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Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition. Objectives: We hypothesized that the unbiased integration of different COPD lung omics using a novel multilayer approach might unravel mechanisms associated with clinical characteristics. Methods: We profiled mRNA, microRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer), we built a patient network on the basis of molecular similarity. The three networks were used to build a multilayer network, and optimization of multiplex modularity was used to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features. Measurements and Main Results: We identified five patient communities in the multilayer network that were molecularly distinct and related to clinical characteristics, such as FEV 1 and blood eosinophils. Two communities (C#3 and C#4) had both similarly low FEV 1 values and emphysema but were molecularly different: C#3, but not C#4, presented B- and T-cell signatures and a downregulation of secretory (SCGB1A1/SCGB3A1) and ciliated cells. A machine learning model was set up to discriminate C#3 and C#4 in our cohort and to validate them in an independent cohort. Finally, using spatial transcriptomics, we characterized the small airway differences between C#3 and C#4, identifying an upregulation of T-/B-cell homing chemokines and bacterial response genes in C#3. Conclusions: A novel multilayer network analysis is able to identify clinically relevant COPD patient communities. Patients with similarly low FEV 1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation.

Rationale: Chronic obstructive pulmonary disease (COPD) results from gene-environment interactions over the lifetime. These interactions are captured by epigenetic changes, such as DNA methylation. Objectives: To systematically review the evidence form epigenome-wide association studies related to COPD and lung function. Methods: A systematic literature search performed on PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases identified 1,947 articles that investigated epigenetic changes associated with COPD and/or lung function; 17 of them met our eligibility criteria, from which data were manually extracted. Differentially methylated positions (DMPs) and/or annotated genes were considered replicated if identified by two or more studies with a P  < 1 × 10 -4 . Measurements and Main Results: Ten studies profiled DNA methylation changes in blood and seven in respiratory samples, including surgically resected lung tissue ( n  = 3), small airway epithelial brushings ( n  = 2), BAL ( n  = 1), and sputum ( n  = 1). Main results showed: 1 ) high variability in study design, covariates, and effect sizes, which prevented a formal meta-analysis; 2 ) in blood samples, 51 DMPs were replicated in relation to lung function and 12 related to COPD; 3 ) in respiratory samples, 42 DMPs were replicated in relation to COPD but none in relation to lung function; and 4 ) in COPD versus control studies, 123 genes (2.6% of total) were shared between one or more blood and one or more respiratory samples and associated with chronic inflammation, ion transport, and coagulation. Conclusions: There is high heterogeneity across published COPD and/or lung function epigenome-wide association studies. A few genes ( n  = 123; 2.6%) were replicated in blood and respiratory samples, suggesting that blood can recapitulate some changes in respiratory tissues. These findings have implications for future research. Systematic Review [protocol] registered with Open Science Framework (OSF).

Background and Objective: It is now well established that there are different life-long lung function trajectories in the general population, and that some are associated with better or worse health outcomes. Yet, the prevalence, clinical characteristics and risk factors of individuals with supranormal FEV 1 or FVC values (above the upper-limit of normal [ULN]) in different age-bins through the lifetime in the general population are poorly understood., Method: To address these questions, we investigated the prevalence of supranormal FEV 1 and FVC values in the LEAD (Lung, hEart, sociAl and boDy) study, a general population cohort in Austria that includes participants from 6 to 82 years of age., Results: We found that: (1) the prevalence of supranormal pre-bronchodilator FEV 1 and FVC values was 3.4% and 3.1%, respectively, and that these figures remained relatively stable through different age-bins except for participants >60 years., in whom they increased (5.0% and 4.2%, respectively). Approximately 50% of supranormal individuals had both increased FEV 1 and FVC values; (2) supranormal spirometric values were consistently accompanied by higher static lung volumes and lower specific airway resistance through the lifespan, indicating better overall lung function; and (3) multivariate regression analysis identified that female sex, higher muscle mass (FFMI), less diabetes and fewer respiratory symptoms were consistently associated with supranormal FEV 1 and FVC values., Conclusion: Supranormal FEV 1 and/or FVC values occur in about 3% of the general population in different age bins and are associated with better health markers., (© 2023 Asian Pacific Society of Respirology.)

Competing Interests: GlaxoSmithKline (GSK) supports the ANTES programme, which is run by an independent Scientific Committee; ANTES panellists (appendix p 1) were invited to participate in the debate leading to the proposal presented here according to their experience in the area of COPD exacerbations. GSK did not participate in the discussion or contribute to the scientific content of this Comment or the decision to submit for publication. JJS-C reports grants from GSK; speaker fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GSK, Menarini, and Novartis; and consulting fees from Bial, Chiesi, GSK, and Novartis. MM reports speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Kamada, Takeda, Sandoz, Zambon, CSL Behring, Specialty Therapeutics, Grifols, and Novartis; consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GSK, Bial, Gebro Pharma, CSL Behring, Inhibrx, Laboratorios Esteve, Ferrer, Menarini, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma, Takeda, Novartis, Sanofi, and Grifols; and research grants from Grifols. AF-V reports honoraria for lectures, scientific advice, participation in clinical studies, or writing of publications for AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GSK, Grifols, Menarini, and Novartis. JLI reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Grifols, Menarini, Novartis, Orion, Pfizer, Sandoz, and Teva. JLG-R reports speaker fees from Gebro Pharma, Novartis, GSK, Boehringer Ingelheim, AstraZeneca, Chiesi, ALK, Teva, Menarini, Viso, and Sanofi; consulting fees from Novartis, GSK, AstraZeneca, Teva, Boehringer Ingelheim, ALK, Viso, Gebro Pharma, and Sanofi; and research grants from AstraZeneca. BGC reports grants from Boehringer Ingelheim, Menarini, and Teva; speaker fees from AstraZeneca, Sanofi, Chiesi, GSK, Menarini, and Novartis; and consulting fees from AstraZeneca, Chiesi, Teva, Sanofi, GSK, and Novartis. JLL-C reports honoraria during the past 3 years for lectures, scientific advice, participation in clinical studies, or writing of publications for AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, CSL Behring, Ferrer, Gebro, GSK, Grifols, Menarini, Megalabs, Novartis, and Rovi. AA reports grants from AstraZeneca, GSK, and Menarini; speaker fees from AstraZeneca, Chiesi, GSK, Menarini, and Zambon; and consulting fees from AstraZeneca, Chiesi, GSK, and Menarini.

Background: Interest in lifetime lung function trajectories has increased in the context of emerging evidence that chronic obstructive pulmonary disease (COPD) can arise from multiple disadvantaged lung function pathways, including those that stem from poor lung function in childhood. To our knowledge, no previous study has investigated both obstructive and restrictive lifetime patterns concurrently, while accounting for potential overlaps between them. We aimed to investigate lifetime trajectories of the FEV 1 /forced vital capacity (FVC) ratio, FVC, and their combinations, relate these combined trajectory groups to static lung volume and gas transfer measurements, and investigate both risk factors for and consequences of these combined trajectory groups., Methods: Using z scores from spirometry measured at ages 7, 13, 18, 45, 50, and 53 years in the Tasmanian Longitudinal Health Study (n=2422), we identified six FEV 1 /FVC ratio trajectories and five FVC trajectories via group-based trajectory modelling. Based on whether trajectories of the FEV 1 /FVC ratio and FVC were low (ie, low from childhood or adulthood) or normal, four patterns of lifetime spirometry obstruction or restriction were identified and compared against static lung volumes and gas transfer. Childhood and adulthood characteristics and morbidities of these patterns were investigated., Findings: The prevalence of the four lifetime spirometry patterns was as follows: low FEV 1 /FVC ratio only, labelled as obstructive-only, 25·8%; low FVC only, labelled as restrictive-only, 10·5%; both low FEV 1 /FVC ratio and low FVC, labelled as mixed, 3·5%; and neither low FEV 1 /FVC ratio nor low FVC, labelled as reference, 60·2%. The prevalence of COPD at age 53 years was highest in the mixed pattern (31 [37%] of 84 individuals) followed by the obstructive-only pattern (135 [22%] of 626 individuals). Individuals with the mixed pattern also had the highest prevalence of parental asthma, childhood respiratory illnesses, adult asthma, and depression. Individuals with the restrictive-only pattern had lower total lung capacity and residual volume, and had the highest prevalence of childhood underweight, adult obesity, diabetes, cardiovascular conditions, hypertension, and obstructive sleep apnoea., Interpretation: To our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEV 1 /FVC ratio and FVC from childhood to middle age. Mixed and obstructive-only patterns indicate those who might benefit from early COPD interventions. Those with the restrictive-only pattern had evidence of true lung restriction and were at increased risk of multimorbidity by middle age., Funding: National Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline., Competing Interests: Declaration of interests CJL, EHW, AJL, DSB, MJA, JLP, and SCD hold an investigator-initiated grant from GlaxoSmithKline for unrelated research. SCD holds an investigator-initiated grant from AstraZeneca for unrelated research. MJA holds investigator-initiated grants from Pfizer, Boehringer Ingelheim, and Sanofi for unrelated research; has undertaken an unrelated consultancy for and received assistance with conference attendance from Sanofi; and received speaker's fees from GlaxoSmithKline. AJL has received non-financial support from Primus Pharmaceuticals for unrelated research. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objective: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy based on treatable traits (TTs) has been proposed, the prevalence and relationship of TTs to the diagnostic label and disease severity established by the attending physician in a real-world setting are unknown. We assessed how the presence/absence of specific TTs relate to the diagnosis and severity of 'asthma', 'COPD' or 'asthma + COPD'., Methods: The authors selected 30 frequently occurring TTs from the NOVELTY study cohort (NOVEL observational longiTudinal studY; NCT02760329), a large (n = 11,226), global study that systematically collects data in a real-world setting, both in primary care clinics and specialized centres, for patients with 'asthma' (n = 5932, 52.8%), 'COPD' (n = 3898, 34.7%) or both ('asthma + COPD'; n = 1396, 12.4%)., Results: The results indicate that (1) the prevalence of the 30 TTs evaluated varied widely, with a mean ± SD of 4.6 ± 2.6, 5.4 ± 2.6 and 6.4 ± 2.8 TTs/patient in those with 'asthma', 'COPD' and 'asthma + COPD', respectively (p < 0.0001); (2) there were no large global geographical variations, but the prevalence of TTs was different in primary versus specialized clinics; (3) several TTs were specific to the diagnosis and severity of disease, but many were not; and (4) both the presence and absence of TTs formed a pattern that is recognized by clinicians to establish a diagnosis and grade its severity., Conclusion: These results provide the largest and most granular characterization of TTs in patients with airway diseases in a real-world setting to date., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Rationale: Some patients with chronic obstructive pulmonary disease (COPD) suffer accelerated lung function (forced expiratory volume in 1 second [FEV 1 ]) decline over time. Objectives: To investigate the relationship between chronic bronchial infection (CBI) and, in particular, the isolation of Pseudomonas aeruginosa (PA), and FEV 1 decline in COPD. Methods: Post-hoc analysis of a prospective cohort of 201 patients with COPD followed up every 3-6 months for 84 months. CBI was defined as ⩾3 sputum positive cultures of the same pathogenic micro-organism (PPM) over 1 year. Patients were stratified according to the presence of CBI by any PPM, as well by a single or multiple isolation of PA during follow-up. An adjusted mixed-effects linear regression model was used to investigate the independent effects of CBI and PA isolation on FEV 1 decline over time. Results: During follow-up, PPMs were never isolated in 43.3% of patients, in 23.9% of them PPMs were isolated once, and CBI by any PPM was confirmed in 32.8% of participants. FEV 1 decline in the entire cohort was 33.7 (95% confidence interval [CI], 21.4-46.1) ml/year. This was significantly increased in patients with CBI by any PPM (57.1 [95% CI, 28.5-79.3] ml/year) and in those in whom PA was isolated at least once (48.5 [95% CI, 27.3-88.2] ml/year). Multivariable analysis showed that the presence of both CBI by any PPM, and at least one PA isolation, were independent factors associated with faster FEV 1 decline adjusted by baseline FEV 1 , presence of bronchiectasis, body mass index, age, exacerbations, smoking status, symptoms, baseline treatment, and comorbidities. Conclusions: The presence of CBI by any PPM, and one or more PA isolation, were independently associated with FEV 1 decline in patients with COPD.

Purpose: The pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy., Methods: A two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts' consensus degree with each item., Results: A high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations., Conclusion: This study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines., Competing Interests: Dr. Baloira has received speaker fees from: Boehringer Ingelheim, GSK, Novartis, AstraZeneca and Chiesi, and research grants from GSK, AstraZeneca and Novartis. Dr. González-Torralba has received speaker fees in several congresses and scientific sessions from: Boehringer Ingelheim, GSK, Novartis, AstraZeneca, Chiesi, Pfizer, Esteve and Rovi. Dr. J. L. García-Rivero has received speaker fees from: Novartis, GSK, Boehringer-Ingelheim, AstraZeneca, Chiesi, ALK, Teva, Menarini, Viso and Sanofi; and consulting fees from Novartis, GSK, AstraZeneca, Teva, Boehringer-Ingelheim, ALK, Viso, Gebro and Sanofi. Dr. Marta Palop has received fees from: Boehringer-Ingelheim, Novartis, AstraZeneca, GSK, Gebro, Sanofi and MSD. The other authors declare no conflicts of interest directly or indirectly related to the manuscript contents., (© 2022 González-Torralba et al.)

The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent research findings. COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)-an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing., Competing Interests: Declaration of interests AA has received research funds and honoraria as a speaker and consultant from AstraZeneca, GlaxoSmithKline, Chiesi, and Menarini for initiatives related to chronic obstructive pulmonary disease (COPD), outside of the submitted work. EM has received advisory board reimbursements and fees as a speaker from AstraZeneca, Chiesi, Novartis, and Sanofi, outside of the submitted work. DLD has received research funds from the National Institutes of Health, Alpha-1 Foundation, and Bayer, and honoraria from Novartis. RB-K has received honoraria as a speaker from AstraZeneca, GlaxoSmithKline, Menarini, and Novartis. RF has received research funds from AstraZeneca, GlaxoSmithKline, and Menarini, honoraria as a speaker from Chiesi, and consultancy fees from GlaxoSmithKline for COPD-related initiatives outside of the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1 ) young adults with COPD and 2 ) those with pre-COPD at any age.

Tobacco smoking is the main environmental risk factor for chronic obstructive pulmonary disease (COPD), but not all smokers develop the disease. A population of lung-resident mesenchymal stem cells (LR-MSCs) exist in healthy lungs, but how tobacco smoking affects them and their role in COPD have not been assessed yet. Using a sphere-based culture technique, we isolated LR-MSCs from lung tissue obtained from nonsmokers and current and former smokers with and without COPD ( n  = 53). The cells were characterized by flow cytometry and Affymetrix arrays. Their immunomodulatory capacity was assessed in vitro using cocultures with T cells and after preincubation with 2.5% and 5% cigarette smoke extract. We were able to isolate LR-MSCs expressing similar phenotypic markers in all of the study groups. LR-MSCs from current smokers with COPD expressed different levels of CX3CL1 and CCL5 cytokines, and were unable to modulate CD8 + T-cell proliferation. Preincubation of LR-MSCs with cigarette smoke extract reduced their immunomodulatory capacity. In conclusion, 1 ) LR-MSCs can be isolated in similar amounts from never-smokers and smokers with and without COPD; 2 ) their immunomodulatory capacity is impaired in current smokers with COPD, but not in those with normal lung function; and 3 ) this is reversible after smoking cessation and is reproducible in vitro .

Hyaluronic acid (HA) and its degradation products play an important role in lung pathophysiology and airway remodelling in chronic obstructive pulmonary disease (COPD).We investigated if HA and its degrading enzyme hyaluronidase (HYAL)-1 are associated with COPD severity and outcome.Serum HA was assessed in a discovery cohort of 80 COPD patients at stable state and exacerbations. HA, HYAL-1 and HYAL-1 enzymatic activity were evaluated at stable state, exacerbations and 4 weeks after exacerbations in 638 COPD patients from the PROMISE validation cohort.In the discovery cohort, serum HA was higher at exacerbations compared with the stable state (p=0.015). In the validation cohort, HA was higher at moderate and severe exacerbations than at baseline (p<0.001), and remained higher after 4 weeks (p<0.001). HA was strongly predictive for overall survival since it was associated with time to death (p<0.001) independently of adjusted Charlson score, annual exacerbation rate and BODE (body mass, airflow obstruction, dyspnoea, exercise capacity) index. Serum HYAL-1 was increased at moderate (p=0.004) and severe (p=0.003) exacerbations, but decreased after 4 weeks (p<0.001). HYAL-1 enzymatic activity at stable state was inversely correlated with FEV 1 % pred (p=0.034) and survival time (p=0.017).Serum HA is associated with COPD severity and predicts overall survival. Degradation of HA is associated with airflow limitation and impairment of lung function., Competing Interests: Conflict of interest: E. Papakonstantinou has nothing to disclose. Conflict of interest: I. Bonovolias has nothing to disclose. Conflict of interest: M. Roth has nothing to disclose. Conflict of interest: M. Tamm has nothing to disclose. Conflict of interest: D. Schumann has nothing to disclose. Conflict of interest: F. Baty has nothing to disclose. Conflict of interest: R. Louis has nothing to disclose. Conflict of interest: B. Milenkovic has nothing to disclose. Conflict of interest: W. Boersma has nothing to disclose. Conflict of interest: B. Stieltjes has nothing to disclose. Conflict of interest: K. Kostikas has nothing to disclose. Conflict of interest: F. Blasi has nothing to disclose. Conflict of interest: J.G. Aerts has nothing to disclose. Conflict of interest: G.G.U. Rohde has nothing to disclose. Conflict of interest: A. Lacoma has nothing to disclose. Conflict of interest: A. Torres has nothing to disclose. Conflict of interest: T. Welte has nothing to disclose. Conflict of interest: D. Stolz has nothing to disclose., (Copyright ©ERS 2019.)

Background: The role of the extracellular matrix (ECM) structure and remodeling thereof in lung diseases is gaining importance. Pathology-related changes in ECM turnover may result in deleterious changes in lung architecture, leading to disease in the small airways. Here, degradation fragments of type I (C1M), type IV (α1 chain, C4M2), and type IV (α3 chain, C4Ma3) collagen, all degraded by metalloproteinases and the pro-form of collagen type V (PRO-C5) were investigated and associated with COPD severity and outcome., Methods: In a prospective, observational, multicenter study including 498 patients with COPD Gold Initiative for Chronic Obstructive Lung Disease stage 2 to 4, ECM markers were assessed in serum at stable state, exacerbation, and at follow-up 4 weeks after exacerbation., Results: At stable state, there was a significant inverse association between FEV 1 % predicted and C1M, C4Ma3, and Pro-C5. C1M, C4M2, C4Ma3, and Pro-C5 were associated with BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index and the modified Medical Research Council (MMRC) score. C1M, C4M2, C4Ma3, and Pro-C5 were significantly increased from stable state to exacerbation and decreased at follow-up. Furthermore, the biomarkers were significantly higher during severe exacerbation compared with moderate exacerbation. Multivariate analysis adjusted for BMI, MMRC score, unadjusted Charlson score, and FEV 1 %predicted showed a significant influence of C1M, C4Ma3, and C4M2 on time to exacerbation. None of the biomarkers were predictors for mortality., Conclusions: Serologically assessed collagen remodeling appears to play a significant role in COPD severity (airflow limitation, dyspnea) and disease outcome (time to exacerbation and prognosis as assessed by the BODE index)., (Copyright © 2018. Published by Elsevier Inc.)

Background: c-Kit + lung stem cells have been described in the human healthy lung. Their potential relation with smoking and/or chronic obstructive pulmonary disease (COPD) is unknown., Methods: We characterized and compared c-Kit+ cells in lung tissue of 12 never smokers (NS), 15 smokers with normal spirometry (S) and 44 COPD patients who required lung resectional surgery. Flow cytometry (FACS) was used to characterize c-Kit+ cells in fresh lung tissue disaggregates, and immunofluorescence (IF) for further characterization and to determine their location in OCT- embedded lung tissue., Results: We identified 4 c-Kit+ cell populations, with similar proportions in NS, S and COPD: (1) By FACS, c-Kit high /CD45+ cells (4.03 ± 2.97% (NS), 3.96 ± 5.30% (S), and 5.20 ± 3.44% (COPD)). By IF, these cells were tryptase+ (hence, mast cells) and located around the airways; (2) By IF, c-Kit low /CD45+/triptase- (0.07 ± 0.06 (NS), 0.03 ± 0.02 (S), and 0.06 ± 0.07 (COPD) cells/field), which likely correspond to innate lymphoid cells; (3) By FACS, c-Kit low /CD45-/CD34+ (0.95 ± 0.84% (NS), 1.14 ± 0.94% (S) and 0.95 ± 1.38% (COPD)). By IF these cells were c-Kit low /CD45-/CD31+, suggesting an endothelial lineage, and were predominantly located in the alveolar wall; and, (4) by FACS, an infrequent c-Kit low /CD45-/CD34- population (0.09 ± 0.14% (NS), 0.08 ± 0.09% (S) and 0.08 ± 0.11% (COPD)) compatible with a putative lung stem cell population. Yet, IF failed to detect them and we could not isolate or grow them, thus questioning the existence of c-Kit+ lung stem-cells., Conclusions: The adult human lung contains a mixture of c-Kit+ cells, unlikely to be lung stem cells, which are independent of smoking status and/or presence of COPD.

Background: Interferon lambdas (IFNLs) have important anti-viral/bacterial and immunomodulatory functions in the respiratory tract. How do IFNLs impact COPD and its exacerbations?, Methods: Five hundred twenty eight patients were recruited in a prospective observational multicentre cohort (PROMISE) study. The genetic polymorphisms (rs8099917 and rs12979860) within the IFNL3/4 gene region and circulating levels of IFNL3 in COPD patients were determined and associated with disease activity and outcome during a median follow-up of 24 months., Results: The GG genotype significantly influenced severe exacerbation rate (42 vs. 23%; p = 0.032) and time to severe exacerbation (HR = 2.260; p = 0.012). Compared to the TT or TG genotypes, the GG genotype was associated with severe dyspnoea (modified medical research council score ≥ median 3; 22 vs 42%, p = 0.030). The CC genotype of the rs12979860 SNP was associated with a poorer prognosis (body mass index, airflow obstruction, dyspnea and exercise capacity index ≥ median 4; 46 vs. 36% TC vs. 20.5% TT; p = 0.031). Patients with stable COPD and at exacerbation had significantly lower circulating IFNL3 compared to healthy controls (p < 0.001 and p < 0.001, respectively). Circulating IFNL3 correlated to post-bronchodilator FEV 1 %predicted and the tissue maturation biomarker Pro-collagen 3., Conclusion: IFNL3/4 polymorphisms and circulating IFNL3 may be associated with disease activity and outcomes in COPD., Trial Registration: Clinical Trial registration http://www.isrctn.com/ identifier ISRCTN99586989 on 16 April 2008.

Introduction: The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO., Objectives: We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO., Methods: This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO. ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis., Results: In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p =0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p <0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions., Conclusion: Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions., Competing Interests: Disclosure Dr Pérez de Llano reports grants from SEPAR, during the conduct of the study, and grants and personal fees from Novartis, Chiesi, AstraZeneca, and Pfizer, outside the submitted work. Dr Cosío reports grants from SEPAR, during the conduct of the study, and personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants and personal fees from Novartis, Chiesi, Rovi, Menarini, and Esteve, outside the submitted work. Dr Izquierdo reports and has received funds for advisory boards and lectures from Almirall, AstraZeneca, Bayer, GlaxoSmithKline, Novartis, Pfizer, Boehringer Ingelheim, Takeda, Chiesi, and Menarini. Dr Soler-Cataluña reports grants from SEPAR, during the conduct of the study and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Rovi, Menarini, and Esteve, outside the submitted work. Dr Miravitlles reports personal fees from Almirall, Boehringer Ingelheim, AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Teva, Grifols, and Novartis, outside the submitted work. The authors report no other conflicts of interest in this work.

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin, is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD., (Copyright © 2017. Published by Elsevier Ltd.)

Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10 -6 . We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10 -7 ). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10 -7 ) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.

Background: Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD., Methods: In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro-forms of collagen type III (Pro-C3) and type VI (Pro-C6), and neutrophil elastase-generated fragments of elastin (EL-NE) according to enzyme-linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD., Results: Serum levels of C3M, C6M, Pro-C3, Pro-C6, and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation compared with stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59-0.89; P = .002) and Pro-C6 with survival (hazard ratio, 2.09; CI, 1.18-3.71; P = .011)., Conclusions: Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD., Trial Registry: No.: ISRCTN99586989; URL: www.controlled-trials.com., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

This article summarizes how the multilevel (clinical, functional, structural, and biological) and dynamic (i.e., subjected to changes with time) heterogeneity of chronic obstructive pulmonary disease challenges a personalized approach for these patients. In particular, the following issues are discussed: (1) the conceptual differences between personalized and precision medicine, (2) how to frame the complexity and heterogeneity of chronic obstructive pulmonary disease by considering the precise meaning of the terms personalized medicine and precision medicine, and (3) how to translate all these novel concepts into clinical practice and move the field forward.

Background and Objective: Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD., Methods: A total of 638 patients with stable COPD for ≥6 weeks, ≥10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death., Results: A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P < 0.0001). Anti-GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1.04-2.53)., Conclusion: These findings suggest that patients with stable COPD receiving acid-suppressive therapy with proton pump inhibitors remain at high risk of frequent and severe exacerbations., (© 2016 Asian Pacific Society of Respirology.)

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk., (Copyright ©ERS 2016.)

Background: Functional deficiency of mannose-binding lectin (MBL) may contribute to the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that specific MBL2 gene polymorphisms and circulating MBL protein levels are associated with clinically relevant outcomes in the Predicting Outcome using systemic Markers In Severe Exacerbations of COPD PROMISE-COPD cohort., Methods: We followed 277 patients with stable COPD GOLD stage II-IV COPD over a median period of 733 days (IQR 641-767) taking survival as the primary outcome parameter. Patients were dichotomized as frequent (≥ 2 AECOPD/year) or infrequent exacerbators. Serum MBL levels and single nucleotide polymorphisms of the MBL2 gene were assessed at baseline., Results: The MBL2-HYPD haplotype was significantly more prevalent in frequent exacerbators (OR: 3.33; 95% CI, 1.24-7.14, p = 0.01). The median serum MBL concentration was similar in frequent (607 ng/ml, [IQR; 363.0-896.0 ng/ml]) and infrequent exacerbators (615 ng/ml, [IQR; 371.0-942.0 ng/ml]). Serum MBL was not associated with lung function characteristics or bacterial colonization in sputum. However, high serum MBL at stable state was associated with better survival compared to low MBL (p = 0.046, log rank test)., Conclusions: In COPD, the HYPD haplotype of MBL2 gene is associated with frequent exacerbations and high serum MBL is linked to increased survival. The PROMISE-COPD study was registered at www.controlled-trials.com under the identifier ISRCTN99586989.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before., Methods: The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 μM) and/or the HDAC enhancer theophylline (10 μM)., Results: Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1β, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-κB activation., Conclusions: These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity.

Purpose: Several studies have analyzed factors associated to hospitalization in chronic obstructive pulmonary disease (COPD) patients. However, data are lacking on the quality of treatment received by patients prior to hospital admission. The present study analyzed how often patients requiring hospitalization for a COPD exacerbation had received previous treatment for the exacerbation, particularly antibiotics., Methods: This was a multicenter, cross-sectional, observational study conducted in 30 Spanish hospitals among COPD patients aged >40 years who were hospitalized for an acute exacerbation. Patients were grouped according to whether or not they had received treatment prior to admission and, subsequently, according to whether or not they had received antibiotics. Patient eligibility for antibiotic therapy was assessed using both national and European guidelines., Results: The study population consisted of 298 patients, of which 277 (93 %) were men, with a mean [standard deviation (SD)] age of 69.1 (9.5) years. One hundred and thirty-three patients (45 %) had received treatment prior to admission; among these, 76/133 (57 %) had received antibiotic therapy. However, 81-91 % of these patients fulfilled criteria for this therapy. Antibiotic use was significantly associated with yellow or green-yellow sputum prior to the exacerbation, a higher number of exacerbations in the previous year, more visits to emergency departments, and bronchiectasis. On the other hand, 10-20 % of patients who did receive antibiotics were not eligible for this therapy according to guidelines., Conclusions: This study demonstrates a low rate of previous outpatient treatment and antibiotic use among patients with a COPD exacerbation requiring hospital admission.

Background: Chronic obstructive pulmonary disease (COPD) and asthma treatment must be based on appropriate diagnosis. However, patients receiving inhaled therapy in primary care may not be accurately diagnosed according to current guidelines., Aim: To analyse the characteristics of patients treated with inhaled medication, the concordance of tools for differential diagnosis, and the adequacy of prescription of inhaled corticosteroids (ICs) in primary care., Design and Setting: Cross-sectional, multicentre, non-interventional study conducted in 10 primary care centres in Barcelona, Spain., Method: Patients with chronic respiratory disease, aged >40 years were treated with ICs. They provided sociodemographic and clinical information and performed forced spirometry with a bronchodilator test (BDT). The diagnostic accuracy of asthma and COPD diagnoses were tested using two differential diagnosis questionnaires., Results: A total of 328 patients were initially classified as having COPD (64.8%), asthma (15.4%), or indeterminate (19.8%) by their GPs. After spirometry, 40% of patients had moderate-severe airflow obstruction according to the GOLD classification; mean reversibility of forced expiratory volume in 1 second (FEV1) was 8.4%; 18.6% had a positive BDT; and 39.8% had post-bronchodilator FEV1/forced vital capacity >0.7. Concordance of the differential diagnosis tools was moderate (clinical diagnosis versus spirometry and between the two questionnaires), low (clinical diagnosis versus questionnaires), and very low (spirometry versus differential diagnosis). Of the patients diagnosed with COPD, 71.4% were treated with ICs, and 12% of those classified as having asthma were not receiving ICs., Conclusion: Most patients can be classified as having COPD or asthma by primary care physicians. The use of the two questionnaires did not provide a better differential diagnostic compared with symptoms and spirometry with a BDT. Misdiagnosis may lead to inadequate treatment.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries, and its prevalence is projected to increase over the coming decades. According to the World Health Organization, COPD will become the third leading cause of death worldwide by 2020. COPD has a chronic and progressive course, and is often aggravated by exacerbations, which typically arise as a result of bronchial infection. Exacerbations are characterised by periods of increasing acute symptoms, particularly cough, dyspnoea and production of sputum, which worsen airflow obstruction, further impair quality of life and generally require a change in regular medication. Exacerbations are the most common cause of medical visits, hospital admissions and death in patients with COPD, and frequent exacerbations worsen health status and may cause a permanent decline in lung function. Chronic cough and sputum production are common in the general population, but significantly more prevalent in patients with respiratory disorders; these symptoms have been suggested as a risk factor for exacerbations of COPD. This article will review the consequences of chronic cough and sputum production in patients with COPD and analyse whether these risk factors may be useful for identifying a specific phenotype of patient that requires different management to reduce the occurrence of exacerbations., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Spirometry is underused for the assessment of severity of chronic obstructive pulmonary disease (COPD) in primary care (PC). Therefore, simple assessment tools are required in this setting. The aim of the present study was to validate the COPD severity score (COPDSS) for use in PC. A multicentric study was carried out in stable COPD patients in PC. The concurrent validity of the COPDSS was evaluated by examining the association between COPDSS, COPD clinical indicators and the London Chest Activity of Daily Living (LCADL) scale, European quality of life (EuroQOL) questionnaires and Charlson comorbidity index. A total of 837 patients with COPD were analysed (males 84.3%; mean+/-sd age 68+/-11 yrs; forced expiratory volume in one second 54.6+/-17.7% of the predicted value). A strong correlation was found between COPDSS and dyspnoea level and a moderate correlation between COPDSS and exacerbation number. The COPDSS discriminated between patients with varying degrees of dyspnoea (area under receiver operating characteristic (ROC) curve 0.837), and according to number of exacerbations in the last year (area under ROC curve 0.773). Higher COPDSS scores were significantly associated with lower EuroQOL scores, lower EuroQOL visual analogue scale scores and higher LCADL scores. The present results indicate that the chronic obstructive pulmonary disease severity score is a useful and reliable tool for assessing the severity of chronic obstructive pulmonary disease in primary care.

Influencing the progression of COPD has long been an elusive goal of drug therapy. Directly or indirectly, this has again been investigated in two of the largest, long-term drug trials in COPD: Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT). Neither trial achieved statistical significance in their respective primary outcomes; however, both make considerable contributions to understanding of how the progression of COPD may be influenced. The objective of this article is to review the data from these different trials with a view to what can be learnt about the management of COPD. The long-term improvements in lung function, health-related quality of life, and possibly survival from the use of long-acting bronchodilators in these trials suggest an influence on progression of the disease. With the more optimistic view of benefits from drug treatment of COPD that these trials provide, a review of prescribing practices is warranted.

The evaluation of therapies requires the development of patient-reported outcomes (PROs) that help clinicians to understanding the symptoms, perceptions and feelings of patients with exacerbations of chronic obstructive pulmonary disease (COPD). With the aim of obtaining information on the perceptions of patients with COPD, their exacerbations and expectations of treatment, a random telephone contact survey in six countries was performed. From 83,592 households screened, 1100 subjects with symptoms compatible with COPD were identified. The most frequent symptom was shortness of breath (78%). The most frequent complaint was that due to their COPD: "they could not complete the activities they like to do" (54%); 17% (187) of individuals were afraid that their COPD would cripple, or eventually kill them. Exacerbations generated a mean of 5.1 medical visits/year (SD=4.6) with the mean duration of exacerbation symptoms being 10.5 days. Increased coughing was the exacerbation symptom having the strongest impact on well-being (42%). Fifty-five percent of patients declared that quicker symptom relief was the most desired requirement for treatment. New data are provided on the impact of COPD and its exacerbations on the daily life of patients. These data will help to develop PROs designed to evaluate the effectiveness of different therapies for exacerbated COPD.

Impaired health status may be a risk factor for frequent exacerbations and hospital admission and, in turn, exacerbations and admissions may further impair the health status of patients with COPD. We have investigated the variables associated with frequent exacerbations (3 or more per year) and admission, with particular interest in health status, in a cohort of ambulatory patients with moderate to severe COPD attended by chest physicians in Spain. A total of 227 investigators included 1057 patients with a mean predicted FEV1 of 41.8%. The mean total score on the St. George's Respiratory Questionnaire (SGRQ) was 47.9 units, and 300 patients (28.4%) had 3 or more exacerbations the previous year and 344 (32.6%) were admitted at least once during the same period. In multivariate analysis only the SGRQ total score was significantly associated with both frequent exacerbations (OR = 1.04; 95% CI = 1.01-2.12; p<0.0001) and admission (OR = 1.01; 95% CI = 1.00-1.02; p = 0.0008). Other variables significantly associated with frequent exacerbations were chronic mucus hypersecretion, increased baseline dyspnea, comorbidity, GOLD stage IV and treatment with inhaled corticosteroids. Variables associated with admission were lower educational level, increased number of exacerbations, use of long-term oxygen therapy and use of short acting beta-2 agonists. An impaired health status is associated with an increased number of exacerbations and with admission to hospital in the previous year. These results, together with previous studies, confirm that impairment in health status in COPD is both a marker of risk for, and a consequence of, frequent exacerbations and admissions.

Background: A study was undertaken to evaluate exacerbations and their impact on the health related quality of life (HRQL) of patients with chronic obstructive pulmonary disease (COPD)., Methods: A 2 year follow up study was performed in 336 patients with COPD of mean (SD) age 66 (8.2) years and mean (SD) forced expiratory volume in 1 second (FEV(1)) 33 (8)% predicted. Spirometric tests, questions regarding exacerbations of COPD, and HRQL measurements (St George's Respiratory Questionnaire (SGRQ) and SF-12 Health Survey) were conducted at 6 month intervals., Results: A total of 1015 exacerbations were recorded, and 103 (30.7%) patients required at least one hospital admission during the study. After adjustment for baseline characteristics and season of assessment, frequent exacerbations had a negative effect on HRQL in patients with moderate COPD (FEV(1) 35-50% predicted); the change in SGRQ total score of moderate patients with > or =3 exacerbations was almost two points per year greater (worse) than those with <3 exacerbations during the follow up (p = 0.042). For patients with severe COPD (FEV(1) <35% predicted) exacerbations had no effect on HRQL. The change in SGRQ total score of patients admitted to hospital was almost 2 points per year greater (worse) than patients not admitted, but this effect failed to show statistical significance in any severity group. There was a significant and independent seasonal effect on HRQL since SGRQ total scores were, on average, 3 points better in measurements performed in spring/summer than in those measured in the winter (p<0.001)., Conclusions: Frequent exacerbations significantly impair HRQL of patients with moderate COPD. A significant and independent effect of seasonality was also observed.