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Chronic obstructive pulmonary disease (COPD) is a slowly developing non-communicable disease (NCD), causing non-reversible obstruction and leading to marked morbidity and mortality. Besides traditional risk factors such as smoking, some environmental substances can augment the risk of COPD. The European Human Biomonitoring Initiative (HBM4EU) is a program evaluating citizens' exposure to various environmental substances and their possible health impacts. Within the HBM4EU, eighteen priority substances or substance groups were chosen. In this scoping review, seven of these substances or substance groups are reported to have an association or a possible association with COPD. Main exposure routes, vulnerable and high-exposure risk groups, and matrices where these substances are measured are described. Pesticides in general and especially organophosphate and carbamate insecticides, and some herbicides, lead (Pb), and polycyclic aromatic hydrocarbons (PAHs) showed an association, and cadmium (Cd), chromium (Cr and CrVI), arsenic (As), and diisocyanates, a possible association with COPD and/or decreased lung function. Due to long latency in COPD's disease process, the role of chemical exposure as a risk factor for COPD is probably underestimated. More research is needed to support evidence-based conclusions. Generally, chemical exposure is a growing issue of concern, and prompt action is needed to safeguard public health.

Asthma and COPD are common chronic obstructive respiratory diseases. COPD is associated with increased mortality, but for asthma the results are varying. Their combination has been less investigated, and the results are contradictory. The aim of this prospective study was to observe the overall mortality in obstructive pulmonary diseases and how mortality was related to specific causes using postal questionnaire data. This study included data from 6,062 participants in the FinEsS Helsinki Study (1996) linked to mortality data during a 24-year follow-up. According to self-reported physician diagnosed asthma, COPD, or smoking status, the population was divided into five categories: combined asthma and COPD, COPD alone and asthma alone, ever-smokers without asthma or COPD and never-smokers without asthma or COPD (reference group). For the specific causes of death both the underlying and contributing causes of death were used. Participants with asthma and COPD had the highest hazard of mortality 2.4 (95% CI 1.7–3.5). Ever-smokers without asthma or COPD had a 9.5 (3.7–24.2) subhazard ratio (sHR) related to lower respiratory tract disease specific causes. For asthma, COPD and combined, the corresponding figures were 10.8 (3.4–34.1), 25.0 (8.1–77.4), and 56.1 (19.6–160), respectively. Ever-smokers without asthma or COPD sHR 1.7 (95% CI 1.3–2.5), and participants with combined asthma and COPD 3.5 (1.9–6.3) also featured mortality in association with coronary artery disease. Subjects with combined diseases had the highest hazard of overall mortality and combined diseases also showed the highest hazard of mortality associated with lower respiratory tract causes or coronary artery causes. Abbreviations:Cig Cigarette COPD Chronic obstructive pulmonary disease CVD Cardiovascular disease FEV1 Forced Expiratory Volume in one second FVC Forced Vital Capacity FinEsS Finland, Estonia, and Sweden study on chronic obstructive pulmonary diseases HR Hazard Ratio sHR Subhazard Ratio ICD-10 International Statistical Classifications of Diseases and Related Health Problems (Version 10). publishedVersion

Bruno Balbi,1 Claudia Sangiorgi,1 Isabella Gnemmi,1 Ilaria Ferrarotti,2 Davide Vallese,1 Elena Paracchini,1 Lorena Delle Donne,1 Luciano Corda,3 Paolo Baderna,4 Angelo Corsico,2 Mauro Carone,1 Paola Brun,5 Francesco Cappello,6,7 Fabio LM Ricciardolo,8 Paolo Ruggeri,9 Sharon Mumby,10 Ian M Adcock,10 Gaetano Caramori,9 Antonino Di Stefano11Istituti Clinici Scientifici Maugeri, IRCCS, Division of Pneumology and Laboratory of Cytoimmunopathology of the Heart and Lung, Veruno, Italy; 2Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; 3Medicina Respiratoria, Seconda Medicina Interna, Spedali Civili, Brescia, Italy; 4Division of Pneumology, Aosta Hospital, Aosta, Italy; 5Department of Molecular Medicine, University of Padova, Padova, Italy; 6Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Anatomia Umana, Università di Palermo, Palermo, Italy; 7Euro-mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy; 8Department of Clinical and Biological Sciences, A.O.U., San Luigi Gonzaga, Orbassano, University of Turin, Turin, Italy; 9UOC Di Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e Delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy; 10Airways Disease Section, National Heart and Lung Institute, Imperial College London, UKCorrespondence: Antonino Di StefanoIstituti Clinici Scientifici Maugeri Irccs, Via Maugeri, 4, Pavia 27100, ItalyTel +39 032 288 4711Fax +39 032 288 4776Email antonino.distefano@icsmaugeri.itBackground: Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated.Methods: We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR.Results: AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels (p=0.0446, p=0.0135), total bacterial load (16S) (p=0.0081, p=0.0223), M. catarrhalis (p=0.0115, p=0.0127) and S. pneumoniae (p=0.0013, p=0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD (p=0.0297) and these positively correlated with FEV1% predicted values (r=0.578, p=0.0307).Conclusions: Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes.Keywords: alpha-1antitrypsin deficiency, COPD, chronic airway inflammation, respiratory disability, sputum

Objective: To investigate the current prevalence of physician-diagnosed obstructive airway diseases by respiratory symptoms and by sex in Sweden and Finland. Method: In 2016, a postal questionnaire was answered by 34,072 randomly selected adults in four study areas: Västra Götaland and Norrbotten in Sweden, and Seinäjoki-Vaasa and Helsinki in Finland. Results: The prevalence of asthma symptoms was higher in Norrbotten (13.2%), Seinäjoki-Vaasa (14.8%) and Helsinki (14.4%) than in Västra Götaland (10.7%), and physician-diagnosed asthma was highest in Norrbotten (13.0%) and least in Västra Götaland (10.1%). Chronic productive cough was most common in the Finnish areas (7.7–8.2% versus 6.3–6.7%) while the prevalence of physician-diagnosed chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD) varied between 1.7 and 2.7% in the four areas. Among individuals with respiratory symptoms, the prevalence of asthma was most common in Norrbotten, while a diagnosis of COPD or CB was most common in Västra Götaland and Seinäjoki-Vaasa. More women than men with respiratory symptoms reported a diagnosis of asthma in Sweden and Seinäjoki-Vaasa but there were no sex differences in Helsinki. In Sweden, more women than men with symptoms of cough or phlegm reported a diagnosis of CB or COPD, while in Finland the opposite was found. Conclusion: The prevalence of respiratory symptoms and corresponding diagnoses varied between and within the countries. The proportion reporting a diagnosis of obstructive airway disease among individuals with respiratory symptoms varied, indicating differences in diagnostic patterns both between areas and by sex. Accepted author version posted online: 30 May 2020Published online: 13 Jun 2020

International audience; Purpose: Respiratory hazards of farming have been identified for centuries, with little focus on gender differences. We used data from the AGRICOH consortium, a collective of prospective cohorts of agricultural workers, to assess respiratory disease prevalence among adults in 18 cohorts representing over 200,000 farmers, farm workers, and their spouses from six continents.Methods: Cohorts collected data between 1992 and 2016 and ranged in size from 200 to >128,000 individuals; 44% of participants were female. Farming practices varied from subsistence farming to large-scale industrial agriculture. All cohorts provided respiratory outcome information for their cohort based on their study definitions. The majority of outcomes were based on self-report using standard respiratory questionnaires; the greatest variability in assessment methods was associated with chronic obstructive pulmonary disease (COPD).Results: For all three respiratory symptoms (cough, phlegm, and wheeze), the median prevalence in men was higher than in women, with the greatest difference for phlegm (17% vs. 10%). For asthma, women had a higher prevalence (7.8% vs 6.5%), with the difference associated with allergic asthma. The relative proportion of allergic asthma varied among cohorts. In two of eight cohorts for women and two of seven cohorts for men, allergic asthma was more common than non-allergic asthma.Conclusions: These findings indicate that respiratory outcomes are common among farmers around the world despite differences in agricultural production. As women in the general population are at higher risk of asthma, exploring gender differences in occupational studies is critical for a deeper understanding of respiratory disease among agricultural workers.

Rationale: Evidence supporting the association of chronic obstructive pulmonary disease or airflow obstruction with use of solid fuels is conflicting and inconsistent. Objectives: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. Methods: We analyzed 18,554 adults from the BOLD (Burden of Obstructive Lung Disease) study, who had provided acceptable post-bronchodilator spirometry measurements, and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analyzed. We performed similar analyses for spirometric restriction, chronic cough, and chronic phlegm. Measurements and Main Results: We found no association between airflow obstruction and use of solid fuels for cooking or heating (odds ratio [OR] for men, 1.20 [95% confidence interval (CI), 0.94–1.53]; OR for women, 0.88 [95% CI, 0.67–1.15]). This was true for low-/middle- and high-income sites. Among never-smokers, there was also no evidence of an association of airflow obstruction with use of solid fuels (OR for men, 1.00 [95% CI, 0.57–1.76]; OR for women, 1.00 [95% CI, 0.76–1.32]). Overall, we found no association of spirometric restriction, chronic cough, or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never-smokers and those who had been exposed for 20 years or longer. Conclusions: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

The clinical manifestations of chronic obstructive pulmonary disease (COPD) reflect an aggregate of multiple pulmonary and extrapulmonary processes. It is increasingly clear that full assessment of these processes is essential to characterize disease burden and to tailor therapy. Medical imaging has advanced such that it is now possible to obtain in vivo insight in the presence and severity of lung disease-associated features. In this review, we have assembled data from multiple disciplines of medical imaging research to review the role of imaging in characterization of COPD. Topics include imaging of the lungs, body composition, and extrapulmonary tissue metabolism. The primary focus is on imaging modalities that are widely available in clinical care settings and that potentially contribute to describing COPD heterogeneity and enhance our insight in underlying pathophysiological processes and their structural and functional effects.

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease (ILD) affecting older West Highland white terriers (WHWTs). According to one classification, CIPF is a familial fibrotic ILD in the group of idiopathic interstitial pneumonias. Etiology is unknown but likely arises from interplay between genetic and environmental factors. CIPF shares features with human idiopathic pulmonary fibrosis and human nonspecific interstitial pneumonia. This article describes clinical signs, findings in physical examination, arterial oxygenation, diagnostic imaging, bronchoscopy, bronchoalveolar lavage, histopathology, disease course, and outcome of WHWTs with CIPF; compares canine and human diseases; summarizes biomarker research; and gives an overview of potential treatment.

Background and objective Life expectancy data of COPD patients in comparison to the general population are primarily based upon long-term population cohort studies. These studies are limited by a poor definition of clinically significant COPD. The key element in the course of COPD is a clinical exacerbation. Therefore, this study investigated 15-year survival following hospitalization for an exacerbation of COPD in comparison to the general population. Methods A number of 4229 subjects was studied, including 845 hospitalized COPD patients and 3384 age and sex matched controls. Mortality risks were assessed using Kaplan–Meier survival curves, and hazard rate ratios for death were estimated using Cox proportional hazards regression models, for each Gold Class separately. Results Overall 15-year survival was 7.3% in the COPD group and 40.6% in the general population. Survival was 24%, 11.1%, 5.3% and 0% for COPD GOLD I-IV. The mean life expectancy following hospitalization was 9.7, 7.1, 6.1 and 3.4 years for stage GOLD I-IV and 10.2 years for the general population. Overall, negative prognostic factors were age, male gender, low FEV1, low TLCO, respiratory insufficiency, Charlson comorbidity class, ICU-admission and exacerbation frequency. Factors differed among GOLD stages. Conclusions The 15-year survival for hospitalized COPD patients is reduced by 82% in comparison to the general population. This indicates a more deleterious course of clinically significant COPD in comparison to population cohorts. As such, every possible effort should be taken to reduce exacerbations in a personalized way.

Rationale: \ud Evidence supporting the association of COPD or airflow obstruction with use of solid fuels is conflicting and inconsistent.\ud \ud Objective: \ud To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating.\ud \ud Methods: \ud We analysed 18,554 adults from the BOLD study, who had provided acceptable post-bronchodilator spirometry measurements and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analysed. We carried out similar analyses for spirometric restriction, chronic cough and chronic phlegm.\ud \ud Measurements and main results: \ud We found no association between airflow obstruction and use of solid fuels for cooking or heating (ORmen=1.20, 95%CI 0.94-1.53; ORwomen=0.88, 95%CI 0.67-1.15). This was true for low/middle and high income sites. Among never smokers there was also no evidence of an association of airflow obstruction with use of solid fuels (ORmen=1.00, 95%CI 0.57-1.76; ORwomen=1.00, 95%CI 0.76-1.32). Overall, we found no association of spirometric restriction, chronic cough or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never smokers and those who had been exposed for ≥20 years.\ud \ud Conclusion: \ud Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0–50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3+ (fold change per year calculated as GL2 minus GL1 2.68, 95% CI 1.87–3.84), CD4+ (1.91, 95% CI 1.33–2.75) and CD8+ cells (1.71, 95% CI 1.15–2.53), and mast cells (1.91, 95% CI 1.36–2.68). The sputum total cell counts increased significantly in GL2 (1.90, 95% CI 1.42–2.54), as did counts of macrophages (2.10, 95% CI 1.55–2.86), neutrophils (1.92, 95% CI 1.39–2.65) and lymphocytes (2.01, 95% CI 1.46–2.78).ICS discontinuation increases airway inflammation in patients with moderate-severe COPD, suggesting that the anti-inflammatory effects of ICS in COPD are not maintained after ICS discontinuation.

OBJECTIVE: In lung cancer screening, the prevalence of chronic respiratory symptoms is high among heavy smokers. The purpose of this study was to compare CT-derived airway wall measurements between male smokers with and those without chronic respiratory symptoms.MATERIALS AND METHODS: Fifty male heavy smokers with chronic respiratory symptoms (cough, excessive mucus secretion, dyspnea, and wheezing) and 50 without any respiratory symptom were randomly selected from the Dutch-Belgian Randomized Lung Cancer Screening Trial. Thin-slice low-dose CT images were evaluated with dedicated software for airway measurements. Wall area percentage and airway wall thickness were measured from trachea to bronchi in five different pulmonary lobes of airways with a luminal diameter of 5 mm or greater. Association between airway wall measurements and respiratory symptoms was analyzed by multiple linear regression adjusted for age, body mass index, smoking status, emphysema, and pulmonary function.RESULTS: After adjustment for relevant factors, a significant positive association between airway wall measurements and respiratory symptoms was found in airways with a luminal diameter between 5 to 10 mm (p < 0.01), but not in airways measuring 10 mm or greater (p > 0.05). At the airway level between 5 to 10 mm, the mean wall area percentages were 51.5% ± 7.9%. Airway wall thicknesses were 1.54 ± 0.39 mm and 1.37 ± 0.35 mm (p < 0.001).CONCLUSION: Male heavy smokers with chronic respiratory symptoms in lung cancer screening, who are at high-risk of chronic bronchitis, have bronchial wall thickening in airways with a luminal diameter of 5-10 mm but not in larger airways.

Cross-sectional studies have shown that occupational exposure to vapors, gases, dusts, and fumes (VGDF) and pesticides is associated with a lower level of lung function. These associations seem to be stronger in ever smokers. In the current study, we aimed to assess whether occupational exposure to VGDF and pesticides is associated with longitudinal decline in lung function. We used 12,772 observations from 2,527 participants in the Vlagtwedde-Vlaardingen Study, a general-population-based cohort study that followed subjects for 25 years, from 1965 to the last survey in 1989/1990. Job-specific exposure was estimated with the ALOHA+ job exposure matrix. Associations between exposures and annual changes in forced expiratory volume in 1 second (FEV1) and FEV1 as a percentage of inspiratory vital capacity (FEV1%VC) were assessed with linear mixed-effect models including sex, age, and level of lung function at the first measurement and pack-years of smoking at the last measurement. We tested for interaction between smoking and occupational exposure and assessed associations separately for never smokers and ever smokers. Exposure to VGDF was not associated with accelerated lung function decline after adjustment for co-exposure to pesticides. Exposure to pesticides, both in the last-held job and as a cumulative measure, was associated with accelerated decline in FEV1 and FEV1%VC, especially among ever smokers, where we found an excess change in FEV1 of -6.9 mL/year (95% confidence interval: -10.2, -3.7) associated with high pesticide exposure.

Jan Willem H Kocks,1,2 Jan Willem K van den Berg,3 Huib AM Kerstjens,2,4 Steven M Uil,3 Judith M Vonk,2,5 Ynze P de Jong,3 Ioanna G Tsiligianni,1,2 Thys van der Molen1,2 1Department of General Practice, 2Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, 3Department of Pulmonary Diseases, Isala Klinieken, Zwolle, 4Department of Pulmonary Diseases and Tuberculosis, 5Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major burden to patients and to society. Little is known about the possible role of day-to-day patient-reported outcomes during an exacerbation. This study aims to describe the day-to-day course of patient-reported health status during exacerbations of COPD and to assess its value in predicting clinical outcomes. Methods: Data from two randomized controlled COPD exacerbation trials (n = 210 and n = 45 patients) were used to describe both the feasibility of daily collection of and the day-to-day course of patient-reported outcomes during outpatient treatment or admission to hospital. In addition to clinical parameters, the BORG dyspnea score, the Clinical COPD Questionnaire (CCQ), and the St George's Respiratory Questionnaire were used in Cox regression models to predict treatment failure, time to next exacerbation, and mortality in the hospital study. Results: All patient-reported outcomes showed a distinct pattern of improvement. In the multivariate models, absence of improvement in CCQ symptom score and impaired lung function were independent predictors of treatment failure. Health status and gender predicted time to next exacerbation. Five-year mortality was predicted by age, forced expiratory flow in one second % predicted, smoking status, and CCQ score. In outpatient management of exacerbations, health status was found to be less impaired than in hospitalized patients, while the rate and pattern of recovery was remarkably similar. Conclusion: Daily health status measurements were found to predict treatment failure, which could help decision-making for patients hospitalized due to an exacerbation of COPD. Keywords: health status, Clinical COPD Questionnaire, hospital, admission, prediction

Background: The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown.\ud \ud Methods and results: Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release.\ud \ud Conclusion: Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.\ud

Background: Many countries in sub-Saharan Africa have the highest risk of developing chronic diseases and are the least able to cope with them.Aims: To assess the current knowledge of the prevalence and impact of asthma and chronic obstructive pulmonary disease (COPD) in sub-Saharan Africa.Methods: A literature search was conducted using Medline (1995-2010) and Google Scholar.Results: Eleven studies of the prevalence of asthma in sub-Saharan Africa were identified, all of which showed a consistent increase, particularly in urban regions. The data on asthma show a wide variation (5.7-20.3%), with the highest prevalence in 'westernised' urban areas. Only two studies of the prevalence of COPD in sub-Saharan Africa have been performed. Nevertheless, COPD has become an increasing health problem in sub-Saharan Africa due to tobacco smoking and exposure to biomass fuels. In most countries of sub-Saharan Africa, 90% of the rural households depend on biomass fuel for cooking and heating, affecting young children (acute lower respiratory infections) and women (COPD). This is the cause of significant mortality and morbidity in the region.Conclusions: Asthma and COPD in sub-Saharan Africa are under-recognised, under-diagnosed, under-treated, and insufficiently prevented. A major priority is to increase the awareness of asthma and COPD and their risk factors, particularly the damage caused by biomass fuel. Surveys are needed to provide local healthcare workers with the possibility of controlling asthma and COPD. (C) 2011 Primary Care Respiratory Society UK. All rights reserved. F van Gemert et al. Prim Care Respir J 2011; 20(3): 240-248 http://dx.doi.org/10.4104/pcrj.2011.00027

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airflow obstruction and a progressive lung function decline. Although widely used, the efficacy of inhaled corticosteroids (ICS) in the treatment of COPD remains a matter of debate.Areas covered in this review: This article reviews the evidence about the effects of inhaled corticosteroids in the treatment of CORD.What the reader will gain: Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. Based on these findings, it was concluded that the use of ICS did not influence the natural course of COPD. However, this conclusion has been challenged by two subsequent studies, TORCH and GLUCOLD, which both showed a reduction in lung-function decline over time with the use of ICS. These two studies indicate that ICS might indeed influence the natural course of the disease, at least in a subgroup of COPD patients.Take home message: Further studies are needed to identify which individuals have a favorable short- and long-term response to ICS treatment.

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airflow obstruction and a progressive lung function decline. Although widely used, the efficacy of inhaled corticosteroids (ICS) in the treatment of COPD remains a matter of debate. Areas covered in this review: This article reviews the evidence about the effects of inhaled corticosteroids in the treatment of CORD. What the reader will gain: Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. Based on these findings, it was concluded that the use of ICS did not influence the natural course of COPD. However, this conclusion has been challenged by two subsequent studies, TORCH and GLUCOLD, which both showed a reduction in lung-function decline over time with the use of ICS. These two studies indicate that ICS might indeed influence the natural course of the disease, at least in a subgroup of COPD patients. Take home message: Further studies are needed to identify which individuals have a favorable short- and long-term response to ICS treatment.

Rationale: Smoking has detrimental effects on asthma outcome, such as increased cough, wheezing, sputum production, and frequency of asthma attacks. This results in accelerated lung function decline. The underlying pathological process of smoke-induced deterioration of asthma is unknown.Objectives: To compare bronchial inflammation and remodeling in never-smokers, ex-smokers, and current smokers with asthma.Methods: A total of 147 patients with asthma (66 never-smokers, 46 ex-smokers, and 35 current smokers) were investigated.Measurements and Main Results: Lung function, exhaled nitric oxide levels, and symptom questionnaires were assessed, and induced sputum and bronchial biopsies were obtained for determination of airway inflammation and remodeling. Smokers with asthma had lower FEV(1) and alveolar and bronchial nitric oxide levels than never-smokers. Smokers also had more goblet cells and mucus-positive epithelium, increased epithelial thickness, and a higher proliferation rate of intact and basal epithelium than ex-smokers and never-smokers. Smokers had higher numbers of mast cells and lower numbers of eosinophils than never-smokers. Ex-smokers had similar goblet cell numbers and mucus-positive epithelium, epithelial thickness, epithelial proliferation rate, and mast cell numbers as never-smokers.Conclusions: Smokers with asthma have epithelial changes that are associated with increased asthma symptoms, such as shortness of breath and phlegm production. The fact that epithelial characteristics in ex-smokers are similar to those in never-smokers suggests that the smoke-induced changes can be reversed by smoking cessation.

The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved.

Summary Objective To review the topic of behavioural research on patients with COPD over the past 50 years in order to help inform clinical management and future research on psychosocial aspects of COPD. Method Narrative literature review. Results Nine orientations in behavioural research on COPD patients are identified and concisely examined: psychoanalytic approach, psychosomatics, neuropsychology, quality of life, psychomaintenance, patient education, coping and illness cognitions, self-management, and collaborative care. These approaches form a historical sequence of psychosocial perspectives on COPD, of successively increasing utility in COPD research and care. Discussion and conclusion In the past 50 years behavioural research on COPD patients has evolved considerably. Over time, a trend for the patient to become the central actor in the management of the illness is discernable. Evidence-based reviews indicate that self-management offers COPD patients effective options for managing their illness, leading to positive outcomes such as reduced frequency of hospitalization, greater exercise tolerance, and enhanced quality of life. Future research should focus on how self-management skills can be incorporated formally into medical care. In addition to offering suggestions on how clinicians may be instrumental in improving self-management behaviour in COPD patients, and thereby improve care outcomes, we highlight the importance of gaining insight into the perceptions of patients of their own situation, and incorporating a respect for patient perspectives into the philosophy of care.

The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved.

Purpose: Update of a clinical practice guideline for the physiotherapy management of patients with chronic obstructive pulmonary disease supporting the clinical decision-making process.Methods: A systematic computerized literature search was performed on different modalities for improving physical exercise capacity, reducing exertional dyspnoea, improving airway clearance and encouraging changes in physical activity behaviour. Methodological quality was scored with the PEDro Scale. Scientific conclusions were graded according to the criteria of the `Dutch Evidence Based Guideline Development Platform'. These, together with practical considerations, were used to formulate recommendations for clinical practice.Results: A total of 103 studies were included in the systematic review, consisting of five meta-analyses of randomized controlled trials, 84 randomized controlled trials and 14 uncontrolled studies. Twenty scientific conclusions supported six recommendations on physical exercise training. Nineteen scientific conclusions supported eight recommendations on interventions for reducing dyspnoea. Five scientific conclusions supported seven recommendations concerning treatment modalities to improve mucus clearance, and two scientific conclusions supported two recommendations on strategies for encouraging permanent changes in physical activity behaviour.Conclusions: Strong recommendations support the use of physical exercise training to improve health-related quality of life and functional exercise capacity. Future research should investigate whether additional interventions for reducing exertional dyspnoea have a place as adjuncts to physical exercise training in selected patients. In addition, treatment of impaired mucus clearance, especially during acute exacerbations, requires further research. With the advance of new technologies for objective measurements of physical activities in daily life more research is needed concerning interventions to initiate and maintain physical activity behaviour change during and after supervised physical exercise training programmes

The long-term risk of a subsequent exacerbation of chronic obstructive pulmonary disease (COPD) after treatment with oral corticosteroids without (OS) or with antibiotics (OSA) was compared in a historical general practice-based cohort. Eligible patients were ≥50 yrs of age, had a registered diagnosis of COPD, were on maintenance respiratory drugs, and had experienced at least one exacerbation defined as a prescription OS or OSA. Times to second and third exacerbations were assessed using Kaplan-Meier survival analysis; the risk of a subsequent exacerbation was assessed in a Cox proportional hazards analysis; and all-cause mortality was assessed using Kaplan-Meier survival and Cox proportional hazards analyses. A total of 842 patients had one or more exacerbations. The median time from first to second exacerbation was comparable for the OS and OSA groups, but the time from second to third exacerbation differed: 189 versus 258 days, respectively. The protective effect of OSA was most pronounced during the first 3 months following treatment (hazards ratio 0.72, 95% confidence interval 0.62-0.83). Exposure to antibiotics unrelated to a course of oral corticosteroids almost halved the risk of a new exacerbation. Mortality during follow-up was considerably lower in the OSA group. Adding antibiotics to oral corticosteroids was associated with: reduced riskof subsequent exacerbation, particularly in patients with recurrent exacerbations; and reduced risk of all-cause mortality. Copyright

Background: Attempts have been made to use dynamic spirometry to define restrictive lung function, but the definition of a restrictive spirometric pattern (RSP) varies between studies such as BOLD and NHANES. The aim of this study was to estimate the prevalence and risk factors of RSP among adults in northern Sweden based on different definitions. Methods: In 2008-2009 a general population sample aged 21-86y within the obstructive lung disease in northern Sweden (OLIN) studies was examined by structured interview and spirometry, and 726 subjects participated (71% of invited). The prevalence of RSP was calculated according to three different definitions based on pre-as well as post-bronchodilator spirometry: 1) FVC 0.7 2) FVC LLN 3) FVC LLN Results: The three definitions yielded RSP prevalence estimates of 10.5%, 11.2% and 9.4% respectively, when based on pre-bronchodilator values. The prevalence was lower when based on post-bronchodilator values, i.e. 7.3%, 7.9% and 6.6%. According to definition 1 and 2, the RSP prevalence increased by age, but not according to definition 3. The overlap between the definitions was substantial. When corrected for confounding factors, manual work in industry and diabetes with obesity were independently associated with an increased risk for RSP regardless of definition. Conclusions: The prevalence of RSP was 7-11%. The prevalence estimates differed more depending on the choice of pre-compared to post-bronchodilator values than on the choice of RSP definition. RSP was, regardless of definition, independently associated with manual work in industry and diabetes with obesity. (C) 2016 The Authors. Published by Elsevier Ltd.

Background: Treatment with systemic corticosteroids for exacerbations of COPD results in improvement in clinical outcomes. On hospitalization, corticosteroids are generally administered IV. It has not been established whether oral administration is equally effective. We conducted a study to demonstrate that therapy with oral prednisolone was not inferior to therapy with IN prednisolone using a double-blind, double-dummy design. Methods: Patients hospitalized for an exacerbation of COPD were randomized to receive 5 days of therapy with prednisolone, 60 mg IV or orally. Treatment failure, the primary outcome, was defined as death, admission to the ICU, readmission to the ICU because of COPD, or the intensification of pharmacologic therapy during a 90-day follow-up period. Results: A total of 435 patients were referred for a COPD exacerbation warranting hospitalization; 107 patients were randomized to receive IV therapy, and 103 to receive oral therapy. Overall treatment failure within 90 days was similar, as follows: IV prednisolone, 61.7%; oral prednisolone, 56.3% (one-sided lower bound of the 95% confidence interval [CI], -5.8%). There were also no differences in early (ie, within 2 weeks) treatment failure (17.8% and 18.4%, respectively; one-sided lower bound of the 95% CI, -9.4%), late (ie, after 2 weeks) treatment failure (54.0% and 47.0%, respectively; one-sided lower bound of the 95% CI, -5.6%), and mean (+/- SD) length of hospital stay (11.9 +/- 8.6 and 11.2 +/- 6.7 days, respectively). Over I week, clinically relevant improvements were found in spirometry and health-related quality of life, without significant differences between the two treatment groups. Conclusion: Therapy with oral prednisolone is not inferior to IV treatment in the first 90 days after starting therapy. We suggest that the oral route is preferable in the treatment of COPD exacerbations. Trial registration: Clinicaltrials.gov Identifier: NCT00311961.

Chest physical therapy (CPT) is a widely used intervention for patients with airway diseases. The main goal is to facilitate secretion transport and thereby decrease secretion retention in the airways. Historically, conventional CPT has consisted of a combination of forced expirations (directed cough or huff), postural drainage, percussion, and/or shaking. CPT improves mucus transport, but it is not entirely clear which groups of patients benefit from which CPT modalities. In general, the patients who benefit most from CPT are those with airways disease and objective signs of secretion retention (eg, persistent rhonchi or decreased breath sounds) or subjective signs of difficulty expectorating sputum, and with progression of disease that might be due to secretion retention (eg, recurrent exacerbations, infections, or a fast decline in pulmonary function). The most effective and important part of conventional CPT is directed cough. The other components of conventional CPT add little if any benefit and should not be used routinely. Alternative airway clearance modalities (eg, high-frequency chest wall compression, vibratory positive expiratory pressure, and exercise) are not proven to be more effective than conventional CPT and usually add little benefit to conventional CPT. Only if cough and huff are insufficiently effective should other CPT modalities be considered. The choice between the CPT alternatives mainly depends on patient preference and the individual patient's response to treatment.

Rationale: The few prospective studies aimed at assessing the incidence of chronic obstructive pulmonary disease (COPD) in relation to the presence of chronic cough/phlegm have produced contrasting results.Objectives: To assess the incidence of COPD in a cohort of young adults and to test whether chronic cough/phlegm and dyspnea are independent predictors of COPD. Methods: An international cohort of 5,002 subjects without asthma (ages 20-44 yr) with normal lung function (FEV1/FVC ratio >= 70%) from 12 countries was followed from 1991-2002 in the frame of the European Community Respiratory Health Survey II. Incident cases of COPD were those who had an FEV1/FVC ratio less than 70% at the end of the follow-up, but did not report having had a doctor diagnose asthma during the follow-up.Main Results: The incidence rate of COPD was 2.8 cases/1,000/yr (95% confidence interval [CI], 2.3-3.3). Chronic cough/phlegm was an independent and statistically significant predictor of COPD (incidence rate ratio [IRR], 1.85; 95% Cl, 1.17-2.93) after adjusting for smoking habits and other potential confounders, whereas dyspnea was not associated with the disease (IRR = 0.98; 95% Cl, 0.64-1.50). Subjects who reported chronic cough/phlegm both at baseline and at the follow-up had a nearly threefold-increased risk of developing COPD with respect to asymptomatic subjects (IRR = 2.88; 95% Cl, 1.44-5.79).Conclusions: The incidence of COPD is substantial even in young adults. The presence of chronic cough/phlegm identifies a subgroup of subjects with a high risk of developing COPD, independently of smoking habits.

Global estimates suggest that Chronic Obstructive Pulmonary Disease (COPD) is emerging as a leading cause of death in developing countries but there are few spirometry-based general population data on its prevalence and risk factors in sub-Saharan Africa. We used the Burden of Obstructive Lung Disease (BOLD) protocol to select a representative sample of adults aged 40 years and above in Ile-Ife, Nigeria. All the participants underwent spirometry and provided information on smoking history, biomass and occupational exposures as well as diagnosed respiratory diseases and symptoms. Chronic Airflow Obstruction (CAO) was defined as the ratio of post-bronchodilator (BD) one second Forced Expiratory Volume (FEV 1) to Forced Vital Capacity (FVC) below the lower limit of normal (LLN) of the population distribution for FEV 1/FVC. The overall prevalence of obstruction (post-BD FEV 1/FVC < LLN) was 7.7% (2.7% above LLN) using Global Lung Function Initiative (GLI) equations. It was associated with few respiratory symptoms; 0.3% reported a previous doctor-diagnosed chronic bronchitis, emphysema or COPD. Independent predictors included a lack of education (OR 2·5, 95% CI: 1.0, 6.4) and a diagnosis of either TB (OR 23.4, 95% CI: 2.0, 278.6) or asthma (OR 35.4, 95%CI: 4.9, 255.8). There was no association with the use of firewood or coal for cooking or heating. The vast majority of this population (89%) are never smokers. We conclude that the prevalence of CAO is low in Ile-Ife, Nigeria and unrelated to biomass exposure. The key independent predictors are poor education, and previous diagnosis of tuberculosis or asthma.

OBJECTIVES: To assess how suitable current chronic obstructive pulmonary disease (COPD) cost-effectiveness models are to evaluate personalized treatment options for COPD by exploring the type of heterogeneity included in current models and by validating outcomes for subgroups of patients.METHODS: A consortium of COPD modeling groups completed three tasks. First, they reported all patient characteristics included in the model and provided the level of detail in which the input parameters were specified. Second, groups simulated disease progression, mortality, quality-adjusted life-years (QALYs), and costs for hypothetical subgroups of patients that differed in terms of sex, age, smoking status, and lung function (forced expiratory volume in 1 second [FEV1] % predicted). Finally, model outcomes for exacerbations and mortality for subgroups of patients were validated against published subgroup results of two large COPD trials.RESULTS: Nine COPD modeling groups participated. Most models included sex (seven), age (nine), smoking status (six), and FEV1% predicted (nine), mainly to specify disease progression and mortality. Trial results showed higher exacerbation rates for women (found in one model), higher mortality rates for men (two models), lower mortality for younger patients (four models), and higher exacerbation and mortality rates in patients with severe COPD (four models).CONCLUSIONS: Most currently available COPD cost-effectiveness models are able to evaluate the cost-effectiveness of personalized treatment on the basis of sex, age, smoking, and FEV1% predicted. Treatment in COPD is, however, more likely to be personalized on the basis of clinical parameters. Two models include several clinical patient characteristics and are therefore most suitable to evaluate personalized treatment, although some important clinical parameters are still missing.

Smoking cessation is the only treatment in patients with chronic obstructive pulmonary disease (COPD) effective in slowing down disease progression. Its effect on airway inflammation in COPD is unknown, although cross-sectional studies suggest ongoing inflammation in ex-smokers. In order to elucidate the effect of smoking cessation on airway inflammation, 28 smokers with COPD (mean age: 55 yrs; forced expiratory volume in one second: 71% predicted) and 25 asymptomatic smokers with normal lung function (aged 50 yrs) were included in a 1-yr smoking cessation programme. Effects of smoking cessation on airway inflammation were investigated in bronchial biopsies (baseline, 12 months) and sputum samples (baseline, 2, 6 and 12 months). In the 12 candidates with COPD who successfully ceased smoking, airway inflammation persisted in bronchial biopsies, while the number of sputum neutrophils, lymphocytes, interleukin (IL)-8 and eosinophilic-cationic-protein levels significantly increased at 12 months. In the 16 asymptomatic smokers who successfully quitted, inflammation significantly reduced (i.e. number of sputum macrophages, percentage of eosinophils and IL-8 levels) or did not change. The current authors suggest that the observed persistent airway inflammation in patients with chronic obstructive pulmonary disease is related to repair of tissue damage in the airways. It remains to be elucidated whether this reflects a beneficial or detrimental effect.

Introduction: beta-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. Design: A double-blind, placebo-controlled, randomized, cross-over study. Setting: An ambulatory, hospital outpatient clinic of pulmonary diseases. Patients: Patients with mild-to-moderate irreversible COPD and AHR. Intervention: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >= 3 days. On day 4 of treatment, FEV1 and PC20 were assessed. Immediately hereafter, formoterol (12 mu g) was administered and FEV1 was measured for up to 30 min. Results: PC20 was significantly lower (p

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD.We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs.Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value −5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12).Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.

Robert Wilson,1 Antonio Anzueto,2 Marc Miravitlles,3 Pierre Arvis,4 Daniel Haverstock,5 Mila Trajanovic,6 Sanjay Sethi7 1Host Defence Unit, Royal Brompton Hospital, London, UK; 2University of Texas Health Science Center, South Texas Veterans Health Care System, San Antonio, TX, USA; 3Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Bayer HealthCare Pharmaceuticals, Loos, France; 5Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA; 6Bayer HealthCare Pharmaceuticals, Toronto, ON, Canada; 7University atBuffalo, Buffalo, NY, USA Background: Acute exacerbations represent a significant burden for patients with moderate-to-severe chronic obstructive pulmonary disease. Each exacerbation episode is frequently associated with a lengthy recovery and impaired quality of life. Prognostic factors for outpatients that may predict poor outcome after treatment with antibiotics recommended in the guidelines, are not fully understood. We aimed to identify pretherapy factors predictive of clinical failure in elderly (≥60 years old) outpatients with acute Anthonisen type 1 exacerbations.Trial registration: NCT00656747.Methods: Based on the moxifloxacin in AECOPDs (acute exacerbations of chronic obstructive pulmonary disease) trial (MAESTRAL) database, this study evaluated pretherapy demographic, clinical, sputum bacteriological factors using multivariate logistic regression analysis, with internal validation by bootstrap replicates, to investigate their possible association with clinical failure at end of therapy (EOT) and 8 weeks posttherapy.Results: The analyses found that the independent factors predicting clinical failure at EOT were more frequent exacerbations, increased respiratory rate and lower body temperature at exacerbation, treatment with long-acting anticholinergic drugs, and in vitro bacterial resistance to study drug. The independent factors predicting poor outcome at 8 weeks posttherapy included wheezing at preexacerbation, mild or moderate (vs extreme) sleep disturbances, lower body temperature at exacerbation, forced expiratory volume in 1 second

Marjolein Brusse-Keizer,1 Paul VanderValk,2 Rogier W van der Zanden,3 Lars Nijdam,4 Job van der Palen,1,5 Ron Hendrix,6,7 Kris Movig4 1Medical School Twente, 2Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede, 3Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, 4Department of Clinical Pharmacy, Medisch Spectrum Twente, 5Department of Research Methodology, Measurement and Data Analysis, University of Twente, 6Regional Laboratory of Public Health, Enschede, 7Department of Medical Microbiology, University Medical Centre Groningen, and University of Groningen, Groningen, the NetherlandsBackground: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are often treated with antibiotics. Theoretically, to be maximally effective, the antibiotic concentration at sites of infection should exceed the minimum inhibitory concentration at which 90% of the growth of potential pathogens is inhibited (MIC90). A previous study showed that most hospitalized COPD patients had sputum amoxicillin concentrations&nbsp

One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with beta-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting beta(2)-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting beta(2)-agents. The majority, of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently, large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

OBJECTIVES: Occupational exposures are important and possibly modifiable contributors to the global burden of chronic obstructive pulmonary disease (COPD). Exposure to vapours, gases, dusts and fumes (VGDF) has been associated with a two- to threefold higher COPD risk. Less is known about effects of occupational exposure to pesticides and solvents. In the current study, we assessed if VGDF, pesticides and solvents are associated with the level of lung function and the prevalence of airway obstruction in the general population.METHODS: We included 11 851 subjects aged 18-89 years from the LifeLines cohort study. Regression models assessing associations between occupational exposures (no/low/high), level of lung function (prebronchodilator FEV(1), FEV(1)/FVC) and mild and moderate/severe airway obstruction were adjusted for sex, age, height, weight, current/ex-smoking and packyears. Additionally, we stratified by smoking status and gender and tested for interaction. A second general population cohort (n=2364) was used to verify our initial findings.RESULTS: Occupational exposure to VGDF and pesticides was associated with a lower level of FEV(1) and FEV(1)/FVC and with a higher prevalence of mild and moderate/severe airway obstruction in the two general populations investigated. There were no associations with exposure to solvents.CONCLUSIONS: Occupational exposure to both VGDF and pesticides is associated with airway obstruction in the general population.

Background A recently-licensed 10-valent pneumococcal conjugate vaccine (PHiD-CV; Synflorix, GSK) uses Protein D from Haemophilus influenzae as a carrier protein. PHiD-CV therefore has the potential to provide additional protection against nontypeable H. influenzae (NTHi). NTHi frequently causes respiratory tract infections and is associated with significant morbidity and mortality worldwide and there is currently no vaccine. Methods We developed mouse models of NTHi infection and influenza/NTHi superinfection. Mice were immunized with PHiD-CV, heat-killed NTHi, or a 13-valent pneumococcal conjugate vaccine that did not contain Protein D (PCV13; Prevenar, Pfizer) and then infected intranasally with NTHi. Results Infection with NTHi resulted in weight loss, inflammation and airway neutrophilia. In a superinfection model, prior infection with pandemic H1N1 influenza virus (strain A/England/195/2009) augmented NTHi infection severity, even with a lower bacterial challenge dose. Immunization with PHiD-CV produced high levels of antibodies that were specific against Protein D, but not heat-killed NTHi. Immunization with PHiD-CV led to a slight reduction in bacterial load, but no change in disease outcome. Conclusions PHiD-CV induced high levels of Protein D-specific antibodies, but did not augment pulmonary clearance of NTHi. We found no evidence to suggest that PHiD-CV will offer added benefit by preventing NTHi lung infection.

Background Chronic obstructive pulmonary disease (COPD) is often accompanied by bronchial hyperresponsiveness (BHR). Measurement of BHR may give information about airway inflammation. Objective To investigate the role of airway inflammation in hyperresponsiveness to adenosine 5'-monophosphate (AMP) in COPD. Methods We investigated inflammatory indices in induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies in subjects with COPD with and without hyperresponsiveness to AMP. Twelve nonatopic subjects with COPD with hyperresponsiveness to AMP (mean +/- SD, age 63 +/- 8 years, FEV1% predicted 56 +/- 13%), six without BHR (age 60 +/- 6 years, FEV1% predicted 65 +/- 11%) and 11 healthy nonatopic controls without BHR (age 58 +/- 8 years, FEV1% predicted 104 +/- 11%) participated in the study. Results Subjects with COPD with BHR had significantly higher numbers of mucosal CD8 + and higher percentages of sputum eosinophils than those without BHR (median, 550 cells/mm(2); range, 30-1340 vs 280 cells/mm(2); range, 110-450, P = 0.045; and median, 2.7%; range, 0.5-8.5 vs 0.6%; range, 0-0.8 %, P = 0.0036, respectively). No differences were observed in BAL fluid. Conclusion We conclude that hyperresponsiveness to AMP in COPD is associated with airway inflammation that is characterized by increased numbers of mucosal CD8 + cells and percentages of sputum eosinophils. Hyperresponsiveness to AMP may be used as a marker of airway inflammation in COPD, but its significance in the clinical course remains to be determined.

BACKGROUND—Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke. METHODS—Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV1) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV1 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. RESULTS—Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm2, p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm2, p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p= 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p

Background-Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways; of patients with COPD who do not currently smoke. Methods-Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (EEV1) 59 (13)% predicted and II non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV1 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. Results-Patients with COPD had more mucosal EG2+ cells (eosinophils) (median cells/mm(2), p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm(2), p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p = 0.008), BAL fluid eosinophills (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p

Chronic obstructive pulmonary disease (COPD) constitutes an enormous, and growing, health problem, the treatment of which has been less than satisfactory so far. COPD is a chronic inflammatory process in the airway wall of the large and peripheral airways as well as in the parenchyma. Because of this inflammation, glucocorticosteroids (steroids) have been investigated in more than 100 studies. By tradition, the forced expiratory volume in 1 s (FEV1) has been utilized as the main outcome parameter. More recently, exacerbation frequency and health status (quality of life) have been added as end points. Oral steroids have been demonstrated to be useful during exacerbations, although the effects are smaller than in exacerbations of asthma. In stable COPD, 10% more patients respond favorably to a 2-wk course of steroids than to placebo. The long-term effects of oral steroids have not been evaluated in randomized controlled trials. There have now been 10 studies of inhaled steroids of short duration, defined as up to 3 mo, in general, there was no effect on FEV1. No other parameters of lung function were consistently measured. Several studies showed a small effect on some inflammatory parameters, but none of these were comparable between studies and therefore await further confirmation and elaboration. In total, eight studies evaluated inhaled steroids over a long period, i.e., at least 6 mo. Five of these have been published, and three major targe-scale studies have been presented as abstracts at major meetings but not yet published in full. On the basis of these studies, there seems to be an effect of inhaled steroids during the first 3-6 mo of use, but thereafter no effect on the subsequent decline of lung function has been found. Two studies have documented a reduction in exacerbation frequency and an improvement in health status. In summary, as far as FEV, is concerned, there is only a short-term benefit of inhaled steroids at best. The improvements in exacerbations and health status need to be confirmed and valued, but could well be important to patients. There is an urgent need to identify those patients within the large heterogeneous group of patients with COPD who benefit from steroids. For this, it would be useful to pool data from the long-term studies.

Chronic obstructive pulmonary disease (COPD) constitutes an enormous, and growing, health problem, the treatment of which has been less than satisfactory so far. COPD is a chronic inflammatory process in the airway wall of the large and peripheral airways as well as in the parenchyma. Because of this inflammation, glucocorticosteroids (steroids) have been investigated in more than 100 studies. By tradition, the forced expiratory volume in 1 s (FEV1) has been utilized as the main outcome parameter. More recently, exacerbation frequency and health status (quality of life) have been added as end points. Oral steroids have been demonstrated to be useful during exacerbations, although the effects are smaller than in exacerbations of asthma. In stable COPD, 10% more patients respond favorably to a 2-wk course of steroids than to placebo. The long-term effects of oral steroids have not been evaluated in randomized controlled trials. There have now been 10 studies of inhaled steroids of short duration, defined as up to 3 mo, in general, there was no effect on FEV1. No other parameters of lung function were consistently measured. Several studies showed a small effect on some inflammatory parameters, but none of these were comparable between studies and therefore await further confirmation and elaboration. In total, eight studies evaluated inhaled steroids over a long period, i.e., at least 6 mo. Five of these have been published, and three major targe-scale studies have been presented as abstracts at major meetings but not yet published in full. On the basis of these studies, there seems to be an effect of inhaled steroids during the first 3-6 mo of use, but thereafter no effect on the subsequent decline of lung function has been found. Two studies have documented a reduction in exacerbation frequency and an improvement in health status. In summary, as far as FEV, is concerned, there is only a short-term benefit of inhaled steroids at best. The improvements in exacerbations and health status need to be confirmed and valued, but could well be important to patients. There is an urgent need to identify those patients within the large heterogeneous group of patients with COPD who benefit from steroids. For this, it would be useful to pool data from the long-term studies.