Rationale: Serum IgG deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD), but it is unclear whether concentrations in the lower end of the normal range still confer risk. Objectives: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. Methods: Former and current smokers in SPIROMICS (the Subpopulations and Intermediate Outcome Measures of COPD study) (n = 1,497) were studied: 1,026 with COPD and 471 at risk for COPD. In a subset (n = 1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographic characteristics, current smoking, smoking history, FEV1 percent predicted, inhaled corticosteroids, and serum IgA. Measurements and Main Results: The 35th percentile (1,225 mg/dl in this cohort) of IgG was the best cutoff by Akaike information criterion. Below this, there was increased exacerbation risk (incidence rate ratio [IRR], 1.28; 95% confidence interval [CI], 1.08-1.51). Among subclasses, IgG1 and IgG2 below the 35th percentile (354 and 105 mg/dl, respectively) were associated with increased risks of severe exacerbation (IgG1, IRR, 1.39; 95% CI, 1.06-1.84; IgG2, IRR, 1.50; 95% CI, 1.14-1.1.97). These associations remained significant when additionally adjusting for a history of exacerbations. Conclusions: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting that subtle impairment of humoral immunity may be associated with exacerbations.

Rationale: In World Health Organization (WHO) Group 1 pulmonary hypertension (PH), females show higher prevalence, yet males experience greater mortality. Similarly, males with chronic obstructive pulmonary disease (COPD)-associated PH may face worse mortality than females. We investigated whether COPD-PH exhibits this sex divergence, using the Genetic Epidemiology of COPD (COPDGene) data alongside a validated imaging biomarker of PH, the pulmonary artery to aorta (PA:A) ratio. Methods: COPDGene enrolled 10,198 ever smokers aged 45-80 in the United States. Study visits occurred every five years, including health history, symptom questionnaires, spirometry, six-minute walk distance (6MWD), and chest computed tomography (CT). We included participants with GOLD grade 1-4 COPD who had CTs at enrollment (P1) and 5-year follow-up (P2). We measured the PA:A ratio, with PA:A>1 indicating pulmonary arterial enlargement (PAE). Participants were categorized into four groups based on PAE status at P1 and P2. Generalized logit models estimated PAE prevalence by sex. Cox proportional hazard models evaluated associations between PAE and all-cause mortality. Negative binomial models assessed PAE associations with COPD exacerbations (ECOPD). Logistic regression was used to examine associations between PAE and both 6MWD decline (>15% decrease) and new-onset hypoxemia (new oxygen prescription) between P1 and P2. Analyses were adjusted for age, race, body mass index, GOLD grade and comorbidities (heart failure, venous thromboembolism, and sleep apnea). Results: We included 2,041 participants, with PAE observed at P1 and/or P2 in 25.7% of females and 12.5% of males. Females had higher odds of PAE at P1 only [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.91-3.53] and both P1+P2 (OR 3.32, 95%CI 2.14-5.14), but not P2 only (incident PAE; OR 1.72, 95%CI 0.98-3.03). PAE at P1 and/or P2 [(hazard ratio (HR) 1.59, 95%CI 1.32-1.92, p<0.01] and male sex (HR 1.56, 95%CI 1.32-1.84, p<0.01) were associated with higher mortality, without significant interactions observed between sex and PAE (Figure). Females demonstrated a greater risk of severe ECOPD (risk ratio 1.41, p<0.01) and new-onset hypoxemia (OR 1.18, p=0.036). Compared to participants without PAE, those with incident PAE had a greater likelihood of 6MWD decline (OR 1.67, p=0.025), and those with PAE at both P1+P2 had more new-onset hypoxemia (OR 2.41, p<0.01). Conclusions: In the COPDGene cohort, females had higher prevalence of PAE and greater risk of severe ECOPD and new-onset hypoxemia, whereas males exhibited higher mortality. These findings recapitulate the sex divergence observed in WHO Group 1 PH. PAE trajectory in COPD-PH warrants further investigation.

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown. Objectives: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history. Methods: We analyzed data from COPDGene study participants with ⩾10 pack-years of cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator FEV1/FVC greater than or equal to the lower limit of normal and FEV1 greater than or equal to the lower limit of normal. We examined whether respiratory exacerbations occurring between Visit 1 and the 5-year follow-up visit (Visit 2) were associated with FEV1 decline and all-cause mortality. Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between Visits 1 and 2 was associated with a 2.96 ml/yr FEV1 decline (95% confidence interval [CI], 1.81 to 4.12; P < 0.001) at Visit 2. Experiencing one or more severe exacerbations between Visits 1 and 2 was associated with 14.6 ml/yr FEV1 decline relative to those with no severe exacerbations (95% CI, 8.56 to 20.6; P < 0.001). Individuals with one or more severe exacerbations between Visits 1 and 2 had increased mortality compared with those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio, 1.97; 95% CI, 1.40 to 2.77; P < 0.001). Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated with lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

Background COPD has high mortality, compounded by comorbid cardiovascular disease. We investigated two ECG markers, Cardiac Infarction Injury Score (CIIS) and P pulmonale, as prognostic tools for adverse cardiopulmonary events in COPD. Methods This was a post hoc analysis of the IMPACT trial. Outcomes included odds (odds ratio, 95% confidence intervals) of adverse cardiopulmonary events stratified by CIIS threshold (<20 versus >= 20) and P pulmonale (baseline). Events included all-cause death, hospitalisation or death, cardiovascular adverse event of special interest, severe COPD exacerbations, and moderate/severe COPD exacerbations. We also assessed the effects of fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol or umeclidinium/vilanterol based on CIIS and P pulmonale. Results We included 9448 patients. Patients with CIIS >= 20 had greater odds of all-cause death (1.73[1.27-2.37]; p<0.001), hospitalisation/death (1.33[1.17-1.50]; p<0.001), CVAESI (1.27[1.08-1.48]; p<0.005), severe COPD exacerbations (1.41[1.21-1.64]; p<0.001) and moderate/severe COPD exacerbations (1.25[1.13-1.40]; p<0.001) versus CIIS <20. Patients with P pulmonale (versus without) had greater odds of all-cause death (2.25[1.54-3.29]; p<0.001), hospitalisation/death (1.51[1.28-1.79]; p<0.001), severe COPD exacerbations (2.00[1.65-2.41]; p<0.001) and moderate/severe COPD exacerbations (1.25[1.08-1.46]; p<0.001). A combined model demonstrated patients with CIIS >= 20 and P pulmonale had increased risk of all-cause death (3.38[1.23-9.30]; p=0.019), hospitalisation/death (1.61[1.14-2.22]; p=0.004), and rate of severe COPD exacerbations (1.89[1.22-2.91]; p=0.004) and moderate/severe COPD exacerbations (1.25[1.00-1.56]; p=0.046). The risk of all-cause death and CVAESI was reduced with FF/UMEC/VI versus UMEC/VI in patients with CIIS >= 20, but not CIIS <20. Conclusions These findings suggest potential clinical relevance of CIIS and P pulmonale as risk indicators for adverse cardiopulmonary events in COPD.

Whether socioeconomic status is associated with pulmonary conditions in BMT survivors is unknown. In this study, we used data from the BMT Survivor Study (BMTSS) to determine the association between low annual household income and adverse pulmonary conditions (asthma, chronic cough or dyspnea, dyspnea at rest, recurrent pneumonia, current oxygen use) and health status in a retrospective cohort of BMT survivors. BMTSS includes individuals who received BMT between 1974 and 2014 and survived for ≥ 2y after BMT at one of three participating sites. BMT survivors completed the BMTSS survey, providing details on demographics (including annual household income) and chronic health conditions as diagnosed by their healthcare providers. We used logistic regression models to determine the odds of low annual household income (≤49,999) associated with a post-BMT pulmonary condition in BMT survivors, adjusting for relevant clinical and sociodemographic variables. Our analysis included 2,814 participants (median age 58y; 44

Background The efficacy and safety of ensifentrine, a novel PDE3/PDE4 inhibitor, were previously evaluated in the ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057) trials. Here, we present a pooled post-hoc subgroup analysis of patients according to background chronic obstructive pulmonary disease (COPD) maintenance medication regimens. Objective This analysis aimed to explore the efficacy and safety of ensifentrine in patients receiving long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA + ICS). Methods Eligible patients had moderate to severe COPD, were aged 40–80 years, and were symptomatic at randomization. Patients were randomized 5:3, receiving twice-daily ensifentrine 3 mg or placebo via standard jet nebulizer over 24 weeks. Results The pooled post-hoc analysis included 485 LAMA patients and 272 LABA + ICS patients. Ensifentrine showed lung function improvement over placebo at week 12, including average FEV1 AUC0–12 h in the LAMA (placebo-corrected least squares mean change from baseline [LSMC], 92 mL; 95% CI, 54, 131; p < 0.001) and LABA + ICS subgroups (LSMC, 74 mL; 95% CI, 27, 121; p = 0.002). Ensifentrine reduced the rate and risk of exacerbations in both LAMA (48% and 50%, respectively) and LABA + ICS (51% and 56%, respectively) subgroups. Ensifentrine-treated patients reported improvement in symptoms and quality of life over 24 weeks. The safety profile of ensifentrine in each subgroup was similar to the profile in the pooled modified intention-to-treat population. Conclusions Nebulized ensifentrine offers a novel non-steroidal anti-inflammatory and bronchodilator treatment added to existing LAMA or LABA + ICS treatment options in patients with moderate to severe, symptomatic COPD.

BACKGROUND:Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the alpha-1 antitrypsin (AAT) serpin antiprotease, leading to protease-antiprotease imbalance. Weekly intravenous AAT therapy (augmentation) is the only specific treatment available. Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy. Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD. METHODS:We conducted two complementary, double-blind, randomised, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 and 240 mg twice daily without augmentation. Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (Aα-Val360 and desmosine/isodesmosine) as well as safety and tolerability. RESULTS:We enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS). Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at alvelestat 240 mg twice daily. There was no effect of alvelestat 120 mg on disease activity biomarkers, while 240 mg demonstrated significant reduction in Aα-Val360 and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected. CONCLUSIONS:Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice-daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice-daily dose into a clinical end-point study.

Rationale: Among tobacco-exposed persons with preserved spirometry (TEPSs), 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: We sought to determine differential disease characteristics and trajectories associated with lung volume indices among TEPSs in the SPIROMICS cohort. Methods: We categorized TEPSs (n = 814) by tertiles (low, intermediate, and high) of TLC or residual volume-to-TLC ratio (RV/TLC) derived from baseline computed tomography 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 computed tomography-measured emphysema (Hounsfield units [HU] ⩽-950; parametric response mapping [PRM] of emphysema), air trapping (HU⩽-856; PRM of functional small airway disease; a disease probability measure for non-emphysematous gas trapping), airway geometry (the mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), respiratory symptoms (on the modified Medical Research Council Dyspnea Scale; COPD Assessment Test [CAT]; St. George's Respiratory Questionnaire [SGRQ]; and Short Form-12 [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 vs. former smoker) and burden (pack-years). Results: In TEPSs, the pattern of spirometric disease progression differed between participants with [TLC]high and those with [RV/TLC]high: There was increased forced vital capacity with stable forced expiratory volume in 1 second in participants with [TLC]high, versus unchanged forced vital capacity but nominally decreased forced expiratory volume in 1 second in those with [RV/TLC]high. Compared with participants with [TLC]high, TEPSs with [RV/TLC]high had less emphysema (by HU ⩽-950) but more airway disease (by HU ⩽-856; PRM of functional small airway disease; disease probability measure for gas trapping, and mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), more respiratory symptoms (on the modified Medical Research Council Dyspnea Scale, CAT, SGRQ, and SF12), and more severe exacerbations at baseline. Over an average follow-up of 4.1 ± 2.4 years (range = 0.5-8.5 yr), TEPSs with [RV/TLC]high also had a higher likelihood of developing more severe spirometric disease (preserved ratio impaired spirometry or Global Initiative for Chronic Obstructive Lung Disease Classification 2) and worsening of their respiratory symptoms (on the CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not significantly different between the two categories over the follow-up period, TEPSs with [RV/TLC]high were more likely to have been prescribed a respiratory inhaler at their last follow-up visit. Conclusions: In these TEPSs from the 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 in the COPDGene cohort using TLC versus FRC/TLC stratification.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) experience high levels of psychological stress. Stress may affect respiratory rate, leading to more symptoms for individuals with expiratory flow limitation. The impact of stress on important clinical outcomes including symptoms, health-related quality of life (HRQOL), and tobacco use is unknown. In this study, we aim to estimate associations of perceived stress with symptoms, quality of life, and tobacco use. Methods: Participants were recruited from the SPIROMICS study. Perceived stress was measured by the Perceived Stress Scale (PSS) (range 0-40). Symptoms were measured by the COPD Assessment Test (CAT)(range 0-40). HRQOL was measured by the St. George's Respiratory Questionnaire (SGRQ) (range 0-100). Tobacco use was self-reported. Pearson's correlation was used to determine the correlation between stress and symptoms and HRQOL. Multivariable linear regression models were used to estimate associations between stress and symptoms and HRQOL measures. Logistic regression was used to measure the association between stress and current tobacco use Results: A total of 311 participants with COPD were included in the study, of which 46% were female and 18% were of a minority race. Nearly 25% of the participants were current smokers and 70% had either moderate or severe airflow obstruction. Perceived stress was moderately correlated with CAT score (r = 0.49; p = <0.001) and weakly correlated with SQRQ score (r = 0.34; p = <0.001) (Figure 1). In linear regression models adjusted for age, gender, race, current smoking status, and FEV1 % predicted, PSS was positively associated with CAT score (Beta[SE]: 0.42(0.06), p=<0.001) and SGRQ score (Beta[SE]: 0.41 (0.14); p<0.001). In a logistic regression model adjusting for age, gender, race, and FEV1% predicted, PSS was not significantly associated with current tobacco use (AOR 1.01 (0.96, 1.06). Conclusion: Perceived stress is common and significantly associated with symptom burden and poor HRQOL in adjusted models. In this population, an increase in stress level was not associated with current tobacco use. Stress-reduction has been shown to be important for improving quality of life in other chronic health conditions and our findings suggest that high perceived stress may be a therapeutic target in COPD.

Chronic obstructive pulmonary disease (COPD) among individuals living in rural areas is associated with worse health outcomes. New strategies are needed to study interventions and deliver proven therapies to people with COPD in rural areas. This statement from the COPD Foundation Medical and Scientific Advisory Committee highlights specific challenges in capturing the key characteristics of rural residents and identifies approaches to improve research for COPD in rural areas. Specifically, geographic isolation, access to specialist care, lack of broadband access, and complex tobacco and exposure histories are drivers of COPD health disparities in rural populations that are not captured by conventional definitions of rurality. To improve the design of research studies among people with COPD living in rural settings, certain actions are identified. These include the inclusion of specific covariates such as distance and travel time to health care services and multidimensional assessment tools for societal and individual health determinants in data collection; deploying qualitative and mixed-methods research designs to assess cultural differences driving health care access and health behaviors; decentralized carousel recruitment models in study design; and operationalizing research partnerships to improve support for primary care providers engaged in research. These approaches will permit robust assessment of the complex matrices driving disparate health outcomes among people with COPD in rural areas.

Background: Identifying priority challenges of older adults with chronic obstructive pulmonary disease (COPD) is critical to designing interventions aimed at improving their well-being and independence. Objective :To prioritize challenges of older adults with COPD and those who care for them to guide refinement of a telephonic nurse coach intervention for patients with COPD and their family caregivers (EPIC: Empowering People to Independence in COPD). Design: Multiphase study guided by Baltes Theory of Successful Aging and the 5Ms Framework: Phase 1: Nominal group technique (NGT), a structured process of prioritizing responses to a question through group consensus. Phase 2: Rapid qualitative analysis. Phase 3: Intervention mapping and refinement. Setting: Ambulatory, virtual. Participants: Older adults with COPD, family caregivers, clinic staff (nurses, respiratory therapists), clinicians (physicians, nurse practitioners), and health system leaders. Results: NGT sessions were conducted by constituency group with 37 participants (n = 7 patients, n = 6 family caregivers, n = 8 clinic staff, n = 9 clinicians, n = 7 health system leaders) (Phase 1). Participants generated 92 statements across five themes (Phase 2): (1) "Barriers to care", (2) "Family caregiver needs", (3) "Functional status and mobility issues", (4) "Illness understanding", and (5) "COPD care complexities". Supplemental oxygen challenges emerged as a critical problem, and prioritized challenges differed by group. Patients and clinic staff prioritized "Functional status and mobility issues", family caregivers prioritized "Family caregiver needs", and clinicians and health system leaders prioritized "COPD care complexities". Intervention mapping (Phase 3) guided EPIC refinement focused on meeting patient priorities of independence and mobility but accounting for all priorities. Conclusions: Diverse constituency groups identified priority challenges for older adults with COPD. Functional status and mobility issues, particularly related to supplemental oxygen, emerged as patient prioritized challenges. Implications :Patient-centered interventions for older adults with COPD must account for their prioritized functional and supplemental oxygen needs and explore diverse constituent perspectives to facilitate intervention enrichment.

BACKGROUND:Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS:Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS:Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS:Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

"Bronchiectasis-COPD Overlap: A ROSE by Any Other Name?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.