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Exacerbations of chronic obstructive pulmonary disease (COPD) are episodes of worsening of symptoms, leading to substantial morbidity and mortality.,COPD exacerbations are associated with increased airway and systemic inflammation and physiological changes, especially the development of hyperinflation.,They are triggered mainly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation.,Some patients are particularly susceptible to exacerbations, and show worse health status and faster disease progression than those who have infrequent exacerbations.,Several pharmacological interventions are effective for the reduction of exacerbation frequency and severity in COPD such as inhaled steroids, long-acting bronchodilators, and their combinations.,Non-pharmacological therapies such as pulmonary rehabilitation, self-management, and home ventilatory support are becoming increasingly important, but still need to be studied in controlled trials.,The future of exacerbation prevention is in assessment of optimum combinations of pharmacological and non-pharmacological therapies that will result in improvement of health status, and reduction of hospital admission and mortality associated with COPD. | The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood.,Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events.,In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40-85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses.,Results are presented for subjects in the full cohort, followed for 1 year.,Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses.,The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50).,At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus.,Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)).,When NTHi was detected, the increased risk of exacerbation was greater in high season (October-March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)).,Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%).,A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031).,AECOPD aetiology varies with season.,Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection.,Results, NCT01360398. | 1 |
This study aimed to measure the true burden of COPD by calculating incremental direct and indirect costs.,Direct medical resource use, productivity metrics, and COPD-specific resource use and costs were also evaluated.,This was a retrospective, observational, matched cohort study using administrative claims data from the Truven Health MarketScan® Commercial Claims and Encounters and the Health and Productivity Management databases (2007-2010).,Working-age (18-65 years) patients with COPD were identified as having at least one hospitalization or one emergency department visit or two outpatient visits.,Patients in the non-COPD cohort did not have a diagnosis of COPD during the study period.,Outcomes were evaluated in the first full calendar year after the year of identification (index).,Of the 5,701 patients with COPD identified, 3.6% patients were frequent exacerbators (≥2), 10.4% patients were infrequent exacerbators (1), and 86% patients were non-exacerbators (0).,When compared with the 17,103 patients without COPD, the incremental direct cost of COPD was estimated at $6,246/patient/year (95% confidence interval: $4,620, $8,623; P<0.001).,Loss in productivity was significantly greater in patients with COPD, with an average of 5 more days/year of absence from work and incremental indirect costs from short-term disability of $641 (P<0.001).,Direct costs for frequent exacerbators ($17,651/year) and infrequent exacerbators ($14,501/year) were significantly higher than those for non-exacerbators ($11,395, P<0.001).,Working-age patients with COPD incur statistically significantly higher direct and indirect costs and use more resources compared with those who do not have COPD. | Chronic obstructive pulmonary disease (COPD) is a very prevalent and invalidating disease.,The aim of this study was to analyze the burden borne by informal caregivers of patients with COPD.,We used the Survey on Disabilities, Personal Autonomy, and Dependency Situations (Encuesta sobre Discapacidad, Autonomía personal y Situaciones de Dependencia [EDAD]-2008) to obtain information on the characteristics of disabled individuals with COPD and their caregivers in Spain.,Additionally, statistical multivariate analyses were performed to analyze the impact that an increase in dependence would have on the problems for which caregivers provide support, in terms of health, professional, and leisure/social dimensions.,A total of 461,884 individuals with one or more disabilities and with COPD were identified, and 220,892 informal caregivers were estimated.,Results showed that 35% of informal caregivers had health-related problems due to the caregiving provided; 83% had leisure/social-related problems; and among caregivers of working age, 38% recognized having profession-related problems.,The probability of a problem arising was significantly associated with the degree of dependence of the patient receiving care.,Caregivers of patients with great dependence showed a 39% higher probability of presenting health-related problems, 27% more professional problems, and 23% more leisure problems compared with those with nondependent patients.,The results show the large impact on society in terms of the welfare of informal caregivers of patients with COPD.,A higher level of dependence was associated with more severe problems in caregivers, in all dimensions. | 1 |
Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail.,Using the baseline data of the COSYCONET cohort we addressed this question.,Data from 1746 COPD patients (GOLD stage 1-4; mean age 64.6 y, mean FEV1%pred 57%) were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex (CVC; including arterial hypertension, cardiac failure, ischemic heart disease).,Risk factors comprised age, gender, BMI, and packyears of smoking.,The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters.,Hyperlipidemia (prevalence 42.9%) was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV1) when adjusting for its multiple relationships to risk factors and other comorbidities.,These findings were robust in various statistical analyses.,The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data.,In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD.,This surprising result might be due to different COPD phenotypes in these patients or related to effects of medication. | On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD).,However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear.,Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster.,Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD.,Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression.,Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated.,We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001).,Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV1 (p = 0.0024) and the FEV1/VC ratio (p = 0.0005).,Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression.,Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code.,Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD. | 1 |
Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD).,Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer.,The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials.,Bronchodilator responses and safety assessments supported dose selection.,Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 μg twice daily [BID]) or aclidinium bromide 400 μg BID.,The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV1).,Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE.,Lung function data collected in both studies were pooled.,The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects.,On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups.,Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV1 (12.5 μg BID: 0.122 L; 25 μg BID: 0.123 L; 50 μg BID: 0.137 L) and FEV1 AUC0-12 (12.5 μg BID: 0.145 L; 25 μg BID: 0.178 L; 50 μg BID: 0.180 L).,The improvements in lung function for the glycopyrrolate 25 and 50 μg BID doses were comparable to those with aclidinium bromide 400 μg BID (FEV1: 0.149 L; FEV1 AUC0−12: 0.172 L).,Acceptable safety profiles were observed across all groups in both studies.,The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 μg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD.,The online version of this article (10.1186/s12931-017-0681-z) contains supplementary material, which is available to authorized users. | Exercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD).,We assessed the effects of glycopyrronium bromide (NVA237), a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD.,Patients were randomized to a cross-over design of once-daily NVA237 50 μg or placebo for 3 weeks, with a 14-day washout.,Exercise endurance, inspiratory capacity (IC) during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales), and transition dyspnea index were measured on Days 1 and 21 of treatment.,The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21.,A total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted).,Ninety-five patients completed the study.,On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001); the effect was also significant from Day 1, with an increase of 10%.,Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study.,This was accompanied by inverse decreases in residual volume and functional residual capacity.,NVA237 was superior to placebo (P < 0.05) in decreasing leg discomfort (Borg CR10 scale) on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime).,The safety profile of NVA237 was similar to that of the placebo.,NVA237 50 μg once daily produced immediate and significant improvement in exercise tolerance from Day 1.,This was accompanied by sustained reductions in lung hyperinflation (indicated by sustained and significant improvements in IC at isotime), and meaningful improvements in trough FEV1 and dyspnea.,Improvements in exercise endurance increased over time, suggesting that mechanisms beyond improved lung function may be involved in enhanced exercise tolerance.,(ClinicalTrials.gov Identifier: NCT01154127). | 1 |
The expression of HDAC2 is reported as reduced in chronic obstructive pulmonary disease (COPD).,We assessed HDAC2 expression within the airways of smokers and subjects with COPD and effects of inhaled corticosteroids (ICS), using immuno-histology to contrast with previous molecular methodology.,Endobronchial biopsies (ebb) from current smokers with COPD (COPD-CS; n = 15), ex-smokers with COPD (COPD-ES; n = 17), smokers with normal lung function (NS; n = 16) and normal controls (NC; n = 9) were immunostained for HDAC2.,A double-blinded, randomized, placebo-controlled 6 months intervention study assessed effects of ICS on HDAC2 in 34 COPD subjects.,There was no difference in epithelial HDAC2 staining in all groups.,There was a significant reduction in total cell numbers in the lamina propria (LP) in COPD-CS and NS (p<0.05).,LP cellularity correlated inversely with smoking history in COPD-CS (R = −0.8, p<0.003).,HDAC2 expression increased markedly in NS (p<0.001); in contrast COPD-CS was associated with suppressed signal (p<0.03), while normal in COPD-ES.,ICS did not affect HDAC2 cell staining.,Our findings suggest that airway HDAC2 expression is increased in the LP by smoking itself, but is reduced in COPD.,Ex-smokers have normalised HDAC2 cell expression, but ICS had no effect.,The paper emphasise the pit-falls of relying on molecular data alone to define airway changes.,Clinical Trial Registration Information:,The Australian New Zealand Clinical Trials Registry (ANZCTR),ACTRN12612001111864 | 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 |
Alpha-1-antitrypsin deficiency is a relatively prevalent, but under-diagnosed, genetic disease.,The objective of this study was to assess whether the systematic screening for alpha-1-antitrypsin deficiency in all patients with chronic obstructive pulmonary disease from a tertiary service has an impact on the number of patients being diagnosed with this condition.,Chronic obstructive pulmonary disease patients were screened for alpha-1-antitrypsin deficiency using immunonephelometry.,The presence of a mutation was confirmed by molecular study of the SERPINA1 gene or by genetic sequencing, as needed.,A total of 551 patients with chronic obstructive pulmonary disease were analyzed.,Among these, 40 (7.2%) had some genetic mutation, while 11 (2%) had a Pi*ZZ genotype, resulting in severe respiratory illness.,The systematic evaluation of chronic obstructive pulmonary disease patients revealed that screening is an effective method to diagnose alpha-1-antitrypsin deficiency.,Early diagnosis may facilitate smoking cessation and initiation of treatment to maintain lung function. | Early life events may predispose to the development of chronic lung disease in adulthood.,To provide an update on current knowledge of early nongenetic origins of COPD.,Systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,A total of 16 studies, comprising 69,365 individuals, met the predefined criteria and were included in the present review.,Studies have shown that in utero tobacco exposure, low birth weight, preterm birth, and respiratory diseases, primarily asthma and pneumonia, in early childhood are associated with lung function impairment later in childhood, and by that predispose to subsequent development of COPD, although the causal association between childhood respiratory diseases and COPD has been questioned in one study.,Environmental tobacco exposure has also been shown to have negative impact on lung function in childhood possibly leading to COPD in adulthood, although it is at present not possible to clearly distinguish between the impact of active and the environmental tobacco exposure on subsequent development of COPD.,Tobacco exposure in utero and early life is a risk factor for subsequent development of COPD.,Furthermore, low birth weight, lower respiratory tract infections and asthma, including wheezy bronchitis, in childhood also seem to be important determinants for later development of COPD.,Early life insults may, therefore, be crucial to COPD development. | 1 |
The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms.,The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.,In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks.,The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26.,Overall, 676 patients completed the study.,The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met.,QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001).,QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001).,QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use.,However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.,Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%).,The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%).,These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year. | Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms and pathological consequences.,Although primarily viewed as a respiratory disease, COPD has both pulmonary and extrapulmonary effects, which have an impact on many aspects of physical, emotional, and mental well-being.,Traditional assessment of COPD relies heavily on measuring lung function, specifically forced expiratory volume in 1 second (FEV1).,However, the evidence suggests that FEV1 is a relatively poor correlate of symptoms such as breathlessness and the impact of COPD on daily life.,Furthermore, many consequences of the disease, including anxiety and depression and the ability to perform daily activities, can only be described and reported reliably by the patient.,Thus, in order to provide a comprehensive view of the effects of interventions in clinical trials, it is essential that spirometry is accompanied by assessments using patient-reported outcome (PRO) instruments.,We provide an overview of patient-reported outcome concepts in COPD, such as breathlessness, physical functioning, and health status, and evaluate the tools used for measuring these concepts.,Particular attention is given to the newly developed instruments emerging in response to recent regulatory guidelines for the development and use of PROs in clinical trials.,We conclude that although data from the development and validation of these new PRO instruments are emerging, to build the body of evidence that supports the use of a new instrument takes many years.,Furthermore, new instruments do not necessarily have better discriminative or evaluative properties than older instruments.,The development of new PRO tools, however, is crucial, not only to ensure that key COPD concepts are being reliably measured but also that the relevant treatment effects are being captured in clinical trials.,In turn, this will help us to understand better the patient’s experience of the disease. | 1 |
Several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment.,These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group.,This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD.,In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy.,We used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD.,Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points.,Disease severity was using Forced Expiratory Volume in one second (FEV1); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index.,Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking.,COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043-6.64).,Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases).,Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation ≤88% (OR 5.45; 95% CI 1.014-29.2; P = 0.048).,Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07-0.27; P < 0.0001).,COPD is a major risk factor for cognitive impairment.,Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective.,Health care providers should consider screening their COPD patients for cognitive impairment. | Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain.,This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities.,Nine healthy controls were compared with 18 age- and education-matched medically stable COPD patients, half of whom were oxygen-dependent.,Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition.,ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p ≤ 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model.,Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures.,Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance.,Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation).,This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities. | 1 |
Natriuretic peptides (NPs) are a family of prognostic biomarkers in patients with heart failure (HF).,HF is one of the most frequent comorbidities in patients with chronic obstructive pulmonary disease (COPD).,However, the prognostic role of NP in COPD patients remains unclear.,The aim of this meta-analysis was to evaluate the relation between NP and all-cause mortality in COPD patients.,We performed a systematic review and meta-analysis of observational studies assessing prognostic implications of elevated NP levels on all-cause mortality in COPD patients.,Nine studies were considered for qualitative analysis for a total of 2788 patients.,Only two studies focused on Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and brain natriuretic peptide (BNP), respectively, but seven studies focused on pro-BNP (NT-proBNP) and were included in the quantitative analysis.,Elevated NT-proBNP values were related to increased risk of all-cause mortality in COPD patients both with and without exacerbation (hazard ratio (HR): 2.87, p < 0.0001 and HR: 3.34, p = 0.04, respectively).,The results were confirmed also after meta-regression analysis for confounding factors (previous cardiovascular history, hypertension, HF, forced expiratory volume at 1 second and mean age).,NT-proBNP may be considered a reliable predictive biomarker of poor prognosis in patients with COPD. | The purpose of this study was to describe the prevalence of renal and hepatic disease, related laboratory abnormalities, and potentially hepatotoxic and nephrotoxic medication use in a population-based cohort of persons with chronic obstructive pulmonary disease (COPD).,This was a retrospective case-control cohort analysis of COPD patients enrolled in one regional health system for at least 12 months during a 36-month study period (n = 2284).,Each COPD patient was matched by age and gender to up to three persons not diagnosed with COPD (n = 5959).,The mean age for cases and controls was 70.3 years, and 52.5% were women.,The COPD cohort had significantly higher prevalences (cases/100) of acute, chronic, and unspecified renal failure as compared with controls (1.40 versus 0.59, 2.89 versus 0.79, and 1.09 versus 0.44, respectively).,Among the cases, 31.3% had at least one renal or urinary tract diagnosis during the study period, as compared with 21.1% of controls.,COPD cases also had more gallbladder disease (2.76 versus 1.63) and pancreatic disease (1.40 versus 0.60), but not hepatic disease.,COPD patients were more likely to have at least one serum creatinine level (5.1 versus 2.1) or liver aspartate aminotransferase level (4.5 versus 2.7) that was more than twice the upper limit of normal.,COPD patients had prescription fills for an average of 17.6 potentially nephrotoxic and 27.4 hepatotoxic drugs during the study period, as compared with 13.6 and 19.9 for the controls (P value for all comparisons < 0.01).,COPD patients have a substantially increased prevalence of renal, gallbladder, and pancreatic diseases, as well as abnormal renal and hepatic laboratory values, but not diagnosed liver disease.,COPD patients are also more likely to be prescribed medications with potentially toxic renal or hepatic side effects. | 1 |
Background: There is a paucity of lung specific biomarkers to diagnose exacerbations of chronic obstructive pulmonary disease (COPD) and to track their progression.,Surfactant protein D (SP-D) is a pulmonary collectin regulating the innate immunity of the lung and its serum expression is perturbed in COPD.,However, it is not known whether serum levels change during exacerbations.,We sought to determine whether serum SP-D levels are raised in COPD exacerbations.,Objectives: To determine whether or not patients with exacerbations have elevated serum SP-D levels compared with asymptomatic controls, stable disease.,Study design: case control study.,Methods: We measured serum SP-D levels from patients with stable COPD (n = 14), patients experiencing acute exacerbations (n = 13) and in control subjects (n = 54) using a specific immunoassay and compared the levels using analysis of variance.,Results: Serum SP-D levels were significantly increased in patients who experienced an acute exacerbation (227 ± 120 ng/mL) compared to patients with stable disease (151 ± 83 ng/mL) or control subjects (128 ± 65 ng/mL; p = 0.003).,Serum SP-D levels were also found to be inversely related to various lung function parameters including FEV1/FVC% predicted.,Conclusions: Our study suggests that serum SP-D levels are increased in patients during exacerbations and may be a potential diagnostic biomarker for COPD exacerbations. | There is a paucity of surrogate lung-specific biological markers that can be used to track disease progression and predict clinical outcomes in chronic obstructive pulmonary disease (COPD).,The principal aim of this pilot study was to determine whether circulating surfactant protein D (SPD) or Clara Cell protein-16 (CC16) levels are associated with lung function or health status in patients with severe COPD.,We studied 23 patients with advanced COPD.,Lung function measurements, Chronic Respiratory Disease Questionnaire (CRQ) scores, and serum levels of SPD, CC16, and C-reactive protein (CRP) were determined at baseline and at 3 months.,At baseline, FEV1 was inversely associated with serum SPD levels (P = 0.045) but not with CC16 (P = 0.675) or CRP levels (P = 0.549).,Over a 3 month period, changes in SPD levels correlated significantly with changes in CRQ scores (adjusted P = 0.008) such that patients who had the largest declines in serum SPD levels experienced the largest gains in health status.,The association was particularly notable between circulating SPD level and the dyspnea domain of the CRQ score (P = 0.018).,Changes in CC16 or CRP levels did not correlate with changes in CRQ scores.,Changes in serum SPD levels tracked well with changes in health status over a 3 month period in patients with severe COPD.,These data suggest that circulating SPD levels may be useful biomarkers to track health outcomes of COPD patients. | 1 |
The morbidity and mortality associated with COPD exacts a considerable economic burden.,Comorbidities in COPD are associated with poor health outcomes and increased costs.,Our objective was to assess the impact of comorbidities on COPD-associated costs in a large administrative claims dataset.,This was a retrospective observational study of data from the Truven Health MarketScan Commercial Claims and Encounters and the MarketScan Medicare Supplemental Databases from January 1, 2009, to September 30, 2012.,Resource consumption was measured from the index date (date of first occurrence of non-rule-out COPD diagnosis) to 360 days after the index date.,Resource use (all-cause and disease-specific [ie, COPD- or asthma-related] ED visits, hospitalizations, office visits, other outpatient visits, and total length of hospital stay) and health-care costs (all-cause and disease-specific costs for ED visits, hospitalizations, office visits, and other outpatient visits and medical, prescription, and total health-care costs) were assessed.,Generalized linear models were used to evaluate the impact of comorbidities on total health-care costs, adjusting for age, sex, geographic location, baseline health-care use, employment status, and index COPD medication.,Among 183,681 patients with COPD, the most common comorbidities were cardiovascular disease (34.8%), diabetes (22.8%), asthma (14.7%), and anemia (14.2%).,Most patients (52.8%) had one or two comorbidities of interest.,The average all-cause total health-care costs from the index date to 360 days after the index date were highest for patients with chronic kidney disease ($41,288) and anemia ($38,870).,The impact on total health-care costs was greatest for anemia ($10,762 more, on average, than a patient with COPD without anemia).,Our analysis demonstrated that high resource use and costs were associated with COPD and multiple comorbidities. | To examine quality of life, work productivity, and health care resource use among employed adults ages 40-64 years with chronic obstructive pulmonary disease (COPD) in the United States.,Data from the 2009 National Health and Wellness Survey were used.,All employed adults ages 40-64 years with or without a self-reported diagnosis of COPD were included in the study.,Impact on quality of life (using the mental and physical component summary scores and health utilities from the Short Form-12v2), work productivity and activity impairment (using the Work Productivity and Activity Impairment questionnaire), and resource use were analyzed using regression modeling.,There were 1112 employed adults with COPD versus 18,912 employed adults without COPD.,After adjusting for demographics and patient characteristics, adults with COPD reported significantly lower mean levels of mental component summary (46.8 vs 48.5), physical component summary (45.6 vs 49.2), and health utilities (0.71 vs 0.75) than adults without COPD.,Workers with COPD reported significantly greater presenteeism (18.9% vs 14.3%), overall work impairment (20.5% vs 16.3%), and impairment in daily activities (23.5% vs 17.9%) than adults without COPD.,Employed adults with COPD also reported more mean emergency room visits (0.21 vs 0.12) and more mean hospitalizations (0.10 vs 0.06) in the previous 6 months than employed adults without COPD.,All of the above differences were significant at two-sided P < 0.05.,After adjusting for various confounders, employed adults with COPD reported significantly lower quality of life and work productivity, and increased health care resource utilization than employed adults without COPD.,These results highlight the substantial impact and burden of COPD in the United States workforce. | 1 |
To evaluate fluticasone propionate/formoterol (FP/FORM) in COPD.,COPD patients with forced expiratory volume in 1 s (FEV1) ≤50% predicted and ≥1 moderate/severe COPD exacerbation in the last 12 months were randomized to FP/FORM 500/20 or 250/10 µg bid, or formoterol (FORM) 12 µg bid for 52 weeks.,The primary outcome was the annualized rate of moderate/severe COPD exacerbations.,In total, 1,765 patients were randomized.,There were fewer discontinuations with FP/FORM 500/20 µg (20.6%) and 250/10 µg (24.0%) compared with FORM (26.1%).,None of the two FP/FORM doses reduced the moderate/severe exacerbation rate versus FORM (rate ratios [RR]: 0.93; P≤0.402).,There was a trend toward a lower moderate/severe exacerbation rate with FP/FORM 500/20 µg versus FORM in patients with ≥2 exacerbations in the preceding year (RR: 0.79; P=0.084).,Pre- and post-dose FEV1 and forced vital capacity were greater with FP/FORM 500/20 µg versus FORM (P≤0.039).,There was a trend toward a lower EXAcerbations of Chronic pulmonary disease Tool (EXACT) exacerbation rate with FP/FORM 500/20 µg versus FORM (RR: 0.87; P=0.077).,There were more St George’s Respiratory Questionnaire for COPD (SGRQ-C) responders with FP/FORM 500/20 µg than FORM (odds ratios [OR] at weeks 6, 23 and 52 ≥1.28; P≤0.054).,EXACT-respiratory symptoms total and breathlessness scores were lower with both FP/FORM 500/20 µg and 250/10 µg versus FORM (P≤0.066).,Acute β2-agonist-induced effects and 24-hour Holter findings were similar for all treatments.,Mean 24-hour urinary cortisol was similarly reduced with both FP/FORM doses.,Radiologically confirmed pneumonia was seen in 2.4%, 3.2% and 1.5% of FP/FORM 500/20 µg, FP/FORM 250/10 µg and FORM-treated patients, respectively.,Adverse events were otherwise similar across treatment groups.,FP/FORM did not reduce exacerbation rates versus FORM.,Numerical benefits were observed with FP/FORM 500/20 µg versus FORM for secondary variables, including lung function, EXACT exacerbations, SGRQ-C and EXACT-respiratory symptoms total and breathlessness scores.,Few efficacy differences were evident between FP/FORM 250/10 µg and FORM.,Pneumonia was more frequent in FP/FORM-treated patients, although the absolute difference was low.,Adverse events were otherwise similar between treatments. | Initial use of inhaled corticosteroid therapy is common in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A or B chronic obstructive pulmonary disease, contrary to GOLD guidelines.,We investigated UK prescribing of inhaled corticosteroid therapy in these patients, to identify predictors of inhaled corticosteroid use in newly diagnosed chronic obstructive pulmonary disease patients.,A cohort of newly diagnosed GOLD A/B chronic obstructive pulmonary disease patients was identified from the UK Clinical Practice Research Datalink (June 2005-June 2015).,Patients were classified by prescribed treatment, with those receiving inhaled corticosteroid-containing therapy compared with those receiving long-acting bronchodilators without inhaled corticosteroid.,In all, 29,815 patients with spirometry-confirmed chronic obstructive pulmonary disease were identified.,Of those prescribed maintenance therapy within 3 months of diagnosis, 63% were prescribed inhaled corticosteroid-containing therapy vs. 37% prescribed non-inhaled corticosteroid therapy.,FEV1% predicted, concurrent asthma diagnosis, region, and moderate exacerbation were the strongest predictors of inhaled corticosteroid use in the overall cohort.,When concurrent asthma patients were excluded, all other co-variates remained significant predictors.,Other significant predictors included general practitioner practice, younger age, and co-prescription with short-acting bronchodilators.,Trends over time showed that initial inhaled corticosteroid prescriptions reduced throughout the study, but still accounted for 47% of initial prescriptions in 2015.,These results suggest that inhaled corticosteroid prescribing in GOLD A/B patients is common, with significant regional variation that is independent of FEV1% predicted.,Inhaled steroids are often prescribed to early-stage chronic lung disease patients in the UK despite guidelines to the contrary.,Patients newly diagnosed with early-stage chronic obstructive pulmonary disease (COPD) should not be prescribed inhaled corticosteroids (ICS), because they carry an increased risk of side effects such as pneumonia and osteoporosis.,ICS should be reserved for patients with severe COPD and frequent exacerbations.,James Chalmers at the Scottish Centre for Respiratory Research, Dundee, and co-workers examined prescribed medication data from the UK spanning 10 years, to determine key predictors of ICS prescription during early-stage COPD.,Of 29,815 patients identified, an average of 63% were prescribed ICS upon diagnosis, regardless of disease severity.,Younger patients were more likely to receive ICS, possibly due to co-morbidity with chronic asthma, and particular UK regions and medical practices prescribed ICS more readily than others. | 1 |
Research has suggested a significant burden for patients with asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS).,However, few studies have studied this population in the People’s Republic of China, a region in the midst of rapid epidemiological change with respect to respiratory disease.,The aim of this study was to assess the prevalence of ACOS and its association with patient outcomes in urban China.,Data from the 2010, 2012, and 2013 China National Health and Wellness Survey, an Internet-based survey of adults in urban China, were used (N=59,935).,Respondents were categorized into one of four groups based on self-reported physician diagnoses: ACOS, asthma only, COPD only, or control (ie, no asthma or COPD).,A propensity score matching procedure was conducted to cull the control group into a subgroup (ie, matched controls) who resembled patients with ACOS, asthma only, and COPD only.,These four groups (ACOS, asthma only, COPD only, matched controls) were then compared with respect to health status (Short Form-12 version 2/Short Form-36 version 2), work productivity, and health care resource use using generalized linear models.,Patients with ACOS (N=366) comprised 0.61% of the adult population, 30.73% of the asthma population, and 18.60% of the COPD population in the People’s Republic of China.,Patients with ACOS reported significantly worse health status (eg, health utilities =0.63, 0.66, 0.63, and 0.69 for ACOS, COPD only, asthma only, and matched controls, respectively) and significantly greater work impairment (eg, overall work impairment =43.65%, 35.19%, 48.55%, and 29.80%, respectively) and health care resource use (eg, physician visits in the past 6 months =5.13, 3.84, 4.65, and 2.39, respectively) compared with matched controls and patients with COPD only.,Few significant differences were observed between patients with ACOS and asthma only.,Patients with ACOS have a greater comorbidity burden and significantly worse health outcomes compared with COPD only patients and matched controls.,Better management of these patients may help to improve their outcomes. | Epidemiologic studies investigating the differences in respiratory outcomes between asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) and chronic obstructive pulmonary disease (COPD) in an Asian population are lacking.,We conducted a population-based cohort study to compare the incidence of acute respiratory events between ACOS and COPD cohorts in Taiwan.,This study investigated the incidence of acute respiratory events, namely, pneumonia, acute exacerbation, acute respiratory failure, and cardiopulmonary arrest, in 8571 patients with physician-diagnosed ACOS between 2000 and 2007 from the Longitudinal Health Insurance Database.,The comparison cohort comprised 17,088 COPD patients, frequency-matched according to age, sex, and the index-year.,The duration of follow-up was measured for each patient from the index date to 5 years thereafter.,We used univariable and multivariable Poisson regression models to analyze the risk of acute respiratory events by including the variables of sex, age, and comorbidity.,The overall prevalence of ACOS was approximately 17.4% in patients with COPD.,The prevalence of ACOS increased with age.,During the 5-year follow-up, a greater incidence of acute respiratory events was observed in the ACOS cohort than in the COPD cohort (11.5 and 4.62, per 100 person-years, respectively) with an adjusted incidence rate ratio (IRR) of 1.72 (95% confidence interval [CI] = 1.63-1.81).,Compared with the COPD cohort, the ACOS patients had a 1.13-fold adjusted IRR of pneumonia (95% CI = 1.07-1.20) and a 2.58-fold adjusted IRR of acute exacerbation (95% CI = 2.43-2.74).,Clinicians should be aware of frequent exacerbation of ACOS and prescribe appropriate treatment. | 1 |
Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline.,Pathological inflammation is worsened by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens.,Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium.,Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes.,This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria.,The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage.,AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA).,SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils.,Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1.,We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria. | Early life events may predispose to the development of chronic lung disease in adulthood.,To provide an update on current knowledge of early nongenetic origins of COPD.,Systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,A total of 16 studies, comprising 69,365 individuals, met the predefined criteria and were included in the present review.,Studies have shown that in utero tobacco exposure, low birth weight, preterm birth, and respiratory diseases, primarily asthma and pneumonia, in early childhood are associated with lung function impairment later in childhood, and by that predispose to subsequent development of COPD, although the causal association between childhood respiratory diseases and COPD has been questioned in one study.,Environmental tobacco exposure has also been shown to have negative impact on lung function in childhood possibly leading to COPD in adulthood, although it is at present not possible to clearly distinguish between the impact of active and the environmental tobacco exposure on subsequent development of COPD.,Tobacco exposure in utero and early life is a risk factor for subsequent development of COPD.,Furthermore, low birth weight, lower respiratory tract infections and asthma, including wheezy bronchitis, in childhood also seem to be important determinants for later development of COPD.,Early life insults may, therefore, be crucial to COPD development. | 1 |
We aimed to characterise and quantify the incidence of common infectious agents in acute exacerbations of chronic obstructive pulmonary disease (COPD) requiring ventilation, with a focus on respiratory viruses.,An epidemiological study conducted over 3 years.,A 12-bed intensive care unit (ICU).,ICU patients over 45 years of age with a primary diagnosis of COPD exacerbation requiring non-invasive ventilation (NIV) or ventilation via endotracheal tube (ETT).,Nasopharyngeal aspirates (NPA) and posterior pharyngeal swabs (PS) were tested for viruses with immunofluorescence assay (IFA), virus culture (VC) and polymerase chain reaction (PCR).,Paired virus and atypical pneumonia serology assays were taken.,Blood, sputum and endotracheal aspirates were cultured for bacteria.,107 episodes in 105 patients were recorded.,Twenty-three (21%) died within 28 days.,A probable infectious aetiology was found in 69 patient episodes (64%).,A virus was identified in 46 cases (43%), being the sole organism in 35 cases (33%) and part of a mixed infection in 11 cases (10%).,A probable bacterial aetiology was found in 25 cases (23%).,There was no statistically significant difference in clinical characteristics or outcomes between the group with virus infections and that without.,Forty-six (43%) of the patients with COPD exacerbation requiring mechanical ventilation had a probable viral pathogen.,Prodromal, clinical and outcome parameters did not distinguish virus from non-virus illness.,PCR was the most sensitive whilst virus culture was the least of virus assays.,The electronic reference of this article is http://dx.doi.org/10.1007/s00134-006-0202-x.,The online full-text version of this article includes electronic supplementary material.,This material is available to authorised users and can be accessed by means of the ESM button beneath the abstract or in the structured full-text article.,To cite or link to this article you can use the above reference. | Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation.,Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood.,Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists.,We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients.,We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II).,Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage.,All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage.,These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1.,There were no severe exacerbations or other adverse events.,Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation. | 1 |
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. | Fat-free mass (FFM) depletion marks the imbalance between tissue protein synthesis and breakdown in chronic obstructive pulmonary disease (COPD).,To date, the role of essential amino acid supplementation (EAAs) in FFM repletion has not been fully acknowledged.,A pilot study was undertaken in patients attending pulmonary rehabilitation.,28 COPD patients with dynamic weight loss > 5% over the last 6 months were randomized to receive EAAs embedded in a 12-week rehabilitation program (EAAs group n = 14), or to the same program without supplementation (C group n = 14).,Primary outcome measures were changes in body weight and FFM, using dual X-ray absorptiometry (DEXA).,At the 12th week, a body weight increment occurred in 92% and 15% of patients in the EAAs and C group, respectively, with an average increase of 3.8 ± 2.6 kg (P = 0.0002) and −0.1 ± 1.1 kg (P = 0.81), respectively.,A FFM increment occurred in 69% and 15% of EAAs and C patients, respectively, with an average increase of 1.5 ± 2.6 kg (P = 0.05) and −0.1 ± 2.3 kg (P = 0.94), respectively.,In the EAAs group, FFM change was significantly related to fasting insulin (r2 0.68, P < 0.0005), C-reactive protein (C-RP) (r2 = 0.46, P < 0.01), and oxygen extraction tension (PaO2x) (r2 = 0.46, P < 0.01) at end of treatment.,These three variables were highly correlated in both groups (r > 0.7, P < 0.005 in all tests).,Changes in FFM promoted by EAAs are related to cellular energy and tissue oxygen availability in depleted COPD.,Insulin, C-RP, and PaO2x must be regarded as clinical markers of an amino acid-stimulated signaling to FFM accretion. | 1 |
Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide.,Genetic risk loci provide novel insights into disease pathogenesis.,We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.,We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function.,Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium.,Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types.,We found 14 COPD loci shared with either asthma or pulmonary fibrosis.,COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations.,Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD. | Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations.,We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities.,We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses.,Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci.,Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.,Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.,Pulmonary function is influenced by environmental factors, lifestyle, and genetics.,Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry. | 1 |
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies.,Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking.,Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions.,Exosomal miRNAs have been studied in relation to many diseases.,However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF.,Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts.,Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration.,Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL.,NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers.,Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively.,Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls.,Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets. | Infection-related exacerbations of respiratory diseases are a major health concern; thus understanding the mechanisms driving them is of paramount importance.,Despite distinct inflammatory profiles and pathological differences, asthma and COPD share a common clinical facet: raised airway ATP levels.,Furthermore, evidence is growing to suggest that infective agents can cause the release of extracellular vesicle (EVs) in vitro and in bodily fluids.,ATP can evoke the P2X7/caspase 1 dependent release of IL-1β/IL-18 from EVs; these cytokines are associated with neutrophilia and are increased during exacerbations.,Thus we hypothesized that respiratory infections causes the release of EVs in the airway and that the raised ATP levels, present in respiratory disease, triggers the release of IL-1β/IL-18, neutrophilia and subsequent disease exacerbations.,To begin to test this hypothesis we utilised human cell-based assays, ex vivo murine BALF, in vivo pre-clinical models and human samples to test this hypothesis.,Data showed that in a murine model of COPD, known to have increased airway ATP levels, infective challenge causes exacerbated inflammation.,Using cell-based systems, murine models and samples collected from challenged healthy subjects, we showed that infection can trigger the release of EVs.,When exposed to ATP the EVs release IL-1β/IL-18 via a P2X7/caspase-dependent mechanism.,Furthermore ATP challenge can cause a P2X7 dependent increase in LPS-driven neutrophilia.,This preliminary data suggests a possible mechanism for how infections could exacerbate respiratory diseases and may highlight a possible signalling pathway for drug discovery efforts in this area. | 1 |
To explore the ways in which participation in a community singing group contributed to the health and well-being of patients with chronic obstructive pulmonary disease (COPD).,Qualitative description, based on transcripts from individual interviews and a focus group meeting with people with COPD participating in the singing group, regarding their experience.,Urban community, Wellington, New Zealand.,23 people (13 women and 10 men), 51-91 years with COPD (21) or interstitial lung disease (2).,The weekly singing group was a well-attended activity, with self-reported benefits to health and well-being. 4 key themes were identified: being in the ‘right space’, connection, purpose and growth, and participation in a meaningful physical activity.,This study helps us to better understand how participation in a community singing group can benefit the health and well-being of patients with COPD.,ACTRN12615000736549; Results. | COPD is a progressive lung disorder with rates of mortality between 36-50%, within 2 years after admission for an acute exacerbation.,While treatment with inhaled bronchodilators and steroids may partially relieve symptoms and oxygen therapy may prolong life, for many patients the course of the disease is one of inexorable decline.,Very few palliative care intervention studies are available for this population.,This trial seeks to determine the effectiveness of the introduction of specialized palliative care on hospital, intensive care unit and emergency admissions of patients with severe and very severe COPD.,The study is a three year single centre, randomized controlled trial using a 2 arms parallel groups design conducted in a tertiary center (University Hospitals; Geneva).,For the intervention group, an early palliative care consultation is added to standard care; the control group benefits from standard care only.,Patients with COPD defined according to GOLD criteria with a stage III or IV disease and/or long term treatment with domiciliary oxygen and/or home mechanical ventilation and/or one or more hospital admissions in the previous year for an acute exacerbation are eligible to participate.,Allocation concealment is achieved using randomisation by sealed envelopes.,Our sample size of 90 patients/group gives the study a 80% power to detect a 20% decrease in intensive care unit and emergency admissions - the primary endpoint.,All data regarding participants will be analysed by a researcher blinded to treatment allocation, according to the "Intention to treat" principle.,Given the trends toward aggressive and costly care near end-of-life among patients with COPD, a timely introduction of palliative care may limit unnecessary and burdensome personal and societal costs, and invasive approaches.,The results of this study may provide directions for future palliative care interventions in this particular population.,This trial has been registered at clinicaltrials.gov underNCT02223780 | 1 |
Exacerbations of COPD (ECOPD) are a frequent cause of hospitalization that seemed to ameliorate during the COVID outbreak.,We aimed to evaluate the clinical characteristics of COPD-related hospital admissions and mortality in relation to the presence of COVID-19.,We conducted a case-control study of patients admitted in four teaching hospitals throughout Spain between March 15 and April 30, 2020.,Hospital admissions of respiratory cause with and without PCR-proven SARS-CoV-2 infection in patients with COPD were evaluated.,Baseline and episode-related clinical characteristics were analyzed.,Logistic regression analysis was performed to evaluate the risk for mortality.,During the study period, 2101 patients were admitted for respiratory worsening, 1200 (57.1%) with COVID-19.,A total of 228 (10.8%) were admitted due to COPD worsening, of whom 52 (22.8%) tested positive for COVID-19.,COPD patients with COVID-19, when compared to those without COVID-19, were more frequently males with better lung function (FEV1 postbronchodilator 71% vs 46% respectively, p<0.001) and had higher mortality (44.9% vs 13.6% respectively, p<0.001) despite similar age, comorbidities, total days of hospitalization and admission to intensive care unit.,COVID-19 and eosinopenia were the strongest risk factors for mortality in the multivariate analysis in the overall COPD population.,Inhaled corticosteroid use was not associated to mortality.,Hospitalizations for ECOPD without COVID-19 were more frequent than COPD with COVID-19 during the first outbreak, but the latter were associated with higher mortality and low eosinophil counts that warrant further analysis. | 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. | 1 |
Chronic obstructive pulmonary disease (COPD) has seriously impacted the health of individuals and populations.,In this study, proton nuclear magnetic resonance (1H NMR)-based metabonomics combined with multivariate pattern recognition analysis was applied to investigate the metabolic signatures of patients with COPD.,Serum and urine samples were collected from COPD patients (n = 32) and healthy controls (n = 21), respectively.,Samples were analyzed by high resolution 1H NMR (600 MHz), and the obtained spectral profiles were then subjected to multivariate data analysis.,Consistent metabolic differences have been found in serum as well as in urine samples from COPD patients and healthy controls.,Compared to healthy controls, COPD patients displayed decreased lipoprotein and amino acids, including branched-chain amino acids (BCAAs), and increased glycerolphosphocholine in serum.,Moreover, metabolic differences in urine were more significant than in serum.,Decreased urinary 1-methylnicotinamide, creatinine and lactate have been discovered in COPD patients in comparison with healthy controls.,Conversely, acetate, ketone bodies, carnosine, m-hydroxyphenylacetate, phenylacetyglycine, pyruvate and α-ketoglutarate exhibited enhanced expression levels in COPD patients relative to healthy subjects.,Our results illustrate the potential application of NMR-based metabonomics in early diagnosis and understanding the mechanisms of COPD. | Little information is available regarding the vulnerability of patients with chronic obstructive pulmonary disease (COPD) in China.,We aimed to assess this according to patient gender.,A cross-sectional study was conducted in the rural area of Xuzhou in China.,We interviewed and administered questionnaires to 2825 male and 2825 female patients with COPD and subjected the data generated to statistical analysis.,We compared differences between proportions of male and female patients using the χ2 test.,The rate of current smoking in men was 30.1%, whereas that in women was 10.9%, and 31.5% of men had a history of using biomass fuel compared with 75.3% of women.,Further, 26.0% of the male patients and 16.4% of the female patients did not take theophylline regularly when their disease was stable.,During acute exacerbations, 65.8% of the male patients and 39.7% of the female patients took theophylline or similar drugs.,The average potential shortening of life expectancy was 1.76 years for men and 1.18 years for women.,The average indirect economic burden was 11158.4 yuan for men and 7481.2 yuan for women.,The quality of life was worse in female patients than in male patients.,We found that patients with COPD were vulnerable and that factors determining vulnerability were different for men than for women.,Therefore, we recommend adopting different measures for men and women when attempting to prevent, control, and treat COPD, rehabilitate these patients, and improve their quality of life. | 1 |
The overprescription of inhaled corticosteroids (ICS) in the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A and B patients with chronic obstructive pulmonary disease (COPD) is not uncommon in clinical practice.,The aim of this study was to explore the factors associated with the use of ICS in these patients.,The Taiwan obstructive lung disease (TOLD) study was a retrospective, observational nationwide survey of COPD patients conducted at 12 hospitals (n=1,096) in Taiwan.,Multivariate logistic regression models were used to explore the predictors of ICS prescription in GOLD group A and B patients.,Among the group A (n=179) and group B (n=398) patients, 198 (34.3%) were prescribed ICS (30.2% in group A and 36.2% in group B, respectively).,The wheezing phenotype was present in 28.5% of group A and 34.2% of group B patients.,Wheezing was the most significant factor for an ICS prescription in group A (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.14-4.75; P=0.020), group B (OR, 1.93; 95% CI, 1.24-2.99; P=0.004), and overall (OR, 2.04; 95% CI, 1.40-2.96; P<0.001).,The COPD assessment test score was also associated with an ICS prescription in group B (OR, 1.04; 95% CI, 1.00-1.07; P=0.038).,About one-third of the GOLD group A and B patients with COPD in Taiwan are prescribed ICS.,Our findings suggest that wheezing and COPD assessment test score are related to the prescription of ICS in these patients. | Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events.,The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known.,A post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD®) database.,Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk.,With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478).,For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol.,With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968).,This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk.,Boehringer Ingelheim and Pfizer.,Clinical trial registration number: ClinicalTrials.gov NCT00563381.,The online version of this article (doi:10.1007/s12325-015-0216-2) contains supplementary material, which is available to authorized users. | 1 |
Few studies have researched the independent effect of COPD severity on the risk of future exacerbations adjusted by previous exacerbation frequency.,We aimed to analyse the independent effect of COPD severity on the risk of exacerbations in the following year, and whether this effect was stronger or not than the effect of a previous history of exacerbations.,We conducted a retrospective population-based cohort study including 900 patients with confirmed COPD.,Exacerbation frequency was observed for the previous year and for the following year.,Patients were defined as ‘Frequent Exacerbator’ (FE) phenotype if they suffered ⩾2 exacerbations in a year, and were categorised according to the severity of COPD (GOLD Grades 1-4).,Odds ratios (ORs) were estimated by logistic regression adjusting for age, gender, smoking status, severity of COPD and being FE in the previous year.,The main predictor of being FE among all grades of COPD severity was a history of frequent exacerbations in the previous year: adjusted OR 4.97; 95% confidence interval (CI) (3.54-6.97).,COPD severity was associated with a higher risk of being FE: Crude OR GOLD Grade 4 3.86; 95% CI (1.50-9.93).,However, this association diminished after adjusting for being FE in the previous year: adjusted OR 2.08; 95% CI (0.75-5.82).,Our results support that a history of frequent exacerbations in the previous year is the most important independent predictor of exacerbations in the following year, also among the most severe COPD patients.,Severity of COPD would be associated with a higher risk of exacerbations, but this effect would be partly determined by the exacerbations suffered in the previous year. | Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible disease responsible for the deaths of 3 million people worldwide in 2005, and predicted to be the third leading cause of death worldwide by 2030.,Many COPD models developed to date have followed a Markov structure, in which patients or populations can move between defined health states over successive time periods or cycles.,In COPD, health states are typically based on disease severity defined solely by lung function, as described by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.,These current modelling methods may restrict the ability to reflect the disease progression/clinical pathway or clinical practice.,Given these limitations in previous COPD models, the authors aimed to develop a more flexible model that could improve on the description of the clinical disease pathway.,The overall objective of this model was to inform the development of policies, guidelines or cost-effectiveness analyses.,A second objective was to validate the model in relation to existing epidemiology studies of COPD.,A patient simulation model was developed in Microsoft Excel™.,The predictability of the model was tested by populating it with data from natural history of disease studies as well as with clinical trial data.,Each patient moves through the model with demographic characteristics randomly generated from a set distribution.,These characteristics determine the risk of clinical events occurring in the model.,The validation with these studies found the model to have generally good predictive ability, yielding in this way a good degree of external validity.,The micro-simulation model is a flexible approach for modelling COPD that allows consideration of complex COPD treatment pathways.,The model was found to be generally robust in terms of predicting clinical outcomes of published studies when tested against other studies.,It has significant potential as a tool for supporting future COPD treatment positioning decisions as well as to inform the development of policies, guidelines or cost-effectiveness analyses. | 1 |
Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD).,To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function.,We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11). | Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood.,A number of candidate genes have been proposed on the basis of the pathogenesis of COPD.,These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD.,Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.,To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations.,We used logistic regression to adjust for age, gender, centre and smoking history.,Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.,Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94).,The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129).,This implicates haplotypes of MMP-12 as modifiers of disease severity. | 1 |
Self-treatment of acute exacerbations of COPD with antibiotics and/or oral corticosteroids has emerged as a promising strategy to reduce hospitalization rates, mortality and health costs.,However, for reasons little understood, the effect of self-treatment, particularly when not part of comprehensive self-management programs, remains unclear.,Therefore, this study aims to get insight into the patients’ perspective on self-treatment of acute exacerbations of COPD, focusing specifically on how patients decide for the right moment to start treatment with antibiotics and/or oral corticosteroids, what they consider important when making this decision and aspects which might interfere with successful implementation.,We interviewed 19 patients with chronic obstructive pulmonary disease using qualitative semi-structured interviews, and applied thematic analysis for data analysis.,Patients were well equipped with experiential knowledge to recognize and promptly respond to worsening COPD symptoms.,Worries regarding potential adverse effects of antibiotics and oral corticosteroids played an important role in the decision to start treatment and could result in hesitation to start treatment.,Although self-treatment represented a practical and appreciated option for some patients with predictable symptom patterns and treatment effect, all patients favoured assistance from a medical professional when their perceived competence reached its limits.,However, a feeling of obligation to succeed with self-treatment or distrust in their doctors or the health care system could keep patients from timely help seeking.,COPD patients regard self-treatment of exacerbations with antibiotics and/or oral corticosteroids as a valuable alternative.,How they engage in self-treatment depends on their concerns regarding the medications’ adverse effects as well as on their understanding of and preferences for self-treatment as a means of health care.,Caregivers should address these perspectives in a collaborative approach when offering COPD patients the opportunity for self-treatment of exacerbations.,The online version of this article (doi:10.1186/s12875-017-0582-8) contains supplementary material, which is available to authorized users. | Although many hospitals promote self-management to chronic obstructive pulmonary disease (COPD) patients post discharge from hospital, the clinical effectiveness of this is unknown.,We undertook a systematic review of the evidence as part of a Health Technology Assessment review.,A comprehensive search strategy with no language restrictions was conducted across relevant databases from inception to May 2012.,Randomized controlled trials of patients with COPD, recently discharged from hospital after an acute exacerbation and comparing a self-management intervention with control, usual care or other intervention were included.,Study selection, data extraction, and risk of bias assessment were undertaken by two reviewers independently.,Of 13,559 citations, 836 full texts were reviewed with nine randomized controlled trials finally included in quantitative syntheses.,Interventions were heterogeneous.,Five trials assessed highly supported multi-component interventions and four trials were less supported with fewer contacts with health care professionals and mainly home-based interventions.,Total sample size was 1,466 (range 33-464 per trial) with length of follow-up 2-12 months.,Trials varied in quality; poor patient follow-up and poor reporting was common.,No evidence of effect in favor of self-management support was observed for all-cause mortality (pooled hazard ratio =1.07; 95% confidence interval [0.74 to 1.55]; I2=0.0%, [n=5 trials]).,No clear evidence of effect on all-cause hospital admissions was observed (hazard ratio 0.88 [0.61, 1.27] I2=66.0%).,Improvements in St George’s Respiratory Questionnaire score were seen in favor of self-management interventions (mean difference =3.84 [1.29 to 6.40]; I2=14.6%), although patient follow-up rates were low.,There is insufficient evidence to support self-management interventions post-discharge.,There is a need for good quality primary research to identify effective approaches. | 1 |
Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD).,Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling.,While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored.,We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C).,DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93).,DNA amplifications (polymerase chain reaction) were performed for each SNP.,Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae.,Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined.,No significant inter-group differences in frequency of any TLR SNP existed.,However both TLR9 single nucleotide polymorphisms were expressed in high frequency.,Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C).,Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037).,Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD. | The C-type lectin receptor Dectin-1 is expressed mainly on myeloid cells mediating the immune response targeting respiratory pathogens such as Aspergillus fumigatus and Mycobacterium tuberculosis.,The pulmonary epithelium serves as an important interface for interactions between these pathogens and the respiratory tract.,Therefore, we analyzed the expression pattern of Dectin-1 in the human lung.,Immunohistochemically stained human lung sections from 17 out of 19 individuals were positive for Dectin-1, which was expressed mainly apically on bronchial and alveolar epithelium.,Our results showed no correlation with chronic obstructive pulmonary disease (COPD) or the smoking habits of the patients.,Nontypeable Haemophilus influenzae (NTHI), an important bacterial pathogen of the respiratory tract with significant importance in COPD, has also been proposed to be recognized by Dectin-1, suggesting a possible impact on the NTHI-dependent immune response in human airways.,Therefore, the involvement of Dectin-1 in NTHI-triggered cytokine responses was investigated in primary normal human bronchial epithelial (NHBE) cells and in the A549 cell line stably transfected with Dectin-1.,The presence of Dectin-1 significantly increased cytokine release in response to NTHI in NHBE and A549 cells.,In addition, phosphorylation of the Dectin-1 hem-immunoreceptor tyrosine-based activation motif (hemITAM) was essential for the Dectin-1-triggered response to NTHI in A549 cells.,In conclusion, in human airways, epithelium-expressed Dectin-1 may play a significant role in generating an NTHI-mediated, proinflammatory immune response.,In this study, we demonstrated, for the first time, the expression of Dectin-1 on human lung tissues and, in particular, pulmonary epithelium by making use of immunohistochemical staining.,The epithelial lining of the human airways is an important interface for host-pathogen interactions.,Therefore, our data suggest that epithelium-expressed Dectin-1 is of considerable importance for the interaction of the human airways with pathogens detected by this receptor, such as A. fumigatus and M. tuberculosis.,Moreover, we further demonstrated that, in pulmonary epithelial cells, Dectin-1 enhances the proinflammatory immune response to NTHI.,In COPD patients, NTHI is a major cause of respiratory tract infections and is associated with proinflammatory immune responses in the lower airways.,Therefore, our data suggest that the functional interaction of Dectin-1 with NTHI in human airways may have an important impact on the pathogenesis of COPD. | 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 prevalence and mortality of chronic obstructive pulmonary disease (COPD) in elderly patients are increasing worldwide.,Low body mass index (BMI) is a well-known prognostic factor for COPD.,However, the obesity paradox in elderly patients with COPD has not been well elucidated.,We investigated the association between BMI and in-hospital mortality in elderly COPD patients.,Using the Diagnosis Procedure Combination database in Japan, we retrospectively collected data for elderly patients (>65 years) with COPD who were hospitalized between July 2010 and March 2013.,We performed multivariable logistic regression analysis to compare all-cause in-hospital mortality between patients with BMI of <18.5 kg/m2 (underweight), 18.5-22.9 kg/m2 (low-normal weight), 23.0-24.9 kg/m2 (high-normal weight), 25.0-29.9 kg/m2 (overweight), and ≥30.0 kg/m2 (obesity) with adjustment for patient backgrounds.,In all, 263,940 eligible patients were identified.,In-hospital mortality was 14.3%, 7.3%, 4.9%, 4.3%, and 4.4%, respectively, in underweight, low-normal weight, high-normal weight, overweight, and obese patients.,Underweight patients had a significantly higher mortality than low-normal weight patients (odds ratio [OR]: 1.55, 95% confidence interval [CI]: 1.48-1.63), whereas lower mortality was associated with high-normal weight (OR: 0.76, CI: 0.70-0.82), overweight (OR: 0.73, CI: 0.66-0.80), and obesity (OR: 0.67, CI: 0.52-0.86).,Higher mortality was significantly associated with older age, male sex, more severe dyspnea, lower level of consciousness, and lower activities of daily living.,Overweight and obese patients had a lower mortality than low-normal weight patients, which supports the obesity paradox. | 1 |
COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function.,Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy.,This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID.,CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings.,Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD).,In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included.,ClinicalTrials.gov number: NCT01985334.,Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments.,The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]).,Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]).,In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice. | Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as β2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments.,The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD.,This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing ≥12 weeks’ LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only).,Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.,Eighteen studies (23 trials) were eligible (N=20,185).,LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively).,LABA/LAMA improved transitional dyspnea index and St George’s Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively).,LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]).,Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]).,LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]).,The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD.,These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use. | 1 |
Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function.,In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections.,As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients.,To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients.,Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life.,We performed a randomized, double-blind, placebo-controlled pilot trial.,Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months.,Study visits were conducted at baseline, and at 3 and 6 months after randomization.,During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed.,In addition, participants kept a diary card in which they registered respiratory symptoms.,At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group.,Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P<0.001).,Primary outcomes, respiratory muscle strength and physical performance, did not differ between the groups after 6 months.,In addition, no differences were found in the 6-minute walking test results, handgrip strength, pulmonary function, exacerbation rate, or quality of life.,Vitamin D supplementation did not affect (respiratory) muscle strength or physical performance in this pilot trial in vitamin D-deficient COPD patients. | Community-acquired pneumonia (CAP) is more common in patients with COPD than in the adult general population, with studies of hospitalized CAP patients consistently reporting COPD as a frequent comorbidity.,However, despite an increasing recognition of its importance, large studies evaluating the incidence patterns over time, risk factors and burden of CAP in COPD are currently lacking.,A retrospective observational study using a large UK-based database of linked primary and secondary care records was conducted.,Patients with a diagnosis of COPD aged ≥40 years were followed up for 5 years from January 1, 2010.,CAP and exacerbation episodes were identified from hospital discharge data and primary care coding records, and rates were calculated per month, adjusting for mortality, and displayed over time.,In addition, baseline factors predicting future risk of CAP and hospital admission with CAP were identified.,A total of 14,513 COPD patients were identified: 13.4% (n=1,938) had ≥1 CAP episode, of whom 18.8% suffered from recurrent (≥2) CAP.,Highest rates of both CAP and exacerbations were seen in winter.,A greater proportion of frequent, compared to infrequent, exacerbators experienced recurrent CAP (5.1% versus 2.0%, respectively, P<0.001); 75.6% of CAP episodes were associated with hospital admission compared to 22.1% of exacerbations.,Older age and increasing grade of airflow limitation were independently associated with increased odds of CAP and hospital admission with CAP.,Other independent predictors of future CAP included lower body mass index, inhaled corticosteroid use, prior frequent exacerbations and comorbidities, including ischemic heart disease and diabetes.,CAP in COPD demonstrates clear seasonal patterns, with patient characteristics predictive of the odds of future CAP and hospital admission with CAP.,Highlighting this burden of COPD-associated CAP during the winter period informs us of the likely triggers and the need for more effective preventive strategies. | 1 |
Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year.,To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort.,We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105).,We classified participants according to yearly exacerbation frequency.,Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none.,During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none.,Only 2·1% had ≥2 AECOPD in each year.,An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%).,In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8).,Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year.,Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year.,In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8. | COPD symptoms show a diurnal variability.,However, morning and night variability has generally not been taken into consideration in disease management plans.,The aims of this study were to cross-sectionally assess morning and night symptom prevalence and correlation with health status and disease severity in COPD, and to determine to what extent they could predict longitudinal outcomes, exacerbations and health status.,A further aim is to explore whether the CCQ is able to depict this morning/night symptomatology.,We included 2,269 primary care COPD patients (58% male, 49% current smokers, with a mean age of 65±11 years) from a Dutch Asthma/COPD service.,Spirometry, patient history, the Clinical COPD Questionnaire(CCQ) and the Asthma Control Questionnaire(ACQ) were assessed; we used the latter to evaluate morning (question 2) and night symptoms (question 1).,A total of 1159 (51.9%) patients reported morning symptoms (ACQ question 2>0) and 879 (39.4%) had night complaints (ACQ question 1>0).,Patients with morning/night symptoms were mostly smokers and had on average poorer lung function, higher CCQ scores and used more rescue inhalers (P<0.0001).,Patients using long-acting muscarinic antagonists (LAMAs) had less night symptoms, showing a possible favourable effect.,Only a small proportion of stable or slightly unstable patients (CCQ total scores <2) had severe morning symptoms (ACQ 2⩾4: n=19, 1.1%) or severe night symptoms (ACQ 1⩾4: n=11, 0.7%).,Night symptoms seemed to predict future exacerbations; however, baseline exacerbations were the strongest predictors (n=346, OR:4.13, CI: 2.45−6.95, P<0.000).,Morning symptoms increased the odds of poor health status at follow-up (n=346, OR:12.22, CI:4.76−31.39, P<0.000).,Morning and night symptoms in COPD patients are common, and they are associated with poor health status and predicted future exacerbations.,Our study showed that patients with morning/night symptoms have higher scores in CCQ, and therefore we do not really miss patients with high morning/night symptomatology when we only measure CCQ.,Severe morning symptoms predicted worsening of COPD health status. | 1 |
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.,Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities.,COPD exacerbations and comorbidities contribute to the overall severity in individual patients.,Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age.,Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations.,However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide.,This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale.,Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases.,All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases.,In this review, we focus on the major comorbidities that affect COPD patients.,We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs.,We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity. | 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 |
The aim of this study is to quantify the burden of chronic obstructive pulmonary disease (COPD) - incidence, prevalence, and mortality - and identify trends in Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America.,A structured literature search was performed (January 2000 to September 2010) of PubMed and EMBASE, identifying English-language articles reporting COPD prevalence, incidence, or mortality.,Of 2838 articles identified, 299 full-text articles were reviewed, and data were extracted from 133 publications.,Prevalence data were extracted from 80 articles, incidence data from 15 articles, and mortality data from 58 articles.,Prevalence ranged from 0.2%-37%, but varied widely across countries and populations, and by COPD diagnosis and classification methods.,Prevalence and incidence were greatest in men and those aged 75 years and older.,Mortality ranged from 3-111 deaths per 100,000 population.,Mortality increased in the last 30-40 years; more recently, mortality decreased in men in several countries, while increasing or stabilizing in women.,Although COPD mortality increased over time, rates declined more recently, likely indicating improvements in COPD management.,In many countries, COPD mortality has increased in women but decreased in men.,This may be explained by differences in smoking patterns and a greater vulnerability in women to the adverse effects of smoking.,Point your SmartPhone at the code above.,If you have a QR code reader the video abstract will appear.,Or use: http://dvpr.es/Nl3LKT | Never smokers comprise a substantial proportion of patients with COPD.,Their characteristics and possible risk factors in this population are not yet well defined.,We analyzed data from 14 countries that participated in the international, population-based Burden of Obstructive Lung Disease (BOLD) study.,Participants were aged ≥ 40 years and completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors.,A diagnosis of COPD was based on the postbronchodilator FEV1/FVC ratio, according to current GOLD (Global Initiative for Obstructive Lung Disease) guidelines.,In addition to this, the lower limit of normal (LLN) was evaluated as an alternative threshold for the FEV1/FVC ratio.,Among 4,291 never smokers, 6.6% met criteria for mild (GOLD stage I) COPD, and 5.6% met criteria for moderate to very severe (GOLD stage II+) COPD.,Although never smokers were less likely to have COPD and had less severe COPD than ever smokers, never smokers nonetheless comprised 23.3% (240/1,031) of those classified with GOLD stage II+ COPD.,This proportion was similar, 20.5% (171/832), even when the LLN was used as a threshold for the FEV1/FVC ratio.,Predictors of COPD in never smokers include age, education, occupational exposure, childhood respiratory diseases, and BMI alterations.,This multicenter international study confirms previous evidence that never smokers comprise a substantial proportion of individuals with COPD.,Our data suggest that, in addition to increased age, a prior diagnosis of asthma and, among women, lower education levels are associated with an increased risk for COPD among never smokers. | 1 |
The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7.,Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative.,We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis.,In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years.,Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated.,The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography.,Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively.,The GOLD classification led to more false positives, the LLNs to more false negative diagnoses.,The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC).,Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses.,The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN.,GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis.,Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice. | While adverse effects of exposure to air pollutants on respiratory health are well studied, little is known about the effect of a reduction in air pollutants on chronic respiratory symptoms and diseases.,We investigated whether different declines in air pollution levels in industrialised and rural areas in Germany were associated with changes in respiratory health over a period of about 20 years.,We used data from the SALIA cohort study in Germany (Study on the influence of Air pollution on Lung function, Inflammation and Aging) to assess the association between the prevalence of chronic obstructive pulmonary disease (COPD) and chronic respiratory symptoms and the decline in air pollution exposure.,In 1985-1994, 4874 women aged 55-years took part in the baseline investigation.,Of these, 2116 participated in a questionnaire follow-up in 2006 and in a subgroup of 402 women lung function was tested in 2008-2009.,Generalized estimating equation (GEE) models were used to estimate the effect of a reduction in air pollution on respiratory symptoms and diseases.,Ambient air concentrations of particulate matter with aerodynamic size < 10 μm (PM10) declined in average by 20 μg/m3.,Prevalence of chronic cough with phlegm production and mild COPD at baseline investigation compared to follow-up was 9.5% vs.,13.3% and 8.6% vs.,18.2%, respectively.,A steeper decline of PM10 was observed in the industrialized areas in comparison to the rural area, this was associated with a weaker increase in prevalence of respiratory symptoms and COPD.,Among women who never smoked, the prevalence of chronic cough with phlegm and mild COPD was estimated at 21.4% and 39.5%, respectively, if no air pollution reduction was assumed, and at 13.3% and 17.5%, respectively, if air pollution reduction was assumed.,We concluded that parallel to the decline of ambient air pollution over the last 20 years in the Ruhr area the age-related increase in chronic respiratory diseases and symptoms appears to attenuate in the population of elderly women. | 1 |
The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response.,According to disease severity in individual patients, exacerbations and comorbidities frequently occur.,The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes.,Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD.,Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype.,Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety.,Altogether, these characteristics result in a high safety and tolerability profile.,This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. | Several small studies found night-time awakenings due to COPD symptoms were associated with decreased health status.,In this study, night-time awakenings in patients with COPD were examined and effects of tiotropium therapy evaluated.,This study was a post hoc, exploratory, pooled analysis of twin, multicenter, double-blind, randomized, placebo-controlled, parallel-group trials.,Patients with stable moderate-to-severe COPD were randomized to tiotropium HandiHaler® (n = 550) or placebo (n = 371) and followed for 13 weeks.,During a 2-week, pre-treatment baseline period and for 13 weeks on treatment, self-reported night-time awakenings due to COPD symptoms, rescue medication (albuterol) use, and morning and evening peak expiratory flow rate (PEFR) were recorded daily.,Nightly, COPD-related awakenings were scored: 0 = no awakenings; 1 = 1 awakening; 2 = 2-3 awakenings; or 3 = awake most of the night.,Health-related quality-of-life (HRQoL) and energy-fatigue questionnaires were completed at baseline and during treatment.,Patients were aged 65.2 ± 8.7 years (mean ± SD), with a mean pre-bronchodilator FEV1 of 36.1 ± 13.5 % predicted normal at baseline.,Data for night-time awakenings and albuterol use were available for 543 (99 %) patients on tiotropium and 352 (95 %) on placebo.,At baseline, 280 (51.5 %) patients on tiotropium and 179 (50.1 %) on placebo reported ≥1 COPD-related night-time awakening per week.,Over the 13-weeks’ treatment, tiotropium was associated with fewer night-time awakenings, with mean ± SE overall awakening scores per week of 0.356 ± 0.006 compared with 0.421 ± 0.007 for placebo (p < 0.001); means were significantly lower for tiotropium versus placebo in patients with baseline awakenings (p < 0.001), but not for those without baseline awakenings.,COPD-related night-time awakenings were associated with increased nocturnal rescue medication use and lower HRQoL ratings in both treatment arms.,Following start of treatment, tiotropium decreased patients’ use of rescue medication compared with placebo, and morning and evening adjusted means for PEFR were higher for tiotropium compared with placebo.,Tiotropium is associated with decreased COPD-related night-time awakenings.,Night-time awakenings are associated with increased nocturnal rescue medication use and may be a surrogate marker of symptom control in patients with COPD.,The online version of this article (doi:10.1186/s12931-016-0340-9) contains supplementary material, which is available to authorized users. | 1 |
The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders.,Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases.,Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers and smokers by bronchoscopic brushing.,Eleven distinct cell populations were identified, including major and rare epithelial cells, and immune/inflammatory cells.,There was cell type-specific expression of genes relevant to the risk of the inherited pulmonary disorders, genes associated with risk of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and (non-mutated) driver genes for lung cancers.,Cigarette smoking significantly altered the cell type-specific transcriptomes and disease risk-related genes.,This data provides new insights into the possible contribution of specific lung cells to the pathogenesis of lung disorders. | Inflammatory gene expression is modulated by posttranscriptional regulation via RNA-binding proteins (RBPs), which regulate mRNA turnover and translation by binding to conserved mRNA sequences.,Their role in COPD is only partially defined.,This study evaluated RBPs tristetraprolin (TTP), human antigen R (HuR), and AU-rich element-binding factor 1 (AUF-1) expression using lung tissue from COPD patients and control subjects and probed their function in epithelial responses in vitro.,RBPs were detected by immunohistochemistry in bronchial and peripheral lung samples from mild-to-moderate stable COPD patients and age/smoking history-matched controls; RBPs and RBP-regulated genes were evaluated by Western blot, ELISA, protein array, and real-time PCR in human airway epithelial BEAS-2B cell line stimulated with hydrogen peroxide, cytokine combination (cytomix), cigarette smoke extract (CSE), and following siRNA-mediated silencing.,Results were verified in a microarray database from bronchial brushings of COPD patients and controls.,RBP transcripts were measured in peripheral blood mononuclear cell samples from additional stable COPD patients and controls.,Specific, primarily nuclear immunostaining for the RBPs was detected in structural and inflammatory cells in bronchial and lung tissues.,Immunostaining for AUF-1, but not TTP or HuR, was significantly decreased in bronchial epithelium of COPD samples vs controls.,In BEAS-2B cells, cytomix and CSE stimulation reproduced the RBP pattern while increasing expression of AUF-1-regulated genes, interleukin-6, CCL2, CXCL1, and CXCL8.,Silencing expression of AUF-1 reproduced, but not enhanced, target upregulation induced by cytomix compared to controls.,Analysis of bronchial brushing-derived transcriptomic confirmed the selective decrease of AUF-1 in COPD vs controls and revealed significant changes in AUF-1-regulated genes by genome ontology.,Downregulated AUF-1 may be pathogenic in stable COPD by altering posttranscriptional control of epithelial gene expression. | 1 |
The aim of this study was to assess health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) and to discuss the different tools available for its assessment.,The most widely used assessments are the St.,George respiratory questionnaire (SGRQ) and the COPD assessment test (CAT) questionnaire.,Both have a different difficulty in exam completion, calculation, and scoring.,No studies exist that analyze the validity and internal consistency of using both questionnaires on patients admitted to the hospital for a COPD exacerbation.,A multicenter, cross-sectional analytic observational study of patients admitted to the hospital due to a COPD exacerbation (CIE 491.2).,During their hospital stay, they were administered the SGRQ and the CAT questionnaire within the framework of a therapeutic education program (APRENDEPOC).,Descriptive and comparative analysis, correlations between the scales (Pearson’s correlation index), consistency and reliability calculations (Cronbach’s α), and a forward stepwise multiple linear regression were performed, with significant correlations in both questionnaires considered p < 0.01 with the total scores.,A statistical significance of p < 0.05 was assumed.,Altogether, 231 patients were admitted for a COPD exacerbation (n = 77) at Hospital Clínic of Barcelona (HCB) and (n = 154) at Hospital Universitario General of Castellón (HUGC).,The sample profile was not homogeneous between both centers, with significant differences in HRQL between hospitals.,Correlation were noted between both scales (p < 0.01), along with high levels of internal consistency and reliability (CAT 0.836 vs.,SGRQ 0.827).,The HRQL is related to dyspnea, wheezing, daytime drowsiness, and edema, as well as to the need to sleep in a sitting position, anxiety, depression, and dependence on others in the execution of daily activities.,Our regression analysis showed that the SGRQ questionnaire could predict more changes in HRQL with a higher number of variables. | Neutrophil to lymphocyte ratio (NLR) in peripheral blood is a useful systemic inflammatory response biomarker.,However, NLR has not been studied in patients with chronic obstructive pulmonary disease (COPD).,This study was aimed to evaluate the usefulness of NLR in patients with COPD.,NLR was prospectively measured and compared in patients with COPD exacerbation (n = 59), patients with stable COPD (n = 61), and healthy controls (n = 28).,NLR in patients with COPD exacerbation was repeatedly measured in the convalescent period.,The correlation between NLR and clinical parameters was evaluated, and the predictors for respiratory hospitalization were analyzed by multivariate logistic regression.,NLR values were significantly higher in patients with COPD exacerbation compared with stable COPD patients and controls (12.4 ± 10.6, 2.4 ± 0.7, 1.4 ± 0.5, respectively; p < 0.001).,NLR was significantly decreased during the convalescent period in patients with COPD exacerbation (4.5 ± 4.6 vs.,11.5 ± 8.8, p < 0.001).,NLR exhibited a significant correlation with the body mass index, degree of airway obstruction, dyspnea, and exercise capacity (BODE) index, the 6-minute walk test, and the modified Medical Research Council scale.,NLR ≥ 2.8 was an independent predictor with a borderline significance for respiratory hospitalization (odds ratio, 2.083; p = 0.079).,Body mass index and forced expiratory volume in 1 second were independent predictors for respiratory hospitalization.,NLR is a straightforward and effective biomarker of COPD exacerbation that may serve as a predictor for respiratory hospitalization in patients with COPD. | 1 |
Computed tomography scan images have been used to identify different radiological COPD phenotypes based on the presence and severity of emphysema, bronchial wall thickening, and bronchiectasis.,Bronchiectasis is defined as an abnormal dilation of the bronchi, usually as a result of chronic airway inflammation and/or infection.,The prevalence of bronchiectasis in patients with COPD is high, especially in advanced stages.,The identification of bronchiectasis in COPD has been defined as a different clinical COPD phenotype with greater symptomatic severity, more frequent chronic bronchial infection and exacerbations, and poor prognosis.,A causal association has not yet been proven, but it is biologically plausible that COPD, and particularly the infective and exacerbator COPD phenotypes, could be the cause of bronchiectasis without any other known etiology, beyond any mere association or comorbidity.,The study of the relationship between COPD and bronchiectasis could have important clinical implications, since both diseases have different and complementary therapeutic approaches.,Longitudinal studies are needed to investigate the development of bronchiectasis in COPD, and clinical trials with treatments aimed at reducing bacterial loads should be conducted to investigate their impact on the reduction of exacerbations and improvements in the long-term evolution of the disease. | Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality.,COPD is typified by persistent, progressive airflow limitation and a range of respiratory and systemic symptoms such as breathlessness, coughing, wheezing, depression, anxiety, general fatigue, and sleeping difficulties.,Despite receiving treatment for COPD, many patients suffer from regular symptoms that affect their daily lives and lead to increased morbidity.,These symptoms vary in severity, frequency, and type, and can occur at any time throughout the 24-h day, with over half of patients with COPD experiencing symptoms in the morning, during the day, and at nighttime.,Despite the prevalence of symptoms, patient and physician perception of the impact of COPD symptoms on patients’ lives is not always in concordance.,Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) has the potential to treat the symptoms of COPD in addition to improving lung function.,This review therefore examines the burden of symptoms experienced throughout the day by patients with COPD and the evidence for combined LAMA/LABA treatment in terms of symptom management.,As patients with COPD experience varying symptoms throughout the course of their disease, the role of tailoring treatment to the individual needs of the patient is also examined.,We conclude that the symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day, and have a substantial impact on patients’ health status and quality of life.,In order to provide effective, patient-orientated care, patients with COPD should be evaluated on the basis of lung function, the frequency of symptoms, and patient-perceived impact of symptoms on their lives.,Therapy should be chosen carefully based on individualized assessment, ensuring personalization to the individual needs of the patient. | 1 |
To date, clinico-physiologic indices have not been compared with quantitative CT imaging indices in determining the risk of chronic obstructive pulmonary disease (COPD) exacerbation.,We therefore compared clinico-physiologic and CT imaging indices as risk factors for COPD exacerbation in patients with COPD.,We retrospectively analyzed 260 COPD patients from pulmonary clinics at 11 hospitals in Korea from June 2005 to November 2009 and followed-up for at least one year.,At the time of enrollment, none of these patients had COPD exacerbations for at least 2 months.,All underwent clinico-physiologic and radiological evaluation for risk factors of COPD exacerbation.,After 1 yr, 106 of the 260 patients had at least one exacerbation of COPD.,Multiple logistic regression analysis showed that old age, high Charlson Index, and low FEV1 were significant in a clinico-physiologic model, with C-statistics of 0.69, and that increased age and emphysema index were significant in a radiologic model, with C-statistics of 0.64.,The difference between the two models was statistically significant (P = 0.04 by bootstrap analysis).,Combinations of clinico-physiologic risk factors may be better than those of imaging risk factors in predicting COPD exacerbation. | Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and responses to therapies are highly variable.,The aim of this study was to identify the predictors of pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD.,A total of 127 patients with stable COPD from the Korean Obstructive Lung Disease (KOLD) Cohort, which were prospectively recruited from June 2005 to September 2009, were analyzed retrospectively.,The prediction models for the FEV1, FVC and IC/TLC changes after 3 months of treatment with salmeterol/fluticasone were constructed by using multiple, stepwise, linear regression analysis.,The prediction model for the FEV1 change after 3 months of treatment included wheezing history, pre-bronchodilator FEV1, post-bronchodilator FEV1 change and emphysema extent on CT (R = 0.578).,The prediction models for the FVC change after 3 months of treatment included pre-bronchodilator FVC, post-bronchodilator FVC change (R = 0.533), and those of IC/ TLC change after 3 months of treatment did pre-bronchodilator IC/TLC and post-bronchodilator FEV1 change (R = 0.401).,Wheezing history, pre-bronchodilator pulmonary function, bronchodilator responsiveness, and emphysema extent may be used for predicting the pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD. | 1 |
Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events.,The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known.,A post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD®) database.,Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk.,With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478).,For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol.,With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968).,This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk.,Boehringer Ingelheim and Pfizer.,Clinical trial registration number: ClinicalTrials.gov NCT00563381.,The online version of this article (doi:10.1007/s12325-015-0216-2) contains supplementary material, which is available to authorized users. | Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 μg versus placebo, inhaled via the Respimat® Soft Mist™ Inhaler (SMI).,The two studies were combined and had 4 co-primary endpoints (trough FEV1 response, Mahler Transition Dyspnea Index [TDI] and St George’s Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year).,A total of 1990 patients with COPD participated (mean FEV1: 1.09 L).,The mean trough FEV1 response of tiotropium 5 or 10 μg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001).,The COPD exacerbation rate was significantly lower with tiotropium 5 μg (RR = 0.78; P = 0.002) and tiotropium 10 μg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co-primary endpoints were significantly improved with both doses (both P < 0.0001).,Adverse events were generally balanced except anticholinergic class effects, which were more frequent with active treatment.,Fatal events occurred in 2.4% (5 μg), 2.7% (10 μg), and 1.6% (placebo) of patients; these differences were not significant.,Tiotropium Respimat® SMI 5 μg demonstrated sustained improvements in patients with COPD relative to placebo and similar to the 10 μg dose but with a lower frequency of anticholinergic adverse events. | 1 |
To explore the role of family with sequence similarity 13 member A (FAM13A) in TGF-β1-induced EMT in the small airway epithelium of patients with chronic obstructive pulmonary disease (COPD).,Small airway wall thickness and protein levels of airway remodeling markers, EMT markers, TGF-β1, and FAM13A were measured in lung tissue samples from COPD and non-COPD patients.,The correlations of FAM13A expression with COPD severity and EMT marker expression were evaluated.,Gain- and loss-of-function assays were performed to explore the functions of FAM13A in cell proliferation, motility, and TGF-β1-induced EMT marker alterations in human bronchial epithelial cell line BEAS-2B.,Independent of smoking status, lung tissue samples from COPD patients exhibited significantly increased small airway thickness and collagen fiber deposition, along with enhanced protein levels of remodeling markers (collagen I, fibronectin, and MMP-9), mesenchymal markers (α-SMA, vimentin, and N-cadherin), TGF-β1, and FAM13A, compared with those from non-COPD patients.,FAM13A expression negatively correlated with FEV1% and PO2 in COPD patients.,In small airway epithelium, FAM13A expression negatively correlated with E-cadherin protein levels and positively correlated with vimentin protein levels.,In BEAS-2B cells, TGF-β1 dose-dependently upregulated FAM13A protein levels.,FAM13A overexpression significantly promoted cell proliferation and motility in BEAS-2B cells, whereas FAM13A silencing showed contrasting results.,Furthermore, FAM13A knockdown partially reversed TGF-β1-induced EMT marker protein alterations in BEAS-2B cells.,FAM13A upregulation is associated with TGF-β1-induced EMT in the small airway epithelium of COPD patients independent of smoking status, serving as a potential therapeutic target for anti-EMT therapy in COPD.,The online version contains supplementary material available at 10.1186/s12931-021-01783-z. | Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality.,The most important pathophysiological change of COPD is airway obstruction.,Airway obstruction can cause airflow restriction and obstructive ventilation dysfunction.,Currently, many studies have shown that there is EMT phenomenon in the process of airway remodeling of COPD.,Cullin4A (CUL4A) is an E3 ubiquitin ligase that interacts with other factors to form the E3 complex.,Studies have shown that CLU4A is associated with EMT in non-small cell lung cancer and other cancers.,However, its relationship with EMT in COPD has not been reported systematically.,In this study, we detected the expression of CUL4A in lung epithelium of COPD patients.,In addition, the regulatory effect and mechanism of CUL4A on EMT in COPD were clarified in small airway epithelial cells.,The expression of CUL4A was assessed by immunohistochemistry in lung epithelium specimens from smokers, non-smokers and patients with chronic obstructive pulmonary disease.,The role of CUL4A on cigarette smoke extract (CSE)-induced epithelial-mesenchymal transition (EMT) in human small airway epithelial cells (HSAEpiCs) was assessed by silencing or overexpression CUL4A in vitro.,Cigarette smoke is recognized as a high-risk factor in the induction of COPD, and its damage to the airway involves airway damage, airway inflammation and airway remodeling.,The results shown that CUL4A expression in small airway epithelium was significantly increased in patients with COPD.,We also observed a significant negative association between CUL4A and FEV1%, a useful clinical marker for the diagnosis and evaluation of COPD severity, in small airway epithelial cells.,In vitro, CSE-induced EMT is associated with high expression of CUL4A, and targeted silencing of CUL4A with shRNA inhibits CSE-induced EMT in human small airway epithelial cells.,Our results showed that CUL4A was overexpressed in lung epithelium of COPD patients, and CUL4A could regulate EMT of human small airway epithelium, which revealed a new mechanism of remodeling of small airway epithelium of COPD patients.,The online version of this article (10.1186/s12931-019-1048-4) contains supplementary material, which is available to authorized users. | 1 |
Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism.,We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smokers with preserved lung function and COPD subjects.,PBMCs were isolated from healthy non-smokers (HNS), healthy smokers (HS) and COPD subjects, cultured and the mitochondrial respiration while utilizing glucose (glycolysis), fatty acids (β-oxidation) or pyruvate (direct Krebs’ cycle substrate) was measured using the XFp Extracellular Flux Analyzer.,Plasma levels of inflammatory cytokines IFN-γ, IL-17, TNF-α, IL-5, IL-9 and IFN-α were measured using flow cytometry.,RAW264.7 cells were exposed to cigarette smoke condensate (CSC) for 1 h and its effect on cell viability, cellular metabolism and phagocytosis ability were also studied.,Patient’s data was analyzed using the Mann Whitney U test, whereas Student’s t test was performed to analyze the in-vitro data.,PBMCs from COPD subjects showed a significant decrease in extracellular acidification rate (ECAR) while utilizing glucose as compared to HNS (151.9 Vs 215%).,Mitochondrial oxygen consumption rate (OCR) on palmitate or pyruvate was also found to be significantly lower in COPD subjects as compared to HS and a strong positive correlation between palmitate OCR in PBMCs and FEV1 (r = 0.74, p < 0.05) and FVC (r = 0.79, p < 0.05) values in HS was observed.,The metabolic shift towards fatty acid metabolism in healthy smokers promoted an inflammatory cytokine response with a greater increase in the levels of IL-5, IL-9 and IFN-α as compared to IFN-γ, IL-17 and TNF-α.,In-vitro experiments with RAW 264.7 cells showed similar metabolic alterations and a reduced ability to phagocytose Streptococcus pneumonia and Haemophilus influenza after cigarette smoke exposure in the presence of glucose or palmitate.,These findings indicate a metabolic basis for the inflammatory response in COPD and could suggest a new therapeutic target for controlling the immune response and delaying the onset of disease.,This observational study was retrospectively registered in the Clinical Trails Registry - India (ICMR - NIMS) on 19th January 2018 with the registration number CTRI/2018/01/011441.,The online version of this article (10.1186/s12931-019-1139-2) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease (COPD) is the leading cause of morbidity and mortality worldwide.,There is evidence to support a connection between COPD and diabetes mellitus (DM), another common medical disorder.,However, additional research is required to improve our knowledge of these relationships and their possible implications.,In this study, we investigated the impact of DM on patient outcomes through the clinical course of COPD.,We conducted a cohort study in patients from the Taiwan Longitudinal Health Insurance Database between 2000 and 2013.,Patients with COPD were identified and assessed for pre-existing and incident DM.,A Cox proportional hazards model was built to identify factors associated with incident DM and to explore the prognostic effects of DM on COPD patients.,A propensity score method was used to match COPD patients with incident DM to controls without incident DM.,Pre-existing DM was present in 332 (16%) of 2015 COPD patients who had a significantly higher hazard ratio (HR) [1.244, 95% confidence interval (CI) 1.010-1.532] for mortality than that of the COPD patients without pre-existing DM.,During the 10-year follow-up period, 304 (19%) of 1568 COPD patients developed incident DM; comorbid hypertension (HR, 1.810; 95% CI, 1.363-2.403), cerebrovascular disease (HR, 1.517; 95% CI, 1.146-2.008) and coronary artery disease (HR, 1.408; 95% CI 1.089-1.820) were significant factors associated with incident DM.,Survival was worse for the COPD patients with incident DM than for the matched controls without incident DM (Log-rank, p = 0.027).,DM, either pre-existing or incident, was associated with worse outcomes in COPD patients.,Targeted surveillance and management of DM may be important in clinical care of the COPD population. | 1 |
Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) is not uniform, COPD guidelines recommend fixed ratio (FR), whereas ATS and ERS define airflow obstruction based on lower limit of normal (LLN).,We aim to determine if there is difference between the two diagnostic criteria for morbidity, mortality, exacerbation.,Four databases and all relevant studies from the references were searched from inception to June 25, 2019, to find studies that described the rate of comorbidity, the exacerbation rates, mortality in COPD patients.,Data analysis was performed using STATA/SE 14.0 and followed the standard of Cochrane Collaboration.,A sensitivity analysis was performed to find the source of heterogeneity.,Thirteen studies and 154,447 participants were finally included in this meta-analysis.,The 11 cohort studies and 2 cross-sectional studies were all high-quality.,Patients with airflow limitation according to either FR or LLN had higher mortality (HRFR+/LLN- = 1.27, 95% CI = 1.14-1.42; HRFR−/LLN+ = 1.83, 95% CI = 1.17-2.86) than those who met neither criteria.,When compared with the FR−/LLN- criteria, those who met the FR criteria were more likely to exacerbate (HR FR+/LLN- = 1.64, 95% CI = 1.09-2.46; HR FR−/LLN+ = 1.58, 95% CI = 0.70-3.55).,The meta-analysis for comorbidities showed no significant difference between patients who met neither criteria and those who met LLN or FR criteria.,The patients with airflow limitations according to FR were more likely to exacerbate than those with LLN only.,Patients that met either FR or LLN were more likely to have higher mortality than FR−/LLN-.,There was no difference between the FR+/LLN- and FR−/LLN+ groups for the occurrence of comorbidities. | Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation.,Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood.,This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation.,Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation.,Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand.,MMP-9 levels increased from 10.5 μg/g [1.2 to 21.1] prior to exacerbation to 17.1 μg/g [9.3 to 48.7] during exacerbation (P < 0.01).,TIMP-1 levels decreased from 3.5 μg/g [0.6 to 7.8] to 1.5 μg/g [0.3 to 4.9] (P = 0.16).,MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05).,Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05).,Macrophage numbers remained level.,MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01).,During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1.,This may suggest a pathway connecting frequent exacerbations with lung function decline. | 1 |
COPD is a leading cause of morbidity and mortality worldwide.,Patients suffer from refractory breathlessness, unrecognized anxiety and depression, and decreased quality of life.,Palliative care improves symptom management, patient reported health-related quality of life, cost savings, and mortality though the majority of patients with COPD die without access to palliative care.,There are many barriers to providing palliative care to patients with COPD including the difficulty in prognosticating a patient’s course causing referrals to occur late in a patient’s disease.,Additionally, physicians avoid conversations about advance care planning due to unique communication barriers present with patients with COPD.,Lastly, many health systems are not set up to provide trained palliative care physicians to patients with chronic disease including COPD.,This review analyzes the above challenges, the available data regarding palliative care applied to the COPD population, and proposes an alternative approach to address the unmet needs of patients with COPD with proactive primary palliative care. | A growing number of prognostic indices for chronic obstructive pulmonary disease (COPD) is developed for clinical use.,Our aim is to identify, summarize and compare all published prognostic COPD indices, and to discuss their performance, usefulness and implementation in daily practice.,We performed a systematic literature search in both Pubmed and Embase up to September 2010.,Selection criteria included primary publications of indices developed for stable COPD patients, that predict future outcome by a multidimensional scoring system, developed for and validated with COPD patients only.,Two reviewers independently assessed the index quality using a structured screening form for systematically scoring prognostic studies.,Of 7,028 articles screened, 13 studies comprising 15 indices were included.,Only 1 index had been explored for its application in daily practice.,We observed 21 different predictors and 7 prognostic outcomes, the latter reflecting mortality, hospitalization and exacerbation.,Consistent strong predictors were FEV1 percentage predicted, age and dyspnoea.,The quality of the studies underlying the indices varied between fairly poor and good.,Statistical methods to assess the predictive abilities of the indices were heterogenic.,They generally revealed moderate to good discrimination, when measured.,Limitations: We focused on prognostic indices for stable disease only and, inevitably, quality judgment was prone to subjectivity.,We identified 15 prognostic COPD indices.,Although the prognostic performance of some of the indices has been validated, they all lack sufficient evidence for implementation.,Whether or not the use of prognostic indices improves COPD disease management or patients' health is currently unknown; impact studies are required to establish this. | 1 |
An important precursor to lung cancer development is chronic obstructive pulmonary disease (COPD), independent of exposure to tobacco smoke.,Both diseases are associated with increased host susceptibility, inflammation, and genomic instability.,However, validation of the candidate genes and functional confirmation to test shared genetic contribution and cellular mechanisms to the development of lung cancer in patients with COPD remains underexplored.,Here, we show that loss of PARK2 (encoding Parkin) increases the expression of proinflammation factors as well as nuclear NF-κB localization, suggesting a role of PARK2 loss in inflammation.,Additional exploration showed that PARK2 deficiency promotes genomic instability and cell transformation.,This role of PARK2 in inflammation and chromosome instability provides a potential link among Parkin, COPD and lung cancer.,A further comprehensive validation of 114 informative single nucleotide polymorphism (SNP) variants of PARK2, in 2,484 cases and controls with well-defined lung cancer and COPD phenotypes, found rs577876, rs6455728 and rs9346917 (p<0.01) to be significantly associated with lung cancer development in people with COPD.,Our findings support the evidence that PARK2 might have a tumor suppressor role in the development of COPD and lung cancer. | Mutations in epithelial growth factor receptor (EGFR), as well as in the EGFR downstream target KRAS are frequently observed in non-small cell lung cancer (NSCLC).,Chronic obstructive pulmonary disease (COPD), an independent risk factor for developing NSCLC, is associated with an increased activation of EGFR.,In this study we determined presence of EGFR and KRAS hotspot mutations in 325 consecutive NSCLC patients subjected to EGFR and KRAS mutation analysis in the diagnostic setting and for whom the pulmonary function has been determined at time of NSCLC diagnosis.,Information about age at diagnosis, sex, smoking status, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) was collected.,Chronic obstructive pulmonary disease(COPD) was defined according to 2013 GOLD criteria.,Chi-Square, student t-test and multivariate logistic regression were used to analyze the data.,A total of 325 NSCLC patients were included, 193 with COPD and 132 without COPD.,COPD was not associated with presence of KRAS hotspot mutations, while EGFR mutations were significantly higher in non-COPD NSCLC patients.,Both female gender (HR 2.61; 95% CI: 1.56-4.39; p<0.001) and smoking (HR 4.10; 95% CI: 1.14-14.79; p = 0.03) were associated with KRAS mutational status.,In contrast, only smoking (HR 0.11; 95% CI: 0.04-0.32; p<0.001) was inversely associated with EGFR mutational status.,Smoking related G>T and G>C transversions were significantly more frequent in females (86.2%) than in males (61.5%) (p = 0.008).,The exon 19del mutation was more frequent in non-smokers (90%) compared to current or past smokers (36.8%).,In conclusion, KRAS mutations are more common in females and smokers, but are not associated with COPD-status in NSCLC patients.,EGFR mutations are more common in non-smoking NSCLC patients. | 1 |
The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms.,The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.,In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks.,The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26.,Overall, 676 patients completed the study.,The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met.,QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001).,QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001).,QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use.,However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.,Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%).,The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%).,These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year. | 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 |
TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.,In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219).,Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4).,Time to first and rate of moderate/severe exacerbations were assessed.,BFF MDI 320/10 µg improved pre-dose trough FEV1 versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4 versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24.,BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI.,Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.,BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.,TELOS: co-suspension delivery technology budesonide/formoterol fumarate dihydrate in a metered dose inhaler improved lung function and time to first and rate of exacerbations versus monocomponents in patients with moderate to very severe COPDhttp://ow.ly/ffWo30lrJL6 | Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.,Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks.,Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.,In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment.,Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies.,Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg.,Incidence of adverse events was comparable between the FDCs and the mono-components.,These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.,Lung function and symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate to very severe COPDhttp://ow.ly/DIKiY | 1 |
Although, to our knowledge, there has been no exhaustive or credible review of the evidence of the disease burden of COPD in China, COPD has become an increasing public health concern to the Chinese medical community.,The purpose of this article is to review the evidence and evaluate and clarify the disease burden of COPD in China with the aim of improving effective management.,We reviewed previous studies of COPD in China, which included data on prevalence, mortality, disease burden, risk factors, diagnosis, and management by searching related Web sites, including PubMed, ProQuest, and Thomson Reuters' Web of Knowledge, as well as major Chinese databases and government Web sites.,Reported COPD prevalence varied between 5% and 13% in different provinces/cities across China.,In 2008, COPD ranked fourth as a leading cause of death in urban areas and third in rural areas.,In addition, COPD accounted for 1.6% of all hospital admissions in China in that year.,The high prevalence of smoking and biomass fuel use acted as major contributors to the high occurrence of COPD in China.,Management of COPD in China should focus on adjusting the distribution of medical resources and on addressing public health policies to facilitate earlier diagnosis in rural areas, aim to reduce smoking prevalence, improve patients' self-management, and keep physicians' knowledge up to date and consistent with current guidelines.,COPD is one of the most challenging medical issues facing China because of its influence on both personal and public health and its impact on the economy.,Optimal management strategies should be adopted and strengthened immediately. | Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability worldwide.,The Global Burden of Disease study has concluded that COPD will become the third leading cause of death worldwide by 2020, and will increase its ranking of disability-adjusted life years lost from 12th to 5th.,Acute exacerbations of COPD (AECOPD) are associated with impaired quality of life and pulmonary function.,More frequent or severe AECOPDs have been associated with especially markedly impaired quality of life and a greater longitudinal loss of pulmonary function.,COPD and AECOPDs are characterized by an augmented inflammatory response.,Macrolide antibiotics are macrocyclical lactones that provide adequate coverage for the most frequently identified pathogens in AECOPD and have been generally included in published guidelines for AECOPD management.,In addition, they exert broad-ranging, immunomodulatory effects both in vitro and in vivo, as well as diverse actions that suppress microbial virulence factors.,Macrolide antibiotics have been used to successfully treat a number of chronic, inflammatory lung disorders including diffuse panbronchiolitis, asthma, noncystic fibrosis associated bronchiectasis, and cystic fibrosis.,Data in COPD patients have been limited and contradictory but the majority hint to a potential clinical and biological effect.,Additional, prospective, controlled data are required to define any potential treatment effect, the nature of this effect, and the role of bronchiectasis, baseline colonization, and other cormorbidities. | 1 |
Chronic obstructive pulmonary disease (COPD) and asthma are common diseases with a heterogeneous distribution worldwide.,Here, we present methods and disease and risk estimates for COPD and asthma from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2015 study.,The GBD study provides annual updates on estimates of deaths, prevalence, and disability-adjusted life years (DALYs), a summary measure of fatal and non-fatal disease outcomes, for over 300 diseases and injuries, for 188 countries from 1990 to the most recent year.,We estimated numbers of deaths due to COPD and asthma using the GBD Cause of Death Ensemble modelling (CODEm) tool.,First, we analysed data from vital registration and verbal autopsy for the aggregate category of all chronic respiratory diseases.,Subsequently, models were run for asthma and COPD relying on covariates to predict rates in countries that have incomplete or no vital registration data.,Disease estimates for COPD and asthma were based on systematic reviews of published papers, unpublished reports, surveys, and health service encounter data from the USA.,We used the Global Initiative of Chronic Obstructive Lung Disease spirometry-based definition as the reference for COPD and a reported diagnosis of asthma with current wheeze as the definition of asthma.,We used a Bayesian meta-regression tool, DisMod-MR 2.1, to derive estimates of prevalence and incidence.,We estimated population-attributable fractions for risk factors for COPD and asthma from exposure data, relative risks, and a theoretical minimum exposure level.,Results were stratified by Socio-demographic Index (SDI), a composite measure of income per capita, mean years of education over the age of 15 years, and total fertility rate.,In 2015, 3·2 million people (95% uncertainty interval [UI] 3·1 million to 3·3 million) died from COPD worldwide, an increase of 11·6% (95% UI 5·3 to 19·8) compared with 1990.,There was a decrease in age-standardised death rate of 41·9% (37·7 to 45·1) but this was counteracted by population growth and ageing of the global population.,From 1990 to 2015, the prevalence of COPD increased by 44·2% (41·7 to 46·6), whereas age-standardised prevalence decreased by 14·7% (13·5 to 15·9).,In 2015, 0·40 million people (0·36 million to 0·44 million) died from asthma, a decrease of 26·7% (−7·2 to 43·7) from 1990, and the age-standardised death rate decreased by 58·8% (39·0 to 69·0).,The prevalence of asthma increased by 12·6% (9·0 to 16·4), whereas the age-standardised prevalence decreased by 17·7% (15·1 to 19·9).,Age-standardised DALY rates due to COPD increased until the middle range of the SDI before reducing sharply.,Age-standardised DALY rates due to asthma in both sexes decreased monotonically with rising SDI.,The relation between with SDI and DALY rates due to asthma was attributed to variation in years of life lost (YLLs), whereas DALY rates due to COPD varied similarly for YLLs and years lived with disability across the SDI continuum.,Smoking and ambient particulate matter were the main risk factors for COPD followed by household air pollution, occupational particulates, ozone, and secondhand smoke.,Together, these risks explained 73·3% (95% UI 65·8 to 80·1) of DALYs due to COPD.,Smoking and occupational asthmagens were the only risks quantified for asthma in GBD, accounting for 16·5% (14·6 to 18·7) of DALYs due to asthma.,Asthma was the most prevalent chronic respiratory disease worldwide in 2015, with twice the number of cases of COPD.,Deaths from COPD were eight times more common than deaths from asthma.,In 2015, COPD caused 2·6% of global DALYs and asthma 1·1% of global DALYs.,Although there are laudable international collaborative efforts to make surveys of asthma and COPD more comparable, no consensus exists on case definitions and how to measure disease severity for population health measurements like GBD.,Comparisons between countries and over time are important, as much of the chronic respiratory burden is either preventable or treatable with affordable interventions.,Bill & Melinda Gates Foundation. | The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed.,Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD.,We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012.,Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence.,86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both.,Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence.,Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low.,As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence.,Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence.,Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment. | 1 |
Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD).,However, choice of parameters and score complexity restrict clinical applicability.,Our aim was to provide and validate a simplified COPD risk index independent of lung function.,The PROMISE study (n=530) was used to develop a novel prognostic index.,Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality.,External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).,Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C.,It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05).,Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively).,External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).,The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.,The B-AE-D indices allow a simple and accurate assessment of COPD-related risk in the absence of lung functionhttp://ow.ly/XFBox | 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 |
Among patients with chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM) is a common comorbidity and is probably associated with increased systemic inflammation and worse prognosis.,Metformin, with its pleiotropic anti-inflammatory and antioxidant actions, may offer theoretical benefits in COPD patients with DM.,Thus, this study aimed to investigate the effects of DM and metformin use on mortality in the clinical trajectory of COPD.,This was a retrospective cohort study comprising patients with spirometry-confirmed COPD and an age of ≥40 years from 2008 to 2014.,The primary outcome of interest was all-cause mortality.,We evaluated the effects of DM on mortality through the clinical course of COPD and we also assessed the impact of metformin use on survival of the COPD population.,Among 4231 COPD patients, 556 (13%) had DM, and these patients had 1.62 times higher hazards of 2-year mortality than those without DM (95% confidence interval [CI], 1.15-2.28) after adjusting for age, gender, COPD stage, comorbidities and prior COPD hospitalization.,Over a 2-year period, metformin users had a significantly lower risk of death (hazard ratio, 0.46; 95% CI, 0.23-0.92) compared with non-metformin users in patients with coexistent COPD and DM.,Moreover, metformin users had similar survival to COPD patients without DM.,This study shows that DM is associated with an increased risk of death in COPD patients and metformin use seems to mitigate the hazard.,Our findings suggest a potential role of metformin in the management of DM in COPD.,The online version of this article (10.1186/s12931-019-1035-9) contains supplementary material, which is available to authorized users. | Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD).,AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism.,However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema.,Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury.,To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 μM).,Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C.,AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence.,Knockdown of AMPKα1/α2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells.,Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice.,This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement.,Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs.,In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema. | 1 |
The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).,In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily.,Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value.,The primary endpoint was trough FEV1 at 12 and 28 weeks.,Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.,At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001).,More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074).,The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9).,Adverse events were minor in both studies.,Aclidinium is effective and well tolerated in patients with moderate to severe COPD.,ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II). | Most patients with chronic obstructive pulmonary disease (COPD) receive inhaled long-acting bronchodilators and inhaled corticosteroids.,Conventional meta-analyses established that these drugs reduce COPD exacerbations when separately compared with placebo.,However, there are relatively few head-to-head comparisons and conventional meta-analyses focus on single comparisons rather than on a simultaneous analysis of competing drug regimens that would allow rank ordering of their effectiveness.,Therefore we assessed, using a network meta-analytic technique, the relative effectiveness of the common inhaled drug regimes used to reduce exacerbations in patients with COPD.,We conducted a systematic review and searched existing systematic reviews and electronic databases for randomized trials of ≥ 4 weeks' duration that assessed the effectiveness of inhaled drug regimes on exacerbations in patients with stable COPD.,We extracted participants and intervention characteristics from included trials and assessed their methodological quality.,For each treatment group we registered the proportion of patients with ≥ 1 exacerbation during follow-up.,We used treatment-arm based logistic regression analysis to estimate the absolute and relative effects of inhaled drug treatments while preserving randomization within trials.,We identified 35 trials enrolling 26,786 patients with COPD of whom 27% had ≥ 1 exacerbation.,All regimes reduced exacerbations statistically significantly compared with placebo (odds ratios ranging from 0.71 (95% confidence interval [CI] 0.64 to 0.80) for long-acting anticholinergics to 0.78 (95% CI 0.70 to 0.86) for inhaled corticosteroids).,Compared with long-acting bronchodilators alone, combined treatment was not more effective (comparison with long-acting beta-agonists: odds ratio 0.93 [95% CI 0.84 to 1.04] and comparison with long-acting anticholinergics: odds ratio 1.02 [95% CI 0.90 to 1.16], respectively).,If FEV1 was ≤ 40% predicted, long-acting anticholinergics, inhaled corticosteroids, and combination treatment reduced exacerbations significantly compared with long-acting beta-agonists alone, but not if FEV1 was > 40% predicted.,This effect modification was significant for inhaled corticosteroids (P = 0.02 for interaction) and combination treatment (P = 0.01) but not for long-acting anticholinergics (P = 0.46).,A limitation of this analysis is its exclusive focus on exacerbations and lack of FEV1 data for individual patients.,We found no evidence that one single inhaled drug regimen is more effective than another in reducing exacerbations.,Inhaled corticosteroids when added to long-acting beta-agonists reduce exacerbations only in patients with COPD with FEV1 ≤ 40%. | 1 |
Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.,Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks.,Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.,In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment.,Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies.,Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg.,Incidence of adverse events was comparable between the FDCs and the mono-components.,These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.,Lung function and symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate to very severe COPDhttp://ow.ly/DIKiY | 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. | 1 |
•COPD is a risk factor for lung cancer beyond their shared aetiology.,•Both are driven by oxidative stress.,•Both are linked to cellular aging, senescence and telomere shortening.,•Both have been linked to genetic predisposition.,•Both show altered epigenetic regulation of gene expression.,COPD is a risk factor for lung cancer beyond their shared aetiology.,Both are driven by oxidative stress.,Both are linked to cellular aging, senescence and telomere shortening.,Both have been linked to genetic predisposition.,Both show altered epigenetic regulation of gene expression.,Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden.,Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking.,Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying genetic predisposition, telomere shortening, mitochondrial dysfunction or premature aging.,In the majority of smokers, the burden of smoking may be dealt with by the body’s defense mechanisms: anti-oxidants such as superoxide dismutases, anti-proteases and DNA repair mechanisms.,However, in the case of both diseases these fail, leading to cancer if mutations occur or COPD if damage to the cell and proteins becomes too great.,Alternatively COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage, chronic exposure to pro-inflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation.,Understanding the mechanisms that drive these processes in primary cells from patients with these diseases along with better disease models is essential for the development of new treatments. | Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the world.,Although smoking is the main risk factor for this disease, only a minority of smokers develop COPD.,Why this happens is largely unknown.,Recent discoveries by the human microbiome project have shed new light on the importance and richness of the bacterial microbiota at different body sites in human beings.,The microbiota plays a particularly important role in the development and functional integrity of the immune system.,Shifts or perturbations in the microbiota can lead to disease.,COPD is in part mediated by dysregulated immune responses to cigarette smoke and other environmental insults.,Although traditionally the lung has been viewed as a sterile organ, by using highly sensitive genomic techniques, recent reports have identified diverse bacterial communities in the human lung that may change in COPD.,This review summarizes the current knowledge concerning the lung microbiota in COPD and its potential implications for pathogenesis of the disease. | 1 |
Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition sharing risk factors with lung cancer.,Lung cancer screening may provide an opportunity to improve COPD diagnosis.,Using Pan-Canadian Early Detection of Lung Cancer (PanCan) study data, the present study sought to determine the following: 1) What is the prevalence of COPD in a lung cancer screening population?,2) Can a model based on clinical and screening low-dose CT scan data predict the likelihood of COPD?,The single arm PanCan study recruited current or former smokers age 50-75 who had a calculated risk of lung cancer of at least 2% over 6 years.,A baseline health questionnaire, spirometry, and low-dose CT scan were performed.,CT scans were assessed by a radiologist for extent and distribution of emphysema.,With spirometry as the gold standard, logistic regression was used to assess factors associated with COPD.,Among 2514 recruited subjects, 1136 (45.2%) met spirometry criteria for COPD, including 833 of 1987 (41.9%) of those with no prior diagnosis, 53.8% of whom had moderate or worse disease.,In a multivariate model, age, current smoking status, number of pack-years, presence of dyspnea, wheeze, participation in a high-risk occupation, and emphysema extent on LDCT were all statistically associated with COPD, while the overall model had poor discrimination (c-statistic = 0.627 (95% CI of 0.607 to 0.650).,The lowest and the highest risk decile in the model predicted COPD risk of 27.4 and 65.3%.,COPD had a high prevalence in a lung cancer screening population.,While a risk model had poor discrimination, all deciles of risk had a high prevalence of COPD, and spirometry could be considered as an additional test in lung cancer screening programs.,(Clinical Trial Registration: ClinicalTrials.gov, number NCT00751660, registered September 12, 2008),The online version contains supplementary material available at 10.1186/s12890-020-01344-y. | We studied the prevalence, burden and potential risk factors for chronic bronchitis symptoms in the Burden of Obstructive Lung Disease study.,Representative population-based samples of adults aged ≥40 years were selected in participating sites.,Participants completed questionnaires and spirometry.,Chronic bronchitis symptoms were defined as chronic cough and phlegm on most days for ≥3 months each year for ≥2 years.,Data from 24 855 subjects from 33 sites in 29 countries were analysed.,There were significant differences in the prevalence of self-reported symptoms meeting our definition of chronic bronchitis across sites, from 10.8% in Lexington (KY, USA), to 0% in Ile-Ife (Nigeria) and Blantyre (Malawi).,Older age, less education, current smoking, occupational exposure to fumes, self-reported diagnosis of asthma or lung cancer and family history of chronic lung disease were all associated with increased risk of chronic bronchitis.,Chronic bronchitis symptoms were associated with worse lung function, more dyspnoea, increased risk of respiratory exacerbations and reduced quality of life, independent of the presence of other lung diseases.,The prevalence of chronic bronchitis symptoms varied widely across the studied sites.,Chronic bronchitis symptoms were associated with significant burden both in individuals with chronic airflow obstruction and those with normal lung function.,Chronic bronchitis symptoms are associated with significant burden regardless of the presence of airflow obstructionhttp://ow.ly/kP9P30eFELK | 1 |
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. | 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 |
Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction.,We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.,Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination.,The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers.,Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08).,A similar pattern was observed in overweight smokers.,In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (-8.33 ± 0.172 logM vs -8.10 ± 0.118 logM; P = .001 for EC50).,In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003).,GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.,ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov | Purpose.,This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD.,Patients and Methods.,We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction (“at risk”; AR).,In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA.,Data were analyzed using simple and logistic regression and receiver operating characteristic analyses.,Results.,Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p < 0.01).,Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV1 predicted < 50%; p = 0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA ≥ 8.0; p = 0.001).,Conclusion.,Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD. | 1 |
Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.,Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face.,Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.,Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P<0.001) to diagnose COPD and frequently included validated patient-reported outcome measures (PCPs 67%, respiratory specialists 81%; P<0.001).,Respiratory specialists were more likely than PCPs to report awareness of the GOLD global strategy (93% versus 58%, P<0.001); however, when presented with patient scenarios, they did not always perform better than PCPs with regard to recommending GOLD-concordant treatment options.,The proportion of PCPs and respiratory specialists providing first- or second-choice treatment options concordant with GOLD strategy for a GOLD B-type patient was 38% versus 67%, respectively.,For GOLD C and D-type patients, the concordant proportions for PCPs and respiratory specialists were 40% versus 38%, and 57% versus 58%, respectively.,This survey of physicians in 12 countries practicing in the primary care and respiratory specialty settings showed high awareness of COPD-management guidelines.,Frequent use of guideline-recommended COPD diagnostic practices was reported; however, gaps in the application of COPD-treatment recommendations were observed, warranting further evaluation to understand potential barriers to adopt guideline recommendations. | Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea.,These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD.,Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥2 per year) independently of disease severity.,Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis.,The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS).,While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance.,Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation.,Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations.,Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations. | 1 |
The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively.,We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD.,207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 μg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 μg via HandiHaler.,Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) < 50% predicted, or FEV1 < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year.,The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12.,Secondary endpoints included CFB in trough FEV1 at Day 84 and 85.,Other endpoints included serial FEV1 and health status outcomes at Week 12.,Safety was evaluated descriptively.,The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732).,FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [− 13, 43]; Study 207609: 11 mL [− 20, 41]).,FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies.,No treatment differences were seen in health status outcomes.,Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies.,FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD.,Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen.,GSK (207608/207609; NCT03478683/NCT03478696). | This longitudinal, retrospective cohort study of patients with COPD describes baseline characteristics, adherence, and persistence following initiation of inhaled corticosteroids (ICS)/long-acting β2-agonists (LABA)/long-acting muscarinic antagonists (LAMA) from multiple inhaler triple therapy (MITT).,Patients aged ≥40 years receiving MITT between January 2012 and September 2015 were identified from the IQVIA™ Real-world Data Adjudicated Claims-USA database.,MITT was defined as subjects with ≥1 overlapping days’ supply of three COPD medications (ICS, LABA, and LAMA).,Adherence (proportion of days covered, PDC) and discontinuation (defined as a gap of 1, 30, 60, or 90 days of supply in any of the three components of the triple therapy) were calculated for each patient over 12 months of follow-up.,In addition, analyses were stratified by number of inhalers.,In total, 14,635 MITT users were identified (mean age, 62 years).,Mean PDC for MITT at 12 months was 0.37%.,Mean PDC for the ICS/LABA and LAMA component at 12 months was 49% (0.49±0.31; median, 0.47) and 54% (0.54±0.33; 0.56), respectively.,The proportion of adherent patients (PDC ≥0.8) at 12 months was 14% for MITT.,Allowing for a 30-day gap from last day of therapy, 86% of MITT users discontinued therapy during follow-up.,Patients with COPD had low adherence to and persistence with MITT in a real-world setting.,Mean PDC for each single inhaler component was higher than the mean PDC observed with MITT.,Reducing the number of inhalers may improve overall adherence to intended triple therapy. | 1 |
Little is known about the interactions between the lung microbiome and host response in chronic obstructive pulmonary disease (COPD).,We performed a longitudinal 16S ribosomal RNA gene-based microbiome survey on 101 sputum samples from 16 healthy subjects and 43 COPD patients, along with characterization of host sputum transcriptome and proteome in COPD patients.,Dysbiosis of sputum microbiome was observed with significantly increased relative abundance of Moraxella in COPD versus healthy subjects and during COPD exacerbations, and Haemophilus in COPD ex-smokers versus current smokers.,Multivariate modeling on sputum microbiome, host transcriptome and proteome profiles revealed that significant associations between Moraxella and Haemophilus, host interferon and pro-inflammatory signaling pathways and neutrophilic inflammation predominated among airway host-microbiome interactions in COPD.,While neutrophilia was positively correlated with Haemophilus, interferon signaling was more strongly linked to Moraxella.,Moreover, while Haemophilus was significantly associated with host factors both in stable state and during exacerbations, Moraxella-associated host responses were primarily related to exacerbations.,Our study highlights a significant airway host-microbiome interplay associated with COPD inflammation and exacerbations.,These findings indicate that Haemophilus and Moraxella influence different components of host immune response in COPD, and that novel therapeutic strategies should consider targeting these bacteria and their associated host pathways in COPD.,The online version of this article (10.1186/s12931-019-1085-z) contains supplementary material, which is available to authorized users. | Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.,We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations.,Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center.,Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation.,Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators.,Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters.,The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology.,Three exacerbation biologic clusters were identified.,Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria.,Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes.,Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes.,A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD.,The sputum mediator and microbiome profiles were distinct between clusters. | 1 |
Interactions between spirometry and patient-reported outcomes in COPD are not well understood.,This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy.,Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations.,Mean and standard deviations of treatment effects were extracted for each arm of each study.,Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling.,The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score.,Thirty-six studies (≥3 months) were included.,Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data.,Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ.,The correlation strengthened with increasing study duration from 3 to 12 months.,Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1.,The association between change in FEV1 and other patient-reported outcomes was generally weak.,Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status. | Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterized by airflow limitation that is not fully reversible.,It is a major cause of morbidity and mortality and represents substantial economic and social burden throughout the world.,A range of interventions has been developed that decrease symptoms and address complications associated with COPD.,However, to date few interventions have been unequivocally demonstrated to modify disease progression.,Assessment of the potential for interventions to modify disease progression is complicated by the lack of a clear definition of disease modification and disagreement over appropriate markers by which modification should be evaluated.,To clarify these issues, a working group of physicians and scientists from the USA, Canada and Europe was convened.,The proposed working definition of disease modification resulting from the group discussions was “an improvement in, or stabilization of, structural or functional parameters as a result of reduction in the rate of progression of these parameters which occurs whilst an intervention is applied and may persist even if the intervention is withdrawn”.,According to this definition, pharmacologic interventions may be considered disease-modifying if they provide consistent and sustained improvements in structural and functional parameters.,Smoking cessation and lung volume reduction surgery would both qualify as disease-modifying interventions. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant increases in resource utilization and cost to the health care system.,COPD patients with chronic bronchitis and a history of exacerbations pose an additional burden to the system.,This study examined health care utilization and cost among these patients.,For this retrospective analysis, data were extracted from a large national health plan with a predominantly Medicare population.,This study involved patients who were aged 40-89 years, had been enrolled continuously for 24 months or more, had at least two separate insurance claims for COPD with chronic bronchitis (International Classification of Diseases, Ninth Revision, Clinical Modification code 491.xx), and had pharmacy claims for COPD maintenance medications between January 1, 2007, and March 31, 2009.,Two years of data were examined for each patient; the index date was defined as the first occurrence of COPD.,Baseline characteristics were obtained from the first year of data, with health outcomes tracked in the second year.,Severe exacerbation was defined by COPD-related hospitalization or death; moderate exacerbation was defined by oral or parenteral corticosteroid use.,Adjusted numbers of exacerbations and COPD-related costs per patient were estimated controlling for demographic and clinical characteristics.,The final study sample involved 8554 patients; mean age was 70.1 ± 8.6 years and 49.8% of the overall population had exacerbation, 13.9% had a severe exacerbation only, 29.1% had a moderate exacerbation only, and 6.8% had both a severe and moderate exacerbation.,COPD-related mean annual costs were $4069 (all figures given in US dollars) for the overall population and $6381 for patients with two or more exacerbations.,All-cause health care costs were $18,976 for the overall population and $23,901 for patients with history of two or more exacerbations.,Severity of exacerbations, presence of cardiovascular disease, diabetes, and long-term oxygen use were associated with higher adjusted costs.,The results indicate that despite treatment with maintenance medications, COPD patients continue to have exacerbations resulting in higher costs.,New medications and disease management interventions are warranted to reduce the severity and frequency of exacerbations and the related cost impact of the disease. | Background: Chronic obstructive pulmonary disease (COPD) is a disease of increasing significance in terms of economic and social burden due to its increasing prevalence and high costs.,Direct costs of COPD are mostly associated with hospitalization expenditures.,In this study, our objective was to investigate the costs of hospitalization and factors affecting these costs in patients hospitalized due to acute exacerbation of COPD (AECOPD).,Methods: A total of 284 patients hospitalized AECOPD were included in the study.,Data were examined retrospectively using the electronic hospital charts.,Results: Mean duration of hospitalization was 11.38 ± 6.94 days among study patients.,Rates of admission to the intensive care unit, initiation of non-invasive mechanical ventilation (NIMV) and invasive mechanical ventilation (MIV) were 37.3% (n=106), 44.4% (n=126) and 18.3% (n=52) respectively.,The rate of mortality was 14.8% (n=42).,Mean cost of a single patient hospitalized for an AECOPD was calculated as $1765 ± 2139.,Mean cost of admission was $889 ± 533 in standard ward, and $2508 ± 2857 in intensive care unit (ICU).,The duration of hospitalization, a FEV1% predicted value below 30%, having smoked 40 package-years or more, the number of co-morbidities, NIMV, IMV, ICU, exitus and the number of hospitalizations in the past year were among the factors that increased costs significantly.,Hospital acquired pneumonia, chronic renal failure and anemia also increased the costs of COPD significantly.,Conclusion: The costs of treatment increase with the severity of COPD or with progression to a higher stage.,Efforts and expenditures aimed at preventing COPD exacerbations might decrease the costs in COPD. | 1 |
The bronchial microbiome in severe COPD during stability and exacerbation in patients chronically colonised by Pseudomonas aeruginosa (PA), has not been defined.,Our objective was to determine the characteristics of the bronchial microbiome of severe COPD patients colonised and not colonised by P. aeruginosa and its changes during exacerbation.,COPD patients with severe disease and frequent exacerbations were categorised according to chronic colonisation by P. aeruginosa.,Sputum samples were obtained in stability and exacerbation, cultured, and analysed by 16S rRNA gene amplification and pyrosequencing.,Sixteen patients were included, 5 of them showing chronic colonisation by P. aeruginosa.,Pseudomonas genus had significantly higher relative abundance in stable colonised patients (p = 0.019), but no significant differences in biodiversity parameters were found between the two groups (Shannon, 3 (2-4) vs 3 (2-3), p = 0.699; Chao1, 124 (77-159) vs 140 (115-163), p = 0.364).,In PA-colonised patients bronchial microbiome changed to a microbiome similar to non-PA-colonised patients during exacerbations.,An increase in the relative abundance over 20 % during exacerbation was found for Streptococcus, Pseudomonas, Moraxella, Haemophilus, Neisseria, Achromobacter and Corynebacterium genera, which include recognised potentially pathogenic microorganisms, in 13 patients colonised and not colonised by P. aeruginosa with paired samples.,These increases were not identified by culture in 5 out of 13 participants (38.5 %).,Stable COPD patients with severe disease and PA-colonised showed a similar biodiversity to non-PA-colonised patients, with a higher relative abundance of Pseudomonas genus in bronchial secretions.,Exacerbation in severe COPD patients showed the same microbial pattern, independently of previous colonisation by P. aeruginosa.,The online version of this article (doi:10.1007/s10096-013-2044-0) contains supplementary material, which is available to authorized users. | Exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant increases in resource utilization and cost to the health care system.,COPD patients with chronic bronchitis and a history of exacerbations pose an additional burden to the system.,This study examined health care utilization and cost among these patients.,For this retrospective analysis, data were extracted from a large national health plan with a predominantly Medicare population.,This study involved patients who were aged 40-89 years, had been enrolled continuously for 24 months or more, had at least two separate insurance claims for COPD with chronic bronchitis (International Classification of Diseases, Ninth Revision, Clinical Modification code 491.xx), and had pharmacy claims for COPD maintenance medications between January 1, 2007, and March 31, 2009.,Two years of data were examined for each patient; the index date was defined as the first occurrence of COPD.,Baseline characteristics were obtained from the first year of data, with health outcomes tracked in the second year.,Severe exacerbation was defined by COPD-related hospitalization or death; moderate exacerbation was defined by oral or parenteral corticosteroid use.,Adjusted numbers of exacerbations and COPD-related costs per patient were estimated controlling for demographic and clinical characteristics.,The final study sample involved 8554 patients; mean age was 70.1 ± 8.6 years and 49.8% of the overall population had exacerbation, 13.9% had a severe exacerbation only, 29.1% had a moderate exacerbation only, and 6.8% had both a severe and moderate exacerbation.,COPD-related mean annual costs were $4069 (all figures given in US dollars) for the overall population and $6381 for patients with two or more exacerbations.,All-cause health care costs were $18,976 for the overall population and $23,901 for patients with history of two or more exacerbations.,Severity of exacerbations, presence of cardiovascular disease, diabetes, and long-term oxygen use were associated with higher adjusted costs.,The results indicate that despite treatment with maintenance medications, COPD patients continue to have exacerbations resulting in higher costs.,New medications and disease management interventions are warranted to reduce the severity and frequency of exacerbations and the related cost impact of the disease. | 1 |
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. | The relationship between prior health care utilization and respiratory medication prescriptions in an unselected population of patients with COPD is not known.,We determined the prescribed respiratory medications and respiratory and nonrespiratory health care encounters in 523 Veterans with COPD at the Cincinnati Veterans Affairs Medical Center between 2000 and 2005.,Prescribed treatments were compared with the GOLD guidelines and each patient was classified as receiving less medications than recommended in the guidelines (<G), medications according to the guidelines (=G), or more medications than recommended (>G).,Respiratory medications were <G for 54%, =G in 33%, and >G for 14% of the patients studied.,For GOLD stages 1 and 2, <G patients had the fewest and >G patients the most prior respiratory encounters during a 12 month period (0.31 ± 0.073 (0.21, 0.47), 0.75 ± 0.5 (0.37, 1.5), 1.1 ± 0.27 (0.74, 1.6) visits/person/year, <G, =G, >G, respectively, mean + standard error of mean (SEM) (95% confidence limits) 2 degrees of freedom (df) ANOVA P < 0.001 for prescription effect).,For GOLD stages 3 and 4, <G was associated with significantly fewer prior respiratory visits than was =G (0.78 ± 0.11 (0.6, 1.0) and 2.4 ± 0.47 (1.9, 3.1) visits/person/year, respectively, P < 0.001).,There were no differences in nonrespiratory health care visits for GOLD stages 1 and 2 by prescription level (3.1 ± 0.24 (2.6, 3.5), 3.1 ± 0.46 (2.1, 4.6) and 4.1 ± 0.55 (3.3, 5.1) visits/person/year, <G, =G, >G respectively, 2 df ANOVA P = 0.096) or for GOLD stages 3 and 4 (3.6 ± 0.25 (3.2, 4.1) and 4.0 ± 0.44 (3.3, 4.9) visits/person/year, <G and =G, respectively, P = 0.36).,Respiratory medications prescribed for an unselected population with a broad range of COPD severity complied poorly with the GOLD pharmacologic treatment guidelines but correlated with the number of prior respiratory health care visits. | 1 |
Culture-independent microbial sequencing techniques have revealed that the respiratory tract harbours a complex microbiome not detectable by conventional culturing methods.,The contribution of the microbiome to chronic obstructive pulmonary disease (COPD) pathobiology and the potential for microbiome-based clinical biomarkers in COPD are still in the early phases of investigation.,Sputum is an easily obtainable sample and has provided a wealth of information on COPD pathobiology, and thus has been a preferred sample type for microbiome studies.,Although the sputum microbiome likely reflects the respiratory microbiome only in part, there is increasing evidence that microbial community structure and diversity are associated with disease severity and clinical outcomes, both in stable COPD and during the exacerbations.,Current evidence has been limited to mainly cross-sectional studies using 16S rRNA gene sequencing, attempting to answer the question ‘who is there?’,Longitudinal studies using standardised protocols are needed to answer outstanding questions including differences between sputum sampling techniques.,Further, with advancing technologies, microbiome studies are shifting beyond the examination of the 16S rRNA gene, to include whole metagenome and metatranscriptome sequencing, as well as metabolome characterisation.,Despite being technically more challenging, whole-genome profiling and metabolomics can address the questions ‘what can they do?’,and ‘what are they doing?’,This review provides an overview of the basic principles of high-throughput microbiome sequencing techniques, current literature on sputum microbiome profiling in COPD, and a discussion of the associated limitations and future perspectives. | COPD is a long-term condition associated with considerable disability with a clinical course characterized by episodes of worsening respiratory signs and symptoms associated with exacerbations.,Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal conditions in the general population and has emerged as a comorbidity of COPD.,GERD may be diagnosed by both symptomatic approaches (including both typical and atypical symptoms) and objective measurements.,Based on a mix of diagnostic approaches, the prevalence of GERD in COPD ranges from 17% to 78%.,Although GERD is usually confined to the lower esophagus in some individuals, it may be associated with pulmonary microaspiration of gastric contents.,Possible mechanisms that may contribute to GERD in COPD originate from gastroesophageal dysfunction, including altered pressure in the lower esophageal sphincter (which normally protect against GERD) and changes in esophageal motility.,Proposed respiratory contributions to the development of GERD include respiratory medications that may alter esophageal sphincter tone and changes in respiratory mechanics, with increased lung hyperinflation compromising the antireflux barrier.,Although the specific cause and effect relationship between GERD and COPD has not been fully elucidated, GERD may influence lung disease severity and has been identified as a significant predictor of acute exacerbations of COPD.,Further clinical effects could include a poorer health-related quality of life and an increased cost in health care, although these factors require further clarification.,There are both medical and surgical options available for the treatment of GERD in COPD and while extensive studies in this population have not been undertaken, this comorbidity may be amenable to treatment. | 1 |
There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways.,Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC).,This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs.,Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition.,HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted.,For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component.,Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC.,Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively).,Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD.,This is consistent with the extrafine formulation of BDP/FF/GB. | To evaluate the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) vs twice-daily budesonide/formoterol (BUD/FOR) in patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations, from the Spanish National Healthcare System perspective.,The validated GALAXY-COPD model was used to simulate disease progression and predict healthcare costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) over a 3-year time horizon for a Spanish population.,Patient characteristics from published literature were supplemented by data from FULFIL (NCT02345161), which compared FF/UMEC/VI vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations.,Treatment effects, extrapolated to 3 years, were based on Week 24 results in the FULFIL intent-to-treat population, including change in forced expiratory volume in 1 second, St.,George’s Respiratory Questionnaire score, and exacerbation rates.,Treatment, exacerbations, and COPD management costs (2019€) were informed by Spanish public sources and published literature.,A 3% discount rate for costs and benefits was applied.,One-way sensitivity and scenario analyses, and probabilistic sensitivity analysis (PSA), were performed.,FF/UMEC/VI treatment led to fewer moderate and severe exacerbations (2.126 and 0.306, respectively) vs BUD/FOR (2.608 and 0.515, respectively), with a mean incremental cost of €69 and gain of 0.107 QALYs, which resulted in an ICER of €642 per QALY gained.,In sensitivity analyses, the ICER was most sensitive to treatment effect variations in exacerbations and healthcare resource utilization/event costs.,Overall, 95% of 1000 PSA simulations resulted in an ICER less than €11,000 per QALY gained for FF/UMEC/VI vs BUD/FOR, confirming robustness of the results.,The probability of FF/UMEC/VI being cost-effective vs BUD/FOR was 100% at a willingness-to-pay threshold of €30,000 per QALY gained.,At the accepted Spanish ICER threshold of €30,000, FF/UMEC/VI represents a cost-effective treatment option vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations. | 1 |
We evaluated whether a chronic obstructive pulmonary disease (COPD) assessment test (CAT) with adjusted weights for the CAT items could better predict future respiratory-related hospitalizations than the original CAT.,Two focus groups (respiratory nurses and physicians) generated two adjusted CAT algorithms.,Two multivariate logistic regression models for infrequent (≤1/year) versus frequent (>1/year) future respiratory-related hospitalizations were defined: one with the adjusted CAT score that correlated best with future hospitalizations and one with the original CAT score.,Patient characteristics related to future hospitalizations (p ≤ 0.2) were also entered.,Eighty-two COPD patients were included.,The CAT algorithm derived from the nurse focus group was a borderline significant predictor of hospitalization risk (odds ratio (OR): 1.07; 95% confidence interval (CI): 1.00-1.14; p = 0.050) in a model that also included hospitalization frequency in the previous year (OR: 3.98; 95% CI: 1.30-12.16; p = 0.016) and anticholinergic risk score (OR: 3.08; 95% CI: 0.87-10.89; p = 0.081).,Presence of ischemic heart disease and/or heart failure appeared ‘protective’ (OR: 0.17; 95% CI: 0.05-0.62; p = 0.007).,The original CAT score was not significantly associated with hospitalization risk.,In conclusion, as a predictor of respiratory-related hospitalizations, an adjusted CAT score was marginally significant (although the original CAT score was not).,‘Previous respiratory-related hospitalizations’ was the strongest factor in this equation. | The appropriate use of generic preference-based measures determines the accuracy of disease assessment and further decision on healthcare policy using quality adjusted life years.,The discriminative capacity of different instruments would differ across disease groups.,Our study was to examine the difference in utility scores for COPD patients measured by EQ-5D and SF-6D and to assist the choice of a proper instrument in this disease group.,Differences of mean utility scores of EQ-5D and SF-6D in groups defined by socio-demographic characteristics, comorbidities, health service utilisation and severity of illness were tested using Mann-Whitney test, t-test, Kruskal-Wallis test, Pearson’s correlation coefficient and ANOVA, as appropriate.,The discriminative properties of the two instruments were compared against indicators of quality of life using receiver operating characteristic curves.,The statistical significance of the area under the curves (AUC) was tested by ANOVA and F-statistics used to compare the efficiency with which each instrument discriminated between disease severity groups.,Mean utility scores of EQ-5D and SF-6D were 0.644 and 0.629 respectively in the 154 subjects included in the analysis.,EQ-5D scores were significantly higher than SF-6D in groups less severe and these differences corresponded to a minimally important difference of greater than 0.03 (p<0.001).,EQ-5D and SF-6D scores were strongly correlated across the whole sample (r = 0.677, p<0.001) and in pre-defined groups (r>0.5 and p<0.05 for all correlation coefficients).,AUCs were above 0.5 against the indicators of health-related quality of life for both instruments.,F-ratios suggested SF-6D was more efficient in discriminating cases of different disease severity than EQ-5D.,Both EQ-5D and SF-6D appeared to be valid preference-based measures in Chinese COPD patients.,SF-6D was more efficient in detecting differences among subgroups with differing health status.,EQ-5D and SF-6D measured different things and might not be used interchangeably in COPD patients. | 1 |
Lung epithelial cell-specific loss of function of Miz1 causes spontaneous COPD-like phenotype and up-regulates Ace2 in mice.,Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Here we show that mice with lung epithelial cell-specific loss of function of Miz1, which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD.,Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2.,Concomitant partial loss of NF-κB/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice.,Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke.,Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19. | Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide.,Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs).,Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release.,Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD.,Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages.,The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach.,In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated.,Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs.,IV).,MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13).,In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin.,In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS.,In addition, GC refractory MMP-9 expression was only associated with neutrophil activation.,As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs.,Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD. | 1 |
Comorbidities including cardiovascular diseases are very common in chronic obstructive pulmonary disease (COPD) secondary to tobacco smoking and contribute to the overall severity of the disease.,In non-smoking COPD, which accounts for about 25% of COPD cases worldwide, current knowledge on the frequency and determinants of comorbidities remains scarce.,The aims of the current study were to assess the frequency of major comorbidities and to evaluate their determinants in a group of non-selected patients with mild-to-moderate COPD who were exposed to organic dust (dairy farmers), to tobacco smoking, or to both, and in controls without COPD who were exposed to organic dust (dairy farmers), or to tobacco smoking, or to both, or who were without exposure.,A total of 4665 subjects (2323 dairy farmers and 2342 non-farmers) including 355 patients with COPD and 4310 controls with normal spirometry were recruited through a large COPD screening program.,Self-reported physician-diagnosed diseases with plausible links to COPD were recorded in this cross-sectional study.,Whatever the exposure, cardiovascular comorbidities were not more frequent in patients with COPD than their counterparts without airflow limitation.,A higher risk of major cardiovascular comorbidities was associated with tobacco smoking and a lower risk was associated with exposure to organic dusts.,Tobacco smoking (but not COPD) is associated with higher frequency of cardiovascular comorbidities.,By contrast, being a dairy farmer exposed to organic dusts is associated with a lower frequency of the same comorbidities.,This reinforces the crucial need for controlling established cardiovascular risk factors even in patients with mild-to-moderate COPD. | The study aimed to investigate the demographic characteristics, clinical features, diagnoses, and treatments of hospitalized exacerbation COPD patients, as well as their disease prognoses and economic costs.,The study planned to enroll 7600 hospitalized patients (aged ≥18 years with main diagnosis as AECOPD).,Study patients were recruited since September 2017, followed up with a 3-year observing period.,In the baseline visit, information on demographic characteristics, clinical features, diagnoses, and treatments were collected.,In the following visits, treatments and examinations, recurrence of AECOPD, re-admission to hospital, complications, and mortality were recorded.,Several validated questionnaires were applied at specific visits.,This study included data from 1 September 2017 until 31 December 2022.,The data would be used to estimate all-cause mortality during hospital stay, AECOPD recurrence within 1 month after discharge, all-cause and cause-specific mortality, frequency of AECOPD recurrence, lung function, life quality, healthcare costs in the study period, etc. | 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. | COPD is the third leading cause of death in the world and its global burden is predicted to increase further.,Even though the prevalence of COPD is well studied, only few studies examined the incidence of COPD in a prospective and standardized manner.,In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged ≥45, COPD was diagnosed based on a pre-bronchodilator obstructive spirometry (FEV1/FVC < 0.70).,In absence of an interpretable spirometry within the Rotterdam Study, cases were defined as having COPD diagnosed by a physician on the basis of clinical presentation and obstructive lung function measured by the general practitioner or respiratory physician.,Incidence rates were calculated by dividing the number of incident cases by the total number of person years of subjects at risk.,In this cohort of 14,619 participants, 1993 subjects with COPD were identified of whom 689 as prevalent ones and 1304 cases as incident ones.,The overall incidence rate (IR) of COPD was 8.9/1000 person-years (PY); 95 % Confidence Interval (CI) 8.4-9.4.,The IR was higher in males and in smokers.,The proportion of female COPD participants without a history of smoking was 27.2 %, while this proportion was 7.3 % in males.,The prevalence of COPD in the Rotterdam Study is 4.7 % and the overall incidence is approximately 9/1000 PY, with a higher incidence in males and in smokers.,The proportion of never-smokers among female COPD cases is substantial.,The online version of this article (doi:10.1007/s10654-016-0132-z) contains supplementary material, which is available to authorized users. | 1 |
The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).,This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension.,Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo.,The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0-12 hours (AUC0-12 h FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment.,Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.,The largest improvements in AUC0-12 h FEV1 were observed with MF/F 400/10 μg and MF/F 200/10 μg.,Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period.,Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment.,Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments.,At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported.,No unexpected AEs were observed.,Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.,In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD. | Mortality due to chronic obstructive pulmonary disease continues to rise, whereas mortality rates related to cardiovascular disease appear to be slowing, or even declining.,This is due at least in part to more widespread use of preventative therapies that have been shown to reduce cardiovascular mortality, raising the question of whether appropriate use of therapies for chronic obstructive pulmonary disease which potentially reduce mortality could have a similar impact.,This article discusses approaches used successfully in managing heart disease and considers whether these can be applied to chronic obstructive pulmonary disease and whether a better understanding of the strongest predictors of mortality in chronic obstructive pulmonary disease is needed.,It reviews the role of inhaled corticosteroids, both alone and in combination with long-acting β2-agonists, in individuals with chronic obstructive pulmonary disease, including the role of combination therapy with inhaled corticosteroids/long-acting β2-agonists (budesonide/formoterol or salmeterol/fluticasone propionate) in decreasing exacerbations and improving health status, potentially providing survival benefits in chronic obstructive pulmonary disease.,This review also discusses the potential impact of treatments indicated for cardiovascular disease on chronic obstructive pulmonary disease and possible links between the two diseases. | 1 |
The aim of this study was to explore to what extent a combined counselling and pulmonary rehabilitation program (PR) influences the perception of physical activity (PA) and motivation for behavioral change in PA in individuals with COPD.,The results of previous quantitative trial that investigated the effect of this combined treatment on daily PA were inconclusive.,It is conjectured that a more targeted tailoring of the counselling and PR intervention could improve its effectiveness.,Eighteen individuals with COPD (median age 69, 8 females) who had participated in the PneumoReha program were interviewed twice (following PR and at three-month follow-up).,These interviews were transcribed and analyzed thematically.,Based on the codes thus identified, three categories ‘perception of PA intensity’, ‘quality of motivation to perform PA’, and ‘strategies to cope with barriers’ were used to differentiate ‘types’ of participants.,Four different types of COPD individuals were distinguished.,Study findings indicate that those individuals who participated in the PR program combined with embedded counselling tended to be more active and intrinsically motivated.,A typology of four types of people with COPD was developed, characterized by their perception of activity, individual motivation and strategies for managing barriers.,The patients’ physical activity level might be influenced by their concept of physical activity and the quality of motivation.,Recognizing patients’ different activity behaviors is important for improving the quality of outpatient PR programs and developing tailored (according to each type) counselling interventions embedded in outpatient PR programs.,The study was registered on the website of https://www.clinicaltrials.gov/ with the identifier NCT02455206 (27/05/2015), as well as on the Swiss National Trails Portal SNCTP000001426 (05/21/2015). | 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 |
COPD often coexists with chronic conditions that may influence disease prognosis.,We investigated associations between chronic (co)morbidities and exacerbations in primary care COPD patients.,Retrospective cohort study based on 2012-2013 electronic health records from 179 Dutch general practices.,Comorbidities from patients with physician-diagnosed COPD were categorized according to International Classification of Primary Care (ICPC) codes.,Chi-squared tests, uni- and multivariable logistic, and Cox regression analyses were used to study associations with exacerbations, defined as oral corticosteroid prescriptions.,Fourteen thousand six hundred three patients with COPD could be studied (mean age 67 (SD 12) years, 53% male) for two years.,At baseline 12,826 (88%) suffered from ≥1 comorbidities, 3263 (22%) from ≥5.,The most prevalent comorbidities were hypertension (35%), coronary heart disease (19%), and osteoarthritis (18%).,Several comorbidities showed statistically significant associations with frequent (i.e., ≥2/year) exacerbations: heart failure (odds ratio [OR], 95% confidence interval: 1.72; 1.38-2.14), blindness & low vision (OR 1.46; 1.21-1.75), pulmonary cancer (OR 1.85; 1.28-2.67), depression 1.48; 1.14-1.91), prostate disorders (OR 1.50; 1.13-1.98), asthma (OR 1.36; 1.11-1.70), osteoporosis (OR 1.41; 1.11-1.80), diabetes (OR 0.80; 0.66-0.97), dyspepsia (OR 1.25; 1.03-1.50), and peripheral vascular disease (OR 1.20; 1.00-1.45).,From all comorbidity categories, having another chronic respiratory disease beside COPD showed the highest risk for developing a new exacerbation (Cox hazard ratio 1.26; 1.17-1.36).,Chronic comorbidities are highly prevalent in primary care COPD patients.,Several chronic comorbidities were associated with having frequent exacerbations and increased exacerbation risk. | Excluding the tropics, exacerbations of chronic obstructive pulmonary disease (COPD) are more frequent in winter.,However, studies that directly relate hospitalizations for exacerbation of COPD to ambient temperature are lacking.,The aim of this study was to assess the influence of temperature on the number of hospitalizations for COPD.,This was a population-based study in a metropolitan area.,All hospital discharges for acute exacerbation of COPD during 2009 in Barcelona and its metropolitan area were analyzed.,The relationship between the number of hospitalizations for COPD and the mean, minimum, and maximum temperatures alongside comorbidity, humidity, influenza rate, and environmental pollution were studied.,A total of 9,804 hospitalization discharges coded with COPD exacerbation as a primary diagnosis were included; 75.4% of cases were male with a mean age of 74.9±10.5 years and an average length of stay of 6.5±6.1 days.,The highest number of admissions (3,644 [37.2%]) occurred during winter, followed by autumn with 2,367 (24.1%), spring with 2,347 (23.9%), and summer with 1,446 (14.7%; P<0.001).,The maximum, minimum, and mean temperatures were associated similarly with the number of hospitalizations.,On average, we found that for each degree Celsius decrease in mean weekly temperature, hospital admissions increased by 5.04% (r2=0.591; P<0.001).,After adjustment for humidity, comorbidity, air pollution, and influenza-like illness, only mean temperatures retained statistical significance, with a mean increase of 4.7% in weekly admissions for each degree Celsius of temperature (r2=0.599, P<0.001).,Mean temperatures are closely and independently related to the number of hospitalizations for COPD. | 1 |
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are episodes of symptom worsening which have significant adverse consequences for patients.,Exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiological changes.,The frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment and increased mortality.,They are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation.,A proportion of patients appear to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations.,Exacerbations also contribute significantly to healthcare expenditure.,Prevention and mitigation of exacerbations are therefore key goals of COPD management. | Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation.,These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases.,Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent.,We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema.,Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days.,Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity.,Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages.,Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls.,Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress.,Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC.,Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation.,Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype.,Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12. | 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. | Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD).,We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals.,We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2.,Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. | 1 |
: To verify the accordance of functional and morphometric parameters during the development of emphysema.,: BALB/c mice received a nasal drop of either papain or saline solution and were studied after 1, 3, 15, 28, and 40 days.,Functional parameters, such as airway resistance, tissue damping, and tissue elastance, were analyzed.,To evaluate the structural changes and possible mechanisms involved in this disease, we measured the mean linear intercept, the volume proportions of elastic and collagen fibers, the number of macrophages, the numbers of cells expressing metalloprotease 12 and 8-isoprostane in lung parenchyma.,: We only observed decreases in tissue elastance and tissue damping on the 28th day, with a concomitant increase in the mean linear intercept, indicating the presence of emphysema.,However, only the mean linear intercept values remained increased until the 40th day.,The volume proportion of collagen fibers was increased from the 15th day to the 40th day, whereas the volume proportion of elastic fibers was only increased on the 40th day.,The number of macrophages increased beginning on the 1st day.,The expression of metalloproteinase 12 was increased from the 3rd day until the 40th day.,However, 8-isoprostane expression was only increased on the 1st and 3rd days.,: In this study, morphometric parameters were found to be more reliable for detecting the presence of emphysema than the functional parameters measured by respiratory mechanics.,Further investigations are necessary to understand how the extracellular matrix remodeling observed in the lung parenchyma could be involved in this process. | Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation.,These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases.,Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent.,We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema.,Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days.,Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity.,Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages.,Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls.,Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress.,Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC.,Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation.,Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype.,Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12. | 1 |
Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin.,NRP1+ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity.,In agreement with this, NRP1+ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs.,NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells.,Human NRP1+ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1− cells, which express CD45RA.,The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1+ ILC3s.,NRP1+ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.,•NRP1+ ILC3s are present in lymphoid tissues, but not in the peripheral blood or skin•NRP1+ ILC3s express CD45RO and produce higher amounts of cytokines than NRP1− ILC3s•NRP1 is a marker for human ILC3s with LTi phenotype and in vitro LTi activity•NRP1+ ILC3s are present in lung tissues from smokers and COPD patients,NRP1+ ILC3s are present in lymphoid tissues, but not in the peripheral blood or skin,NRP1+ ILC3s express CD45RO and produce higher amounts of cytokines than NRP1− ILC3s,NRP1 is a marker for human ILC3s with LTi phenotype and in vitro LTi activity,NRP1+ ILC3s are present in lung tissues from smokers and COPD patients,Shikhagaie et al. find that NRP1 expressing human ILC3s are LTi-like cells, which are present in fetal tissues and adult lymphoid tissues, but not in peripheral blood or skin.,NRP1+ ILC3s cells are primed and migrate in response to VEGF-A.,In addition, their presence in the lungs of smokers and COPD patients provides insight into the formation of ectopic lymphoid aggregates. | Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain.,This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.,Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects.,In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.,Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort.,Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects.,In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups.,Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.,MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression.,Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. | 1 |
Guidelines are critical for facilitating cost-effective COPD care.,Development and implementation in low-and middle-income countries (LMICs) is challenging.,To guide future strategy, an overview of current global COPD guidelines is required.,We systematically reviewed national COPD guidelines, focusing on worldwide availability and identification of potential development, content, context, and quality gaps that may hamper effective implementation.,Scoping review of national COPD management guidelines.,We assessed: (1) global guideline coverage; (2) guideline information (authors, target audience, dissemination plans); (3) content (prevention, diagnosis, treatments); (4) ethical, legal, and socio-economic aspects; and (5) compliance with the eight Institute of Medicine (IOM) guideline standards.,LMICs guidelines were compared with those from high-income countries (HICs).,Of the 61 national COPD guidelines identified, 30 were from LMICs.,Guidelines did not cover 1.93 billion (30.2%) people living in LMICs, whereas only 0.02 billion (1.9%) in HICs were without national guidelines.,Compared with HICs, LMIC guidelines targeted fewer health-care professional groups and less often addressed case finding and co-morbidities.,More than 90% of all guidelines included smoking cessation advice.,Air pollution reduction strategies were less frequently mentioned in both LMICs (47%) and HICs (42%).,LMIC guidelines fulfilled on average 3.37 (42%) of IOM standards, compared with 5.29 (66%) in HICs (P < .05).,LMICs scored significantly lower compared with HICs regarding conflicts of interest management, updates, articulation of recommendations, and funding transparency (all, P < .05).,Several development, content, context, and quality gaps exist in COPD guidelines from LMICs that may hamper effective implementation.,Overall, COPD guidelines in LMICs should be more widely available and should be transparently developed and updated.,Guidelines may be further enhanced by better inclusion of local risk factors, case findings, and co-morbidity management, preferably tailored to available financial and staff resources. | The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high.,We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases.,We conducted a systematic search of Medline, EMBASE and Global Health for original, population-based studies providing spirometry-based prevalence rates of COPD across the world from January 1990 to December 2014.,Random effects meta-analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta-estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural).,We developed a meta-regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more.,Our search returned 37 472 publications.,A total of 123 studies based on a spirometry-defined prevalence were retained for the review.,From the meta-regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%-14.0%) in this age group.,The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%-15.0%).,This increase of 68.9% was mainly driven by global demographic changes.,Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010).,The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%).,In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%).,In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%).,The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%-15.3%) compared to 7.6% (95% CI 7.0%-8.2%) in women.,Our findings suggest a high and growing prevalence of COPD, both globally and regionally.,There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region.,There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally. | 1 |
Rationale: The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations.,Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.,Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.,Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg following a run-in on their COPD therapies.,Time to ACM was prespecified.,Additional vital status data collection and subsequent analyses were performed post hoc.,Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI.,For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI.,Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient’s COPD.,Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations. | Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD).,However, choice of parameters and score complexity restrict clinical applicability.,Our aim was to provide and validate a simplified COPD risk index independent of lung function.,The PROMISE study (n=530) was used to develop a novel prognostic index.,Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality.,External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).,Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C.,It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05).,Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively).,External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).,The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.,The B-AE-D indices allow a simple and accurate assessment of COPD-related risk in the absence of lung functionhttp://ow.ly/XFBox | 1 |
Although, to our knowledge, there has been no exhaustive or credible review of the evidence of the disease burden of COPD in China, COPD has become an increasing public health concern to the Chinese medical community.,The purpose of this article is to review the evidence and evaluate and clarify the disease burden of COPD in China with the aim of improving effective management.,We reviewed previous studies of COPD in China, which included data on prevalence, mortality, disease burden, risk factors, diagnosis, and management by searching related Web sites, including PubMed, ProQuest, and Thomson Reuters' Web of Knowledge, as well as major Chinese databases and government Web sites.,Reported COPD prevalence varied between 5% and 13% in different provinces/cities across China.,In 2008, COPD ranked fourth as a leading cause of death in urban areas and third in rural areas.,In addition, COPD accounted for 1.6% of all hospital admissions in China in that year.,The high prevalence of smoking and biomass fuel use acted as major contributors to the high occurrence of COPD in China.,Management of COPD in China should focus on adjusting the distribution of medical resources and on addressing public health policies to facilitate earlier diagnosis in rural areas, aim to reduce smoking prevalence, improve patients' self-management, and keep physicians' knowledge up to date and consistent with current guidelines.,COPD is one of the most challenging medical issues facing China because of its influence on both personal and public health and its impact on the economy.,Optimal management strategies should be adopted and strengthened immediately. | Chronic obstructive pulmonary disease (COPD) patients present a high prevalence of cardiovascular disease.,This excess of comorbidity could be related to a common pathogenic mechanism, but it could also be explained by the existence of common risk factors.,The objective of this study was to determine whether COPD patients present greater cardiovascular comorbidity than control subjects and whether COPD can be considered a risk factor per se.,1200 COPD patients and 300 control subjects were recruited for this multicenter, cross-sectional, case-control study.,Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease (12.5% versus 4.7%; P < 0.0001), cerebrovascular disease (10% versus 2%; P < 0.0001), and peripheral vascular disease (16.4% versus 4.1%; P < 0.001).,In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease.,In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18-4.24; P = 0.014).,COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factors. | 1 |
Over the past two decades, there have been significant changes in the pharmacological management of COPD, due to an explosion of inhaler trials, and timely updation of national and international guidelines.,We sought to describe temporal changes in prescribing practices in the United Kingdom, and some of the factors that may have influenced them.,COPD patients were identified from UK primary care nationally representative electronic healthcare records (Clinical Practice Research Datalink), between 2000 and 2016.,Prescription data were described by the three maintenance inhaled medication classes used, inhaled corticosteroids (ICS), long-acting beta agonist (LABA), long-acting muscarinic antagonist (LAMA), and their combinations, dual LABA-ICS, dual LAMA-LABA, or triple therapy LABA-ICS-LAMA.,Differing patient characteristics across the six different therapy regimens were measured in 2016.,COPD patients were identified: 187,588 prevalent and incident inhaler users and 169,511 incident inhaler users.,Since 2002, LAMA showed increasing popularity, while ICS alone exhibited an inverse trend.,Triple therapy prescriptions rapidly increased as the first-line therapy until 2014 when LAMA-LABA prescriptions started to increase.,By 2014, 41% of all COPD patients were maintained on triple therapy, and 13% were maintained on LAMA only.,Characterizing the patients in 2016 revealed that those on triple therapy were more likely to have more severe disease, yet, over a third of patients on triple therapy had only mild disease.,UK prescribing practices were not in keeping with national guidelines but did appear to align with evidence from major drug trials and updated international guidelines.,There has been a huge upsurge in triple therapy but incident data show this trend is beginning to reverse for initial management. | Acute Exacerbations of COPD (AECOPD) identified from electronic healthcare records (EHR) are important for research, public health and to inform healthcare utilisation and service provision.,However, there is no standardised method of identifying AECOPD in UK EHR.,We aimed to validate the recording of AECOPD in UK EHR.,We randomly selected 1385 patients with COPD from the Clinical Practice Research Datalink.,We selected dates of possible AECOPD based on 15 different algorithms between January 2004 and August 2013.,Questionnaires were sent to GPs asking for confirmation of their patients’ AECOPD on the dates identified and for any additional relevant information.,Responses were reviewed independently by two respiratory physicians.,Positive predictive value (PPV) and sensitivity were calculated.,The response rate was 71.3%.,AECOPD diagnostic codes, lower respiratory tract infection (LRTI) codes, and prescriptions of antibiotics and oral corticosteroids (OCS) together for 5-14 days had a high PPV (>75%) for identifying AECOPD.,Symptom-based algorithms and prescription of antibiotics or OCS alone had lower PPVs (60-75%).,A combined strategy of antibiotic and OCS prescriptions for 5-14 days, or LRTI or AECOPD code resulted in a PPV of 85.5% (95% CI, 82.7-88.3%) and a sensitivity of 62.9% (55.4-70.4%).,Using a combination of diagnostic and therapy codes, the validity of AECOPD identified from EHR can be high.,These strategies are useful for understanding health-care utilisation for AECOPD, informing service provision and for researchers.,These results highlight the need for common coding strategies to be adopted in primary care to allow easy and accurate identification of events. | 1 |
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. | 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 |
To comprehensively evaluate the association between the polymorphism of matrix metalloproteinase-9 (MMP-9)-C1562T (rs3918242) and susceptibility to chronic obstructive pulmonary disease (COPD) in middle-aged and elderly patients through Meta-analysis.,PubMed, EMBASE, CNKI, Wanfang, VIP, and other databases were searched by computer in the inception to August 2019 to collect all the case-control studies that met the inclusion criteria in this literature.,Meta-analysis was performed using Stata 15.0, including the OR value calculations of the association between the merged MMP-9-C1562T polymorphism and the COPD susceptibility.,Subgroup analysis, sensitivity analysis, and publication bias test were also performed.,A total of 13 literature were included in this Meta-analysis with a total of 2512 cases and 2716 controls.,The results have shown that the OR of MMP-9-C1562T T allele to C allele was 0.35 (95% confidence interval [CI]: 0.23-0.52, P < .01).,The subgroup analysis of ethnicity result showed that the merged OR of MMP-9-C1562T T allele to C allele was 0.24 (95% CI: 0.17-0.34, P < .01) in Caucasian while the merged OR was 0.62 (95% CI: 0.22-1.70, P > .05) in Asian.,However, there were no statistically significant models in the dominant, recessive, homozygote and heterozygote genetic models.,The MMP-9-C1562T polymorphism was associated with the susceptibility to middle-aged and elderly COPD patients.,Compared with T allele, C allele increased the risk of disease, especially in Caucasian, but not found in Asian. | Chronic obstructive pulmonary disease (COPD) is combination of progressive lung diseases.,The diagnosis of COPD is generally based on the pulmonary function testing, however, difficulties underlie in prognosis of smokers or early stage of COPD patients due to the complexity and heterogeneity of the pathogenesis.,Computational analyses of omics technologies are expected as one of the solutions to resolve such complexities.,We obtained transcriptomic data by in vitro testing with exposures of human bronchial epithelial cells to the inducers for early events of COPD to identify the potential descriptive marker genes.,With the identified genes, the machine learning technique was employed with the publicly available transcriptome data obtained from the lung specimens of COPD and non-COPD patients to develop the model that can reflect the risk continuum across smoking and COPD.,The expression levels of 15 genes were commonly altered among in vitro tissues exposed to known inducible factors for earlier events of COPD (exposure to cigarette smoke, DNA damage, oxidative stress, and inflammation), and 10 of these genes and their corresponding proteins have not previously reported as COPD biomarkers.,Although these genes were able to predict each group with 65% accuracy, the accuracy with which they were able to discriminate COPD subjects from smokers was only 29%.,Furthermore, logistic regression enabled the conversion of gene expression levels to a numerical index, which we named the “potential risk factor (PRF)” index.,The highest significant index value was recorded in COPD subjects (0.56 at the median), followed by smokers (0.30) and non-smokers (0.02).,In vitro tissues exposed to cigarette smoke displayed dose-dependent increases of PRF, suggesting its utility for prospective risk estimation of tobacco products.,Our experimental-based transcriptomic analysis identified novel genes associated with COPD, and the 15 genes could distinguish smokers and COPD subjects from non-smokers via machine-learning classification with remarkable accuracy.,We also suggested a PRF index that can quantitatively reflect the risk continuum across smoking and COPD pathogenesis, and we believe it will provide an improved understanding of smoking effects and new insights into COPD. | 1 |
Pooled data were analyzed to evaluate the safety and tolerability of indacaterol, a once-daily inhaled long-acting β2-agonist for chronic obstructive pulmonary disease (COPD).,Data were pooled from clinical studies of 3-12 months’ duration in patients with moderate-to-severe COPD receiving double-blind indacaterol 75 μg (n = 449), 150 μg (n = 2611), 300 μg (n = 1157), or 600 μg once daily (n = 547); formoterol 12 μg twice daily (n = 556); salmeterol 50 μg twice daily (n = 895); placebo (n = 2012); or tiotropium 18 μg once daily, given open label or blinded (n = 1214).,Outcomes were adverse events, serious adverse events and deaths, plasma potassium, blood glucose, and QTc interval and vital signs.,The commonest adverse events with indacaterol were COPD worsening, nasopharyngitis, and headache; most cases were mild or moderate and incidence was generally similar to placebo and other active treatments.,The risk of acute respiratory serious adverse events (leading to hospitalization, intubation, or death) was not significantly increased with any of the active treatments compared with placebo.,COPD exacerbation rates (analyzed in the intent-to-treat population) were significantly reduced with all active treatments versus placebo.,Hazard ratios versus placebo for major cardiovascular adverse events were <1 for all indacaterol doses.,Notable values for vital signs and measures of systemic β2-adrenoceptor activity were rare with indacaterol.,The number of deaths adjusted per patient-year was lower with indacaterol (all doses combined) than with placebo (relative risk 0.21 [95% confidence interval 0.07-0.660], P = 0.008).,Indacaterol has a good profile of safety and tolerability that is appropriate for the maintenance treatment of patients with COPD. | Current methods for assessing clinical outcomes in COPD mainly rely on physiological tests combined with the use of questionnaires.,The present review considers commonly used outcome measures such as lung function, health status, exercise capacity and physical activity, dyspnoea, exacerbations, the multi-dimensional BODE score, and mortality.,Based on current published data, we provide a concise overview of the principles, strengths and weaknesses, and discuss open questions related to each methodology.,Reviewed is the current set of markers for measuring clinically relevant outcomes with particular emphasis on their limitations and opportunities that should be recognized when assessing and interpreting their use in clinical trials of COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods.,We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials.,Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD.,Patients were permitted to continue using their usual COPD medications except for other anticholinergics.,The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening.,The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4.,The effect of treatments on CERO was similarly assessed.,A power analysis helped calculate the sample size needed to achieve outcome differences between treatments.,The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively.,The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92).,Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies.,A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials.,In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo.,NCT00144339.,The online version of this article (doi:10.1186/s12931-016-0361-4) contains supplementary material, which is available to authorized users. | COPD is prevalent in Western society and its incidence is rising in the developing world.,Acute exacerbations of COPD, about 50% of which are unreported, lead to deterioration in quality of life and contribute significantly to disease burden.,Quality of life deteriorates with time; thus, most of the health burden occurs in more severe disease.,COPD severity and frequent and more severe exacerbations are all related to an increased risk of mortality.,Inhaled corticosteroids (ICS) have similar effects on quality of life but ICS/long-acting bronchodilator combinations and the long-acting antimuscarinic tiotropium all improve health status and exacerbation rates and are likely to have an effect on mortality but perhaps only with prolonged use.,Erythromycin has been shown to decrease the rate of COPD exacerbations.,Pulmonary rehabilitation and regular physical activity are indicated in all severities of COPD and improve quality of life.,Noninvasive ventilation is associated with improved quality of life.,Long-term oxygen therapy improves mortality but only in hypoxic COPD patients.,The choice of an inhaler device is a key component of COPD therapy and this requires more attention from physicians than perhaps we are aware of.,Disease management programs, characterized as they are by patient centeredness, improve quality of life and decrease hospitalization rates.,Most outcomes in COPD can be modified by interventions and these are well tolerated and have acceptable safety profiles. | 1 |
Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality worldwide.,Estimation of incidence, prevalence and disease burden through routine insurance data is challenging because of under-diagnosis and under-treatment, particularly for early stage disease in health care systems where outpatient International Classification of Diseases (ICD) diagnoses are not collected.,This poses the question of which criteria are commonly applied to identify COPD patients in claims datasets in the absence of ICD diagnoses, and which information can be used as a substitute.,The aim of this systematic review is to summarize previously reported methodological approaches for the identification of COPD patients through routine data and to compile potential criteria for the identification of COPD patients if ICD codes are not available.,A systematic literature review was performed in Medline via PubMed and Google Scholar from January 2000 through October 2018, followed by a manual review of the included studies by at least two independent raters.,Study characteristics and all identifying criteria used in the studies were systematically extracted from the publications, categorized, and compiled in evidence tables.,In total, the systematic search yielded 151 publications.,After title and abstract screening, 38 publications were included into the systematic assessment.,In these studies, the most frequently used (22/38) criteria set to identify COPD patients included ICD codes, hospitalization, and ambulatory visits.,Only four out of 38 studies used methods other than ICD coding.,In a significant proportion of studies, the age range of the target population (33/38) and hospitalization (30/38) were provided.,Ambulatory data were included in 24, physician claims in 22, and pharmaceutical data in 18 studies.,Only five studies used spirometry, two used surgery and one used oxygen therapy.,A variety of different criteria is used for the identification of COPD from routine data.,The most promising criteria set in data environments where ambulatory diagnosis codes are lacking is the consideration of additional illness-related information with special attention to pharmacotherapy data.,Further health services research should focus on the application of more systematic internal and/or external validation approaches. | To support patients with COPD in their self-management of symptom worsening, we developed Adaptive Computerized COPD Exacerbation Self-management Support (ACCESS), an innovative software application that provides automated treatment advice without the interference of a health care professional.,Exacerbation detection is based on 12 symptom-related yes-or-no questions and the measurement of peripheral capillary oxygen saturation (SpO2), forced expiratory volume in one second (FEV1), and body temperature.,Automated treatment advice is based on a decision model built by clinical expert panel opinion and Bayesian network modeling.,The current paper describes the validity of ACCESS.,We performed secondary analyses on data from a 3-month prospective observational study in which patients with COPD registered respiratory symptoms daily on diary cards and measured SpO2, FEV1, and body temperature.,We examined the validity of the most important treatment advice of ACCESS, ie, to contact the health care professional, against symptom- and event-based exacerbations.,Fifty-four patients completed 2,928 diary cards.,One or more of the different pieces of ACCESS advice were provided in 71.7% of all cases.,We identified 115 symptom-based exacerbations.,Cross-tabulation showed a sensitivity of 97.4% (95% CI 92.0-99.3), specificity of 65.6% (95% CI 63.5-67.6), and positive and negative predictive value of 13.4% (95% CI 11.2-15.9) and 99.8% (95% CI 99.3-99.9), respectively, for ACCESS’ advice to contact a health care professional in case of an exacerbation.,In many cases (71.7%), ACCESS gave at least one self-management advice to lower symptom burden, showing that ACCES provides self-management support for both day-to-day symptom variations and exacerbations.,High sensitivity shows that if there is an exacerbation, ACCESS will advise patients to contact a health care professional.,The high negative predictive value leads us to conclude that when ACCES does not provide the advice to contact a health care professional, the risk of an exacerbation is very low.,Thus, ACCESS can safely be used in patients with COPD to support self-management in case of an exacerbation. | 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 aim of this study is to quantify the burden of chronic obstructive pulmonary disease (COPD) - incidence, prevalence, and mortality - and identify trends in Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America.,A structured literature search was performed (January 2000 to September 2010) of PubMed and EMBASE, identifying English-language articles reporting COPD prevalence, incidence, or mortality.,Of 2838 articles identified, 299 full-text articles were reviewed, and data were extracted from 133 publications.,Prevalence data were extracted from 80 articles, incidence data from 15 articles, and mortality data from 58 articles.,Prevalence ranged from 0.2%-37%, but varied widely across countries and populations, and by COPD diagnosis and classification methods.,Prevalence and incidence were greatest in men and those aged 75 years and older.,Mortality ranged from 3-111 deaths per 100,000 population.,Mortality increased in the last 30-40 years; more recently, mortality decreased in men in several countries, while increasing or stabilizing in women.,Although COPD mortality increased over time, rates declined more recently, likely indicating improvements in COPD management.,In many countries, COPD mortality has increased in women but decreased in men.,This may be explained by differences in smoking patterns and a greater vulnerability in women to the adverse effects of smoking.,Point your SmartPhone at the code above.,If you have a QR code reader the video abstract will appear.,Or use: http://dvpr.es/Nl3LKT | 1 |
Few studies have evaluated the contribution of both viruses and bacteria in acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,This study estimated the burden of both types of pathogens among adults seeking care for an AECOPD during two consecutive winter seasons.,Patients 50 years or older who consulted within 10 days of AECOPD onset were eligible.,Clinical data were collected on a standardized questionnaire, and nasopharyngeal aspirates (NPA), paired sera, and non-induced sputum were collected.,Polymerase chain reaction (PRC) assays were used to identify viral, atypical and bacterial pathogens in NPA specimen.,Overall, 108 patients with AECOPD were included, 88% of patients were admitted and 2 patients (2%) received intensive care.,A third of patients (31%) had evidence of a viral infection, 9% with influenza A, 7% RSV and 7% with PIV-3.,One patient was positive for Mycoplasma pneumoniae.,Bacterial pathogens were identified in 49% of patients with available sputum, most frequently Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae.,Among virus-infected patients, 14 (58%) also had bacteria in their sputum, but co-infected patients did not present with different symptoms than patients with single infections.,These results suggest that influenza and RSV are frequent contributors of AECOPD, and that coinfection with bacteria does not appear to be more severe among virus-infected patients.,Clinicians should be aware that AECOPD may be frequently triggered by viruses, and may consider antivirals and proper infection control measures in appropriate epidemiological setting. | Inflammation increases during exacerbations of COPD, but only a few studies systematically assessed these changes.,Better identification of these changes will increase our knowledge and potentially guide therapy, for instance by helping with quicker distinction of bacterially induced exacerbations from other causes.,To identify which inflammatory parameters increase during COPD exacerbations compared to stable disease, and to compare bacterial and non-bacterial exacerbations.,In 45 COPD patients (37 male/8 female, 21 current smokers, mean age 65, FEV1 52% predicted, pack years 38) sputum was collected during a stable phase and subsequently during an exacerbation.,Sputum total cell counts (9.0 versus 7.9 × 106/mL), eosinophils (0.3 versus 0.2 × 106/mL), neutrophils (6.1 versus 5.8 × 106/mL), and lymphocytes (0.07 versus 0.02 × 106/mL) increased significantly during an exacerbation compared to stable disease.,A bacterial infection was demonstrated by culture in 8 sputum samples obtained during an exacerbation.,These exacerbations had significantly increased sputum total cell and neutrophil counts, leukotriene-B4, myeloperoxidase, interleukin-8 and interleukin-6, and tumor necrosis factor-α (TNF-α) levels, and were also associated with more systemic inflammation compared to exacerbations without a bacterial infection.,Sputum TNF-α level during an exacerbation had the best test characteristics to predict a bacterial infection.,Sputum eosinophil, neutrophil, and lymphocyte counts increase during COPD exacerbations.,The increase in systemic inflammation during exacerbations seems to be limited to exacerbations caused by bacterial infections of the lower airways.,Sputum TNF-α is a candidate marker for predicting airway bacterial infection. | 1 |
COPD prevalence and consequent burden are expected to rapidly increase worldwide.,Until now, there has been no community-based study of COPD in Thailand.,We aimed to compare the prevalence, clinical characteristics, disease severity, previous diagnosis, and management of COPD between urban and rural communities.,A population-based cross-sectional study was designed to compare COPD prevalence and burden in rural and urban communities in Chiang Mai Province, Thailand.,The COPD subjects were diagnosed and severity categories assigned using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.,The prevalence between the groups was compared using risk regression analysis.,Unpaired t-test and chi-square were used to compare differences between the groups.,There were 574 and 293 enrolled subjects with acceptable spirometry, in rural and urban communities respectively.,The prevalence of COPD in general and COPD in females was higher in the rural group (6.8% vs 3.7% and 4.4% vs 0.9%, respectively) across all independent variables.,However, after adjustment for age, sex, and smoking status, no significant differences were demonstrated.,Although the pulmonary function and disease severity between the two groups were not significantly different, the tendency was more pronounced in the rural group (COPD stage III-IV: 65.0% vs 33.3%).,Most of the COPD patients in both groups were underdiagnosed (80.0% vs 77.2%) and undertreated (85.0% vs 81.9%).,None of the patients in the study had participated in exercise training programs.,The prevalence of COPD in general and particularly COPD in females tended to be higher, with more severe disease in the rural community.,However, both groups were similarly underdiagnosed and undertreated. | The management of COPD is complex and patient adherence to treatment recommendations is known to be poor.,In this paper the methods used for evaluating adherence in COPD are compared.,Self-reporting has satisfactory reliability and offers a cheap, simple and easy method for assessing adherent behaviors.,Unlike the objective measures of adherence such as electronic monitoring, self-reporting helps in identifying the reasons for nonadherence, which in turn would be useful in addressing adherence issues.,Patients do not follow their treatment recommendations either intentionally or unintentionally.,Intentional deviations are driven by patient beliefs and experiences about illness and treatment, which are in turn influenced by social and cultural factors.,Unintentional deviations are often due to cognitive impairment and lack of routines.,Factors associated with adherence in COPD have been explained using the Becker-Maiman model.,Strategies for overcoming nonadherence have to be formulated based on the nature and reasons for nonadherence.,In the event of unintentional nonadherence, the use of adherence aids like Dosette boxes, calendar packs and reminders should be promoted.,Understanding patient beliefs and experiences, patient education focusing on the pathology of COPD and the role of treatment, periodic monitoring and reinforcement are critical for overcoming the barriers of intentional nonadherence. | 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 | 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 |
Chronic Obstructive Pulmonary Disease (COPD) is a chronic, progressive disease that is not curable.,However, there are effective treatments available.,In the UK, long-acting bronchodilators are first-line treatments for COPD patients requiring maintenance therapy, and there are several options available.,The aim of this study is to establish, from the UK National Health Service (NHS) perspective, the cost-effectiveness profile of indacaterol, the first once-daily long-acting beta2-agonist (LABA), compared with tiotropium and salmeterol, in patients with moderate to severe COPD.,In assessing the cost-effectiveness of COPD therapies, this study has the advantage of using real world evidence on the resource use associated with COPD management across the spectrum of the disease.,A Markov model was developed with four health states following the GOLD classification for severity of airflow limitation.,The model time horizon was 3 years, and the cycle length was 3 months.,From each state, patients could experience a severe or non-severe exacerbation, move to a different COPD state, remain in the current state or die.,Transition probabilities were based on data from the indacaterol clinical trials.,The majority of the resource use data was taken from the Optimum Patient Care Research Database (OPCRD), which contains data from over 20,000 COPD patients in England and Scotland.,Cost data were taken from UK-based sources and published literature and presented for the cost year 2011.,Health-related quality of life was the main outcome of interest and utility data for the COPD states were based on data from the indacaterol clinical trials and disutility due to exacerbations were taken from the literature.,Both one way and probabilistic sensitivity analyses were performed to test the robustness of the results.,Indacaterol dominated in the comparison with salmeterol producing an incremental QALY gain of 0.008 and cost savings of £110 per patient over a 3-year time horizon.,In the comparison with tiotropium over the same time horizon, indacaterol remained the dominant strategy, producing an incremental QALY gain of 0.008 and cost savings of £248 per patient.,The one-way sensitivity analysis indicates that the proportion of patients in each of the COPD stages and the mortality rate associated with Very Severe COPD are the variables with the largest impact on the results.,The probabilistic sensitivity analyses showed that over 72 % and 89 % of the iterations when compared with salmeterol and tiotropium, respectively, produced dominant results for indacaterol.,The analyses demonstrate that indacaterol dominates both tiotropium and salmeterol in the base case and is likely to remain cost-effective under a range of assumptions. | The purpose of this study was to update our network meta-analysis in order to compare the efficacy of indacaterol 75 μg with that of a fixed-dose combination of formoterol and budesonide (FOR/BUD) and a fixed-dose combination salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on evidence identified previously in addition to two new randomized clinical trials.,Fifteen randomized, placebo-controlled clinical trials including COPD patients were evaluated: indacaterol 75 μg once daily (n = 2 studies), indacaterol 150 μg once daily (n = 5), indacaterol 300 μg once daily (n = 4), FOR/BUD 9/160 μg twice daily (n = 2), FOR/BUD 9/320 μg twice daily (n = 2), SAL/FP 50/500 μg twice daily (n = 4), and SAL/FP 50/250 μg twice daily (n = 1).,All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained.,Treatment-by-covariate interactions were included where possible to improve the similarity of the trials.,Outcomes of interest were trough forced expiratory volume in 1 second (FEV1) and transitional dyspnea index at 12 weeks.,Based on the results without adjustment for covariates, indacaterol 75 μg resulted in a greater improvement in FEV1 at 12 weeks compared with FOR/BUD 9/160 μg (difference in change from baseline 0.09 L [95% credible interval 0.04-0.13]) and FOR/BUD 9/320 μg (0.07 L [0.03-0.11]) and was comparable with SAL/FP 50/250 μg (0.00 L [−0.07-0.07]) and SAL/FP 50/500 μg (0.01 L [−0.04-0.05]).,For transitional dyspnea index, data was available only for indacaterol 75 μg versus SAL/FP 50/500 μg (−0.49 points [−1.87-0.89]).,Based on results of a network meta-analysis with and without covariates, indacaterol 75 μg is expected to be at least as efficacious as FOR/BUD (9/320 μg and 9/160 μg) and comparable with SAL/FP (50/250 μg and 50/500 μg) in terms of lung function.,In terms of breathlessness (transitional dyspnea index) at 12 weeks, the results are inconclusive given the limited data. | 1 |
COPD is a complex, heterogeneous condition.,Even in the early clinical stages, COPD carries a significant burden, with breathlessness frequently leading to a reduction in exercise capacity and changes that correlate with long-term patient outcomes and mortality.,Implementation of an effective management strategy is required to reduce symptoms, preserve lung function, quality of life, and exercise capacity, and prevent exacerbations.,However, current clinical practice frequently differs from published guidelines on the management of COPD.,This review focuses on the current scientific evidence and expert opinion on the management of moderate COPD: the symptoms arising from moderate airflow obstruction and the burden these symptoms impose, how physical activity can improve disease outcomes, the benefits of dual bronchodilation in COPD, and the limited evidence for the benefits of inhaled corticosteroids in this disease.,We emphasize the importance of maximizing bronchodilation in COPD with inhaled dual-bronchodilator treatment, enhancing patient-related outcomes, and enabling the withdrawal of inhaled corticosteroids in COPD in well-defined patient groups. | Umeclidinium/vilanterol (UMEC/VI) is a novel fixed dose combination of a long-acting muscarinic receptor antagonist (LAMA) and a long-acting beta 2 receptor antagonist (LABA) agent.,This analysis evaluated the incremental cost-effectiveness ratio (ICER) of UMEC/VI compared with tiotropium (TIO), from the Spanish National Health System (NHS) perspective.,A previously published linked equations cohort model based on the epidemiological longitudinal study ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) was used.,Patients included were COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% and the presence of respiratory symptoms measured with the modified Medical Research Council dyspnea scale (modified Medical Research Council ≥2).,Treatment effect, expressed as change in FEV1 from baseline, was estimated from a 24-week head-to-head phase III clinical trial comparing once-daily UMEC/VI with once-daily TIO and was assumed to last 52 weeks following treatment initiation (maximum duration of UMEC/VI clinical trials).,Spanish utility values were derived from a published local observational study.,Unitary health care costs (€2015) were obtained from local sources.,A 3-year time horizon was selected, and 3% discount was applied to effects and costs.,Results were expressed as cost/quality-adjusted life years (QALYs).,Univariate and probabilistic sensitivity analysis (PSA) was performed.,UMEC/VI produced additional 0.03 QALY and €590 vs TIO, leading to an ICER of €21,475/QALY.,According to PSA, the probability of UMEC/VI being cost-effective was 80.3% at a willingness-to-pay of €30,000/QALY.,UMEC/VI could be considered as a cost-effective treatment alternative compared with TIO in symptomatic COPD patients from the Spanish NHS perspective. | 1 |
To identify factors that hinder discussions regarding chronic obstructive pulmonary disease (COPD) between primary care physicians (PCPs) and their patients in Sweden.,Primary health care centres (PHCCs) in Stockholm, Sweden.,A total of 59 PCPs.,Semi-structured individual and focus-group interviews between 2012 and 2014.,Data were analysed inspired by grounded theory methods (GTM).,Time-pressured patient-doctor consultations lead to deprioritization of COPD.,During unscheduled visits, deprioritization resulted from focusing only on acute health concerns, while during routine care visits, COPD was deprioritized in multi-morbid patients.,The reasons PCPs gave for deprioritizing COPD are: “Not becoming aware of COPD”, “Not becoming concerned due to clinical features”, “Insufficient local routines for COPD care”, “Negative personal attitudes and views about COPD”, “Managing diagnoses one at a time”, and “Perceiving a patient’s motivation as low’’.,De-prioritization of COPD was discovered during PCP consultations and several factors were identified associated with time constraints and multi-morbidity.,A holistic consultation approach is suggested, plus extended consultation time for multi-morbid patients, and better documentation and local routines.,Key pointsUnder-diagnosis and insufficient management of chronic obstructive pulmonary disease (COPD) are common in primary health care.,A patient-doctor consultation offers a key opportunity to identify and provide COPD care.,Time pressure, due to either high number of patients or multi-morbidity, leads to omission or deprioritization of COPD during consultation.Deprioritization occurs due to lack of awareness, concern, and local routines, negative personal views, non-holistic consultation approach, and low patient motivation.Better local routines, extended consultation time, and a holistic approach are needed when managing multi-morbid patients with COPD.,Under-diagnosis and insufficient management of chronic obstructive pulmonary disease (COPD) are common in primary health care.,A patient-doctor consultation offers a key opportunity to identify and provide COPD care.,Time pressure, due to either high number of patients or multi-morbidity, leads to omission or deprioritization of COPD during consultation.Deprioritization occurs due to lack of awareness, concern, and local routines, negative personal views, non-holistic consultation approach, and low patient motivation.Better local routines, extended consultation time, and a holistic approach are needed when managing multi-morbid patients with COPD.,Time pressure, due to either high number of patients or multi-morbidity, leads to omission or deprioritization of COPD during consultation.,Deprioritization occurs due to lack of awareness, concern, and local routines, negative personal views, non-holistic consultation approach, and low patient motivation.,Better local routines, extended consultation time, and a holistic approach are needed when managing multi-morbid patients with COPD. | Many people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide.,There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach.,In this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice.,Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost-effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.,All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible.,Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not.,Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.,The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic).,A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.,A trial-based analysis will be undertaken using costs and outcomes collected during the trial.,Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and primary care staff views of each approach.,This will be the largest RCT of its kind, and should inform how best to identify undiagnosed patients with COPD in the UK and other similar healthcare systems.,Sensitivity analyses will help local policy-makers decide which sub-groups of the population to target first.,Current controlled trials ISRCTN14930255,The online version of this article (doi:10.1186/1471-2466-14-157) contains supplementary material, which is available to authorized users. | 1 |
A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association.,We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data.,RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level.,We found evidence of local genetic correlation with particular regions of the genome.,Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD.,Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues.,An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD.,A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008).,In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.,The online version of this article (10.1186/s12931-019-1036-8) contains supplementary material, which is available to authorized users. | An abstract, including parts of the results, has been presented at an oral session at the European Respiratory Society International Conference, London, UK, September 2016.,Cardiovascular comorbidity contributes to increased mortality among subjects with COPD.,However, the prognostic value of ECG abnormalities in COPD has rarely been studied in population-based surveys.,To assess the impact of ischemic ECG abnormalities (I-ECG) on mortality among individuals with COPD, compared to subjects with normal lung function (NLF), in a population-based study.,During 2002-2004, all subjects with FEV1/VC <0.70 (COPD, n=993) were identified from population-based cohorts, together with age- and sex-matched referents without COPD.,Re-examination in 2005 included interview, spirometry, and 12-lead ECG in COPD (n=635) and referents [n=991, whereof 786 had NLF].,All ECGs were Minnesota-coded.,Mortality data were collected until December 31, 2010.,I-ECG was equally common in COPD and NLF.,The 5-year cumulative mortality was higher among subjects with I-ECG in both groups (29.6% vs 10.6%, P<0.001 and 17.1% vs 6.6%, P<0.001).,COPD, but not NLF, with I-ECG had increased risk for death assessed as the mortality risk ratio [95% confidence interval (CI)] when compared with NLF without I-ECG, 2.36 (1.45-3.85) and 1.65 (0.94-2.90) when adjusted for common confounders.,When analyzed separately among the COPD cohort, the increased risk for death associated with I-ECG persisted after adjustment for FEV1 % predicted, 1.89 (1.20-2.99).,A majority of those with I-ECG had no previously reported heart disease (74.2% in NLF and 67.3% in COPD) and the pattern was similar among them.,I-ECG was associated with an increased risk for death in COPD, independent of common confounders and disease severity.,I-ECG was of prognostic value also among those without previously known heart disease. | 1 |
Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure.,Whether the LCS episode is useful for early detection of COPD is not well established.,Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial.,Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a “lung health check” between November 2015 and July 2017.,Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT.,COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry.,Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema.,Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed “undiagnosed.”,Emphysema prevalence in those with known and “undiagnosed” COPD was 73% and 68%, respectively.,A total of 32% of those with “undiagnosed COPD” had no emphysema on LDCT.,Inhaler use and symptoms were more common in the “known” than the “undiagnosed” COPD group (63% vs. 33% with persistent cough [P < 0.001]; 73% vs. 33% with dyspnea [P < 0.001]).,Comorbidities were common in all groups.,Adjusted odds ratio (aOR) of respiratory symptoms were more significant for airflow obstruction (aOR GOLD 1 and 2, 1.57; confidence interval [CI], 1.14-2.17; aOR GOLD 3 and 4, 4.6; CI, 2.17-9.77) than emphysema (aOR mild, 1.12; CI, 0.81-1.55; aOR moderate, 1.33; CI, 0.85-2.09; aOR severe, 4.00; CI, 1.57-10.2).,Conclusions: There is high burden of “undiagnosed COPD” and emphysema in LCS participants.,Adding spirometry findings to the LDCT enhances identification of individuals with COPD.,Clinical trial registered with www.clinicaltrials.gov (NCT02558101). | •COPD is a risk factor for lung cancer beyond their shared aetiology.,•Both are driven by oxidative stress.,•Both are linked to cellular aging, senescence and telomere shortening.,•Both have been linked to genetic predisposition.,•Both show altered epigenetic regulation of gene expression.,COPD is a risk factor for lung cancer beyond their shared aetiology.,Both are driven by oxidative stress.,Both are linked to cellular aging, senescence and telomere shortening.,Both have been linked to genetic predisposition.,Both show altered epigenetic regulation of gene expression.,Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden.,Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking.,Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying genetic predisposition, telomere shortening, mitochondrial dysfunction or premature aging.,In the majority of smokers, the burden of smoking may be dealt with by the body’s defense mechanisms: anti-oxidants such as superoxide dismutases, anti-proteases and DNA repair mechanisms.,However, in the case of both diseases these fail, leading to cancer if mutations occur or COPD if damage to the cell and proteins becomes too great.,Alternatively COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage, chronic exposure to pro-inflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation.,Understanding the mechanisms that drive these processes in primary cells from patients with these diseases along with better disease models is essential for the development of new treatments. | 1 |
COPD (chronic obstructive pulmonary disease) is a major incurable global health burden and will become the third largest cause of death in the world by 2020.,It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation.,This inflammation, where macrophages, neutrophils and T-cells are prominent, leads to oxidative stress, emphysema, small airways fibrosis and mucus hypersecretion.,The mechanisms and mediators that drive the induction and progression of chronic inflammation, emphysema and altered lung function are poorly understood.,Current treatments have limited efficacy in inhibiting chronic inflammation, do not reverse the pathology of disease and fail to modify the factors that initiate and drive the long-term progression of disease.,Therefore there is a clear need for new therapies that can prevent the induction and progression of COPD.,Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies.,The present review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and whether they can be used to predict the efficacy of new therapeutics for COPD. | Mouse models of chronic obstructive pulmonary disease (COPD) focus on airway inflammation and lung histology, but their use has been hampered by the lack of pulmonary function data in their assessment.,Systemic effects such as muscle dysfunction are also poorly modeled in emphysematous mice.,We aimed to develop a cigarette-smoke-induced emphysema mouse model in which serial lung function and muscular dysfunction could be assessed, allowing the disease to be monitored more appropriately.,C57Bl6 mice were nose-only exposed to cigarette smoke or filtered air for 3-6 months.,Lung function tests were repeated in the same mice after 3 and 6 months of cigarette smoke or air exposure and compared with lung histological changes.,Contractile properties of skeletal muscles and muscle histology were also determined at similar time points in separate groups of mice.,Serial lung function measurements documented hyperinflation after 3 and 6 months of cigarette smoke exposure, with a significant 31-37% increase in total lung capacity (TLC) and a significant 26-35% increase in compliance (Cchord) when compared with animals exposed to filtered air only (P<0.001 after 3 and after 6 months).,These functional changes preceded the changes in mean linear intercept, which became only significant after 6 months of cigarette smoke exposure and which correlated very well with TLC (r=0.74, P=0.004) and Cchord (r=0.79, P=0.001).,After 6 months of cigarette smoke exposure, a significant fiber-type shift from IIa to IIx/b was also observed in the soleus muscle (P<0.05), whereas a 20% reduction of force was present at high stimulation frequencies (80 Hz; P=0.09).,The extensor digitorum longus (EDL) muscle was not affected by cigarette smoke exposure.,These serial pulmonary function variables are sensitive outcomes to detect emphysema progression in a nose-only cigarette-smoke-exposed animal model of COPD.,In this model, muscular changes became apparent only after 6 months, particularly in muscles with a mixed fiber-type composition. | 1 |
Combination of the inhaled long-acting muscarinic antagonist umeclidinium (UMEC; GSK573719) with the long-acting β2-agonist vilanterol (VI) is an approved maintenance treatment for COPD in the US and EU.,We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry.,In this 24-week, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were randomized 1:1:1 to UMEC/VI 125/25 μg, UMEC/VI 62.5/25 μg, or placebo.,The primary efficacy end point was trough forced expiratory volume in 1 second (FEV1) on day 169; secondary end points were Transition Dyspnea Index (TDI) focal score at week 24 and weighted mean (WM) FEV1 over 0-6 hours postdose on day 1.,Additional end points and safety were also assessed.,Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo (UMEC/VI 125/25 μg, 0.216 L, [95% confidence interval [CI] 0.175-0.257]; UMEC/VI 62.5/25 μg, 0.151 L, 95% CI 0.110-0.191; both P<0.001).,Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo (UMEC/VI 125/25 μg, 0.9, 95% CI 0.3-1.4, P=0.002; UMEC/VI 62.5/25 μg, 0.7, 95% CI 0.1-1.2, P=0.016).,On day 1, both UMEC/VI groups improved 0-6-hour WM FEV1 versus placebo (UMEC/VI 125/25 μg, 0.182 L 95% CI 0.161-0.203; UMEC/VI 62.5/25 μg, 0.160 L, 95% CI 0.139-0.181; both P<0.001).,Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1-24 (puffs/day, both P<0.001).,The incidence of adverse events was similar across groups.,In Asian patients with COPD, once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg resulted in clinically meaningful and statistically significant improvements in lung-function end points versus placebo.,Symptomatic and quality of life measures also improved.,The safety profile of UMEC/VI was consistent with previous studies. | Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD).,The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed.,In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a.,At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints).,Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint).,All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy.,Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk.,Aclidinium/formoterol may be an effective treatment for patients with COPD.,ClinicalTrials.gov: NCT01462942.,The online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users. | 1 |
The burden of asthma and COPD among patients is high and people affected are frequently hospitalized due to exacerbations.,There are numerous reasons for the lack of disease control in asthma and COPD patients.,It is associated with non-adherence to guidelines on the part of the health care provider and with poor inhalation technique and/or non-adherence to the prescribed treatment plan by the patient.,This study aims to present data on inhaler technique and its impact on quality of life (QoL) and symptom control in a typical population of patients with chronic lung disease from a randomized controlled trial on medication adherence.,For this cross-sectional analysis, 165 asthma and COPD patients were analyzed.,Correct application of inhaler devices was tested using pre-defined checklists for each inhaler type.,QoL and symptom control were investigated using COPD Assessment Test (CAT) and Asthma Control Test (ACT).,Spirometry was used to measure forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).,Overall, incorrect inhalation technique ranged from 0 to 53% depending on the type of inhaler.,COPD patients with incorrect device application had a higher CAT sum score compared to those with a correct device application (P = .02).,Moreover, COPD patients with incorrect device application were more likely to suffer from cough (P = .03) and were more breathless while walking uphill or a flight of stairs (P = .02).,While there was no significance found in asthma patients, COPD patients who used their devices correctly had a significantly better mean FEV1% predicted at baseline compared to those who applied their devices incorrectly (P = .04).,Correct inhalation of prescribed medication is associated with improved health status and lung function.,These findings should encourage health professionals to provide instructions on correct inhalation technique and to regularly re-evaluate the patients’ inhalation technique.,ClinicalTrials.gov: NCT0238672, Registered 14 February 2014. | The study aims at investigating the influence of several factors on the probability of receiving one of the two tiotropium formulations (Respimat or Handihaler).,Drug utilisation study.,All residents in the Region Umbria, Italy, aged ≥45 years, who received prescriptions of tiotropium during 2011-2012.,Two groups of patients were studied: (1) incident users of the two tiotropium formulations (ie, without tiotropium prescriptions in the previous 6 months); (2) switchers from Handihaler to Respimat.,Users of the two formulations were compared with regard to baseline characteristics and medical history.,The adjusted OR of receiving Respimat was estimated for several factors.,Incident users of the two formulations (4390 participants) had similar characteristics.,They were older and with more comorbidities than patients included in randomised control trials (RCTs).,Among prevalent users of Handihaler, the probability of switching to Respimat was greater in patients with severe respiratory disease (users of ≥4 respiratory drugs: adjusted OR=4.62; 95% CI 2.46 to 8.69) and among β-blocker users (adjusted OR=1.76; 95% CI 1.13 to 2.75).,Age above 75 years and lipid-lowering drug use reduced the probability of switching.,A positive association was also found between neurological conditions and the use of Respimat.,When starting tiotropium treatment, the choice between the two formulations is weakly affected by comorbidities and chronic obstructive pulmonary disease severity.,Instead, these characteristics influence the likelihood of switching from Handihaler to Respimat.,Since tiotropium users in clinical practice are more severe than those included in RCTs, further aetiological studies are needed to compare the safety profile of the two formulations in routine care. | 1 |
This longitudinal, retrospective cohort study of patients with COPD describes baseline characteristics, adherence, and persistence following initiation of inhaled corticosteroids (ICS)/long-acting β2-agonists (LABA)/long-acting muscarinic antagonists (LAMA) from multiple inhaler triple therapy (MITT).,Patients aged ≥40 years receiving MITT between January 2012 and September 2015 were identified from the IQVIA™ Real-world Data Adjudicated Claims-USA database.,MITT was defined as subjects with ≥1 overlapping days’ supply of three COPD medications (ICS, LABA, and LAMA).,Adherence (proportion of days covered, PDC) and discontinuation (defined as a gap of 1, 30, 60, or 90 days of supply in any of the three components of the triple therapy) were calculated for each patient over 12 months of follow-up.,In addition, analyses were stratified by number of inhalers.,In total, 14,635 MITT users were identified (mean age, 62 years).,Mean PDC for MITT at 12 months was 0.37%.,Mean PDC for the ICS/LABA and LAMA component at 12 months was 49% (0.49±0.31; median, 0.47) and 54% (0.54±0.33; 0.56), respectively.,The proportion of adherent patients (PDC ≥0.8) at 12 months was 14% for MITT.,Allowing for a 30-day gap from last day of therapy, 86% of MITT users discontinued therapy during follow-up.,Patients with COPD had low adherence to and persistence with MITT in a real-world setting.,Mean PDC for each single inhaler component was higher than the mean PDC observed with MITT.,Reducing the number of inhalers may improve overall adherence to intended triple therapy. | 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 |
Chronic obstructive pulmonary disease (COPD) exacerbations account for a substantial proportion of COPD-related costs.,To describe COPD exacerbation patterns and assess the association between exacerbation frequency and health care resource utilization (HCRU) and costs in patients with COPD in a Medicare population.,A retrospective cohort study utilizing data from a large US national health plan was conducted including patients with a COPD diagnosis during January 1, 2007 to December 31, 2012, aged 40-89 years and continuously enrolled in a Medicare Advantage Prescription Drug plan.,Exacerbation frequency, HCRU, and costs were assessed during a 24-month period following the first COPD diagnosis (follow-up period).,Four cohorts were created based on exacerbation frequency (zero, one, two, and ≥three).,HCRU and costs were compared among the four cohorts using chi-square tests and analysis of variance, respectively.,A trend analysis was performed to assess the association between exacerbation frequency and costs using generalized linear models.,Of the included 52,459 patients, 44.3% had at least one exacerbation; 26.3%, 9.5%, and 8.5% had one, two, and ≥three exacerbations in the 24-month follow-up period, respectively.,HCRU was significantly different among cohorts (all P<0.001).,In patients with zero, one, two, and ≥three exacerbations, the percentages of patients experiencing all-cause hospitalizations were 49.7%, 66.4%, 69.7%, and 77.8%, respectively, and those experiencing COPD-related hospitalizations were 0%, 40.4%, 48.1%, and 60.5%, respectively.,Mean all-cause total costs (medical and pharmacy) were more than twofold greater in patients with ≥three exacerbations compared to patients with zero exacerbations ($27,133 vs $56,033; P<0.001), whereas a greater than sevenfold difference was observed in mean COPD-related total costs ($1,605 vs $12,257; P<0.001).,COPD patients frequently experience exacerbations.,Increasing exacerbation frequency is associated with a multiplicative increase in all-cause and COPD-related costs.,This underscores the importance of identifying COPD patients at risk of having frequent exacerbations for appropriate disease management. | There are limited data describing patients with moderate COPD exacerbations and evaluating comparative effectiveness of maintenance treatments in this patient population.,The study examined COPD patients with moderate COPD exacerbations.,COPD-related outcomes were compared between patients initiating fluticasone propionate-salmeterol 250/50 mcg (FSC) vs anticholinergics (ACs) following a moderate COPD exacerbation.,This retrospective observational study used a large administrative claims database (study period: 2003-2009) to identify and describe patients with an initial, moderate COPD exacerbation.,A descriptive analysis of patients with moderate COPD exacerbations was done evaluating maintenance treatment rates, subsequent COPD exacerbation rates, and COPD-related costs during a 1-year period.,A cohort analysis compared COPD exacerbation rates and associated costs during a variable-length follow-up period between patients initiating maintenance therapy with FSC or ACs.,COPD exacerbations were reported as rate per 100 patient-years, and monthly costs were reported (standardized to USD 2009).,COPD exacerbation rates between cohorts were evaluated using Cox proportional hazards models, and costs were analyzed using generalized linear models with log-link and gamma distribution.,21,524 patients with a moderate COPD exacerbation were identified.,Only 25% initiated maintenance therapy, and 13% had a subsequent exacerbation.,Annual costs averaged $594 per patient.,A total of 2,849 treated patients (FSC = 925; AC = 1,924) were eligible for the cohort analysis.,The FSC cohort had a significantly lower rate of COPD exacerbations compared to the AC cohort (20.8 vs 32.8; P = 0.04).,After adjusting for differences in baseline covariates, the FSC cohort had a 42% significantly lower risk of a COPD exacerbation (HR = 0.58; 95% CI: 0.38, 0.91).,The FSC cohort incurred significantly higher adjusted pharmacy costs per patient per month by $37 (95% CI: $19, $72) for COPD-related medications vs the AC cohort.,However, this increase was offset by a significant reduction in adjusted monthly medical costs per patient for the FSC vs the AC cohort ($82 vs $112; P < 0.05).,Total monthly COPD-related costs, as a result, did not differ between cohorts.,Only a quarter of patients with a moderate COPD exacerbation were subsequently treated with maintenance therapy.,Initiation of FSC among those treated was associated with better clinical and economic outcomes compared to AC. | 1 |
Chronic obstructive pulmonary disease (COPD) represents a major health problem in Central and Eastern European (CEE) countries; however, there are no data regarding clinical phenotypes of these patients in this region.,Participation in the Phenotypes of COPD in Central and Eastern Europe (POPE) study was offered to stable patients with COPD in a real-life setting.,The primary aim of this study was to assess the prevalence of phenotypes according to predefined criteria.,Secondary aims included analysis of differences in symptom load, comorbidities and pharmacological treatment.,3362 patients with COPD were recruited in 10 CEE countries. 63% of the population were nonexacerbators, 20.4% frequent exacerbators with chronic bronchitis, 9.5% frequent exacerbators without chronic bronchitis and 6.9% were classified as asthma-COPD overlap.,Differences in the distribution of phenotypes between countries were observed, with the highest heterogeneity observed in the nonexacerbator cohort and the lowest heterogeneity observed in the asthma-COPD cohort.,There were statistically significant differences in symptom load, lung function, comorbidities and treatment between these phenotypes.,The majority of patients with stable COPD in CEE are nonexacerbators; however, there are distinct differences in surrogates of disease severity and therapy between predefined COPD phenotypes.,Distinct phenotypes of COPD in Central and Eastern Europe have differences in symptoms, comorbidities and treatmenthttp://ow.ly/oMZI307ndr5 | As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy.,Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive.,This led to the question of whether a responsive subset existed that could be investigated further.,The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.,The pooled analysis included 2686 randomized patients.,Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026).,Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014).,The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).,This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS.,These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.,ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729. | 1 |
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