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Competing Interests: SPB reports grants from the National Institutes of Health; research support from Nuvaira and Sanofi/Regeneron; consulting or advisory board fees from Sanofi/Regeneron, GSK, and Boehringer Ingelheim; honorarium from Integrity Continuing Education for continued medical education. AA declares grants from GSK, AstraZeneca, Chiesi, Sanofi, and Menarini; and consulting or advisory board fees from GSK, AstraZeneca, Chiesi, Menarini, Cipla, Zambon, Sanofi, and Regeneron. BRC reports consulting or advisory board fees or honoraria from GSK, AstraZeneca, Menarini, Sanofi, Axios, and Chiesi; and fees for participation in data safety monitoring boards from AstraZeneca, Sanofi, and Vertex. BEM serves as a contractor and consultant for the COPD Foundation. NP reports grants from the National Institutes of Health; and fees for participation on data safety monitoring boards for CSL Behring, GSK, and Pharmacosmos. NP reports grants from the National Institutes of Health, the American Lung Association, and the Department of Defense; royalties from Up To Date; serves on the Board of Directors of the COPD Foundation (unpaid); and consulting fees from AstraZeneca, Genentech, GSK, Novartis, Pulmonx, and Teva. All other authors declare no competing interests.

Most patients with chronic obstructive pulmonary disease (COPD) have at least one additional, clinically relevant chronic disease. Those with the most severe airflow obstruction will die from respiratory failure, but most patients with COPD die from non-respiratory disorders, particularly cardiovascular diseases and cancer. As many chronic diseases have shared risk factors (eg, ageing, smoking, pollution, inactivity, and poverty), we argue that a shift from the current paradigm in which COPD is considered as a single disease with comorbidities, to one in which COPD is considered as part of a multimorbid state-with co-occurring diseases potentially sharing pathobiological mechanisms-is needed to advance disease prevention, diagnosis, and management. The term syndemics is used to describe the co-occurrence of diseases with shared mechanisms and risk factors, a novel concept that we propose helps to explain the clustering of certain morbidities in patients diagnosed with COPD. A syndemics approach to understanding COPD could have important clinical implications, in which the complex disease presentations in these patients are addressed through proactive diagnosis, assessment of severity, and integrated management of the COPD multimorbid state, with a patient-centred rather than a single-disease approach., Competing Interests: Declaration of interests LMF declares consulting fees from Chiesi Farmaceutici; payment or honoraria for lectures, presentations, manuscript writing, or educational events from Novartis, Chiesi Farmaceutici, Chiesi Italia, GSK, AstraZeneca, and Alfasigma; and participation on a data safety monitoring board (DSMB) for Novartis and Chiesi, all outside of the submitted work. LMF was formerly a member of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). BRC declares consultancy fees from GSK, AstraZeneca, Menarini, Sanofi Aventis, and Axios; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Menarini, Chiesi, and Regeneron; support for attending meetings or travel from GSK and Sanofi Aventis; and participation on a DSMB or advisory board for GSK, AstraZeneca, AZ Therapeutics, Sanofi Aventis, and Vertex, all outside of the submitted work. BRC is a member of GOLD. AA declares grants for research projects from GSK, AstraZeneca, and Menarini; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron, all outside of the submitted work. AA holds the Chair of the Board of Directors of GOLD. GJC is member of GOLD. MTD declares grants paid to his institution from the US Department of Defense, American Lung Association, and National Institutes of Health; royalties from UpToDate; consulting fees from AstraZeneca, GSK, Novartis, Pulmonx, and Teva; and an unpaid role on the Board of Directors of the COPD Foundation, all outside of the submitted work. MD declares consulting fees from Sanofi Regeneron, outside of the submitted work. JKK declares grants paid to her institution from the American Thoracic Society Fellowship in Health Equity, Research Assistance for Primary Parents Award, COMMUNITY Center Investigator Development Core, Weill Cornell Medicine Dean's Diversity and Healthcare Disparity Research Award, and the National Institutes of Health (T32 HL134629); medical writing support from Novartis; medication samples delivered to her institution by Boehringer Ingelheim and GSK; and a donor gift to her institution from the Donna Redel Research Fund, all outside of the submitted work. LL declares fees to her institution from AstraZeneca for expert consultation, Chiesi for a lecture, and IPSA vzw, for lectures, outside of the submitted work. MM declares honoraria for lectures on COPD from AstraZeneca and GSK, outside of the submitted work. MMdO is a member of GOLD. SSS declares payments to his institution from Cipla for lectures, presentations, speakers bureaus, manuscript writing, or educational events. SSS has an unpaid leadership or fiduciary role with the Indian Chest Society, outside of the submitted work, and is a member of GOLD. DS declares grants to her institution from Curetis and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi; and participation on a DSMB or advisory board for CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi, all outside of the submitted work. LEGWV declares research grants to his institution from The Family Kamprad Foundation (20190024), the Swedish government and country council (ALF grant ALFGBG-824371), The Swedish Heart and Lung Foundation (20200150), and Svensk Lungmedicinsk Förening; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Boehringer, Novartis, Chiesi, Resmed, and Pulmonx, all outside of the submitted work. CFV declares grants to his institution from the German Ministry of Education and Science, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Grifols, and Novartis; consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, and Nuvaira; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, Roche, and Sanofi, all outside the submitted work. CFV holds the Chair of the Science Committee of GOLD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This document summarizes the work of the COPD Technical Expert Panel working group. For patients with COPD, the most pressing current coverage barriers identified were onerous diagnostic requirements focused on oxygenation (rather than ventilation) and difficulty obtaining bilevel devices with backup rate capabilities. Because of these difficulties, many patients with COPD were instead sometimes prescribed home mechanical ventilators. Critical evidence supports changes to current policies, including randomized controlled trial evidence suggesting a mortality benefit from bilevel positive airway pressure with backup rate and updated clinical practice guidelines from the American Thoracic Society as well as the European Respiratory Society. To achieve optimal access to noninvasive ventilation for patients with COPD, we make the following key recommendations: (1) removal of the need for overnight oximetry testing; (2) the ability to initiate therapy using bilevel devices with backup rate capability; and (3) increased duration of time to meet adherence criteria (ie, a second 90-day trial period) in those patients actively engaged in their care. Clear guidelines based on medical necessity are also included for patients who require initiation of or switch to a home mechanical ventilator. Adoption of these proposed recommendations would result in the right device, for the right type of patient with COPD, at the right time. Finally, we emphasize the need for adequate clinical support during initiation and maintenance of home noninvasive ventilation in such patients., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy., Methods: In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40-75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24-52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV 1 from baseline to weeks 16-24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov (NCT03546907)., Findings: Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32-1·97) in the placebo group and 1·30 (1·05-1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61-1·07], p=0·13), and least squares mean prebronchodilator FEV 1 change from baseline to weeks 16-24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01-0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39-0·85], p=0·0061) and FEV 1 improvement (least squares mean difference 0·09 L [0·02-0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74-1·61], p=0·65) or FEV 1 (least squares mean difference 0·02 [-0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%])., Interpretation: The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD., Funding: Sanofi and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests KFR reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Roche, and Sanofi, and federal funding of the German Ministry for Research and Technology for the German Center for Lung Research. BRC reports consulting and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Pulmonx, Regeneron, and Sanofi. MEW reports personal fees from Boehringer Ingelheim, Cohero Health, Equillium, Gala Therapeutics, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pulmatrix, Regeneron Pharmaceuticals, resTORbio, and Sentien Biotechnologies; and grants and personal fees from AstraZeneca, Sanofi, and Teva. JEH, AB, MAF, MKR, MCN, NA, DMW, and GDY report employment by and are shareholders of Regeneron Pharmaceuticals. RMA, XL, MMB, HS, and HG report employment by and might hold stock or stock options in Sanofi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (Dlco) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low Dlco has not been explored., Research Question: Could a Dlco threshold help define an increased risk of death and a different clinical presentation in these patients?, Study Design and Methods: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 ± 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for Dlco was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality., Results: A Dlco cutoff value of <60% predicted was associated with all-cause mortality (Dlco ≥ 60%: 9% vs Dlco < 60%: 23%, P = .01). At a same FEV 1 % predicted and Charlson score, patients with Dlco < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a Dlco < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a Dlco < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression., Research Question: What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression?, Study Design and Methods: We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time., Results: The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV 1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039)., Interpretation: Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function., Trial Registry: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab., Methods: We analysed individual study and pooled results from GALATHEA and TERRANOVA. At study enrolment, patients from GALATHEA and TERRANOVA were aged 40-85 years, had moderate to very severe airflow limitation, had elevated blood eosinophil counts, and at least two exacerbations or one severe exacerbation in the previous year despite dual inhaled therapy (inhaled corticosteroids plus long-acting β 2 -agonists or long-acting β 2 -agonists plus long-acting muscarinic antagonists) or triple inhaled therapy (inhaled corticosteroids plus long-acting β 2 -agonists plus long-acting muscarinic antagonists). We analysed data for 3910 patients who received benralizumab (30 mg or 100 mg subcutaneously every 8 weeks; first three doses every 4 weeks) or placebo with dual or triple therapy to identify factors consistently associated with annual exacerbation rate reduction. We evaluated the annual exacerbation rate for benralizumab versus placebo as the primary endpoint. GALATHEA and TERRANOVA are registered with ClinicalTrials.gov, NCT02138916 and NCT02155660, respectively., Findings: For 2665 patients with elevated blood eosinophil counts, treatment effect with benralizumab every 8 weeks at 100 mg, but not at 30 mg, occurred for patients with a history of more frequent exacerbations, poorer baseline lung function, or greater baseline lung function improvement with short-acting bronchodilators. Patients with baseline blood eosinophil counts of 220 cells per μL or greater with: three or more exacerbations in the previous year receiving benralizumab every 8 weeks versus placebo, had rate ratios (RRs) of 0·69 (95% CI 0·56-0·83) for 100 mg and 0·86 (0·71-1·04) for 30 mg; postbronchodilator FEV 1 of less than 40% had RRs of 0·76 (0·64-0·91) for 100 mg and 0·90 (0·76-1·06) for 30 mg; and postbronchodilator response of at least 15% had RRs of 0·67 (0·54-0·83) for 100 mg and 0·87 (0·71-1·07) for 30 mg. When combined factors were examined, patients with elevated baseline blood eosinophil counts, with three or more exacerbations in the previous year, and who were receiving triple therapy were identified as likely to benefit from benralizumab 100 mg every 8 weeks versus placebo (RR 0·70 [95% CI 0·56-0·88]). Benralizumab 30 mg every 8 weeks did not benefit patients meeting these criteria compared with placebo (RR 0·99 [95% CI 0·79-1·23])., Interpretation: Elevated blood eosinophil counts combined with clinical characteristics identified a subpopulation of patients with COPD who had reductions in exacerbations with benralizumab treatment. These hypothesis-generating analyses identified the potential efficacy of benralizumab 100 mg for this subpopulation. These findings require prospective evaluation in clinical trials., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The number of pharmacological medications available to treat patients with COPD has increased over the past few decades. Most of the improvement has come from the modification of older compounds that are now more potent, of longer duration, and delivered in improved devices. They are now available as single, double, and even triple combinations that, although attempting to simplify administration, have also resulted in a large number of preparations. These medications are clearly effective and should be used as a central component of the multidimensional approach to the patient affected with COPD. The preferred route remains the inhaled direct delivery to the airways, but the favorable results obtained with systemic agents such as macrolides and roflumilast and the preliminary results of some biologicals are opening the door for the development of new drugs or reformulation of medications that have been used for other indications. Perhaps the most pressing need is to study the effect of these agents at early points in the course of the disease, because until now most, if not all, studies have been conducted in patients usually older than age 60 years, when most of the natural course of the disease has already been run. This monograph reviews the available pharmacological therapy based on current evidence and provides practical recommendations to health providers caring for patients with COPD., (Copyright © 2018. Published by Elsevier Inc.)

Background: Skeletal muscle dysfunction and poor functional capacity are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD), especially in COPD patients on long-term O 2 therapy (LTOT). Beside the role of pulmonary rehabilitation, the effect of nutritional interventions is still controversial, and there are knowledge gaps on the effective role of nutraceutical supplementation on hard endpoints. The aim of this study was to investigate the effects of nutritional supplementation with Coenzyme Q10 (QTer ® ) - a powerful antioxidant with the potential to reduce oxidative stress and improve mitochondrial function - and Creatine on functional, nutritional, and metabolomic profile in COPD patients on long-term O 2 therapy., Methods: One-hundred and eight patients with COPD from 9 Italian hospitals were enrolled in this double-blinded randomized placebo-controlled clinical study. At baseline and after 2 months of therapy, the patients underwent spirometry, 6-minute walk test (6MWT), bioelectrical impedance analysis, and activities of daily living questionnaire (ADL). Also, dyspnea scores and BODE index were calculated. At both time points, plasma concentration of CoQ10 and metabolomic profiling were measured., Findings: Ninety patients, who randomly received supplementation with QTer ® and Creatine or placebo, completed the study. Compared with placebo, supplemented patients showed improvements in 6MWT (51 ± 69 versus 15 ± 91 m, p < 0.05), body cell mass and phase angle, sodium/potassium ratio, dyspnea indices and ADL score. The CoQ10 plasma concentration increased in the supplementation group whereas it did not change in the placebo group. The metabolomics profile also differed between groups. Adverse events were similar in both groups., Interpretation: These results show that in patients with COPD, dietary supplementation with CoQ10 and Creatine improves functional performance, body composition and perception of dyspnea. A systemic increase in some anti-inflammatory metabolites supports a pathobiological mechanism as a reason for these benefits. Further trials should help clarifying the role of QTer ® and Creatine supplementation in patients with COPD., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: Paradoxical bronchoconstriction with resulting decreased airflow occurs in some patients after administration of bronchodilators. This study assessed the frequency of paradoxical bronchoconstriction in a real-life clinical setting at a large academic medical center., Procedures: We analyzed data from 4593 patients who underwent pre- and post-bronchodilator spirometry testing. We assessed the forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) before and after the administration of an inhaled short-acting β 2 -agonist. Patients were categorized into 3 groups: bronchodilation, no significant change and paradoxical bronchoconstriction., Main Findings: When assessing response to bronchodilators, 201 (4.4%) patients demonstrated significant bronchoconstriction, whereas 849 (18.5%) showed bronchodilation. The majority (3543 or 77.1%) had no significant change. There were no significant relationships noted between paradoxical bronchoconstriction and sex, race/ethnicity or body mass index., Conclusions: A significant subset of patients experience paradoxical bronchoconstriction after albuterol administration. Further research to better understand the clinical implications of paradoxical acute bronchoconstriction is needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: COPD exacerbations are associated with accelerated lung function decline, but whether they are causal is unknown. We evaluated the effect of a single exacerbation on rate of lung function change using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT ® ) trial., Methods: Retrospective analysis of annual rates of decline in FEV 1 and FVC before and after a single (and the only) moderate-to-severe exacerbation in patients during UPLIFT ® (exacerbator subgroup), compared with changes between the first and second half of the study in a non-exacerbator subgroup. A sensitivity analysis examined annual rates of decline in matched pairs of exacerbators and non-exacerbators., Results: Following the single moderate-to-severe exacerbation, mean annual decline in post-bronchodilator lung function increased compared with the rate of decline before the exacerbation (FEV 1 76.5 vs. 39.1 mL/year, p = 0.003; FVC 106.5 vs. 34.7 mL/year, p = 0.011). In non-exacerbators, there were no differences in rates of decline between the first and second halves of the study (post-bronchodilator FEV 1 38.2 vs. 41.8 mL/year, FVC 45.3 vs. 43.9 mL/year. Before the single (moderate-to-severe) exacerbation in the exacerbator subgroup, declines in post-bronchodilator FEV 1 or FVC were similar to non-exacerbators in the first half of the study; after the single exacerbation they were significantly higher than for non-exacerbators in the second half of the study. The sensitivity analysis showed similar results., Conclusion: A single COPD exacerbation may result in significant increase in the rate of decline in lung function., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The clinical characteristics of patients with emphysema but without airway limitations remain unknown. The goal of this study was to compare the clinical features of current and former smokers without airflow limitation who have radiologic emphysema on chest CT scans vs a control group of current and ex-smokers without emphysema., Methods: Subjects enrolled had anthropometric characteristics recorded, provided a medical history, and underwent low-dose chest CT scanning. The following parameters were also evaluated: pulmonary function tests including diffusion capacity for carbon monoxide (Dlco), the modified Medical Research Council dyspnea score, COPD assessment test (CAT), and 6-min walk test (6MWT). A comparison was conducted between those with and without CT-confirmed emphysema., Results: Of the 203 subjects, 154 had emphysema, and 49 did not. Adjusted group comparisons revealed that a higher proportion of patients with emphysema according to low-dose chest CT scanning had an abnormal Dlco value (< 80%) (46% vs 19%; P = .02), a decrease in percentage of oxygen saturation > 4% during the 6MWT (8.5% vs 0; P = .04), and an altered quality of life (CAT score ≥ 10) (32% vs 14%; P = .01). A detailed analysis of the CAT questionnaire items revealed that more patients with emphysema had a score ≥ 1 in the "chest tightness" (P = .05) and "limitation when doing activities at home" (P < .01) items compared with those with no emphysema. They also experienced significantly more exacerbations in the previous year (0.19 vs 0.04; P = .02)., Conclusions: A significant proportion of smokers with emphysema according to low-dose chest CT scanning but without airway limitation had alterations in their quality of life, number of exacerbations, Dlco values, and oxygen saturation during the 6MWT test., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exercise-induced oxygen desaturation (EID) is related to mortality in patients with chronic obstructive pulmonary disease (COPD). We investigated: (1) the prevalence of EID; (2) the relative-weight of several physiological determinants of EID including pulmonary emphysema, and (3) the relationship of EID with certain patients' clinical characteristics. Data from 2050 COPD patients (age: 63.3 ± 7.1years; FEV 1 : 48.7 ± 15.7%pred.) were analyzed. The occurrence of EID (SpO 2 post ≤88%) at the six-minute walking test (6MWT) was investigated in association with emphysema quantified by computed-tomography (QCT), and several clinical characteristics. 435 patients (21%) exhibited EID. Subjects with EID had more QCT-emphysema, lower exercise capacity and worse health-status (BODE, ADO indexes) compared to non-EID. Determinant of EID were obesity (BMI≥30 kg/m 2 ), impaired FEV 1 (≤44%pred.), moderate or worse emphysema, and low SpO 2 at rest (≤93%). Linear regression indicated that each 1-point increase on the ADO-score independently elevates odds ratio (≤1.5fold) for EID. About one in five COPD patients in the ECLIPSE cohort present EID. Advanced emphysema is associated with EID. In addition, obesity, severe airflow limitation, and low resting oxygen saturation increase the risk for EID. Patients with EID in GOLD stage II have higher odds to have moderate or worse emphysema compared those with EID in GOLD stage III-IV. Emphysematous patients with high ADO-score should be monitored for EID., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk., Methods: In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40-80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676., Findings: Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1-15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1-14]), but not vilanterol (difference -2 mL per year [95% CI -8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75-1·14]) with similar findings for fluticasone furoate (0·90 [0·72-1·11]) and vilanterol (0·99 [0·80-1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups., Interpretation: In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline., Funding: GlaxoSmithKline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The COPD-Lung Cancer Screening Score (COPD-LUCSS) is a tool designed to help identify patients with COPD with the highest risk of developing lung cancer (LC). The COPD-LUCSS includes the determination of radiological emphysema, a potential limitation for its implementation in clinical practice. The diffusing capacity for carbon monoxide (DLCO) is a surrogate marker of emphysema and correlates well with CT-determined emphysema., Objective: To explore the use of the COPD-LUCSS using the DLCO instead of radiological emphysema, as a tool to identify patients with COPD at higher risk of LC death., Methods: The Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Performance international cohort database was analyzed. By logistic regression analysis, we confirmed that the other parameters included in the COPD-LUCSS (age > 60, pack-years > 60, BMI < 25) were independently associated with LC death. We selected the best cutoff value for DLCO that independently predicted LC death. We then integrated the new COPD-LUCSS-DLCO assigning points to each parameter according to its hazard ratio value in the Cox regression model. The score ranges from 0 to 8 points., Results: By regression analysis, age > 60, BMI <25 kg/m(2), pack-year history > 60, and DLCO < 60% were independently associated with LC diagnosis. Two COPD-LUCSS-DLCO risk categories were identified: low risk (scores 0-3) and high risk (scores 3.5-8). In comparison to patients at low risk, risk of death from LC increased 2.4-fold (95% CI, 2.0-2.7) in the high-risk category., Conclusions: The COPD-LUCSS using DLCO instead of CT-determined emphysema is a useful tool to identify patients with COPD at risk of LC death and may help in its implementation in clinical practice., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

In addition to the six-min walk distance (6 MWD), other six-min walk test (6 MWT) derived variables, such as mean walk-speed (6MWSpeed), 6-min walk-work (6 MWW), distance-saturation product (DSP), exercise-induced oxygen desaturation (EID), and unintended stops may be useful for the prediction of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). We studied the association between 6 MWT-derived variables and mortality as well as hospitalization in COPD patients and compared it with the BODE index. A three-year prospective study (ECLIPSE) to evaluate the prognostic value of 6 MWT-derived variables in 2010 COPD patients. Cox's proportional-hazard regressions were performed to estimate 3-year mortality and hospitalization. During the follow-up, 193 subjects died and 622 were hospitalized. An adjusted Cox's regression model of hazard ratio [HR] for impaired 6 MWT-derived variables was significant referring to: mortality (6 MWD ≤334 m [2.30], 6MWSpeed ≤0.9 m/sec [2.15], 6 MWW ≤20000 m kg [2.17], DSP ≤290 m% [2.70], EID ≤88% [1.75], unintended stops [1.99]; and hospitalization (6 MWW ≤27000 m kg [1.23], EID ≤88% [1.25], BODE index ≥3 points [1.40]; all p ≤ 0.05). The 6 MWT-derived variables have an additional predictive value of mortality in patients with COPD. The 6 MWW, EID and the BODE index refine the prognosis of hospitalization., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: There is no universal consensus on the best staging system for chronic obstructive pulmonary disease (COPD). Although documents (eg, the Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2007) have traditionally used forced expiratory volume in 1 s (FEV1) for staging, clinical parameters have been added to some guidelines (eg, GOLD 2011) to improve patient management. As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aimed to investigate how individual patients were categorised by GOLD 2007 and 2011, and compare the prognostic accuracy of the staging documents for mortality., Methods: We searched reports published from Jan 1, 2008, to Dec 31, 2014. Using data from cohorts that agreed to participate and had a minimum amount of information needed for GOLD 2007 and 2011, we did a patient-based pooled analysis of existing data. With use of raw data, we recalculated all participant assignments to GOLD 2007 I-IV classes, and GOLD 2011 A-D stages. We used survival analysis, C statistics, and non-parametric regression to model time-to-death data and compare GOLD 2007 and GOLD 2011 staging systems to predict mortality., Findings: We collected individual data for 15 632 patients from 22 COPD cohorts from seven countries, totalling 70 184 person-years. Mean age of the patients was 63·9 years (SD 10·1); 10 751 (69%) were men. Based on FEV1 alone (GOLD 2007), 2424 (16%) patients had mild (I), 7142 (46%) moderate (II), 4346 (28%) severe (III), and 1670 (11%) very severe (IV) disease. We compared staging with the GOLD 2007 document with that of the new GOLD 2011 system in 14 660 patients: 5548 (38%) were grade A, 2733 (19%) were grade B, 1835 (13%) were grade C, and 4544 (31%) were grade D. GOLD 2011 shifted the overall COPD severity distribution to more severe categories. There were nearly three times more COPD patients in stage D than in former stage IV (p<0·05). The predictive capacity for survival up to 10 years was significant for both systems (p<0·01) but area under the curves were only 0·623 (GOLD 2007) and 0·634 (GOLD 2011), and GOLD 2007 and 2011 did not differ significantly. We identified the percent predicted FEV1 thresholds of 85%, 55% and 35% as better to stage COPD severity for mortality, which are similar to the ones used previously., Interpretation: Neither GOLD COPD classification schemes have sufficient discriminatory power to be used clinically for risk classification at the individual level to predict total mortality for 3 years of follow-up and onwards. Increasing intensity of treatment of patients with COPD due to their GOLD 2011 reclassification is not known to improve health outcomes. Evidence-based thresholds should be searched when exploring the prognostic ability of current and new COPD multicomponent indices., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations., Methods: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion., Results: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD., Conclusions: This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.

Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Whether Native American ancestry (NAA) is associated with COPD or lung function in a racially admixed Hispanic population is unknown., Methods: We recruited 578 Costa Ricans with and without COPD into a hybrid case-control/family-based cohort, including 316 members of families of index case subjects. All participants completed questionnaires and spirometry and gave a blood sample for DNA extraction. Genome-wide genotyping was conducted with the Illumina Human610-Quad and HumanOmniExpress BeadChip kits (Illumina Inc), and individual ancestral proportions were estimated from these genotypic data and reference panels. For unrelated individuals, linear or logistic regression was used for the analysis of NAA and COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage II or greater) or lung function. For extended families, linear mixed models and generalized estimating equations were used for the analysis. All models were adjusted for age, sex, educational level, and smoking behavior; models for FEV1 were also adjusted for height., Results: The average proportion of European, Native American, and African ancestry among participants was 62%, 35%, and 3%, respectively. After adjustment for current smoking and other covariates, NAA was inversely associated with COPD (OR per 10% increment, 0.55; 95% CI, 0.41-0.75) but positively associated with FEV1, FVC, and FEV1/FVC. After additional adjustment for pack-years of smoking, the association between NAA and COPD or lung function measures was slightly attenuated. We found that about 31% of the estimated effect of NAA on COPD is mediated by pack-years of smoking., Conclusions: NAA is inversely associated with COPD but positively associated with FEV1 or FVC in Costa Ricans. Ancestral effects on smoking behavior partly explain the findings for COPD but not for FEV1 or FVC.

Background: Exacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials., Methods: Data were pooled from six randomized, double-blind, placebo-controlled trials (6 to ≥ 12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of >1 respiratory symptom lasting for ≥ 3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at 1 year for studies ≥ 1 year., Results: In total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p < 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p < 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p < 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events., Conclusions: Tiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 μg daily, in patients with COPD (FEV1/FVC &lt; 70%; postbronchodilator FEV1 &lt; 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 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 (P &lt; .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = .007)., Conclusions: 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., Trial Registry: ClinicalTrials.gov; No.: NCT00525512; URL: www.clinicaltrials.gov.

Background: COPD is an independent risk factor for lung cancer, especially in patients with mild to moderate disease., Objective: To determine if performing lung cancer screening in GOLD 1 and 2 COPD patients, results in reduced lung cancer mortality., Methods: This study compared patients with mild to moderate COPD from 2 cohorts matched for age, gender, BMI, FEV1%, pack-yrs history and smoking status. The screening group (SG) had an annual low dose computed tomography (LDCT). The control group (CG) was prospectively followed with usual care. Lung cancer incidence and mortality densities were compared between groups., Results: From an initial sample of 410 (SG) and 735 (CG) patients we were able to match 333 patients from each group. At the same follow-up time lung cancer incidence density was 1.79/100 person-years in the SG and 4.14/100 person-years in the CG (p = 0.004). The most frequent histological type was adenocarcinoma in both SG and CG (65% and 46%, respectively), followed by squamous cell carcinoma (25% and 37%, respectively). Eighty percent of lung cancers in the SG (16/20) were diagnosed in stage I, and all of CG cancers (35/35) were in stage III or IV. Mortality incidence density from lung cancer (0.08 vs. 2.48/100 person-years, p < 0.001) was lower in the SG., Conclusions: This pilot study in patients with mild to moderate COPD suggests that screening with LDCT detects lung cancer in early stages, and could decrease lung cancer mortality in that high risk group. Appropriately designed studies should confirm these important findings., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The new Global Initiative for Chronic Obstructive Lung Disease (GOLD) update includes airflow limitation, history of COPD exacerbations, and symptoms to classify and grade COPD severity. We aimed to determine their distribution in 11 well-defined COPD cohorts and their prognostic validity up to 10 years to predict time to death., Methods: Spirometry in all 11 cohorts was postbronchodilator. Survival analysis and C statistics were used to compare the two GOLD systems by varying time points., Results: Of 3,633 patients, 1,064 (33.6%) were in new GOLD patient group A (low risk, less symptoms), 515 (16.3%) were B (low risk, more symptoms), 561 (17.7%) were C (high risk, less symptoms), and 1,023 (32.3%) were D (high risk, more symptoms). There was great heterogeneity of this distribution within the cohorts ( x (2) , P < .01). No differences were seen in the C statistics of old vs new GOLD grading to predict mortality at 1 year (0.635 vs 0.639, P = .53), at 3 years (0.637 vs 0.645, P = .21), or at 10 years (0.639 vs 0.642, P = .76)., Conclusions: The new GOLD grading produces an uneven split of the COPD population, one third each in A and D patient groups, and its prognostic validity to predict time to death is no different than the old GOLD staging based in spirometry only.

Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated.

Background: Observational and randomized studies have demonstrated that lung volume reduction surgery (LVRS) improves symptoms, lung function, and survival in selected patients with emphysema. In spite of an approximately 3.8 million patient prevalence of the disease in the US, only 119 LVRS procedures were performed nationwide under Medicare during 2008. In order to obtain evidence-based estimate on the size of the patient pool potentially suitable for LVRS, we analyzed the database from our clinical practice that is representative of a substantial segment of the general emphysema population., Methods: Our pulmonary function test laboratory database between 1996 and 2006 was searched for patients with stage III and IV global initiative for chronic obstructive lung disease (GOLD) who also had lung volumes and carbon monoxide diffusing capacity data. Patients without available chest computed tomographic scans (CT) or with primary diagnoses other than emphysema were excluded. The resultant emphysema cohort was screened using clinical inclusion and exclusion criteria adopted from the National Emphysema Treatment Trial. A suitable clinical profile combined with CT scan evidence of 40% or greater involvement of the lungs and predominantly upper lobe distribution of emphysema were regarded as favorable markers for LVRS., Results: Pulmonary function test criteria were met by 959 patients and CT scans were available in 588 patients, but 175 patients were excluded because of primary diagnoses other than emphysema. In the remaining 413 patients, 61 or 15% exhibited favorable clinical profiles and anatomy for LVRS., Conclusions: In a subset of patients that resembles a substantial segment of the general population with advanced emphysema, up to 15% appeared potential candidates for LVRS. Formation of a task force by relevant medical specialty and patient advocate organizations to address the apparent underutilization of LVRS is recommended., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume., Methods: In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O(2) pulse=VO(2)/HR) at baseline and 6 months. Medical and surgical patients were divided into "deflators" and "non-deflators" based on change in RV/TLC from baseline (∆RV/TLC). We defined deflation as the ∆RV/TLC experienced by 75% of surgical patients. We examined changes in O(2) pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs., Results: In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O(2) pulse (median ∆RV/TLC -18.0% vs. -9.3%, p=0.0003; median ∆O(2) pulse 13.6% vs. 1.8%, p=0.12). Surgical deflators also improved iso-work O(2) pulse (0.53 mL/beat, p=0.04 at 20 W). In the validation cohort, surgical deflators experienced a greater improvement in peak O(2) pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O(2) pulse at rest and during unloaded pedaling (0.32 mL/beat, p<0.0001 and 0.47 mL/beat, p<0.0001, respectively) corresponded with significant reductions in HR and improvements in VO(2). On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O(2) pulse (OR 1.88, 95% CI 1.30-2.72, p=0.0008)., Conclusion: In COPD, decreased hyperinflation through lung volume reduction is associated with improved O(2) pulse., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The diagnosis of COPD is based on spirometric evidence of airways obstruction following bronchodilator administration. Although it used to be commonly believed that patients with COPD have largely irreversible airflow obstruction, evidence now suggests that a considerable proportion of patients exhibit clinically significant bronchodilator reversibility. The complexity and inherent variability of a patient's acute response to a bronchodilator and the lack of a standardized procedure for assessing bronchodilator reversibility have led to significant confusion surrounding this concept. Although bronchodilator reversibility commonly is defined based on thresholds for improvement in FEV(1), lung volume-based measures of pulmonary function may be of particular importance in patients with severe COPD. The usefulness of acute reversibility to short-acting bronchodilators in predicting a patient's long-term response to bronchodilator maintenance therapy is also unclear, although most studies suggest that a lack of acute response to short-acting bronchodilators does not preclude a beneficial long-term response to maintenance bronchodilator treatment. This review outlines recent findings about the prevalence and usefulness of bronchodilator reversibility in patients with COPD based on the available literature and proposes areas of future research.

Background: Chronic obstructive pulmonary disease (COPD) patients are thought to have limited bronchodilator response, determined by changes in forced expiratory volume in 1s (FEV(1)). In this study, we assessed bronchodilator response in patients with COPD using not only FEV(1) but also changes in lung volume expressed as forced vital capacity (FVC) and inspiratory capacity (IC). We also evaluated the speed of onset of bronchodilation., Methods: Data were from 2 randomized, double-blind, placebo-controlled studies (6-months [NCT00206154]; 12-months [NCT00206167]) in patients with moderate to very severe COPD., Treatments: twice daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9μg, budesonide/formoterol pMDI 160/9μg, formoterol dry powder inhaler (DPI) 9μg, placebo., Results: The percentage of patients with FEV(1) improvement (≥12% and ≥200mL; American Thoracic Society [ATS] criterion) was 34-39% post-albuterol (screening). On day of randomization (DOR), a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min: FEV(1) (57-59%). Similar results were seen for IC (50-61%) and FVC (57-67%) using the same improvement criteria. The time to ≥15% FEV(1) improvement on DOR was 5.0, 4.8, and 7.3min for budesonide/formoterol 320/9, budesonide/formoterol 160/9, and formoterol, respectively. Time to ≥15% FEV(1) improvement was better maintained with budesonide/formoterol than formoterol at treatment end (6 and 12 months)., Conclusions: Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment. Budesonide/formoterol pMDI also has a rapid (within 5min) onset of bronchodilation that is maintained over time compared with formoterol alone., (Copyright © 2011. Published by Elsevier Ltd.)

Rationale: COPD is a debilitating disease with increasing mortality worldwide. The BODE index evaluates disease severity and the St George's Respiratory Questionnaire (SGRQ) measures health status., Objective: To identify the relationship between BODE index and the SGRQ and to test the predictive value of both tools against survival., Methods: Open cohort study of 1398 COPD patients (85% male) followed for up to 10 years., Measurements and Main Results: At the time of the inclusion, clinical data, forced spirometry and 6 min walking distance were determined and BODE index and SGRQ were calculated. Vital status and cause of death were documented at the end of follow-up., Results: The cohort's mean of FEV1% predicted was 46 ± 18%, BODE index was 3.6 ± 2.5, and SGRQ% total score was 49 ± 20. The SGRQ scores increased progressively as severity of COPD increased by BODE quartiles. The correlation between SGRQ and BODE index was good (r = 0.58, p < 0.0001). Both tests correlated with COPD survival (BODE = -0.4 vs. SGRQ = -0.20, p < 0.0001). The area under the curve (AUC) for the BODE index was 0.77 vs. 0.66 for the SGRQ % total score (p < 0.001)., Conclusions: Health status as measured by SGRQ worsens with disease severity evaluated by the BODE index. Both tools predict mortality and provide complimentary information in the evaluation of patients with COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Observational and randomized studies provide convincing evidence that lung volume reduction surgery (LVRS) improves symptoms, lung function, exercise tolerance, and life span in well-defined subsets of patients with emphysema. Yet, in the face of an estimated 3 million patients with emphysema in the United States, < 15 LVRS operations are performed monthly under the aegis of Medicare, in part because of misleading reporting in lay and medical publications suggesting that the operation is associated with prohibitive risks and offers minimal benefits. Thus, a treatment with proven potential for palliating and prolonging life may be underutilized. In an attempt to lower risks and cost, several bronchoscopic strategies (bronchoscopic emphysema treatment [BET]) to reduce lung volume have been introduced. The following three methods have been tested in some depth: (1) unidirectional valves that allow exit but bar entry of gas to collapse targeted hyperinflated portions of the lung and reduce overall volume; (2) biologic lung volume reduction (BioLVR) that involves intrabronchial administration of a biocompatible complex to collapse, inflame, scar, and shrink the targeted emphysematous lung; and (3) airway bypass tract (ABT) or creation of stented nonanatomic pathways between hyperinflated pulmonary parenchyma and bronchial tree to decompress and reduce the volume of oversized lung. The results of pilot and randomized pivotal clinical trials suggest that the bronchoscopic strategies are associated with lower mortality and morbidity but are also less efficient than LVRS. Most bronchoscopic approaches improve quality-of-life measures without supportive physiologic or exercise tolerance benefits. Although there is promise of limited therapeutic influence, the available information is not sufficient to recommend use of bronchoscopic strategies for treating emphysema.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in adults. Although FEV(1) remains the most important physiologic indicator of the severity of airflow obstruction in COPD, its predictive value for mortality is weak when it is higher than 50% of predicted. Furthermore, other easily obtainable clinical variables predict mortality better than the FEV(1) in COPD patients with a wide range of airflow limitation. Chief among these predictors are functional dyspnea, exercise capacity, and the body mass index (BMI), although emerging research suggests a potential role for biomarker profiles in outcome predictions. The validated multidimensional BMI (B), degree of airflow obstruction as expressed by the FEV(1) (O), dyspnea with the modified medical research council (D), and exercise (E) measured with the 6min walk or BODE index encompasses the predictive validity of the best of these variables into a single surrogate measure of disease severity and survival. This article reviews these predictors of mortality in COPD., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: The 6-min walking test (6MWT) is widely used to assess exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Given the prognostic significance of the 6MWT, it is important to identify why some COPD patients perform poorly in terms of this outcome. We aimed to identify clinical determinants of a poor 6-min walking distance (<350 m) in patients with COPD., Methods: 1795 individuals with a diagnosis of COPD underwent spirometry; bio-electrical impedance analysis; low-dose computed tomography scans of the chest; 6MWT; ATS-DLD co-morbidity questionnaire; Center for Epidemiologic Studies of Depression Scale; COPD-specific St Georges Respiratory Questionnaire; modified Medical Research Council (mMRC) dyspnea scale as part of the baseline assessment of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study., Results: Patients with COPD have significant differences in performance in the 6MWT even after stratification for GOLD stages. Moreover, severe airflow limitation by GOLD stage, degree of emphysema by CT, oxygen use during/after the 6MWT, presence of depressive symptoms and moderate to severe symptoms of dyspnea (mMRC grade >/=2) are significant clinical determinants of poor 6MWD performance (<350 m)., Conclusions: The determinants of poor 6MWD are complex and depend on both physical (both pulmonary and non-pulmonary factors) and psychological factors as evaluated from a large multinational cohort of well-characterised patients with clinically stable moderate to very severe COPD., (Copyright 2009 Elsevier Ltd. All rights reserved.)