Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT.

Rationale: There is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear. Objectives: To examine the relationship between BMI and adverse outcomes in COPD. Methods: This post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m2], normal weight [BMI 20 to <25 kg/m2], overweight [BMI 25 to <30 kg/m2], obesity class I [BMI 30 to <35 kg/m2], obesity class II [BMI 35 to <40 kg/m2], and obesity class III [BMI ⩾ 40 kg/m2]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. Results: In TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62-2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16-1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR. Conclusions: These results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD.

Aclidinium bromide/formoterol fumarate as a treatment for COPD: an update.

Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium/formoterol has been demonstrated consistently in patients with moderate-to-severe COPD versus placebo and monocomponents, with a comparable safety profile.Areas covered: This review examines recent research findings that expand our understanding of the impact of aclidinium/formoterol on the burden of COPD. Reviewed outcomes include improvements in lung function, respiratory symptoms, health-related quality of life, exercise tolerance, exacerbation rates, and clinically important deteriorations. In addition, the reported cardiovascular safety of aclidinium and current LAMA/LABA treatment recommendations are discussed.Expert opinion: Aclidinium/formoterol reduces disease burden in patients with COPD, including those that are treatment-naïve, without a significant increase in safety risk compared with monotherapies. Furthermore, evidence supports an improvement in lung function over a 24-hour period with aclidinium/formoterol treatment versus monotherapy and placebo, which may offer an advantage over some once-daily LAMA/LABA combinations. In summary, the recent evidence discussed in this review adds weight to the use of LAMA/LABA combinations as an initial therapy for certain patients newly diagnosed with COPD.

Bronchoalveolar Lavage and Plasma Cathelicidin Response to 25-Hydroxy Vitamin D Supplementation: A Pilot Study.

INTRODUCTION: Cathelicidin is a vitamin D-regulated, antimicrobial peptide involved in the innate immune response of the airways. Reduced plasma cathelicidin concentrations are independently associated with worse pulmonary outcomes in current and former smokers. This study aimed to determine whether oral vitamin D supplementation in vitamin D-deficient current smokers increases plasma and bronchoalveolar lavage (BAL) cathelicidin levels. METHODS: Vitamin D-deficient (25-hydroxy vitamin D [25-OH vitamin D] <20 ng/ml) smokers (n=17) underwent collection of plasma and BAL for cathelicidin and 25-OH vitamin D measurements before and after 8 weeks of oral supplementation with 50,000 IU vitamin D3 weekly. Differences between baseline and 8-week levels of cathelicidin and 25-OH vitamin D in blood and BAL were assessed along with correlations between serum 25-OH vitamin D, plasma cathelicidin, and BAL cathelicidin. RESULTS: At baseline, there was no correlation between BAL and plasma cathelicidin. There was a significant increase in 25-OH vitamin D (median 17.0 to 43.3 ng/mL, p<0.001) after 8 weeks of vitamin D supplementation. There was no change in plasma cathelicidin (p=0.86), BAL cathelicidin (p=0.31), or BAL 25-OH vitamin D (p=0.89). There was no correlation between serum 25-OH vitamin D and either BAL or plasma cathelicidin post-supplementation. CONCLUSIONS: Oral vitamin D supplementation, while increasing serum 25-OH vitamin D levels, does not increase plasma or BAL cathelicidin levels in vitamin D-deficient, active smokers. The lack of increased BAL cathelicidin may be explained by multiple factors related to dosing, smoking effects, or putative mechanisms of engagement. Future studies are needed to determine the effects of vitamin D supplementation on lung and blood functional activity.

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.

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

BACKGROUND: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain. METHODS: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 µg, umeclidinium (a LAMA) at a dose of 62.5 µg, and vilanterol (a LABA) at a dose of 25 µg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 µg and 25 µg, respectively) and umeclidinium-vilanterol (at doses of 62.5 µg and 25 µg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). CONCLUSIONS: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial.

IMPORTANCE: Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. OBJECTIVE: To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS: Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS: Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE: Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01052116.

Maternal vitamin A supplementation and lung function in offspring.

BACKGROUND: Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic alveolar formation, and vitamin A deficiency in a mother during pregnancy could have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or beta carotene in women before, during, and after pregnancy on the lung function of their offspring, in a population with chronic vitamin A deficiency. METHODS: We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997. RESULTS: Of 1894 children who were alive at the end of the original trial, 1658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1371 of the children (83% of those eligible) between October 2006 and March 2008. Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV(1)) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV(1), 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV(1) and FVC values that were similar to those of children whose mothers had received placebo (FEV(1), 14 ml higher with beta carotene; 95% CI, -24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, -21 to 55). CONCLUSIONS: In a chronically undernourished population, maternal repletion with vitamin A at recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years.

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Feasibility of retinoids for the treatment of emphysema study.

BACKGROUND: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. METHODS: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.0% of predicted] and CT density mask (38.5 +/- 12.8% of voxels <- 910 Hounsfield units) [mean +/- SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. RESULTS: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. CONCLUSIONS: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.