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The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 μg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD.,Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair® dry powder inhaler for 8 weeks.,From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals).,The primary end point was trough functional residual capacity (FRC) at Week 4.,Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI).,Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise.,After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690).,However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001).,AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively).,AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo.,Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo.,AB/FF 400/12 μg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI.,A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF. | Tiotropium-olodaterol, formulated in the Respimat soft-mist inhaler, is an inhaled fixed-dose combination (FDC) of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), commercialized under the name of Spiolto or Stiolto.,The efficacy of tiotropium-olodaterol 5-5 μg once daily in adult patients with COPD was documented in eleven large, multicenter trials of up to 52 weeks duration.,Tiotropium-olodaterol 5-5 μg not only improved spirometric values to a significantly greater extent than placebo but also resulted in statistically significant beneficial effects on dyspnea, markers of hyperinflation, use of rescue medication, health-related quality of life, and exercise endurance.,Improvements exceeded the minimal clinically important difference (MCID) for forced expiratory volume in 1 second (FEV1), dyspnea, and quality of life.,Differences between tiotropium-olodaterol 5-5 μg and the respective monocomponents were statistically significant for FEV1, dyspnea, markers of hyperinflation, use of rescue medication, and health-related quality of life, but did not reach the MCID.,However, dual bronchodilatation significantly increased the number of patients who exceeded the MCID for dyspnea and quality of life.,Moreover, tiotropium-olodaterol 5-5 μg was significantly more effective than salmeterol-fluticasone (FDC) twice daily at improving pulmonary function.,Differences between tiotropium-olodaterol and other LAMA/LABA FDCs were not observed for FEV1 or other efficacy markers.,Therefore, tiotropium-olodaterol is a valuable option in the treatment of COPD patients who remain symptomatic under monotherapy. | 1 |
Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society.,The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options.,Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system.,This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support) to manage severe exacerbations, and strategies to prevent readmission to hospital.,Risk factors that are amenable to change have been highlighted.,A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation.,Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD.,Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management. | Parasympathetic pulmonary nerves release acetylcholine that induces smooth muscle constriction.,Disruption of parasympathetic pulmonary nerves improves lung function and COPD symptoms.,To evaluate ‘targeted lung denervation’ (TLD), a novel bronchoscopic therapy based on ablation of parasympathetic pulmonary nerves surrounding the main bronchi, as a potential therapy for COPD.,This 1-year, prospective, multicentre study evaluated TLD in patients with COPD forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (FEV1/FVC <0.70; FEV1 30%-60% predicted).,Patients underwent staged TLD at 20 watts (W) or 15 W following baseline assessment off bronchodilators.,Assessments were repeated on tiotropium before treatment and off bronchodilators at 30, 90, 180, 270 and 365 days after TLD.,The primary endpoint was freedom from documented and sustained worsening of COPD directly attributable to TLD to 1 year.,Secondary endpoints included technical feasibility, change in pulmonary function, exercise capacity, and quality of life.,Twenty-two patients were included (n=12 at 20 W, n=10 at 15 W).,The procedures were technically feasible 93% of the time.,Primary safety endpoint was achieved in 95%.,Asymptomatic bronchial wall effects were observed in 3 patients at 20 W.,The clinical safety profiles were similar between the two energy doses.,At 1 year, changes from baseline in the 20 W dose compared to the 15 W dose were: FEV1 (+11.6%±32.3 vs +0.02%±15.1, p=0.324), submaximal cycle endurance (+6.8 min±12.8 vs 2.6 min±8.7, p=0.277), and St George's Respiratory Questionnaire (−11.1 points ±9.1 vs −0.9 points ±8.6, p=0.044).,Bronchoscopic TLD, based on the concept of ablating parasympathetic pulmonary nerves, was feasible, safe, and well tolerated.,Further investigation of this novel therapy is warranted.,NCT01483534. | 1 |
The Global initiative for chronic Obstructive Lung Disease guidelines recommend assessment of COPD severity, which includes symptomatology using the modified Medical Research Council (mMRC) or COPD assessment test (CAT) score in addition to the degree of airflow obstruction and exacerbation history.,While there is great interest in incorporating symptomatology, little is known about how patient reported symptoms are associated with future exacerbations and exacerbation-related costs.,The mMRC and CAT were mailed to a randomly selected sample of 4,000 Medicare members aged >40 years, diagnosed with COPD (≥2 encounters with International Classification of Dis eases-9th Edition Clinical Modification: 491.xx, 492.xx, 496.xx, ≥30 days apart).,The exacerbations and exacerbation-related costs were collected from claims data during 365-day post-survey after exclusion of members lost to follow-up or with cancer, organ transplant, or pregnancy.,A logistic regression model estimated the predictive value of exacerbation history and symptomatology on exacerbations during follow-up, and a generalized linear model with log link and gamma distribution estimated the predictive value of exacerbation history and symptomatology on exacerbation-related costs.,Among a total of 1,159 members who returned the survey, a 66% (765) completion rate was observed.,Mean (standard deviation) age among survey completers was 72.0 (8.3), 53.7% female and 91.2% white.,Odds ratios for having post-index exacerbations were 3.06, 4.55, and 16.28 times for members with 1, 2, and ≥3 pre-index exacerbations, respectively, relative to members with 0 pre-index exacerbations (P<0.001 for all).,The odds ratio for high vs low symptoms using CAT was 2.51 (P<0.001).,Similarly, exacerbation-related costs were 73% higher with each incremental pre-index exacerbation, and over four fold higher for high-vs low-symptom patients using CAT (each P<0.001).,The symptoms using mMRC were not statistically significant in either model (P>0.10).,The patient-reported symptoms contribute important information related to future COPD exacerbations and exacerbation-related costs beyond that explained by exacerbation history. | Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among US adults and is projected to be the third by 2020.,In anticipation of the increasing burden imposed on healthcare systems and payers by patients with COPD, a means of identifying COPD patients who incur higher healthcare utilization and costs is needed.,This retrospective, cross-sectional analysis of US managed care administrative claims data describes a practical way to identify COPD patients.,We analyze 7.79 million members for potential inclusion in the COPD cohort, who were continuously eligible during a 1-year study period.,A younger commercial population (7.7 million) is compared with an older Medicare population (0.115 million).,We outline a novel approach to stratifying COPD patients using "complexity" of illness, based on occurrence of claims for given comorbid conditions.,Additionally, a unique algorithm was developed to identify and stratify COPD exacerbations using claims data.,A total of 42,565 commercial (median age 56 years; 51.4% female) and 8507 Medicare patients (median 75 years; 53.1% female) were identified as having COPD.,Important differences were observed in comorbidities between the younger commercial versus the older Medicare population.,Stratifying by complexity, 45.0%, 33.6%, and 21.4% of commercial patients and 36.6%, 35.8%, and 27.6% of older patients were low, moderate, and high, respectively.,A higher proportion of patients with high complexity disease experienced multiple (≥2) exacerbations (61.7% commercial; 49.0% Medicare) than patients with moderate- (56.9%; 41.6%), or low-complexity disease (33.4%; 20.5%).,Utilization of healthcare services also increased with an increase in complexity.,In patients with COPD identified from Medicare or commercial claims data, there is a relationship between complexity as determined by pulmonary and non-pulmonary comorbid conditions and the prevalence of exacerbations and utilization of healthcare services.,Identification of COPD patients at highest risk of exacerbations using complexity stratification may facilitate improved disease management by targeting those most in need of treatment. | 1 |
Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space.,However, mechanisms involved in its development are not fully understood.,Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated.,Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research.,Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema.,Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema.,This review also includes some reflections and suggestions on the research to come. | Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD).,However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear.,Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD.,These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung.,They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury.,This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD.,In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients. | 1 |
Recent advances in multidetector computed tomography (MDCT) facilitate acquiring important clinical information for managing patients with COPD.,MDCT can detect the loss of lung tissue associated with emphysema as a low-attenuation area (LAA) and the thickness of airways as the wall area percentage (WA%).,The percentage of small pulmonary vessels <5 mm2 (% cross-sectional area [CSA] <5) has been recently recognized as a parameter for expressing pulmonary perfusion.,We aimed to analyze the longitudinal changes in structural abnormalities using these CT parameters and analyze the effect of exacerbation and smoking cessation on structural changes in COPD patients.,We performed pulmonary function tests (PFTs), an MDCT, and a COPD assessment test (CAT) in 58 patients with COPD at the time of their enrollment at the hospital and 2 years later.,We analyzed the change in clinical parameters including CT indices and examined the effect of exacerbations and smoking cessation on the structural changes.,The CAT score and forced expiratory volume in 1 second (FEV1) did not significantly change during the follow-up period.,The parameters of emphysematous changes significantly increased.,On the other hand, the WA% at the distal airways significantly decreased or tended to decrease, and the %CSA <5 slightly but significantly increased over the same period, especially in ex-smokers.,The parameters of emphysematous change were greater in patients with exacerbations and continued to progress even after smoking cessation.,In contrast, the WA% and %CSA <5 did not change in proportion to emphysema progression.,The WA% at the distal bronchi and the %CSA <5 did not change in parallel with parameters of LAA over the same period.,We propose that airway disease and vascular remodeling may be reversible to some extent by smoking cessation and appropriate treatment.,Optimal management may have a greater effect on pulmonary vascularity and airway disease than parenchymal deconstruction in the early stage of COPD. | This study assessed the effects of inhaled corticosteroid (ICS) on airway vascular remodeling in chronic obstructive pulmonary disease (COPD).,Thirty-four subjects with mild-to-moderate COPD were randomly allocated 2:1 to ICS or placebo treatment in a double-blinded clinical trial over 6 months.,Available tissue was compared before and after treatment for vessel density, and expression of VEGF, TGF-β1, and TGF-β1-related phosphorylated transcription factors p-SMAD 2/3.,This clinical trial has been registered and allocated with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 17/10/2012 with reference number ACTRN12612001111864.,There were no significant baseline differences between treatment groups.,With ICS, vessels and angiogenic factors did not change in hypervascular reticular basement membrane, but in the hypovascular lamina propria (LP), vessels increased and this had a proportionate effect on lung air trapping.,There was modest evidence for a reduction in LP vessels staining for VEGF with ICS treatment, but a marked and significant reduction in p-SMAD 2/3 expression.,Six-month high-dose ICS treatment had little effect on hypervascularity or angiogenic growth factors in the reticular basement membrane in COPD, but normalized hypovascularity in the LP, and this was physiologically relevant, though accompanied by a paradoxical reduction in growth factor expression. | 1 |
Early morning respiratory symptoms impact quality of life and are often the most troublesome for patients with COPD.,Reduction in symptoms and their impact are important treatment outcomes for COPD.,The Early Morning Symptoms of COPD Instrument (EMSCI) is a daily diary designed to collect patients’ report of the occurrence, severity, and impact of morning COPD symptoms.,To assess the psychometric properties of the EMSCI, a split-half sample of data from a COPD clinical trial where participants completed the EMSCI daily was used for conducting descriptive statistics, factor analyses, and Rasch model analyses to examine item performance and inform scoring.,Once the final scoring algorithm was determined, data from the second split-half sample were used to examine the properties of the EMSCI.,Test-retest reliability was assessed using intraclass correlation coefficient (ICC).,Correlations with other study assessments were used to evaluate convergent and known-groups validity.,Data from 1,663 patients with COPD aged 40-93 years were analyzed.,Factor analysis and Rasch analysis confirmed a one-factor structure for the 6 individual symptom items.,Item analyses supported the generation of 4 scores.,All scores demonstrated good test-retest reliability: 6-item symptom severity (ICC, 0.84); overall morning symptom severity (ICC, 0.84); activity limitation (ICC, 0.85); and rescue medication (ICC, 0.62).,Significant correlations between EMSCI scores, St George’s Respiratory Questionnaire scores, and EXAcerbations of Chronic pulmonary disease Tool (EXACT)-Respiratory Symptoms scores supported the tool’s convergent validity.,Significant differences (p<0.0001) in all EMSCI domain scores were found between known-groups based on median split St George’s Respiratory Questionnaire and EXACT-Respiratory Symptoms scores.,The EMSCI consists of 4 scores: 6-item symptom severity, overall symptom severity, activity limitation, and rescue medication.,The EMSCI is a reliable and valid instrument for evaluating patients’ experience of early morning COPD symptoms. | Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD).,We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) scale (formerly EXACT-RS).,Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction.,Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D.,Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed.,Of 1210 patients, 1167 had data available for GOLD classification.,Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted.,Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group.,The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D.,Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients’ level of symptoms at baseline.,Net treatment benefit was similar in patients with low or high levels of symptoms.,ATTAIN (ClinicalTrials.gov identifier: NCT01001494) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397).,The online version of this article (doi:10.1186/s12931-016-0372-1) contains supplementary material, which is available to authorized users. | 1 |
Health utilities are widely used in health economics as a measurement of an individual’s preference and show the value placed on different health states over a specific period.,Thus, health utilities are used as a measure of the benefits of health interventions in terms of quality-adjusted life years.,This study aimed to determine the demographic and clinical variables significantly associated with health utilities for chronic obstructive pulmonary disease (COPD) patients.,This was a multicenter, observational, cross-sectional study conducted between October 2012 and April 2013.,Patients were aged ≥40 years, with spirometrically confirmed COPD.,Utility values were derived from the preference-based generic questionnaire EQ-5D-3L applying weighted Spanish societal preferences.,Demographic and clinical variables associated with utilities were assessed by univariate and multivariate linear regression models.,Three hundred and forty-six patients were included, of whom 85.5% were male.,The mean age was 67.9 (standard deviation [SD] =9.7) years and the mean forced expiratory volume in 1 second (%) was 46.2% (SD =15.5%); 80.3% were former smokers, and the mean smoking history was 54.2 (SD =33.2) pack-years.,Median utilities (interquartile range) were 0.81 (0.26) with a mean value of 0.73 (SD =0.29); 22% of patients had a utility value of 1 (ceiling effect) and 3.2% had a utility value lower than 0.,The factors associated with utilities in the multivariate analysis were sex (beta =-0.084, 95% confidence interval [CI]: −0.154; -0.013 for females), number of exacerbations the previous year (−0.027, 95% CI: −0.044; -0.010), and modified Medical Research Council Dyspnea Scale (mMRC) score (−0.123 [95% CI: −0.185; −0.061], −0.231 [95% CI: −0.301; −0.161], and −0.559 [95% CI: −0.660; −0.458] for mMRC scores 2, 3, and 4 versus 1), all P<0.05.,Multivariate analysis showed that female sex, frequent exacerbations, and an increased level of dyspnea were the main factors associated with reduced utility values in patients with COPD. | 1) To estimate the annual cost of patients with stable chronic obstructive pulmonary disease (COPD) followed in primary care in Spain; 2) To analyze the possible cost predictor variables.,A multicenter, epidemiological, observational, descriptive study.,Sociodemographic data, severity of disease, associated comorbidity, treatment followed by patients, quality of life (SF-12 questionnaire), health care resource utilization in the previous 12 months and duration of working disability due to COPD were collected.,A total of 10,711 patients (75.6% men; 24.4% women) with a mean age of 67.1 ± 9.66 years were evaluated.,The mean forced expiratory volume in one second (FEV1) value was 57.4 ± 13.4%.,The total cost per patient per year was €1,922.60 ± 2,306.44.,The largest component of this cost was hospitalization (€788.72 ± 1,766.65), followed by cost of drugs (€492.87 ± 412.15) and visits to emergency rooms (€134.32 ± 195.44).,Linear regression analysis found associated heart disease, FEV1, physical component of quality of life, number of medical visits (primary care physician, pneumologist and emergency room), hospital admissions (frequency and duration of stay) and duration of working disability to be significant predictors of the total annual cost.,The total annual cost of a COPD patient followed in primary care in Spain was considered high in this study.,The presence of associated heart disease, severity of airflow obstruction, physical component of quality of life, health care resource utilization and duration of work disability were found to be predictor of cost. | 1 |
Asthma and chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is an increasingly recognized phenotype.,Few randomized clinical trials have been conducted in patients with ACOS; therefore, scientific evidence concerning ACOS is scarce and a therapeutic approach remains unclear.,The aim of this study was to evaluate current treatment trends for patients with ACOS, identified as those with a dual definition of asthma and COPD, in a real-world COPD cohort.,Data were analyzed from patients with asthma and COPD in the USA, France, Germany, Italy, Spain, and the UK who participated in the 2012 and 2013 Adelphi Respiratory Disease Specific Programmes (DSPs).,Patients with ACOS were identified in the COPD population; these patients had a physician-confirmed, concomitant asthma diagnosis.,Physicians completed a patient record form providing information on patient and disease characteristics including prescribed respiratory treatment.,Pairwise comparisons were made between the ACOS, asthma, and COPD populations using χ2 tests.,In total, 9,042 patients with asthma-only, 7,119 patients with COPD-only, and 523 patients with ACOS (a dual diagnosis of asthma and COPD) participated in the study.,The most commonly prescribed regimens were inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) + long-acting muscarinic antagonist (LAMA); (ACOS 30%, asthma 1.4%, and COPD 32%), ICS/LABA (19%, 41.5%, and 17%, respectively), and LAMA (6%, 0.4%, and 19%, respectively); 18% of patients with ACOS were not prescribed an ICS.,Patients with ACOS had a significantly higher incidence of gastroesophageal reflux disease, diabetes, and obesity and experienced more exacerbations in the past year than those with COPD or asthma.,The majority of patients with ACOS, as defined in this research, were prescribed similar treatment to those with COPD.,There is a need, however, for better treatment for patients with ACOS, as indicated by symptoms and exacerbation levels.,A clearer therapeutic approach for patients with ACOS is required. | The coexistence of COPD and asthma is widely recognized but has not been well described.,This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.,We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.,119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma.,These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001).,More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001).,Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001).,Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT.,There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.,Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life.,They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.,ClinicalTrials.gov: NCT00608764 | 1 |
Bronchiectasis revealed by chest computed tomography in COPD patients and its comorbid effect on prognosis have not been addressed by large-sized studies.,Understanding the presence of bronchiectasis in COPD is important for future intervention and preventing disease progression.,Observational studies were identified from electronic literature searches in Cochrane library, PubMed, ScienceDirect databases, American Thoracic Society and European Respiratory Society meeting abstracts.,A systematic review and meta-analysis of studies was performed to summarize the factors associated with bronchiectasis in COPD patients.,Primary outcomes included the risks for exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality.,Odds ratios (ORs) were pooled by random effects models.,Fourteen observational studies were eligible for the study.,Compared with COPD without bronchiectasis, comorbid bronchiectasis in COPD increased the risk of exacerbation (1.97, 95% CI, 1.29-3.00), isolation of a potentially pathogenic microorganism (4.11, 95%CI, 2.16-7.82), severe airway obstruction (1.31, 95% CI, 1.09-1.58) and mortality (1.96, 95% CI, 1.04-3.70).,The presence of bronchiectasis in patients with COPD was associated with exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality. | Bronchiectasis is prevalent in patients with COPD.,The objective of this study was to assess the clinical characteristics and prognostic value of bronchiectasis in patients with COPD in China.,Data from patients diagnosed with COPD at the Shanghai Pulmonary Hospital between January 2009 and December 2013 were retrospectively collected and analyzed.,SPSS statistical software was used to analyze the data.,Data from 896 patients with COPD were analyzed.,Bronchiectasis was present in 311 patients.,The isolation of pseudomonas aeruginosa (PA) from sputum was the variable most significantly associated with the presence of bronchiectasis in patients with COPD (hazard ratio (HR), 2.93; 95% confidence interval (CI), 1.35-6.37; P = 0.007).,During follow-up (median of 21 months; interquartile range: 10-39 months), there were 75 deaths, of which 39 were in the bronchiectasis group.,The presence of bronchiectasis (HR, 1.77; 95% CI, 1.02-3.08; P = 0.043) was associated with an increase in all-cause mortality in patients with COPD.,These results suggest that bronchiectasis in patients with COPD was associated with the isolation of PA from the sputum.,Bronchiectasis was an independent risk factor for all-cause mortality in patients with COPD. | 1 |
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects against oxidative stress which is important in the pathogenesis of chronic obstructive pulmonary disease (COPD).,Three single nucleotide polymorphisms and 1 triplet repeat polymorphism are found in the promoter region of the Nrf2 gene.,Molecular haplotyping of the Nrf2 promoter region was performed using DNA obtained from the peripheral blood of 69 COPD patients.,The luciferase activities of Nrf2 promoter constructs containing all possible combinations of the 4 polymorphisms were determined and found to differ among the 16 haplotypes.The haplotypes isolated from the subjects were divided into 3 groups (L: low; M: medium; H: high) on the basis of luciferase activities.,The proportions of subjects belonging to global initiative for chronic obstructive lung disease stage 3 or 4 decreased from the group with the LL haplotype to that with the HH haplotype.,Presence of the LH or MM haplotype (hazard ratio, 3.36; 95% confidence interval, 1.16-9.69), gender (0.13; 0.02-0.67), and post-bronchodilator FEV1 value of predicted (0.95; 0.91-0.99) are significant predictors of respiratory failure development.The haplotype of the Nrf2 gene promoter affects its activity, and is associated with the severity and the development of respiratory failure in COPD. | The first changes associated with smoking are in the small airway epithelium (SAE).,Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a “COPD-like” SAE transcriptome.,SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes.,Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (ISAE), with healthy smokers grouped into “high” and “low” responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker.,Smokers demonstrated significant variability in SAE transcriptome with ISAE ranging from 2.9 to 51.5%.,While the SAE transcriptome of “low” responder healthy smokers differed from both “high” responders and smokers with COPD, the transcriptome of the “high” responder healthy smokers was indistinguishable from COPD smokers.,The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria.,This identifies a group of smokers with a “COPD-like” SAE transcriptome. | 1 |
COPD, characterized by chronic inflammation and airway remodeling, has significant pathological alterations in composition and deposition of the extracellular matrix.,The expression of procollagen 1 C-terminal peptide (PICP) and collagen type 1 C-terminal telopeptide (ICTP), two major by-products in the synthesis and degradation of collagen, was shown to be positively correlated with inflammatory mediator levels in previous studies.,In this study, we investigated whether the serum concentrations of PICP and ICTP were associated with the inflammation level for patients with stable COPD.,We collected serum samples from 25 control subjects and 20 patients with stable COPD from December 2011 to October 2012 in Shanghai Zhongshan Hospital and Shanghai Dahua Hospital.,We determined concentrations of PICP, ICTP, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF)-α by using enzyme-linked immunosorbent assay methods.,Demographic characteristics were comparable between the two groups.,In patients with stable COPD, serum levels of CRP, IL-6, IL-8, and TNF-α were all elevated compared to control subjects, but only changes of IL-6 achieved statistical significance.,Serum concentration of PICP was significantly elevated in patients with COPD, and level of ICTP was slightly decreased.,Moreover, serum concentrations of PICP were positively correlated with the levels of both IL-6 and IL-8.,The increased levels of serum PICP in COPD might indicate the condition of airway remodeling, and IL-6 and/or IL-8 might play an important role in stimulating collagen synthesis. | Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM).,Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs.,During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes.,The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study.,The COPDGene study recruited 10,300 COPD patients in 21 centers.,A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE).,Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed.,The circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05).,EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%.,C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = −0.344, p = 0.001), as was EL-NE (r = −0.302, p = 0.004) and Pro-C6 (r = −0.259, p = 0.015).,In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36.,C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively).,These data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema.,Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials. | 1 |
The first changes associated with smoking are in the small airway epithelium (SAE).,Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a “COPD-like” SAE transcriptome.,SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes.,Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (ISAE), with healthy smokers grouped into “high” and “low” responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker.,Smokers demonstrated significant variability in SAE transcriptome with ISAE ranging from 2.9 to 51.5%.,While the SAE transcriptome of “low” responder healthy smokers differed from both “high” responders and smokers with COPD, the transcriptome of the “high” responder healthy smokers was indistinguishable from COPD smokers.,The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria.,This identifies a group of smokers with a “COPD-like” SAE transcriptome. | Despite the status of chronic obstructive pulmonary disease (COPD) as a major global health problem, no currently available therapies can limit COPD progression.,Therefore, an urgent need exists for the development of new and effective treatments for COPD.,An improved understanding in the molecular pathogenesis of COPD can potentially identify molecular targets to facilitate the development of new therapeutic modalities.,Among the best approaches for understanding the molecular basis of COPD include gene expression profiling techniques, such as serial analysis of gene expression or microarrays.,Using these methods, recent studies have mapped comparative gene expression profiles of lung tissues from patients with different stages of COPD relative to healthy smokers or non-smokers.,Such studies have revealed a number of differentially-regulated genes associated with COPD progression, which include genes involved in the regulation of inflammation, extracellular matrix, cytokines, chemokines, apoptosis, and stress responses.,These studies have shed new light on the molecular mechanisms of COPD, and suggest novel targets for clinical treatments. | 1 |
This study aimed to explore cytokine serum levels and the ratio of type 1 T helper (Th1)/Th2 cells in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,A total 245 patients diagnosed with AECOPD and 193 patients who progressed to stable COPD after the initiation of treatment in hospital were selected, while a further 50 healthy individuals served as controls.,All patients with COPD were diagnosed using Global Initiative for Chronic Obstructive Lung Disease criteria.,Serum concentrations of interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-10, IL-17, and immunoglobulin (Ig)E were measured using enzyme-linked immunosorbent assays.,AECOPD patients had higher levels of IL-2, IFN-γ, IL-4, IL-10, IL-17, and IgE than those with stable COPD or controls.,Intriguingly, the ratios of Th1/Th2 and IL-17/IgE were lower in AECOPD patients compared with the other two groups.,These data suggest that AECOPD patients produce more IgE and have more differentiated Th2 cells than other groups.,Our findings suggest that an imbalance of circulating CD4+ T cell subsets correlates with AECOPD, and that a shift of Th1/Th2 and IL-17/IgE ratios may be caused by increased Th2 cell production. | The changes in the microbial community structure during acute exacerbations of severe chronic obstructive pulmonary disease (COPD) in hospitalized patients remain largely uncharacterized.,Therefore, further studies focused on the temporal dynamics and structure of sputum microbial communities during acute exacerbation of COPD (AECOPD) would still be necessary.,In our study, the use of molecular microbiological techniques provided insight into both fungal and bacterial diversities in AECOPD patients during hospitalization.,In particular, we examined the structure and varieties of lung microbial community in 6 patients with severe AECOPD by amplifying 16S rRNA V4 hyper-variable and internal transcribed spacer (ITS) DNA regions using barcoded primers and the Illumina sequencing platform.,Sequence analysis showed 261 bacterial genera representing 20 distinct phyla, with an average number of genera per patient of >157, indicating high diversity.,Acinetobacter, Prevotella, Neisseria, Rothia, Lactobacillus, Leptotrichia, Streptococcus, Veillonella, and Actinomyces were the most commonly identified genera, and the average total sequencing number per sputum sample was >10000 18S ITS sequences.,The fungal population was typically dominated by Candia, Phialosimplex, Aspergillus, Penicillium, Cladosporium and Eutypella.,Our findings highlight that COPD patients have personalized structures and varieties in sputum microbial community during hospitalization periods. | 1 |
Comorbidities are frequent in chronic obstructive pulmonary disease (COPD) and significantly impact on patients’ quality of life, exacerbation frequency, and survival.,There is increasing evidence that certain diseases occur in greater frequency amongst patients with COPD than in the general population, and that these comorbidities significantly impact on patient outcomes.,Although the mechanisms are yet to be defined, many comorbidities likely result from the chronic inflammatory state that is present in COPD.,Common problems in the clinical management of COPD include recognizing new comorbidities, determining the impact of comorbidities on patient symptoms, the concurrent treatment of COPD and comorbidities, and accurate prognostication.,The majority of comorbidities in COPD should be treated according to usual practice, and specific COPD management is infrequently altered by the presence of comorbidities.,Unfortunately, comorbidities are often under-recognized and under-treated.,This review focuses on the epidemiology of ten major comorbidities in patients with COPD.,Further, we emphasize the clinical impact upon prognosis and management considerations.,This review will highlight the importance of comorbidity identification and management in the practice of caring for patients with COPD. | The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable.,We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value.,Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction.,Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09).,One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04).,The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels.,Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers.,The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript.,The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung.,Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) often experience depression and anxiety, but little information is available regarding Chinese patients with these conditions.,The present study assessed depression and anxiety in Chinese patients with COPD.,A case-controlled study was designed with 1100 patients with COPD enrolled in the case group and1100 residents without COPD and respiratory symptoms selected as the control group.,Anxiety and depression in both groups were evaluated using the Hospital Anxiety and Depression Scale (HADS).,The body mass index,degree of airflow obstruction, dyspnea, and exercise capacity (BODE ) index was used to assess COPD severity.,Binary logistic regression models were used to test the association between anxiety and depression.,The patients with COPD were more likely than controls to experience depression (cases, HADS 10.5 ± 3.6, prevalence 35.7%; controls, HADS 8.7 ± 2.7, prevalence 7.2%) and anxiety (cases, HADS 10.4 ± 3.1, prevalence 18.3%; controls, HADS 8.6 ± 2.1, prevalence 5.3%).,Subjects with anxious and depressive symptoms had poorer health outcomes including a higher BODE index, a shorter 6-minute-walk distance (6MWD), more dyspnea, and a higher St George’s respiratory questionnaire (SGRQ) score.,The prevalence of anxious and depressive symptoms increased with increasing BODE scores.,On the basis of binary logistic regression, the BODE index was significantly correlated with anxiety (OR = 1.47, p < 0.001) and depression (OR = 1.51, p < 0.001).,Anxious and depressive symptoms were also associated with several factors including younger age, female sex, higher education level, lower household income and history of smoking.,This study confirmed the high prevalence of anxiety and depression in Chinese outpatients with COPD.,Patients with COPD who had anxiety and/or depression had a poorer health-related quality of life.,Chinese Clinical Trials Registration(ChiCTR-TRC-12001958) | The aim of this study was to measure HrQoL during acute exacerbations of COPD using generic and disease-specific instruments, and to assess completeness, proportion with best or worst health state, sensitivity to change and discriminative ability for each instrument.,EQ-5D, SF-12 and SGRQ were obtained from COPD patients with GOLD stage III and IV hospitalized for an acute exacerbation both at admission and discharge.,To assess the instruments' properties, utility values were calculated for EQ-5D and SF-12, and a total score was derived from the SGRQ.,Mean utilities ranged from 0.54 (SF-12, stage IV) to 0.62 (EQ-5D, stage III) at admission, and from 0.58 (SF-12, stage IV) to 0.84 (EQ-5D, stage III) at discharge.,Completeness was best for EQ-5D and SGRQ, while no utility value for the SF-12 could be calculated for more than 30%.,For SGRQ subscales, the minimal score occurred in up to 11% at admission, while full health was observed for the EQ-5D at discharge in 13%.,Sensitivity to change was generally good, whereas discrimination between COPD stages was low for the EQ-5D.,Acute exacerbations seriously impair health status and quality of life.,The EQ-5D is generally suitable to measure HrQoL in exacerbations of severe COPD, although the high proportion of patients reporting full health at discharge poses a problem.,The main issue with the SF-12 is the high proportion of missing values in a self-assessed setting.,Properties of the SGRQ were satisfactory.,However, since no utility values can be derived from this disease-specific instrument, it is not suitable for cost-utility analyses in health-economic evaluations. | 1 |
Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma.,In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017.,Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex.,Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases.,We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs.,In 2017, 544·9 million people (95% uncertainty interval [UI] 506·9-584·8) worldwide had a chronic respiratory disease, representing an increase of 39·8% compared with 1990.,Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia.,The age-sex-specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically.,Chronic respiratory diseases were the third leading cause of death in 2017 (7·0% [95% UI 6·8-7·2] of all deaths), behind cardiovascular diseases and neoplasms.,Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578-4 044 819) in 2017, an increase of 18·0% since 1990, while total DALYs increased by 13·3%.,However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14·3% decrease), age-standardised death rates (42·6%), and age-standardised DALY rates (38·2%).,In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD.,In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes.,Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world.,Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions.,Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men.,Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region.,Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.,Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis.,Bill & Melinda Gates Foundation. | Chronic obstructive pulmonary disease (COPD) imparts a substantial economic burden on western health systems.,Our objective was to analyze the determinants of elevated healthcare utilization among patients with COPD in a single-payer health system.,Three-hundred eighty-nine adults with COPD were matched 1:3 to controls by age, gender and area of residency.,Total healthcare cost 5 years prior recruitment and presence of comorbidities were obtained from a computerized database.,Health related quality of life (HRQoL) indices were obtained using validated questionnaires among a subsample of 177 patients.,Healthcare utilization was 3.4-fold higher among COPD patients compared with controls (p < 0.001).,The "most-costly" upper 25% of COPD patients (n = 98) consumed 63% of all costs.,Multivariate analysis revealed that independent determinants of being in the "most costly" group were (OR; 95% CI): age-adjusted Charlson Comorbidity Index (1.09; 1.01 - 1.2), history of: myocardial infarct (2.87; 1.5 - 5.5), congestive heart failure (3.52; 1.9 - 6.4), mild liver disease (3.83; 1.3 - 11.2) and diabetes (2.02; 1.1 - 3.6).,Bivariate analysis revealed that cost increased as HRQoL declined and severity of airflow obstruction increased but these were not independent determinants in a multivariate analysis.,Comorbidity burden determines elevated utilization for COPD patients.,Decision makers should prioritize scarce health care resources to a better care management of the "most costly" patients. | 1 |
One‐way endobronchial valves (EBV) insertion to reduce pulmonary air trapping has been used as therapy for chronic obstructive pulmonary disease (COPD) patients.,However, local inflammation may result and can contribute to worsening of clinical status in these patients.,We hypothesized that combined EBV insertion and intrabronchial administration of mesenchymal stromal cells (MSCs) would decrease the inflammatory process, thus mitigating EBV complications in severe COPD patients.,This initial study sought to investigate the safety of this approach.,For this purpose, a phase I, prospective, patient‐blinded, randomized, placebo‐controlled design was used.,Heterogeneous advanced emphysema (Global Initiative for Chronic Lung Disease [GOLD] III or IV) patients randomly received either allogeneic bone marrow‐derived MSCs (108 cells, EBV+MSC) or 0.9% saline solution (EBV) (n = 5 per group), bronchoscopically, just before insertion of one‐way EBVs.,Patients were evaluated 1, 7, 30, and 90 days after therapy.,All patients completed the study protocol and 90‐day follow‐up.,MSC delivery did not result in acute administration‐related toxicity, serious adverse events, or death.,No significant between‐group differences were observed in overall number of adverse events, frequency of COPD exacerbations, or worsening of disease.,Additionally, there were no significant differences in blood tests, lung function, or radiological outcomes.,However, quality‐of‐life indicators were higher in EBV + MSC compared with EBV.,EBV + MSC patients presented decreased levels of circulating C‐reactive protein at 30 and 90 days, as well as BODE (Body mass index, airway Obstruction, Dyspnea, and Exercise index) and MMRC (Modified Medical Research Council) scores.,Thus, combined use of EBV and MSCs appears to be safe in patients with severe COPD, providing a basis for subsequent investigations using MSCs as concomitant therapy.,Stem Cells Translational Medicine 2017;6:962-969 | Bone marrow-derived mesenchymal stem cells (MSCs) have been identified as one possible strategy for the treatment of chronic obstructive pulmonary disease (COPD).,Our previous studies have demonstrated that MSC administration has therapeutic potential in airway inflammation and emphysema via a paracrine mechanism.,We proposed that MSCs reverse the inflammatory process and restore impaired lung function through their interaction with macrophages.,In our study, the rats were exposed to cigarette smoke (CS), followed by the administration of MSCs into the lungs for 5 weeks.,Here we show that MSC administration alleviated airway inflammation and emphysema through the down-regulation of cyclooxygenase-2 (COX-2) and COX-2-mediated prostaglandin E2 (PGE2) production, possibly through the effect on alveolar macrophages.,In vitro co-culture experiments provided evidence that MSCs down-regulated COX-2/PGE2 in macrophages through inhibition of the activation-associated phosphorylation of p38 MAPK and ERK.,Our data suggest that MSCs may relieve airway inflammation and emphysema in CS-exposed rat models, through the inhibition of COX-2/PGE2 in alveolar macrophages, mediated in part by the p38 MAPK and ERK pathways.,This study provides a compelling mechanism for MSC treatment in COPD, in addition to its paracrine mechanism. | 1 |
According to the current clinical practice guidelines for chronic obstructive pulmonary disease (COPD), the addition of inhaled corticosteroids (ICS) to long-acting β2 agonist therapy is recommended in patients with moderate-to-severe disease and an increased risk of exacerbations.,However, ICS are largely overprescribed in clinical practice, and most patients are unlikely to benefit from long-term ICS therapy.,Evidence from recent randomized-controlled trials supports the hypothesis that ICS can be safely and effectively discontinued in patients with stable COPD and in whom ICS therapy may not be indicated, without detrimental effects on lung function, health status, or risk of exacerbations.,This article summarizes the evidence supporting the discontinuation of ICS therapy, and proposes an algorithm for the implementation of ICS withdrawal in patients with COPD in clinical practice.,Given the increased risk of potentially serious adverse effects and complications with ICS therapy (including pneumonia), the use of ICS should be limited to the minority of patients in whom the treatment effects outweigh the risks. | Observational studies using case-control designs have showed an increased risk of pneumonia associated with inhaled corticosteroid (ICS)-containing medications in patients with chronic obstructive pulmonary disease (COPD).,New-user observational cohort designs may minimize biases associated with previous case-control designs.,To estimate the association between ICS and pneumonia among new users of ICS relative to inhaled long-acting bronchodilator (LABD) monotherapy.,Pneumonia events in COPD patients ≥45 years old were compared among new users of ICS medications (n = 11,555; ICS, ICS/long-acting β2-agonist [LABA] combination) and inhaled LABD monotherapies (n = 6,492; LABA, long-acting muscarinic antagonists) using Cox proportional hazards models, with propensity scores to adjust for confounding.,Setting: United Kingdom electronic medical records with linked hospitalization and mortality data (2002-2010).,New users were censored at earliest of: pneumonia event, death, changing/discontinuing treatment, or end of follow-up.,Outcomes: severe pneumonia (primary) and any pneumonia (secondary).,Following adjustment, new use of ICS-containing medications was associated with an increased risk of pneumonia hospitalization (n = 322 events; HR = 1.55, 95% CI: 1.14, 2.10) and any pneumonia (n = 702 events; HR = 1.49, 95% CI: 1.22, 1.83).,Crude incidence rates of any pneumonia were 48.7 and 30.9 per 1000 person years among the ICS-containing and LABD cohorts, respectively.,Excess risk of pneumonia with ICS was reduced when requiring ≥1 month or ≥ 6 months of new use.,There was an apparent dose-related effect, with greater risk at higher daily doses of ICS.,There was evidence of channeling bias, with more severe patients prescribed ICS, for which the analysis may not have completely adjusted.,The results of this new-user cohort study are consistent with published findings; ICS were associated with a 20-50% increased risk of pneumonia in COPD, which reduced with exposure time.,This risk must be weighed against the benefits when prescribing ICS to patients with COPD. | 1 |
Given the heterogeneity of chronic obstructive pulmonary disease (COPD), personalized clinical management is key to optimizing patient outcomes.,Important treatment goals include minimizing disease activity and preventing disease progression; however, quantification of these components remains a challenge.,Growing evidence suggests that decline over time in forced expiratory volume in 1 s (FEV1), traditionally the key marker of disease progression, may not be sufficient to fully determine deterioration across COPD populations.,In addition, there is a lack of evidence showing that currently available multidimensional COPD indexes improve clinical decision-making, treatment, or patient outcomes.,The composite clinically important deterioration (CID) endpoint was developed to assess disease worsening by detecting early deteriorations in lung function (measured by FEV1), health status (assessed by the St George’s Respiratory Questionnaire), and the presence of exacerbations.,Post hoc and prospective analyses of clinical trial data have confirmed that the multidimensional composite CID endpoint better predicts poorer medium-term outcomes compared with any single CID component alone, and that it can demonstrate differences in treatment efficacy in short-term trials.,Given the widely acknowledged need for an individualized holistic approach to COPD management, monitoring short-term CID has the potential to facilitate early identification of suboptimal treatment responses and patients at risk of increased disease progression.,CID monitoring may lead to better-informed clinical management decisions and potentially improved prognosis. | The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD.,This is a prespecified analysis of the DYNAGITO data in Japanese patients.,Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months.,Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese.,The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations.,The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality.,Safety data were analyzed descriptively.,Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434).,The risk of a first moderate-to-severe COPD exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; p=0.1379), although this difference was not statistically significant.,The annualized rate of COPD exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; p=0.5654).,The adverse event incidence was balanced between treatment arms.,In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations.,Both treatments were well tolerated. | 1 |
There is a need to increase and maintain physical activity in patients with chronic obstructive pulmonary disease (COPD).,We assessed 12-month efficacy and effectiveness of the Urban Training intervention on physical activity in COPD patients.,This randomised controlled trial (NCT01897298) allocated 407 COPD patients from primary and hospital settings 1:1 to usual care (n=205) or Urban Training (n=202).,Urban Training consisted of a baseline motivational interview, advice to walk on urban trails designed for COPD patients in outdoor public spaces and other optional components for feedback, motivation, information and support (pedometer, calendar, physical activity brochure, website, phone text messages, walking groups and a phone number).,The primary outcome was 12-month change in steps·day−1 measured by accelerometer.,Efficacy analysis (with per-protocol analysis set, n=233 classified as adherent to the assigned intervention) showed adjusted (95% CI) 12-month difference +957 (184-1731) steps·day−1 between Urban Training and usual care.,Effectiveness analysis (with intention-to-treat analysis set, n=280 patients completing the study at 12 months including unwilling and self-reported non-adherent patients) showed no differences between groups.,Leg muscle pain during walks was more frequently reported in Urban Training than usual care, without differences in any of the other adverse events.,Urban Training, combining behavioural strategies with unsupervised outdoor walking, was efficacious in increasing physical activity after 12 months in COPD patients, with few safety concerns.,However, it was ineffective in the full population including unwilling and self-reported non-adherent patients.,Urban Training in COPD increased physical activity after 12 months but not in self-reported non-adherent patientshttp://ow.ly/dc2C30lnAEs | In patients with COPD progressive dyspnoea leads to a sedentary lifestyle.,To date, no studies exist investigating the effects of Nordic Walking in patients with COPD.,Therefore, the aim was to determine the feasibility of Nordic Walking in COPD patients at different disease stages.,Furthermore we aimed to determine the short- and long-term effects of Nordic Walking on COPD patients' daily physical activity pattern as well as on patients exercise capacity.,Sixty COPD patients were randomised to either Nordic Walking or to a control group.,Patients of the Nordic Walking group (n = 30; age: 62 ± 9 years; FEV1: 48 ± 19% predicted) underwent a three-month outdoor Nordic Walking exercise program consisting of one hour walking at 75% of their initial maximum heart rate three times per week, whereas controls had no exercise intervention.,Primary endpoint: daily physical activities (measured by a validated tri-axial accelerometer); secondary endpoint: functional exercise capacity (measured by the six-minute walking distance; 6MWD).,Assessment time points in both groups: baseline, after three, six and nine months.,After three month training period, in the Nordic Walking group time spent walking and standing as well as intensity of walking increased (Δ walking time: +14.9 ± 1.9 min/day; Δ standing time: +129 ± 26 min/day; Δ movement intensity: +0.40 ± 0.14 m/s2) while time spent sitting decreased (Δ sitting time: -128 ± 15 min/day) compared to baseline (all: p < 0.01) as well as compared to controls (all: p < 0.01).,Furthermore, 6MWD significantly increased compared to baseline (Δ 6MWD: +79 ± 28 meters) as well as compared to controls (both: p < 0.01).,These significant improvements were sustained six and nine months after baseline.,In contrast, controls showed unchanged daily physical activities and 6MWD compared to baseline for all time points.,Nordic Walking is a feasible, simple and effective physical training modality in COPD.,In addition, Nordic Walking has proven to positively impact the daily physical activity pattern of COPD patients under short- and long-term observation.,Nordic Walking improves daily physical activities in COPD: a randomised controlled trial - ISRCTN31525632 | 1 |
Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood.,Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease.,Genome-wide association studies in combination with expression profiling have identified a number of new candidates including IREB2.,A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility.,We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls.,Genotype information was obtained for seven SNPs in the IREB2 gene, and for four SNPs in the TGFbeta1 gene.,Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated.,The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre.,Our data replicate the association of IREB2 SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053.,No significant associations were identified for TGFbeta1.,These studies have therefore confirmed that the IREB2 locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis. | Genetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD).,Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies.,This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFα polymorphisms.,424 unrelated subjects of the PiZZ genotype were assessed for history of chronic bronchitis, impairment of lung function and radiological presence of emphysema and bronchiectasis.,A subset of subjects with 3 years consecutive lung function data was assessed for decline of lung function.,Four single nucleotide polymorphisms (SNPs) tagging TNFα were genotyped using TaqMan® genotyping technologies and compared between subjects affected by each phenotype and those unaffected.,Plasma TNFα levels were measured in all PiZZ subjects.,All SNPs were in Hardy-Weinberg equilibrium.,A significant difference in rs361525 genotype (p = 0.01) and allele (p = 0.01) frequency was seen between subjects with and without chronic bronchitis, independent of the presence of other phenotypes.,TNFα plasma level showed no phenotypic or genotypic associations.,Variation in TNFα is associated with chronic bronchitis in AATD. | 1 |
Plasma FABP4 levels were higher in females with COPD compared with both males with COPD and healthy females.,FABP4 levels correlated inversely with lung function, and positively with adiponectin and TNFα in COPD.,COPD (chronic obstructive pulmonary disease) is characterized by airway inflammation and increases the likelihood of the development of atherosclerosis.,Recent studies have indicated that FABP4 (fatty-acid-binding protein 4), an intracellular lipid chaperone of low molecular mass, plays an important role in the regulation of inflammation and atherosclerosis.,We carried out a preliminary clinical study aiming at investigating the relationships between circulating FABP4 levels in patients with COPD and inflammation and lung function.,We enrolled 50 COPD patients and 39 healthy controls in the study.,Lung function tests were performed in all subjects.,Plasma levels of FABP4 and adiponectin, TNFα (tumour necrosis factor α) and CRP (C-reactive protein) were measured.,The correlations between FABP4 and lung function, adipokine (adiponectin), inflammatory factors and BMI (body mass index) were analysed.,Compared with both males with COPD and healthy females, plasma FABP4 levels in females with COPD were significantly increased.,Adiponectin and CRP levels were significantly higher in patients with COPD.,Furthermore, we found that FABP4 levels were inversely correlated with FEV1% predicted (FEV1 is forced expiratory volume in 1 s) and positively correlated with adiponectin and TNFα in COPD patients.,In addition, a positive correlation between plasma FABP4 and CRP was found in females with COPD.,However, FABP4 levels were not correlated with BMI.,Our results underline a gender difference in FABP4 secretion in stable COPD patients.,Further studies are warranted to clarify the exact role of FABP4 in the pathogenesis of COPD. | Individuals with COPD have systemic inflammation that can be assessed by measuring C-reactive protein (CRP).,In this paper we evaluated whether CRP is related to COPD, lung function and rate of lung function decline.,We included 1237 randomly selected subjects (mean age 42, range 28-56 years) from three centers in the European Community Respiratory Health Survey: Reykjavik, Uppsala and Tartu.,CRP was measured at the end of the follow-up (mean 8.3 years) and the values were divided into 4 quartiles.,Fifty-three non-asthmatic subjects fulfilled spirometric criteria for COPD (FEV1/FVC < 70%).,COPD occurred more often in the 4th CRP quartile (OR (95% CI) 3.21 (1.13-9.08)) after adjustment for age, gender, body weight and smoking.,High CRP levels were related to lower FEV1 values in both men (−437 (−596, −279) mL) and women (−144 (−243, −44) mL).,The negative association between CRP and FEV1 was significantly larger in men than women (p = 0.04).,The decline in FEV1 was larger (16 (5, 27) mL) in men with high CRP levels whereas no significant association between CRP and FEV1 decline was found in women.,Higher CRP values are significantly associated with COPD and lower lung function in men and women.,In men higher CRP values are related to a larger decline in FEV1. | 1 |
HMGB1 is an alarmin, a protein that warns and activates inflammation.,Chronic obstructive pulmonary disease (COPD) is characterised by a progressive airflow obstruction and airway inflammation.,Current anti-inflammatory therapies are poorly effective in maintaining lung function and symptoms of COPD.,This underlines the need for finding new molecular targets involved in disease pathogenesis in order to block pathology progression.,This review aims to analyse latest advances on HMGB1 role, utilisation, and potential application in COPD.,To this purpose we reviewed experimental studies that investigated this alarmin as marker as well as a potential treatment in chronic obstructive pulmonary disease.,This systematic review was conducted according to PRISMA guidelines.,In almost all the studies, it emerged that HMGB1 levels are augmented in smokers and in patients affected by COPD.,It emerged that cigarette smoking, the most well-known causative factor of COPD, induces neutrophils death and necrosis.,The necrosis of neutrophil cells leads to HMGB1 release, which recruits other neutrophils in a self-maintaining process.,According to the results reported in the paper both inhibiting HMGB1 and its receptor (RAGE) and blocking neutrophils necrosis (inducted by cigarette smoking) could be the aim for further studies. | Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers.,We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers.,Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD.,To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing.,Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway.,In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers.,The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers.,These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers.,Strategies to normalize cilia length may be an important avenue for novel COPD therapies. | 1 |
Prescribing patterns in chronic obstructive pulmonary disease (COPD) are often inconsistent with published guidelines.,This retrospective, observational study utilised data from the Optimum Patient Care Research Database to examine the changes in COPD prescribing patterns over time and to identify predictors of physician treatment choice for patients newly diagnosed with COPD.,Initial therapy was defined as the treatment(s) prescribed at or within 1 year before COPD diagnosis.,Changes over time were assessed in three cohorts based on the date of diagnosis: (1) 1997-2001; (2) 2002-2006; and (3) 2007-2010.,Factors affecting the odds of being prescribed any initial therapy or any initial maintenance therapy were identified by univariable and multivariable logistic regression.,The analysis included 20,154 patients, 45% of whom were prescribed an initial regimen containing an inhaled corticosteroid (ICS), whereas 28% received no initial pharmacological treatment.,Prescribing of ICS monotherapy decreased over time, as did the proportion of patients receiving no therapy at or within 1 year before diagnosis.,Comorbid asthma, a high exacerbation rate, increased symptoms and poor lung function each increased the likelihood of being prescribed any initial therapy or initial maintenance therapy; comorbid asthma and an annual rate of ⩾3 exacerbations were the strongest predictors.,In conclusion, our analyses revealed major differences between actual prescribing behaviour and guideline recommendations for patients with newly diagnosed COPD, with many patients receiving no treatment and large numbers of patients receiving ICS-containing regimens.,Predictors of initial therapy were identified. | Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD.,Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk.,This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.,The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.,This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks.,The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.,Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively).,Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).,Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate.,Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. | 1 |
It is unclear whether cell culture methodology affects the corticosteroid sensitivity of chronic obstructive pulmonary disease (COPD) alveolar macrophages.,We compared the effect of a short and a long isolation procedure on corticosteroid inhibition of lipopolysaccharide (LPS) stimulated cytokine release from COPD alveolar macrophages.,We also investigated signalling pathways associated with macrophage activation during cell isolation.,Macrophages cultured using a short isolation protocol released higher unstimulated levels of tumour necrosis factor (TNF)-α and chemokine C-X-C motif ligand (CXCL) 8; these macrophages were less sensitive to corticosteroid inhibition of LPS stimulated TNF-α and CXCL8 release when compared to a long isolation procedure.,This was associated with increased p38 mitogen activated kinase (MAPK) activation.,The p38 MAPK inhibitor, BIRB-796, significantly reduced unstimulated cytokine release.,A key finding of this study was that both cell culture methods showed no difference in the corticosteroid sensitivity between COPD and control macrophages.,We conclude that the culture of alveolar macrophages using a short isolation procedure alters cytokine production through p38 MAPK activation; this is associated with a change in corticosteroid sensitivity. | We have previously reported that the lungs of patients with very severe chronic obstructive pulmonary disease (COPD) contain significantly higher numbers of alveolar macrophages than those of non-smokers or smokers.,M1 and M2 macrophages represent pro- and anti-inflammatory populations, respectively.,However, the roles of M1 and M2 alveolar macrophages in COPD remain unclear.,Immunohistochemical techniques were used to examine CD163, CD204 and CD206, as M2 markers, expressed on alveolar macrophages in the lungs of patients with mild to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (mild) n = 11, II (moderate) n = 9, III (severe) n = 2, and IV (very severe) n = 16).,Fifteen smokers and 10 non-smokers were also examined for comparison.,There were significantly higher numbers of alveolar macrophages in COPD patients than in smokers and non-smokers.,The numbers and percentages of CD163+, CD204+ or CD206+ alveolar macrophages in patients with COPD at GOLD stages III and IV were significantly higher than in those at GOLD stages I and II, and those in smokers and non-smokers.,In patients with COPD, there was a significant negative correlation between the number of CD163+, CD204+ or CD206+ alveolar macrophages and the predicted forced expiratory volume in one second.,Overexpression of CD163, CD204 and CD206 on lung alveolar macrophages may be involved in the pathogenesis of COPD. | 1 |
Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression.,A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs).,PQTLs consistently replicated between the two cohorts.,Features of pQTLs were compared to previously reported expression QTLs (eQTLs).,Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests.,We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested.,Most pQTL SNPs were novel with low overlap to eQTL SNPs.,The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC).,Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes.,Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins.,The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates.,Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema.,In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms.,Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group. | Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease.,In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer.,High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules).,Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema.,114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study.,Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ −950 HU, ≤ − 910 HU and mean lung attenuation at the 15th percentile on lung attenuation curve (LP15A).,Multiple regression analysis was performed to determine plasma biomarkers associated with emphysema independent of covariates age, gender, smoking status, body mass index and FEV1.,The findings were subsequently validated using baseline blood samples from a separate cohort of 388 subjects enrolled in the Treatment of Emphysema with a Selective Retinoid Agonist (TESRA) study.,Regression analysis identified multiple biomarkers associated with CT-assessed emphysema in COPDGene, including advanced glycosylation end-products receptor (AGER or RAGE, p < 0.001), intercellular adhesion molecule 1 (ICAM, p < 0.001), and chemokine ligand 20 (CCL20, p < 0.001).,Validation in the TESRA cohort revealed significant associations with RAGE, ICAM1, and CCL20 with radiologic emphysema (p < 0.001 after meta-analysis).,Other biomarkers that were associated with emphysema include CDH1, CDH 13 and SERPINA7, but were not available for validation in the TESRA study.,Receiver operating characteristics analysis demonstrated a benefit of adding a biomarker panel to clinical covariates for detecting emphysema, especially in those without severe airflow limitation (AUC 0.85).,Our findings, suggest that a panel of blood biomarkers including sRAGE, ICAM1 and CCL20 may serve as a useful surrogate measure of emphysema, and when combined with clinical covariates, may be useful clinically in predicting the presence of emphysema compared to just using covariates alone, especially in those with less severe COPD.,Ultimately biomarkers may shed light on disease pathogenesis, providing targets for new treatments.,The online version of this article (doi:10.1186/s12931-014-0127-9) contains supplementary material, which is available to authorized users. | 1 |
Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status versus monotherapy.,The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD.,This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (n = 1747).,Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis.,The primary endpoint was trough forced expiratory volume in 1 s (FEV1).,St George’s Respiratory Questionnaire (SGRQ) score, rescue medication use, and a novel composite endpoint of short-term clinically important deterioration (CID; ≥100 ml decrease in trough FEV1, ≥4-unit increase in SGRQ score, or a COPD exacerbation) were also assessed.,UMEC/VI improved trough FEV1 versus TIO at day 169 [least squares mean (95% confidence interval): MN: 146 ml (102-189) and ITT: 95 ml (71-118); both P < 0.001].,Both UMEC/VI and TIO improved SGRQ and rescue use in the two populations, with greater improvements in rescue use with UMEC/VI versus TIO.,UMEC/VI reduced the risk of short-term clinically important deterioration versus TIO [hazard ratio; 95% confidence interval: MN: 0.66 (0.51-0.85); ITT: 0.62 (0.54-0.71), both P ≤ 0.001].,Adverse events were similar across both populations and treatments.,Early use of dual-bronchodilator therapy has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to monotherapy in symptomatic patients with COPD.,Clinical trial registration: GSK analysis 202066 (NCT01316900/DB2113360, NCT01316913/DB2113374, NCT01777334/ZEP117115).,Funding: This study was funded by GSK.,The online version of this article (doi:10.1007/s12325-016-0430-6) contains supplementary material, which is available to authorized users. | Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis.,We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD.,The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.,This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations.,Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.,In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%).,The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001).,In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%).,UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).,This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods.,UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy. | 1 |
Physical activity limitation is common in chronic obstructive pulmonary disease (COPD), and is associated with worse health status, and increased hospitalisation and mortality.,Long-acting bronchodilators, either alone or in combination, have been shown to improve exercise intolerance.,However, none of these studies were designed with physical activity as primary outcome.,This study assessed the effect of indacaterol/glycopyrronium fixed dose combination (IND/GLY) 110/50 μg once daily (OD) versus placebo on lung hyperinflation (inspiratory capacity [IC]) and physical activity in patients with moderate-to-severe COPD.,In this multicentre, randomised, double-blind, placebo-controlled crossover study, patients received IND/GLY or placebo OD in two 21-day treatment periods (14-day washout between periods).,Eligible patients were ≥40 years of age, current or ex-smokers (smoking history ≥10 pack-years), with post-salbutamol forced expiratory volume in 1 s (FEV1) 40-80 % predicted, and FEV1:forced vital capacity <0.70.,The co-primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure.,Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day.,Peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days were other secondary endpoints.,A total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV1 61.6 % predicted), with 183 (94.3 %) completing the study.,Compared with placebo, IND/GLY significantly increased peak IC after 21 days (difference 202 mL, p < 0.0001), activity-related energy expenditure (difference 36.7 kcal/day, p = 0.040), and the average number of steps per day (difference 358, p = 0.029), with a trend towards an improvement in the duration of at least moderate activity (difference 4.4 min, p = 0.264).,IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days.,The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo.,In this study, compared with placebo, IND/GLY reduced hyperinflation, and, despite no patient education or lifestyle advice, improved daily physical activity levels.,This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD.,ClinicalTrials.gov number: NCT01996319.,The online version of this article (doi:10.1186/s12890-016-0256-7) contains supplementary material, which is available to authorized users. | Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations.,We hypothesized that short-acting β2-agonist (SABA) reliever use would predict short- and long-term exacerbation risk in COPD patients.,We performed a retrospective analysis of data from a study (ClinicalTrials.gov registration: NCT00419744) comparing budesonide/formoterol 320/9 μg with formoterol 9 μg (both twice daily) in patients with moderate-to-very-severe COPD; reliever salbutamol 90 μg was provided.,First occurrence of reliever use >4 (low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term (3-week) exacerbation risk.,Mean daily reliever use in the week preceding the 2-month visit was investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2-5, 6-9, and ≥10 inhalations/day.,Overall, 810 patients were included (61 % male; mean age 63.2 years; post-bronchodilator forced expiratory volume in 1 s 37.7 % of predicted).,First occurrence of low, medium, or high reliever use was predictive of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with increasing reliever use.,Mean reliever use over 1 week was predictive of long-term exacerbation risk.,Patients with mean use of 2-5, 6-9, and ≥10 inhalations/day exhibited 21 %, 67 %, and 135 % higher exacerbation rates, respectively, in the following 10 months, compared with <2 inhalations/day.,Budesonide/formoterol was associated with lower short- and long-term exacerbation risk than formoterol in all reliever-use groups.,SABA reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol. | 1 |
Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations.,The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract.,The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations.,In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD.,In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes.,This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans. | Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD).,We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD.,Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients.,Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models.,Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells.,None of the TLR4 SNPs was associated with FEV1 level.,Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time.,This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) are progressively limited in their ability to undertake normal everyday activities by a combination of exertional dyspnoea and peripheral muscle weakness.,COPD is characterised by expiratory flow limitation, resulting in air trapping and lung hyperinflation.,Hyperinflation increases acutely under conditions such as exercise or exacerbations, with an accompanying sharp increase in the intensity of dyspnoea to distressing and intolerable levels.,Air trapping, causing increased lung hyperinflation, can be present even in milder COPD during everyday activities.,The resulting activity-related dyspnoea leads to a vicious spiral of activity avoidance, physical deconditioning, and reduced quality of life, and has implications for the early development of comorbidities such as cardiovascular disease.,Various strategies exist to reduce hyperinflation, notably long-acting bronchodilator treatment (via reduction in flow limitation and improved lung emptying) and an exercise programme (via decreased respiratory rate, reducing ventilatory demand), or their combination.,Optimal bronchodilation can reduce exertional dyspnoea and increase a patient's ability to exercise, and improves the chance of successful outcome of a pulmonary rehabilitation programme.,There should be a lower threshold for initiating treatments appropriate to the stage of the disease, such as long-acting bronchodilators and an exercise programme for patients with mild-to-moderate disease who experience persistent dyspnoea. | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
Endothelial cell specific molecule-1, also called as endocan, is a dermatan sulfate proteoglycan, which is expressed by endothelial cells in alveolar walls of the lung and kidney.,High endocan levels are found associated with endothelial dysfunction and inflammation.,We hypothesize that endocan level is also high in COPD due to systemic inflammation and endothelial dysfunction.,We aimed to investigate the expression of endocan in patients with stable COPD.,The study included patients with COPD and control subjects.,COPD patients were classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 criteria.,Demographics, body mass index, smoking history, and comorbidities were recorded.,Endocan levels of COPD patients and controls were compared.,Totally, 88 subjects (47 stable COPD patients, 41 controls) were evaluated.,Endocan levels were significantly higher in COPD patients than control group (860.1±259.8 vs 647.3±316.9 pg/mL, P=0.001).,There was no relationship between GOLD COPD categories and endocan levels.,Also endocan levels were similar between COPD patients with or without hypoxemia.,Serum endocan level was significantly higher in patients with stable COPD.,Further studies should be performed to better understand the relationship between endocan and COPD. | MicroRNAs (MiRNA) are small non-coding RNAs that regulate gene expression.,The aim of this study was to identify miRNAs differentially expressed between mild and moderately emphysematous lung, as well as their functional target mRNAs.,Resected lung from patients with COPD undergoing lung cancer surgery was profiled using miRNA (Agilent Human miRNA profiler G4470 V1.01) and mRNA (OperonV2.0) microarrays.,Cells of lung origin (BEAS-2B and HFL1) were profiled using mRNA microarrays (Illumina HumanHT-12 V3) after in vitro manipulation.,COPD patients had mean (SD) age 68 (6) years, FEV1 72 (17)% predicted and gas transfer (KCO) 70 (10)% predicted.,Five miRNAs (miR-34c, miR-34b, miR-149, miR-133a and miR-133b) were significantly down-regulated in lung from patients with moderate compared to mild emphysema as defined by gas transfer (p < 0.01).,In vitro upregulation of miR-34c in respiratory cells led to down-regulation of predicted target mRNAs, including SERPINE1, MAP4K4, ZNF3, ALDOA and HNF4A.,The fold change in ex-vivo expression of all five predicted target genes inversely correlated with that of miR-34c in emphysematous lung, but this relationship was strongest for SERPINE1 (p = 0.05).,Differences in miRNA expression are associated with emphysema severity in COPD patients.,MiR-34c modulates expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue. | 1 |
Changes in extracellular matrix (ECM) components in the lungs are associated with the progression of respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).,Experimental and clinical studies have revealed that structural changes in ECM components occur under chronic inflammatory conditions, and these changes are associated with impaired lung function.,In bronchial asthma, elastic and collagen fiber remodeling, mostly in the airway walls, is associated with an increase in mucus secretion, leading to airway hyperreactivity.,In COPD, changes in collagen subtypes I and III and elastin, interfere with the mechanical properties of the lungs, and are believed to play a pivotal role in decreased lung elasticity, during emphysema progression.,In ARDS, interstitial edema is often accompanied by excessive deposition of fibronectin and collagen subtypes I and III, which can lead to respiratory failure in the intensive care unit.,This review uses experimental models and human studies to describe how inflammatory conditions and ECM remodeling contribute to the loss of lung function in these respiratory diseases. | The expression and localization of transforming growth factor-β (TGF-β) pathway proteins in different compartments of the lower airways of patients with stable COPD is unclear.,We aimed to determine TGF-β pathway protein expression in patients with stable COPD.,The expression and localization of TGF-β pathway components was measured in the bronchial mucosa and peripheral lungs of patients with stable COPD (n = 44), control smokers with normal lung function (n = 24), and control nonsmoking subjects (n = 11) using immunohistochemical analysis.,TGF-β1, TGF-β3, and connective tissue growth factor expression were significantly decreased in the bronchiolar epithelium, with TGF-β1 also decreased in alveolar macrophages, in patients with stable COPD compared with control smokers with normal lung function.,TGF-β3 expression was increased in the bronchial lamina propria of both control smokers with normal lung function and smokers with mild/moderate stable COPD compared with control nonsmokers and correlated significantly with pack-years of smoking.,However, TGF-β3+ cells decreased in patients with severe/very severe COPD compared with control smokers.,Latent TGF-β binding protein 1 expression was increased in the bronchial lamina propria in subjects with stable COPD of all severities compared with control smokers with normal lung function.,Bone morphogenetic protein and activin membrane-bound inhibitor expression (BAMBI) in the bronchial mucosa was significantly increased in patients with stable COPD of all severities compared with control subjects.,No other significant differences were observed between groups for all the other molecules studied in the bronchial mucosa and peripheral lung.,Expression of TGF-βs and their regulatory proteins is distinct within different lower airway compartments in stable COPD.,Selective reduction in TGF-β1 and enhanced BAMBI expression may be associated with the increase in autoimmunity in COPD. | 1 |
Pulmonary rehabilitation (PR) is an effective intervention for the management of people with chronic obstructive pulmonary disease (COPD).,However, available resources are often limited, and many patients bear with poor availability of programmes.,Sustaining PR benefits and regular exercise over the long term is difficult without any exercise maintenance strategy.,In contrast to traditional centre-based PR programmes, telerehabilitation may promote more effective integration of exercise routines into daily life over the longer term and broaden its applicability and availability.,A few studies showed promising results for telerehabilitation, but mostly with short-term interventions.,The aim of this study is to compare long-term telerehabilitation with unsupervised exercise training at home and with standard care.,An international multicentre randomised controlled trial conducted across sites in three countries will recruit 120 patients with COPD.,Participants will be randomly assigned to telerehabilitation, treadmill and control, and followed up for 2 years.,The telerehabilitation intervention consists of individualised exercise training at home on a treadmill, telemonitoring by a physiotherapist via videoconferencing using a tablet computer, and self-management via a customised website.,Patients in the treadmill arm are provided with a treadmill only to perform unsupervised exercise training at home.,Patients in the control arm are offered standard care.,The primary outcome is the combined number of hospitalisations and emergency department presentations.,Secondary outcomes include changes in health status, quality of life, anxiety and depression, self-efficacy, subjective impression of change, physical performance, level of physical activity, and personal experiences in telerehabilitation.,This trial will provide evidence on whether long-term telerehabilitation represents a cost-effective strategy for the follow-up of patients with COPD.,The delivery of telerehabilitation services will also broaden the availability of PR and maintenance strategies, especially to those living in remote areas and with no access to centre-based exercise programmes.,ClinicalTrials.gov: NCT02258646.,The online version of this article (doi:10.1186/s12890-016-0288-z) contains supplementary material, which is available to authorized users. | An essential element in the treatment of patients with chronic obstructive pulmonary disease (COPD) is rehabilitation, of which supervised training is an important part.,However, not all individuals with severe COPD can participate in the rehabilitation provided by hospitals and municipal training centres due to distance to the training venues and transportation difficulties.,The aim of the study was to assess the feasibility of an individualized home-based training and counselling programme via video conference to patients with severe COPD after hospitalization including assessment of safety, clinical outcomes, patients’ perceptions, organisational aspects and economic aspects.,The design was a pre- and post-test intervention study.,Fifty patients with severe COPD were included.,The telemedicine training and counselling included three weekly supervised exercise sessions by a physiotherapist and up to two supervised counselling and training sessions in energy conservation techniques by an occupational therapist.,The telemedicine videoconferencing equipment was a computer containing a screen, a microphone, an on/off switch and a volume control.,Thirty seven (74%) participants completed the programme, with improvements in health status assessed by the Clinical COPD Questionnaire and physical performance assessed by a sit-to-stand test and a timed-up-and-go test.,There were no cases of patient fall or emergency contact with a general practitioner during the telemedicine training sessions.,The study participants believed the telemedicine training and counselling was essential for getting started with being physically active in a secure manner.,The business case showed that under the current financing system, the reimbursement to the hospital was slightly higher than the hospital expenditures.,Thus, the business case for the hospital was positive.,The organizational analysis indicated that the perceptions of the staff were that the telemedicine service had improved the continuity of the rehabilitation programme for the patients and enabled the patients’ everyday lives to be included in the treatment.,This study showed that home-based supervised training and counselling via video conference is safe and feasible and that telemedicine can help to ensure more equitable access to supervised training in patients with severe COPD.,Clinical Trials NCT02085187 (Date of registration 10.03.2014). | 1 |
Chronic obstructive pulmonary disease (COPD), one of the most common chronic diseases and a leading cause of death, has historically been considered a disease of men.,However, there has been a rapid increase in the prevalence, morbidity, and mortality of COPD in women over the last two decades.,This has largely been attributed to historical increases in tobacco consumption among women.,But the influence of sex on COPD is complex and involves several other factors, including differential susceptibility to the effects of tobacco, anatomic, hormonal, and behavioral differences, and differential response to therapy.,Interestingly, nonsmokers with COPD are more likely to be women.,In addition, women with COPD are more likely to have a chronic bronchitis phenotype, suffer from less cardiovascular comorbidity, have more concomitant depression and osteoporosis, and have a better outcome with acute exacerbations.,Women historically have had lower mortality with COPD, but this is changing as well.,There are also differences in how men and women respond to different therapies.,Despite the changing face of COPD, care providers continue to harbor a sex bias, leading to underdiagnosis and delayed diagnosis of COPD in women.,In this review, we present the current knowledge on the influence of sex on COPD risk factors, epidemiology, diagnosis, comorbidities, treatment, and outcomes, and how this knowledge may be applied to improve clinical practices and advance research. | The impact of COPD on patient’s quality of life is well established, but gender differences have received little attention.,To describe factors associated with the health-related quality of life by gender: A cross-sectional observational study (NCT01007734) was conducted in COPD patients followed by pulmonologists.,The first patient included had to be a woman.,Data concerning the patient, COPD and their management were collected by the physician.,The patient had to fill in several questionnaires: Saint-George Hospital respiratory Questionnaire (SGRQ-C), and motivation to quit smoking.,Four hundred and thirty patients were included: mean age 63.9 ± 11.3 years; 57.4% were women.,Women were significantly younger than men (61.9 vs.,66.6) and their tobacco use was lower (37.1 vs.,40.4 PY).,Cardiovascular comorbidities were more frequent in men while osteoporosis, anxiety and depression were frequent in women.,The frequency of cough, sputum and the severity of dyspnea did not differ significantly between genders.,Lung function impairment was less severe in women than in men (mean FEV1 52% predicted normal vs.,47.,8%).,Anxiety score was higher (score 9.8 vs.,7.1) and quality of life (SGRQ-C) more impaired in women (scores 50.6 vs.,45.4; p < 0.02) than in men.,Moreover, in multivariate analysis, chronic sputum was associated with higher SGRQ-C scores in women but not in men.,This study underlines that despite less airflow limitation, quality of life is more impacted by chronic sputum in women than in men. | 1 |
There is a growing interest to use health status or disease control questionnaires in routine clinical practice.,However, the validity of most questionnaires is established using techniques developed for group level validation.,This study examines a new method, using patient interviews, to validate a short health status questionnaire, the Clinical COPD Questionnaire (CCQ), at the individual patient level.,Patients with COPD who visited an outpatient clinic completed the CCQ before the consultation, and the specialist physician completed it after the consultation.,After the consultation all patients had a semi-structured in-depth interview.,The patients' CCQ scores were compared with those of the treating clinician, and with mean scores from 5 clinicians from a pool of 20 who scored the CCQ after reading the transcript of the in-depth interviews only.,Agreement was assessed using Lin's concordance correlation coefficient (CCC), and Blant and Altman plots.,Interviews with patients with low agreement were reviewed for possible explanations.,A total of 44 COPD patients (32 male, mean age 66 years, FEV1 45% of predicted) participated.,Agreement between the patients' CCQ scores and those of the treating clinicians (CCC = 0.87) and the mean score of the reviewing clinicians (CCC = 0.86) was very high.,No systematic error was detected.,No explanation for individuals with low agreement was found.,The validity of the CCQ on the individual patient level, as assessed by these methods, is good.,Individual health status assessment with the CCQ is therefore sufficiently accurate to be used in routine clinical practice. | The Visual Simplified Respiratory Questionnaire (VSRQ) was designed to assess health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD).,It contains eight items: dyspnea, anxiety, depressed mood, sleep, energy, daily activities, social activities and sexual life.,Psychometric properties were assessed during a clinical trial that evaluated the impact of tiotropium on HRQoL of COPD patients.,These included the determination of structure, internal consistency reliability, concurrent validity with the St George’s Respiratory Questionnaire (SGRQ), test - retest reliability, clinical validity and responsiveness to change over two weeks.,Minimal important difference (MID) was calculated; cumulative response curves (CRC) were based on the dyspnea item.,Psychometric analyses showed that VSRQ structure was unidimensional.,The questionnaire demonstrated good internal consistency reliability (Cronbach’s alpha = 0.84), good concurrent validity with SGRQ (Spearman = −0.70) and clinical validity, good test-retest reproducibility (ICC = 0.77), and satisfactory responsiveness (standardized response mean = 0.57; Guyatt’s statistic = 0.63).,MID was 3.4; CRC median value of the ‘minimally improved’ patients was 3.5.,In conclusion, VSRQ brevity and satisfactory psychometric properties make it a good candidate for large studies to assess HRQoL in COPD patients.,Further validation is needed to extend its use in clinical practice. | 1 |
The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment.,The effect of this combination on symptoms of COPD and exacerbations is less well established.,We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).,Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®.,Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed.,The pooled intent-to-treat population included 3394 patients.,Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05).,Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05).,The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05).,Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies.,Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01).,Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD.,Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo.,NCT01462942 and NCT01437397 (ClinicalTrials.gov),The online version of this article (doi:10.1186/s12931-015-0250-2) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations.,This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).,We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers.,In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.,COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function.,Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage.,The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study.,The distribution of these variables within each GOLD stage was wide.,Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation.,The amount of emphysema increased with GOLD severity.,The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage.,Some gender differences were also identified.,The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease. | 1 |
Chronic obstructive pulmonary disease (COPD) is a severe public health threat world-wide.,Cigarette smoke (CS)-induced airway epithelial cell death is a major pathway of pathogenesis in emphysema, a subtype of COPD.,Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that catalyzes mono- and di-methylation on arginine residues within histone and non-histone proteins to modulate a variety of life processes, such as apoptosis.,However, its role in CS-induced lung epithelial death has not been fully elucidated.,Here we report that PRMT6 was decreased in mouse lung tissues from a cigarette smoke extract (CSE)-mediated experimental emphysematous model and in CSE treated or cigarette smoke exposed lung epithelial cells.,Depletion of PRMT6 increased the protein levels of phosphatase PTEN and PI3K regulatory subunit p85 but decreased a downstream kinase PDK1, resulting in AKT dephosphorylation and thereafter, lung epithelial cell death.,Knockout of PRMT6 inhibited epithelial survival and promoted CSE-mediated epithelial cell death, while ectopic expression of PRMT6 protein partially reversed epithelial cell death via PI3K/AKT-mediated cell survival signaling in CSE cellular models.,These findings demonstrate that PRMT6 plays a crucial role in CS-induced bronchial epithelial cell death that may be a potential therapeutic target against the airway cell death in CS-induced COPD. | COPD is a leading cause of morbidity and mortality, characterized by a chronic abnormal inflammatory response to noxious agents.,Apoptosis is a physiologic process, critical to cellular homeostasis, in which cell death follows a programmed sequence of events.,Apoptosis has been recognized to play an important role in clinical and experimental models of lung diseases.,Abnormal apoptotic events in smokers’ and in emphysematous lungs have been shown in epithelial and endothelial lung cells, neutrophils, lymphocytes, and myocytes.,Many factors associated with COPD, including cigarette smoke, have the potential to cause apoptosis of alveolar epithelial cells, the main sites of vascular endothelial growth factor (VEGF) production.,The decreased expression of VEGF, a known survival factor for endothelial cells, and its receptor, results in lung septal endothelial cell death, leading perhaps to the emphysema observed in COPD.,In smokers who develop COPD there is an activation of adaptive immunity, with an infiltration of CD4+ and, especially, CD8 + cells.,CD8 + cells are cytotoxic to epithelial cells through the release of granzymes and perforin, which can further induce apoptosis of alveolar cells.,Moreover, any reduction in neutrophil apoptosis or dysregulation of macrophage uptake of apoptotic neutrophils could lead to chronic inflammation and tissue injury.,Increased rates of T-cell apoptosis may lead to a defective immune response to infective organisms, contributing to the high frequency of infections seen in COPD.,Increased apoptosis of skeletal muscle could be responsible for the skeletal muscle atrophy, the main cause of unexplained weight loss in patients with COPD.,This paper is a review of the current knowledge on the apoptotic pathways involved in COPD pathogenesis and their interaction with other known contributing factors. | 1 |
Chronic obstructive pulmonary disease (COPD) exacerbations are associated with lung function decline, lower quality of life, and increased mortality, and can be prevented by pharmacological treatment and rehabilitation.,To examine management including examination, treatment, and planned follow-up of COPD exacerbation visits in primary care patients and to explore how measures and management at exacerbation visits are related to subsequent exacerbation risk.,A clinical population of 775 COPD patients was randomly selected from 56 Swedish primary healthcare centres.,Data on patient characteristics and management of COPD exacerbations were obtained from medical record review and a patient questionnaire.,In the study population of 458 patients with at least one exacerbation, Cox regression analyses estimated the risk of a subsequent exacerbation with adjustment for age and sex.,During a follow-up period of 22 months, 238 patients (52%) had a second exacerbation.,A considerable proportion of the patients were not examined and treated as recommended by guidelines.,Patients with a scheduled extra visit to an asthma/COPD nurse following an exacerbation had a decreased risk of further exacerbations compared with patients with no extra follow-up other than regularly scheduled visits (adjusted hazard ratio 0.60 (95% confidence interval 0.37 to 0.99), p=0.045).,Guidelines for examination and emergency treatment at COPD exacerbation visits are not well implemented.,Scheduling an extra visit to an asthma/COPD nurse following a COPD exacerbation may be associated with a decreased risk of further exacerbations in primary care patients. | Clinical care components for people with COPD are recommended in guidelines if high-level evidence exists.,However, there are gaps in their implementation, and factors which act as barriers or facilitators to their uptake are not well described.,The aim of this pilot study was to explore implementation of key high-evidence COPD guideline recommendations in patients admitted to hospital with a disease exacerbation, to inform the development of a larger observational study.,This study recruited consecutive COPD patients admitted to a tertiary hospital.,Patient demographic, disease and admission characteristics were recorded.,Information about implementation of target guideline recommendations (smoking cessation, pulmonary rehabilitation referral, influenza vaccination, medication use and long-term oxygen use if hypoxaemic) was gained from medical records and patient interviews.,Interviews with hospital-based doctors examined their perspectives on recommendation implementation.,Fifteen patients (aged 76(9) years, FEV1%pred 58(15), mean(SD)) and nine doctors participated.,Referral to pulmonary rehabilitation (5/15 patients) was underutilised by comparison with other high-evidence recommendations.,Low awareness of pulmonary rehabilitation was a key barrier for patients and doctors.,Other barriers for patients were access difficulties, low perceived health benefits, and co-morbidities.,Doctors reported they tended to refer patients with severe disease and frequent hospital attendance, a finding supported by the quantitative data.,This study provides justification for a larger observational study to test the hypothesis that pulmonary rehabilitation referral is low in suitable COPD patients, and closer investigation of the reasons for this evidence-practice gap. | 1 |
Quality-of-life (QoL) scores in chronic obstructive pulmonary disease (COPD) have a weak relationship with physiologic impairment.,We investigated factors associated with poor QoL, focusing on psychological measures potentially amenable to intervention.,We utilized a pre-existing Birmingham (UK) COPD cohort to assess factors associated with QoL impairment (COPD Assessment Test [CAT] scores).,Univariate and multivariate regression models were constructed from three categories of variables: demographic, lung function/COPD-related symptoms, and psychosocial/behavioral factors.,Analyses were based on self-report questionnaire data from 735 participants.,The multivariate model of variables independently associated with CAT included depression, dysfunctional breathing symptoms (Nijmegen score), and illness perception, in addition to COPD symptoms (wheeze, cough), exercise capacity, breathlessness, exacerbations, and deprivation; this model explained 72% of CAT score variation.,In a dominance analysis assessing the relative contribution of variables, similar contributions were made by breathlessness (20.2%), illness perception (19.8%), dysfunctional breathing symptoms (17.5%), and depression (12.5%) with other variables contributing <5%.,Psychological factors significantly contribute to disease-specific QoL impairment in COPD, and potentially explain the mismatch between objective physiologic impairment and patients’ experience of their disease.,Interventions targeting psychological factors, illness perception, and dysfunctional breathing should be assessed. | Quadriceps muscle phenotype varies widely between patients with chronic obstructive pulmonary disease (COPD) and cannot be determined without muscle biopsy.,We hypothesised that measures of skeletal muscle adiposity could provide noninvasive biomarkers of muscle quality in this population.,In 101 patients and 10 age-matched healthy controls, mid-thigh cross-sectional area, percentage intramuscular fat and skeletal muscle attenuation were calculated using computed tomography images and standard tissue attenuation ranges: fat -190- -30 HU; skeletal muscle -29-150 HU.,Mean±sd percentage intramuscular fat was higher in the patient group (6.7±3.5% versus 4.3±1.2%, p = 0.03).,Both percentage intramuscular fat and skeletal muscle attenuation were associated with physical activity level, exercise capacity and type I fibre proportion, independent of age, mid-thigh cross-sectional area and quadriceps strength.,Combined with transfer factor of the lung for carbon monoxide, these variables could identify >80% of patients with fibre type shift with >65% specificity (area under the curve 0.83, 95% CI 0.72-0.95).,Skeletal muscle adiposity assessed by computed tomography reflects multiple aspects of COPD related muscle dysfunction and may help to identify patients for trials of interventions targeted at specific muscle phenotypes.,CT-based skeletal muscle adiposity markers reflect muscle quality in COPD and help identify patients with fibre shifthttp://ow.ly/xolWA | 1 |
Increasing evidence suggests that human antigen R (HuR) is involved in the epithelial-mesenchymal transition (EMT) process of several diseases.,However, the role of HuR in EMT in the airway epithelial cells of patients with COPD remains unclear.,BEAS-2B cells were cultured and treated with 3%CSE.,Western blotting, RT-PCR and immunofluoresence were used to detect the expression of HuR, ZEB-1.,RNAi was used to suppress HuR expression.,Then knockdown of HuR, RT-PCR and Western blotting showed that with siHuR-1 and siHuR-3, clear suppression of HuR expression was confirmed.,We chose siHuR-3, the most effective one, to proceed with subsequent experiments.,Immunofluorescence analysis, western blotting were used to detect the expression of E-cadherin, vimentin, ZEB-1 and HuR.,We show that more HuR expression is enhanced in the airways epithelium of smokers with or without COPD than controls (nonsmoker non-COPD patients).,However, there was no definite correlation between HuR expression and FEV1%.,Further study reveals that knockdown of HuR significantly increases the apoptosis of BEAS-2B cells and down-regulates ZEB-1 expression.,EMT is partially enhanced through the HuR-binding proteins and its post-transcriptional regulation role in airway epithelium in COPD. | Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD).,However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear.,Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD.,These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung.,They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury.,This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD.,In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients. | 1 |
Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions.,It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020.,The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality.,Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines.,On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function.,Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes.,On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals.,The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus.,Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease.,Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems. | Nowadays, there is increasing awareness about the frequent chronic comorbidities in patients with chronic obstructive pulmonary disease (COPD) but little information is available to quantify the burden of illness that these conditions cause in this population.,We aimed to identify and describe a population suffering from COPD highlighting the co-morbid conditions that may contribute to poor clinical outcomes.,Epidemiological cross-sectional study conducted using administrative heath services databases.,A cohort of 126,283 COPD patients was identified.,The estimated prevalence in adult population was 3.6%.,Ninety-eight percent of these patients (123,603) received at least one prescription of “non-respiratory drugs” and, considering chronic specific comorbidities (cardiovascular disease, diabetes and depression) 86,351 patients (68.4% of COPD patients) suffered from at least one of these conditions. 80,840 pts (64.4%) were treated for cardiovascular diseases, 17,091 subjects for diabetes (12.4%) and 10,292 for depression (8%).,About 16% of COPD subjects (19,168 patients) had two out of the three considered comorbid conditions and 1352 patients (1.1%) all three.,This study highlights the complex spectrum of comorbidities in COPD patients.,The prevalence of main chronic diseases increases with age, in particular among female group.,An enhanced public awareness about these conditions is necessary, just as a more comprehensive approach in their management. | 1 |
This study is aimed at investigating the relationship between red cell distribution width (RDW) and chronic obstructive pulmonary disease (COPD) patients with pulmonary embolism (PE).,We conducted a retrospective study enrolling a total of 125 patients from January 2013 to December 2019.,The study group consisted of 40 COPD patients with PE, and the control group had 85 COPD patients without PE.,Clinical data including demographic characteristics, comorbidities, and results of imaging examinations and laboratory tests were recorded.,Blood biomarkers, including red blood cell distribution width standard deviation (RDW-SD), red blood cell distribution width coefficient of variation (RDW-CV), and D-Dimer, were included.,RDW-SD and RDW-CV were higher in the COPD patients with the PE group (p < 0.001).,A higher RDW-SD led to a significantly increased risk of PE than a lower RDW-SD (adjusted odds ratio (OR): 1.188; 95% confidence interval (CI): 1.048-1.348).,The area under the curve (AUC) of RDW-SD used for predicting PE was 0.737.,Using 44.55 as the cutoff value of RDW-SD, the sensitivity was 80% and the specificity was 64.7%.,The prediction accuracy of RDW-SD combined with D-Dimer (AUC = 0.897) was higher than that of RDW-SD or D-Dimer alone.,The optimal cutoff value of RDW-SD+D-Dimer for predicting PE was 0.266, which generated a sensitivity of 87.5% and specificity of 83.5%.,RDW is significantly increased in COPD patients with PE and may thus be useful in predicting the occurrence of PE in patients with COPD. | Chronic obstructive pulmonary disease (COPD), a major cause of death and morbidity worldwide, is characterized by expiratory airflow limitation that is not fully reversible, deregulated chronic inflammation, and emphysematous destruction of the lungs.,Despite the fact that COPD is a steadily growing global healthcare problem, the conventional therapies remain palliative, and regenerative approaches for disease management are not available yet.,We aim to provide an overview of key reviews, experimental, and clinical studies addressing lung emphysema development and repair mechanisms published in the past decade.,Novel aspects discussed herein include integral revision of the literature focused on lung microflora changes in COPD, autoimmune component of the disease, and environmental risk factors other than cigarette smoke.,The time span of studies on COPD, including emphysema, chronic bronchitis, and asthmatic bronchitis, covers almost 200 years, and several crucial mechanisms of COPD pathogenesis are described and studied.,However, we still lack the holistic understanding of COPD development and the exact picture of the time-course and interplay of the events during stable, exacerbated, corticosteroid-treated COPD states, and transitions in-between.,Several generally recognized mechanisms will be discussed shortly herein, ie, unregulated inflammation, proteolysis/antiproteolysis imbalance, and destroyed repair mechanisms, while novel topics such as deviated microbiota, air pollutants-related damage, and autoimmune process within the lung tissue will be discussed more extensively.,Considerable influx of new data from the clinic, in vivo and in vitro studies stimulate to search for novel concise explanation and holistic understanding of COPD nowadays. | 1 |
Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD).,Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology.,We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.,Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined.,Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD.,Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.,Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression.,Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR.,ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased.,Healthy smokers were intermediate between healthy nonsmokers and patients with COPD.,Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects.,MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release.,Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation.,Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. | Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide.,Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.,The objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation.,Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β.,Here, we demonstrate an underappreciated role for IL-1α expression in COPD.,While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure.,As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation.,IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.,This study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD. | 1 |
Identifying patients at risk of exacerbations and managing them appropriately to reduce this risk represents an important clinical challenge.,Numerous treatments have been assessed for the prevention of exacerbations and their efficacy may differ by patient phenotype.,Given their centrality in the treatment of COPD, there is strong rationale for maximizing bronchodilation as an initial strategy to reduce exacerbation risk irrespective of patient phenotype.,Therefore, in patients assessed as frequent exacerbators (>1 exacerbation/year) we propose initial bronchodilator treatment with a long-acting muscarinic antagonist (LAMA)/ long-acting β2-agonist (LABA).,For those patients who continue to experience >1 exacerbation/year despite maximal bronchodilation, we advocate treating according to patient phenotype.,Based on currently available data on adding inhaled corticosteroids (ICS) to a LABA, ICS might be added to a LABA/LAMA combination in exacerbating patients who have an asthma-COPD overlap syndrome or high blood eosinophil counts, while in exacerbators with chronic bronchitis, consideration should be given to treating with a phosphodiesterase (PDE)-4 inhibitor (roflumilast) or high-dose mucolytic agents.,For those patients who experience frequent bacterial exacerbations and/or bronchiectasis, addition of mucolytic agents or a macrolide antibiotic (e.g. azithromycin) should be considered.,In all patients at risk of exacerbations, pulmonary rehabilitation should be included as part of a comprehensive management plan.,The online version of this article (doi:10.1186/s12931-016-0425-5) contains supplementary material, which is available to authorized users. | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
Spiromax® is a novel dry-powder inhaler containing formulations of budesonide plus formoterol (BF).,The device is intended to provide dose equivalence with enhanced user-friendliness compared to BF Turbuhaler® in asthma and chronic obstructive pulmonary disease (COPD).,The present study was performed to compare inhalation parameters with empty versions of the two devices, and to investigate the effects of enhanced training designed to encourage faster inhalation.,This randomised, open-label, cross-over study included children with asthma (n = 23), adolescents with asthma (n = 27), adults with asthma (n = 50), adults with COPD (n = 50) and healthy adult volunteers (n = 50).,Inhalation manoeuvres were recorded with each device after training with the patient information leaflet (PIL) and after enhanced training using an In-Check Dial device.,After PIL training, peak inspiratory flow (PIF), maximum change in pressure (∆P) and the inhalation volume (IV) were significantly higher with Spiromax than with the Turbuhaler device (p values were at least <0.05 in all patient groups).,After enhanced training, numerically or significantly higher values for PIF, ∆P, IV and acceleration remained with Spiromax versus Turbuhaler, except for ∆P in COPD patients.,After PIL training, one adult asthma patient and one COPD patient inhaled <30 L/min through the Spiromax compared to one adult asthma patient and five COPD patients with the Turbuhaler.,All patients achieved PIF values of at least 30 L/min after enhanced training.,The two inhalers have similar resistance so inhalation flows and pressure changes would be expected to be similar.,The higher flow-related values noted for Spiromax versus Turbuhaler after PIL training suggest that Spiromax might have human factor advantages in real-world use.,After enhanced training, the flow-related differences between devices persisted; increased flow rates were achieved with both devices, and all patients achieved the minimal flow required for adequate drug delivery.,Enhanced training could be useful, especially in COPD patients. | Guideline recommendations for chronic obstructive pulmonary disease (COPD) are based on the results of large pharmaceutically-sponsored COPD studies (LPCS).,There is a paucity of data on disease characteristics at the primary care level, while the majority of COPD patients are treated in primary care.,We aimed to evaluate the external validity of six LPCS (ISOLDE, TRISTAN, TORCH, UPLIFT, ECLIPSE, POET-COPD) on which current guidelines are based, in relation to primary care COPD patients, in order to inform future clinical practice guidelines and trials.,Baseline data of seven primary care databases (n = 3508) from Europe were compared to baseline data of the LPCS.,In addition, we examined the proportion of primary care patients eligible to participate in the LPCS, based on inclusion criteria.,Overall, patients included in the LPCS were younger (mean difference (MD)-2.4; p = 0.03), predominantly male (MD 12.4; p = 0.1) with worse lung function (FEV1% MD -16.4; p<0.01) and worse quality of life scores (SGRQ MD 15.8; p = 0.01).,There were large differences in GOLD stage distribution compared to primary care patients.,Mean exacerbation rates were higher in LPCS, with an overrepresentation of patients with ≥1 and ≥2 exacerbations, although results were not statistically significant.,Our findings add to the literature, as we revealed hitherto unknown GOLD I exacerbation characteristics, showing 34% of mild patients had ≥1 exacerbations per year and 12% had ≥2 exacerbations per year.,The proportion of primary care patients eligible for inclusion in LPCS ranged from 17% (TRISTAN) to 42% (ECLIPSE, UPLIFT).,Primary care COPD patients stand out from patients enrolled in LPCS in terms of gender, lung function, quality of life and exacerbations.,More research is needed to determine the effect of pharmacological treatment in mild to moderate patients.,We encourage future guideline makers to involve primary care populations in their recommendations. | 1 |
Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities.,They are both reversible electrophiles and peroxisome proliferator-activated receptor γ (PPARγ) agonists, but the physiological implications of their electrophilic activity are poorly understood.,We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice.,NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-κB while upregulating those of PPARγ.,It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction.,Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction.,NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARγ knockout mice, pointing to a PPARγ-independent mechanism of enzyme inhibition.,We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S.,These results demonstrate that NFAs’ electrophilic activity, in addition to their role as PPARγ agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease. | There is a need for novel anti-inflammatory therapies to treat COPD.,The liver X receptor (LXR) is a nuclear hormone receptor with anti-inflammatory properties.,We investigated LXR gene and protein expression levels in alveolar macrophages and whole lung tissue from COPD patients and controls, the effect of LXR activation on the suppression of inflammatory mediators from LPS stimulated COPD alveolar macrophages, and the effect of LXR activation on the induction of genes associated with alternative macrophage polarisation.,The levels of LXR mRNA were significantly increased in whole lung tissue extracts in COPD patients and smokers compared to non-smokers.,The expression of LXR protein was significantly increased in small airway epithelium and alveolar epithelium in COPD patients compared to controls.,No differences in LXR mRNA and protein levels were observed in alveolar macrophages between patient groups.,The LXR agonist GW3965 significantly induced the expression of the LXR dependent genes ABCA1 and ABCG1 in alveolar macrophage cultures.,In LPS stimulated alveolar macrophages, GW3965 suppressed the production of CXCL10 and CCL5, whilst stimulating IL-10 production.,GW3965 did not significantly suppress the production of TNFα, IL-1β, or CXCL8.,Our major finding is that LXR activation has anti-inflammatory effects on CXC10, CCL5 and IL-10 production from alveolar macrophages. | 1 |
Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes.,Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown.,We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome.,This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations.,Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo.,The primary end point was mean in-hospital blood glucose concentration.,Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool.,52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo).,All were included in the primary end point analysis.,The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference −0.9 mmol/L, 95% CI −2.1 to +0.3; p=0.273).,No significant between-group differences were observed on any of the secondary end points.,Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants.,Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes.,ISRCTN66148745 and NCT01247870. | Caveolae are vesicular invaginations of the plasma membrane.,Caveolin-1 is the structural protein component of caveolae.,Caveolin-1 participates in signal transduction processes by acting as a scaffolding protein that concentrates, organizes and functional regulates signaling molecules within caveolar membranes.,Cigarette smoke, a source of oxidants, is an environmental hazard that causes pulmonary emphysema.,Recently, we reported that the development of cigarette smoking-induced pulmonary emphysema was inhibited in caveolin-1 null mice, which do not express caveolin-1.,We demonstrated that lack of caveolin-1 expression in lung fibroblasts dramatically inhibited premature senescence induced by oxidants contained in cigarette smoke.,Mechanistically, we uncovered that premature senescence of lung fibroblasts induced by oxidative stress occurred through activation of an ataxia telangiectasia-mutated (ATM)/p53-depedent pathway following sequestration of the catalytic subunit of protein phosphatase 2A (PP2A-C), an inhibitor of ATM, by caveolin-1 into caveolar membranes.,We propose caveolin-1 as a key player of a novel signaling pathway that links cigarette smoke to premature senescence of lung fibroblasts and development of pulmonary emphysema. | 1 |
Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD).,The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation.,The role of SIRT1/FoxO3 in COPD is largely unknown.,This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway epithelial pro‐inflammatory responses.,Human bronchial epithelial cells (16HBE) and primary bronchial epithelial cells (PBECs) from COPD patients and controls were treated with/without cigarette smoke extract (CSE), Sirtinol or FoxO3 siRNA.,SIRT1, FoxO3 and NF‐κB nuclear accumulation, SIRT1 deacetylase activity, IL‐8 and CCL20 expression/release and the release of 12 cytokines, neutrophil and lymphocyte chemotaxis were assessed.,In PBECs, the constitutive FoxO3 expression was lower in patients with COPD than in controls.,Furthermore, CSE reduced FoxO3 expression only in PBECs from controls.,In 16HBE, CSE decreased SIRT1 activity and nuclear expression, enhanced NF‐κB binding to the IL‐8 gene promoter thus increasing IL‐8 expression, decreased CCL20 expression, increased the neutrophil chemotaxis and decreased lymphocyte chemotaxis.,Similarly, SIRT1 inhibition reduced FoxO3 expression and increased nuclear NF‐κB.,FoxO3 siRNA treatment increased IL‐8 and decreased CCL20 expression in 16HBE.,In conclusion, CSE impairs the function of SIRT1/FoxO3 axis in bronchial epithelium, dysregulating NF‐κB activity and inducing pro‐inflammatory responses. | Studies have suggested that histone modification has a positive impact on various aspects associated with the progression of COPD.,Histone deacetylase 2 (HDAC2) suppresses proinflammatory gene expression through deacetylation of core histones.,To investigate the effect of histone modification on the expression of chemokines in type II alveolar epithelial cells (AEC II) in a rat COPD model and regulation of HDAC2 expression by curcumin in comparison with corticosteroid.,The rat COPD model was established by cigarette smoke exposure and confirmed by histology and pathophysioloy.,AEC II were isolated and cultured in vitro from the COPD models and control animals.,The cells were treated with curcumin, corticosteroid, or trichostatin A, and messenger RNA (mRNA) expression of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2α (MIP-2α) was assessed by quantitative real-time polymerase chain reaction (RT-PCR).,The expression of HDAC2 was measured by Western blot.,Chromatin immunoprecipitation was used to detect H3/H4 acetylation and H3K9 methylation in the promoter region of three kinds of chemokine genes (IL-8, MCP-1, and MIP-2α).,Compared to the control group, the mRNAs of MCP-1, IL-8, and MIP-2α were upregulated 4.48-fold, 3.14-fold, and 2.83-fold, respectively, in the AEC II from COPD model.,The protein expression of HDAC2 in the AEC II from COPD model was significantly lower than from the control group (P<0.05).,The decreased expression of HDAC2 was negatively correlated with the increased expression of IL-8, MCP-1, and MIP-2α mRNAs (all P<0.05).,The level of H3/H4 acetylation was higher but H3K9 methylation in the promoter region of chemokine genes was lower in the cells from COPD model than from the control group (all P<0.05).,Curcumin downregulated the expression of MCP-1, IL-8, and MIP-2α, and the expression was further enhanced in the presence of corticosteroid.,Moreover, curcumin restored HDAC2 expression, decreased the levels of H3/H4 acetylation, and increased H3K9 methylation in the promoter region of chemokine in the presence or absence of dexamethasone (all P<0.05).,Curcumin may suppress chemokines and restore corticosteroid resistance in COPD through modulating HDAC2 expression and its effect on histone modification. | 1 |
The purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor.,Two healthy volunteer, randomized, double-blind, placebo-controlled studies were conducted.,In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period.,In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 µg or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 µg or placebo once daily (OD).,In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 µg or placebo; Part 2, 1,200, 2,000, or 2,400 µg twice daily (BID) or placebo.,Modeling and simulation then compared OD and BID dosing via MDDPI.,There was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI.,CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0-24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0-12 h in Study 2.,Bioavailability waŝ30% higher with MDDPI than SDDPI.,The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration.,CHF6001 was well tolerated with no relationship between dose and adverse events.,CHF6001 demonstrated a good safety profile.,There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition.,BID dosing was associated with a better exposure profile. | COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow.,It is mainly associated with exposure to cigarette smoke.,In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide.,Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells.,Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways.,The aims of these molecules are differentiation, proliferation and recruitment of neutrophils.,Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight.,In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract.,Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity. | 1 |
Sarcopenia is characterized by a progressive and generalized decrease of strength and muscle mass.,Muscle mass loss is prevalent in patients with chronic obstructive pulmonary disease (COPD) as a result of both the disease and aging.,Some methods have been proposed to assess body composition (and therefore identify muscle mass loss) in this population.,Despite the high accuracy of some methods, they require sophisticated and costly equipment.,The purpose of this study was to infer the occurrence of muscle mass loss measured by a sophisticated method (dual energy X-ray absorptiometry [DEXA]) using a more simple and affordable equipment (dynamometer).,Fifty-seven stable subjects with COPD were evaluated for anthropometric characteristics, lung function, functional exercise capacity, body composition, and peripheral muscle strength.,A binary logistic regression model verified whether knee-extension strength (measured by dynamometry) could infer muscle mass loss (from DEXA).,Patients with decreased knee-extension strength were 5.93 times more likely to have muscle mass loss, regardless of sex, disease stage, and functional exercise capacity (P=0.045).,Knee-extension dynamometry was able to infer muscle mass loss in patients with COPD. | Decreased physical activity is associated with higher mortality in subjects with COPD.,The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.,Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV1%) predicted values of 43 ± 16 were included.,The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR).,TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry.,Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics.,Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.,The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary.,The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m2, identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted.,The regression model explained 45.5% (p < 0.001) of the variance in PAL.,The FEV1% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%).,Neither age, gender nor systemic inflammation contributed to the model.,Apart from lung function, walking speed and muscle strength are important correlates of physical activity.,Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted. | 1 |
Nutritional status is a well-recognized prognostic indicator in chronic obstructive pulmonary disease (COPD); however, very little is known about the relationship between lung function and saturated fat intake.,We used data from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) to assess the relationship between saturated fatty acid (SFA) intake and lung function in the general US adult population.,Adults in NHANES (2007-2012) with pre-bronchodilator spirometry measurements and dietary SFA intake were included.,Primary outcomes were lung function including forced expiratory volume in one second (FEV1), FEV1, forced vital capacity (FVC), FEV1/FVC ratio, percent predicted FEV1 and percent predicted FVC.,Multivariable regression models in the general population as well as those with spirometry-defined airflow obstruction were used to assess the relationship between lung function measurements and dietary SFA intake after adjustment for confounders. 11,180 eligible participants were included in this study.,Univariate analysis revealed a statistically significant positive association between total SFA intake and lung function outcomes; however, these relationships were attenuated after adjustment for covariates.,A secondary analysis of individuals with spirometry-defined airflow obstruction (FEV1/FVC < 0.7) revealed that a lower intake of SFA was associated with reduced FEV1 (β = −126.4, p = 0.04 for quartile 1 vs. quartile 4), FVC (β = −165.8. p = 0.01 for quartile 1 vs. quartile 4), and percent predicted FVC (β = −3.3. p = 0.04 for quartile 1 vs. quartile 4), after adjustment for relevant confounders.,No associations were observed for the FEV1/FVC ratio and percent predicted FEV1.,It is possible that characteristics such as food source and fatty acid chain length may influence associations between saturated fatty acid intake and health outcomes. | The obesity paradox in COPD describes protective effects of obesity on lung pathology and inflammation.,However, the underlying relationships between obesity, diet and disease outcomes in COPD are not fully understood.,In this study we measured the response to dietary fatty acids upon markers of inflammation and remodelling in human lung cells from people with and without COPD.,Pulmonary fibroblasts were challenged with ω-3 polyunsaturated fatty acids (PUFAs), ω-6 PUFAs, saturated fatty acids (SFAs) or the obesity-associated cytokine TNFα.,After 48-72 h release of the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8 was measured using ELISA and mRNA expression and deposition of the extracellular matrix (ECM) proteins fibronectin, type I collagen, tenascin and perlecan were measured using qPCR or ECM ELISA, respectively.,Challenge with the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, resulted in increased IL-6 and CXCL8 release from fibroblasts, however IL-6 and CXCL8 release was reduced in COPD (n = 19) compared to non-COPD (n = 36).,AA-induced cytokine release was partially mediated by downstream mediators of cyclooxygenase (COX)-2 in both COPD and non-COPD.,In comparison, TNFα-induced IL-6 and CXCL8 release was similar in COPD and non-COPD, indicating a specific interaction of AA in COPD.,In patients with or without COPD, regression analysis revealed no relationship between BMI and cytokine release.,In addition, AA, but not SFAs or ω-3 PUFAs reduced the basal deposition of fibronectin, type I collagen, tenascin and perlecan into the ECM in COPD fibroblasts.,In non-COPD fibroblasts, AA-challenge decreased basal deposition of type I collagen and perlecan, but not fibronectin and tenascin.,This study shows that AA has disease-specific effects on inflammation and ECM protein deposition.,The impaired response to AA in COPD might in part explain why obesity appears to have less detrimental effects in COPD, compared to other lung diseases.,The online version of this article (10.1186/s12931-018-0919-4) contains supplementary material, which is available to authorized users. | 1 |
The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined.,In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥30 L/min.,This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials.,The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients.,This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population.,Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations.,A total of 1460 (207608/207609) and 3282 (KPNW) patients were included.,There was considerable overlap between spirometric PIF distributions for both populations.,Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥50 L/min, estimated as equivalent to ELLIPTA PIFR ≥30 L/min.,In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF.,Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥30 L/min through the ELLIPTA DPI.,Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities. | Adequate peak inspiratory flow rate (PIFR) is required for drug dispersion with dry powder inhalers (DPIs).,Prevalence of PIFR discordance (suboptimal PIFR with prescribed inhalers) and factors influencing device-specific PIFR are unclear in COPD.,The objective of this study was to determine the prevalence of PIFR discordance and associated clinical factors in a stable COPD population.,An observational, single-center, cohort study was conducted including 66 outpatients with COPD.,PIFR was measured using the In-Check™ Dial with applied resistance of prescribed inhalers.,Participants were defined as discordant if measured PIFR was <30 L/min and <60 L/min for high and low-medium resistance devices, respectively, using an inspiratory effort the participant normally used with their prescribed DPI.,The median age of the COPD participants was 69.4 years, 92% were white and 47% were female.,A total of 48% were using low-medium resistance DPIs (Diskus®/Ellipta®) and 76% used high-resistance DPI (Handihaler®).,A total of 40% of COPD participants were discordant to prescribed inhalers.,Female gender was the only factor consistently associated with lower PIFR.,Shorter height was associated with reduced PIFR for low-medium resistance (r=0.44; P=0.01), but not high resistance (r=0.20; P=0.16).,There was no correlation between PIFR by In-Check™ dial and PIFR measured by standard spirometer.,PIFR is reduced in stable COPD patients, with female gender being the only factor consistently associated with reduced PIFR.,Discordance with prescribed inhalers was seen in 40% of COPD patients, suggesting that many COPD patients do not generate adequate inspiratory force to overcome prescribed DPIs resistance in the course of normal use. | 1 |
To estimate the incidence of pneumonia by COPD status and the excess cost of inpatient primary pneumonia in elders with COPD.,A retrospective, longitudinal study using claims linked to eligibility/demographic data for a 5% sample of fee-for-service Medicare beneficiaries from 2005 through 2007.,Incidence rates of pneumonia were calculated for elders with and without COPD and for elders with COPD and coexistent congestive heart failure (CHF).,Propensity-score matching with multivariate generalized linear regression was used to estimate the excess direct medical cost of inpatient primary pneumonia in elders with COPD as compared with elders with COPD but without a pneumonia hospitalization.,Elders with COPD had nearly six-times the incidence of pneumonia compared with elders without COPD (167.6/1000 person-years versus 29.5/1000 person-years; RR=5.7, p <0 .01); RR increased to 8.1 for elders with COPD and CHF compared with elders without COPD.,The incidence of inpatient primary pneumonia among elders with COPD was 54.2/1000 person-years compared with 7/1000 person-years for elders without COPD; RR=7.7, p<0.01); RR increased to 11.0 for elders with COPD and CHF compared with elders without COPD.,The one-year excess direct medical cost of inpatient pneumonia in COPD patients was $ 22,697 ($45,456 in cases vs. $ 22,759 in controls (p <0.01)); 70.2% of this cost was accrued during the quarter of the index hospitalization.,During months 13 through 24 following the index hospitalization, the excess direct medical cost was $ 5,941 ($23,215 in cases vs. $ 17,274 in controls, p<0.01).,Pneumonia occurs more frequently in elders with COPD than without COPD.,The excess direct medical cost in elders with inpatient pneumonia extends up to 24 months following the index hospitalization and represents $28,638 in 2010 dollars. | Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients.,Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype.,This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes.,These patients are therefore a priority for research and treatment.,The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection.,Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment.,Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype.,This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.,The online version of this article (doi:10.1186/1741-7015-11-181) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide.,The study aimed to determine and compare the prevalence of COPD in the general population aged 45-74 years old according to fixed ratio and lower limit of normal (LLN) thresholds in four cities in the Southern Cone of Latin America.,The Pulmonary Risk in South America (PRISA) study used a 4-stage stratified sampling method to select 5814 participants from 4 cities in the Southern Cone of Latin America (Bariloche and Marcos Paz, Argentina; Temuco, Chile; and Pando-Barros Blancos, Uruguay).,Data on demographic information, medical history, risk factors, pre-bronchodilator and post-bronchodilator spirometry were obtained using a standard protocol.,According to GOLD, COPD was defined as a post-bronchodilator ratio of forced expiratory volume in one second (FEV1) over forced vital capacity (FVC) less than 70%.,The LLN threshold was defined as the lower fifth percentile for predicted FEV1/FVC, and was evaluated as an alternative COPD definition.,Overall COPD prevalence was 9.3% (95% CI 8.4, 10.2%), and men had a higher prevalence [11.8% (95% CI 10.3, 13.3%)] than women [7.3% (95% CI 6.2, 8.3%)] with the fixed ratio.,Overall COPD prevalence using LLN was 4.7% (95% CI 4.1, 5.3%), higher in men: 5.8% (95% CI 4.7, 6.8%) than women: 3.9% (95% CI 3.1, 4.7%).,COPD prevalence was significantly higher among those who were older, had <high-school education and lower body-mass index, were cigarette smokers, and had self-reported history of asthma and tuberculosis.,First, COPD and its risk factors are highly prevalent in the general population of Argentina, Chile, and Uruguay.,Second, the prevalence of COPD by LLN criterion was significantly lower with lesser degrees of severity compared to fixed ratio of FEV1/FVC.,Implementing LLN criterion instead of fixed ratio of FEV1/FVC may reduce the risk of over-diagnosis of COPD, although further prognostic studies of COPD adverse outcomes should be conducted using both definitions.,Third, these data suggest that national efforts on the prevention, treatment, and control of COPD should be a public health priority in the Southern Cone of Latin America.,The online version of this article (10.1186/s12890-017-0537-9) contains supplementary material, which is available to authorized users. | Consistent estimation of the burden of chronic obstructive pulmonary disease (COPD) has been hindered by differences in methods, including different spirometric cut-offs for impaired lung function.,The impact of different definitions on the prevalence of potential airflow obstruction, and its associations with key risk factors, is evaluated using cross-sectional data from two nationally representative population surveys.,Pooled cross-sectional analysis of Wave 2 of the UK Household Longitudinal Survey and the Health Survey for England 2010, including 7879 participants, aged 40-95 years, who lived in England and Wales, without diagnosed asthma and with good-quality spirometry data.,Potential airflow obstruction was defined using self-reported physician-diagnosed COPD; a fixed threshold (FT) forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7 and an age-specific, sex-specific, height-specific and ethnic-specific lower limit of normal (LLN).,Standardised questions elicited self-reported information on demography, smoking history, ethnicity, occupation, respiratory symptoms and cardiovascular disease.,Consistent across definitions, participants classed with obstructed airflow were more likely to be older, currently smoke, have higher pack-years of smoking and be engaged in routine occupations.,The prevalence of airflow obstruction was 2.8% (95% CI 2.3% to 3.2%), 22.2% (21.2% to 23.2%) and 13.1% (12.2% to 13.9%) according to diagnosed COPD, FT and LLN, respectively.,The gap in prevalence between FT and LLN increased in older age groups.,Sex differences in the risk of obstruction, after adjustment for key risk factors, was sensitive to the choice of spirometric cut-off, being significantly higher in men when using FT, compared with no significant difference using LLN.,Applying FT or LLN spirometric cut-offs gives a different picture of the size and distribution of the disease burden.,Longitudinal studies examining differences in unscheduled hospital admissions and risk of death between FT and LLN may inform the choice as to the best way to include spirometry in assessments of airflow obstruction. | 1 |
Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century.,The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD.,Our understanding of the key molecular mechanisms which drive the pathological changes are not complete.,In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation.,We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations.,We discuss the need to specifically target SAD to attenuate the progression of COPD. | Transforming growth factor-beta1 (TGF-β1) is a multipotential cytokine with angiogenic activity.,There are only limited data about its role in airway remodeling in COPD.,We have previously shown that the reticular basement membrane (Rbm) is hypervascular in the airways of current smokers either with or without chronic obstructive pulmonary disease (COPD).,This study evaluated TGF-β1 immunostaining in the Rbm and its relationship to vascularity in smokers with or without COPD.,Bronchial biopsies from 15 smokers with normal lung function, 19 current and 14 ex-smokers with COPD were immunostained for TGF-β1 antibody and compared to 17 healthy controls.,The percentage area of tissue and also number and area of vessels staining positively for TGF-β1 were measured and compared between groups.,Some bronchial biopsies from current smoking COPD subjects were also stained for phosphorylated (active) Smad2/3.,Epithelial TGF- β1 staining was not different between COPD current smokers and normal controls.,TGF-β1 stained vessels in the Rbm were increased in smokers with normal lung function, current smoking COPD and ex-smokers with COPD compared to controls [median (range) for number of vessels/mm Rbm 2.5 (0.0-12.7), 3.4 (0.0-8.1) and 1.0 (0.0-6.3) vs.,0.0 (0.0-7.0), p<0.05].,Percentage of vessels stained was also increased in these clinical groups.,Preliminary data suggest that in current smoking COPD subjects endothelial cells and cells in the Rbm stain positively for phosphorylated Smad2/3 suggesting TGF-β1 is functionally active in this situation.,Vessel-associated TGF-β1 activity is increased in the bronchial Rbm in smokers and especially those with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the main contributors to the global burden of disease.,The aim of this systematic review was to quantify the disease burden of COPD in China and to determine the risk factors of the disease.,The number of studies included in the review was 47 with an average quality assessment score of 7.70 out of 10.,Reported COPD prevalence varied between 1.20% and 8.87% in different provinces/cities across China.,The prevalence rate of COPD was higher among men (7.76%) than women (4.07%).,The disease was more prevalent in rural areas (7.62%) than in urban areas (6.09%).,The diagnostic rate of COPD patients in China varied from 23.61% to 30.00%.,The percentage of COPD patients receiving outpatient treatment was around 50%, while the admission rate ranged between 8.78% and 35.60%.,Tobacco exposure and biomass fuel/solid fuel usage were documented as two important risk factors of COPD.,COPD ranked among the top three leading causes of death in China.,The direct medical cost of COPD ranged from 72 to 3,565 USD per capita per year, accounting for 33.33% to 118.09% of local average annual income.,The most commonly used scales for the assessment of quality of life (QoL) included Saint George Respiratory Questionnaire, Airways Questionnaire 20, SF-36, and their revised versions.,The status of QoL was worse among COPD patients than in non-COPD patients, and COPD patients were at higher risks of depression.,The COPD burden in China was high in terms of economic burden and QoL.,In view of the high smoking rate and considerable concerns related to air pollution and smog in China, countermeasures need to be taken to improve disease prevention and management to reduce disease burdens raised by COPD. | Twenty per cent of chronic obstructive pulmonary disease (COPD) patients are readmitted for acute exacerbation (AECOPD) within 30 days of discharge.,The prognostic significance of early readmission is not fully understood.,The objective of our study was to estimate the mortality risk associated with readmission for acute exacerbation within 30 days of discharge in COPD patients.,The cohort (n = 378) was divided into patients readmitted (n = 68) and not readmitted (n = 310) within 30 days of discharge.,Clinical, laboratory, microbiological, and severity data were evaluated at admission and during hospital stay, and mortality data were recorded at four time points during follow-up: 30 days, 6 months, 1 year and 3 years.,Patients readmitted within 30 days had poorer lung function, worse dyspnea perception and higher clinical severity.,Two or more prior AECOPD (HR, 2.47; 95% CI, 1.51-4.05) was the only variable independently associated with 30-day readmission.,The mortality risk during the follow-up period showed a progressive increase in patients readmitted within 30 days in comparison to patients not readmitted; moreover, 30-day readmission was an independent risk factor for mortality at 1 year (HR, 2.48; 95% CI, 1.10-5.59).,In patients readmitted within 30 days, the estimated absolute increase in the mortality risk was 4% at 30 days (number needed to harm NNH, 25), 17% at 6-months (NNH, 6), 19% at 1-year (NNH, 6) and 24% at 3 years (NNH, 5).,In conclusion a readmission for AECOPD within 30 days is associated with a progressive increased long-term risk of death. | 1 |
Vitronectin, a multifunctional glycoprotein, is involved in coagulation, inhibition of the formation of the membrane attack complex (MAC), cell adhesion and migration, wound healing, and tissue remodeling.,The primary cellular source of vitronectin is hepatocytes; it is not known whether resident cells of airways produce vitronectin, even though the glycoprotein has been found in exhaled breath condensate and bronchoalveolar lavage from healthy subjects and patients with interstitial lung disease.,It is also not known whether vitronectin expression is altered in subjects with asthma and COPD.,In this study, bronchial tissue from 7 asthmatic, 10 COPD and 14 control subjects was obtained at autopsy and analyzed by immunohistochemistry to determine the percent area of submucosal glands occupied by vitronectin.,In a separate set of experiments, quantitative colocalization analysis was performed on tracheobronchial tissue sections obtained from donor lungs (6 asthmatics, 4 COPD and 7 controls).,Vitronectin RNA and protein expressions in bronchial surface epithelium were examined in 12 subjects who undertook diagnostic bronchoscopy.,Vitronectin was found in the tracheobronchial epithelium from asthmatic, COPD, and control subjects, although its expression was significantly lower in the asthmatic group.,Colocalization analysis of 3D confocal images indicates that vitronectin is expressed in the glandular serous epithelial cells and in respiratory surface epithelial cells other than goblet cells.,Expression of the 65-kDa vitronectin isoform was lower in bronchial surface epithelium from the diseased subjects.,The cause for the decreased vitronectin expression in asthma is not clear, however, the reduced concentration of vitronectin in the epithelial/submucosal layer of airways may be linked to airway remodeling. | An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use.,Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear.,We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB.,Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected.,Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205-2.762]) were independent risk factors for TB.,Among the COPD cases, those who developed TB received more oral corticosteroids and oral β-agonists.,Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral β-agonist dose, but not ICS dose, were independent risk factors for TB.,The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios.,Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications.,Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice. | 1 |
To describe the characteristics and prognosis of patients with COPD admitted to the hospital due to SARS-CoV-2 infection.,The SEMI-COVID registry is an ongoing retrospective cohort comprising consecutive COVID-19 patients hospitalized in Spain since the beginning of the pandemic in March 2020.,Data on demographics, clinical characteristics, comorbidities, laboratory tests, radiology, treatment, and progress are collected.,Patients with COPD were selected and compared to patients without COPD.,Factors associated with a poor prognosis were analyzed.,Of the 10,420 patients included in the SEMI-COVID registry as of May 21, 2020, 746 (7.16%) had a diagnosis of COPD.,Patients with COPD are older than those without COPD (77 years vs 68 years) and more frequently male.,They have more comorbidities (hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, ischemic heart disease, peripheral vascular disease, kidney failure) and a higher Charlson Comorbidity Index (2 vs 1, p<0.001).,The mortality rate in COPD patients was 38.3% compared to 19.2% in patients without COPD (p<0.001).,Male sex, a history of hypertension, heart failure, moderate-severe chronic kidney disease, presence of cerebrovascular disease with sequelae, degenerative neurological disease, dementia, functional dependence, and a higher Charlson Comorbidity Index have been associated with increased mortality due to COVID-19 in COPD patients.,Survival was higher among patients with COPD who were treated with hydroxychloroquine (87.1% vs 74.9%, p<0.001) and with macrolides (57.9% vs 50%, p<0.037).,Neither prone positioning nor non-invasive mechanical ventilation, high-flow nasal cannula, or invasive mechanical ventilation were associated with a better prognosis.,COPD patients admitted to the hospital with SARS-CoV-2 infection have more severe disease and a worse prognosis than non-COPD patients. | Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities.,The main cause is smoking tobacco, but other factors have been identified.,Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli.,The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both.,Comorbidities include ischaemic heart disease, diabetes, and lung cancer.,Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids).,Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification.,Future research should be directed towards the development of agents that notably affect the course of disease. | 1 |
Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers.,We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers.,Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD.,To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing.,Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway.,In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers.,The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers.,These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers.,Strategies to normalize cilia length may be an important avenue for novel COPD therapies. | Since the early 1960s, a compelling body of evidence has accumulated to show that proteinases play critical roles in airspace enlargement in chronic obstructive pulmonary disease (COPD).,However, until recently the causative enzymes and their exact roles in pathologic processes in COPD have not been clear.,Recent studies of gene-targeted mice in murine models of COPD have confirmed roles for proteinases not only in airspace enlargement, but also in airway pathologies in COPD.,These studies have also shed light on the specific proteinases involved in COPD pathogenesis, and the mechanisms by which these proteinases injure the lung.,They have also identified important interactions between different classes of proteinases, and between proteinases and other molecules that amplify lung inflammation and injury.,This review will discuss the biology of proteinases and the mechanisms by which they contribute to the pathogenesis of COPD.,In addition, I will discuss the potential of proteinase inhibitors and anti-inflammatory drugs as new treatment strategies for COPD patients. | 1 |
The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a).,The genetic ablation of p66Shc (p66Shc-/-) renders mice resistant to oxidative stress and p53-dependent apoptosis.,We investigated whether p66Shc ablation in mice modifies lung cellular and molecular responses to cigarette smoke (CS) exposure.,No differences between wild type (WT) and p66Shc-/- mice were observed in terms of inflammation and oxidant burden after acute CS exposure; however,p66Shc ablation modifies specific features of chronic inflammation induced by repeated exposure to CS.,Unlike WT mice, p66Shc-/- mice did not develop emphysema, showing protection toward oxidative damage to DNA and apoptosis as revealed by a trivial 8-hydroxyguanosine staining and faint TUNEL and caspase-3 positivity on alveolar epithelial cells.,Unexpectedly, CS exposure in p66Shc-/- mice resulted in respiratory bronchiolitis with fibrosis in surrounded alveoli.,Respiratory bronchiolitis was characterized by peribronchiolar infiltrates of lymphocytes and histiocytes, accumulation of ageing pigmented macrophages within and around bronchioles, and peribronchiolar fibrosis.,The blockage of apoptosis interferes with the macrophage “clearance” from alveolar spaces, favouring the accumulation of aging macrophages into alveoli and the progressive accumulation of iron pigment in long-lived senescent cells.,The presence of areas of interstitial and alveolar fibrosis in peripheral parenchyma often accompanied the bronchiolar changes.,Macrophages from smoking p66Shc-/- mice elaborate M2 cytokines (i.e., IL-4 and IL-13) and enzymes (i.e., chitinase and arginase I), which can promote TGF-beta expression, collagen deposition, and fibrosis in the surrounding areas.,We demonstrate here that resistance to oxidative stress and p53-dependent apoptosis can modify tissue responses to CS caused by chronic inflammation without influencing early inflammatory response to CS exposure. | Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD).,We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls.,This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD.,To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects.,Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable.,The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects.,Rbm fragmentation correlated with smoking history in COPD but not with age.,There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05).,The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004).,In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02).,Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall.,Rbm fragmentation was also present to as great an extent in ex-smokers with COPD.,These characteristics may have potential physiological consequences. | 1 |
Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression.,Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns.,We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways.,We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.,Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach.,To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario.,We used muscle dysfunction and co-morbidity as test cases for this framework.,In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models.,This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions.,In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations.,We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model.,In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.,The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models.,Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them. | A key prerequisite for precision medicine is the estimation of disease progression from the current patient state.,Disease correlations and temporal disease progression (trajectories) have mainly been analysed with focus on a small number of diseases or using large-scale approaches without time consideration, exceeding a few years.,So far, no large-scale studies have focused on defining a comprehensive set of disease trajectories.,Here we present a discovery-driven analysis of temporal disease progression patterns using data from an electronic health registry covering the whole population of Denmark.,We use the entire spectrum of diseases and convert 14.9 years of registry data on 6.2 million patients into 1,171 significant trajectories.,We group these into patterns centred on a small number of key diagnoses such as chronic obstructive pulmonary disease (COPD) and gout, which are central to disease progression and hence important to diagnose early to mitigate the risk of adverse outcomes.,We suggest such trajectory analyses may be useful for predicting and preventing future diseases of individual patients.,Population-wide analyses of healthcare data are challenging and thus often involve only few diseases or comparatively short time scales.,Here the authors use healthcare records of all hospital encounters in Denmark over 15 years to describe how disease diagnoses progress over time. | 1 |
Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia.,Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth.,We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.,We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).,COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions.,Fatty acid oxidation capacity was reduced under unstimulated conditions.,TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate.,In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels.,Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.,Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.,A metabolic shift in airway smooth muscle cells of COPD patients may support their increased growth and survivalhttp://ow.ly/XVkb30eUTLJ | Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US and a major worldwide healthcare problem.,The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood.,While tobacco smoking is the primary risk factor, other disease processes also appear to play a role.,Components of the innate immune system (eg, macrophages and neutrophils) have long been believed to be important in the development of COPD.,More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease.,Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses.,We will further explore the prospective contributions of T-cell derived mediators that could contribute to the inflammation, alveolar wall destruction, and small airway fibrosis of advanced COPD.,A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies. | 1 |
Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies.,To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).,Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years.,We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation.,Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs.,0.9 (1.1) per year, p<0.001) compared to non-inflamed ones.,As a descriptive study our results show associations but do not prove causality.,Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.,Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment. | Inhaled corticosteroids (ICS) reduce COPD exacerbation frequency and slow decline in health related quality of life but have little effect on lung function, do not reduce mortality, and increase the risk of pneumonia.,We systematically reviewed trials in which ICS have been withdrawn from patients with COPD, with the aim of determining the effect of withdrawal, understanding the differing results between trials, and making recommendations for improving methodology in future trials where medication is withdrawn.,Trials were identified by two independent reviewers using MEDLINE, EMBASE and CINAHL, citations of identified studies were checked, and experts contacted to identify further studies.,Data extraction was completed independently by two reviewers.,The methodological quality of each trial was determined by assessing possible sources of systematic bias as recommended by the Cochrane collaboration.,We included four trials; the quality of three was adequate.,In all trials, outcomes were generally worse for patients who had had ICS withdrawn, but differences between outcomes for these patients and patients who continued with medication were mostly small and not statistically significant.,Due to data paucity we performed only one meta-analysis; this indicated that patients who had had medication withdrawn were 1.11 (95% CI 0.84 to 1.46) times more likely to have an exacerbation in the following year, but the definition of exacerbations was not consistent between the three trials, and the impact of withdrawal was smaller in recent trials which were also trials conducted under conditions that reflected routine practice.,There is no evidence from this review that withdrawing ICS in routine practice results in important deterioration in patient outcomes.,Furthermore, the extent of increase in exacerbations depends on the way exacerbations are defined and managed and may depend on the use of other medication.,In trials where medication is withdrawn, investigators should report other medication use, definitions of exacerbations and management of patients clearly.,Intention to treat analyses should be used and interpreted appropriately. | 1 |
The process of aging involves biological changes that increases susceptibility for disease.,In the aging lung disease IPF, GWAS studies identified genes associated with risk for disease.,Recently, several of these genes were also found to be involved in risk for COPD or lung cancer.,This review describes GWAS-derived risk genes for IPF that overlap with risk genes for lung cancer or COPD.,Risk genes that overlap between aging lung diseases, include FAM13A, DSP and TERT.,Most interestingly, disease predisposing alleles for IPF are opposite to those for COPD or lung cancer.,Studies show that the alleles are associated with differential gene expression and with physiological traits in the general population.,The opposite allelic effect sizes suggest the presence of trade-offs in the aging lung.,For TERT, the trade-off involves cellular senescence versus proliferation and repair.,For FAM13A and DSP, trade-offs may involve protection from noxious gases or tissue integrity.,The overlap in risk genes in aging lung diseases provides evidence that processes associated with FAM13A, DSP and TERT are important for healthy aging.,The opposite effect size of the disease risk alleles may represent trade-offs, for which a model involving an apicobasal gene expression gradient is presented. | COPD is characterised by poorly reversible airflow obstruction usually due to cigarette smoking.,The transcription factor clusters of β-catenin/Snail1/Twist has been implicated in the process of epithelial mesenchymal transition (EMT), an intermediate between smoking and airway fibrosis, and indeed lung cancer.,We have investigated expression of these transcription factors and their “cellular localization” in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls.,An immune-histochemical study compared cellular protein expression of β-catenin, Snail1 and Twist, in these subject groups in 3 large airways compartment: epithelium (basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). β-catenin and Snail1 expression was generally high in all subjects throughout the airway wall with marked cytoplasmic to nuclear shift in COPD (P < 0.01).,Twist expression was generalised in the epithelium in normal but become more basal and nuclear with smoking (P < 0.05).,In addition, β-catenin and Snail1 expression, and to lesser extent of Twist, was related to airflow obstruction and to expression of a canonical EMT biomarker (S100A4).,The β-catenin-Snail1-Twist transcription factor cluster is up-regulated and nuclear translocated in smokers and COPD, and their expression is closely related to both EMT activity and airway obstruction. | 1 |
Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens.,This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management.,Both adult-onset asthma and COPD are complex diseases arising from gene-environment interactions.,Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma.,While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD.,Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness.,In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes).,Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation.,The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly.,Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy.,Each of these is associated with error due to overlap and convergence of clinical characteristics.,The management of chronic stable asthma and COPD is similarly convergent.,New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and risk factors.,Short-acting beta-agonists provide effective symptom relief in airway diseases.,Inhalers combining a long-acting beta-agonist and corticosteroid are now widely used for both asthma and COPD.,Written action plans are a cornerstone of asthma management although evidence for self-management in COPD is less compelling.,The current management of chronic asthma in adults is based on achieving and maintaining control through step-up and step-down approaches, but further trials of back-titration in COPD are required before a similar approach can be endorsed.,Long-acting inhaled anticholinergic medications are particularly useful in COPD.,Other distinctive features of management include pulmonary rehabilitation, home oxygen, and end of life care. | Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by chronic airflow limitation.,Unraveling of this heterogeneity is challenging but important, because it might enable more accurate diagnosis and treatment.,Because spirometry cannot distinguish between the different contributing pathways of airflow limitation, and visual scoring is time-consuming and prone to observer variability, other techniques are sought to start this phenotyping process.,Quantitative computed tomography (CT) is a promising technique, because current CT technology is able to quantify emphysema, air trapping, and large airway wall dimensions.,This review focuses on CT quantification techniques of COPD disease components and their current status and role in phenotyping COPD. | 1 |
COPD is a significant cause of morbidity and mortality.,In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation.,Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy.,In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention.,In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13.,The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions.,We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. | Chronic obstructive pulmonary disease (COPD) is a commonly reported cause of death and associated with smoking.,However, COPD mortality is high in poor countries with low smoking rates.,Spirometric restriction predicts mortality better than airflow obstruction, suggesting that the prevalence of restriction could explain mortality rates attributed to COPD.,We have studied associations between mortality from COPD and low lung function, and between both lung function and death rates and cigarette consumption and gross national income per capita (GNI).,National COPD mortality rates were regressed against the prevalence of airflow obstruction and spirometric restriction in 22 Burden of Obstructive Lung Disease (BOLD) study sites and against GNI, and national smoking prevalence.,The prevalence of airflow obstruction and spirometric restriction in the BOLD sites were regressed against GNI and mean pack years smoked.,National COPD mortality rates were more strongly associated with spirometric restriction in the BOLD sites (<60 years: men rs=0.73, p=0.0001; women rs=0.90, p<0.0001; 60+ years: men rs=0.63, p=0.0022; women rs=0.37, p=0.1) than obstruction (<60 years: men rs=0.28, p=0.20; women rs=0.17, p<0.46; 60+ years: men rs=0.28, p=0.23; women rs=0.22, p=0.33).,Obstruction increased with mean pack years smoked, but COPD mortality fell with increased cigarette consumption and rose rapidly as GNI fell below US$15 000.,Prevalence of restriction was not associated with smoking but also increased rapidly as GNI fell below US$15 000.,Smoking remains the single most important cause of obstruction but a high prevalence of restriction associated with poverty could explain the high ‘COPD’ mortality in poor countries. | 1 |
Chronic obstructive pulmonary disease (COPD) is characterized by the progression of irreversible airflow limitation and is a leading cause of morbidity and mortality worldwide.,Although several crucial mechanisms of COPD pathogenesis have been studied, the precise mechanism remains unknown.,Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are released from almost all cell types and are recognized as novel cell-cell communication tools.,They have been shown to carry and transfer a wide variety of molecules, such as microRNAs, messenger RNAs, and proteins, which are involved in physiological functions and the pathology of various diseases.,Recently, EVs have attracted considerable attention in pulmonary research.,In this review, we summarize the recent findings of EV-mediated COPD pathogenesis.,We also discuss the potential clinical usefulness of EVs as biomarkers and therapeutic agents for the treatment of COPD. | Local and systemic inflammation often present in chronic obstructive pulmonary disease (COPD).,Adipokines are secretory protein mediators by adipose tissue, which have been found to involve in inflammatory responses in many chronic inflammatory diseases.,Therefore, we performed this preliminary clinical study to investigate the possible association between 2 adipokines, C1q/tumor necrosis factor-related protein-3 and -5 (CTRP-3 and CTRP-5), with lung function and other markers of inflammation in COPD.,Serum CTRP-3 and CTRP-5 levels were measured in 73 COPD patients and 54 health controls, together with lung function and levels of adiponectin, CRP, TNF-α, and MPO in both groups.,Pearson's partial correlation was used to analyze the correlations between CTRPs and other serum markers or lung function.,Serum CTRP-5 was significantly elevated in COPD patients (0.41 ± 0.35 versus 0.29 ± 0.28 μg/ml, P = 0.01) and correlated inversely with FEV1/FVC ratio in all patients (r = −0.31, P = 0.001).,In COPD patients, CTRP-5 was also correlated negatively with FEV1% predicted (r = −0.464, P < 0.001) and had a positive association with CRP levels (r = 0.262, P = 0.04).,However, serum CTRP-3 levels were not correlated with measures of lung function or systemic inflammation.,In conclusion, circulating CTRP-5 was associated with the severity of airflow obstruction and systemic inflammation in patients with COPD, which suggests that it may be used as a potential novel inflammatory biomarker in COPD.,Further studies should be performed to clarify the exact role of CTRP-5 on the pathogenesis and outcomes of COPD. | 1 |
Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations.,The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract.,The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations.,In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD.,In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes.,This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans. | Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality.,The most widely used marker of disease severity and progression is FEV1.,However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD.,Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD.,Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.,Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.,There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality.,Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity.,The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear.,Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.,Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality. | 1 |
For patients with acute exacerbation of COPD (AECOPD), type 2 diabetes mellitus (T2DM) as comorbidity have poor outcomes.,However, data on the impact of previously diagnosed and new- diagnosed T2DM in such a patient population is lacking.,Inpatients diagnosed with AECOPD in the department of Pulmonary and Critical Care Medicine of The First Hospital of China Medical University during 2011-2017 were enrolled.,Data on demography, prevalence of type 2 DM, other comorbidities, hospital stays and laboratory tests (including arterial partial pressure of oxygen [PaO2]) results were recorded.,Results were compared with AECOPD patients having previously diagnosed and new-diagnosed type 2 diabetes.,Markers associated with development of type 2 DM and the prognosis of AECOPD patients were identified.,Of the 196 patients enrolled in this study, the overall prevalence of T2DM was 26%.,The PaO2 in the newly diagnosed T2DM group was considerably lower versus non-diabetic group.,The T2DM group had a longer hospital stay and higher troponin level versus the non-diabetic group.,AECOPD patients with T2DM were found to be correlated with hypertension.,Age, need for assisted ventilation, increased troponin, and elevated fasting blood glucose on admission were risk factors for death in hospitalized AECOPD patients.,AECOPD patients had a higher prevalence of T2DM than the general population; T2DM comorbidity caused lower PaO2, longer hospital stays, and increased troponin.,Poor blood glucose control may increase the risk of death in AECOPD patients. | COPD is currently the fourth cause of morbidity and mortality in the developed world.,Patients with COPD experience a progressive deterioration and disability, which lead to a worsening in their health-related quality of life (HRQoL).,The aim of this work is to assess the Health-Related Quality of Life (HRQoL) of patients with stable COPD followed in primary care and to identify possible predictors of disease.,It is a multicenter, epidemiological, observational, descriptive study.,Subjects of both sexes, older than 40 years and diagnosed of COPD at least 12 months before starting the study were included.,Sociodemographic data, severity of disease, comorbidity, and use of health resources in the previous 12 months were collected.,All patients were administered a generic quality-of-life questionnaire, the SF-12, that enables to calculate two scores, the physical (PCS-12) and the mental (MCS-12) component summary scores.,10,711 patients were evaluated (75.6% men, 24.4% women), with a mean age of 67.1 years (SD 9.66).,The mean value of FEV1 was 35.9 ± 10.0%.,Mean PCS-12 and MCS-12 scores were 36.0 ± 9.9 and 48.3 ± 10.9, respectively.,Compared to the reference population, patients with COPD had a reduction of PCS-12, even in mild stages of the disease.,The correlation with FEV1 was higher for PCS-12 (r = 0.38) than for MCS-12 (r = 0.12).,Predictors for both HRQoL components were sex, FEV1, use of oxygen therapy, and number of visits to emergency rooms and hospital admissions.,Other independent predictors of PCS-12 were age, body mass index and educational level.,Patients with stable COPD show a reduction of their HRQoL, even in mild stages of the disease.,The factors determining the HRQoL include sex, FEV1, use of oxygen therapy, and number of visits to emergency rooms and hospital admissions. | 1 |
Today, many different tools are developed to execute and visualize physiological models that represent the human physiology.,Most of these tools run models written in very specific programming languages which in turn simplify the communication among models.,Nevertheless, not all of these tools are able to run models written in different programming languages.,In addition, interoperability between such models remains an unresolved issue.,In this paper we present a simulation environment that allows, first, the execution of models developed in different programming languages and second the communication of parameters to interconnect these models.,This simulation environment, developed within the Synergy-COPD project, aims at helping and supporting bio-researchers and medical students understand the internal mechanisms of the human body through the use of physiological models.,This tool is composed of a graphical visualization environment, which is a web interface through which the user can interact with the models, and a simulation workflow management system composed of a control module and a data warehouse manager.,The control module monitors the correct functioning of the whole system.,The data warehouse manager is responsible for managing the stored information and supporting its flow among the different modules.,This simulation environment has been validated with the integration of three models: two deterministic, i.e. based on linear and differential equations, and one probabilistic, i.e., based on probability theory.,These models have been selected based on the disease under study in this project, i.e., chronic obstructive pulmonary disease.,It has been proved that the simulation environment presented here allows the user to research and study the internal mechanisms of the human physiology by the use of models via a graphical visualization environment.,A new tool for bio-researchers is ready for deployment in various use cases scenarios. | Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation.,Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy.,Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate.,In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators.,Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles.,Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization.,These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients. | 1 |
Despite the availability of national and international guidelines, evidence suggests that chronic obstructive pulmonary disease (COPD) treatment is not always prescribed according to recommendations.,This study evaluated the current management of patients with COPD using a large UK primary-care database.,This analysis used electronic patient records and patient-completed questionnaires from the Optimum Patient Care Research Database.,Data on current management were analyzed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group and presence or absence of a concomitant asthma diagnosis, in patients with a COPD diagnosis at ≥35 years of age and with spirometry results supportive of the COPD diagnosis.,A total of 24,957 patients were analyzed, of whom 13,557 (54.3%) had moderate airflow limitation (GOLD Stage 2 COPD).,The proportion of patients not receiving pharmacologic treatment for COPD was 17.0% in the total COPD population and 17.7% in the GOLD Stage 2 subset.,Approximately 50% of patients in both cohorts were receiving inhaled corticosteroids (ICS), either in combination with a long-acting β2-agonist (LABA; 26.7% for both cohorts) or a LABA and a long-acting muscarinic antagonist (LAMA; 23.2% and 19.9%, respectively).,ICS + LABA and ICS + LABA + LAMA were the most frequently used treatments in GOLD Groups A and B.,Of patients without concomitant asthma, 53.7% of the total COPD population and 50.2% of the GOLD Stage 2 subset were receiving ICS.,Of patients with GOLD Stage 2 COPD and no exacerbations in the previous year, 49% were prescribed ICS.,A high proportion of GOLD Stage 2 COPD patients were symptomatic on their current management (36.6% with modified Medical Research Council score ≥2; 76.4% with COPD Assessment Test score ≥10).,COPD is not treated according to GOLD and National Institute for Health and Care Excellence recommendations in the UK primary-care setting.,Some patients receive no treatment despite experiencing symptoms.,Among those on treatment, most receive ICS irrespective of severity of airflow limitation, asthma diagnosis, and exacerbation history.,Many patients on treatment continue to have symptoms. | Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients.,Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype.,This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes.,These patients are therefore a priority for research and treatment.,The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection.,Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment.,Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype.,This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.,The online version of this article (doi:10.1186/1741-7015-11-181) contains supplementary material, which is available to authorized users. | 1 |
COPD is characterised by tissue destruction and inflammation.,Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant.,In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair.,These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD.,Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD.,However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD.,In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. | In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD).,The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models.,A systematic search of electronic databases was performed.,Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3).,The pooled Hedges’s g with 95% confidence intervals (95% CIs) was adopted to assess the effect size.,Random effect model was used due to the heterogeneity between the studies.,A total of 20 eligible studies were included in the current systematic review.,The overall meta-analysis showed that MSC administration was significantly in favor of attenuating acute lung injury (Hedges’s g = -2.325 ± 0.145 with 95% CI: -2.609 ~ -2.040, P < 0.001 for mean linear intercept, MLI; Hedges’s g = -3.488 ± 0.504 with 95% CI: -4.476 ~ -2.501, P < 0.001 for TUNEL staining), stimulating lung tissue repair (Hedges’s g = 3.249 ± 0.586 with 95% CI: 2.103~ 4.394, P < 0.001) and improving lung function (Hedges’s g = 2.053 ± 0.408 with 95% CI: 1.253 ~ 2.854, P< 0.001).,The mechanism of MSC therapy in COPD is through ameliorating airway inflammation (Hedges’s g = -2.956 ± 0.371 with 95% CI: -3.683 ~ -2.229, P< 0.001) and stimulating cytokine synthesis that involves lung tissue repair (Hedges’s g = 3.103 ± 0.734 with 95% CI: 1.664 ~ 4.541, P< 0.001).,This systematic review and meta-analysis suggest a promising role for MSCs in COPD treatment.,Although the COPD models may not truly mimic COPD patients, these pre-clinical studies demonstrate that MSC hold promise in the treatment of chronic lung diseases including COPD.,The mechanisms of MSCs role in preclinical COPD treatment may be associated with attenuating airway inflammation as well as stimulating lung tissue repair. | 1 |
Chronic Obstructive Pulmonary Disease (COPD) is associated with an abnormal pulmonary and systemic immune response to tobacco smoking.,Yet, how do immune cells relate within and between these two biological compartments, how the pulmonary infiltrate influences the lung transcriptome, and what is the role of active smoking vs. presence of disease is unclear.,To investigate these questions, we simultaneously collected lung tissue and blood from 65 individuals stratified by smoking habit and presence of the disease.,The immune cell composition of both tissues was assessed by flow cytometry, whole lung transcriptome was determined with Affymetrix arrays, and we used Weighted Gene Co-expression Network Analysis (WGCNA) to integrate results.,Main results showed that: (1) current smoking and the presence of COPD were both independently associated with a reduction in the proportion of lung T cells and an increase of macrophages, specifically those expressing CD80 + CD163+; (2) changes in the proportion of infiltrating macrophages, smoking status or the level of airflow limitation were associated to different WGCNA modules, which were enriched in iron ion transport, extracellular matrix and cilium organization gene ontologies; and, (3) circulating white blood cells counts were correlated with lung macrophages and T cells.,Mild-moderated COPD lung immune infiltrate is associated with the active smoking status and presence of disease; is associated with changes in whole lung tissue transcriptome and marginally reflected in blood.,The online version of this article (10.1186/s12931-019-1105-z) contains supplementary material, which is available to authorized users. | Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD.,We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.,Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans.,Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT.,Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.,In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema.,The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema.,Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema.,In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.,Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans. | 1 |
Owing to the high and increasing morbidity and mortality, chronic obstructive pulmonary disease (COPD) has become a major public health problem worldwide.,Although the majority of patients with COPD are in the early stages, little attention has been paid to them, in particular regarding to early intervention.,Tiotropium bromide can significantly relieve symptoms and reduce the incidence of acute exacerbations of COPD.,Therefore, we hypothesise that therapy with tiotropium bromide will benefit patients with COPD with early-stage disease.,A randomised, double-blinded, placebo-controlled, parallel-group, multicentre clinical trial (Tiotropium In Early COPD study, Tie-COPD study) is being conducted to evaluate the efficacy and safety of long-term intervention with tiotropium in patients with COPD with early-stage disease.,A total of 839 patients with COPD who satisfied the eligibility criteria were randomly assigned (1:1) to receive a once daily inhaled capsule of either tiotropium bromide (18 μg) or matching placebo for 2 years.,Measurements will include forced expiratory volume in 1 s, health-related quality of life, grade degree of breathlessness related to activities, COPD exacerbations and pharmacoeconomic analysis.,This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University.,Recruitment started in November 2011 and ended in October 2013, with 839 patients randomised.,The treatment follow-up of participants with Tie-COPD is currently ongoing and is due to finish in November 2015.,The authors will disseminate the findings in peer-reviewed publications, conferences and seminar presentations.,ClinicalTrials.gov (NCT01455129). | The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented.,However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.,TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers).,To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ≥ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).,Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV.,SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage.,Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV.,The rates of adverse events were similar across treatment arms and increased with disease severity.,Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.,In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages.,Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease.,The effects were similar to those reported for the study as a whole.,Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.,Clinicaltrial.gov registration NCT00268216; Study number: SCO30003 | 1 |
Today, many different tools are developed to execute and visualize physiological models that represent the human physiology.,Most of these tools run models written in very specific programming languages which in turn simplify the communication among models.,Nevertheless, not all of these tools are able to run models written in different programming languages.,In addition, interoperability between such models remains an unresolved issue.,In this paper we present a simulation environment that allows, first, the execution of models developed in different programming languages and second the communication of parameters to interconnect these models.,This simulation environment, developed within the Synergy-COPD project, aims at helping and supporting bio-researchers and medical students understand the internal mechanisms of the human body through the use of physiological models.,This tool is composed of a graphical visualization environment, which is a web interface through which the user can interact with the models, and a simulation workflow management system composed of a control module and a data warehouse manager.,The control module monitors the correct functioning of the whole system.,The data warehouse manager is responsible for managing the stored information and supporting its flow among the different modules.,This simulation environment has been validated with the integration of three models: two deterministic, i.e. based on linear and differential equations, and one probabilistic, i.e., based on probability theory.,These models have been selected based on the disease under study in this project, i.e., chronic obstructive pulmonary disease.,It has been proved that the simulation environment presented here allows the user to research and study the internal mechanisms of the human physiology by the use of models via a graphical visualization environment.,A new tool for bio-researchers is ready for deployment in various use cases scenarios. | This article describes a Digital Health Framework (DHF), benefitting from the lessons learnt during the three-year life span of the FP7 Synergy-COPD project.,The DHF aims to embrace the emerging requirements - data and tools - of applying systems medicine into healthcare with a three-tier strategy articulating formal healthcare, informal care and biomedical research.,Accordingly, it has been constructed based on three key building blocks, namely, novel integrated care services with the support of information and communication technologies, a personal health folder (PHF) and a biomedical research environment (DHF-research).,Details on the functional requirements and necessary components of the DHF-research are extensively presented.,Finally, the specifics of the building blocks strategy for deployment of the DHF, as well as the steps toward adoption are analyzed.,The proposed architectural solutions and implementation steps constitute a pivotal strategy to foster and enable 4P medicine (Predictive, Preventive, Personalized and Participatory) in practice and should provide a head start to any community and institution currently considering to implement a biomedical research platform. | 1 |
Cardiopulmonary exercise test (CPET) has been gaining importance as a method of functional assessment in Brazil and worldwide.,In its most frequent applications, CPET consists in applying a gradually increasing intensity exercise until exhaustion or until the appearance of limiting symptoms and/or signs.,The following parameters are measured: ventilation; oxygen consumption (VO2); carbon dioxide production (VCO2); and the other variables of conventional exercise testing.,In addition, in specific situations, pulse oximetry and flow-volume loops during and after exertion are measured.,The CPET provides joint data analysis that allows complete assessment of the cardiovascular, respiratory, muscular and metabolic systems during exertion, being considered gold standard for cardiorespiratory functional assessment.1-6,The CPET allows defining mechanisms related to low functional capacity that can cause symptoms, such as dyspnea, and correlate them with changes in the cardiovascular, pulmonary and skeletal muscle systems.,Furthermore, it can be used to provide the prognostic assessment of patients with heart or lung diseases, and in the preoperative period, in addition to aiding in a more careful exercise prescription to healthy subjects, athletes and patients with heart or lung diseases.,Similarly to CPET clinical use, its research also increases, with the publication of several scientific contributions from Brazilian researchers in high-impact journals.,Therefore, this study aimed at providing a comprehensive review on the applicability of CPET to different clinical situations, in addition to serving as a practical guide for the interpretation of that test. | In this study, we analyzed maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) values in a stable COPD population compared with normal subjects.,We evaluated the possible correlation between functional maximal respiratory static pressures and functional and anthropometric parameters at different stages of COPD.,Furthermore, we considered the possible correlation between airway obstruction and MIP and MEP values.,110 patients with stable COPD and 21 age-matched healthy subjects were enrolled in this study.,Patients were subdivided according to GOLD guidelines: 31 mild, 39 moderate and 28 severe.,Both MIP and MEP were lower in patients with severe airway impairment than in normal subjects.,Moreover, we found a correlation between respiratory muscle function and some functional and anthropometric parameters: FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), PEF (peak expiratory flow), TLC (total lung capacity) and height.,MIP and MEP values were lower in patients with severe impairment than in patients with a slight reduction of FEV1.,The measurement of MIP and MEP indicates the state of respiratory muscles, thus providing clinicians with a further and helpful tool in monitoring the evolution of COPD. | 1 |
Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable.,This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers.,A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers.,Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George’s Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework.,A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 μg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks.,The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: −14.2, 42.3]), SGRQ total score (0.18 [−1.28, 1.63]), TDI focal score (−0.30 [−0.73, 0.13]), and rescue medication use (0.02 [−0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [−25.3, 159.4]), SGRQ total score (−0.11 [−1.84, 1.61]), and TDI focal score (0.58 [−0.33, 1.50]); and compared with formoterol plus TIO 18 μg on SGRQ total score (−0.68 [−1.77, 0.39]).,Results at week 12 were consistent with week 24 outcomes.,Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks.,UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints. | The economic burden of chronic obstructive pulmonary disease (COPD) exacerbations is significant, but the impact of other sources on the overall cost of COPD management is largely unknown.,We aimed to estimate overall costs for patients experiencing none, one, or two or more exacerbations per year in the UK.,A retrospective cohort of prevalent COPD patients was identified in the Clinical Practice Research Datalink UK database.,Patients with information recorded for at least 12 months before and after cohort entry date were included (first prevalent COPD diagnosis confirmed by spirometry on/after April 1, 2009).,Patients were categorized as having none, one, or two or more moderate-to-severe COPD exacerbations in the 12 months after cohort entry and further classified by the Global initiative for chronic Obstructive Lung Disease (GOLD) category of airflow obstruction and the Medical Research Council dyspnea scale.,Study outcomes included counts of general practitioner interactions, moderate-severe COPD exacerbations, and non-COPD hospitalizations.,Estimated resource use costs were calculated using National Health Service reference costs for 2010-2011.,The cohort comprised 58,589 patients (mean age 69.5 years, mean dyspnea grade 2.5, females 46.6%, current smokers 33.1%).,The average total annual per patient cost of COPD management, excluding medications, was £2,108 for all patients and £1,523, £2,405, and £3,396 for patients experiencing no, one, or two or more moderate-to-severe exacerbations, respectively.,General practitioner interactions contributed most to these annual costs, accounting for £1,062 (69.7%), £1,313 (54.6%), and £1,592 (46.9%) in patients with no, one, or two or more moderate-to-severe exacerbations, respectively.,Disease management strategies focused on reducing costs in primary care may help reduce total COPD costs significantly. | 1 |
The 3-minute chair rise test (3-minute CRT) and the Disability Related to COPD Tool (DIRECT) are two reproducible and valid short tests that can assess the benefit of pulmonary rehabilitation (PR) in terms of functional capacity and dyspnea in everyday activities.,We determined the minimal clinically important difference (MCID) of the DIRECT questionnaire and 3-minute CRT using distribution methods and anchor encroaches with a panel of eight standard tests in a cohort of 116 COPD patients who completed a PR program in real-life settings.,The estimated MCID for the 3-minute CRT and DIRECT scores was five repetitions and two units, respectively, using separate and combined independent anchors.,The all-patient (body mass index-obstruction-dyspnea-exercise [BODE] scores 0-7), BODE 0-2 (n=42), and BODE 3-4 (n=50) groups showed improvements greater than the MCID in most tests and questionnaires used.,In contrast, the BODE 5-7 group (n=24) showed improvements greater than MCID in only the 3-minute CRT, 6-minute walk test, endurance exercise test, and DIRECT questionnaire.,This study demonstrates that the short and simple DIRECT questionnaire and 3-minute CRT are responsive to capture the beneficial effects of a PR program in COPD patients, including those with severe disease.,NCT03286660. | Dyspnoea is a debilitating and distressing symptom that is reflected in different verbal descriptors.,Evidence suggests that dyspnoea, like pain perception, consists of sensory quality and affective components.,The objective of this study was to develop an instrument that measures overall dyspnoea severity using descriptors that reflect its different aspects.,81 dyspnoea descriptors were administered to 123 patients with chronic obstructive pulmonary disease (COPD), 129 with interstitial lung disease and 106 with chronic heart failure.,These were reduced to 34 items using hierarchical methods.,Rasch analysis informed decisions regarding further item removal and fit to the unidimensional model.,Principal component analysis (PCA) explored the underlying structure of the final item set.,Validity and reliability of the new instrument were further assessed in a separate group of 53 patients with COPD.,After removal of items with hierarchical methods (n = 47) and items that failed to fit the Rasch model (n = 22), 12 were retained.,The “Dyspnoea-12” had good internal reliability (Cronbach’s alpha = 0.9) and fit to the Rasch model (χ2 p = 0.08).,Items patterned into two groups called “physical”(n = 7) and “affective”(n = 5).,In the separate validation study, Dyspnoea-12 correlated with the Hospital Anxiety and Depression Scale (anxiety r = 0.51; depression r = 0.44, p<0.001, respectively), 6-minute walk distance (r = −0.38, p<0.01) and MRC (Medical Research Council) grade (r = 0.48, p<0.01), and had good stability over time (intraclass correlation coefficient = 0.9, p<0.001).,Dyspnoea-12 fulfills modern psychometric requirements for measurement.,It provides a global score of breathlessness severity that incorporates both “physical” and “affective” aspects, and can measure dyspnoea in a variety of diseases. | 1 |
Spirometry is commonly accepted as the gold standard for the diagnosis of COPD, but the reality remains that quality assured spirometry is not or cannot be provided universally around the globe.,Adding PEF measurement to a screening questionnaire may rule out airflow limitation compatible with COPD rationalizing spirometry testing.,We conducted a cross-sectional survey in a sample of individuals 40-80 yrs. old in Dubai, UAE.,They were invited to answer a short socio-demographic questionnaire including a report on current, past history of smoking, and had PEF measured, then they conducted spirometry to identify airflow limitation compatible with COPD.,Overall, 525 (91.0%) participants performed PEF and spirometry (68% male, with a mean age of 59 years, 17% UAE Nationals), 24% reported smoking of different sorts.,Overall, 68 participants (12.9%, 95% C.I.,10.3% to 16.1%) had airflow limitation compatible with COPD.,PEFR alone identified 141participants with airflow limitation compatible with COPD, with specificity of 80% and sensitivity of 73.5%.,PEFR could be an easy, cheap, and non-biased tool to assist with the case-finding of COPD before confirmation with spirometry. | Our objective was to assess the prevalence of chronic bronchitis and chronic obstructive pulmonary disease (COPD) and their correlates among a Lebanese nonsmoker group.,A cross-sectional study was conducted between October 2009 and September 2010, using a multistage cluster sample throughout Lebanon including Lebanese residents aged 40 years and above with no exclusion criteria.,Pre- and postbronchodilator spirometry measurements were performed and carbon monoxide level was measured in exhaled air.,COPD was defined and classified according to the Global Initiative for Chronic Obstructive Lung Disease guidelines or according to the lower limit of normal (forced expiratory volume in 1 second/forced vital capacity postbronchodilator < 5th percentile of the healthy population having the same age and sex).,Chronic bronchitis was defined by the declaration of morning cough and expectorations for more than 3 months a year over more than 2 years in individuals with normal spirometry.,Out of 2201 individuals, 732 were never-smokers: 25 (3.4%) of them had COPD, and 86 (11.75%) fulfilled the definition of chronic bronchitis.,Correlates of COPD included a childhood respiratory disease, house heated by diesel, and older age.,On the other hand, correlates of chronic bronchitis included childhood respiratory diseases, living in southern Lebanon versus other regions, heating home by gas, older age, number of smokers at work, and lower height.,A substantial percentage of the nonsmoking population may exhibit chronic bronchitis or COPD.,The significant correlates mentioned above should be taken into consideration in order to reduce the risk of developing such chronic and debilitating respiratory diseases. | 1 |
Pulmonary surfactant D (SP-D) has important regulatory functions for innate immunity and has been implicated as a biomarker for chronic obstructive pulmonary disease (COPD).,We hypothesized that COPD patients would have reduced bronchoalveolar lavage (BAL) fluid SP-D levels compared to healthy smoking and non-smoking controls.,BAL SP-D and phospholipids were quantified and corrected for dilution in 110 subjects (65 healthy never smokers, 23 smokers with normal spirometry, and 22 smokers with COPD).,BAL SP-D was highest in never smokers (mean 51.9 μg/mL ± 7.1 μg/mL standard error) compared to both smokers with normal spirometry (16.0 μg/mL ± 11.8 μg/mL) and subjects with COPD (19.1 μg/mL ± 12.9 μg/mL; P < 0.0001).,Among smokers with COPD, BAL SP-D correlated significantly with FEV1% predicted (R = 0.43; P < 0.05); however, the strongest predictor of BAL SP-D was smoking status.,BAL SP-D levels were lowest in current smokers (12.8 μg/mL ± 11.0 μg/mL), intermediate in former smokers (25.2 μg/mL ± 14.2 μg/mL; P < 0.008), and highest in never smokers.,BAL phospholipids were also lowest in current smokers (6.5 nmol ± 1.5 nmol), intermediate in former smokers (13.1 nmol ± 2.1 nmol), and highest in never smokers (14.8 nmol ± 1.1 nmol; P < 0.0001).,These data suggest that smokers, and especially current smokers, exhibit significantly reduced BAL SP-D and phospholipids compared to nonsmokers.,Our findings may help better explain the mechanism that leads to the rapid progression of disease and increased incidence of infection in smokers. | Elevated circulating levels of several inflammatory biomarkers have been described in selected patient populations with COPD, although less is known about their population-based distribution.,The aims of this study were to compare the levels of several systemic biomarkers between stable COPD patients and healthy subjects from a population-based sample, and to assess their distribution according to clinical variables.,This is a cross-sectional study design of participants in the EPI-SCAN study (40-80 years of age).,Subjects with any other condition associated with an inflammatory process were excluded.,COPD was defined as a post-bronchodilator FEV1/FVC < 0.70.,The reference group was made of non-COPD subjects without respiratory symptoms, associated diseases or prescription of medication.,Subjects were evaluated with quality-of-life questionnaires, spirometry and 6-minute walk tests.,Serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins (IL-6 and IL-8), alpha1-antitrypsin, fibrinogen, albumin and nitrites/nitrates (NOx) were measured.,We compared 324 COPD patients and 110 reference subjects.,After adjusting for gender, age, BMI and tobacco consumption, COPD patients showed higher levels of CRP (0.477 ± 0.023 vs.,0.376 ± 0.041 log mg/L, p = 0.049), TNF-α (13.12 ± 0.59 vs.,10.47 ± 1.06 pg/mL, p = 0.033), IL-8 (7.56 ± 0.63 vs.,3.57 ± 1.13 pg/ml; p = 0.033) and NOx (1.42 ± 0.01 vs.,1.36 ± 0.02 log nmol/l; p = 0.048) than controls.,In COPD patients, serum concentrations of some biomarkers were related to severity and their exercise tolerance was related to serum concentrations of CRP, IL-6, IL-8, fibrinogen and albumin.,Our results provide population-based evidence that COPD is independently associated with low-grade systemic inflammation, with a different inflammatory pattern than that observed in healthy subjects. | 1 |
The benefits of pharmacotherapy with tiotropium HandiHaler 18 μg for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated.,However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).,To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.,A randomised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily (via HandiHaler) was performed in maintenance therapy-naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ⩾50 and <80%.,A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93 l (66% predicted)).,Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h (AUC0-3h) at week 24 (primary endpoint): 0.19 vs.,−0.03 l (least-squares mean difference 0.23 l, P<0.001).,FVC AUC0-3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001).,Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS).,Physician’s Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24.,The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.,Tiotropium improved lung function and patient-reported outcomes in maintenance therapy-naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early. | The performance of daily activities is a major challenge for people with chronic obstructive pulmonary disease (COPD).,The Functional Performance Inventory (FPI) was developed based on an analytical framework of functional status and qualitative interviews with COPD patients describing these difficulties.,The 65-item FPI was reduced to a 32-item short form (SF) through a systematic process of qualitative and quantitative item reduction and formatted for greater clarity and ease of use.,This study examined the content validity of the reduced, reformatted form of the instrument, the FPI-SF.,Qualitative cognitive interviews were conducted with COPD patients recruited from three geographically diverse pulmonary clinics in the United States.,Interviews were designed to assess respondent interpretation of the instrument, evaluate clarity and ease of completion, and identify any new activities participants found important and difficult to perform that were not represented by the existing items.,Twenty subjects comprised the sample; 12 (60%) were male, 14 (70%) were Caucasian, the mean age was 63.0 ± 11.3 years, 12 (60%) were retired, the mean forced expiratory volume in 1 second (FEV1) was 1.5 ± 0.5 L, and the mean percent predicted FEV1 was 48.4% ± 13.1%.,Participants understood the FPI-SF as intended, including instructions, items, and response options.,Two minor formatting changes were suggested to improve clarity of presentation.,Participants found the content of the FPI-SF to be comprehensive, with items covering activities they felt were important and often difficult to perform.,These results, together with its development history and previously tested quantitative properties, suggest that the FPI-SF is content valid for use in clinical studies of COPD. | 1 |
Exacerbation-associated health-related quality of life (HRQoL) in patients with severe and very severe chronic obstructive pulmonary disease (COPD) is ill-defined.,This study describes patterns, HRQoL, and the work productivity impact of COPD-related moderate and SEV exacerbations in patients with SEV/VSEV COPD, focusing on the chronic bronchitis subtype.,A US sample of SEV and VSEV COPD patients with recent moderate or SEV exacerbation was recruited.,Along with the demographic and clinical data collected from medical records, patients reported on exacerbation frequency, health-related quality of life (HRQoL) (using the St George’s Respiratory Questionnaire for COPD [SGRQ-C] and the European Quality of Life-5 Dimensions [EQ-5D]™ index), and work productivity and activity impairment (using the Work Productivity and Activity Impairment Questionnaire - Specific Health Problem [WPAI-SHP]).,The HRQoL-related impacts of exacerbation frequency, time since exacerbation, and last exacerbation severity were evaluated via linear regressions.,A total of 314 patients (190 SEV/124 VSEV, mean age =68.0 years, 51% male, 28% current smokers) were included.,In the previous 12 months, patients reported an average of 1.8 moderate exacerbations and 0.9 SEV exacerbations.,Overall, 16% of patients were employed and reported a high percentage of overall work impairment (42.4% ± 31.1%).,Activity impairment was positively associated with recent exacerbation severity (SEV 64.6% ± 26.8% versus moderate 55.6% ± 28.2%) (P=0.006).,The HRQoL was significantly worse for SEV versus VSEV COPD (EQ-5D: 0.62 ± 0.23 versus 0.70 ± 0.17, respectively, and SGRQ-C: 70.1 ± 21.3 versus 61.1 ± 19.0, respectively) (P<0.001).,Worse current HRQoL was reported by patients with a SEV versus moderate recent exacerbation (EQ-5D: 0.63 ± 0.21 versus 0.70 ± 0.20, respectively) (P=0.003); SGRQ-C: 70.3 ± 19.9 versus 61.7 ± 20.1, respectively (P<0.001).,One additional exacerbation in the previous 12 months was associated with a 2.4-point SGRQ-C increase and a 0.02-point EQ-5D index decrease.,The severity and frequency of COPD-related moderate/SEV exacerbations in SEV and VSEV COPD patients were positively associated with poor HRQoL and work productivity and activity impairment. | Chronic obstructive pulmonary disease (COPD) exacerbations are the leading cause of hospital admission and death among chronic bronchitis (CB) patients.,This study estimated annual COPD exacerbation rates, related costs, and their predictors among patients treated for CB.,This was a retrospective study using claims data from the HealthCore Integrated Research Database (HIRDSM).,The study sample included CB patients aged ≥ 40 years with at least one inpatient hospitalization or emergency department visit or at least two office visits with CB diagnosis from January 1, 2004 to May 31, 2011, at least two pharmacy fills for COPD medications during the follow-up year, and ≥2 years of continuous enrollment.,COPD exacerbations were categorized as severe or moderate.,Annual rates, costs, and predictors of exacerbations during follow-up were assessed.,A total of 17,382 individuals treated for CB met the selection criteria (50.6% female; mean ± standard deviation age 66.7 ± 11.4 years).,During the follow-up year, the mean ± standard deviation number of COPD maintenance medication fills was 7.6 ± 6.3; 42.6% had at least one exacerbation and 69.5% of patients with two or more exacerbations during the 1 year prior to the index date (baseline period) had any exacerbation during the follow-up year.,The mean ± standard deviation cost per any exacerbation was $269 ± $748 for moderate and $18,120 ± $31,592 for severe exacerbation.,The number of baseline exacerbations was a significant predictor of the number of exacerbations and exacerbation costs during follow-up.,Exacerbation rates remained high among CB patients despite treatment with COPD maintenance medications.,New treatment strategies, designed to reduce COPD exacerbations and associated costs, should focus on patients with high prior-year exacerbations. | 1 |
Home-based models represent one of the solutions to respond to the poor accessibility of pulmonary rehabilitation (PR) services in patients with chronic respiratory disease (CRD).,The main goal of this protocol is to present the implementation of the first nationwide home-based PR program-reabilitAR-in Portugal and the strategies to assess its benefits in patients with CRD.,The program consists of 2 phases: a 12-week intensive phase and a 40-week maintenance phase (total: 52 weeks, 1 year).,The intervention in both phases is composed of presential home visits and phone-call follow ups, including exercise training and the self-management educational program Living Well with COPD.,Dyspnea, impact of the disease, emotional status, and level of dyspnea during activities of daily living are used as patient-reported outcomes measures.,A one-minute sit-to-stand test is used as a functional outcome, and the number of steps as a measure of physical activity.,To ensure safety, fall risk and the cognitive function are assessed.,Data are collected at baseline, at 12 weeks, at 26 weeks and at 52 weeks.,This is the first nationwide protocol on enhancing access to PR, providing appropriate responses to CRD patients’ needs through a structured and personalized home-based program in Portugal. | Pulmonary rehabilitation is a highly effective treatment for people with chronic lung disease but remains underused across the world.,Recent years have seen the emergence of new program models that aim to improve access and uptake, including telerehabilitation and low-cost, home-based models.,This workshop was convened to achieve consensus on the essential components of pulmonary rehabilitation and to identify requirements for successful implementation of emerging program models.,A Delphi process involving experts from across the world identified 13 essential components of pulmonary rehabilitation that must be delivered in any program model, encompassing patient assessment, program content, method of delivery, and quality assurance, as well as 27 desirable components.,Only those models of pulmonary rehabilitation that have been tested in clinical trials are currently considered as ready for implementation.,The characteristics of patients most likely to succeed in each program model are not yet known, and research is needed in this area.,Health professionals should use clinical judgment to determine those patients who are best served by a center-based, multidisciplinary rehabilitation program.,A comprehensive patient assessment is critical for personalization of pulmonary rehabilitation and for effectively addressing individual patient goals.,Robust quality-assurance processes are important to ensure that any pulmonary rehabilitation service delivers optimal outcomes for patients and health services.,Workforce capacity-building and training should consider the skills necessary for emerging models, many of which are delivered remotely.,The success of all pulmonary rehabilitation models will be judged on whether the essential components are delivered and on whether the expected patient outcomes, including improved exercise capacity, reduced dyspnea, enhanced health-related quality of life, and reduced hospital admissions, are achieved. | 1 |
Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.,For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler.,Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).,295 and 291 patients were treated in MORACTO 1 and 2, respectively.,Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001).,Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).,Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies.,Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.,T/O reduces lung hyperinflation in COPD versus T, O or placebo and increases exercise endurance versus placebohttp://ow.ly/ml3G307XW6a | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that reduces lung and respiratory function, with a high mortality rate.,Severe and acute deterioration of COPD can easily lead to respiratory failure, resulting in personal, social, and medical burden.,Recent studies have shown a high correlation between the gut microbiota and lung inflammation.,In this study, we investigated the relationship between gut microbiota and COPD severity.,A total of 60 COPD patients with varying severity according to GOLD guidelines were enrolled in this study.,DNA was extracted from patients’ stool and 16S rRNA data analysis conducted using high-throughput sequencing followed by bioinformatics analysis.,The richness of the gut microbiota was not associated with COPD severity.,The gut microbiome is more similar in stage 1 and 2 COPD than stage 3+4 COPD.,Fusobacterium and Aerococcus were more abundant in stage 3+4 COPD.,Ruminococcaceae NK4A214 group and Lachnoclostridium were less abundant in stage 2-4, and Tyzzerella 4 and Dialister were less abundant in stage 1.,However, the abundance of a Bacteroides was associated with blood eosinophils and lung function.,This study suggests that no distinctive gut microbiota pattern is associated with the severity of COPD.,The gut microbiome could affect COPD by gut inflammation shaping the host immune system. | The aim of the study was to investigate how the expression of adhesion molecules changes as neutrophils migrate from the circulation to the lung and if these changes differ between non-smoking subjects and smokers with and without COPD.,Non-smoking healthy subjects (n=22), smokers without (n=21) and with COPD (n=18) were included.,Neutrophils from peripheral blood, sputum and bronchial biopsies were analysed for cell surface expression of adhesion molecules (CD11b, CD62L, CD162).,Serum, sputum supernatant and BAL-fluid were analysed for soluble adhesion molecules (ICAM-1, -3, E-selectin, P-selectin, VCAM-1, PECAM-1).,Expression of CD11b was increased on circulating neutrophils from smokers with COPD.,It was also increased on sputum neutrophils in both smokers groups, but not in non-smokers, as compared to circulating neutrophils.,Serum ICAM-1 was higher in the COPD group compared to the other two groups (p<0.05) and PECAM-1 was lower in smokers without COPD than in non-smoking controls and the COPD group (p<0.05).,In BAL-fluid ICAM-1 was lower in the COPD group than in the other groups (p<0.05).,Thus, our data strongly support the involvement of a systemic component in COPD and demonstrate that in smokers neutrophils are activated to a greater extent at the point of transition from the circulation into the lungs than in non-smokers. | 1 |
As only some smokers develop COPD with emphysema, we explored the molecular pathogenesis of early-stage COPD with emphysema using gene expression profiling of human lung tissues.,First, 110 subjects who had smoked more than ten pack-years were classified into three groups: COPD with emphysema, COPD without emphysema, and healthy smokers.,COPD and emphysema were confirmed by post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 and by chest computed tomography.,Lung tissues obtained surgically from the 110 subjects were processed and used for RNA-Seq analysis.,Among the 110 subjects, 29 had COPD with emphysema, 21 had COPD without emphysema, and 60 were healthy smokers; their mean post-bronchodilator forced expiratory volume in 1 second values were 78%, 80%, and 94%, respectively.,Using RNA-Seq, we evaluated 16,676 genes expressed in lung tissues.,Among them, 1,226 genes in the COPD with emphysema group and 434 genes in the COPD without emphysema group were differentially expressed genes compared to the expression in healthy smokers.,In the COPD with emphysema group, ACER2 and LMAN2L were markedly increased and decreased, respectively.,In the COPD without emphysema group, the CHRM3 gene, previously reported to be associated with COPD, and HDAC10 were markedly increased and decreased, respectively.,Our study identified differences in gene expression in subjects with COPD according to emphysema status using RNA-Seq transcriptome analysis.,These findings may have mechanistic implications in COPD. | Despite the status of chronic obstructive pulmonary disease (COPD) as a major global health problem, no currently available therapies can limit COPD progression.,Therefore, an urgent need exists for the development of new and effective treatments for COPD.,An improved understanding in the molecular pathogenesis of COPD can potentially identify molecular targets to facilitate the development of new therapeutic modalities.,Among the best approaches for understanding the molecular basis of COPD include gene expression profiling techniques, such as serial analysis of gene expression or microarrays.,Using these methods, recent studies have mapped comparative gene expression profiles of lung tissues from patients with different stages of COPD relative to healthy smokers or non-smokers.,Such studies have revealed a number of differentially-regulated genes associated with COPD progression, which include genes involved in the regulation of inflammation, extracellular matrix, cytokines, chemokines, apoptosis, and stress responses.,These studies have shed new light on the molecular mechanisms of COPD, and suggest novel targets for clinical treatments. | 1 |
Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies.,To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).,Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years.,We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation.,Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs.,0.9 (1.1) per year, p<0.001) compared to non-inflamed ones.,As a descriptive study our results show associations but do not prove causality.,Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.,Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment. | Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease.,However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD).,This is a post-hoc analysis of a study which enrolled a population of adults aged 35-79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000.,In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels.,We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia.,To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures.,In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs.,49.2 (SD 9.1); p < 0.0001].,Among patients with COPD (n = 495) the PF scores (39.9 vs.,45.4) and the PCS (41.9 vs.,45.9) were significantly lower in individuals with anemia compared to those without.,In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003).,There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD.,In patients with moderate to very severe COPD anemia may be associated with worse HRQL.,However, co-morbidities may explain part or all of this association in these patients. | 1 |
Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease.,Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.,To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.,We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality.,Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC.,Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation.,Few studies examined associations with musculoskeletal measures.,Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD.,Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.,CRD42016052075. | Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease.,Comorbidities may frequently occur in COPD patients over 40 yr old.,We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea.,Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea.,Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr.,The prevalence of COPD (FEV1/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%.,Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not.,Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting. | 1 |
Respiratory infections are well-known triggers of chronic respiratory diseases.,Recently, culture-independent tools have indicated that lower airway microbiota may contribute to pathophysiologic processes associated with asthma and chronic obstructive pulmonary disease (COPD).,However, the relationship between upper airway microbiota and chronic respiratory diseases remains unclear.,This study was undertaken to define differences of microbiota in the oropharynx of asthma and COPD patients relative to those in healthy individuals.,To account for the qualitative and quantitative diversity of the 16S rRNA gene in the oropharynx, the microbiomes of 18 asthma patients, 17 COPD patients, and 12 normal individuals were assessed using a high-throughput next-generation sequencing analysis.,In the 259,572 total sequence reads, α and β diversity measurements and a generalized linear model revealed that the oropharynx microbiota are diverse, but no significant differences were observed between asthma and COPD patients.,Pseudomonas spp. of Proteobacteria and Lactobacillus spp. of Firmicutes were highly abundant in asthma and COPD.,By contrast, Streptococcus, Veillonella, Prevotella, and Neisseria of Bacteroidetes dominated in the healthy oropharynx.,These findings are consistent with previous studies conducted in the lower airways and suggest that oropharyngeal airway microbiota are important for understanding the relationships between the various parts of the respiratory tract with regard to bacterial colonization and comprehensive assessment of asthma and COPD. | Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies.,To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).,Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years.,We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation.,Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs.,0.9 (1.1) per year, p<0.001) compared to non-inflamed ones.,As a descriptive study our results show associations but do not prove causality.,Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.,Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment. | 1 |
This study evaluated patterns of pharmacotherapy in chronic obstructive pulmonary disease (COPD) as they relate to recommended guidelines in a prevalent COPD patient population with employer-sponsored health insurance in the US.,Health care claims data from 2007 and 2008 were retrospectively analyzed for the study population defined as patients aged 40 years and older, continuously enrolled during the study period, and having at least one inpatient or one emergency department (ED) visit, or at least two outpatient claims coded with COPD (International Classification of Diseases, 9th Revision, Clinical Modification code 491.xx, 492.xx, 496.xx).,Rates of any pharmacotherapy (both maintenance and reliever), long-acting maintenance pharmacotherapy in patients with an exacerbation history, and short-term treatment of acute exacerbations of COPD were evaluated in the overall population, newly diagnosed, and previously diagnosed patients (including maintenance-naïve and maintenance-experienced).,Stratified analyses were also conducted by age group (40-64 years, ≥65 years) and physician specialty.,A total of 55,361 patients met study criteria of whom 39% were newly diagnosed.,The mean age was 66 years, and 46% were male.,Three-fourths (74%) of all COPD patients had some pharmacotherapy (maintenance or reliever) with less than half (45%) being treated with maintenance medications.,The combination of an inhaled corticosteroid and a long-acting beta-agonist was the most prevalent drug class for maintenance treatment followed by tiotropium.,Only 64% of patients with an exacerbation history had a prescription for a long-acting maintenance medication, and short-term treatment with oral corticosteroids or antibiotics was higher for hospitalization exacerbations compared to ED visit exacerbations (68% vs 44%).,In general, the rates of pharmacotherapy were highest in patients who were maintenance-experienced followed by newly diagnosed and maintenance-naïve.,The majority of COPD patients received maintenance or reliever COPD medications, but less than half received guideline-recommended care, especially those with an exacerbation history or receiving short-term treatment for acute exacerbations. | It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations.,The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations.,914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited.,Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients).,FEV1, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period.,816 patients (89.3%) concluded the study.,FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6.,We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6.,We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. | 1 |
Objective To investigate the long term effectiveness of integrated disease management delivered in primary care on quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with usual care.,Design 24 month, multicentre, pragmatic cluster randomised controlled trial,Setting 40 general practices in the western part of the Netherlands,Participants Patients with COPD according to GOLD (Global Initiative for COPD) criteria.,Exclusion criteria were terminal illness, cognitive impairment, alcohol or drug misuse, and inability to fill in Dutch questionnaires.,Practices were included if they were willing to create a multidisciplinary COPD team.,Intervention General practitioners, practice nurses, and specialised physiotherapists in the intervention group received a two day training course on incorporating integrated disease management in practice, including early recognition of exacerbations and self management, smoking cessation, physiotherapeutic reactivation, optimal diagnosis, and drug adherence.,Additionally, the course served as a network platform and collaborating healthcare providers designed an individual practice plan to integrate integrated disease management into daily practice.,The control group continued usual care (based on international guidelines).,Main outcome measures The primary outcome was difference in health status at 12 months, measured by the Clinical COPD Questionnaire (CCQ); quality of life, Medical Research Council dyspnoea, exacerbation related outcomes, self management, physical activity, and level of integrated care (PACIC) were also assessed as secondary outcomes.,Results Of a total of 1086 patients from 40 clusters, 20 practices (554 patients) were randomly assigned to the intervention group and 20 clusters (532 patients) to the usual care group.,No difference was seen between groups in the CCQ at 12 months (mean difference -0.01, 95% confidence interval -0.10 to 0.08; P=0.8).,After 12 months, no differences were seen in secondary outcomes between groups, except for the PACIC domain “follow-up/coordination” (indicating improved integration of care) and proportion of physically active patients.,Exacerbation rates as well as number of days in hospital did not differ between groups.,After 24 months, no differences were seen in outcomes, except for the PACIC follow-up/coordination domain.,Conclusion In this pragmatic study, an integrated disease management approach delivered in primary care showed no additional benefit compared with usual care, except improved level of integrated care and a self reported higher degree of daily activities.,The contradictory findings to earlier positive studies could be explained by differences between interventions (provider versus patient targeted), selective reporting of positive trials, or little room for improvement in the already well developed Dutch healthcare system.,Trial registration Netherlands Trial Register NTR2268. | Chronic obstructive pulmonary disease (COPD) is a leading cause of disability in all its stages, and death in patients with moderate or severe obstruction.,At present, COPD is suboptimally managed; current health is often not measured properly and hardly taken into account in management plans, and the future risk for patients with regard to health status and quality of life is not being evaluated.,This review addresses the effect of COPD on the lives of patients and examines ways in which existing assessment tools meet physicians’ needs for a standardized, simple method to measure consistently the full impact of COPD on patients in routine clinical practice.,Current assessment of COPD severity tends to focus on airflow limitation, but this does not capture the full impact of the disease and is not well correlated with patient perception of symptoms and health-related quality of life.,Qualitative studies have demonstrated that patients usually consider COPD impact in terms of frequency and severity of symptoms, and physical and emotional wellbeing.,However, patients often have difficulty expressing their disease burden and physicians generally have insufficient time to collect this information.,Therefore, it is important that methods are implemented to help generate a more complete understanding of the impact of COPD.,This can be achieved most efficiently using a quick, reliable, and standardized measure of disease impact, such as a short questionnaire that can be applied in daily clinical practice.,Questionnaires are precision instruments that contribute sensitive and specific information, and can potentially help physicians provide optimal care for patients with COPD.,Two short, easy-to-use, specific measures, ie, the COPD Assessment Test and the Clinical COPD Questionnaire, enable physicians to assess patients’ health status accurately and improve disease management.,Such questionnaires provide important measurements that can assist primary care physicians to capture the impact of COPD on patients’ daily lives and wellbeing, and improve long-term COPD management. | 1 |
Current evidence suggests that a higher blood eosinophil cell count at admission for acute exacerbation of COPD (AECOPD) is associated with a favorable response to systemic steroids.,However, the impact of blood eosinophil counts at admission on post-hospitalization outcomes is still unclear.,The main objective of this study is to investigate readmission outcomes associated with blood eosinophilia following severe COPD exacerbation in patients with infrequent COPD hospitalizations.,This is an observational cohort study design.,We retrospectively analyzed data of patients with a first hospitalization within 5 years for COPD exacerbation between April 2006 and March 2013.,Patients were stratified into the eosinophilic group if the blood eosinophil count on admission was ≥200 cells/µL and/or ≥2% of the total white blood cell (WBC) count.,The primary outcome was 1-year COPD-related readmission.,Secondary outcomes included 1-year all-cause mortality, 1-year all-cause readmission, length of stay, time to COPD-related readmission, and number of 1-year COPD-associated emergency department (ED) and ambulatory visits.,A total of 479 patients were included.,Of whom, 173 were stratified into the eosinophilic group.,Higher blood eosinophil cell count was associated with an increased risk of 1-year COPD-related readmission (OR, 1.83 [95% CI, 1.16-2.89]; P<0.01), a shorter time to first COPD-related readmission (HR, 1.64 [95% CI, 1.14-2.36]; P<0.01), and an increased number of 1-year COPD-related ED visits (incidence rate ratio, 1.78 [95% CI, 1.21-2.61]; P<0.01).,All-cause mortality, all-cause readmission, length of stay, and number of ambulatory visits did not differ between groups.,Higher blood eosinophil cell count at admission for a COPD exacerbation is associated with increased COPD readmission rates in patients with infrequent COPD hospitalizations. | Serum D-dimer is elevated in respiratory disease.,The objective of our study was to investigate the effect of D-dimer on in-hospital and 1-year mortality after acute exacerbations of chronic obstructive pulmonary disease (AECOPD).,Upon admission, we measured 343 AECOPD patients’ serum D-dimer levels and arterial blood gas analysis, and recorded their clinical characteristics.,The level of D-dimer that discriminated survivors and non-survivors was determined using a receiver operator curve (ROC).,The risk factors for in-hospital mortality were identified through univariate analysis and multiple logistic regression analyses.,To evaluate the predictive role of D-dimer for 1-year mortality, univariate and multivariate Cox regression analyses were performed.,In all, 28 patients died, and 315 patients survived in the in-hospital period.,The group of dead patients had lower pH levels (7.35±0.11 vs 7.39±0.05, P<0.0001), higher D-dimer, arterial carbon dioxide tension (PaCO2), C-reactive protein (CRP), and blood urea nitrogen (BUN) levels (D-dimer 2,244.9±2,310.7 vs 768.2±1,078.4 µg/L, P<0.0001; PaCO2: 58.8±29.7 vs 46.1±27.0 mmHg, P=0.018; CRP: 81.5±66, P=0.001; BUN: 10.20±6.87 vs 6.15±3.15 mmol/L, P<0.0001), and lower hemoglobin levels (118.6±29.4 vs 128.3±18.2 g/L, P=0.001).,The areas under the ROC curves of D-dimer for in-hospital death were 0.748 (95% confidence interval (CI): 0.641-0.854).,D-dimer ≥985 ng/L was a risk factor for in-hospital mortality (relative risk =6.51; 95% CI 3.06-13.83).,Multivariate logistic regression analysis also showed that D-dimer ≥985 ng/L and heart failure were independent risk factors for in-hospital mortality.,Both univariate and multivariate Cox regression analyses showed that D-dimer ≥985 ng/L was an independent risk factor for 1-year death (hazard ratio (HR) 3.48, 95% CI 2.07-5.85 for the univariate analysis; and HR 1.96, 95% CI 1.05-3.65 for the multivariate analysis).,D-dimer was a strong and independent risk factor for in-hospital and 1-year death for AECOPD patients. | 1 |
Co-morbidities are common in chronic obstructive pulmonary disease (COPD).,We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients.,Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis.,The prevalence of their co-morbidities was compared with those of 5000 population controls.,The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients.,Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls.,Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments.,Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1.,FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted).,Poor HRQoL also predicted death during the next five years.,The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD. | Comorbidities are frequent in chronic obstructive pulmonary disease (COPD) and significantly impact on patients’ quality of life, exacerbation frequency, and survival.,There is increasing evidence that certain diseases occur in greater frequency amongst patients with COPD than in the general population, and that these comorbidities significantly impact on patient outcomes.,Although the mechanisms are yet to be defined, many comorbidities likely result from the chronic inflammatory state that is present in COPD.,Common problems in the clinical management of COPD include recognizing new comorbidities, determining the impact of comorbidities on patient symptoms, the concurrent treatment of COPD and comorbidities, and accurate prognostication.,The majority of comorbidities in COPD should be treated according to usual practice, and specific COPD management is infrequently altered by the presence of comorbidities.,Unfortunately, comorbidities are often under-recognized and under-treated.,This review focuses on the epidemiology of ten major comorbidities in patients with COPD.,Further, we emphasize the clinical impact upon prognosis and management considerations.,This review will highlight the importance of comorbidity identification and management in the practice of caring for patients with COPD. | 1 |
Few studies have investigated the 24-hour symptom profile in patients with COPD or how symptoms during the 24-hour day are inter-related.,This observational study assessed the prevalence, severity and relationship between night-time, early morning and daytime COPD symptoms and explored the relationship between 24-hour symptoms and other patient-reported outcomes.,The study enrolled patients with stable COPD in clinical practice.,Baseline night-time, early morning and daytime symptoms (symptom questionnaire), severity of airflow obstruction (FEV1), dyspnoea (modified Medical Research Council Dyspnoea Scale), health status (COPD Assessment Test), anxiety and depression levels (Hospital Anxiety and Depression Scale), sleep quality (COPD and Asthma Sleep Impact Scale) and physical activity level (sedentary, moderately active or active) were recorded.,The full analysis set included 727 patients: 65.8% male, mean ± standard deviation age 67.2 ± 8.8 years, % predicted FEV1 52.8 ± 20.5%.,In each part of the 24-hour day, >60% of patients reported experiencing ≥1 symptom in the week before baseline.,Symptoms were more common in the early morning and daytime versus night-time (81.4%, 82.7% and 63.0%, respectively).,Symptom severity was comparable for each period assessed.,Overall, in the week before baseline, 56.7% of patients had symptoms throughout the whole 24-hour day (3 parts of the day); 79.9% had symptoms in ≥2 parts of the 24-hour day.,Symptoms during each part of the day were inter-related, irrespective of disease severity (all p < 0.001).,Early morning and daytime symptoms were associated with the severity of airflow obstruction (p < 0.05 for both).,Night-time, early morning and daytime symptoms were all associated with worse dyspnoea, health status and sleep quality, and higher anxiety and depression levels (all p < 0.001 versus patients without symptoms in each corresponding period).,In each part of the 24-hour day, there was also an association between symptoms and a patient’s physical activity level (p < 0.05 for each period).,More than half of patients experienced COPD symptoms throughout the whole 24-hour day.,There was a significant relationship between night-time, early morning and daytime symptoms.,In each period, symptoms were associated with worse patient-reported outcomes, suggesting that improving 24-hour symptoms should be an important consideration in the management of COPD.,The online version of this article (doi:10.1186/s12931-014-0122-1) contains supplementary material, which is available to authorized users. | Patients with respiratory disease experience disturbed sleep, but there is no widely accepted measure of sleep impairment due to respiratory disease.,We developed and evaluated the psychometric performance of a patient-reported measure to assess the impact on sleep due to respiratory disease, the COPD and Asthma Sleep Impact Scale (CASIS).,Identification of the items forming the CASIS was guided by patient interviews and focus groups.,An observational study involving patients from the US and UK was then conducted to assess the psychometric characteristics of the measure.,Qualitative data from 162 patients were used to develop the CASIS (n = 78 COPD; n = 84 asthma).,The observational study included 311 patients with COPD and 324 patients with asthma.,The final seven items used in the CASIS were identified based on factor and item response theory analyses.,Internal consistency was 0.90 (COPD) and 0.92 (asthma), and test-retest reliability was 0.84 (both groups).,In the COPD sample, CASIS scores were significantly correlated with the Saint George's Respiratory Questionnaire scores (all p < 0.0001) and differed significantly by patient-reported disease severity, exacerbation status, and overall health status (all p ≤ 0.005).,In the asthma sample, CASIS scores were significantly correlated with the Asthma Quality of Life Questionnaire scores (all p < 0.0001) and differed significantly by clinician and patient-reported disease severity, exacerbation status, and overall health status (all p ≤ 0.0005).,The CASIS shows good internal consistency, test-retest reliability, and construct validity and may be useful in helping to understand the impact that COPD and asthma have on sleep outcomes. | 1 |
Background: Although chronic obstructive pulmonary disease (COPD) is a life-limiting disease with a significant symptom burden, the patients are more often referred to nursing homes (NH), than to specialist palliative care (SPC) at the end of life (EOL).,This study aimed to compare patients with COPD in SPC with those in NH and to compare the care provided.,Methods: A national register study was carried out where the Swedish National Airway Register and the Swedish Register of Palliative Care were merged.,COPD patients who died in NHs or short-term facilities were included in the NH group (n = 415) and those who died in SPC were included in the SPC group (n = 355).,Demographic and clinical variables were included from the Swedish National Airway Register and variables concerning EOL care from the Swedish Register of Palliative Care.,Results: Symptom prevalence was similar in NHs and SPC, but symptom assessment (32% vs 20%), symptom relief medication (93-98% in SPC vs 74-90% in NH), EOL discussions (88% vs 66%), and bereavement support (94% vs 67%) were more likely in SPC (in all comparisons p < 0.001).,Younger age and co-habiting increased the probability of dying in SPC (p < 0.001).,Conclusion: Despite similar symptom prevalence, older persons are more likely to be referred to NHs.,If applying a palliative care philosophy in NHs, routine symptom assessment and prescription of rescue medication for frequent symptoms, would be more likely.,Promoting advance care planning and EOL discussions at an earlier stage would result in more prepared patients and families. | Understanding the breadth of patients’ support needs is important for the delivery of person-centered care, particularly in progressive long-term conditions such as chronic obstructive pulmonary disease (COPD).,Existing reviews identify important aspects of managing life with COPD with which patients may need support (support needs); however, none of these comprehensively outlines the full range of support needs that patients can experience.,We therefore sought to systematically determine the full range of support needs for patients with COPD to inform development of an evidence-based tool to enable person-centered care.,We conducted a systematic search and narrative review of the literature.,Medline (Ovid), EMBASE, PsycINFO, Cochrane Library, and CINAHL were systematically searched for papers which included data addressing key aspects of support need, as identified by patients with COPD.,Relevant data were extracted, and a narrative analysis was conducted.,Thirty-one papers were included in the review, and the following 13 domains (broad areas) of support need were identified: 1) understanding COPD, 2) managing symptoms and medication, 3) healthy lifestyle, 4) managing feelings and worries, 5) living positively with COPD, 6) thinking about the future, 7) anxiety and depression, 8) practical support, 9) finance work and housing, 10) families and close relationships, 11) social and recreational life, 12) independence, and 13) navigating services.,These 13 domains of support need were mapped to three of the four overarching categories of need commonly used in relevant national strategy documents (ie, physical, psychological, and social); however, support needs related to the fourth category (spiritual) were notably absent.,This review systematically identifies the comprehensive set of domains of support need for patients with COPD.,The findings provide the evidence base for a tool to help patients identify and express their support needs, which underpins a proposed intervention to enable the delivery of person-centered care: the Support Needs Approach for Patients (SNAP). | 1 |
COPD is among the leading causes of chronic morbidity and mortality in the European Union with an estimated annual economic burden of €25.1 billion.,Various care pathways for COPD exist across Europe leading to different responses to similar problems.,Determining these differences and the similarities may improve health and the functioning of health services.,The aim of this study was to compare COPD patients’ care pathway in five European Union countries including England, Ireland, the Netherlands, Greece, and Germany and to explore health care professionals’ (HCPs) perceptions about the current pathways.,HCPs were interviewed in two stages using a qualitative, semistructured email interview and a face-to-face semistructured interview.,Lack of communication among different health care providers managing COPD and comorbidities was a common feature of the studied care pathways.,General practitioners/family doctors are responsible for liaising between different teams/services, except in Greece where this is done through pulmonologists.,Ireland and the UK are the only countries with services for patients at home to shorten unnecessary hospital stay.,HCPs emphasized lack of communication, limited resources, and poor patient engagement as issues in the current pathways.,Furthermore, no specified role exists for pharmacists and informal carers.,Service and professional integration between care settings using a unified system targeting COPD and comorbidities is a priority.,Better communication between health care providers, establishing a clear role for informal carers, and enhancing patients’ engagement could optimize current care pathways resulting in a better integrated system. | To investigate the magnitude of barriers in access to health services for chronic patients and the socioeconomic and demographic characteristics that affect them.,A cross-sectional study was conducted in 1,594 chronic patients suffering from diabetes, hypertension, COPD and Alzheimer.,Logistic regression analyses were carried out in order to explore the factors related to economic and geographical barriers in access, as well as the determinants of barriers due to waiting lists.,A total of 25% of chronic patients face geographical barriers while 63.5% and 58.5% of them are in front of economic and waiting list barriers, respectively.,Unemployed, low-income and low-educated are more likely to face economic barriers in access.,Moreover, women, low-income patients, and patients with lower health status are more likely to be in front of geographical barriers.,In addition, the probability of waiting lists occurrence is greater for unemployed, employees and low income patients.,Barriers in access can be mainly attributed to income decrease and unemployment.,In this context, health policy measures are essential for removing barriers in access.,Otherwise, inequalities may increase and chronic patients’ health status will be deteriorated.,These consequences imply adverse effects on health expenditure. | 1 |
This study assessed the infectious etiology of patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) with concomitant pneumonia.,Patients admitted to medical wards in an acute hospital were recruited prospectively from May 1, 2004 to April 30, 2005.,Sputum culture, blood culture, paired serology, and nasopharyngeal aspirates (NPA) viral culture and polymerase chain reaction (PCR) studies were performed.,Spirometry was assessed in stable phase at 2-3 months post-hospital discharge.,Seventy eight subjects were admitted for AECOPD with concomitant pneumonia.,The mean (SD) age was 77.1 (7.5) years, with FEV1 of 41.5 (20.8)% predicted normal.,Overall, an infectious etiology could be established in 48.7% of the subjects.,Among the 71 subjects with sputum collected, 40.8% had positive bacterial culture.,The commonest bacteria identified were Streptococcus pneumoniae (8[11.3%]), Pseudomonas aeruginosa (7[9.9%]) and Haemophilus influenzae (7[9.9%]).,Among the 66 subjects with NPA collected, 9.0 and 12.2% had positive viral culture and PCR results, respectively.,The commonest viruses identified by NPA PCR were influenza A (4[6.1%] subjects) and rhinovirus (2[3.0%]).,Paired serology was positive in 4.4%.,Patients on high dose inhaled corticosteroid (ICS) (>1000 mcg beclomethasone-equivalent/day) had a higher rate of positive sputum bacterial culture than those on low-medium dose of ICS (50.0% vs 18.2%, p = 0.02).,An infectious etiology could be established in about half of patients hospitalized with AECOPD and concomitant pneumonia.,The majority of identifiable causes were bacterial.,Patients on high dose ICS might have impaired airway defense as reflected by the higher rate of positive sputum culture. | The inflammatory responses and associated clinical severity of COPD exacerbations are greatly variable, and the determinants of these factors are poorly understood.,We examined the hypothesis that bacteria and viruses may modulate this heterogeneity and that interactions between bacterial and viral infection may affect changes in airway bacterial load and the clinical features and inflammatory responses of exacerbations in patients with COPD.,Prospective cohort study.,Outpatient Department, London Chest Hospital, London, UK.,Thirty-nine patients with COPD.,We prospectively studied 56 COPD exacerbations, obtaining clinical data and paired sputum and serum samples at baseline and exacerbation.,Qualitative and quantitative microbiology, polymerase chain reaction detection for rhinovirus, and estimation of cytokine levels by enzyme-linked immunosorbent assay were performed.,A total of 69.6% of exacerbations were associated with a bacterial pathogen, most commonly Haemophilus influenzae.,Rhinovirus was identified in 19.6% of exacerbations.,The rise in bacterial load at exacerbation correlated with the rise in sputum interleukin (IL)-8 (r = 0.37, p = 0.022) and fall in FEV1 (r = 0.35, p = 0.048).,Exacerbations with both rhinovirus and H influenzae had higher bacterial loads (108.56 cfu/mL vs 108.05cfu/mL, p = 0.018) and serum IL-6 (13.75 pg/mL vs 6.29 pg/mL, p = 0.028) than exacerbations without both pathogens.,In exacerbations with both cold symptoms (a marker of putative viral infection) and a bacterial pathogen, the FEV1 fall was greater (20.3% vs 3.6%, p = 0.026) and symptom count was higher (p = 0.019) than those with a bacterial pathogen alone.,The clinical severity and inflammatory responses in COPD exacerbations are modulated by the nature of the infecting organism: bacterial and viral pathogens interact to cause additional rises in inflammatory markers and greater exacerbation severity. | 1 |
The benefits of pharmacotherapy with tiotropium HandiHaler 18 μg for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated.,However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).,To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.,A randomised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily (via HandiHaler) was performed in maintenance therapy-naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ⩾50 and <80%.,A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93 l (66% predicted)).,Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h (AUC0-3h) at week 24 (primary endpoint): 0.19 vs.,−0.03 l (least-squares mean difference 0.23 l, P<0.001).,FVC AUC0-3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001).,Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS).,Physician’s Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24.,The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.,Tiotropium improved lung function and patient-reported outcomes in maintenance therapy-naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early. | The current mainstay of therapy for chronic obstructive pulmonary disease (COPD) is long-acting bronchodilators.,To date, the effect of indacaterol, a β2-agonist, on activities of daily living in COPD patients is not well understood.,The aim of this study was to evaluate the efficacy of indacaterol with regard to activities of daily living in patients with COPD.,In this nonrandomized open-label study, 23 patients with COPD were instructed to carry an accelerometer for 4 weeks without indacaterol therapy and then for another period of 4 weeks while receiving indacaterol therapy.,The number of steps, duration of moderate or greater physical activity, and energy expenditure were significantly increased after treatment with indacaterol compared with baseline data in all patients with COPD; the metabolic equivalent of task was also significantly enhanced after treatment with indacaterol.,This study provides early evidence that indacaterol improves daily physical activity in patients with COPD. | 1 |
The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role.,Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD).,The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function.,We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD.,Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n = 32), smokers without COPD (n = 212), and smokers with COPD (n = 51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed.,The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers.,Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years.,Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants.,Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups.,A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD.,There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function.,Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung. | Chronic obstructive pulmonary disease (COPD) is associated with increased oxidative and nitrosative stress.,The aim of our study was to assess the importance of these factors in the airways of healthy smokers and symptomatic smokers without airway obstruction, i.e. individuals with GOLD stage 0 COPD.,Exhaled NO (FENO) and induced sputum samples were collected from 22 current smokers (13 healthy smokers without any respiratory symptoms and 9 with symptoms i.e. stage 0 COPD) and 22 healthy age-matched non-smokers (11 never smokers and 11 ex-smokers).,Sputum cell differential counts, and expressions of inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE) were analysed from cytospins by immunocytochemistry.,Eosinophil cationic protein (ECP) and lactoferrin were measured from sputum supernatants by ELISA.,FENO was significantly decreased in smokers, mean (SD) 11.0 (6.7) ppb, compared to non-smokers, 22.9 (10.0), p < 0.0001.,Induced sputum showed increased levels of neutrophils (p = 0.01) and elevated numbers of iNOS (p = 0.004), MPO (p = 0.003), nitrotyrosine (p = 0.003), and 4-HNE (p = 0.03) positive cells in smokers when compared to non-smokers.,Sputum lactoferrin levels were also higher in smokers than in non-smokers (p = 0.02).,Furthermore, we noted four negative correlations between FENO and 1) total neutrophils (r = -0.367, p = 0.02), 2) positive cells for iNOS (r = -0.503, p = 0.005), 3) MPO (r = -0.547, p = 0.008), and 4) nitrotyrosine (r = -0.424, p = 0.03).,However, no major differences were found between never smokers and ex-smokers or between healthy smokers and stage 0 COPD patients.,Our results clearly indicate that several markers of oxidative/nitrosative stress are increased in current cigarette smokers compared to non-smokers and no major differences can be observed in these biomarkers between non-symptomatic smokers and subjects with GOLD stage 0 COPD. | 1 |
To develop reference equations for the Glittre Activities of Daily Living test (Glittre ADL-test) on the basis of anthropometric and demographic variables in apparently healthy individuals.,A secondary objective was to determine the reliability of the equations in a sample of COPD patients.,This was a cross-sectional study including 190 apparently healthy individuals (95 males; median age, 54.5 years [range, 42-65]; median FEV1 = 97% [range, 91-105.2]; and median FVC = 96% [range, 88.5-102]) recruited from the general community and 74 COPD patients (55 males; mean age, 65 ± 8 years; body mass index [BMI] = 25.9 ± 4.7 kg/m2; FEV1 = 36.1 ± 14.1%; and FVC = 62.7 ± 16.1%) recruited from a pulmonary rehabilitation center.,The mean time to complete the Glittre ADL-test was 2.84 ± 0.45 min.,In the stepwise multiple linear regression analysis, age and height were selected as Glittre ADL-test performance predictors, explaining 32.1% (p < 0.01) of the total variance.,Equation 1 was as follows: Glittre ADL-testpredicted = 3.049 + (0.015 × ageyears) + (−0.006 × heightcm).,Equation 2 included age and BMI and explained 32.3% of the variance in the test, the equation being as follows: Glittre ADL-testpredicted = 1.558 + (0.018 × BMI) + (0.016 × ageyears).,The reference equations for the time to complete the Glittre ADL-test were based on age, BMI, and height as independent variables and can be useful for predicting the performance of adult individuals.,The predicted values appear to be reliable when applied to COPD patients. | Cardiovascular diseases and skeletal muscle dysfunction are common comorbidities in COPD.,Hand grip strength (HGS) is related to general muscle strength and is associated with cardiovascular disease and all-cause mortality, while the results from small selected COPD populations are contradictory.,The aim of this population-based study was to compare HGS among the subjects with and without COPD, to evaluate HGS in relation to COPD severity, and to evaluate the impact of heart disease.,Data were collected from the Obstructive Lung disease in Northern Sweden COPD study, where the subjects with and without COPD have been invited to annual examinations since 2005.,In 2009-2010, 441 subjects with COPD (postbronchodilator forced expiratory volume in 1 second [FEV1]/vital capacity <0.70) and 570 without COPD participated in structured interviews, spirometry, and measurements of HGS.,The mean HGS was similar when comparing subjects with and without COPD, but those with heart disease had lower HGS than those without.,When compared by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, the subjects with GOLD 3-4 had lower HGS than those without COPD in both sexes (females 21.4 kg vs 26.9 kg, P=0.010; males 41.5 kg vs 46.3 kg, P=0.038), and the difference persisted also when adjusted for confounders.,Among the subjects with COPD, HGS was associated with FEV1% of predicted value but not heart disease when adjusted for height, age, sex, and smoking habits, and the pattern was similar among males and females.,In this population-based study, the subjects with GOLD 3-4 had lower HGS than the subjects without COPD.,Among those with COPD, HGS was associated with FEV1% of predicted value but not heart disease, and the pattern was similar in both sexes. | 1 |
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