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Objective: Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease, whereas the related interindividual heterogeneity in skeletal muscle dysfunction and adaptations are not yet fully understood. We set out to investigate the effects of exercise training and supplemental oxygen on functional and structural peripheral muscle adaptation., Methods: In this prospective, randomized, controlled, double-blind study, 28 patients with nonhypoxemic chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 45.92% ± 9.06%) performed 6 wk of combined endurance and strength training, three times a week while breathing either supplemental oxygen or medical air. The impact on exercise capacity, muscle strength, and quadriceps femoris muscle cross-sectional area (CSA) was assessed by maximal cardiopulmonary exercise testing, 10-repetition maximum strength test of knee extension, and magnetic resonance imaging, respectively., Results: After exercise training, patients demonstrated a significant increase in functional capacity, aerobic capacity, exercise tolerance, quadriceps muscle strength, and bilateral CSA. Supplemental oxygen affected significantly the training impact on peak work rate when compared with medical air (+0.20 ± 0.03 vs +0.12 ± 0.03 W·kg -1 , P = 0.047); a significant increase in CSA (+3.9 ± 1.3 cm 2 , P = 0.013) was only observed in the training group using oxygen. Supplemental oxygen and exercise-induced peripheral desaturation were identified as significant opposing determinants of muscle gain during this exercise training intervention, which led to different adaptations of CSA between the respective subgroups., Conclusions: The heterogenous functional and structural muscle adaptations seem determined by supplemental oxygen and exercise-induced hypoxia. Indeed, supplemental oxygen may facilitate muscular training adaptations, particularly in limb muscle dysfunction, thereby contributing to the enhanced training responses on maximal aerobic and functional capacity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Background: Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease., Methods: We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain., Results: After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV 1 %pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8-10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C - total score and all subscores)., Conclusions: In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C., Competing Interests: Dr Horst Olschewski reports personal fees and/or non-financial support from Astra Zeneca, Boehringer, Menarini; personal fees from Chiesi, GSK and Novartis, outside the submitted work. Dr Sylvia Hartl reports grants and/or personal fees from GSK, Astra Zeneca, Menarini Pharma, Chiesi Farma, Roche Pharma, and MSD, outside the submitted work. Professor Arschang Valipour reports personal fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, and Menarini, during the conduct of the study. Dr Georg-Christian Funk reports honorary for advisory board from Menarini Pharma. Dr Monika Merkle reports personal fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, Menarini, Sanofi, and Novartis, outside the submitted work. Mrs Eva Wallner and Dr Stephan Brecht are employees of A. Menarini Pharma GmbH. The authors report no other conflicts of interest in this work., (© 2023 Horner et al.)

Background: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study., Methods: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 )/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income., Results: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (β=0.02 L, 95% CI -0.02-0.06 L) or lower FEV 1 /FVC (β=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income., Conclusion: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries., Competing Interests: Conflict of interest: J. Ratanachina, A.F.S. Amaral, S. De Matteis, H. Lawin, K. Mortimer, D.O. Obaseki, I. Harrabi, M. Denguezli, E.F.M. Wouters, C. Janson, A. Gulsvik, H.H. Cherkaski, F. Mejza, P.A. Mahesh, A. Elsony, R. Ahmed, W. Tan, L.C. Loh, A. Rashid, M. Studnicka, A.A. Nafees, T. Seemungal, A. Aquart-Stewart, M. Al Ghobain, J. Zheng, S. Juvekar, S. Salvi, R. Jogi, T. Gislason, A.S. Buist, P. Cullinan and P. Burney have no conflict of interest to disclose. R. Nielsen reports grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis, and receipt of equipment/material/services from ResMed Norway; and is President of the Norwegian Respiratory Society. D. Mannino reports royalties from Up to Date; personal fees from GlaxoSmithKline, AstraZeneca and Schlesinger Law Firm; honoraria from American Association of Respiratory Care; and stock in GlaxoSmithKline; and is the Medical Director of the COPD Foundation., (Copyright ©The authors 2023.)

Background: Small airways obstruction is a common feature of obstructive lung diseases. Research is scarce on small airways obstruction, its global prevalence, and risk factors. We aimed to estimate the prevalence of small airways obstruction, examine the associated risk factors, and compare the findings for two different spirometry parameters., Methods: The Burden of Obstructive Lung Disease study is a multinational cross-sectional study of 41 municipalities in 34 countries across all WHO regions. Adults aged 40 years or older who were not living in an institution were eligible to participate. To ensure a representative sample, participants were selected from a random sample of the population according to a predefined site-specific sampling strategy. We included participants' data in this study if they completed the core study questionnaire and had acceptable spirometry according to predefined quality criteria. We excluded participants with a contraindication for lung function testing. We defined small airways obstruction as either mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF 25-75 ) less than the lower limit of normal or forced expiratory volume in 3 s to forced vital capacity ratio (FEV 3 /FVC ratio) less than the lower limit of normal. We estimated the prevalence of pre-bronchodilator (ie, before administration of 200 μg salbutamol) and post-bronchodilator (ie, after administration of 200 μg salbutamol) small airways obstruction for each site. To identify risk factors for small airways obstruction, we performed multivariable regression analyses within each site and pooled estimates using random-effects meta-analysis., Findings: 36 618 participants were recruited between Jan 2, 2003, and Dec 26, 2016. Data were collected from participants at recruitment. Of the recruited participants, 28 604 participants had acceptable spirometry and completed the core study questionnaire. Data were available for 26 443 participants for FEV 3 /FVC ratio and 25 961 participants for FEF 25-75 . Of the 26 443 participants included, 12 490 were men and 13 953 were women. Prevalence of pre-bronchodilator small airways obstruction ranged from 5% (34 of 624 participants) in Tartu, Estonia, to 34% (189 of 555 participants) in Mysore, India, for FEF 25-75 , and for FEV 3 /FVC ratio it ranged from 5% (31 of 684) in Riyadh, Saudi Arabia, to 31% (287 of 924) in Salzburg, Austria. Prevalence of post-bronchodilator small airways obstruction was universally lower. Risk factors significantly associated with FEV 3 /FVC ratio less than the lower limit of normal included increasing age, low BMI, active and passive smoking, low level of education, working in a dusty job for more than 10 years, previous tuberculosis, and family history of chronic obstructive pulmonary disease. Results were similar for FEF 25-75 , except for increasing age, which was associated with reduced odds of small airways obstruction., Interpretation: Despite the wide geographical variation, small airways obstruction is common and more prevalent than chronic airflow obstruction worldwide. Small airways obstruction shows the same risk factors as chronic airflow obstruction. However, further research is required to investigate whether small airways obstruction is also associated with respiratory symptoms and lung function decline., Funding: National Heart and Lung Institute and Wellcome Trust., Translations: For the Dutch, Estonian, French, Icelandic, Malay, Marathi, Norwegian, Portuguese, Swedish and Urdu translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests DM declares being a consultant to and receiving royalties from GlaxoSmithKline, AstraZeneca, and the COPD Foundation (royalty payments are up to date) and acting as an expert witness for Schlesinger Law Firm, outside of the submitted work. RN reports grants and personal fees from AstraZeneca and GlaxoSmithKline and grants from Boehringer Ingelheim and Novartis, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities., Methods: A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC < 5th percentile of reference values. Self-reports of physician-diagnosed cardiovascular disease (CVD; heart disease or stroke), hypertension, and diabetes were obtained through questionnaires., Results: Overall 31.7% of participants had restricted spirometry. However, prevalence of restricted spirometry varied approximately ten-fold, and was lowest (8.5%) in Vancouver (Canada) and highest in Sri Lanka (81.3%). Crude odds ratios for the association with restricted spirometry were 1.60 (95% CI 1.37-1.86) for CVD, 1.53 (95% CI 1.40-1.66) for hypertension, and 1.98 (95% CI 1.71-2.29) for diabetes. After adjustment for age, sex, education, Body Mass Index (BMI) and smoking, the odds ratios were 1.54 (95% CI 1.33-1.79) for CVD, 1.50 (95% CI 1.39-1.63) for hypertension, and 1.86 (95% CI 1.59-2.17) for diabetes., Conclusion: In this population-based, international, multi-site study, restricted spirometry associates with cardiometabolic diseases. The magnitude of these associations appears unattenuated when cardiometabolic risk factors are taken into account., (© 2022. The Author(s).)

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM 2.5 ) using negative binomial regression. The prevalence of CAO was not independently associated with PM 2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Competing Interests: Competing interests: RN reports grants and personal fees from Boehringer Ingelheim, AstraZeneca and Novartis outside the submitted work. EDB reports personal fees from Novartis, AstraZeneca, Orion, Menarirni, Boehringer Ingelheim and ALK outside the submitted work. KM reports grants from GlaxoSmithKline during the conduct of the study. TW reports grants from Boehringer Ingelheim and Pfizer during the conduct of the study. FM reports fees from Medycyba Praktyczna, Sandoz and Chiesi outside the submitted work. DM reports salary and shares from GlaxoSmithKline outside the submitted work. IH reports grants from Boehringer Ingelheim during the conduct of the study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV 1 -to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Background: Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease (COPD) in all disease stages. Data about the training effects with supplemental oxygen in nonhypoxemic patients remains inconclusive. In this study we set out to investigate the training and oxygen effects on inflammatory markers, vascular function, and endothelial progenitor cells in this population of increased cardiovascular risk., Methods: In this prospective, randomized, double-blind, crossover study, 29 patients with nonhypoxemic COPD performed combined endurance and strength training 3 times a week while breathing medical air or supplemental oxygen for the first 6-week period, and were then reallocated to the opposite gas for the following 6 weeks. Exercise capacity, inflammatory biomarkers, endothelial function (peripheral arterial tone analysis), and endothelial progenitor cells were assessed. Data were also analyzed for a subgroup with endothelial dysfunction (reactive hyperemia index <1.67)., Results: Following 12 weeks of exercise training, patients demonstrated a significant improvement of peak work rate and an associated decrease of blood fibrinogen and leptin. Eosinophils were found significantly reduced after exercise training in patients with endothelial dysfunction. In this subgroup, peripheral arterial tone analysis revealed a significant improvement of reactive hyperemia index. Generally, late endothelial progenitor cells were found significantly reduced after the exercise training intervention. Supplemental oxygen during training positively influenced the effect on exercise capacity without impact on inflammation and endothelial function., Conclusions: This is the first randomized controlled trial in patients with COPD to show beneficial effects of exercise training not only on exercise capacity, but also on systemic/eosinophilic inflammation and endothelial dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Functional impairment caused by chronic obstructive pulmonary disease (COPD) impacts on activities of daily living and quality of life. Indeed, patients' submaximal exercise capacity is of crucial importance. It was the aim of this study to investigate the effects of an exercise training intervention with and without supplemental oxygen on submaximal exercise performance. This is a secondary analysis of a randomized, controlled, double-blind, crossover trial. 29 COPD patients (63.5 ± 5.9 years; FEV 1 46.4 ± 8.6%) completed two consecutive 6-week periods of high-intensity interval cycling and strength training, which was performed three times/week with either supplemental oxygen or medical air (10 L/min). Submaximal exercise capacity as well as the cardiocirculatory, ventilatory, and metabolic response were evaluated at isotime (point of termination in the shortest cardiopulmonary exercise test), at physical work capacity at 110 bpm of heart rate (PWC 110), at the anaerobic threshold (AT), and at the lactate-2 mmol/L threshold. After 12 weeks of exercise training, patients improved in exercise tolerance, shown by decreased cardiocirculatory (heart rate, blood pressure) and metabolic (respiratory exchange ratio, lactate) effort at isotime; ventilatory response was not affected. Submaximal exercise capacity was improved at PWC 110, AT and the lactate-2 mmol/L threshold, respectively. Although supplemental oxygen seems to affect patients' work rate at AT and the lactate-2 mmol/L threshold, no other significant effects were found. The improved submaximal exercise capacity and tolerance might counteract patients' functional impairment. Although cardiovascular and metabolic training adaptations were shown, ventilatory efficiency remained essentially unchanged. The impact of supplemental oxygen seems less important on submaximal training effects., (© 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: Beyond smoking, several risk factors for the development of chronic obstructive pulmonary disease (COPD) have been described, among which socioeconomic status including education is of particular interest. We studied the contribution of education to lung function and symptoms relative to smoking in a group of never-smokers with COPD compared to a group of long-time ex-smokers with COPD., Methods: We used baseline data of the COSYCONET cohort, including patients of GOLD grades 1-4 who were either never-smokers (n=150, age 68.5y, 53.3% female) or ex-smokers (≥10 packyears) for at least 10 years (n=616, 68.3y, 29.9% female). Socioeconomic status was analyzed using education level and mortality was assessed over a follow-up period of 4.5 years. Analyses were performed using ANOVA and regression models., Results: Spirometric lung function did not differ between groups, whereas CO diffusing capacity and indicators of lung hyperinflation/air-trapping showed better values in the never-smoker group. In both groups, spirometric lung function depended on the education level, with better values for higher education. Quality of life and 6-MWD were significantly different in never-smokers as well as patients with higher education. Asthma, alpha-1-antitrypsin deficiency, and bronchiectasis were more often reported in never-smokers, and asthma was more often reported in patients with higher education. Higher education was also associated with reduced mortality (hazard ratio 0.46; 95% CI 0.22-0.98)., Conclusion: Overall, in the COSYCONET COPD cohort, differences in functional status between never-smokers and long-time ex-smokers were not large. Compared to that, the dependence on education level was more prominent, with higher education associated with better outcomes, including mortality. These data indicate that non-smoking COPD patients' socioeconomic factors are relevant and should be taken into account by clinicians., Competing Interests: Johanna I Lutter reports grants from German Federal Ministry of Education and Research (BMBF) with grant number 01GI0882, during the conduct of the study. Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study. Rolf Holle reports grants from German Federal Ministry of Education and Research, during the conduct of the study. Dr. Vogelmeier stated the follwoing:Relevant financial activities outside the submitted work:Grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis and German Federal Ministry of Education and Research (BMBF) Competence Network Asthma und COPD (ASCONET). Furthermore, Dr. Vogelmeier reported personal fees from Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, Berlin Chemie/Menarini, CSL Behring, Nuvaira, MedUpdate. Kathrin Kahnert reports personal fees from Novartis GmbH, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2020 Lutter et al.)

Background: Guidelines for chronic obstructive pulmonary disease (COPD) recommend supplementing pharmacotherapy with non-pharmacological interventions. Little is known about the use of such interventions by patients. We analyzed the utilization of a number of non-pharmacological interventions and identified potential determinants of use., Methods: Based on self-reports, use of interventions (smoking cessation, influenza vaccination, physiotherapy, sports program, patient education, pulmonary rehabilitation) and recommendation to use were assessed in 1410 patients with COPD. The utilization was analyzed according to sex and severity of disease. Potential determinants of utilization included demographic variables and disease characteristics and were analyzed using logistic regression models., Results: Influenza vaccination in the previous autumn/winter was reported by 73% of patients. About 19% were currently participating in a reimbursed sports program, 10% received physiotherapy, 38% were ever enrolled in an educational program, and 34% had ever participated in an outpatient or inpatient pulmonary rehabilitation program. Out of 553 current or former smokers, 24% had participated in a smoking cessation program. While reports of having received a recommendation to use mainly did not differ according to sex, women showed significantly (p < 0.05) higher utilization rates than men for all interventions except influenza vaccination. Smoking was a predictor for not having received a recommendation for utilization and also significantly associated with a reduced odds of utilization. We found a correlation between recommendation to use and utilization., Conclusions: Utilization of non-pharmacological interventions was lower in men and smokers. A recommendation or offer to use by the physician could help to increase uptake., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients., Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded., Results: Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV 1 /FVC <0.7) and 77 were excluded due to missing data. Finally, 850 patients (62.8% men; mean age 66.2 ± 0.3 (SE) years; mean FEV 1 %pred. 51.5 ± 0.6 (SE)) were analyzed. Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation. Mean SGRQ-C total score was 43.1 ± 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively. Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do. In patients with less severe COPD (FEV 1 pred ≥50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD., Conclusion: In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations. Our finding suggests that validated assessment of global health status might decrease these differences of perception., Competing Interests: AH reports expenses for statistical analyses from A. Menarini Pharma GmbH, Vienna Austria. SH reports grants, personal fees from Chiesi Farmacia, Astra Zeneca, GSK, Novartis, MSD, Roche, Takeda, Boehringer Ingelheim, and Menarini, outside the submitted work. MM reports personal fees from Astra-Zeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, and Sanofi outside the submitted work. HO reports personal fees from Actelion, Astra Zeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Inventiva, J&J, Menarini, MSD, Novartis, and Pfizer, outside the submitted work. EMW is an employee of A. Menarini Pharma GmbH. The authors report no other conflicts of interest in this work., (© 2020 Horner et al.)

Background: Forced expiratory volume in one second (FEV 1 ) characterizes the pathophysiology of COPD and different trajectories of FEV 1 decline have been observed in patients with COPD (e.g. gradual or episodic). There is limited information about the development of patient-reported health-related quality of life (HRQL) over the full range of the natural history of COPD. We examined the longitudinal association between change in FEV 1 and change in disease-specific and generic HRQL., Methods: We analysed data of 1734 patients with COPD participating in the COSYCONET cohort with up to 3 years of follow-up. Patients completed the Saint George's Respiratory Questionnaire (SGRQ) and the EQ-5D Visual Analog Scale (EQ VAS). Change score models were used to investigate the relationship between HRQL and FEV 1 and to calculate mean changes in HRQL per FEV 1 change categories [decrease (≤ - 100 ml), no change, increase (≥ 100 ml)] after 3 years. Applying hierarchical linear models (HLM), we estimated the cross-sectional between-subject difference and the longitudinal within-subject change of HRQL as related to a FEV 1 difference or change., Results: We observed a statistically significant deterioration in SGRQ (total score + 1.3 units) after 3 years, which was completely driven by the activity component (+ 4 units). No significant change was found for the generic EQ VAS. Over the same period, 58% of patients experienced a decrease in FEV 1 , 28% were recorded as no change in FEV 1 , and 13% experienced an increase. The relationship between HRQL and FEV 1 was found to be approximately linear with decrease in FEV 1 being statistically significantly associated with a deterioration in SGRQ (+ 3.20 units). Increase in FEV 1 was associated with improvements in SGRQ (- 3.81 units). The associations between change in FEV 1 and the EQ VAS were similar. Results of the HLMs were consistent and highly statistically significant, indicating cross-sectional and longitudinal associations. The largest estimates were found for the association between FEV 1 and the SGRQ activity domain., Conclusions: Difference and change in FEV 1 over time correlate with difference and change in disease-specific and generic HRQL. We conclude, that deterioration of HRQL should induce timely re-examination of physical status and lung function and possibly reassessment of therapeutic regimes., Trial Registration: NCT01245933. Date of registration: 18 November 2010.

There is growing interest in blood eosinophil counts in the management of chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Despite this, typical blood eosinophil levels in the general population, and the impact of potential confounders on these levels have not been clearly defined.We measured blood eosinophil counts in a random sample of 11 042 subjects recruited from the general population in Austria. We then: 1) identified factors associated with high blood eosinophil counts (>75th percentile); and 2) excluded subjects with these factors to estimate median blood eosinophil counts in a "healthy" sub-population (n=3641).We found that: 1) in the entire cohort, age ≤18 years (OR 2.41), asthma (OR 2.05), current smoking (OR 1.72), positive skin prick test (OR 1.64), COPD (OR 1.56), metabolic syndrome (OR 1.41), male sex (OR 1.36) and obesity (OR 1.16) were significantly (p<0.05) associated with high blood eosinophil counts (binary multivariable logistic regression analysis), and had an additive effect; and 2) after excluding these factors, in those older than 18 years, blood eosinophil counts were higher in males than in females (median 120 (5%-95% CI: 30-330) versus 100 (30-310) cells·µL -1 , respectively) and did not change with age.Median blood eosinophil counts in adults are considerably lower than those currently regarded as normal, do not change with age beyond puberty, but are significantly influenced by a variety of factors which have an additive effect. These observations will contribute to the interpretation of blood eosinophil levels in clinical practice., Competing Interests: Conflict of interest: S. Hartl has received unrestricted research grants for the Ludwig Boltzmann Institute of COPD and Respiratory Epidemiology and is on advisory boards for GSK, Boehringer Ingelheim, Novartis, Menarini, Chiesi, AstraZeneca, MSD, Roche, Abbvie, Takeda and TEVA for respiratory oncology and COPD. Conflict of interest: M-K. Breyer reports unrestricted grants for the LEAD study from GlaxoSmithKline, Novartis Pharma, AstraZeneca, Chiesi Pharma, Menarini Pharma, TEVA Ratiopharm, MSD, Air Liquide Health Care, Pfizer Corporation, Boehringer Ingelheim and Mundipharma. Conflict of interest: O.C. Burghuber reports grants from Boehringer Ingelheim, GSK, AstraZeneca, Menarini, Teva, Pfizer, Chiesi, Federal State Goverment Dept of Health and Novartis, non-financial support from AirLiquid and Municipial Dept of Health in Vienna, during the conduct of the study; personal fees for advisory board work and lectures from Boehringer Ingelheim, AstraZeneca, Chiesi, MSD, Menarini and Roche, personal fees for advisory board work from GSK, outside the submitted work. Conflict of interest: A. Ofenheimer has nothing to disclose. Conflict of interest: A. Schrott has nothing to disclose. Conflict of interest: M.H. Urban reports grants from Nycomed Pharma, during the conduct of the study; personal fees for lectures and advisory board work from AstraZeneca and Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Agusti reports personal fees from AstraZeneca, Chiesi and Nuvaira, grants and personal fees from Menarini and GSK, outside the submitted work. Conflict of interest: M. Studnicka reports personal fees for consultancy from Chiesi, AstraZeneca, Novartis, Boehringer and Almirall, and personal fees for lectures from GSK, AstraZeneca, Almirall, Novartis and Boehringer, outside the submitted work. Conflict of interest: E.F.M. Wouters reports personal fees for advisory board work from Nycomed and Boehringer, grants from AstraZeneca and GSK, personal fees for lectures from AstraZeneca, Novartis, GSK and Chiesi, outside the submitted work. Conflict of interest: R. Breyer-Kohansal reports personal fees for presentations and/or participations for AstraZeneca, Boehringer Ingelheim, Chiesi and Novartis outside the submitted work., (Copyright ©ERS 2020.)

Background: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012., Methods: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV 1 /FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV 1 /FVC < 0.7)., Results: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication., Conclusions: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and often co-exists with cardiovascular disease (CVD), hypertension and diabetes. This international study assessed the association between airflow obstruction and these comorbidities. 23,623 participants (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) in 33 centers in the Burden of Obstructive Lung Disease (BOLD) initiative were included. 10.4% of subjects had airflow obstruction. Self-reports of physician-diagnosed CVD (heart disease or stroke), hypertension and diabetes were regressed against airflow obstruction (post-bronchodilator FEV 1 /FVC < 5th percentile of reference values), adjusting for age, sex, smoking (including pack-years), body mass index and education. Analyses were undertaken within center and meta-analyzed across centers checking heterogeneity using the I 2 -statistic. Crude odds ratios for the association with airflow obstruction were 1.42 (95% CI: 1.20-1.69) for CVD, 1.24 (1.02-1.51) for hypertension, and 0.93 (0.76-1.15) for diabetes. After adjustment these were 1.00 (0.86-1.16) (I 2 :6%) for CVD, 1.14 (0.99-1.31) (I 2 :53%) for hypertension, and 0.76 (0.64-0.89) (I 2 :1%) for diabetes with similar results for men and women, smokers and nonsmokers, in richer and poorer centers. Alternatively defining airflow obstruction by FEV 1 /FVC < 2.5th percentile or 0.70, did not yield significant other results. In conclusion, the associations of CVD and hypertension with airflow obstruction in the general population are largely explained by age and smoking habits. The adjusted risk for diabetes is lower in subjects with airflow obstruction. These findings emphasize the role of common risk factors in explaining the coexistence of cardio-metabolic comorbidities and COPD.

Objective: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are the major reason for COPD hospitalization and increased risk for readmissions. The organizational structure of Austrian hospitals provides the opportunity to investigate the impact of specialized respiratory care compared to general care on adherence to guidelines and readmission in AECOPD., Methods: The data from the European COPD audit, a prospective observational non-interventional cohort trial were analyzed. In total, 823 patients admitted due to AECOPD in 26 hospitals (specialized respiratory care vs. general care) within Austria were included. Patients characteristics and outcomes (length of stay, readmission rate, and mortality) were analyzed in relation to hospital resources (personnel and equipment) and adherence to international guidelines., Results: Patients admitted to general care had more comorbidities (Charlson comorbidity index: 2.6 ± 1.7 vs. 2.0 ± 1.4; p < 0.05) and a shorter length of stay (10.7 ± 7.8 days vs. 12.0 ± 10.2 days; p < 0.05). Patients admitted to specialized respiratory care more often underwent blood gas analysis and non-invasive ventilation (98.4% vs. 81.5% and 68.6% vs. 26.7%, p < 0.01; respectively). In multivariate analysis, the risk for AECOPD readmission was lower (odds ratio, OR 0.72 [0.51;0.91]; p < 0.05) in patients admitted to specialized respiratory care., Conclusion: A greater adherence to COPD guidelines with respect to blood gas analysis and non-invasive ventilation and decreased AECOPD readmission risk was observed for patients admitted to specialized respiratory care. Adherence to guidelines may have the potential to decrease COPD readmission rates.

Background: Chronic obstructive pulmonary disease (COPD) is a frequent disease of the lungs. Its prevalence was estimated to be 26% in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and 11% for GOLD II-IV in Austria. Globally, it ranks third in mortality rate. The particular challenge is that care for these patients falls short due to the lack of structured integrated care. The aim was to assess the current status of multiprofessional COPD care in Austria and identify gaps and potentials., Methods: We conducted guided focus group interviews between March and July 2016 addressing current COPD care and treatment gaps with the following professional and interest groups: general practitioners, nurses, patients, pharmacists, physiotherapists and pulmonologists. We interviewed 23 patients and 27 healthcare professionals. The interviews were transcribed verbatim and coded into 12 relevant categories., Results: There needs to be a shift in thinking from treatment-based care to prevention. Patients, just like healthcare professionals, need periodic updates and comprehensive information on this disease. Creating internet platforms with useful information for COPD patients and solving the data privacy issues of the Austrian electronic medical record (ELGA) are also perceived as viable steps. There is a need and request for healthcare professionals to work as a team with clear COPD management guidelines in the outpatient sector, the establishment of outpatient rehabilitation centers as well as creating a new professional profile, the COPD nurse., Conclusion: Current COPD care needs to be reorganized, particularly in the outpatient sector, to address the needs of patients and healthcare professionals.

This study investigated whether different breathing conditions during exercise testing will influence measures of exercise capacity commonly used for training prescription in chronic obstructive pulmonary disease. Twenty-seven patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 sec = 45.6 [9.4]%) performed three maximal exercise tests within 8 days, but at least 48 hrs apart. Subjects were thereby breathing either room air through a tightly fitting face mask like during any cardiopulmonary exercise test (MASK), room air without mask (No-MASK), or 10 l/min of oxygen via nasal cannula (No-MASK + O2). Cycling protocols were identical for all tests (start = 20 watts, increment = 10 males/5 females watts/min). Maximal work rate (90.4 [33.8], 100.3 [34.8], 107.4 [35.9] watts, P < 0.001) and blood lactate at exhaustion (4.3 [1.5], 5.2 [1.6], 5.0 [1.4] mmol/l, P < 0.001) were lowest for MASK when compared with No-MASK and No-MASK + O2, respectively, whereas maximal heart rate did not differ significantly. Submaximal exertion (Borg rating of perceived exertion = 12-14) was perceived at lower intensity (P = 0.008), but higher heart rate (P = 0.005) when MASK was compared with No-MASK and No-MASK + O2. Different breathing conditions during exercise testing resulted in an 18.8% difference in maximal work rate, likely causing underdosing or overdosing of exercise in chronic obstructive pulmonary disease. Face masks reduced whereas supplemental oxygen increased patients' exercise capacity. For accurate prescription of exercise in chronic obstructive pulmonary disease, breathing conditions during testing should closely match training conditions.

We aimed to examine associations between chronic airflow obstruction (CAO) and unemployment across the world.Cross-sectional data from 26 sites in the Burden of Obstructive Lung Disease (BOLD) study were used to analyse effects of CAO on unemployment. Odds ratios for unemployment in subjects aged 40-65 years were estimated using a multilevel mixed-effects generalised linear model with study site as random effect. Site-by-site heterogeneity was assessed using individual participant data meta-analyses.Out of 18 710 participants, 11.3% had CAO. The ratio of unemployed subjects with CAO divided by subjects without CAO showed large site discrepancies, although these were no longer significant after adjusting for age, sex, smoking and education. The site-adjusted odds ratio (95% CI) for unemployment was 1.79 (1.41-2.27) for CAO cases, decreasing to 1.43 (1.14-1.79) after adjusting for sociodemographic factors, comorbidities and forced vital capacity. Of other covariates that were associated with unemployment, age and education were important risk factors in high-income sites (4.02 (3.53-4.57) and 3.86 (2.80-5.30), respectively), while female sex was important in low- to middle-income sites (3.23 (2.66-3.91)).In the global BOLD study, CAO was associated with increased levels of unemployment, even after adjusting for sociodemographic factors, comorbidities and lung function., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Background: COPD prevalence is highly variable and geographical altitude has been linked to it, yet with conflicting results. We aimed to investigate this association, considering well known risk factors., Methods: A pooled analysis of individual data from the PREPOCOL-PLATINO-BOLD-EPI-SCAN studies was used to disentangle the population effect of geographical altitude on COPD prevalence. Post-bronchodilator FEV1/FVC below the lower limit of normal defined airflow limitation consistent with COPD. High altitude was defined as >1500 m above sea level. Undiagnosed COPD was considered when participants had airflow limitation but did not report a prior diagnosis of COPD., Results: Among 30,874 participants aged 56.1 ± 11.3 years from 44 sites worldwide, 55.8% were women, 49.6% never-smokers, and 12.9% (3978 subjects) were residing above 1500 m. COPD prevalence was significantly lower in participants living at high altitude with a prevalence of 8.5% compared to 9.9%, respectively (p < 0.005). However, known risk factors were significantly less frequent at high altitude. Hence, in the adjusted multivariate analysis, altitude itself had no significant influence on COPD prevalence. Living at high altitude, however, was associated with a significantly increased risk of undiagnosed COPD. Furthermore, subjects with airflow limitation living at high altitude reported significantly less respiratory symptoms compared to subjects residing at lower altitude., Conclusion: Living at high altitude is not associated with a difference in COPD prevalence after accounting for individual risk factors. However, high altitude itself was associated with an increased risk of undiagnosed COPD.

Background: Physical exercise training is an evidence-based treatment in chronic obstructive pulmonary disease, and patients' peak work rate is associated with reduced chronic obstructive pulmonary disease mortality. We assessed whether supplemental oxygen during exercise training in nonhypoxemic patients with chronic obstructive pulmonary disease might lead to superior training outcomes, including improved peak work rate., Methods: This was a randomized, double-blind, controlled, crossover trial. Twenty-nine patients with chronic obstructive pulmonary disease (aged 63.5 ± 5.9 years; forced expiratory volume in 1 second percent predicted, 46.4 ± 8.6) completed 2 consecutive 6-week periods of endurance and strength training with progressive intensity, which was performed 3 times per week with supplemental oxygen or compressed medical air (flow via nasal cannula: 10 L/min). Each session of electrocardiography-controlled interval cycling lasted 31 minutes and consisted of a warm-up, 7 cycles of 1-minute intervals at 70% to 80% of peak work rate alternating with 2 minutes of active recovery, and final cooldown. Thereafter, patients completed 8 strength-training exercises of 1 set each with 8 to 15 repetitions to failure. Change in peak work rate was the primary study end point., Results: The increase in peak work rate was more than twice as high when patients exercised with supplemental oxygen compared with medical air (0.16 ± 0.02 W/kg vs 0.07 ± 0.02 W/kg; P < .001), which was consistent with all other secondary study end points related to exercise capacity. The impact of oxygen on peak work rate was 39.1% of the overall training effect, whereas it had no influence on strength gain (P > .1 for all exercises)., Conclusions: We report that supplemental oxygen in nonhypoxemic chronic obstructive pulmonary disease doubled the effect of endurance training but had no effect on strength gain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Studies report high in-hospital and post-discharge mortality of chronic obstructive pulmonary disease (COPD) exacerbations varying depending upon patient characteristics, hospital resources and treatment standards. This study aimed to investigate the patient, resource and organisational factors associated with in-hospital and 90-day post-discharge mortality and readmission of COPD exacerbations within the European COPD Audit. The audit collected data of COPD exacerbation admissions from 13 European countries.On admission, only 49.7% of COPD patients had spirometry results available and only 81.6% had blood gases taken. Using logistic regression analysis, the risk associated with in-hospital and post-discharge mortality was higher age, presence of acidotic respiratory failure, subsequent need for ventilatory support and presence of comorbidity. In addition, the 90-day risk of COPD readmission was associated with previous admissions. Only the number of respiratory specialists per 1000 beds, a variable related to hospital resources, decreased the risk of post-discharge mortality.The European COPD Audit identifies risk factors associated with in-hospital and post-discharge mortality and COPD readmission. Addressing the deficiencies in acute COPD care such as making spirometry available and measuring blood gases and providing noninvasive ventilation more regularly would provide opportunities to improve COPD outcomes., (Copyright ©ERS 2016.)

Background: COPD ranks within the top three causes of mortality in the global burden of disease, yet it remains largely underdiagnosed. We assessed the underdiagnosis of COPD and its determinants in national and international surveys of general populations., Methods: We analyzed representative samples of adults aged ≥ 40 years randomly selected from well-defined administrative areas worldwide (44 sites from 27 countries). Postbronchodilator FEV1/FVC < lower limit of normal (LLN) was used to define chronic airflow limitation consistent with COPD. Undiagnosed COPD was considered when participants had postbronchodilator FEV1/FVC < LLN but were not given a diagnosis of COPD., Results: Among 30,874 participants with a mean age of 56 years, 55.8% were women, and 22.9% were current smokers. Population prevalence of (spirometrically defined) COPD ranged from 3.6% in Barranquilla, Colombia, to 19.0% in Cape Town, South Africa. Only 26.4% reported a previous lung function test, and only 5.0% reported a previous diagnosis of COPD, whereas 9.7% had a postbronchodilator FEV1/FVC < LLN. Overall, 81.4% of (spirometrically defined) COPD cases were undiagnosed, with the highest rate in Ile-Ife, Nigeria (98.3%) and the lowest rate in Lexington, Kentucky (50.0%). In multivariate analysis, a greater probability of underdiagnosis of COPD was associated with male sex, younger age, never and current smoking, lower education, no previous spirometry, and less severe airflow limitation., Conclusions: Even with substantial heterogeneity in COPD prevalence, COPD underdiagnosis is universally high. Because effective management strategies are available for COPD, spirometry can help in the diagnosis of COPD at a stage when treatment will lead to better outcomes and improved quality of life.

Purpose: Evidence-based medicine promotes the current best evidence from clinical trials to guide decisions for individual patients. We assessed whether chronic obstructive pulmonary disease (COPD) patients included in exercise training studies and pharmacologic trials match those from a non-selected COPD target population sample., Methods: Exercise training studies were identified in a literature search. Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) were chosen to represent pharmacologic trials. Burden of Obstructive Lung Disease (BOLD) data were used to characterize target COPD population (BOLD target), defined as the presence of dyspnea (modified Medical Research Council ≥2) and non-reversible airway obstruction (post-bronchodilator FEV1/FVC ≤0.7 and FEV1% predicted ≤70 %)., Results: Overall 240 exercise training studies with 13,901, TORCH and UPLIFT with 12,105, and BOLD with 16,218 participants were evaluated. Males were overrepresented in exercise training studies (67.5%) and pharmacologic trials (TORCH 75.8%; UPLIFT 74.6%), whereas in BOLD target 55.8% were males (p < 0.001). In exercise training studies, 7.2% were never-smokers, 0.0% in TORCH and UPLIFT, but 36.0% in BOLD target (p < 0.001). Subjects with cardiac comorbidity were excluded from 75.4% of exercise training studies, entirely from TORCH and UPLIFT, but comprised 24.5% of BOLD target., Conclusions: COPD patients recruited in exercise training studies and in pharmacologic trials differ from target population of symptomatic COPD. Females, never-smokers, and patients with cardiac comorbidities are more likely excluded from the clinical trials.

Background: COPD is a progressive disease of the airways that is characterized by neutrophilic inflammation, a condition known to promote the excessive formation of neutrophil extracellular traps (NETs). The presence of large amounts of NETs has recently been demonstrated for a variety of inflammatory lung diseases including cystic fibrosis, asthma and exacerbated COPD., Objective: We test whether excessive NET generation is restricted to exacerbation of COPD or whether it also occurs during stable periods of the disease, and whether NET presence and amount correlates with the severity of airflow limitation., Patients, Materials and Methods: Sputum samples from four study groups were examined: COPD patients during acute exacerbation, patients with stable disease, and smoking and non-smoking controls without airflow limitation. Sputum induction followed the ECLIPSE protocol. Confocal laser microscopy (CLSM) and electron microscopy were used to analyse samples. Immunolabelling and fluorescent DNA staining were applied to trace NETs and related marker proteins. CLSM specimens served for quantitative evaluation., Results: Sputum of COPD patients is clearly characterised by NETs and NET-forming neutrophils. The presence of large amounts of NET is associated with disease severity (p < 0.001): over 90 % in exacerbated COPD, 45 % in stable COPD, and 25 % in smoking controls, but less than 5% in non-smokers. Quantification of NET-covered areas in sputum preparations confirms these results., Conclusions: NET formation is not confined to exacerbation but also present in stable COPD and correlates with the severity of airflow limitation. We infer that NETs are a major contributor to chronic inflammatory and lung tissue damage in COPD.

Polymorphonuclear neutrophils have in recent years attracted new attention due to their ability to release neutrophil extracellular traps (NETs). These web-like extracellular structures deriving from nuclear chromatin have been depicted in ambiguous roles between antimicrobial defence and host tissue damage. NETs consist of DNA strands of varying thickness and are decorated with microbicidal and cytotoxic proteins. Their principal structure has in recent years been characterised at molecular and ultrastructural levels but many features that are of direct relevance to cytotoxicity are still incompletely understood. These include the extent of chromatin decondensation during NET formation and the relative amounts and spatial distribution of the microbicidal components within the NET. In the present work, we analyse the structure of NETs found in induced sputum of patients with acutely exacerbated chronic obstructive pulmonary disease (COPD) using confocal laser microscopy and electron microscopy. In vitro induced NETs from human neutrophils serve for purposes of comparison and extended analysis of NET structure. Results demonstrate that COPD sputa are characterised by the pronounced presence of NETs and NETotic neutrophils. We provide new evidence that chromatin decondensation during NETosis is most extensive and generates substantial amounts of double-helix DNA in 'beads-on-a-string' conformation. New information is also presented on the abundance and location of neutrophil elastase (NE) and citrullinated histone H3 (citH3). NE occurs in high densities in nearly all non-fibrous constituents of the NETs while citH3 is much less abundant. We conclude from the results that (i) NETosis is an integral part of COPD pathology; this is relevant to all future research on the etiology and therapy of the disease; and that (ii) release of 'beads-on-a-string' DNA studded with non-citrullinated histones is a common feature of in vivo NETosis; this is of relevance to both the antimicrobial and the cytotoxic effects of NETs.

Background: Chronic obstructive pulmonary disease (COPD) is a major public health burden and profoundly affects individuals suffering from the disease. However, the majority of subjects with COPD are still undiagnosed., Objectives: To evaluate COPD prevalence and detection strategies for COPD in the primary-care setting., Methods: The study was conducted in a random sample of general practitioner (GP) offices in Salzburg (Austria). A questionnaire and post-bronchodilator (PBD) spirometry was administered to patients aged ≥ 40 years. Nonreversible airway obstruction was considered when PBD FEV1/FVC was <0.70. Severity of spirometrically defined COPD was graded according to the GOLD recommendations., Results: 60 GP offices were randomly selected for study participation, however only 30 (50.0%) were willing to participate. 1,230 of 9,820 (12.52%) patients consented to the protocol. Quality of PBD spirometry was evaluated, and 882 (71.7%) met ATS/ERS quality criteria. 7.5% (95% CI: 5.7-9.4%) of the patients had COPD grade II+ (FEV1/FVC <0.7 and FEV1 <80% of predicted), but only 22.4% of them reported a prior physician's diagnosis of COPD. Similar results were seen for the 2005 Salzburg BOLD (Burden of Obstructive Lung Disease) sample with regard to COPD GOLD II+ prevalence (10.7%) and proportion of underdiagnosis (82.3%)., Conclusion: COPD in the primary-care setting is as prevalent and underdiagnosed as reported recently for the BOLD study. The surprisingly low participation rate of GPs and patients indicates that prevention of COPD is not a health priority, and that awareness for COPD has to heightened before case-finding strategies will be successful.

The aim of this study was to describe the impact of chronic obstructive pulmonary disease (COPD) on health status in the Burden of Obstructive Lung Disease (BOLD) populations. We conducted a cross-sectional, general population-based survey in 11 985 subjects from 17 countries. We measured spirometric lung function and assessed health status using the Short Form 12 questionnaire. The physical and mental health component scores were calculated. Subjects with COPD (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.70, n = 2269) had lower physical component scores (44±10 versus 48±10 units, p<0.0001) and mental health component scores (51±10 versus 52±10 units, p = 0.005) than subjects without COPD. The effect of reported heart disease, hypertension and diabetes on physical health component scores (-3 to -4 units) was considerably less than the effect of COPD Global Initiative for Chronic Obstructive Lung Disease grade 3 (-8 units) or 4 (-11 units). Dyspnoea was the most important determinant of a low physical and mental health component scores. In addition, lower forced expiratory volume in 1 s, chronic cough, chronic phlegm and the presence of comorbidities were all associated with a lower physical health component score. COPD is associated with poorer health status but the effect is stronger on the physical than the mental aspects of health status. Severe COPD has a greater negative impact on health status than self-reported cardiovascular disease and diabetes.

Background: Current guidelines recommend spirometry to confirm a diagnosis of chronic obstructive pulmonary disease (COPD)., Aims: To investigate whether a self-reported diagnosis of COPD is associated with prior spirometry and whether a correct diagnosis of COPD is more likely when spirometry was performed., Methods: We used data from the population-based Austrian Burden of Obstructive Lung Disease (BOLD) study. Participants were aged >40 years and completed post-bronchodilator spirometry. Reported COPD diagnosis and reported prior lung function test were based on questionnaire. Persistent airflow limitation was defined as post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio <0.7, corresponding with COPD Global initiative for chronic Obstructive Lung Disease (GOLD) grade I+, and GOLD grade II+ was also investigated. A correct diagnosis of COPD was defined as a reported physician's diagnosis of COPD and the presence of persistent airflow limitation., Results: 68 (5.4%) of 1,258 participants reported a prior physician's diagnosis of COPD. Of these, only 17 (25.0%) reported a lung function test within the past 12 months and 46 (67.6%) at any time in the past. The likelihood for a correct COPD GOLD grade I+ diagnosis was similar among subjects reporting a lung function test during the last 12 months (likelihood ratio 2.07, 95% CI 0.89 to 5.50) and those not reporting a lung function during the last 12 months (likelihood ratio 2.78, 95% CI 1.58 to 4.87). Similar likelihood ratios were seen when GOLD grade II+ was investigated and when lung function was reported at any time in the past., Conclusions: One-third of subjects with a reported diagnosis of COPD never had a lung function test. When spirometry was reported, this did not increase the likelihood of a correct COPD diagnosis.

This study aimed to compare strategies for chronic obstructive pulmonary disease (COPD) case finding using data from the Burden of Obstructive Lung Disease study. Population-based samples of adults aged ≥40 yrs (n = 9,390) from 14 countries completed a questionnaire and spirometry. We compared the screening efficiency of differently staged algorithms that used questionnaire data and/or peak expiratory flow (PEF) data to identify persons at risk for COPD and, hence, needing confirmatory spirometry. Separate algorithms were fitted for moderate/severe COPD and for severe COPD. We estimated the cost of each algorithm in 1,000 people. For moderate/severe COPD, use of questionnaire data alone permitted high sensitivity (97%) but required confirmatory spirometry in 80% of participants. Use of PEF necessitated confirmatory spirometry in only 19-22% of subjects, with 83-84% sensitivity. For severe COPD, use of PEF achieved 91-93% sensitivity, requiring confirmatory spirometry in <9% of participants. Cost analysis suggested that a staged screening algorithm using only PEF initially, followed by confirmatory spirometry as needed, was the most cost-effective case-finding strategy. Our results support the use of PEF as a simple, cost-effective initial screening tool for conducting COPD case-finding in adults aged ≥40 yrs. These findings should be validated in real-world settings such as the primary care environment.

Background: Never smokers comprise a substantial proportion of patients with COPD. Their characteristics and possible risk factors in this population are not yet well defined., Methods: We analyzed data from 14 countries that participated in the international, population-based Burden of Obstructive Lung Disease (BOLD) study. Participants were aged ≥ 40 years and completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. A diagnosis of COPD was based on the postbronchodilator FEV₁/FVC ratio, according to current GOLD (Global Initiative for Obstructive Lung Disease) guidelines. In addition to this, the lower limit of normal (LLN) was evaluated as an alternative threshold for the FEV₁/FVC ratio., Results: Among 4,291 never smokers, 6.6% met criteria for mild (GOLD stage I) COPD, and 5.6% met criteria for moderate to very severe (GOLD stage II+) COPD. Although never smokers were less likely to have COPD and had less severe COPD than ever smokers, never smokers nonetheless comprised 23.3% (240/1,031) of those classified with GOLD stage II+ COPD. This proportion was similar, 20.5% (171/832), even when the LLN was used as a threshold for the FEV₁/FVC ratio. Predictors of COPD in never smokers include age, education, occupational exposure, childhood respiratory diseases, and BMI alterations., Conclusion: This multicenter international study confirms previous evidence that never smokers comprise a substantial proportion of individuals with COPD. Our data suggest that, in addition to increased age, a prior diagnosis of asthma and, among women, lower education levels are associated with an increased risk for COPD among never smokers.

Background: Chronic obstructive pulmonary disease (COPD) is increasing worldwide and thus its associated morbidity and mortality. However, COPD often goes undiagnosed., Objectives: We evaluated the rate of non-diagnosed irreversible airway obstruction (AO) and characterized this patient group. We further assessed the possible effects of conducting targeted spirometry in a population sample in Salzburg, Austria, as part of the Burden of Obstructive Lung Disease (BOLD) study., Methods: 1,258 adults ≥40 years of age completed a questionnaire and performed spirometry before and after bronchodilator therapy (post-BD). Irreversible AO was defined as post-BD FEV(1)/FVC below the lower limit of normal; we used the FEV(1)% predicted (pred.) to further grade the disease. Participants without a physician diagnosis of COPD who reported respiratory symptoms and a history of risk factors (ever smoking or occupational risk) were defined as eligible for targeted spirometry., Results: 85.9% (171/199) of the participants with irreversible AO did not report a prior diagnosis of COPD. Non-diagnosed AO was inversely related to severity, age, self-reported prior respiratory diseases and cough as a respiratory symptom. 343 participants were eligible for targeted spirometry and irreversible AO was present in 86 (25.1%) participants. Therefore, targeted spirometry could reduce the underdiagnosis of irreversible AO of any severity by 50.3% (86 of 171). The diagnosis of 1 person with FEV(1) <80% pred. would require spirometry in 8.4 subjects (95% confidence interval 6.2-11.1)., Conclusion: Although several factors are associated with non-diagnosed AO, spirometry in individuals with respiratory symptoms and exposure to risk factors could reduce undiagnosed irreversible AO by half., (Copyright © 2010 S. Karger AG, Basel.)

Rationale: The presence of airway obstruction is currently defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines on the basis of the post-bronchodilator (BD) FEV(1)/FVC. It has been proposed that the traditional FVC can be replaced with the shorter and less demanding FEV(6) for detecting airway obstruction., Objectives: A comparison of FEV(1)/FVC and FEV(1)/FEV(6) for the detection of airway obstruction in population-based post-bronchodilator spirometry data., Methods: A population-based sample of 1,349 adults participated in the Burden of Obstructive Lung Disease study in Austria. Specially trained and certified technicians conducted pre-BD and post-BD spirometry according to American Thoracic Society guidelines and administered standardized questionnaires. A total of 93% of the post-BD test sessions were acceptable, and were included in this analysis. The Third National Health and Nutrition Examination Survey reference equations were used to calculate predicted values and lower limits of normal (LLN) for FEV(1), FEV(6), FVC, FEV(1)/FVC, and FEV(1)/FEV(6)., Measurements and Main Results: The post-BD FEV(1)/FVC was below the LLN in 199 (15.8%) subjects. The sensitivity of the FEV(1)/FEV(6) for airway obstruction depended greatly on the threshold of percent predicted FEV(1) also used in the definition. The overall sensitivity of FEV(1)/FEV(6) for a diagnosis of airway obstruction, as defined by FEV(1)/FVC (including participants with an FEV(1) above the LLN), was 72.9%, with 98.8% specificity. The sensitivity increased to 98.0% when a low FEV(1) was also required to diagnose post-BD airway obstruction. The discordant cases had long forced expiratory times, often showed a flow-volume curve pattern consistent with two-compartment emptying, and were more often never-smokers., Conclusions: Six-second spirometry maneuvers (which measure FEV(6)) are as sensitive and specific for post-BD airway obstruction as traditional (prolonged exhalation time) FVC maneuvers only when the definition of airway obstruction includes a low FEV(1).

Background: In 2020 Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death world-wide causing considerable health costs. Epidemiological data to estimate the future development of COPD in Austria were not available so far., Methods: In the context of the international Burden of Obstructive Lung Disease (BOLD) study, a random sample of the population of Salzburg was surveyed to determine the prevalence of COPD. The definition of COPD followed the GOLD classification. A prior physician's diagnosis of COPD, emphysema or chronic bronchitis was evaluated by questionnaire. The age- and sex-specific prevalence of COPD was extrapolated using demographic data of the Austrian population for the years 2005, 2010, 2015 and 2020. Undiagnosed COPD was considered present, whenever irreversible airways obstruction was measured (FEV1/FVC < 0.7), but a doctor's diagnosis of COPD, emphysema or chronic bronchitis has not been made., Results: For 2005 1.047.150 Austrians aged 40 years and older were estimated in GOLD stage I-IV. 431.080 persons over 40 years were affected by COPD in GOLD stage II-IV needing therapy. The percentage of undiagnosed COPD was 88,5%. For the years 2010, 2015 and 2020 GOLD stage I-IV COPD was projected to rise by 7,8%, 16.1% and 24%, respectively., Conclusion: Measures to prevent COPD are absolutely necessary to forestall the projected burden of this disease in Austria.

Background: COPD is projected to be the third leading cause of death worldwide by 2020. The Burden of Obstructive Lung Disease initiative was started to measure the prevalence of COPD in a standardized way and to provide estimates of the social and economic burden of disease., Methods: We surveyed a gender-stratified, population-based sample of 2,200 adults >or= 40 years of age. The findings of prebronchodilator and postbronchodilator spirometry, as well as information on smoking and reported respiratory disease was recorded. Irreversible airflow obstruction was defined as a postbronchodilator FEV(1)/FVC ratio of < 0.70., Results: For 1,258 participants with good-quality postbronchodilator spirometry findings, the overall prevalence of COPD at stage I or higher was 26.1%, and was equal in men and women. The prevalence of COPD stage II or higher (FEV(1)/FVC ratio, < 0.7; FEV(1), < 80% predicted) was 10.7%. The prevalence of COPD stage I+, and COPD stage II+, increased with age and cigarette smoking. A doctor diagnosis of COPD was reported by only 5.6% of participants., Conclusion: One quarter of residents of Salzburg County (Austria) who were >or= 40 years of age had at least mild irreversible airflow obstruction. The high prevalence of COPD highlights the impending health-care crisis that will affect many countries as a result of this greatly underappreciated condition.

The prevalence of COPD when using spirometry data lies between 4% and 10%. However, health statistics do not fully account for COPD patients either, given the underdiagnosis of this disease reported between 30% and 50%. In the late stage, COPD is associated with a great impact on quality of life and repeated costly hospital stays. Given that COPD in its early stage would be easily preventable by means of smoking cessation, measures of early detection are urgently needed to prevent the COPD epidemic of the years to come.