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Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.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?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 FEVBoth 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 FEVDemonstration 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.

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Background Small airways are known to be affected early in the course of chronic obstructive pulmonary disease (COPD); however, traditional spirometric indices may not accurately identify small airways disease. Research Question Can FEV3/FEV6 identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? Study Design and Methods We included eight hundred thirty-two current and former smokers with post-bronchodilator FEV1/FVC ≥0.7 from the SPIROMICS cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 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 FEV3/FEV6 Interpretation FEV3/FEV6 is a routinely available and repeatable spirometric index which can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV3/FEV6 can identify those at risk for future development of COPD and respiratory exacerbations.

Background Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies. Research Question What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)? Study Design and Methods Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis. Results The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes. Interpretation Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

BACKGROUND: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. METHODS: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV(1)/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV(1). RESULTS: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. CONCLUSIONS: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

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 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

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

Background The mechanism by which various classes of medication reduce COPD exacerbation risk remains unknown. We hypothesized a correlation between reduced exacerbation risk and improvement in airway patency as measured according to FEV1. Methods By systematic review, COPD trials were identified that reported therapeutic changes in predose FEV1 (dFEV1) and occurrence of moderate to severe exacerbations. Using meta-regression analysis, a model was generated with dFEV1 as the moderator variable and the absolute difference in exacerbation rate (RD), ratio of exacerbation rates (RRs), or hazard ratio (HR) as dependent variables. Results The analysis of RD and RR included 119,227 patients, and the HR analysis included 73,475 patients. For every 100-mL change in predose FEV1, the HR decreased by 21% (95% CI, 17-26; P Conclusions A significant correlation between increased FEV1 and lower COPD exacerbation risk suggests that airway patency is an important mechanism responsible for this effect.

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 (FEV(1)/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

An 18-year-old woman with no previous medical history presented to an outside hospital facility with acute chest pain. She had mild shortness of breath, particularly with exertion, for the prior 2 months.

Background: Disease progression in COPD is associated with a decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years. Methods: This was a randomized, double-blind, placebo-controlled trial of tiotropium, 18 m g daily, in patients with COPD (FEV 1 /FVC , 70%; postbronchodilator FEV 1 , 65%). The primary end point was ET at 90% of baseline maximum work rate at 96 weeks. Secondary end points were ET at other visits, ET by smoking status, spirometry, and St. George’s Respiratory Questionnaire (SGRQ). Results: A total of 519 patients were randomized (tiotropium 260, placebo 259). Mean age was 65 years, 77% were men, 34% were continuing smokers, and mean FEV 1 was 1.25 L (44% predicted). Signifi cantly more patients discontinued placebo (hazard ratio [95% CI], 0.61 [0.44-0.83]). Baseline ET was 301 s (improvement tiotropium/placebo was 13% overall; P 5 .009; 18% at 48 weeks, P 5 .004; 13% at 96 weeks, P 5 .106). In patients with baseline ET between 2 and 10 min (n 5 404), improvement at 96 weeks was 19% ( P 5 .04). Current smokers had higher ET with tiotropium vs placebo ( P 5 .018). FEV 1 /FVC improved with tiotropium ( P , .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units ( P 5 .007). Conclusions: Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, the 96-week difference was not statistically signifi cant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefi ts of long-acting bronchodilator therapy. Trial registry: ClinicalTrials.gov; No.: NCT00525512; URL: www.clinicaltrials.gov CHEST 2013; 144(2):490–497

Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.

Quantitative analysis of high-resolution chest CT scan (QCT) is an established method for determining the severity and distribution of lung parenchymal destruction inpatients with emphysema. Diffusing capacity of the lung for carbon monoxide (D(LCO)) is a traditional physiologic measure of emphysema severity and is probably influenced more by destruction of the alveolar capillary bed than by membrane diffusion per se. We reasoned that D(LCO) should correlate with tissue volume from QCT.A total of 460 patients with upper-lobe-predominant emphysema were enrolled in the study. Th e mean (SD) of percent predicted values for FEV 1 , total lung capacity, and D(LCO) were 30.6% (8.0%), 129.5% (18.1%), and 6.7% (13.1%), respectively. QCT was performed using custom soft ware; the relationship between D(LCO) and various metrics from QCT were evaluated using Pearson correlation coefficients.On average, whole-body plethysmography volumes were higher by 841 mL compared with QCT-calculated total lung volume. However, there was a strong correlation between these measurements (r=0.824, P.0001). D(LCO) correlated with total lung volume (r=0.314, P.0001), total tissue volume (r=0.498, P.0001), and percentage of lung with low density (-950 Hounsfield units) (r=-0.337, P.0001).In patients with severe emphysema, D(LCO) correlates best with total tissue volume,supporting the hypothesis that pulmonary capillary blood volume is the main determinant of D(LCO) in the human lung. Th e relationships between D(LCO) and various anatomic metrics of lung parenchymal destruction from QCT inform our understanding of the relationship between structure and function of the human lung.

Disease progression in COPD is associated with a decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years.This was a randomized, double-blind, placebo-controlled trial of tiotropium, 18 μg daily, in patients with COPD (FEV1/FVClt; 70%; postbronchodilator FEV1lt; 65%). The primary end point was ET at 90% of baseline maximum work rate at 96 weeks. Secondary end points were ET at other visits, ET by smoking status, spirometry, and St. George's Respiratory Questionnaire (SGRQ).A total of 519 patients were randomized (tiotropium 260, placebo 259). Mean age was 65 years, 77% were men, 34% were continuing smokers, and mean FEV1 was 1.25 L (44% predicted). Significantly more patients discontinued placebo (hazard ratio [95% CI], 0.61 [0.44-0.83]). Baseline ET was 301 s (improvement tiotropium/placebo was 13% overall; P = .009; 18% at 48 weeks, P = .004; 13% at 96 weeks, P = .106). In patients with baseline ET between 2 and 10 min (n = 404), improvement at 96 weeks was 19% (P = .04). Current smokers had higher ET with tiotropium vs placebo (P = .018). FEV1/FVC improved with tiotropium (Plt; .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = .007).Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, the 96-week difference was not statistically significant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefits of long-acting bronchodilator therapy.ClinicalTrials.gov; No.: NCT00525512; URL: www.clinicaltrials.gov.

Background: Supplemental oxygen usually increases exercise capacity in hypoxemic COPD, but some patients are refractory because of venous admixture. An arteriovenous fi stula (AVF) with left-to-right shunt increases mixed venous oxygen content and cardiac output; therefore, this might improve arterial oxygen delivery. We hypothesized that creation of an AVF would therefore increase exercise capacity in severe COPD. Methods: We created an AVF in 12 patients with severe hypoxemic COPD: mean (SD) age, 66 (6) years; Pa o 2, 57.5 (3.0) mm Hg, and FEV 1 , 19% (8%) predicted. We measured 6-min walk distance (6MWD ) while the subjects were breathing room air and again while they were breathing portable supplemental oxygen at baseline, 6 weeks, and 12 weeks after creation of an AVF in the iliofemoral region. Results: After surgery, the mean (SEM) 6MWD increased from 217 (63) m at baseline to 272 (18) m and 276 (25) m, 6 weeks and 12 weeks after surgery, respectively. Patients who walked . 54 m further while breathing supplemental oxygen at baseline (n 5 5) increased 6MWD while breathing room air by 129 (34) m after 6 weeks ( P 5 .02) and by 124 (29) m after 12 weeks ( P 5 .004). Walk- ing distance did not change in patients who did not have a clinically meaningful response to oxygen at baseline. Conclusions: An iliofemoral AVF increased 6MWD patients with severe COPD, matching the improvement seen with supplemental oxygen. An initial response to supplemental oxygen pre- dicted a therapeutic response to the AVF.

Pulmonary rehabilitation (PR) improves exercise tolerance in COPD patients. Tiotropium is a once-daily, inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction. We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR.In a randomized, double-blind, placebo-controlled trial (tiotropium, n = 47; placebo, n = 44), tiotropium (18 microg qd) was administered to COPD patients participating in 8 weeks of PR (treadmill training three times a week;/= 30 min per session) at 17 sites. Study drug was administered 5 weeks prior to, 8 weeks during, and 12 weeks following PR. The primary end point was treadmill walking (0% incline) endurance time at 80% of maximum speed attained in an initial incremental test. The transition dyspnea index (TDI), St. George's respiratory questionnaire (SGRQ), and rescue albuterol use were secondary end points.Mean age of the 93 participants was 67 years, 57% were men, and mean FEV(1) was 0.88 L (34% predicted).Mean endurance time differences (tiotropium minus placebo) prior to PR, at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p0.05). At 12 weeks after PR, TDI focal scores were 1.75 for tiotropium and 0.08 for placebo (p0.05). Relative to placebo, tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p/= 0.05 for 17 of 25 weeks).Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinically meaningful improvements in dyspnea and health status compared to PR alone. Improvements with tiotropium were sustained for 3 months following PR completion.

Uncertainty exists as to whether pectus excavatum causes true physiologic impairments to exercise performance as opposed to lack of fitness due to reluctance to exercise. The purpose of this study was to examine the effect of pectus excavatum on ventilatory and cardiovascular responses to incremental exercise in physically active patients.Twenty-one patients with pectus excavatum (age range, 13 to 50 years; mean [+/- SD] age, 23.6 +/- 8.9 years; severity index range, 3.7 to 8.0; mean severity index, 5.1 +/- 1.2) were referred for preoperative evaluation. Eighteen of the patients (85%) had a history of performing aerobic activity ranging from 30 min to 2 h per day (mean duration, 1.0 +/- 0.61 h per day) for 3 +/- 1.5 days per week. Patients performed pulmonary function tests, and submaximal and maximal incremental exercise testing.On maximal exercise testing, the maximum oxygen uptake (O(2)max), and oxygen-pulse were significantly lower than the reference values (t(20) = 6.17 [p0.0001] and t(20) = 4.52 [p0.0001], respectively). Furthermore, patients exhibited cardiovascular limitation, but not ventilatory limitation. Despite their high level of habitual exercise activity, the overall metabolic threshold for lactate accumulation was abnormally low (ie, 41% of the reference value for O(2)max) especially in those with a pectus severity index (PSI) of4.0 (39% of the reference value of O(2)max), which is consistent with cardiovascular impairment rather than physical deconditioning. Patients with a PSI of4.0 were also eight times more likely to have reduced aerobic capacity than patients who had a low severity index, despite their level of exercise participation. On submaximal testing, we found that the time constant for O(2) uptake kinetics was 37.4 s for the on-transit and 41.6 s for the off-transit. The observed values for FVC, FEV(1), maximum voluntary ventilation, and diffusing capacity of the lung for carbon monoxide were significantly lower than reference values, but those for total lung capacity and residual volume were not significantly lower than reference values.The information derived from this study supports the opinion that pectus excavatum is associated with true physiologic impairment and reduced exercise capacity, predominantly due to impaired cardiovascular performance rather than ventilatory limitation. Furthermore, the impairment is not explained by physical deconditioning.

Background Habitual smoking of alkaloidal cocaine (crack) has been reported to be associated with a number of cardiopulmonary complications that may not be clinically obvious but could potentially interfere with normal physiologic responses to exercise and thus impair maximum exercise performance. Study objective To evaluate the impact of regular use of cocaine on maximum exercise. Design Observational study in crack users and age- and gender-matched control subjects. Subjects Thirty-five habitual cocaine smokers (21 male and 14 female) and 29 age-matched sedentary control nonsmokers of cocaine (15 male and 14 female), all of whom were in good general health. Methods In these subjects, we compared physiologic responses to symptom-limited, incremental maximal exercise performed on a cycle ergometer using a ramp protocol. Comparisons were made for men and women separately. Results For both men and women, long-term cocaine smokers had a reduced aerobic capacity (maximum oxygen consumption) compared with control nonsmokers but did not show evidence of ventilatory limitation, reduced gas exchange threshold, increased physiologic dead space, or gas exchange abnormality at maximum exercise compared with the healthy control subjects. Although cocaine smokers had reduced maximum heart rates compared with control subjects, the relationship between submaximal heart rate and oxygen uptake was normal, indicating a normal cardiovascular response pattern. However, effort perception was similar between the two groups despite the difference in heart rate at maximum exercise, suggesting the possibility of perceptual dysfunction for effort. Differences in aerobic capacity between the crack users and nonusers could not be explained by differences in physical fitness or altered perception of dyspnea. Conclusion In the subjects we studied, long-term cocaine smoking was associated with reduced maximum exercise performance, probably due to poor motivation or altered effort perception. No other identifiable physiologic abnormality appeared to limit exercise in the habitual crack users.