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Rationale: Chronic obstructive pulmonary disease (COPD) is defined by fixed spirometric ratio, FEV1/FVC < 0.70 after inhaled bronchodilators. However, the implications of variable obstruction (VO), in which the prebronchodilator FEV1/FVC ratio is less than 0.70 but increases to 0.70 or more after inhaled bronchodilators, have not been determined. Objectives: We explored differences in physiology, exacerbations, and health status in participants with VO compared with reference participants without obstruction. Methods: Data from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort were obtained. Participants with VO were compared with reference participants without obstruction. Measurements and Main Results: We assessed differences in baseline radiographic emphysema and small airway disease at study entry, baseline, and change in lung function by spirometry, functional capacity by 6-minute walk, health status using standard questionnaires, exacerbation rates, and progression to COPD between the two groups. All models were adjusted for participant characteristics, asthma history, and tobacco exposure. We assessed 175 participants with VO and 603 reference participants without obstruction. Participants with VO had 6.2 times the hazard of future development of COPD controlling for other factors (95% confidence interval, 4.6-8.3; P < 0.001). Compared with reference participants, the VO group had significantly lower baseline pre- and post-bronchodilator (BD) FEV1, and greater decline over time in post-BD FEV1, and pre- and post-BD FVC. There were no significant differences in exacerbations between groups. Conclusions: Significant risk for future COPD development exists for those with pre- but not post-BD airflow obstruction. These findings support consideration of expanding spirometric criteria defining COPD to include pre-BD obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT01969344). [ABSTRACT FROM AUTHOR]

Rationale: African American individuals have worse outcomes in chronic obstructive pulmonary disease (COPD). Objectives: To assess whether race-specific approaches for estimating lung function contribute to racial inequities by failing to recognize pathological decrements and considering them normal. Methods: In a cohort with and at risk for COPD, we assessed whether lung function prediction equations applied in a race-specific versus universal manner better modeled the relationship between FEV1, FVC, and other COPD outcomes, including the COPD Assessment Test, St. George's Respiratory Questionnaire, computed tomography percent emphysema, airway wall thickness, and 6-minute-walk test. We related these outcomes to differences in FEV1 using multiple linear regression and compared predictive performance between fitted models using root mean squared error and Alpaydin's paired F test. Measurements and Main Results: Using race-specific equations, African American individuals were calculated to have better lung function than non-Hispanic White individuals (FEV1, 76.8% vs. 71.8% predicted; P = 0.02). Using universally applied equations, African American individuals were calculated to have worse lung function. Using Hankinson's Non-Hispanic White equation, FEV1 was 64.7% versus 71.8% (P < 0.001). Using the Global Lung Initiative's Other race equation, FEV1 was 70.0% versus 77.9% (P < 0.001). Prediction errors from linear regression were less for universally applied equations compared with race-specific equations when examining FEV1% predicted with the COPD Assessment Test (P < 0.01), St. George's Respiratory Questionnaire (P < 0.01), and airway wall thickness (P < 0.01). Although African American participants had greater adversity (P < 0.001), less adversity was only associated with better FEV1 in non-Hispanic White participants (P for interaction = 0.041). Conclusions: Race-specific equations may underestimate COPD severity in African American individuals.Clinical trial registered with www.clinicaltrials.gov (NCT01969344). [ABSTRACT FROM AUTHOR]

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease who have minimal or no airflow obstruction. Objectives: To develop a multidimensional definition of a lung-related "resilient smoker" that is useful in research studies and then identify a resilient smoker subgroup in the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort using this definition. Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ⩾80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. Results: Consensus was achieved on 6 of 12 diagnostic items, which include cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in forced expiratory volume in 1 second. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of CRP (C-reactive protein) and sTNFRSF1A (soluble tumor necrosis receptor factor1A) was lower in resilient than nonresilient smokers (P = 0.02 and P = 0.03). Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "nonresilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from nonresilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344). [ABSTRACT FROM AUTHOR]

Rationale: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates.Objective: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19.Methods: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective.Results: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury.Conclusions: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation.Clinical Trial Registration: This trial was prospectively registered (NCT04329832) before enrollment of the first patient. [ABSTRACT FROM AUTHOR]

Fine particulate matter <2.5 µm (PM2.5) air pollution is implicated in global mortality, especially from cardiovascular causes. A large body of evidence suggests a link between PM2.5 and elevation in blood pressure (BP), with the latter implicated as a potential mediator of cardiovascular events. We sought to determine if the outcomes of intensive BP lowering (systolic BP <120 mm Hg) on cardiovascular events are modified by PM2.5 exposure in the SPRINT (Systolic BP Intervention Trial). We linked annual PM2.5 exposure estimates derived from an integrated model to subjects participating in SPRINT. We evaluated the effect of intensive BP lowering by PM2.5 exposure on the primary outcome in SPRINT using cox-proportional hazard models. A total of 9286 participants were linked to PM2.5 levels (mean age 68±9 years). Intensive BP-lowering decreased risk of the primary outcome more among patients exposed to higher PM2.5 (Pinteraction=0.047). The estimate for lowering of primary outcome was numerically lower in the highest than in the lower quintiles. The benefits of intensive BP-lowering were larger among patients chronically exposed to PM2.5 levels above US National Ambient Air Quality Standards of 12 µg/m3 (hazard ratio, 0.47 [95% CI, 0.29-0.74]) compared with those living in cleaner locations (hazard ratio, 0.81 [95% CI, 0.68-0.97]), Pinteraction=0.037. This exploratory nonprespecified post hoc analysis of SPRINT suggests that the benefits of intensive BP lowering on the primary outcome was greater in patients exposed to higher PM2.5, suggesting that the magnitude of benefit may depend upon the magnitude of antecedent PM2.5 exposure. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832). [ABSTRACT FROM AUTHOR]

The article focuses on the consequences of this undervaluing of pilot and feasibility studies and offer suggestions to improve the overall efficiency of the clinical research. Topics include information on scientific nihilism, is a collective impatience with the actual work of clinical science; need to avoid the presentation of false inferences regarding efficacy; and impact of issues like budget limits, practical emphasis on acquisition of pilot data on research efficiency.

Rationale: There is an unmet need to investigate the lower airways in chronic obstructive pulmonary disease (COPD) to define pathogenesis and to identify potential markers to accelerate therapeutic development. Although bronchoscopy is well established to sample airways in various conditions, a comprehensive COPD research protocol has yet to be published.Objectives: To evaluate the safety and tolerability of a comprehensive research bronchoscopy procedure suitable for multicenter trials and to identify factors associated with adverse events.Methods: We report the detailed methodology used to conduct the bronchoscopy used in SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study). The protocol entailed collection of tongue scrapings and oral rinses as well as bronchoscopy with airway inspection, bronchoalveolar lavage (BAL), protected brushings, and endobronchial biopsies. Visual airway characteristics were graded on a scale of 0 (normal appearance) to 3 (severe abnormality) in four domains: erythema, edema, secretions, and friability. Adverse events were defined as events requiring intervention. Logistic regression modeling assessed associations between adverse event occurrence and key variables.Results: We enrolled 215 participants. They were 61 ± 9 years old, 71% were white, 53% were male, and post-bronchodilator forced expiratory volume in 1 second was 89 ± 19% predicted. Self-reported asthma was present in 22% of bronchoscopy participants. Oral samples were obtained in greater than or equal to 99% of participants. Airway characteristics were recorded in 99% and were most often characterized as free of edema (61.9%). Less than 50% reported secretions, friability, or erythema. BAL yielded 111 ± 57 ml (50%) of the 223 ± 65 ml of infusate, brushes were completed in 98%, and endobronchial biopsies were performed in 82% of procedures. Adverse events requiring intervention occurred in 14 (6.7%) of 208 bronchoscopies. In logistic regression models, female sex (risk ratio [RR], 1.10; 95% confidence interval [CI], 1.02-1.19), self-reported asthma (RR, 1.17; 95% CI, 1.02-1.34), bronchodilator reversibility (RR, 1.17; 95% CI, 1.04-1.32), COPD (RR, 1.10; 95% CI, 1.02-1.20), forced expiratory volume in 1 second (RR, 0.97; 95% CI, 0.95-0.99), and secretions (RR, 1.85; 1.08-3.16) or friability (RR, 1.64; 95% CI, 1.04-2.57) observed during bronchoscopy were associated with adverse events.Conclusions: A research bronchoscopy procedure that includes oral sampling, BAL, endobronchial biopsy, and brushing can be safely performed. Airway characteristics during bronchoscopy, demographics, asthma or COPD, and lung function may convey increased risk for procedure-related events necessitating intervention. [ABSTRACT FROM AUTHOR]

Background: Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown.Methods: Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC < 70%). Acute exacerbations of COPD (AECOPD) were prospectively ascertained through quarterly structured telephone questionnaires up to 3 years and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring ED visit or hospitalization). Aspirin users were matched one-to-one with nonusers, based on propensity score. The association of aspirin use with total, moderate, and severe AECOPD was investigated using zero-inflated negative binomial models. Linear or logistic regression was used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance.Results: Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, -2.2; 95% CI, -4.1 to -0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, -1.1; 95% CI, -1.9 to -0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, -14.3 to 15.6).Conclusions: Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding.Trial Registry: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Rationale: Despite awareness of chronic obstructive pulmonary disease (COPD) treatment recommendations, uptake is poor. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) spans 2010-2016, providing an opportunity to assess integration of 2011 Global Initiative for Obstructive Lung Disease (GOLD) treatment strategies over time in a large observational cohort study.Objectives: To evaluate how COPD treatment aligns with 2011 GOLD strategies and determine factors associated with failure to align with recommendations.Methods: Information on inhaled medication use collected via questionnaire annually for 4 years was compiled into therapeutic classes (long-acting antimuscarinic agent, long-acting β-agonist, inhaled corticosteroids [ICS], and combinations thereof). Medications were not modified by SPIROMICS investigators. 2011 GOLD COPD categories A, B, C, and D were assigned. Alignment of inhaler regimen with first-/second-line GOLD recommendations was determined, stratifying into recommendation aligned or nonaligned. Recommendation-nonaligned participants were further stratified into overuse and underuse categories.Results: Of 1,721 participants with COPD, at baseline, 52% of regimens aligned with GOLD recommendations. Among participants with nonaligned regimens, 46% reported underuse, predominately owing to lack of long-acting inhalers in GOLD category D. Of the 54% reporting overuse, 95% were treated with nonindicated ICS-containing regimens. Among 431 participants with 4 years of follow-up data, recommendation alignment did not change over time. When we compared 2011 and 2017 recommendations, we found that 47% did not align with either set of recommendations, whereas 35% were in alignment with both recommendations.Conclusions: Among SPIROMICS participants with COPD, nearly 50% reported inhaler regimens that did not align with GOLD recommendations. Nonalignment was driven largely by overuse of ICS regimens in milder disease and lack of long-acting inhalers in severe disease. [ABSTRACT FROM AUTHOR]

Rationale: Quantitative computed tomographic (CT) imaging can aid in chronic obstructive pulmonary disease (COPD) phenotyping. Few studies have identified whether occupational exposures are associated with distinct CT imaging characteristics.Objectives: To examine the association between occupational exposures and CT-measured patterns of disease in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study).Methods: Participants underwent whole-lung multidetector helical CT at full inspiration and expiration. The association between occupational exposures (self-report of exposure to vapors, gas, dust, or fumes [VGDF] at the longest job) and CT metrics of emphysema (percentage of total voxels < -950 Hounsfield units at total lung capacity), large airways (wall area percent [WAP] and square-root wall area of a single hypothetical airway with an internal perimeter of 10 mm [Pi10]), and small airways (percent air trapping [percent total voxels < -856 Hounsfield units at residual volume] and parametric response mapping of functional small-airway abnormality [PRM fSAD]) were explored by multivariate linear regression, and for central airway measures by generalized estimating equations to account for multiple measurements per individual. Models were adjusted for age, sex, race, current smoking status, pack-years of smoking, body mass index, and site. Airway measurements were additionally adjusted for total lung volume.Results: A total of 2,736 participants with available occupational exposure data (n = 927 without airflow obstruction and 1,809 with COPD) were included. The mean age was 64 years, 78% were white, and 54% were male. Forty percent reported current smoking, and mean (SD) pack-years was 49.3 (26.9). Mean (SD) post-bronchodilator forced expiratory volume in 1 second (FEV1) was 73 (27) % predicted. Forty-nine percent reported VGDF exposure. VGDF exposure was associated with higher emphysema (β = 1.17; 95% confidence interval [CI], 0.44-1.89), greater large-airway disease as measured by WAP (segmental β = 0.487 [95% CI, 0.320-0.654]; subsegmental β = 0.400 [95% CI, 0.275-0.527]) and Pi10 (β = 0.008; 95% CI, 0.002-0.014), and greater small-airway disease was measured by air trapping (β = 2.60; 95% CI, 1.11-4.09) and was nominally associated with an increase in PRM fSAD (β = 1.45; 95% CI, 0.31-2.60). These findings correspond to higher odds of percent emphysema, WAP, and air trapping above the 95th percentile of measurements in nonsmoking control subjects in individuals reporting VGDF exposure.Conclusions: In an analysis of SPIROMICS participants, we found that VGDF exposure in the longest job was associated with an increase in emphysema, and in large- and small-airway disease, as measured by quantitative CT imaging. [ABSTRACT FROM AUTHOR]

Rationale: Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear.Objectives: In this work, we sought to determine the independent association between rural residence and COPD-related outcomes, including COPD exacerbations, airflow obstruction, and symptom burden.Methods: A total of 1,684 SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) participants with forced expiratory volume in 1 second/forced vital capacity < 0.70 had geocoding-defined rural-urban residence status determined (N = 204 rural and N = 1,480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes, including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of the home address to the block level at the time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures. The primary outcome measures were exacerbations determined over a 1-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. The odds ratio (OR) and incidence rate ratio (IRR) of exacerbations that required treatment with medications, including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates.Results: Rural residence was independently associated with a 70% increase in the odds of total exacerbations (OR, 1.70 [95% confidence interval (CI), 1.13-2.56]; P = 0.012) and a 46% higher incidence rate of total exacerbations (IRR 1.46 [95% CI, 1.02-2.10]; P = 0.039). There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation in the analysis attenuated the association between rural residence and the odds and incidence rate of total exacerbations (OR, 1.52 [95% CI, 1.00-2.32]; P = 0.05 and IRR 1.39 [95% CI, 0.97-1.99]; P = 0.07). There was no difference in symptoms or airflow obstruction between rural and urban participants.Conclusions: Rural residence is independently associated with increased odds and incidence of total, but not severe, COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of the increased risk of COPD exacerbations in the rural population. [ABSTRACT FROM AUTHOR]

Rationale: The relationship between air pollution and pneumonia is poorly understood.Objectives: To examine relationships between short-term air pollution exposure and number and severity of pneumonia cases along the Wasatch Front in Utah, a region with periodic high levels of outdoor air pollution.Methods: We applied time-stratified case-crossover analyses with distributed lag to patients presenting to seven emergency departments with pneumonia over a 2-year period. We compared levels of particulate matter less than or equal to 2.5 μm in aerodynamic diameter, nitrogen dioxide, and ozone at patient residences with emergency department cases, hospitalizations, objectively defined severe pneumonia, and mortality. We calculated direct cost impacts of particulate matter less than or equal to 2.5 μm in aerodynamic diameter reduction.Results: We evaluated 4,336 pneumonia cases in seven hospitals. Among adults aged 65 years and older, we found consistently positive associations between particulate matter less than or equal to 2.5 μm in aerodynamic diameter within 6 days of presentation and instances of pneumonia (Lag Day 1 adjusted odds ratio, 1.35 per 10 μg/m3 over 12 μg/m3; 95% confidence interval, 1.16-1.57), severe pneumonia (Lag Day 1 adjusted odds ratio, 1.38; 95% confidence interval, 1.06-1.80), and inpatient mortality (Lag Day 5 adjusted odds ratio, 1.50; 95% confidence interval, 1.03-2.16). Smaller associations were found between nitrogen dioxide exposure and pneumonia occurrence, severity, and inpatient and 30-day mortality. Ozone exposure was modestly associated with increased instance and severity of pneumonia in younger adults. Particulate matter less than or equal to 2.5 μm in aerodynamic diameter and nitrogen dioxide effects were greatest in colder months, and ozone effects were greatest in warmer months. Reduction of particulate matter less than or equal to 2.5 μm in aerodynamic diameter levels to less than 12.0 mg/m3 could prevent 76-112 cases of pneumonia per year in these hospitals serving approximately half of the Wasatch Front's population, reducing direct medical facility costs by $807,000 annually.Conclusions: Among older adults, short-term ambient particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure is associated with more emergency department visits and hospitalizations for pneumonia, severe pneumonia, increased mortality, and increased healthcare costs. Nitrogen dioxide and ozone modestly increase pneumonia risk and illness severity. [ABSTRACT FROM AUTHOR]

Objective: Younger persons with COPD report worse health-related quality of life (HRQL) than do older individuals. The factors explaining these differences remain unclear. The objective of this article was to explore factors associated with age-related differences in HRQL in COPD.Methods: Cross-sectional analysis of participants with COPD, any Global Initiative for Chronic Obstructive Lung Disease grade of airflow limitation, and ≥ 50 years old in two cohorts: the Genetic Epidemiology of COPD (COPDGene) study and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). We compared St. George's Respiratory Questionnaire (SGRQ) scores by age group: middle-aged (age, 50-64) vs older (age, 65-80) adults. We used multivariate linear modeling to test associations of age with HRQL, adjusting for demographic and clinical characteristics and comorbidities.Results: Among 4,097 participants in the COPDGene study (2,170 middle-aged and 1,927 older adults) SGRQ total scores were higher (worse) among middle-aged (mean difference, -4.2 points; 95% CI, -5.7 to -2.6; P < .001) than older adults. Age had a statistically significant interaction with dyspnea (P < .001). Greater dyspnea severity (modified Medical Research Council ≥ 2, compared with 0-1) had a stronger association with SGRQ score among middle-aged (β, 24.6; 95% CI, 23.2-25.9) than older-adult (β, 21.0; 95% CI, 19.6-22.3) participants. In analyses using SGRQ as outcome in 1,522 participants in SPIROMICS (598 middle-aged and 924 older adults), we found similar associations, confirming that for the same severity of dyspnea there is a stronger association with HRQL among younger individuals.Conclusions: Age-related differences in HRQL may be explained by a higher impact of dyspnea among younger subjects with COPD.Trial Registry: ClinicalTrials.gov; No.: NCT00608764 and No.: NCT01969344; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.Methods: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest.Results: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.Conclusions: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.). [ABSTRACT FROM AUTHOR]

Rationale: Ground-glass opacities (GGOs) in the absence of interstitial lung disease are understudied. Objectives: To assess the association of GGOs with white blood cells (WBCs) and progression of quantified chest computed tomography emphysema. Methods: We analyzed data of participants in the SPIROMICS study (Subpopulations and Intermediate Outcome Measures in COPD Study). Chest radiologists and pulmonologists labeled regions of the lung as GGOs, and the adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGOs (%GGO AMFM ). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGO AMFM with WBCs, changes in percentage emphysema, and clinical outcomes. Measurements and Main Results: Among 2,714 participants, 1,680 had chronic obstructive pulmonary disease (COPD) and 1,034 had normal spirometry. Among participants with COPD, on the basis of multivariable analysis, current smoking and chronic productive cough were associated with higher %GGO AMFM . Higher %GGO AMFM was cross-sectionally associated with higher WBC and neutrophil concentrations. Higher %GGO AMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at 1-year follow-up visit by 11.7% (relative increase; 95% confidence interval, 7.5-16.1%; P  < 0.001). We found no association between %GGO AMFM and 1-year FEV 1 decline, but %GGO AMFM was associated with exacerbations and all-cause mortality during a median follow-up of 1,544 days (interquartile interval, 1,118-2,059). Among normal spirometry participants, we found similar results, except that %GGO AMFM was associated with progression to COPD at 1-year follow-up. Conclusions: Our findings suggest that GGO AMFM is associated with increased systemic inflammation and emphysema progression.

Background- Among tobacco-exposed persons with preserved spirometry (TEPS), we previously demonstrated that different lung volume indices, specifically elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity-to-TLC (FRC/TLC), identify different lung disease characteristics in the COPDGene cohort. Objective- Determine differential disease characteristics and trajectories associated with the lung volume indices among TEPS in the SPIROMICS cohort. Methods- We categorized TEPS (n=814) by tertiles (low, intermediate, high) of TLC or residual volume-to-TLC (RV/TLC) derived from baseline CT images, and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC] high ) versus high RV/TLC without high TLC ([RV/TLC] high ). We examined differences in CT-measured emphysema (HU≤-950; PRM EMPH ), airway trapping (HU≤-856; PRM fSAD ; DPM GasTrap ), and airway geometry (Pi10), respiratory symptoms (mMRC; CAT; SGRQ; SF12), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current versus former) and burden (pack-years). Results- In TEPS participants, the pattern of spirometric disease progression differed between [TLC]high and [RV/TLC] high : increased FVC with stable FEV 1 in [TLC] high versus unchanged FVC but nominally decreased FEV 1 in [RV/TLC] high . Compared to [TLC] high , TEPS with [RV/TLC] high had less emphysema (by HU≤-950) but more airway disease (by HU≤-856; PRM fSAD ; DPM GasTrap , and Pi10), more respiratory symptoms (by mMRC; CAT; SGRQ; SF12), and more severe exacerbations at baseline. Over an average follow-up time of 4.1±2.4 years (range: 0.5 to 8.5 years), [RV/TLC] high TEPS also had higher likelihood of developing more severe spirometric disease (PRISm or GOLD-2) and worsening of their respiratory symptoms (by CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not different between the two categories over the follow-up time, [RV/TLC] high TEPS were more likely to have been placed on a respiratory inhaler at their last follow-up visit. Conclusions- In these TEPS from SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described from COPDGene cohort using TLC versus FRC/TLC stratification.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation ( n  = 1,367) versus above 4,000 ft (1,219 m) elevation ( n  = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV 1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSAD TLC )., Objectives: To evaluate an AI model for estimating fSAD TLC and study its clinical associations in chronic obstructive pulmonary disease (COPD)., Methods: We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a subset ( n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSAD TLC in the remaining 1458 SPIROMICS participants. We compared fSAD TLC with dual volume, parametric response mapping fSAD PRM . We investigated univariate and multivariable associations of fSAD TLC with FEV 1 , FEV 1 /FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV 1 decline. The results were validated in a subset ( n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV 1 , smoking pack years, smoking status, and percent emphysema., Measurements and Main Results: Inspiratory fSAD TLC was highly correlated with fSAD PRM in SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. In SPIROMICS, fSAD TLC was associated with FEV 1 (L) (adj.β = -0.034, P < 0.001), FEV 1 /FVC (adj.β = -0.008, P < 0.001), SGRQ (adj.β = 0.243, P < 0.001), and FEV 1 decline (mL / year) (adj.β = -1.156, P < 0.001). fSAD TLC was also associated with FEV 1 (L) (adj.β = -0.032, P < 0.001), FEV 1 /FVC (adj.β = -0.007, P < 0.001), SGRQ (adj.β = 0.190, P = 0.02), and FEV 1 decline (mL / year) (adj.β = -0.866, P = 0.001) in COPDGene. We found fSAD TLC to be more repeatable than fSAD PRM with intraclass correlation of 0.99 (95% CI: 0.98, 0.99) vs. 0.83 (95% CI: 0.76, 0.88)., Conclusions: Inspiratory fSAD TLC captures small airways disease as reliably as fSAD PRM and is associated with FEV 1 decline.

The aryl hydrocarbon receptor (AHR) is a receptor/transcription factor widely expressed in the lung. The physiological roles of AHR expressed in the alveolar epithelium remain unclear. In this study, we tested the hypothesis that alveolar epithelial AHR activity plays an important role in modulating inflammatory responses and maintaining alveolar integrity during lung injury and repair. AHR is expressed in alveolar epithelial cells (AECs) and is active. AHR activation with the endogenous AHR ligand, FICZ (5,11-dihydroindolo[3,2-b] carbazole-6-carboxaldehyde), significantly suppressed inflammatory cytokine expression in response to inflammatory stimuli in primary murine AECs and in the MLE-15 epithelial cell line. In an LPS model of acute lung injury in mice, coadministration of FICZ with LPS suppressed protein leak, reduced neutrophil accumulation in BAL fluid, and suppressed inflammatory cytokine expression in lung tissue and BAL fluid. Relevant to healing following inflammatory injury, AHR activation suppressed TGF-β-induced expression of genes associated with epithelial-mesenchymal transition. Knockdown of AHR in primary AECs with shRNA or in CRISPR-Cas-9-induced MLE-15 cells resulted in upregulation of α-smooth muscle actin (αSma), Col1a1, and Fn1 and reduced expression of epithelial genes Col4a1 and Sdc1. MLE-15 clones lacking AHR demonstrated accelerated wound closure in a scratch model. AHR activation with FICZ enhanced barrier function (transepithelial electrical resistance) in primary murine AECs and limited decline of transepithelial electrical resistance following inflammatory injury. AHR activation in AECs preserves alveolar integrity by modulating inflammatory cytokine expression while enhancing barrier function and limiting stress-induced expression of mesenchymal genes., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need., Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression., Methods: We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV 1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways., Measurements and Main Results: The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV 1 . Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins., Conclusion: We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

Rationale: The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. Objectives: To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). Methods: Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. Measurements and Main Results: Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations ( P  < 0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included Alloprevotella , Oribacterium , and Veillonella species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of Streptococcus , Actinobacillus , Actinomyces , and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV 1 regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in Prevotella , Leptotrichia , and Neisseria species. In contrast, the rapid decline group (FEV 1 slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in Streptococcus species. Conclusions: In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Perimenstrual worsening of asthma occurs in up to 40% of women with asthma, leading to increased acute exacerbations requiring clinical care. The role of sex hormones during these times remains unclear. In the current study, we used a translational approach to determine whether progesterone exacerbates allergic inflammation in the traditional chicken egg ovalbumin (OVA) model in BALB/c mice. Simultaneously, we used peripheral blood mononuclear cells (PBMC) from healthy human donors to assess the effects of progesterone on circulating group 2 innate lymphoid cells (ILC2). Briefly, lungs of ovariectomized (OVX) or sham-operated female (F-Sham) controls were implanted with a progesterone (P4, 25 mg) (OVX-P4) or placebo pellet (OVX-Placebo), followed by sensitization and challenge with ovalbumin (OVA). Progesterone increased total inflammatory histologic scores, increased hyper-responsiveness to methacholine (MCh), increased select chemokines in the bronchoalveolar lavage (BAL) and serum, and increased ILC2 and neutrophil numbers, along the airways compared with F-Sham-OVA and OVX-Placebo-OVA animals. Lung ILC2 were sorted from F-Sham-OVA, OVX-Placebo-OVA and OVX-P4-OVA treated animals and stimulated with IL-33. OVX-P4-OVA lung ILC2 were more responsive to interleukin 33 (IL-33) compared with F-Sham-OVA treated, producing more IL-13 and chemokines following IL-33 stimulation. We confirmed the expression of the progesterone receptor (PR) on human ILC2, and showed that P4 + IL-33 stimulation also increased IL-13 and chemokine production from human ILC2. We establish that murine ILC2 are capable of responding to P4 and thereby contribute to allergic inflammation in the lung. We confirmed that human ILC2 are also hyper-responsive to P4 and IL-33 and likely contribute to airway exacerbations following allergen exposures in asthmatic women with increased symptoms around the time of menstruation. NEW & NOTEWORTHY There is a strong association between female biological sex and severe asthma. We investigated the allergic immune response, lung pathology, and airway mechanics in the well-described chicken egg ovalbumin (OVA) model with steady levels of progesterone delivered throughout the treatment period. We found that progesterone enhances the activation of mouse group 2 innate lymphoid cells (ILC2). Human ILC2 are also hyper-responsive to progesterone and interleukin 33 (IL-33), and likely contribute to airway exacerbations following allergen exposures in women with asthma.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n  = 188, 1-year ΔEI > 1%), nonprogressors ( n  = 301, 1-year ΔEI ± 0.5%), and never-smokers ( n  = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAAR seg ]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAAR seg (0.73 ± 0.29 vs. 0.67 ± 0.23; P  = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P  = 5.0 × 10 -12 ), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P  = 6.1 × 10 -13 ), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P  = 1.9 × 10 -7 ). In adjusted analyses, an increment of 1 standard deviation in PAAR seg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P  = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P  = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions., Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers., Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk., Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18)., Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk., (JCOPDF © 2024.)

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome., Competing Interests: T.G.L., J.A.F., J.L.J., Y.L., K.A.P., and J.B.V. received other support from the CFF (CC132-16AD, LIOU14Y0, LIOU14P0) and the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL125520) and received support during the current study for performing clinical trials from Abbvie, Calithera Biosciences, Corbus Pharmaceuticals, Gilead Sciences, Laurent Pharmaceuticals, Nivalis Therapeutics, Novartis, Proteostasis, Savara Pharmaceuticals, Translate Bio, and Vertex Pharmaceuticals. F.R.A. received additional other support from the NHLBI/NIH (R01 HL125520), the National Science Foundation (EMSW21-RTG), and the Margolis Family Foundation of Utah. P.S.B. received other support from the CFF (Center and TDC grants) and the NHLBI/NIH (U01 HL114623) and received support for a clinical trial from Alcresta Therapeutics. B.A.C. received other support from the CFF (C112–12, C112-TDC09Y, 10063SUB, 41339154.s132P010379SUB) and received support for clinical trials from Genentech, Novartis, and Vertex Pharmaceuticals. C.L.D. received other support from the CFF (C004–11, C004-TDC09Y, DAINES11Y3) and from the Health Resources and Services Administration (T72MC00012). J.A.F. transitioned to become an employee of ICON plc, a clinical research organization involved in various trials pertinent to CF during the study and is now an employee of Vertex Pharmaceuticals; JAF, ICON, and Vertex had no direct involvement in performance of the study following the initial change in affiliation. T.H. received other support from the CFF (PACE, Center Grant) and received support for clinical trials from Celtaxsys and Vertex Pharmaceuticals. J.R.H. received other support from the NHLBI/NIH (HHSN268200900018C) and the Veterans Administration Healthcare System (I01 BX001533). J.L. received other support from the CFF (C017-11AF). C.N. received other support from the CFF (C138-12). P.R. received other support from the CFF (C003–12, C003-TDC09Y). S.D.S. received other support from the CFF (AQUADEK12K1, SAGEL11CS0, GOAL13K2, NICK13A0, SAGEL14K1, NICK15R0) and the NHLBI/NIH (U54 HL096458) and the NCATS/NIH (Colorado CTSA Grant Number UL1 TR002535). J.L.T.-C. received other support from the CFF (TDC) and the NHLBI/NIH (HL103801) and received support for clinical trials from Vertex Pharmaceuticals. K.N.O. was funded by the intramural research program of the NHLBI, NIH, during the study. Neither the project sponsors nor any sources of other support had direct roles in development and conduct of the study. None of the sponsors of clinical trials mentioned earlier participated in any way with this trial., (© 2024 The Author(s).)

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO 2 ) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO 2 , using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV 1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV 1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV 1 decline differed by smoking status. Among former smokers, every 10 μg/m 3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV 1 ( P  = 0.044). Among current smokers, FEV 1 decline did not differ by indoor PM. The results of indoor NO 2 suggest trends similar to those for PM ⩽2.5 μm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.

The National Institutes of Health's (NIH) K99/R00 Pathway to Independence Award offers promising postdoctoral researchers and clinician-scientists an opportunity to receive research support at both the mentored and the independent levels with the goal of facilitating a timely transition to a tenure-track faculty position. This transitional program has been generally successful, with most K99/R00 awardees successfully securing R01-equivalent funding by the end of the R00 period. However, often highly promising proposals fail because of poor grantsmanship. This overview provides guidance from the perspective of long-standing members of the National Heart, Lung, and Blood Institute's Mentored Transition to Independence study section for the purpose of helping mentors and trainees regarding how best to assemble competitive K99/R00 applications., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies., Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS)., Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021., Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls., Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema., Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001)., Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Rationale: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals., Objectives: To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis., Methods: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1 , in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu 366 Lys, rs28929474)., Measurements and Main Results: We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p =0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p =0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV 1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p <0.0001; FEV 1 to forced vital capacity [FVC] ratio=0.54[0.17] versus 0.63[SD=0.16], p <0.0001). Participants with bronchiectasis had greater emphysema (%voxels ≤-950 Hounsfield units, 11%[SD=12] versus 6.3%[SD=9], p <0.0001) and parametric response mapping functional small airways disease (26[SD=15] versus 19[SD=15], p <0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40 [52%] versus N=283 of 707[40%], odds ratio [OR]=1.97; 95% confidence interval [CI]=1.002, 3.90, p =0.049), an association attributed to White individuals (OR=1.98; 95%CI = 0.9956, 3.9; p =0.051)., Conclusions: Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support alpha-1antitrypsin guideline recommendations to screen for alpha-1 antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history., (JCOPDF © 2023.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (JCOPDF © 2023.)

Objective: The aim of the study is to determine whether aggregate measures of occupational exposures are associated with chronic obstructive pulmonary disease (COPD) outcomes in the Subpopulations and Intermediate Outcome Measures in COPD study cohort., Methods: Individuals were assigned to six predetermined exposure hazard categories based on self-reported employment history. Multivariable regression, adjusted for age, sex, race, current smoking status, and smoking pack-years determined the association of such exposures to odds of COPD and morbidity measures. We compared these with the results of a single summary question regarding occupational exposure., Results: A total of 2772 individuals were included. Some exposure estimates, including "gases and vapors" and "dust and fumes" exposures resulted in associations with effect estimates over two times the estimated effect size when compared with a single summary question., Conclusions: Use of occupational hazard categories can identify important associations with COPD morbidity while use of single-point measures may underestimate important differences in health risks., Competing Interests: Conflicts of interest: M.K.H. received stock options from Meissa Vaccines and Altesa Biopharma. E.A.H.. is founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa, and serves as an unpaid member of the Siemens photon counting CT advisory board. M.B.D. has an additional funding from ongoing consulting to Optimum Patient Care and Becker Pharmaceutical Group, with past consulting to Polarean, American Society Hospital Pharmacists, and Midmark., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Exposure to e-cigarette vapors alters important biologic processes including phagocytosis, lipid metabolism, and cytokine activity in the airways and alveolar spaces. Little is known about the biologic mechanisms underpinning the conversion to e-cigarette, or vaping, product use-associated lung injury (EVALI) from normal e-cigarette use in otherwise healthy individuals. We compared cell populations and inflammatory immune populations from bronchoalveolar lavage fluid in individuals with EVALI to e-cigarette users without respiratory disease and healthy controls and found that e-cigarette users with EVALI demonstrate a neutrophilic inflammation with alveolar macrophages skewed towards inflammatory (M1) phenotype and cytokine profile. Comparatively, e-cigarette users without EVALI demonstrate lower inflammatory cytokine production and express features associated with a reparative (M2) phenotype. These data indicate macrophage-specific changes are occurring in e-cigarette users who develop EVALI., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV 1 ) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV 1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD., (© 2023. The Author(s).)

Background: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features., Research Question: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?, Study Design and Methods: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV 1 (FEV 1 -BDR), change in FVC (FVC-BDR), and change in in FEV 1 , FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV 1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV 1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD)., Results: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV 1 -BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV 1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group., Interpretation: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease., (Published by Elsevier Inc.)

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC ≤100 ) in people with COPD to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC ≤100 phenotype is inadequately characterized, especially in advanced COPD., Research Question: Are there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes?, Study Design and Methods: We used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC ≤100 vs BEC > 100 (BEC 100+ ) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS., Results: We identified n = 485 with BEC ≤100 (n = 61 GOLD group D) and n = 929 people with BEC 100+ (n = 124 GOLD group D). BEC ≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC 100+ , BEC ≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC ≤100 vs BEC 100+ , -50 vs -39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC ≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of -68 mL/y vs -23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029)., Interpretation: In non-ICS-treated GOLD group D COPD, people with BEC ≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov., (Copyright © 2023. Published by Elsevier Inc.)

Rationale: Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge., Methods: Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques., Results: Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2., Conclusions: Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF., Methods: We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy., Results: We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events., Discussion: We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need., Competing Interests: HL is a paid consultant to Partner Therapeutics and has stock options. KP, TB, and CR, are employees of Partner Therapeutics and have stock options. ER at the time of drafting of this manuscript was an employee of Partner Therapeutics and has stock options. TW, EB, MD, RP, and RG received funds from Partner Therapeutics within the past 3 years, but none in relation to this publication. HL is a paid consultant to Pluri-Biotech, Inc. TW acknowledges support from Savara, Kiniksa, Kinevant (for participation on a DSMB or advisory board), the PAP Foundation (serves as the vice president and clinical director of the PAP Foundation) and is a paid consultant to IQVIA. EL acknowledges funding from the NIH, myCME, is a paid consultant to Guidepoint Global, and received support for travel from the PAP Foundation. EB acknowledges support from Genentech, Novartis, and Lilly, and received funds from Apexigen, Shionogi, Bristol Myers Squibb, Nektar, Instilbio, and Xilio for consulting within the past 3 years. MD received funds from Neolukin Therapeutics (and has stock options), Moderna, Aditum, OREC, Tillotts Pharma, SQZ Biotech, AzurRx, and Mallinckrodt for consulting within the past 3 years, and acknowledges support from UpToDate, Sandoz Academy, Experts at Your Fingertips, and WebMD. DA acknowledges funding from the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. RP acknowledges support to his institution from the US Department of Veterans Affairs and the NHLBI. RG is a consultant to NexImmune Inc., Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, and a Medical Director within FFF Enterprises Inc. and AZAC Inc. RG serves on the Board of Directors of the Russian Foundation for Cancer Research Support and is on the Scientific Advisory Board of StemRad Ltd., (Copyright © 2023 Lazarus, Pitts, Wang, Lee, Buchbinder, Dougan, Armstrong, Paine, Ragsdale, Boyd, Rock and Gale.)

Atmospheric aging of combustion particles alters their chemical composition and morphology. Previous studies have reported differences in toxicological responses after exposure to fresh versus aged particles, with chemical composition being the prime suspect behind the differences. However, less is known about the contribution of morphological differences in atmospherically aged particles to toxicological responses, possibly due to the difficulty in resolving the two properties (composition and morphology) that change simultaneously. This study altered the shape of lab-generated combustion particles, without affecting the chemical composition, from fractal-like to a more compact spherical shape, using a water condensation-evaporation method. The two shapes were exposed to a co-culture of human airway epithelial (A549) and differentiated human monocyte (THP-1) cells at air-liquid interface (ALI) conditions. The particles with different shapes were deposited using an electrostatic field-based ALI chamber. For the same mass dose, both shapes were internalized by cells, induced a pro-inflammatory response (IL-8 and TNFα), and enhanced CYP1A1 gene expression compared to air controls. The more compact spherical particles (representative of atmospherically aged particles) induced more early apoptosis and release of TNFα compared to the more fractal-like particles. These results suggest a contribution of morphology to the increased toxicity of aged combustion-derived particles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Preterm infants and patients with lung disease often have excess fluid in the lungs and are frequently treated with oxygen, however long-term exposure to hyperoxia results in irreversible lung injury. Although the adverse effects of hyperoxia are mediated by reactive oxygen species, the full extent of the impact of hyperoxia on redox-dependent regulation in the lung is unclear. In this study, neonatal mice overexpressing the beta-subunit of the epithelial sodium channel (β-ENaC) encoded by Scnn1b and their wild type (WT; C57Bl6) littermates were utilized to study the pathogenesis of high fraction inspired oxygen (FiO 2 )-induced lung injury. Results showed that O 2 -induced lung injury in transgenic Scnn1b mice is attenuated following chronic O 2 exposure. To test the hypothesis that reversible cysteine-redox-modifications of proteins play an important role in O 2 -induced lung injury, we performed proteome-wide profiling of protein S-glutathionylation (SSG) in both WT and Scnn1b overexpressing mice maintained at 21% O 2 (normoxia) or FiO 2 85% (hyperoxia) from birth to 11-15 days postnatal. Over 7700 unique Cys sites with SSG modifications were identified and quantified, covering more than 3000 proteins in the lung. In both mouse models, hyperoxia resulted in a significant alteration of the SSG levels of Cys sites belonging to a diverse range of proteins. In addition, substantial SSG changes were observed in the Scnn1b overexpressing mice exposed to hyperoxia, suggesting that ENaC plays a critically important role in cellular regulation. Hyperoxia-induced SSG changes were further supported by the results observed for thiol total oxidation, the overall level of reversible oxidation on protein cysteine residues. Differential analyses reveal that Scnn1b overexpression may protect against hyperoxia-induced lung injury via modulation of specific processes such as cell adhesion, blood coagulation, and proteolysis. This study provides a landscape view of protein oxidation in the lung and highlights the importance of redox regulation in O 2 -induced lung injury., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Neighborhood poverty has been associated with poor health outcomes. Previous studies have also identified adverse respiratory effects of long-term ambient ozone. Factors associated with neighborhood poverty may accentuate the adverse impact of ozone on respiratory health., Objectives: To evaluate whether neighborhood poverty modifies the association between ambient ozone exposure and respiratory morbidity including symptoms, exacerbation risk, and radiologic parameters, among participants of the SPIROMICS AIR cohort study., Methods: Spatiotemporal models incorporating cohort-specific monitoring estimated 10-year average outdoor ozone concentrations at participants' homes. Adjusted regression models were used to determine the association of ozone exposure with respiratory outcomes, accounting for demographic factors, education, individual income, body mass index (BMI), and study site. Neighborhood poverty rate was defined by percentage of families living below federal poverty level per census tract. Interaction terms for neighborhood poverty rate with ozone were included in covariate-adjusted models to evaluate for effect modification., Results: 1874 participants were included in the analysis, with mean (± SD) age 64 (± 8.8) years and FEV 1 (forced expiratory volume in one second) 74.7% (±25.8) predicted. Participants resided in neighborhoods with mean poverty rate of 9.9% (±10.3) of families below the federal poverty level and mean 10-year ambient ozone concentration of 24.7 (±5.2) ppb. There was an interaction between neighborhood poverty rate and ozone concentration for numerous respiratory outcomes, including COPD Assessment Test score, modified Medical Research Council Dyspnea Scale, six-minute walk test, and odds of COPD exacerbation in the year prior to enrollment, such that adverse effects of ozone were greater among participants in higher poverty neighborhoods., Conclusion: Individuals with COPD in high poverty neighborhoods have higher susceptibility to adverse respiratory effects of ambient ozone exposure, after adjusting for individual factors. These findings highlight the interaction between exposures associated with poverty and their effect on respiratory health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Belz reports grant support from NIH/NHLBI. Mark Dransfield reports grant support from NIH, DOD, and the American Lung Association; consulting from AstraZeneca, GlaxoSmithKline, Pulmonx, Teva; and contracted clinical trials through Boerhinger Ingelheim, Gala, and Pulmonx. MeiLan Han reports consulting for Novartis, Sunovion, Cipla, Chiesi, Teva, Verona, Merck, Mylan, Sanofi, GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca as well as research support from Novartis and Sunovion. Jerry Krishnan reports research grants from NIH, PCORI, and Sergey Brin Family Foundation as well as consulting fees from GlaxoSmithKline for monoclonal antibody against SARS-CoV-2. Nadia Hansel reports grants from NIH, grants from COPD Foundation, grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, personal fees from Mylan during the conduct of the study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease., Research Question: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV 3 /FEV 6 ) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?, Study Design and Methods: The study included 832 current and former smokers with post-bronchodilator FEV 1 /FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV 3 /FEV 6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV 3 and FEV 6 . Regression modeling was used to evaluate the relationship between baseline FEV 3 /FEV 6 and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD., Results: FEV 3 /FEV 6 less than the LLN at baseline, defined as reduced compared with FEV 3 /FEV 6 at or above the LLN, was associated with lower FEV 1 , poorer health status (St. George's Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV 3 and FEV 6 showed excellent agreement between repeat measurements. A reduced FEV 3 /FEV 6 was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV 3 /FEV 6 was also associated with development of COPD according to spirometry results (post-bronchodilator FEV 1 /FVC < 0.7) during study follow-up., Interpretation: FEV 3 /FEV 6 is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV 3 /FEV 6 can identify those at risk for future development of COPD and respiratory exacerbations., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov: ClinicalTrials.gov., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Air liquid interface (ALI) exposure systems are gaining interest, and studies suggest enhanced response of lung cells exposed to particles at ALI as compared to submerged exposure, although the results have been somewhat inconsistent. Previous studies have used monocultures and measured particle deposition using assumptions including consistent particle deposition, particle density, and shape. This study exposed co-cultures of A549 and differentiated THP-1 cells to flame-generated particles using three exposure methods: ALI, pseudo-ALI, and submerged. The dose at ALI was measured directly, reducing the need for assumptions about particle properties and deposition. For all exposure methods an enhanced pro-inflammatory response (TNFα) and Cytochrome P450 (CYP1A1) gene expression, compared to their corresponding negative controls, was observed. ALI exposure induced a significantly greater TNFα response compared to submerged exposure. The submerged exposures exhibited greater induction of CYP1A1 than other exposure methods, although not statistically significant. Some of the factors behind the observed difference in responses for the three exposure methods include differences in physicochemical properties of particles in suspending media, delivered dose, and potential contribution of gas-phase species to cellular response in ALI exposure. However, given the difficulty and expense of ALI exposures, submerged exposure may still provide relevant information for particulate exposures.

Background: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD., Methods: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV 1 , forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF 25-75% ). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344)., Findings: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV 1 and FEF 25-75% , and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV 1 , FEV 1 /FVC, FEF 25-75% , and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years., Interpretation: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents., Funding: National Institutes of Health; National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests RGB reports grants from the National Institutes of Health (NIH), Foundation for the NIH (FNIH), and the COPD Foundation, during the study, and grants from NIH outside the submitted work. ERB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Johnson & Johnson (Janssen), Novartis, Regeneron, and Sanofi Genzyme. ERB has also served as a paid consultant for AstraZeneca, MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. SAC reports personal fees from AstraZeneca, GlaxoSmithKline, Amgen, Glenmark, Sunovion, Genentech, and UpToDate, outside the submitted work. CBC reports grants from NIH/National Heart, Lung, and Blood Institute (NHLBI), FNIH, and COPD Foundation, during the conduct of the study. CBC reports personal fees from PulmonX, Nuvaira, and MGC Diagnostics, and is a Global Medical Expert for GlaxoSmithKline, outside the submitted work. MKH reports grants from NHLBI during the conduct of the study, personal fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Merck, Mylan, Teva, and Verona, and research support from Sanofi, Sunovion, and Novartis, outside the submitted work. NNH reports grants from NIH and COPD Foundation, grants and personal fees from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim, and personal fees from Mylan, outside the submitted work. ATH reports grants from NHLBI and FNIH during the conduct of the study. EAH reports grants from NIH during the conduct of the study. EAH is a founder and shareholder of VIDA Diagnostics, outside the submitted work. FJM reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Raziel, during the conduct of the study. FJM reports personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Miller Communications, National Society for Continuing Education, PeerView Communications, Chiesi, Sunovion, Physicians Education Resource, Canadian Respiratory Network, Teva, CSL Behring, and Sanofi/Regeneron; non-financial support from ProterixBio, Gilead, Nitto, Zambon, and twoXAR; personal fees, non-financial support, and non-personnel travel support from Genentech; personal fees from MD Magazine, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Patara/Respivant, Bayer, American Thoracic Society, Rockpointe, CME Outfitters, Dartmouth University, DevPro, Gala, Integritas, IQVIA, Projects in Knowledge, Vindico, and Academy for Continuing Healthcare Learning; IPF Study Steering Committee for Afferent/Merck, Biogen, Veracyte, Prometic, and Bayer; IPF Advisor for Bridge Biotherapeutics; IPF teleconference with AbbVie; and grants from NIH, Rare Disease Healthcare Communications, and Promedior/Roche, outside the submitted work. RP reports grants from NHLBI and COPD Foundation, during the conduct of the study. RP reports grants from the Department of Veterans Affairs, and personal fees from Partner Therapeutics, outside the submitted work. PGW reports personal fees from Sanofi, Regeneron, Glenmark Pharmaceuticals, Theravance, GlaxoSmithKline, and NGM Pharma, outside the submitted work. WKO'N reports grants from NIH/NHLBI, during the conduct of the study. RCB reports grants from NIH, during the conduct of the study; and personal fees from Parion Sciences, outside the submitted work. MK reports grants from NIH, during the conduct of the study; contracts from Genentech, Gala Therapeutics, AstraZeneca, Ionis Pharmaceuticals, and personal fees from Boehringer Ingelheim and Amgen, outside the submitted work. In addition, MK has a patent (methods for diagnosing or predicting chronic bronchitis) pending. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV 1 /FVC., Research Question: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease?, Study Design and Methods: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV 1 /FVC ≥ 0.7 and FEV 1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV 1 /FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV 1 /SVC of ≥ 0.7 and 120 with postbronchodilator FEV 1 /SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV 1 /SVC < 0.7 with those characteristics and outcomes., Results: Participants with FEV 1 /SVC < 0.7 were older and had lower FEV 1 and more emphysema than those with FEV 1 /SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV 1 /SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV 1 /SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV 1 /SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV 1 /SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV 1 /SVC < 0.7 or FEV 1 /SVC less than the lower limit of normal with chest CT scan features and progression to COPD., Interpretation: Low FEV 1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future., Trial Registry: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov., (Published by Elsevier Inc.)