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Bernt Boegvald Aarli,1,2 Peter MA Calverley,3 Robert L Jensen,4 Raffaele Dellacà,5 Tomas ML Eagan,1,2 Per S Bakke,1 Jon A Hardie1 1Department of Clinical Science, University of Bergen, 2Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway; 3Clinical Science Centre, University Hospital Aintree, Liverpool, UK; 4LDS Hospital, Pulmonary Division, Salt Lake City, UT, USA; 5TBM-Lab, Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano University, Milano, Italy Background: Tidal expiratory flow limitation (EFLT) is frequently found in patients with COPD and can be detected by forced oscillations when within-breath reactance of a single-breath is ≥0.28 kPa·s·L-1. The present study explored the association of within-breath reactance measured over multiple breaths and EFLT with 6-minute walk distance (6MWD), exacerbations, and mortality.Methods: In 425 patients, spirometry and forced oscillation technique measurements were obtained on eight occasions over 3 years. 6MWD was assessed at baseline and at the 3-year visit. Respiratory symptoms, exacerbations, and hospitalizations were recorded. A total of 5-year mortality statistics were retrieved retrospectively. We grouped patients according to the mean within-breath reactance (ΔXrs), measured over several breaths at baseline, calculated as mean inspiratory–mean expiratory reactance over the sampling period. In addition to the established threshold of EFLT, an upper limit of normal (ULN) was defined using the 97.5th percentile of ΔXrs of the healthy controls in the study; 6MWDs were compared according to ΔXrs, as normal, ≥ ULN < EFLT, or ≥ EFLT. Annual exacerbation rates were analyzed using a negative binomial model in the three groups, supplemented by time to first exacerbation analysis, and dichotomizing patients at the ULN.Results: In patients with COPD and baseline ΔXrs below the ULN (0.09 kPa·s·L-1), 6MWD was stable. 6MWD declined significantly in patients with ΔXrs ≥ ULN. Worse lung function and more exacerbations were found in patients with COPD with ΔXrs ≥ ULN, and patients with ΔXrs ≥ ULN had shorter time to first exacerbation and hospitalization. A significantly higher mortality was found in patients with ΔXrs ≥ ULN and FEV1 >50%.Conclusion: Patients with baseline ΔXrs ≥ ULN had a deterioration in exercise performance, more exacerbations, and greater hospitalizations, and, among those with moderate airway obstruction, a higher mortality. ΔXrs is a novel independent marker of outcome in COPD. Keywords: forced oscillation technique, reactance, COPD, exacerbations, 6-minute walk test, mortality

Göran Eriksson,1 Peter M Calverley,2 Christine R Jenkins,3,4 Antonio R Anzueto,5 Barry J Make,6 Magnus Lindberg,7 Malin Fagerås,7 Dirkje S Postma8 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 3Concord Clinical School, University of Sydney, 4The George Institute for Global Health, Sydney, Australia; 5Department of Pulmonary Medicine and Critical Care, University of Texas Health Sciences Center and South Texas Veterans’ Health Care System, San Antonio, Texas, 6Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, Colorado, USA; 7AstraZeneca R&D, Mölndal, Sweden; 8Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, GRIAC Research Institute, University of Groningen, Groningen, the Netherlands Background: When discontinuation in COPD randomized controlled trials (RCTs) is unevenly distributed between treatments (differential dropout), the capacity to demonstrate treatment effects may be reduced. We investigated the impact of the time of differential dropout on exacerbation outcomes in RCTs, in relation to study duration and COPD severity.Methods: A post hoc analysis of 2,345 patients from three RCTs of 6- and 12-month duration was performed to compare budesonide/formoterol and formoterol in moderate, severe, and very severe COPD. Outcomes were exacerbation rate, time-to-first exacerbation, or discontinuation; patients were stratified by disease severity. Outcomes were studied by censoring data monthly from 1 to 12 months.Results: In patients treated with budesonide/formoterol, annualized exacerbation rates (AERs) were comparable for each study duration (rate ratio [RR] =0.6). With formoterol, the AER decreased with study duration (RR =1.20 at 1 month to RR =0.86 at 12 months). There was a treatment-related difference in exacerbation rates of 45%–48% for shorter study durations (≤4 months) and 27% for 12-month duration. This treatment-related difference in exacerbation rates was comparable for the three disease severities in studies ≤4 months (range: 39%–51%), but this difference decreased with longer study durations, especially in more severe groups (22% and 29% at 12 months). There were fewer discontinuations with budesonide/formoterol; the treatment-related difference in time-to-first discontinuation decreased by study duration (35%, 30%, 26%, and 22% at 3, 6, 9, and 12 months, respectively). Numbers of differential dropouts increased with increasing disease severity, being greatest during second, third, and fourth months.Conclusions: COPD severity and study duration impact exacerbation as an outcome in double-blind RCTs. This effect is most obvious in patients with severe/very severe COPD and in studies that are longer than 4 months. Early differential dropout particularly impacts study outcome, producing a “healthy survivor effect,” which reduces estimations of treatment impact on exacerbations. Keywords: healthy survivor effect, exacerbation outcomes, early differential dropout, RCT, disease severity

Peter M Calverley,1 Göran Eriksson,2 Christine R Jenkins,3 Antonio R Anzueto,4 Barry J Make,5 Anders Persson,6 Malin Fagerås,6 Dirkje S Postma7 1Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 2Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 3George Institute for Global Health, The University of Sydney and Concord Clinical School, Sydney, Australia; 4Department of Pulmonary Medicine and Allergology, University of Texas Health Sciences Center and South Texas Veterans’ Health Care System, San Antonio, Texas, 5Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, Colorado, USA; 6AstraZeneca R&D, Gothenburg, Sweden; 7Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Background and objective: Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting β2-agonist combinations in patients with chronic obstructive pulmonary disease (COPD). It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity. Methods: Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very-severe COPD. Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 µg or placebo, twice daily; in one study, tiotropium 18 µg once daily was also given. Results: Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with ≥1 exacerbation, respectively). This was true in each COPD severity group. Compared with placebo, B/F treatment led to significantly lower 3-month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD. Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity. B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo. Conclusion: Treatment with B/F decreased exacerbations in patients with moderate-to-very-severe COPD within 3 months of commencing treatment. This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity. Keywords: bronchodilator agents, clinical respiratory medicine, clinical trials, COPD

Roberto Rodriguez-Roisin,1 Kay Tetzlaff,2,3 Henrik Watz,4 Emiel FM Wouters,5 Bernd Disse,2 Helen Finnigan,6 Helgo Magnussen,4 Peter MA Calverley7 1Respiratory Institute, Servei de Pneumologia, Hospital Clínic IDIBAPS-CIBERES, Universitat de Barcelona, Barcelona, Spain; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 3Department of Sports Medicine, University of Tübingen, Tübingen, Germany; 4Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 5Department of Respiratory Medicine, University Hospital Maastricht, Maastricht University, Maastricht, the Netherlands; 6Department of Biostatistics and Data Sciences, Boehringer Ingelheim, Bracknell, UK; 7Institute of Ageing and Chronic Disease, Aintree University Hospital, Liverpool, UK Abstract: The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland–Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of -0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis. Keywords: FEV1, home-based spirometry, inhaled corticosteroid, lung function, severe COPD

Peter M Calverley,1 Dirkje S Postma,2 Antonio R Anzueto,3,4 Barry J Make,5 Göran Eriksson,6 Stefan Peterson,7 Christine R Jenkins8 1Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 2Department of Pulmonary Medicine and Tuberculosis, Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 3Division of Pulmonary Diseases and Critical Care Medicine, University of Texas Health Sciences Center, School of Medicine, University of Texas, 4South Texas Veterans Health Care System, San Antonio, TX, 5Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, USA; 6Department of Respiratory Medicine and Allergology, University Hospital, 7StatMind AB, Lund, Sweden; 8George Institute for Global Health, Concord Clincal School, The University of Sydney, Sydney, NSW, Australia Background: Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates.Methods: This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2–12. Responders were defined by ≥100 mL improvement in prebronchodilator FEV1 and ≥4-point decrease in SGRQ total score.Results: Overall, 2,331 and 1,799 patients were included in the 0–2- and 0–12-month responder analyses, respectively, and 2,360 patients in the 2–12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2-month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14–7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83–5.31). Two-month response in FEV1 (P

Daniel Dusser,1 Robert A Wise,2 Ronald Dahl,3 Antonio Anzueto,4,5 Kerstine Carter,6 Andy Fowler,7 Peter M Calverley8 1Service de Pneumologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 2Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Allergy Centre, Odense University Hospital, Odense C, Denmark; 4Pulmonary/Critical Care, University of Texas, 5South Texas Veterans Health Care System, San Antonio, TX, USA; 6Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA; 7Boehringer Ingelheim Pharma Ltd, Bracknell, UK; 8Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK Background: The aim of this study was to evaluate whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification could predict mortality risk factors and whether baseline treatment intensity would relate to mortality within each group, using data from TIOSPIR®, the largest randomized clinical trial in COPD performed to date.Methods: A total of 17,135 patients from TIOSPIR® were pooled and grouped by GOLD grading (A–D) according to baseline Medical Research Council breathlessness score, exacerbation history, and spirometry. All-cause mortality and adjudicated cardiovascular (CV) and respiratory mortality were assessed.Results: Of the 16,326 patients classified, 1,248 died on treatment. Group B patients received proportionally more CV treatment at baseline. CV mortality risk, but not all-cause mortality risk, was significantly higher in Group B than Group C patients (CV mortality – hazard ratio [HR] =1.74, P=0.004; all-cause mortality – HR =1.18, P=0.11). Group D patients had a higher incidence of all-cause mortality than Group B patients (10.9% vs 6.6%). Similar trends were observed regardless of respiratory or CV medication at baseline. In contrast, respiratory deaths increased consistently from Groups A–D (0.3%, 0.8%, 1.6%, and 4.2% of patients, respectively).Conclusion: The data obtained from the TIOSPIR® trial, supporting earlier studies, suggest that proportionally more CV medication and CV deaths occur in GOLD Group B COPD patients, although deaths attributed to respiratory causes are more prevalent in Groups C and D. Keywords: TIOSPIR®, GOLD, cardiovascular comorbidity, mortality, respiratory death, cardiovascular death

Barry J Make,1 Göran Eriksson,2 Peter M Calverley,3 Christine R Jenkins,4 Dirkje S Postma,5 Stefan Peterson,6 Ollie Östlund,7 Antonio Anzueto8 1Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado Denver School of Medicine, Denver, CO, USA; 2Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 3Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 4George Institute for Global Health, The University of Sydney and Concord Clinical School, Woolcock Institute of Medical Research, Sydney, NSW, Australia; 5Department of Pulmonology, University of Groningen and GRIAC Research Institute, University Medical Center Groningen, Groningen, The Netherlands; 6StatMind AB, Lund, Sweden; 7Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; 8Department of Pulmonary/Critical Care, University of Texas Health Sciences Center and South Texas Veterans Healthcare System, San Antonio, TX, USA Background: There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year. Methods: Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables. Results: The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting ß2-agonist (salbutamol). Conclusion: SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk. Keywords: chronic obstructive pulmonary disease, exacerbation, model, predictor, inhaled corticosteroids, bronchodilators

Stephen I Rennard,1 Shawn X Sun,2 Stavros Tourkodimitris,2 Paul Rowe,2 Udo M Goehring,3 Dirk Bredenbröker,3 Peter M A Calverley4 1Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, NE, USA; 2Forest Research Institute, Jersey City, NJ, USA; 3Takeda Pharmaceuticals International GmbH, Zurich, Switzerland; 4Department of Clinical Science, University of Liverpool, Liverpool, UK Purpose: Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD. Patients and methods: To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted. Results: In this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P

Peter MA Calverley,1 Fernando J Martinez,2 Leonardo M Fabbri,3 Udo-Michael Goehring,4 Klaus F Rabe5–71Clinical Science Center, University Hospital Aintree, Liverpool, United Kingdom; 2Department of Internal Medicine, University of Michigan, MI, USA; 3Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy; 4Nycomed (a Takeda company), Konstanz, Germany; 5University of Kiel, Kiel, Germany; 6Krankenhaus Grosshansdorf, Center for Pulmonology and Thoracic Surgery, Grosshansdorf, Germany; 7Department of Pulmonology, Leiden University Medical Center, Leiden, The NetherlandsBackground: Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis – and a history of frequent exacerbations – as an add-on to bronchodilators.Purpose: The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials.gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.Patients and methods: REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 µg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.Conclusion: It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described.Keywords: chronic obstructive pulmonary disease, roflumilast, protocol, LABA, ICS, exacerbation

Background: Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids (ICSs). Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD. We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study.Methods: This was a 2-year, double-blind, double-dummy parallel study of 1,323 patients randomized to salmeterol/fluticasone propionate 50/500 μg bid (SFC) or tiotropium 18 μg once daily (Tio). Baseline demographics, including serum C-reactive protein (CRP) levels, were measured, and daily record cards (DRCs) were completed.Results: We identified 87 pneumonia reports from adverse event records (SFC=62; Tio=25) in 74 patients (SFC=50; Tio=24), compared with 2,255 exacerbations (SFC=1,185; Tio=1,070). Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level>10 mg/L. Numbers of de novo pneumonias (events that were not preceded by symptoms of an exacerbation) were similar between treatment groups, but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs (SFC=32; Tio=7). Similar results were seen when analysis was confined to radiologically confirmed events.Conclusions: Pneumonia is much less frequent than exacerbation in COPD. The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations. Earlier identification and treatment of these events to prevent pneumonia merits further investigation.Trial Registry: ClinicalTrials.gov; No.: NCT00361959; Study No.: SC040036; URL: clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

RATIONALE: There is limited knowledge regarding sex differences and outcomes in patients with chronic obstructive pulmonary disease (COPD). Objectives: Determine sex differences in survival, causes of death, and patient-centered outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study. METHODS: A total of 1,481 women and 4,631 men with COPD were enrolled in TORCH, a trial comparing salmeterol, 50 [mu]g, plus fluticasone propionate, 500 [mu]g, twice a day and each component individually. Causes of death were determined by an endpoint committee. Sex differences in survival were explored using a Cox proportional hazards model adjusted for other baseline factors. Exacerbation rate was compared using a negative binomial model. Dyspnea was evaluated using the Medical Research Council scale and health status using the St. George's Respiratory Questionnaire. MEASUREMENTS AND MAIN RESULTS: At baseline, women were younger (63 vs. 66 yr), had higher FEV(1) (47% vs. 44% predicted), and worse St. George's Respiratory Questionnaire (51.3 vs. 48.7) and Medical Research Council score. During the study, 707 (15.3%) men and 168 (11.3%) women died. After adjusting for differences in baseline factors, the risk of dying was 16% higher in men than in women; however, this was not statistically significant (hazard ratio 1.16 [95% CI, 0.98-1.39]). Causes of death were similar in women and men. Exacerbation rate was 25% higher in women than in men. CONCLUSIONS: Women enrolled in TORCH had a lower mortality rate than men but similar causes of death. The risk of dying was similar in women and men after adjusting for important baseline variables. Women reported more exacerbations, and worse dyspnea and health status scores than men. Clinical trial registered with www.clinicaltrials.gov (NCT00268216). [ABSTRACT FROM AUTHOR]

Background: Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-antitrypsin, but whether they have an increased risk of COPD is uncertain.Methods: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease.Results: PI MZ was associated with a 3.5% lower FEV₁/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV₁/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies.Conclusions: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV₁/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals. [ABSTRACT FROM AUTHOR]

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study.Methods: A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 microg), FP (500 microg), or SFC (SAL 50 microg/FP 500 microg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded.Results: At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was -3.1% for placebo, -1.7% for SAL, -2.9% for FP, and -3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, -0.3%, and -0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%).Conclusions: Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo.Trial Registration: ClinicalTrials.gov Identifier: NTC00268216. [ABSTRACT FROM AUTHOR]

Rationale: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families.Objectives: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD.Methods: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema.Measurements and Main Results: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD.Conclusions: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes. [ABSTRACT FROM AUTHOR]

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. OBJECTIVES: In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg, either component alone or placebo, on the rate of post-bronchodilator FEV(1) decline in patients with moderate or severe COPD. METHODS: A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. MEASUREMENTS AND MAIN RESULTS: Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV(1) was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV(1) decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7-25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5-22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV(1) declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV(1) decline. CONCLUSIONS: Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV(1) in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216). [ABSTRACT FROM AUTHOR]

RATIONALE: Breathing supplemental oxygen reduces breathlessness during exercise in patients with chronic obstructive pulmonary disease (COPD). Replacing nitrogen with helium reduces expiratory flow resistance and may improve lung emptying. Combining these treatments should be independently effective. OBJECTIVES: Study the effect of changing oxygen or helium concentration in inspired gas during exercise in patients with stable COPD. METHODS: In 82 patients (mean age, 69.7 yr; mean FEV(1), 42.6% predicted), we measured endurance shuttle walking distance, resting and exercise oxygen saturation, and end-exercise dyspnea (Borg scale) while patients breathed Heliox28 (72% He/28% O(2)), Heliox21 (79% He/21% O(2)), Oxygen28 (72% N(2)/28% O(2)), or medical air (79% N(2)/21% O(2)). Gases were administered using a randomized, blinded, crossover design via a face mask and an inspiratory demand valve. RESULTS: Breathing Heliox28 increased walking distance (mean+/-SD, 147+/-150 m) and reduced Borg score (-1.28+/-1.30) more than any other gas mixture. Heliox21 significantly increased walking distance (99+/-101 m) and reduced dyspnea (Borg score, -0.76+/-0.77) compared with medical air. These changes were similar to those breathing Oxygen28. The effects of helium and oxygen in Heliox28 were independent. The increase in walking distance while breathing Heliox28 was inversely related to baseline FEV(1) breathing air. Conclusion: Reducing inspired gas density can improve exercise performance in COPD as much as increasing inspired oxygen. These effects can be combined as Heliox28 and are most evident in patients with more severe airflow obstruction. [ABSTRACT FROM AUTHOR]

We have studied the effects of chlormethiazole infusion on the ventilatory response to progressive isocapnic hypoxia in seven healthy volunteers, during both normocapnia and induced hypercapnia. The dose of chlormethiazole was such that it produced the same degree of hypnosis as would be expected from oral administration of two capsules each containing 192 mg of base in arachis oil. Ventilation did not change significantly during chlormethiazole administration. The ventilatory response to hypoxia was unaffected by chlormethiazole during normocapnia and was enhanced during hypercapnia. In these subjects, giving chlormethiazole intravenously was not associated with depression of the resting ventilation nor the hypoxia ventilatory response. [ABSTRACT FROM AUTHOR]