected airway-based features. INTERPRETATION:Our results show that sex-specific models outperform combined-sex models for identifying those with and at risk of COPD, particularly in female patients, by capturing different disease-relevant features. These findings highlight that combined-sex models can obscure sex-specific biology, and adopting sex-specific prediction strategies may improve early detection and risk stratification and may allow for treatment targeting.

Background It is unknown whether subclinical emphysema-like changes, quantified at chest CT, are associated with loss of bone mineral density (BMD) in individuals without clinical chronic obstructive pulmonary disease (COPD). Purpose To identify early imaging markers of lung and bone health using deep learning-based imaging analysis in a large multiethnic cohort. Materials and Methods Chest CT scans obtained using the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) protocol during examination 5 and 6 of the prospective Multi-Ethnic Study of Atherosclerosis (MESA) were secondarily analyzed (April 2010-March 2018). Percentage emphysema was quantified at examination, and thoracic vertebral BMD was assessed at both examinations using a validated deep learning-based segmentation model. Participants with clinical COPD as determined on the basis of spirometry or self-reports were excluded. Linear mixed-effects models were constructed and adjusted for demographic characteristics and covariates, including smoking status, physical activity, and scanner type, and the interaction effect of sex was analyzed. Results The cross-sectional analysis included 2312 participants (median age, 67 years [IQR, 61-75 years]; 1285 female participants), and the longitudinal study included 1109 participants (median age, 65 years [IQR, 60-72 years]; 614 female participants) with available follow-up CT data. A greater percentage of emphysema-like changes was associated with lower BMD (β = -1.14 mg/cm3 [95% CI: -1.76, -0.53]) cross-sectionally and with greater annual BMD loss (β = -0.07 mg/cm3 per year [95% CI: -0.13, -0.01]) longitudinally. Interaction effects were identified for sex (P < .001) and race or ethnicity (P = .049). In stratified models, the associations were significant for men (β = -0.38 mg/cm3 per year [95% CI: -0.48, -0.28]) and Black/African American participants (β = -0.24 mg/cm3 per year [95% CI: -0.39, -0.09]). The Johnson-Neyman method revealed more than 2.7% emphysema as a threshold for a decrease in BMD among men, which corresponded to 39% of the male participants. The results remained robust after adjustment for pulmonary function and chronic respiratory symptoms. Conclusion In individuals without COPD, a greater percentage of emphysema-like changes was independently associated with faster vertebral bone loss, particularly in men, suggesting that subclinical emphysema may be a novel imaging marker of systemic skeletal decline. Clinical trial registration no. NCT0000548 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Fukuda in this issue.

Background:The limited data on functional capacity among older Americans suggest lower 6-min walk distance (6MWD) among African American than among White persons. We aimed to investigate the association of race and ethnicity with 6MWD while accounting for sociodemographic, behavioral, health care, and comorbid conditions. Methods:We performed a cross-sectional analysis of the Multi-Ethnic Study of Atherosclerosis cohort, composed of men and women ages 45-84 y who self-reported being African American, Chinese, Hispanic, or White, were free of clinically evident cardiovascular disease (CVD) between 2000 and 2002, and attended the sixth exam (2016-2018). 6MWD was obtained by participants walking at their own pace along a flat 20-m course under staff supervision. Linear regression models were utilized to adjust for age, sex, height, body mass index, site, education, income, private health insurance, health behaviors, health status, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, CVD risk factors, and heart and lung function parameters. Results:Among 1829 participants (mean age, 73 y; age range, 59-96 y; 53% female; 24% African American; 14% Chinese; 21% Hispanic; 41% White), mean 6MWD was 33 to 56 m lower for non-White than for White participants. Differences in 6MWD narrowed after adjustment for covariates but remained significant for African American (-13 m; 95% confidence interval: -22, -3) compared with White participants. Conclusions:Among older adults who identified as White, Chinese, African American, or Hispanic, differences in 6MWD were smaller than what is considered clinically meaningful or not significantly different after consideration of socioeconomic status, health behaviors, comorbid conditions, cardiovascular parameters, and pulmonary function.

Rationale:Small airways disease (SAD) and hyperinflation are common in precapillary pulmonary hypertension (PH). Activin signaling plays an important role in airway and bronchial function. Objective:To determine whether treatment with sotatercept, an activin signaling inhibitor, for severe precapillary PH is associated with improvements in physiologic markers of SAD and hyperinflation. Methods:We conducted a single-center, retrospective cohort study of participants who received sotatercept for the treatment of severe precapillary PH despite background PH treatments who also had pulmonary function tests (PFT) before and after initiation of sotatercept treatment. Measurements and Main Results:Forty-eight participants were included (median age 68 years, 77% female). Median BMI was 26.7 kg/m2 (IQR 23.6-31.4). All participants were functional class III or IV. Follow-up PFTs obtained a median of 4.4 months after sotatercept initiation showed significant improvements: FEV1 +155 mL (11%, 95% confidence interval [CI], 100-215 mL; p<0.001), FVC +180 mL (10%, 95% CI, 125-245 mL; p<0.001), FEF25-75% +0.15 L/sec (16%, 95% CI, 0.03-0.28 L/sec; p=0.015), DLCO +0.79 mL/min/mmHg (10%, 95% CI, 0.30-1.25 mL/min/mmHg; p<0.01). In participants with paired lung volume measurements (n=22), RV decreased 210 mL (12%, 95% CI, -340 to -85 mL; p<0.01), RV/TLC decreased 5% (95% CI, -7% to -3%; p<0.001), and ERV increased 175 mL (29%, 95% CI, 50-385 mL; p=0.02). There was no overall change in TLC or FRC. Conclusions:In a real-world cohort of patients with severe precapillary PH from a variety of causes, sotatercept was associated with improvements in markers of SAD and hyperinflation.

Evidence on metformin’s skeletal effects remains conflicting. We emulated a target trial to evaluate associations between metformin therapy and deep learning–based CT-derived vertebral bone mineral density (vBMD). We also assessed variation across prespecified subgroups. Within the Multi-Ethnic Study of Atherosclerosis (MESA), incident metformin users (Exams 4 and 5) were compared with propensity score–matched controls. Noncontrast chest CT scans from Exams 5 and 6 were processed using a previously validated deep learning–based vertebral segmentation and calibration pipeline to quantify trabecular vBMD from T1 to T10. Median imaging follow-up was 6.4 years. Linear mixed-effects models estimated annualized Fracture Risk Assessment Tool (FRAX) absolute vBMD change, applying inverse probability of censoring weights. Prespecified subgroup analyses examined demographic, metabolic, and inflammatory modifiers. Among 238 trial entries (86 metformin, 152 controls), metformin was not associated with overall vBMD change (time × treatment interaction β, 0.27 mg/cm3 per year; 95

Associations between exposure to ambient air pollution and progression of emphysema have been identified in longitudinal observational studies. However, previous work has not used statistical causal inference methods tailored to address bias from time-varying confounding. The objective of this study is to propose an analytical approach for estimating longitudinal health effects of air pollution while accounting for time-varying confounding using marginal structural models and to re-analyze data on air pollution and emphysema progression from the Multi-Ethnic Study of Atherosclerosis using this analytical approach. We estimate weights for continuous exposure levels using two techniques: quantile binning of the exposure and a semiparametric model for the requisite conditional densities. The latter approach incorporates flexible machine learning methods. We find evidence for the harmful effects of ambient ozone pollution during study follow-up on the progression of emphysema, consistent with previously reported results. We find no evidence of effects of NOx during study follow-up. This investigation demonstrates that analyses based on marginal structural models are feasible in studies of the health effects of air pollution and may address possible sources of bias that traditional regression-based methods fail to address. Further investigation is warranted to understand differences between our findings and previously published results.

BACKGROUND:Patients with advanced COPD have pulmonary vascular dysfunction and destruction; thus, it is unclear whether they are responsive to selective pulmonary vasodilators. RESEARCH QUESTION:What is the effect of inhaled nitric oxide (iNO) on exercise capacity in patients without hypoxemia with mild-to-severe COPD without pulmonary hypertension, and are there structural and/or functional predictors of response? STUDY DESIGN AND METHODS:Sixty-one patients with mild-to-severe COPD (mean FEV1, 65% ± 18% predicted) were recruited to this randomized, placebo-controlled, double-anonymized, crossover trial. Assessments included pulmonary function, echocardiography, and quantitative CT scan. Small vessel volume fraction, defined as the vascular volume of blood vessels with a cross-sectional area < 5 mm2 (BV5) divided by total vascular volume (TVV), was used as an index of small vessel perfusion or pulmonary vascular pruning. Participants received iNO or placebo (randomized) during 2 separate incremental exercise tests to determine exercise capacity (peak rate of oxygen consumption [Vo2peak]). RESULTS:The mean effect of iNO on Vo2peak was 0.36 mL/kg/min (95% CI, -0.18 to 0.89) in an unadjusted linear mixed effects model. In prespecified analyses, there was evidence of iNO effect modification by BV5/TVV, whereby higher BV5/TVV was associated with greater iNO-induced improvement in Vo2peak (adjusted mean change, 0.14 mL/kg/min; 95% CI, 0.02-0.26 per 1% increment in BV5/TVV), independent of severity of airflow obstruction, pulmonary diffusing capacity, emphysema, or total lung capacity. iNO-induced increases in Vo2peak were associated with improved ventilatory efficiency and reduced dyspnea (both P < .05). INTERPRETATION:Our results show that despite a null mean effect of iNO on Vo2peak in unadjusted analysis, a significant drug-induced improvement in Vo2peak was observed in patients with higher BV5/TVV. Improvements in Vo2peak with iNO were associated with improved ventilatory efficiency and reduced dyspnea. Our findings suggest a potential COPD pulmonary vascular endotype responsive to inhaled pulmonary vasodilators, characterized by greater small vessel perfusion or less vascular pruning, that is independent of severity of airflow obstruction, diffusing capacity, emphysema, or lung size. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03679312; URL: www. CLINICALTRIALS:gov.

RATIONALE:Mucus plugs occur in chronic obstructive pulmonary disease (COPD), but little is known about their size and airway location or whether these mucus plug features change as emphysema worsens. METHODS:Computed tomographic lung scans from 31 participants with COPD from the SubPopulations and InteRmediate Outcomes In COPD Study (SPIROMICS) cohort were analyzed to quantify mucus plug size and airway location and extent of emphysema. Radiologist annotations of mucus plugs were incorporated in an image processing pipeline to generate size and location information. Emphysema was quantified as the percentage of voxels less than -950 Hounsfield units. MEASUREMENTS AND MAIN RESULTS:The length distribution of 563 annotated mucus plugs varied from 2 to 50 mm. The distribution was multimodal, and an 11-mm length defined short ("stubby," ≤11 mm) and long ("stringy," >11 mm) plug phenotypes, with stubby plugs being most common (64%). Mucus plugs localized predominantly to airway generations 6 to 9, and their prevalence was highest in lower lobes. On a lobar basis, the mucus plug number decreased as emphysema percentage increased, whereas average mucus plug volume tended to increase. CONCLUSION:COPD is characterized by mucus plugs of varying size and shape, and emphysematous lung regions may be differentially susceptible to formation of these plugs. The location of mucus plugs in segmental and subsegmental airways in COPD makes them amenable to treatment with inhaled medications or bronchoscopy.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and burdensome disease that develops over decades. Treatments for COPD are most commonly prescribed in later stages of the disease, leaving missed opportunities to modify the course of disease at earlier stages. This workshop was conducted to promote progress in the design and conduct of clinical trials of treatments that modify progression to COPD. The aims of the workshop were to provide an operational definition of pre-COPD and to discuss the elements and design of potential clinical trials in pre-COPD. The key focus areas of this workshop included: 1) defining a study population for pre-COPD clinical trials; 2) endpoints in pre-COPD clinical trials; and 3) design considerations for pre-COPD clinical trials.

BACKGROUNDThere are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post-COVID-19 pulmonary fibrosis.METHODSWe tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTSAmong 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATIONNot applicable.FUNDINGDepartment of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.

BACKGROUND:Lung cancer (LC) remains the deadliest cancer, often diagnosed at advanced stages. Screening reduces mortality in high-risk individuals. Eligibility criteria in European and US screening guidelines have recently expanded. Therefore, we conducted an updated systematic review of risk-based models for identifying candidates for low-dose computed tomography screening and post-screening nodule classification. METHODS:We systematically searched Embase and Medline (January 2020-January 2026), identifying studies proposing new risk models in the context of LC screening. We separated models by pre- and post-screening risk stratification. Data extraction included study design, population, model type, risk horizon and model performance metrics. We performed an exploratory meta-regression of areas under the curve (AUCs) to assess whether sample size, model type, validation type and inclusion of biomarkers were associated with performance. RESULTS:Of 2462 records, 91 were included. 56 models were for screening selection (30 included biomarkers) and 35 for post-screening nodule classification. Regression-based models predominated, though machine-learning approaches were increasingly common. Discrimination ranged from moderate (AUC∼0.70) to excellent (>0.90), with biomarker and imaging-enhanced models often outperforming models without. Calibration was inconsistently reported and fewer than half underwent external validation. CONCLUSION:We identified 91 risk prediction models for LC, developed after 2020. Although many demonstrated promising discrimination across both screening selection and post-screening management, most remain insufficiently mature for clinical adoption, as their performance and practical value outside the original study setting are uncertain. Future work should prioritise external validation, updating and comparative evaluation of existing models, and prospective implementation studies rather than continued development of additional models.

The average wall thickness of a theoretical airway with a lumen perimeter of 10 mm (Pi10) and the slope of the luminal perimeter of airways against their wall thickness (PiSlope) are CT-derived biomarkers of airway remodeling in chronic obstructive pulmonary disease (COPD). However, numerous calculation methods for Pi10 have been used across studies, leading to substantial variability in Pi10 values. This study evaluated reliability among 10 Pi10/PiSlope methodologies and their associations with lung function. CanCOLD participants underwent full-inspiration CT scans; CT airway segmentation was performed using VIDA software. Ten literature-based methods were used to calculate Pi10 (regression-derived wall thickness at 10 mm perimeter) and PiSlope (slope of wall area/perimeter plot). The 10 methods varied in their approaches: some focused on specific airway sizes (Patel, Van Tho, Nakano, Telenga), others limited measurements to certain airway generations (Gietema, Park, Dudurych) or covered broader airway size ranges and generations (Bhatt, Jobst, Smith). Reliability was assessed via intraclass correlation (ICC); lung function associations were assessed using regression. Pi10 and PiSlope were calculated for 1351 participants (67 ± 10 years; 550 women). Pi10 and PiSlope measurement methods with higher airway counts (Patel, Nakano, Smith, Jobst, Bhatt) showed excellent reliability (ICC > 0.90, p < 0.05). Compared to Pi10, PiSlope demonstrated stronger, consistent negative associations with FEV1, FEV1/FVC, and FEF25–75

Rationale. Reference ranges for tests of pulmonary function have been defined upon their distribution in cross-sectional samples of “healthy” participants since the mid-Nineteenth Century. Currently, “healthy” participants are defined as participants recruited from the general population without respiratory symptoms or diseases and without a smoking history. However, reporting of all these factors is known to be imprecise. To better understand the variability of this approach, we investigated the stability of a “healthy” sample over 12 years in a prospective, population-based cohort study. Methods. The Multi-Ethnic Study of Atherosclerosis (MESA) recruited a multiethnic sample of participants ages 45-84 free of clinical cardiovascular disease in 2000-02. The MESA Lung Study performed standardized spirometry in 2004-07, 2010-11, and 2016-18. We defined subpopulations of healthy normal never-smoking participants at each exam in which spirometry was measured according to: self-reported history of never smoking; self-reported absence of respiratory diseases; and self-reported absence of respiratory symptoms (wheezing, persistent cough, phlegm production, and breathless walking on level ground). Stability of the sample over time was assessed with the Kappa statistic. For each exam, we used the healthy never-smoking group to derive sex-stratified reference equations for pre-bronchodilator forced expiratory volume in 1 second (FEV1) by linear regression with predictors of age and height2. Lower limits of normal (LLN) FEV1 were calculated as predicted FEV1-1.645[asterisk]standard error of the estimate, with age=70 years and height=158 cm and 172 cm for female and male, respectively. Results. There were 1,101 (26%) healthy normals of 4,272 participants at baseline (28% White, 20% Black, 22% Hispanic, 30% Asian), 1,075 (34%) of 3,200 at first follow-up, and 614 (24%) of 2,597 at second follow-up. Of 1,863 participants who participated in all three exams, 299 were labeled healthy normal in all exams, 278 were healthy normal in two of three exams, and 188 were healthy normal in only one exam (κ=0.60 across the three exams). Of the 1,129 who reported no symptoms at second follow-up, 32% had reported at least one symptom in at least one previous exam. The different healthy normal groups led to estimates of LLN FEV1 that varied across exams by 60-90 mL (female: 1,356-1,419mL, SD=34; male: 1,963-2,053mL, SD=29). Conclusions. The healthy normal never-smoking sample in a longitudinal cohort study was only moderately stable over time, with modest implications for the estimation of the LLN. These findings raise further questions about the current, cross-sectional approach to the definition of normal pulmonary function.

BACKGROUND:Identification of chronic obstructive pulmonary disease (COPD) diagnosed before 50 years of age ("young COPD") will help enable the study of preventive and therapeutic interventions for classically diagnosed COPD in later life. However, there remains uncertainty about the definition of young COPD and its prognostic significance. METHODS:We assessed the prevalence of young COPD, defined here as spirometric airflow obstruction plus symptoms of cough, phlegm, and dyspnea or 10 or more pack-years of smoking, among 18-to-49-year-old participants from four pooled, prospective U.S. cohorts. We evaluated the association of young COPD with premature mortality and respiratory and cardiovascular events over follow-up, using multivariable-adjusted proportional hazards models. RESULTS:Among 10,680 participants (median age, 40 years; 56.8% women; 41.7% Black; 51.1% unexposed to smoking), the prevalence of people meeting our case definition of young COPD was 4.5%. Compared with nonobstructed participants, the adjusted hazard ratio (an adjusted hazard ratio greater than unity indicates more incident cases) for participants with young COPD for death before 75 years of age was 1.43 (95% confidence interval [CI], 1.19 to 1.73; P<0.001); for incident hospitalization or death due to chronic lower respiratory disease, the adjusted hazard ratio was 2.56 (95% CI, 2.05 to 3.20); for coronary heart disease, the adjusted hazard ratio was 1.12 (95% CI, 0.85 to 1.47); and for heart failure, the adjusted hazard ratio was 1.72 (95%CI, 1.26 to 2.35). The hazards of the clinical outcomes in participants with simple obstruction (spirometric obstruction without symptoms and <10 pack-years; prevalence, 2.4%) were similar to those of nonobstructed participants. CONCLUSIONS:Young COPD was present in 4.5% of adults under 50 years of age in the cohorts examined. The diagnosis was associated with premature mortality as well as respiratory and heart-failure events. (Funded by the National Heart, Lung, and Blood Institute and others.).

Background:Approximately 70% of adults with chronic obstructive pulmonary disease (COPD) remain undiagnosed. Opportunistic screening using chest computed tomography (CT) scans, commonly acquired in clinical practice, may be used to improve COPD detection through simple, clinically applicable deep-learning models. We developed a lightweight, convolutional neural network (COPDxNet) that utilizes minimally processed chest CT scans to detect COPD. Methods:We analyzed 13,043 inspiratory chest CT scans from the COPDGene participants, (9,675 standard-dose and 3,368 low-dose scans), which we randomly split into training (70%) and test (30%) sets at the participant level to no individual contributed to both sets. COPD was defined by postbronchodilator FEV /FVC < 0.70. We constructed a simple, four-block convolutional model that was trained on pooled data and validated on the held-out standard- and low-dose test sets. External validation was performed using standard-dose CT scans from 2,890 SPIROMICS participants and low-dose CT scans from 7,893 participants in the National Lung Screening Trial (NLST). We evaluated performance using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, Brier scores, and calibration curves. Findings:On COPDGene standard-dose CT scans, COPDxNet achieved an AUC of 0.92 (95% CI: 0.91 to 0.93), sensitivity of 80.2%, and specificity of 89.4%. On low-dose scans, AUC was 0.88 (95% CI: 0.86 to 0.90). When the COPDxNet model was applied to external validation datasets, it showed an AUC of 0.92 (95% CI: 0.91 to 0.93) in SPIROMICS and 0.82 (95% CI: 0.81 to 0.83) on NLST. The model was well-calibrated, with Brier scores of 0.11 for standard-dose and 0.13 for low-dose CT scans in COPDGene, 0.12 in SPIROMICS, and 0.17 in NLST. Interpretation:COPDxNet demonstrates high discriminative accuracy and generalizability for detecting COPD on standard- and low-dose chest CT scans, supporting its potential for clinical and screening applications across diverse populations.