ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma.

BACKGROUND: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings. OBJECTIVE: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma. METHODS: Induced sputum, blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and serum periostin were obtained twice during the 6-week run-in period in a clinical trial that enrolled patients 12 years and older with symptomatic, mild persistent asthma without controller therapy. The optimal threshold for each biomarker was based on achieving 80% or greater sensitivity. Performance of biomarkers (area under the receiver operating characteristics curve [AUC], range 0.0-1.0) in predicting sputum eosinophilia 2% or greater was determined; AUCs of 0.8 to 0.9 and more than 0.9 define excellent and outstanding discrimination, respectively. RESULTS: Of 564 participants, 27% were sputum eosinophilic, 83% were atopic, 70% had BEC of 200/uL or higher or FeNO of 25 ppb or greater; 64% of participants without sputum eosinophilia had elevated BEC or FeNO. The AUCs for BEC, FeNO, and both together in predicting sputum eosinophilia were all below the threshold for excellent discrimination (AUC 0.75, 0.78, and 0.79, respectively). Periostin (in adults) had poor discrimination (AUC 0.59; P = .02). CONCLUSIONS: In untreated mild persistent asthma, there is substantial discordance between sputum eosinophilia, BEC, and FeNO. Until prospective trials test the ability of alternative biomarkers to predict ICS response, BEC or FeNO phenotyping may be an option to consider ICS through a shared decision-making process with consideration of other clinical features.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

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.

Questions in Mild Asthma: An Official American Thoracic Society Research Statement.

Background: Patients with mild asthma are believed to represent the majority of patients with asthma. Disease-associated risks such as exacerbations, lung function decline, and death have been understudied in this patient population. There have been no prior efforts from major societies to describe research needs in mild asthma. Methods: A multidisciplinary, diverse group of 24 international experts reviewed the literature, identified knowledge gaps, and provided research recommendations relating to mild asthma definition, pathophysiology, and management across all age groups. Research needs were also investigated from a patient perspective, generated in conjunction with patients with asthma, caregivers, and stakeholders. Of note, this project is not a systematic review of the evidence and is not a clinical practice guideline. Results: There are multiple unmet needs in research on mild asthma driven by large knowledge gaps in all areas. Specifically, there is an immediate need for a robust mild asthma definition and an improved understanding of its pathophysiology and management strategies across all age groups. Future research must factor in patient perspectives. Conclusions: Despite significant advances in severe asthma, there remain innumerable research areas requiring urgent attention in mild asthma. An important first step is to determine a better definition that will accurately reflect the heterogeneity and risks noted in this group. This research statement highlights the topics of research that are of the highest priority. Furthermore, it firmly advocates the need for engagement with patient groups and for more support for research in this field.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative Losartan Effects on Emphysema Progression Clinical Trial.

Rationale: There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression. Methods: The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George's Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function-Short Form 20a. Measurements and Main Results: A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61-73) years and 48 (36-59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67-2.03) in the losartan group versus 0.66% (0.09-1.23) in the placebo group (P = NS). Conclusions: Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT02696564).

Lung Function and the Risk of Exacerbation in the ß-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Trial.

Rationale: The BLOCK COPD (ß-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) study found that metoprolol was associated with a higher risk of severe exacerbation. Objectives: To determine the mechanism underlying these results, we compared changes in lung function over the course of the study between treatment groups and evaluated whether baseline bronchodilator response or early reduction in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) was associated with exacerbation risk. Methods: We compared changes in lung function (FEV1 and FVC) over the treatment period between treatment groups using linear mixed-effect models. Cox proportional hazards models were used to evaluate the association between baseline bronchodilator responsiveness (FEV1, FVC, and combined FEV1 and FVC), early post-randomization (14 d) change in lung function, and the interaction between treatment assignment and these measures with risk of any or severe or very severe exacerbations. Negative binomial models were used to evaluate the relationship between bronchodilator responsiveness, the interaction between bronchodilator responsiveness and treatment assignment, and exacerbation rate. Results: Over the 336-day treatment period, individuals in the metoprolol group had a significantly greater decrease in logarithmic FEV1 from baseline to visit on Day 28 than individuals in the placebo group. Individuals in the metoprolol group had a significantly greater decrease in FVC from baseline to visits on Days 14 and 28, and also a significantly greater decrease in logarithmic FVC from baseline to visits on Days 42 and 112 than individuals in the placebo group. There were no associations between early lung function reduction or interactions between lung function reduction and treatment assignment and time to any or severe or very severe exacerbations. There were no interactions between treatment arm and baseline bronchodilator responsiveness measures on risk or rate of exacerbations. However, those with baseline FVC bronchodilator responsiveness had a higher rate of severe or very severe exacerbations (adjusted rate ratio, 1.62; 95% confidence interval, 1.04-2.48). Conclusions: Metoprolol was associated with reduced lung function during the early part of the treatment period, but these effects were modest and did not persist. Early lung function reduction and baseline bronchodilator responsiveness did not interact with the treatment arm to predict exacerbations; however, baseline FVC bronchodilator responsiveness was associated with a 60% higher rate of severe or very severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT02587351).

Biomarkers to Predict Response to Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists in Adolescents and Adults with Mild Persistent Asthma.

Rationale: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. Objectives: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 µg or 220 µg twice/d), LAMA (tiotropium, 5 µg/d), or placebo in adults (⩾18 yr) and adolescents (12-17 yr) separately. Methods: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV1]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7-0.8 is considered acceptable, more than 0.8-0.9 is considered excellent, and more than 0.9 is considered outstanding. Results: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (FeNO) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53-0.69], 0.64 [95% CI, 0.56-0.72], and 0.62 [95% CI, 0.54-0.70], respectively; all P < 0.01); the AUC for blood eosinophil levels and FeNO together was 0.66 (95% CI, 0.58-0.74; P < 0.001). In 58 adolescents, the number of positive aeroallergens and total serum immunoglobulin E each predicted ICS response (AUCs: 0.69 [95% CI, 0.52-0.85] and 0.73 [95% CI, 0.58-0.87], respectively; both P < 0.03); the AUC for both together was 0.73 (95% CI, 0.58-0.87; P = 0.003). After ipratropium bromide, FEV1 reversibility predicted LAMA response in adults (AUC: 0.61 [95% CI, 0.53-0.69], P = 0.007) but not in adolescents. Conclusions: The AUCs of the type 2 inflammatory biomarkers and physiological biomarkers we examined may not be high enough to confidently identify individuals with asthma who respond to ICS and LAMA. However, our findings indicate that the biomarkers that predict response to ICS or LAMA may differ in adults versus adolescents with uncontrolled mild persistent asthma. Prospective, biomarker-stratified clinical trials are needed to confirm these findings and to identify first-line controllers tailored for each population.

Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. METHODS: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). RESULTS: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10-04) and hospitalization (P = 5.21 × 10-03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). CONCLUSION: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.

BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 µg in children, 100 µg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 µg twice daily in children and 500 µg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 µg twice daily in children, 250 µg twice daily in adolescents and adults), and 5 × ICS versus 100 µg fluticasone plus a LABA (salmeterol 50 µg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 µg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.

Age-Dependent Associations Between 25-Hydroxy Vitamin D Levels and COPD Symptoms: Analysis of SPIROMICS.

INTRODUCTION: Age and vitamin D levels may affect symptom burden in chronic obstructive pulmonary disease (COPD). We used the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) to determine independent associations between vitamin D levels and COPD symptoms in different age strata. METHODS: Serum 25-hydroxy (OH)-vitamin D levels were modeled continuously and categorically (<20 ng/ml versus ≥20 ng/ml). Stratifying by age group (middle-age: 40-64 years old and older: >65 years old), multivariable modeling was performed to identify relationships between 25-OH-vitamin D levels and the COPD Assessment Test (CAT), the modified Medical Research Council score (mMRC), the St George's Respiratory Questionnaire (SGRQ) total and subdomain scores, the Veterans' Specific Activity Questionnaire, and the 6-minute walk test distance. RESULTS: InIn the middle-aged group, each 5 ng/ml higher 25-OH-vitamin D level was independently associated with more favorable CAT score (-0.35 [-0.67 to -0.03], P=0.03), total SGRQ (-0.91 [-1.65 to -0.17]; P=0.02), and the SGRQ subdomains (Symptoms:-1.07 [-1.96 to -0.18], P=0.02; Impact: -0.77 [-1.53 to -0.003], P=0.049; Activity: -1.07 [-1.96 to -0.18], P=0.02). These associations persisted after the addition of comorbidity score, reported vitamin D supplementation, outdoor time, or season of blood draw to models. No associations were observed between 25-OH-vitamin D levels and symptom scores in the older age group. DISCUSSION: When controlled for clinically relevant covariates, higher 25-OH-vitamin D levels are associated with more favorable respiratory-specific symptoms and quality-of-life assessments in middle-age but not older COPD individuals. Study of the role of vitamin D supplementation in the symptom burden of younger COPD patients is needed.

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV1 and peripheral oxygen saturation (P < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (P < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) (P < 0.001).Conclusions: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Novel Respiratory Disability Score Predicts COPD Exacerbations and Mortality in the SPIROMICS Cohort.

Rationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype. Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death. Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls). Measurements: We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George's Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20. Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point -1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability. Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.

Serum IgG Levels and Risk of COPD Hospitalization: A Pooled Meta-analysis.

BACKGROUND: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations. RESEARCH QUESTION: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD. STUDY DESIGN AND METHODS: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status. RESULTS: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001. INTERPRETATION: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials.

BACKGROUND: Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk. OBJECTIVE: We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations. METHODS: One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760). RESULTS: Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]). CONCLUSION: Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).