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Cardiovascular diseases (CVDs) are arguably the most important comorbidities in chronic obstructive pulmonary disease (COPD).,CVDs are common in people with COPD, and their presence is associated with increased risk for hospitalization, longer length of stay and all-cause and CVD-related mortality.,The economic burden associated with CVD in this population is considerable and the cumulative cost of treating comorbidities may even exceed that of treating COPD itself.,Our understanding of the biological mechanisms that link COPD and various forms of CVD has improved significantly over the past decade.,But despite broad acceptance of the prognostic significance of CVDs in COPD, there remains widespread under-recognition and undertreatment of comorbid CVD in this population.,The reasons for this are unclear; however institutional barriers and a lack of evidence-based guidelines for the management of CVD in people with COPD may be contributory factors.,In this review, we summarize current knowledge relating to the prevalence and incidence of CVD in people with COPD and the mechanisms that underlie their coexistence.,We discuss the implications for clinical practice and highlight opportunities for improved prevention and treatment of CVD in people with COPD.,While we advocate more active assessment for signs of cardiovascular conditions across all age groups and all stages of COPD severity, we suggest targeting those aged under 65 years.,Evidence indicates that the increased risks for CVD are particularly pronounced in COPD patients in mid-to-late-middle-age and thus it is in this age group that the benefits of early intervention may prove to be the most effective. | COPD is often associated with cardiovascular comorbidity.,Treatment guidelines recommend therapy with bronchodilators as first choice.,We investigated the acute effect of single-dose indacaterol on lung hyperinflation in COPD subjects, for the first time evaluating the potential effects on right heart performance.,In this Phase IV, randomized, interventional, double-blind, crossover clinical study, we recruited 40 patients (50-85 years of age) with stable COPD.,Patients were treated with 150 μg indacaterol or placebo and after 60 minutes (T60) and 180 minutes (T180) the following tests were performed: trans-thoracic echocardiography (TTE), plethysmography, diffusing capacity of the lung for carbon monoxide, saturation of peripheral oxygen, and visual analog scale dyspnea score.,Patients underwent a crossover re-challenge after a further 72 hours of pharmacological washout.,All TTE measurements were conducted blindly by the same operator and further interpreted by two different blinded operators.,Consensus decisions were taken on every value and parameter.,The primary outcome was the effect of the reduction of residual volume and functional residual capacity on right heart systolic and diastolic function indexes evaluated by TTE in patients treated with indacaterol, as compared to placebo.,Vital capacity, inspiratory capacity, and forced expiratory volume in 1 second were significantly increased by indacaterol, when compared with placebo, while residual volume, intrathoracic gas volume, and specific airway resistance were significantly reduced in patients treated with indacaterol.,Tricuspid annular plane systolic excursion was significantly increased versus placebo, paralleled by an increase of tricuspid E-wave deceleration time.,The cardiac frequency was also significantly reduced in indacaterol-treated patients.,Indacaterol significantly reduces lung hyperinflation in acute conditions, with a clinically relevant improvement of dyspnea.,These modifications are associated with a significant increase of the right ventricular compliance indexes and may have a role in improving left ventricular preload leading to a reduction in cardiac frequency. | 1 |
Chronic obstructive pulmonary disease (COPD) significantly increases the risk of developing cancer.,Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls.,Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences-COmorbidities NETwork (COSYCONET) study provide the patient and biomaterial base for discovering predictive molecular markers.,We asked whether microRNA (miRNA) profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type.,From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history.,Genome-wide miRNA profiles were generated and evaluated using machine learning techniques.,For patients developing cancer we identified nine miRNAs with significantly decreased abundance (two-tailed unpaired t-test adjusted for multiple testing P < 0.05), including members of the miR-320 family.,The identified miRNAs regulate different cancer-related pathways including the MAPK pathway (P = 2.3 × 10−5).,We also observed the impact of confounding factors on the generated miRNA profiles, underlining the value of our matched analysis.,For selected miRNAs, qRT-PCR analysis was applied to validate the results.,In conclusion, we identified several miRNAs in blood of COPD patients, which could serve as candidates for biomarkers to help identify COPD patients at risk of developing cancer. | Chronic obstructive pulmonary disease (COPD) is a common, highly debilitating disease of the airways, primarily caused by smoking.,Chronic inflammation and structural remodelling are key pathological features of this disease, in part caused by the aberrant function of airway smooth muscle (ASM) cells under the regulation of transforming growth factor (TGF)‐β. miRNA are short, noncoding gene transcripts involved in the negative regulation of specific target genes, through their interactions with mRNA.,Previous studies have proposed that mRNA‐145 (miR‐145) may interact with SMAD3, an important downstream signalling molecule of the TGF‐β pathway.,TGF‐β was used to stimulate primary human ASM cells isolated from healthy nonsmokers, healthy smokers and COPD patients.,This resulted in a TGF‐β‐dependent increase in CXCL8 and IL‐6 release, most notably in the cells from COPD patients.,TGF‐β stimulation increased SMAD3 expression, only in cells from COPD patients, with a concurrent increased miR‐145 expression.,Regulation of miR‐145 was found to be negatively controlled by pathways involving the MAP kinases, MEK‐1/2 and p38 MAPK.,Subsequent, overexpression of miR‐145 (using synthetic mimics) in ASM cells from patients with COPD suppressed IL‐6 and CXCL8 release, to levels comparable to the nonsmoker controls.,Therefore, this study suggests that miR‐145 negatively regulates pro‐inflammatory cytokine release from ASM cells in COPD by targeting SMAD3. | 1 |
Blood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers.,We used two MSD multiplex panels to measure 9 cytokines and chemokines in 2123 subjects from COPDGene and 1117 subjects from SPIROMICS.,These biomarkers included: interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, eotaxin/CCL-11, eotaxin-3/CCL-26, and thymus and activation-regulated chemokine (TARC)/CCL-17.,Regression models adjusted for clinical covariates were used to determine which biomarkers were associated with the following COPD phenotypes: airflow obstruction (forced expiratory flow at 1 s (FEV1%) and FEV1/forced vital capacity (FEV1/FVC), chronic bronchitis, COPD exacerbations, and emphysema.,Biomarker-genotype associations were assessed by genome-wide association of single nucleotide polymorphisms (SNPs).,Eotaxin and IL-6 were strongly associated with airflow obstruction and accounted for 3-5% of the measurement variance on top of clinical variables.,IL-6 was associated with progressive airflow obstruction over 5 years and both IL-6 and IL-8 were associated with progressive emphysema over 5 years.,None of the biomarkers were consistently associated with chronic bronchitis or COPD exacerbations.,We identified one novel SNP (rs9302690 SNP) that was associated with CCL17 plasma measurements.,When assessing smoking related pulmonary disease, biomarkers of inflammation such as IL-2, IL-6, IL-8, and eotaxin may add additional modest predictive value on top of clinical variables alone.,COPDGene (ClinicalTrials.gov Identifier: NCT02445183).,Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) (ClinicalTrials.gov Identifier: NCT 01969344).,The online version of this article (10.1186/s12931-017-0662-2) contains supplementary material, which is available to authorized users. | To evaluate differentially expressed long noncoding RNAs (lncRNAs) and the potential role of lncRNA TUG1 in patients with chronic obstructive pulmonary disease (COPD).,Total RNA was extracted from both COPD and non-COPD lung tissues, and microarray analysis was performed with 25,628 lncRNA probes and 20,106 mRNA probes.,In addition, five up-regulated and five down-regulated lncRNAs were selected for identification using quantitative real-time polymerase chain reaction.,COPD cell model was established by transforming growth factor β (TGF-β) treatment.,Cell Counting Kit-8 assay was used to detect BEAS-2B and HFL1 cell proliferation after TUG-siRNA transfection with TGF-β treatment.,In addition, the expression levels of α-SMA and fibronectin proteins were determined using Western blot in BEAS-2B and HFL1 cells after TUG-siRNA transfection with TGF-β treatment.,There were 8,376 (32.7%) differentially expressed lncRNAs and 5,094 (25.3%) differentially expressed mRNAs in COPD lung tissues compared with non-COPD lung tissues.,Five of the analyzed lncRNAs (BC038205, BC130595, TUG1, MEG3, and LOC646329) were markedly increased, while five lncRNAs (LOC729178, PLAC2, LOC339529, LINC00229, and SNHG5) were significantly decreased in COPD lung tissues compared with non-COPD lung tissues (n=20) (***P<0.001).,Knockdown of lncRNA TUG1 promotes BEAS-2B and HFL1 cell proliferation after TGF-β treatment through inhibiting the expression levels of α-SMA and fibronectin.,Abundant, differentially expressed lncRNAs and mRNAs were identified by microarray analysis and these might play a partial or key role in the diagnosis of patients with COPD.,LncRNA TUG1 may become a very important class of biomarker and may act as a potential diagnostic and therapeutic target for patients with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression.,Blood biomarkers have been variably associated with subtype, severity, and disease progression.,Just as combined clinical variables are more highly predictive of outcomes than individual clinical variables, we hypothesized that multiple biomarkers may be more informative than individual biomarkers to predict subtypes, disease severity, disease progression, and mortality.,Fibrinogen, C-Reactive Protein (CRP), surfactant protein D (SP-D), soluble Receptor for Advanced Glycation Endproducts (sRAGE), and Club Cell Secretory Protein (CC16) were measured in the plasma of 1465 subjects from the COPDGene cohort and 2746 subjects from the ECLIPSE cohort.,Regression analysis was performed to determine whether these biomarkers, individually or in combination, were predictive of subtypes, disease severity, disease progression, or mortality, after adjustment for clinical covariates.,In COPDGene, the best combinations of biomarkers were: CC16, sRAGE, fibrinogen, CRP, and SP-D for airflow limitation (p < 10−4), SP-D, CRP, sRAGE and fibrinogen for emphysema (p < 10−3), CC16, fibrinogen, and sRAGE for decline in FEV1 (p < 0.05) and progression of emphysema (p < 10−3), and all five biomarkers together for mortality (p < 0.05).,All associations except mortality were validated in ECLIPSE.,The combination of SP-D, CRP, and fibrinogen was the best model for mortality in ECLIPSE (p < 0.05), and this combination was also significant in COPDGene.,This comprehensive analysis of two large cohorts revealed that combinations of biomarkers improve predictive value compared with clinical variables and individual biomarkers for relevant cross-sectional and longitudinal COPD outcomes.,The online version of this article (doi:10.1186/s12931-017-0597-7) contains supplementary material, which is available to authorized users. | Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients.,Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype.,This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes.,These patients are therefore a priority for research and treatment.,The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection.,Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment.,Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype.,This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.,The online version of this article (doi:10.1186/1741-7015-11-181) contains supplementary material, which is available to authorized users. | 1 |
Pneumonia is a frequent lung infection and a serious illness, which is often diagnosed among patients hospitalized with acute exacerbations of COPD.,The aim of this study was to estimate the attributable costs due to pneumonia among patients hospitalized with pneumonia compared to a matched general population control group without pneumonia hospitalization.,This study includes citizens older than 18 years from three municipalities (n=142,344).,Based on national registers and municipal data, the health and social care costs of pneumonia in the second half of 2013 are estimated and compared with propensity score-matched population controls.,The average health care costs of 383 patients hospitalized with pneumonia in the second half of 2013 were US$34,561 per patient.,Among pneumonia patients with COPD, the costs were US$35,022.,The attributable costs of patients with pneumonia compared to the population control group for the 6-month period were US$24,155 per case.,Overall, the attributable costs for the 383 pneumonia cases amounted to US$9.25 million.,Subgroup analyses showed that costs increased with age.,The attributable costs due to pneumonia were highest among the 18-59-year-old and the 70-79-year-old patients.,This difference is likely to reflect an increased risk of mortality among the pneumonia patients.,Men have higher costs than women in the pneumonia group.,The costs of pneumonia are considerable.,In three Danish municipalities, the attributable costs due to pneumonia were US$24,155 per case or US$64,992 per 1,000 inhabitants in the second half of 2013.,Similar high health care and social care costs were found for pneumonia patients with COPD - the largest group having pneumonia episodes.,The municipalities are responsible for 49% of the costs, while a closer focus on the prevention of pneumonia may be advisable, eg, starting with citizens having COPD. | COPD is associated with a relevant burden of disease and a high mortality worldwide.,Only recently, the importance of comorbidities of COPD has been recognized.,Studies postulated an association with inflammatory conditions potentially sharing pathogenic pathways and worsening overall prognosis.,More evidence is required to estimate the role of comorbidities of COPD.,Our aim was to investigate the prevalence and clustering of comorbidities associated with COPD, and to estimate their impact on clinically relevant outcomes.,In this population-based case-control study, a nation-wide database provided by the Swiss Federal Office for Statistics enclosing every hospital entry covering the years 2002-2010 (n = 12′888′075) was analyzed using MySQL and R statistical software.,Statistical methods included non-parametric hypothesis testing by means of Fisher’s exact test and Wilcoxon rank sum test, as well as linear models with generalized estimating equation to account for intra-patient variability.,Exploratory multivariate approaches were also used for the identification of clusters of comorbidities in COPD patients.,In 2.6% (6.3% in patients aged >70 years) of all hospitalization cases an active diagnosis of COPD was recorded.,In 21% of these cases, COPD was the main reason for hospitalization.,Patients with a diagnosis of COPD had more comorbidities (7 [IQR 4-9] vs.,3 [IQR 1-6]; ), were more frequently rehospitalized (annual hospitalization rate 0.33 [IQR 0.20-0.67] vs.,0.25 [IQR 0.14-0.43]/year; ), had a longer hospital stay (9 [IQR 4-15] vs.,5 [IQR 2-11] days; ), and had higher in-hospital mortality (5.9% [95% CI 5.8%-5.9%] vs.,3.4% [95% CI 3.3%-3.5%]; ) compared to matched controls.,A set of comorbidities was associated with worse outcome.,We could identify COPD-related clusters of COPD-comorbidities. | 1 |
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, mainly due to cigarette smoking, which represents the third cause of mortality worldwide.,The mechanisms driving its epithelial salient features remain largely elusive.,We aimed to evaluate the activation and the role of the canonical, β-catenin-dependant WNT pathway in the airway epithelium from COPD patients.,The WNT/β-catenin pathway was first assessed by WNT-targeted RNA sequencing of the air/liquid interface-reconstituted bronchial epithelium from COPD and control patients.,Airway expression of total and active β-catenin was assessed in lung sections, as well as WNT components in laser-microdissected airway epithelium.,Finally, we evaluated the role of WNT at the bronchial epithelial level by modulating the pathway in the reconstituted COPD epithelium.,We show that the WNT/β-catenin pathway is upregulated in the COPD airway epithelium as compared with that of non-smokers and control smokers, in targeted RNA-sequencing of in vitro reconstituted airway epithelium, and in situ in lung tissue and laser-microdissected epithelium.,Extrinsic activation of this pathway in COPD-derived airway epithelium inhibited epithelial differentiation, polarity and barrier function, and induced TGF-β-related epithelial-to-mesenchymal transition (EMT).,Conversely, canonical WNT inhibition increased ciliated cell numbers, epithelial polarity and barrier function, whilst inhibiting EMT, thus reversing COPD features.,In conclusion, the aberrant reactivation of the canonical WNT pathway in the adult airway epithelium recapitulates the diseased phenotype observed in COPD patients, suggesting that this pathway or its downstream effectors could represent a future therapeutic target.,This study was supported by the Fondation Mont-Godinne, the FNRS and the WELBIO. | Free iron in lung can cause the generation of reactive oxygen species, an important factor in chronic obstructive pulmonary disease (COPD) pathogenesis.,Iron accumulation has been implicated in oxidative stress in other diseases, such as Alzheimer’s and Parkinson’s diseases, but little is known about iron accumulation in COPD.,We sought to determine if iron content and the expression of iron transport and/or storage genes in lung differ between controls and COPD subjects, and whether changes in these correlate with airway obstruction.,Explanted lung tissue was obtained from transplant donors, GOLD 2-3 COPD subjects, and GOLD 4 lung transplant recipients, and bronchoalveolar lavage (BAL) cells were obtained from non-smokers, healthy smokers, and GOLD 1-3 COPD subjects.,Iron-positive cells were quantified histologically, and the expression of iron uptake (transferrin and transferrin receptor), storage (ferritin) and export (ferroportin) genes was examined by real-time RT-PCR assay.,Percentage of iron-positive cells and expression levels of iron metabolism genes were examined for correlations with airflow limitation indices (forced expiratory volume in the first second (FEV1) and the ratio between FEV1 and forced vital capacity (FEV1/FVC)).,The alveolar macrophage was identified as the predominant iron-positive cell type in lung tissues.,Futhermore, the quantity of iron deposit and the percentage of iron positive macrophages were increased with COPD and emphysema severity.,The mRNA expression of iron uptake and storage genes transferrin and ferritin were significantly increased in GOLD 4 COPD lungs compared to donors (6.9 and 3.22 fold increase, respectively).,In BAL cells, the mRNA expression of transferrin, transferrin receptor and ferritin correlated with airway obstruction.,These results support activation of an iron sequestration mechanism by alveolar macrophages in COPD, which we postulate is a protective mechanism against iron induced oxidative stress. | 1 |
Infection is as an important trigger for acute asthma and chronic obstructive pulmonary disease (COPD).,The aim of this article was to determine the prevalence and impact of virus and bacterial infections in acute asthma and COPD.,Subjects were recruited, within 24 h of hospital admission for acute exacerbations of asthma and COPD.,Nose/throat swabs and sputum samples were collected and examined by multiplex polymerase chain reaction for respiratory viruses and cultured for bacteria.,The primary outcomes were length of stay (LOS) and readmission to hospital within 60 days.,A total of 199 subjects were recruited (96 had asthma and 103 COPD) for 235 events (36 re‐presented).,A virus was detected in 79 subjects (40%), bacteria in 41 (21%), and of these, 18 had both.,Rhinovirus A was the most frequently isolated virus.,A multivariate analysis was performed to control for confounders.,It found that detection of a virus, a virus and bacteria, forced expiratory volume in 1 s (FEV1) and a diagnosis of COPD were all independent predictors of prolonged LOS, while risk of readmission within 60 days was increased with virus infection alone, virus and bacterial infection, lower FEV1 and current smoking.,Virus infection, especially in the presence of chronic bacterial infection, is an important determinant of more severe acute exacerbations in both asthma and COPD, and patients with co‐infections are more likely to be readmitted to hospital following their exacerbation.,A virus infection with rhinovirus A has been demonstrated to be a likely trigger of acute asthma and COPD.,Virus infection, in combination with a chronic bacterial infection, is an important determinant of more severe acute exacerbations and is more likely to result in hospital readmission following severe acute exacerbation. | 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) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation.,In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers.,Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues.,Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease. | Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal and chronic inflammatory response in the lung that underlies the chronic airflow obstruction of the small airways, the inexorable decline of lung function, and the severity of the disease.,The control of this inflammation remains a key strategy for treating the disease; however, there are no current anti-inflammatory treatments that are effective.,Although glucocorticoids (GCs) effectively control inflammation in many diseases such as asthma, they are less effective in COPD.,The molecular mechanisms that contribute to the development of this relative GC-insensitive inflammation in the lung of patients with COPD remain unclear.,However, recent studies have indicated novel mechanisms and possible therapeutic strategies.,One of the major mechanisms proposed is an oxidant-mediated alteration in the signaling pathways in the inflammatory cells in the lung, which may result in the impairment of repressor proteins used by the GC receptor to inhibit the transcription of proinflammatory genes.,Although these studies have described mechanisms and targets by which GC function can be restored in cells from patients with COPD, more work is needed to completely elucidate these and other pathways that may be involved in order to allow for more confident therapeutic targeting.,Given the relative GC-insensitive nature of the inflammation in COPD, a combination of therapies in addition to a restoration of GC function, including effective alternative anti-inflammatory targets, antioxidants, and proresolving therapeutic strategies, is likely to provide better targeting and improvement in the management of the disease. | 1 |
Tiotropium bromide is an effective therapy for COPD patients.,Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.,The TIOSPIR® trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed).,The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation.,A spirometry substudy evaluates the bronchodilator efficacy.,The trial is a randomized, double-blind, double dummy, event-driven, parallel group study.,Participants can use any background treatment for COPD except inhaled anticholinergic agents.,The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included.,Clinical sites are international and include both primary care as well as specialists.,To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years.,TIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort. | For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction.,The delivery characteristics, patients’ correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies.,The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD).,The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD.,Patients’ correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use.,Patients’ preference was assessed after completion of both study periods.,Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler.,For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively.,In the second study, correct use of Breezhaler and HandiHaler was achieved by >77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01).,Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities.,Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler.,These are important factors for optimum dose delivery and successful COPD management. | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the main contributors to the global burden of disease.,The aim of this systematic review was to quantify the disease burden of COPD in China and to determine the risk factors of the disease.,The number of studies included in the review was 47 with an average quality assessment score of 7.70 out of 10.,Reported COPD prevalence varied between 1.20% and 8.87% in different provinces/cities across China.,The prevalence rate of COPD was higher among men (7.76%) than women (4.07%).,The disease was more prevalent in rural areas (7.62%) than in urban areas (6.09%).,The diagnostic rate of COPD patients in China varied from 23.61% to 30.00%.,The percentage of COPD patients receiving outpatient treatment was around 50%, while the admission rate ranged between 8.78% and 35.60%.,Tobacco exposure and biomass fuel/solid fuel usage were documented as two important risk factors of COPD.,COPD ranked among the top three leading causes of death in China.,The direct medical cost of COPD ranged from 72 to 3,565 USD per capita per year, accounting for 33.33% to 118.09% of local average annual income.,The most commonly used scales for the assessment of quality of life (QoL) included Saint George Respiratory Questionnaire, Airways Questionnaire 20, SF-36, and their revised versions.,The status of QoL was worse among COPD patients than in non-COPD patients, and COPD patients were at higher risks of depression.,The COPD burden in China was high in terms of economic burden and QoL.,In view of the high smoking rate and considerable concerns related to air pollution and smog in China, countermeasures need to be taken to improve disease prevention and management to reduce disease burdens raised by COPD. | The aim of this study was to measure HrQoL during acute exacerbations of COPD using generic and disease-specific instruments, and to assess completeness, proportion with best or worst health state, sensitivity to change and discriminative ability for each instrument.,EQ-5D, SF-12 and SGRQ were obtained from COPD patients with GOLD stage III and IV hospitalized for an acute exacerbation both at admission and discharge.,To assess the instruments' properties, utility values were calculated for EQ-5D and SF-12, and a total score was derived from the SGRQ.,Mean utilities ranged from 0.54 (SF-12, stage IV) to 0.62 (EQ-5D, stage III) at admission, and from 0.58 (SF-12, stage IV) to 0.84 (EQ-5D, stage III) at discharge.,Completeness was best for EQ-5D and SGRQ, while no utility value for the SF-12 could be calculated for more than 30%.,For SGRQ subscales, the minimal score occurred in up to 11% at admission, while full health was observed for the EQ-5D at discharge in 13%.,Sensitivity to change was generally good, whereas discrimination between COPD stages was low for the EQ-5D.,Acute exacerbations seriously impair health status and quality of life.,The EQ-5D is generally suitable to measure HrQoL in exacerbations of severe COPD, although the high proportion of patients reporting full health at discharge poses a problem.,The main issue with the SF-12 is the high proportion of missing values in a self-assessed setting.,Properties of the SGRQ were satisfactory.,However, since no utility values can be derived from this disease-specific instrument, it is not suitable for cost-utility analyses in health-economic evaluations. | 1 |
Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD).,Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product “Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)” in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients.,Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products.,Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-α, IL-1β, IL-12, and IFN-γ), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice.,The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs).,Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation.,In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients.,Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration.,In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials. | In the last two decades, mesenchymal stem cells (MSCs) have been pre-clinically utilized in the treatment of a variety of kinds of diseases including chronic obstructive pulmonary disease (COPD).,The aim of the current study was to systematically review and conduct a meta-analysis on the published pre-clinical studies of MSC administration in the treatment of COPD in animal models.,A systematic search of electronic databases was performed.,Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3).,The pooled Hedges’s g with 95% confidence intervals (95% CIs) was adopted to assess the effect size.,Random effect model was used due to the heterogeneity between the studies.,A total of 20 eligible studies were included in the current systematic review.,The overall meta-analysis showed that MSC administration was significantly in favor of attenuating acute lung injury (Hedges’s g = -2.325 ± 0.145 with 95% CI: -2.609 ~ -2.040, P < 0.001 for mean linear intercept, MLI; Hedges’s g = -3.488 ± 0.504 with 95% CI: -4.476 ~ -2.501, P < 0.001 for TUNEL staining), stimulating lung tissue repair (Hedges’s g = 3.249 ± 0.586 with 95% CI: 2.103~ 4.394, P < 0.001) and improving lung function (Hedges’s g = 2.053 ± 0.408 with 95% CI: 1.253 ~ 2.854, P< 0.001).,The mechanism of MSC therapy in COPD is through ameliorating airway inflammation (Hedges’s g = -2.956 ± 0.371 with 95% CI: -3.683 ~ -2.229, P< 0.001) and stimulating cytokine synthesis that involves lung tissue repair (Hedges’s g = 3.103 ± 0.734 with 95% CI: 1.664 ~ 4.541, P< 0.001).,This systematic review and meta-analysis suggest a promising role for MSCs in COPD treatment.,Although the COPD models may not truly mimic COPD patients, these pre-clinical studies demonstrate that MSC hold promise in the treatment of chronic lung diseases including COPD.,The mechanisms of MSCs role in preclinical COPD treatment may be associated with attenuating airway inflammation as well as stimulating lung tissue repair. | 1 |
We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.,This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy.,Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa.,The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population.,The incidence of adverse events was also assessed.,In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population.,UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001].,Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14).,Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.,In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD.,Both treatments had similar safety profiles.,These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.,ClinicalTrials.gov identifier NCT02799784.,GlaxoSmithKline.,The online version of this article (doi:10.1007/s12325-017-0626-4) contains supplementary material, which is available to authorized users. | Symptomatic relief is an important treatment goal for patients with COPD.,To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines.,The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need.,The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation.,The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.,This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international).,Subjects completed the E-RS as part of a daily eDiary.,Tests of reliability, validity, and responsiveness were conducted in each dataset.,In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74).,RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p < 0.01, all comparisons listed here): FEV1% predicted (−0.19, −0.14, −0.15); St.,George’s Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (−0.30, −0.14) and incremental shuttle walk (ISWT) (−0.18) tests.,Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity.,RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001).,RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001).,Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.,Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.,MPEX: NCT00739648; AZ1: NCT00949975; AZ 2: NCT01023516,The online version of this article (doi:10.1186/s12931-014-0124-z) contains supplementary material, which is available to authorized users. | 1 |
It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation.,We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation.,Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed.,Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation.,The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD.,The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV.,The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21-5.70, P=0.000-0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages.,From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness.,Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%-75.3%) and specificities (70.3%-75.7%).,We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation. | There is an ongoing debate about the appropriate spirometric criterion for airway obstruction to detect COPD.,Furthermore, the association of different criteria with comorbidity prevalence and inflammatory biomarkers in advanced age is unclear.,Spirometry was performed in a population-based study (n=2,256) covering an age range of 41-90 years.,COPD was spirometrically determined either by a fixed ratio (FR) of <0.7 for forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or by FEV1/FVC below the lower limit of normal (LLN).,Comorbidity prevalences and circulating biomarker levels (C-reactive protein [CRP], interleukin [IL]-6) were compared between subjects with or without COPD by the two criteria using logistic and multiple regression models, adjusting for sex and age.,The prevalence of spirometrically defined COPD by FR increased with age from 10% in subjects aged <65 years to 26% in subjects aged ≥75 years.,For LLN-defined COPD, it remained below 10% for all age groups.,Overall, COPD diagnosis was not associated with specific comorbidities, except for a lower prevalence of obesity in both FR- and LLN-defined cases.,Both CRP and IL-6 tended to be higher in cases by both criteria.,In a population-based cohort of adults up to the age of 90 years, the prevalence of spirometrically defined COPD was higher for the FR criterion than for the LLN criterion.,This difference increased with age.,Neither prevalences of common comorbidities nor levels of the biomarkers, CRP or IL-6, were conclusively associated with the selection of the COPD criterion.,Results have to be considered in light of the predominantly mild cases of airway obstruction in the examined study population. | 1 |
Oxidative stress occurs when free radicals and other reactive species overwhelm the availability of antioxidants.,Reactive oxygen species (ROS), reactive nitrogen species, and their counterpart antioxidant agents are essential for physiological signaling and host defense, as well as for the evolution and persistence of inflammation.,When their normal steady state is disturbed, imbalances between oxidants and antioxidants may provoke pathological reactions causing a range of nonrespiratory and respiratory diseases, particularly chronic obstructive pulmonary disease (COPD).,In the respiratory system, ROS may be either exogenous from more or less inhalative gaseous or particulate agents such as air pollutants, cigarette smoke, ambient high-altitude hypoxia, and some occupational dusts, or endogenously generated in the context of defense mechanisms against such infectious pathogens as bacteria, viruses, or fungi.,ROS may also damage body tissues depending on the amount and duration of exposure and may further act as triggers for enzymatically generated ROS released from respiratory, immune, and inflammatory cells.,This paper focuses on the general relevance of free radicals for the development and progression of both COPD and pulmonary emphysema as well as novel perspectives on therapeutic options.,Unfortunately, current treatment options do not suffice to prevent chronic airway inflammation and are not yet able to substantially alter the course of COPD.,Effective therapeutic antioxidant measures are urgently needed to control and mitigate local as well as systemic oxygen bursts in COPD and other respiratory diseases.,In addition to current therapeutic prospects and aspects of genomic medicine, trending research topics in COPD are presented. | Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung and whole body caused mainly by tobacco smoking.,Patients with advanced COPD are in a state of undernutrition, referred to as pulmonary cachexia; the exercise performance and quality of life (QOL) of these patients are deteriorated, the vital prognosis is unfavorable, and the medico-economic burden posed by poorly nourished COPD patients is high.,The mainstays of COPD treatment are pharmacotherapy, mainly with bronchodilators, and non-pharmacotherapeutic approaches such as respiratory rehabilitation and nutrition counseling.,Nutritional supplement therapy, consisting primarily of high calorie intake, has been demonstrated to be effective for maintaining and improving the muscle strength and exercise tolerance in poorly nourished COPD patients.,The efficacy of intake of various nutrients, besides a high calorie intake, for amelioration of the disease state of COPD has also been reported.,The roles of adipokines in the pathophysiology of COPD have begun to receive attention recently, and not only their regulatory effects on appetite and nutritional status, but also their influence on systemic inflammation have been increasingly clarified.,We review the papers on COPD and nutrition and discuss the role of nutritional supplement therapy in the treatment of COPD. | 1 |
Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented.,However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited.,Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons.,We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002).,Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects.,No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA.,Co-occurrence analysis suggests the presence of networks of co-occurring bacteria.,Four communities of positively correlated bacteria were revealed.,The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype.,Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells.,This might result in a changed interplay with the host immune system. | 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 |
Individuals with severe alpha-1 antitrypsin deficiency (AATD) have an increased risk of developing COPD.,However, outcomes during long-term oxygen therapy (LTOT) in patients with severe AATD and hypoxemia are unknown.,This was a prospective, population-based, consecutive cohort study of patients on LTOT due to COPD in the period from January 1, 1987, to June 30, 2015, in the Swedish National Registry for Respiratory Failure (Swedevox).,Severe AATD was identified using the Swedish AATD registry and confirmed by isoelectric focusing.,Data on lung transplantation (LTx) were obtained from the two lung transplantation centers in Sweden.,Mortality and causes of death were assessed based on the National Causes of Death Registry and analyzed using multivariable Cox regression.,A total of 14,644 patients who started LTOT due to COPD were included in this study.,No patient was lost to follow up.,Patients with AATD were younger, included more males and more never smokers, and had fewer comorbidities.,During a median follow-up of 1.6 years (interquartile range [IQR], 2.7) on LTOT, patients without severe AATD had a higher mortality, hazard ratio [HR] 1.53 (95% CI, 1.24-1.88), adjusting for age, sex, smoking status, body mass index, performance status, level of hypoxemia, and comorbidities.,Cardiovascular deaths were increased.,A higher proportion of AATD patients underwent LTx, 53 (19%) vs 118 (1%).,Survival after LTx was similar for AATD and non-AATD patients and was predicted by age.,In oxygen-dependent COPD, patients with severe AATD have a longer survival time on LTOT, but they have a similar prognosis after lung transplantation compared with patients without AATD. | Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD).,The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.,Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354).,Eligible studies were those of any treatment used in severe AATD.,Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible.,All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months).,Risk of bias was assessed appropriately according to study methodology.,In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation).,Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments.,Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes.,Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02).,Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD.,Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.,Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density.,There is paucity of data around other treatments in AATD.,Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group. | 1 |
The purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation.,The GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler® device.,The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12.,Other outcomes included additional spirometric end points, transition dyspnea index, St George’s Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary.,Safety was also assessed during the study.,Of the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase.,Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo.,Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George’s Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12.,Safety was comparable between the treatment groups.,Significant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation. | Glycopyrronium is a once-daily (od) long-acting muscarinic antagonist for the maintenance treatment of chronic obstructive pulmonary disease (COPD).,The GLOW7 study evaluated the efficacy and safety of od glycopyrronium 50 μg in predominantly Chinese patients with moderate-to-severe COPD.,In this 26-week, multi-center, double-blind, placebo-controlled, parallel-group study, men and women ≥40 years with moderate-to-severe COPD were randomized to glycopyrronium 50 μg od or placebo (2:1).,The primary objective was to confirm the significant improvement of trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment with glycopyrronium compared with placebo.,Secondary objectives included the effect of glycopyrronium on health status (St George’s Respiratory Questionnaire), breathlessness (Transition Dyspnea Index), other lung function parameters, rescue medication use, and COPD exacerbations.,Safety and tolerability were also evaluated.,Of the 460 patients randomized, 459 were included in the full analysis set (glycopyrronium, n=306; placebo, n=154; mean age 64.7 years; mean post-bronchodilator FEV1: 50.8% predicted); 425 (92.4%) completed the study.,At Week 12, glycopyrronium signifcantly improved trough FEV1 with a least square means treatment difference of 141 mL (95% confidence interval 111 mL, 171 mL; P<0.001) compared with placebo.,The mean treatment effect of glycopyrronium was greater than the minimum clinically important difference versus placebo in both St George’s Respiratory Questionnaire total score (−4.92; P<0.001) and Transition Dyspnea Index focal score (1.0; P<0.001) at week 26.,Glycopyrronium reduced the risk of exacerbations in terms of time to first moderate or severe exacerbation by 28% (P=0.153) and rate of moderate or severe COPD exacerbation by 29% (P=0.119) compared with placebo.,Incidence of death was 1.3% with glycopyrronium and 0% in placebo during the treatment period.,Overall incidence of adverse events (glycopyrronium 43.6%; placebo 47.4%) and serious adverse events (glycopyrronium 5.6%; placebo 9.1%) were similar.,In predominantly Chinese patients with moderate-to-severe COPD, od glycopyrronium 50 μg significantly improved lung function, dyspnea, and health status compared with placebo.,The safety and tolerability profile of glycopyrronium was comparable to placebo. | 1 |
Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century.,The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD.,Our understanding of the key molecular mechanisms which drive the pathological changes are not complete.,In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation.,We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations.,We discuss the need to specifically target SAD to attenuate the progression of COPD. | Tumor necrosis factor alpha (TNFα) is the most widely studied pleiotropic cytokine of the TNF superfamily.,In pathophysiological conditions, generation of TNFα at high levels leads to the development of inflammatory responses that are hallmarks of many diseases.,Of the various pulmonary diseases, TNFα is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).,In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFα in the cytotoxicity.,Thus, pharmacological agents that can either suppress the production of TNFα or block its biological actions may have potential therapeutic value against a wide variety of diseases.,Despite some immunological side effects, anti-TNFα therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death. | 1 |
Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD).,Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety.,Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this.,Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities.,However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability.,Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs.,We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type.,We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design. | Randomized interventional trials generally recruit highly selected patients.,In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations.,DACCORD (Die ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland [Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany]) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD).,Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years, and were initiating or changing COPD maintenance medication.,The only exclusion criteria were asthma and participation in a randomized clinical trial.,Exacerbation data were collected every 3 months.,COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period.,In the 6 months prior to baseline, 26.5% of the 3,974 patients experienced ≥1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384).,Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk.,There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations.,COPD Assessment Test mean change from baseline was −1.9, with 48.9% of patients reporting a clinically relevant improvement.,Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year.,DACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully. | 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 | This study compared reticular basement membrane (Rbm) and vascular remodelling within the bronchial mucosa of subjects with chronic obstructive pulmonary disease (COPD) with those from patients with asthma, to test the ‘Dutch hypothesis’ of whether these are essentially the same or different pathological conditions.,Bronchoscopic biopsies were stained with anti-collagen IV antibody; 18 current smoking COPD, 10 symptomatic asthmatics and 13 healthy non-smoking controls were studied.,The Rbm in COPD was fragmented, non-homogeneous, variable in thickness and hypervascular, whereas in asthma the Rbm was compact and homogeneous with no evidence of increased vascularity compared to controls.,Length of Rbm splitting presented as percentage of Rbm length was used to measure fragmentation; it was greater in COPD than in controls and asthmatics [median (range) 20.7% (0.4-68.5) versus 5.3% (0.0-21.7) versus 1.5% (0.0-15.1), P < 0.001].,The number of Rbm vessels/mm Rbm [median (range) 10.1 (1.6-23.0) versus 4.5 (0.0-26.4) versus 4.4 (0.4-8.1), P < 0.01] and area of Rbm vessels, μm2/mm Rbm [median (range) 953 (115-2456) versus 462 (0-3263) versus 426 (32-2216), P < 0.05] was also increased in COPD compared to normal subjects and asthmatics.,The characteristics of Rbm remodelling are quite different in asthma and COPD. | 1 |
Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema.,No cohorts have examined the association between sRAGE and progressive decline of lung function.,There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population.,This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction.,A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.,sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399).,We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).,Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001).,In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density.,After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort.,Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.,Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed.,In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling.,Thus, genotype should be included in sRAGE evaluations.,The online version contains supplementary material available at 10.1186/s12931-021-01686-z. | A multidimensional approach in the risk assessment of chronic obstructive pulmonary disease (COPD) is preferable.,The aim of this study is to compare the prognostic ability for mortality by different COPD assessment systems; spirometric staging, classification by GOLD 2011, GOLD 2017, the age, dyspnea, obstruction (ADO) and the dyspnea, obstruction, smoking, exacerbation (DOSE) indices.,A total of 490 patients diagnosed with COPD were recruited from primary and secondary care in central Sweden in 2005.,The cohort was followed until 2017.,Data for categorization using the different assessment systems were obtained through questionnaire data from 2005 and medical record reviews between 2000 and 2003.,Kaplan-Meier survival analyses and Cox proportional hazard models were used to assess mortality risk.,Receiver operating characteristic curves estimated areas under the curve (AUC) to evaluate each assessment systems´ ability to predict mortality.,By the end of follow-up, 49% of the patients were deceased.,The mortality rate was higher for patients categorized as stage 3-4, GOLD D in both GOLD classifications and those with a DOSE score above 4 and ADO score above 8.,The ADO index was most accurate for predicting mortality, AUC 0.79 (95% CI 0.75-0.83) for all-cause mortality and 0.80 (95% CI 0.75-0.85) for respiratory mortality.,The AUC values for stages 1-4, GOLD 2011, GOLD 2017 and DOSE index were 0.73, 0.66, 0.63 and 0.69, respectively, for all-cause mortality.,All of the risk assessment systems predict mortality.,The ADO index was in this study the best predictor and could be a helpful tool in COPD risk assessment. | 1 |
Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD.,Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD.,Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release “danger signal”.,These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation.,In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells.,Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs).,Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD.,This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD. | Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells along with enhanced intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface.,Regulatory T cells were investigated in BALF from nine COPD subjects and compared to fourteen smokers with normal lung function and nine never-smokers.,In smokers with normal lung function, the expression of CD25+CD4+ was increased, whereas the proportions of FoxP3+ and CD127+ were unchanged compared to never-smokers.,Among CD4+ cells expressing high levels of CD25, the proportion of FoxP3+ cells was decreased and the percentage of CD127+ was increased in smokers with normal lung function.,CD4+CD25+ cells with low/absent CD127 expression were increased in smokers with normal lung function, but not in COPD, when compared to never smokers.,The reduction of FoxP3 expression in BALF from smokers with normal lung function indicates that the increase in CD25 expression is not associated with the expansion of regulatory T cells.,Instead, the high CD127 and low FoxP3 expressions implicate a predominantly non-regulatory CD25+ helper T-cell population in smokers and stable COPD.,Therefore, we suggest a smoking-induced expansion of predominantly activated airway helper T cells that seem to persist after COPD development. | 1 |
Chronic obstructive pulmonary disease (COPD) and asthma may overlap and converge in older people (overlap syndrome).,It was hypothesized that patients with overlap syndrome may have different clinical characteristics such as sputum eosinophilia, and better responsiveness to treatment with inhaled corticosteroid (ICS).,Sixty-three patients with stable COPD (forced expiratory volume in 1 second [FEV1] ≤80%) underwent pulmonary function tests, including reversibility of airflow limitation, arterial blood gas analysis, analysis of inflammatory cells in induced sputum, and chest high-resolution computed tomography.,The inclusion criteria for COPD patients with asthmatic symptoms included having asthmatic symptoms such as episodic breathlessness, wheezing, cough, and chest tightness worsening at night or in the early morning (COPD with asthma group).,The clinical features of COPD patients with asthmatic symptoms were compared with those of COPD patients without asthmatic symptoms (COPD without asthma group).,The increases in FEV1 in response to treatment with ICS were significantly higher in the COPD with asthma group.,The peripheral eosinophil counts and sputum eosinophil counts were significantly higher.,The prevalence of patients with bronchial wall thickening on chest high-resolution computed tomography was significantly higher.,A significant correlation was observed between the increases in FEV1 in response to treatment with ICS and sputum eosinophil counts, and between the increases in FEV1 in response to treatment with ICS and the grade of bronchial wall thickening.,Receiver operating characteristic curve analysis revealed 82.4% sensitivity and 84.8% specificity of sputum eosinophil count for detecting COPD with asthma, using 2.5% as the cutoff value.,COPD patients with asthmatic symptoms had some clinical features.,ICS should be considered earlier as a potential treatment in such patients.,High sputum eosinophil counts and bronchial wall thickening on chest high-resolution computed tomography might therefore be a good predictor of response to ICS. | 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 |
Bronchodilators such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) are central to the pharmacological management of COPD.,Dual bronchodilation with umeclidinium/vilanterol (UMEC/VI; 62.5/25 μg) is a novel LAMA/LABA combination approved for maintenance treatment for patients with COPD.,The objective of this study was to assess the cost-effectiveness of maintenance treatment with UMEC/VI compared with tiotropium (TIO) 18 μg, open dual LAMA + LABA treatment, or no long-acting bronchodilator treatment in patients with moderate to very severe COPD.,A Markov model was developed to estimate the costs and outcomes associated with UMEC/VI treatment in patients with moderate to very severe COPD (GSK study number: HO-13-13411).,Clinical efficacy, costs, utilities, and mortality obtained from the published literature were used as the model inputs.,Costs are presented in US dollars based on 2015 prices.,The model outputs are total costs, drug costs, other medical costs, number of COPD exacerbations, and quality-adjusted life-years (QALYs).,Costs and outcomes were discounted at a 3% annual rate.,Incremental cost-effectiveness ratios were calculated.,One-way and probabilistic sensitivity analyses were conducted to assess the effects of changing parameters on the uncertainty of the results.,UMEC/VI treatment for moderate to very severe COPD was associated with lower lifetime medical costs ($82,344) compared with TIO ($88,822), open dual LAMA + LABA treatment ($114,442), and no long-acting bronchodilator ($86,751).,Fewer exacerbations were predicted to occur with UMEC/VI treatment compared with no long-acting bronchodilator treatment.,UMEC/VI provided an 0.11 and 0.25 increase in QALYs compared with TIO and no long-acting bronchodilator treatment, and as such, dominated these cost-effectiveness analyses.,Sensitivity analyses confirmed that the results were robust.,The results from this model suggest that UMEC/VI treatment would be dominant compared with TIO and no long-acting bronchodilator treatment, and less costly than open dual LAMA + LABA treatment in patients with moderate to very severe COPD. | The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting β2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD).,This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population.,This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study.,Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25 μg (via ELLIPTA® dry powder inhaler) or PBO for 12 weeks.,The primary endpoint was St George’s Respiratory Questionnaire (SGRQ) total score at day 84.,Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1-12 and trough forced expiratory volume in 1 second on day 84.,Adverse events were also assessed.,A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups.,UMEC/VI 62.5/25 μg provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: −4.03 [95% confidence interval {CI}: −6.28, −1.79]; P<0.001).,UMEC/VI 62.5/25 μg resulted in a statistically significant reduction in rescue albuterol use versus PBO (−0.7 puffs/day [95% CI: −1.1, −0.4]; P<0.001).,UMEC/VI 62.5/25 μg provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P<0.001).,The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 μg and PBO groups, respectively).,The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear.,This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo.,Backward elimination via Cox’s proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation.,Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216.,Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk.,BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI <25 kg/m2.,The modelled probability of pneumonia varied between 3 and 12% during the first year.,Higher exacerbation risk was associated with a history of exacerbations, poorer lung function (GOLD stage), female sex and absence of ICS treatment.,The influence of the other exacerbation risk factors was not modified by ICS treatment.,Modelled probabilities of an exacerbation varied between 31 and 82% during the first year.,The probability of an exacerbation was considerably higher than for pneumonia.,ICS reduced exacerbations but did not influence the effect of risks associated with prior exacerbation history, GOLD stage, or female sex.,The only identified risk factor for ICS-induced pneumonia was BMI <25 kg/m2.,Analyses of this type may help the development of COPD risk equations. | 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 |
Objective: The objective was to assess the effects of a nasal restriction device for inspiratory muscle training, called Feelbreathe®, added to a rehabilitation program (RP) on exercise capacity, quality of life, dyspnea and inspiratory muscle strength in patients with stable COPD.,Methods: Patients were randomized into three groups, one performed a supervised RP using the Feelbreathe® device (FB group), the second group developed the same RP with oronasal breathing without FB (ONB group) and the third was the control group (CG).,We evaluated inspiratory muscle strength (PImax), dyspnea (mMRC), quality of life (CAT) and exercise capacity (6MWT) before and after 8-week of RP.,Results: A total of 16 patients completed the study, seven in FB group, five in ONB group and four in the CG.,After the RP, the FB group showed a significant increase in PImax (93.3 ± 19.1 vs.,123.0 ± 15.8 mmHg) and in the 6MWT distance (462.9 ± 71.8 m vs.,529.1 ± 50.1 m) and a decrease in the CAT score (9.7 ± 6.5 vs.,5.9 ± 6.0) and in the mMRC dyspnea score.,FB provides greater improvement in PImax, dyspnea, quality of life and 6MWT than ONB.,Conclusions: The Feelbreathe® device provides greater improvements in quality of life, dyspnea, exercise capacity and inspiratory muscle strength compared to patients that did not use it. | Dynamic hyperinflation has important clinical consequences in patients with chronic obstructive pulmonary disease (COPD).,Given that most of these patients have respiratory and peripheral muscle weakness, dyspnea and functional exercise capacity may improve as a result of inspiratory muscle training (IMT).,The aim of the study was to analyze the effects of IMT on exercise capacity, dyspnea, and inspiratory fraction (IF) during exercise in patients with COPD.,Daily inspiratory muscle strength and endurance training was performed for 8 weeks in 10 patients with COPD GOLD II and III.,Ten patients with COPD II and III served as a control group.,Maximal inspiratory pressure (Pimax) and endurance time during resistive breathing maneuvers (tlim) served as parameter for inspiratory muscle capacity.,Before and after training, the patients performed an incremental symptom limited exercise test to maximum and a constant load test on a cycle ergometer at 75% of the peak work rate obtained in the pretraining incremental test.,ET was defined as the duration of loaded pedaling.,Following IMT, there was a statistically significant increase in inspiratory muscle performance of the Pimax from 7.75 ± 0.47 to 9.15 ± 0.73 kPa (P < 0.01) and of tlim from 348 ± 54 to 467 ± 58 seconds (P < 0.01).,A significant increase in IF, indicating decreased dynamic hyperinflation, was observed during both exercise tests.,Further, the ratio of breathing frequency to minute ventilation (bf/V′E) decreased significantly, indicating an improved breathing pattern.,A significant decrease in perception of dyspnea was also measured.,Peak work rate during the incremental cycle ergometer test remained constant, while ET during the constant load test increased significantly from 597.1 ± 80.8 seconds at baseline to 733.6 ± 74.3 seconds (P < 0.01).,No significant changes during either exercise tests were measured in the control group.,The present study found that in patients with COPD, IMT results in improvement in performance, exercise capacity, sensation of dyspnea, and improvement in the IF prognostic factor. | 1 |
Both the COPD Assessment Test (CAT) and the Clinical COPD Questionnaire (CCQ) were recommended as comprehensive symptom measures by the Global Initiative for Chronic Obstructive Lung disease.,The main objective of this work was to compare the evaluation of symptom severity with the CAT and the CCQ and find a cutoff value of the CCQ for the Chinese clinical population.,Patients diagnosed with stable COPD in the outpatient department who completed the CAT and CCQ were enrolled from November 2015 to December 2016.,Scores of 0-10, 11-20, 21-30, and 31-40 represent low, medium, high, and very high impact level, respectively, by CAT.,Scores of the CCQ can be considered as acceptable (CCQ<1), acceptable for moderate disease (1≤CCQ<2), instable-severe limited (2≤CCQ<3), and very instable-very severe limited (CCQ≥3).,According to the CAT, only 20.4% of patients belonged to the high (21≤CAT≤30) and very high (31≤CAT≤40) impact levels, which were statistically lower than those of the CCQ, which classified over half of the population (51.1%) into the instable-severe limited (2≤CCQ<3) and very instable-very severe limited (CCQ≥3) categories (P<0.001).,The kappa of agreement for the symptom groups by CAT and CCQ (cutoff point 1.5) was 0.495, but only slight agreement (0.144) was found between the CAT and CCQ with the cutoff point of 1.0.,The CAT and the total CCQ had a strong correlation (rho=0.776, P<0.01).,The CCQ 1.0 and 1.5 corresponded to CAT 4.2 and 9.7, respectively.,The CAT 10.0 was equivalent to 1.53 of the CCQ.,In addition, with higher scores of the CAT and CCQ, subjects displayed more impairment in lung function, higher levels on modified Medical Research Council, and higher exacerbation rates in the last year (P<0.001).,Similarly, patients with more exacerbations presented worse scores on the CAT and total CCQ as well as its 3 domains (P<0.001).,Compared with the CAT, the CCQ was more likely to classify the patients into more severe categories, and 1.5 might be a better cutoff point for the CCQ than 1.0.,Both the CAT and the overall CCQ with its 3 domains were able to discriminate between groups of patients that differ in COPD severity. | 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. | 1 |
Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented.,However, knowledge about specific microbiome structures in the human lung associated with CT defined abnormalities is limited.,Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons.,We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002).,Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects.,No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA.,Co-occurrence analysis suggests the presence of networks of co-occurring bacteria.,Four communities of positively correlated bacteria were revealed.,The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype.,Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells.,This might result in a changed interplay with the host immune system. | Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia.,These features are partially attributed to activation of the epidermal growth factor receptor (EGFR).,Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists.,We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation.,114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted.,Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies.,Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression.,Epithelial features were not different between short-term quitters (<3.5 years) and current smokers.,Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs.,14.4%, p = 0.005; 7.9% vs.,13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs.,18.6%, p < 0.001).,Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years).,NCT00158847 | 1 |
Today, many different tools are developed to execute and visualize physiological models that represent the human physiology.,Most of these tools run models written in very specific programming languages which in turn simplify the communication among models.,Nevertheless, not all of these tools are able to run models written in different programming languages.,In addition, interoperability between such models remains an unresolved issue.,In this paper we present a simulation environment that allows, first, the execution of models developed in different programming languages and second the communication of parameters to interconnect these models.,This simulation environment, developed within the Synergy-COPD project, aims at helping and supporting bio-researchers and medical students understand the internal mechanisms of the human body through the use of physiological models.,This tool is composed of a graphical visualization environment, which is a web interface through which the user can interact with the models, and a simulation workflow management system composed of a control module and a data warehouse manager.,The control module monitors the correct functioning of the whole system.,The data warehouse manager is responsible for managing the stored information and supporting its flow among the different modules.,This simulation environment has been validated with the integration of three models: two deterministic, i.e. based on linear and differential equations, and one probabilistic, i.e., based on probability theory.,These models have been selected based on the disease under study in this project, i.e., chronic obstructive pulmonary disease.,It has been proved that the simulation environment presented here allows the user to research and study the internal mechanisms of the human physiology by the use of models via a graphical visualization environment.,A new tool for bio-researchers is ready for deployment in various use cases scenarios. | Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades.,The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems.,We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes.,To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD.,The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span.,Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COPD | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and debilitating diseases in adults worldwide and is associated with a deleterious effect on the quality of life of affected patients.,Although it remains one of the leading causes of global mortality, the prognosis seems to have improved in recent years.,Even so, the number of patients with COPD and multiple comorbidities has risen, hindering their management and highlighting the need for futures changes in the model of care.,Together with standard medical treatment and therapy adherence - essential to optimizing disease control - several nonpharmacological therapies have proven useful in the management of these patients, improving their health-related quality of life (HRQoL) regardless of lung function parameters.,Among these are improved diagnosis and treatment of comorbidities, prevention of COPD exacerbations, and greater attention to physical disability related to hospitalization.,Pulmonary rehabilitation reduces symptoms, optimizes functional status, improves activity and daily function, and restores the highest level of independent physical function in these patients, thereby improving HRQoL even more than pharmacological treatment.,Greater physical activity is significantly correlated with improvement of dyspnea, HRQoL, and mobility, along with a decrease in the loss of lung function.,Nutritional support in malnourished COPD patients improves exercise capacity, while smoking cessation slows disease progression and increases HRQoL.,Other treatments such as psychological and behavioral therapies have proven useful in the treatment of depression and anxiety, both of which are frequent in these patients.,More recently, telehealthcare has been associated with improved quality of life and a reduction in exacerbations in some patients.,A more multidisciplinary approach and individualization of interventions will be essential in the near future. | Pulmonary rehabilitation programs have been shown to increase functional exercise capacity and quality of life in COPD patients.,However, following the completion of pulmonary rehabilitation the benefits begin to decline unless the program is of longer duration or ongoing maintenance exercise is followed.,Therefore, the aim of this study is to determine if supervised, weekly, hospital-based exercise compared to home exercise will maintain the benefits gained from an eight-week pulmonary rehabilitation program in COPD subjects to twelve months.,Following completion of an eight-week pulmonary rehabilitation program, COPD subjects will be recruited and randomised (using concealed allocation in numbered envelopes) into either the maintenance exercise group (supervised, weekly, hospital-based exercise) or the control group (unsupervised home exercise) and followed for twelve months.,Measurements will be taken at baseline (post an eight-week pulmonary rehabilitation program), three, six and twelve months.,The exercise measurements will include two six-minute walk tests, two incremental shuttle walk tests, and two endurance shuttle walk tests.,Oxygen saturation, heart rate and dyspnoea will be monitored during all these tests.,Quality of life will be measured using the St George's Respiratory Questionnaire and the Hospital Anxiety and Depression Scale.,Participants will be excluded if they require supplemental oxygen or have neurological or musculoskeletal co-morbidities that will prevent them from exercising independently.,Pulmonary rehabilitation plays an important part in the management of COPD and the results from this study will help determine if supervised, weekly, hospital-based exercise can successfully maintain functional exercise capacity and quality of life following an eight-week pulmonary rehabilitation program in COPD subjects in Australia. | 1 |
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments.,In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression.,The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology.,The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription.,Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression).,However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling.,Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD.,Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression.,This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD. | Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a serious event that is responsible for the progress of the disease, increases in medical costs and high mortality.,The aim of the present study was to identify AECOPD-specific biomarkers by evaluating the dynamic gene expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD on days 1, 3 and 10 after hospital admission and to compare the derived data with data from healthy controls or patients with stable COPD.,We found that 14 genes were co-differentially upregulated and 2 downregulated greater than 10-fold in patients with COPD or AECOPD compared with the healthy individuals.,Eight co-differentially upregulated genes and six downregulated genes were identified as a panel of AECOPD-specific genes.,Downregulation of TCF7 in PBMCs was found to be associated with the severity of COPD.,Dynamic changes of Aminolevulinate-delta-synthase 2 and carbonic anhydrase I had similar patterns of Digital Evaluation Score System scores and may serve as potential genes of interest during the course of AECOPD.,Thus, our findings indicate a panel of altered gene expression patterns in PBMCs that can be used as AECOPD-specific dynamic biomarkers to monitor the course of AECOPD.,The online version of this article (doi:10.1186/s13054-014-0508-y) contains supplementary material, which is available to authorized users. | 1 |
There is a need to increase and maintain physical activity in patients with chronic obstructive pulmonary disease (COPD).,We assessed 12-month efficacy and effectiveness of the Urban Training intervention on physical activity in COPD patients.,This randomised controlled trial (NCT01897298) allocated 407 COPD patients from primary and hospital settings 1:1 to usual care (n=205) or Urban Training (n=202).,Urban Training consisted of a baseline motivational interview, advice to walk on urban trails designed for COPD patients in outdoor public spaces and other optional components for feedback, motivation, information and support (pedometer, calendar, physical activity brochure, website, phone text messages, walking groups and a phone number).,The primary outcome was 12-month change in steps·day−1 measured by accelerometer.,Efficacy analysis (with per-protocol analysis set, n=233 classified as adherent to the assigned intervention) showed adjusted (95% CI) 12-month difference +957 (184-1731) steps·day−1 between Urban Training and usual care.,Effectiveness analysis (with intention-to-treat analysis set, n=280 patients completing the study at 12 months including unwilling and self-reported non-adherent patients) showed no differences between groups.,Leg muscle pain during walks was more frequently reported in Urban Training than usual care, without differences in any of the other adverse events.,Urban Training, combining behavioural strategies with unsupervised outdoor walking, was efficacious in increasing physical activity after 12 months in COPD patients, with few safety concerns.,However, it was ineffective in the full population including unwilling and self-reported non-adherent patients.,Urban Training in COPD increased physical activity after 12 months but not in self-reported non-adherent patientshttp://ow.ly/dc2C30lnAEs | Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease associated with various systemic comorbidities including osteoporosis.,Osteoporosis and its related fractures are common and have significant impacts on quality of life and even respiratory function in patients with COPD.,COPD-associated osteoporosis is however extremely undertreated.,Recent studies have suggested that both decreased bone mineral density (BMD) and impaired bone quality contribute to bone fragility, causing fractures in COPD patients.,Various clinical risk factors of osteoporosis in COPD patients, including older age, emaciation, physical inactivity, and vitamin D deficiency, have also been described.,It is critically important for pulmonologists to be aware of the high prevalence of osteoporosis in COPD patients and evaluate them for such fracture risks.,Routine screening for osteoporosis will enable physicians to diagnose COPD patients with comorbid osteoporosis at an early stage and give them appropriate treatment to prevent fracture, which may lead to improved quality of life as well as better long-term prognosis. | 1 |
One of the challenges faced by the practising physician is the interpretation of patient-reported outcomes (PROs) in clinical trials and the relevance of such data to their patients.,This is especially true when caring for patients with progressive diseases such as COPD.,In an attempt to incorporate the patient perspective, many clinical trials now include assessments of PROs.,These are formalized methods of capturing patient-centered information.,Given the importance of PROs in evaluating the potential utility of an intervention for a patient with COPD, it is important that physicians are able to critically interpret (and critique) the results derived from them.,Therefore, in this paper, a series of questions is posed for the practising physician to consider when reviewing the treatment effectiveness as assessed by PROs.,The focus is on the St George’s Respiratory Questionnaire for worked examples, but the principles apply equally to other symptom-based questionnaires.,A number of different ways of presenting PRO data are discussed, including the concept of the minimum clinically important difference, whether there is a ceiling effect to PRO results, and the strengths and weaknesses of responder analyses.,Using a worked example, the value of including a placebo arm in a study is illustrated, and the influence of the study on PRO results is considered, in terms of the design, patient withdrawal, and the selection of the study population.,For the practising clinician, the most important consideration is the importance of individualization of treatment (and of treatment goals).,To inform such treatment, clinicians need to critically review PRO data.,The hope is that the questions posed here will help to build a framework for this critical review. | Real-world prescription pathways leading to triple therapy (TT) (inhaled corticosteroid [ICS] plus long-acting β2-agonist bronchodilator [LABA] plus long-acting muscarinic antagonist) differ from Global initiative for chronic Obstructive Lung Disease [GOLD] and National Institute for Health and Care Excellence treatment recommendations.,This study sets out to identify COPD patients without asthma receiving TT, and determine the pathways taken from diagnosis to the first prescription of TT.,This was a historical analysis of COPD patients without asthma from the Optimum Patient Care Research Database (387 primary-care practices across the UK) from 2002 to 2010.,Patient disease severity was classified using GOLD 2013 criteria.,Data were analyzed to determine prescribing of TT before, at, and after COPD diagnosis; the average time taken to receive TT; and the impact of lung function grade, modified Medical Research Council dyspnea score, and exacerbation history on the pathway to TT.,During the study period, 32% of patients received TT.,Of these, 19%, 28%, 37%, and 46% of patients classified as GOLD A, B, C, and D, respectively, progressed to TT after diagnosis (P<0.001).,Of all patients prescribed TT, 25% were prescribed TT within 1 year of diagnosis, irrespective of GOLD classification (P=0.065).,The most common prescription pathway to TT was LABA plus ICS.,It was observed that exacerbation history did influence the pathway of LABA plus ICS to TT.,Real life UK prescription data demonstrates the inappropriate prescribing of TT and confirms that starting patients on ICS plus LABA results in the inevitable drift to overuse of TT.,This study highlights the need for dissemination and implementation of COPD guidelines to physicians, ensuring that patients receive the recommended therapy. | 1 |
Complete blood count parameters provide novel inflammatory markers, namely neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR).,We aimed to assess any differences in these novel inflammatory markers according to exacerbation severity in patients with COPD in both eosinophilic and neutrophilic endotypes.,This retrospective cross-sectional study was conducted at a tertiary education hospital.,Previously diagnosed COPD patients admitted to the hospital with acute COPD exacerbation (AECOPD) were enrolled into the study.,Patients were grouped according to COPD endotype, eosinophilic (peripheral blood eosinophil rate ≥2%) and neutrophilic (peripheral blood eosinophil rate <2%), and further subdivided according to place of admission (outpatient clinic, ward, or intensive care unit [ICU]) as an indicator of disease severity.,Complete blood count, biochemistry, C-reactive protein (CRP), NLR, PLR, and platelet to mean platelet volume values were recorded from an electronic hospital database system and compared among all groups.,Of the 10,592 patients included in the study, 7,864 were admitted as outpatients, 2,233 to the wards, and 495 to ICU.,Neutrophilic COPD patients (n=6,536, 62%) had increased inflammatory markers compared with eosinophilic COPD patients (n=4,056, 38%); median NLR was 5.11 vs 2.62 (P<0.001), PLR was 175.66 vs 130.00 (P<0.001), and CRP was 11.6 vs 7.7 (P<0.001).,All values increased relative to admission to the outpatient clinic, ward, or ICU: median NLR was 3.20, 6.33, and 5.94, respectively, median PLR was 140.43, 208.46, and 207.39, respectively, and median CRP was 6.4, 15.0, and 22.8, respectively.,The median NLR values of patients in outpatients/ward/ICU increased in neutrophilic and eosinophilic endotypes: 4.21/7.57/8.60 (P<0.001) and 2.50/3.43/3.42 (P=0.81), respectively.,CRP showed a similar increased pattern according to severity of AECOPD endotypes.,In COPD exacerbation, the inflammatory markers show different increases in each COPD endotypes.,These findings may be crucial for defining exacerbation endotypes, the severity of exacerbation, and treatment response during follow-up in COPD patients. | A higher risk of atherothrombotic cardiovascular events, which are platelet-driven processes, has been described during acute exacerbations of chronic obstructive pulmonary disease (AECOPD).,However, the relevance of platelet reactivity during AECOPD and whether this is affected by antiplatelet agents are not fully elucidated to date.,This study aimed to evaluate whether platelet reactivity is augmented during an exacerbation in COPD patients with and without antiplatelet therapy and its association with systemic inflammatory parameters.,Prospective, observational, ex vivo investigation was conducted in consecutive patients suffering an exacerbation of COPD.,Platelet reactivity was assessed during AECOPD and at stable state.,Platelet function assays included: 1) vasodilator-stimulated phosphoprotein assay expressed as P2Y12 reactivity index (PRI), 2) multiple electrode aggregometry and 3) optical aggregometry.,Systemic inflammatory parameters such as leukocyte count, interleukin-6 and fibrinogen were also assessed.,Higher platelet reactivity was observed during AECOPD compared to stability measured by vasodilator-stimulated phosphoprotein (PRI: 75.2%±1.9% vs 68.8%±2.4%, p=0.001).,This augmented platelet aggregability was also observed in the subset of patients on antiplatelet therapy (PRI: 72.8%±3.1% vs 61.7%±7.5%, p=0.071).,Consistent findings were observed with all other platelet function tests.,Patients with greater enhancement of inflammatory markers during AECOPD were more likely to present a higher increase in platelet reactivity.,Platelet reactivity is increased during AECOPD, which may contribute to the augmented cardiovascular risk of these patients.,Additionally, the increase in platelet reactivity might be associated with an increment in inflammatory markers during exacerbations. | 1 |
It has been shown that home mechanical ventilation improves quality of life, but it has not been widely studied which particular patient groups benefit the most from starting this type of therapy.,The purpose of this prospective observational study was to evaluate quality of life change patterns 6 months after initiation of home mechanical ventilation in patients suffering from chronic respiratory failure using patient reported outcomes.,We enrolled 74 chronic respiratory failure patients starting invasive or noninvasive home mechanical ventilation through the Semmelweis University Home Mechanical Ventilation Program.,Quality of life was evaluated at baseline and at 6 months after initiation of home mechanical ventilation using the Severe Respiratory Insufficiency Questionnaire.,Overall quality of life showed 10.5% improvement 6 months after initiation of home mechanical ventilation (p < 0.001).,The greatest improvement was observed in Respiratory complaint (20.4%, p = 0.015), Sleep and attendant symptoms (19.3%, p < 0.001), and Anxiety related subscales (14.4%, p < 0.001).,Interface (invasive versus noninvasive ventilation) was not associated with improvement in quality of life (p = 0.660).,Severely impaired patients showed the greatest improvement (CC = -0.328, p < 0.001).,Initial diagnosis contributed to the observed change (p = 0.025), with chronic obstructive pulmonary disease and obesity hypoventilation syndrome patients showing the greatest improvement, while amyotrophic lateral sclerosis patients showed no improvement in quality of life.,We found that patients who were started on long term ventilation in an acute setting, required oxygen supplementation and had low baseline quality of life, showed the most improvement during the six-month study period.,Our study highlights the profound effect of home mechanical ventilation on quality of life in chronic respiratory failure patients that is indifferent of ventilation interface but is dependent on initial diagnosis and some baseline characteristics, like acute initiation, oxygen supplementation need and baseline quality of life.,This study was approved by and registered at the ethics committee of Semmelweis University (SE TUKEB 251/2017; 20th of December, 2017). | The Severe Respiratory Insufficiency (SRI) questionnaire is a specific measure of health-related quality of life (HRQoL) in patients treated with long-term mechanical ventilation (LTMV).,The aim of the present study was to examine whether SRI sum scores and related subscales are associated with mortality in LTMV patients.,The study included 112 LTMV patients (non-invasive and invasive) from the Norwegian LTMV registry in Western Norway from 2008 with follow-up in August 2014.,SRI data were obtained through a postal questionnaire, whereas mortality data were obtained from the Norwegian Cause of Death Registry.,The SRI questionnaire contains 49 items and seven subscales added into a summary score (range 0-100) with higher scores indicating a better HRQoL.,The association between the SRI score and mortality was estimated as hazard ratios (HRs) with 95% confidence intervals (95% CI) using Cox regression models and HRs were estimated per one unit change in the SRI score.,Of the 112 participating patients in 2008, 52 (46%) had died by August 2014.,The mortality rate was the highest in patients with chronic obstructive pulmonary disease (75%), followed by patients with neuromuscular disease (46%), obesity hypoventilation syndrome (31%) and chest wall disease (25%) (p < 0.001).,Higher SRI sum scores in 2008 were associated with a lower mortality risk after adjustment for age, education, hours a day on LTMV, time since initiation of LTMV, disease category and comorbidity (HR 0.98, 95% CI: 0.96-0.99).,In addition, SRI-Physical Functioning (HR 0.98, 95% CI: 0.96-0.99), SRI-Psychological Well-Being (HR 0.98, 95% CI: 0.97-0.99), and SRI-Social Functioning (HR 0.98, 95% CI: 0.97-0.99) remained significant risk factors for mortality after covariate adjustment.,In the subgroup analyses of patient with neuromuscular diseases we found significant inverse associations between some of the SRI subscales and mortality.,SRI score is associated with mortality in LTMV-treated patients.,We propose the use of SRI in the daily clinic with repeated measurements as part of individual follow-up.,Randomized clinical trials with interventions aimed to improve HRQoL in LTMV patients should consider the SRI questionnaire as the standard HRQoL measurement.,The online version of this article (10.1186/s12890-018-0768-4) contains supplementary material, which is available to authorized users. | 1 |
In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations.,We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥1 exacerbation in the 12 months prior to the study.,Patients received BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice-daily.,Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study.,Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study.,BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups.,The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI.,In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results.,The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count.,In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations. | Reducing the need for hospitalisation in patients with chronic obstructive pulmonary disease (COPD) is an important goal in COPD management.,The aim of this study was to evaluate re-hospitalisation, treatment, comorbidities and mortality in patients with COPD who were hospitalised for the first time due to a COPD exacerbation.,This was a retrospective, population-based observational cohort study of Swedish patients using linked data from three mandatory national health registries to assess re-hospitalisation rates, medication use and mortality.,Rate of hospitalisation was calculated using the number of events divided by the number of person-years at risk; risk of all-cause and COPD-related mortality were assessed using Cox proportional hazard models.,In total, 51,247 patients were identified over 10 years; 35% of patients were not using inhaled corticosteroid, long-acting muscarinic antagonist or long-acting β2-agonist treatment prior to hospitalisation, 38% of whom continued without treatment after being discharged.,Re-hospitalisation due to a second severe exacerbation occurred in 11.5%, 17.8% and 24% of the patients within 30, 90 and 365 days, respectively.,Furthermore, 24% died during the first year following hospitalisation and risk of all-cause and COPD-related mortality increased with every subsequent re-hospitalisation.,Comorbidities, including ischaemic heart disease, heart failure and pneumonia, were more common amongst patients who were re-hospitalised than those who were not.,Following hospitalisation for first severe COPD exacerbation, many patients did not collect the treatment recommended by current guidelines.,Risk of mortality increased with every subsequent re-hospitalisation.,Patients with concurrent comorbidities had an increased risk of being re-hospitalised.,Point your SmartPhone at the code above.,If you have a QR code reader the video abstract will appear.,Or use:,https://youtu.be/11uPtnnXGTQ | 1 |
The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo.,In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods.,Primary end points were peak plasma concentration (Cmax,ss), and area under the plasma concentration-time profile (AUC0-6h,ss), both at steady state.,The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity).,Safety was evaluated as adverse events and by electrocardiogram/Holter.,Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices.,The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss, indicating that bioequivalence was not established.,Dose ordering for bronchodilation was observed.,Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation.,All treatments were well tolerated with no apparent relation to dose or device.,Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD. | Tiotropium bromide is an effective therapy for COPD patients.,Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.,The TIOSPIR® trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed).,The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation.,A spirometry substudy evaluates the bronchodilator efficacy.,The trial is a randomized, double-blind, double dummy, event-driven, parallel group study.,Participants can use any background treatment for COPD except inhaled anticholinergic agents.,The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included.,Clinical sites are international and include both primary care as well as specialists.,To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years.,TIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort. | 1 |
Early identification of preventable risk factors of COPD progression is important.,Whether exacerbations have a negative impact on disease progression is largely unknown.,We investigated whether the long-term occurrence of exacerbations is associated with lung function decline at early stages of COPD.,Patients diagnosed with mild/moderate COPD (obstruction and FEV1% predicted 50-90%), aged ≥35 years, and a smoking history, who had ≥6 years of UK electronic medical records after initiation of maintenance therapy were studied.,Multilevel mixed-effect linear regression was performed to determine the association between the count of any year in which the patient had ≥1 exacerbation over a 6-year period and FEV1 decline, adjusted for sex, age, anthropometrics and smoking habits.,Exacerbations were defined as any prescription for an acute oral corticosteroid course and/or lower respiratory-related antibiotics and/or any COPD-related emergency or inpatient hospitalization.,Of 11,337 patients included (mean age 65 years; 49% female) 31.6%, 23.3%, 16.6%, 11.6%, 8.1%, 5.3% and 3.4% had 0, 1, 2, 3, 4, 5 and 6 years with ≥1 exacerbation.,The mean annual FEV1 decline accelerated by 1.50 mL/year (95% Confidence Interval 1.02; 1.98) with every additional year with ≥1 exacerbation from 31.0 mL/year in subjects without any exacerbation to 40.0 mL/year in patients experiencing ≥1 exacerbation every year.,Patients with more years with ≥1 exacerbation had a lower mean FEV1 at first diagnosis: 14.7 mL (11.7; 17.8) lower with every additional year with exacerbations.,When counting years with ≥2 exacerbations, greater effects were observed (2.19 [1.50; 2.88] mL/year excess decline per year with ≥2 exacerbations; 16.5 mL [12.1; 20.8] lower FEV1 at diagnosis).,Patients who experienced a greater exacerbation burden after initiation of maintenance therapy had worse lung function at diagnosis and a more rapid lung function decline thereafter, which emphasizes the need for better treatment strategies. | 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 |
GOLD guidelines classify COPD patients into A-D groups based on health status as assessed by COPD Assessment Test (CAT) or mMRC tools and exacerbations and recommend single or dual long-acting bronchodilators as maintenance therapy, with additional inhaled corticosteroids (ICS) if the disease remains uncontrolled.,We aimed to classify primary care COPD patients into A-D groups, assess usual treatment and adherence to guidelines, potential mismatches between CAT-and mMRC-based classification and described symptoms within groups.,A total of 257 primary care COPD patients were enrolled between 2015 and 2016 in Greece.,Physicians used structured interviews to collect cross-sectional data including demographics, symptoms, CAT, mMRC scores, and medications.,Patients were classified into A-D groups based on CAT and mMRC, and prevalence of symptoms and medication was estimated within A-D groups.,Interviews with physicians were also performed to explore additional issues about treatment and adherence to guidelines.,Mean (SD) age was 65 (12.3) years with 79% males.,The majority of patients reported uncontrolled symptoms (91% and 61% with ≥10 CAT or ≥2 mMRC scores, respectively).,Thirty-seven percentage had $2 exacerbations in the past year.,Group B was the largest followed by Groups D, A, and C.,Patients were classified as more severe by CAT than by mMRC.,In all groups, the majority were treated with combined long-acting beta agonist/ICS (> 50%).,When patients were asked to report their main symptoms, dyspnea and cough were the most important symptoms mentioned, and there was a great variation between the A-D groups.,However, Groups A-C reported mainly morning symptoms, whereas Group D suffered symptoms all day.,Physicians reported a significant number of barriers to implementing guidelines, eg, frequent lack of guideline updates, access to diagnostic procedures, and prescription-reimbursement issues.,Our study confirms poor adherence to guidelines regarding treatment with an overuse of ICS and important barriers to implementation.,A mismatch in classification occurs depending on the tool used, which can mislead clinicians in their choice of treatment. | Combined inhaled long-acting beta-agonists and corticosteroids (LABA+ICS) are costly.,They are recommended in severe or very severe chronic obstructive pulmonary disease (COPD).,They should not be prescribed in mild or moderate disease.,In COPD ICS are associated with side-effects including risk of pneumonia.,We quantified appropriateness of prescribing and examined the risks and costs associated with overuse.,Data were extracted from the electronic and paper records of 41 London general practices (population 310,775) including spirometry, medications and exacerbations.,We classified severity, assessed appropriateness of prescribing using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for 2009, and performed a sensitivity analysis using the broader recommendations of the 2011 revision.,3537 patients had a diagnosis of COPD.,Spirometry was recorded for 2458(69%). 709(29%) did not meet GOLD criteria. 1749(49%) with confirmed COPD were analysed: 8.6% under-treated, 38% over-treated.,Over-prescription of ICS in GOLD stage I or II (n=403, 38%) and in GOLD III or IV without exacerbations (n=231, 33.6%) was common.,An estimated 12 cases (95%CI 7-19) annually of serious pneumonia were likely among 897 inappropriately treated. 535 cases of overtreatment involved LABA+ICS with a mean per patient cost of £553.56/year (€650.03).,Using the broader indications for ICS in the 2011 revised GOLD guideline 25% were still classified as over-treated.,The estimated risk of 15 cases of pneumonia (95%CI 8-22) in 1074 patients currently receiving ICS would rise by 20% to 18 (95%CI 9.8-26.7) in 1305 patients prescribed ICS if all with GOLD grade 3 and 4 received LABA+ICS.,Over-prescription of ICS in confirmed COPD was widespread with considerable potential for harm.,In COPD where treatment is often escalated in the hope of easing the burden of disease clinicians should consider both the risks and benefits of treatment and the costs where the benefits are unproven. | 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. | This study is an analysis of a pilot COPD clinical audit that evaluated adherence to guidelines for patients with COPD in a stable disease phase during a routine visit in specialized secondary care outpatient clinics in order to identify the variables associated with the decision to step-up or step-down pharmacological treatment.,This study was a pilot clinical audit performed at hospital outpatient respiratory clinics in the region of Andalusia, Spain (eight provinces with over eight million inhabitants), in which 20% of centers in the area (catchment population 3,143,086 inhabitants) were invited to participate.,Treatment changes were evaluated in terms of the number of prescribed medications and were classified as step-up, step-down, or no change.,Three backward stepwise binominal multivariate logistic regression analyses were conducted to evaluate variables associated with stepping up, stepping down, and inhaled corticosteroids discontinuation.,The present analysis evaluated 565 clinical records (91%) of the complete audit.,Of those records, 366 (64.8%) cases saw no change in pharmacological treatment, while 99 patients (17.5%) had an increase in the number of drugs, 55 (9.7%) had a decrease in the number of drugs, and 45 (8.0%) noted a change to other medication for a similar therapeutic scheme.,Exacerbations were the main factor in stepping up treatment, as were the symptoms themselves.,In contrast, rather than symptoms, doctors used forced expiratory volume in 1 second and previous treatment with long-term antibiotics or inhaled corticosteroids as the key determinants to stepping down treatment.,The majority of doctors did not change the prescription.,When changes were made, a number of related factors were noted.,Future trials must evaluate whether these therapeutic changes impact clinically relevant outcomes at follow-up. | 1 |
The COPD Assessment Test (CAT) contains eight items (cough, phlegm, chest tightness, breathlessness, limited activities, confidence leaving home, sleeplessness and energy).,The current study aimed 1) to better understand the impact of the respiratory and non-respiratory CAT item scores on the CAT total score; and 2) to determine the impact of pulmonary rehabilitation (PR) on CAT items and CAT total score.,CAT total score of ≥10 or ≥ 18 points was used to classify patients as highly symptomatic, a decrease of 2 points was considered as clinically relevant improvement.,‘Cough’, ‘phlegm’, ‘chest tightness’, ‘breathlessness’ were defined as respiratory items; ≥3 points on each item was defined as highly symptomatic.,In total, 497 clinically stable patients (55% male, age 64.0 (57.5-71.0) years, FEV1 46.0 (32.0-63.0)% predicted, CAT total score 22.0 (17.5-26.0) points) were included. 95% had CAT score ≥ 10 points and 75% ≥18 points.,Respectively, 45% and 54% of subjects scored high on 3 or 4 of the respiratory CAT items.,Following PR, 220 patients (57.7%) reported an improved health status as assessed by CAT total score (− 3.0 (− 7.0-1.0) points).,Change in CAT item scores ranged from 0.0 (− 1.0-0.0) to − 1.0 (− 2.0-0.0) points) with best improvements in ‘energy’ (− 1.0 (− 2.0-0.0)points).,A substantial number of patients classified as highly symptomatic did not report a high level of respiratory symptoms, indicating that non-respiratory symptoms impact on disease classification and treatment algorithm.,The impact of PR on CAT item scores varied by individual item.,Netherlands National Trial Register (NTR3416).,Registered 2 May 2012.,The online version of this article (10.1186/s12955-018-1034-4) contains supplementary material, which is available to authorized users. | To determine the prevalence, change in breathlessness status over time, and risk factors for disabling and persistent disabling breathlessness in relation to treatments in chronic obstructive pulmonary disease (COPD).,Longitudinal analysis of data from the Swedish National Register of COPD with breathlessness measured using modified Medical Research Council (mMRC) scores at two subsequent visits.,Prevalence of disabling breathlessness (mMRC ≥2 at baseline) and persistent disabling breathlessness (disabling breathlessness at baseline and follow-up) was investigated in relation to COPD treatment.,Risk factors for disabling breathlessness, change from non-disabling to disabling breathlessness, and persistent disabling breathlessness were analyzed using multiple logistic regression.,A total of 1,689 patients were included in the study with a median follow-up of 12 months (interquartile range: 4 months).,Prevalence of disabling breathlessness was 54% at baseline.,Persistent disabling breathlessness was present in 43% of patients despite treatment and in 74% of patients despite combined inhaled triple therapy and physiotherapy.,Risk factors for disabling breathlessness or change to disabling breathlessness were higher age, lower lung function, frequent exacerbations, obesity, heart failure, depression, and hypoxic respiratory failure (all P<0.05).,Persistent disabling breathlessness was associated with lower lung function and ischemic heart disease (all P<0.05).,Disabling breathlessness is common in COPD despite treatment, which calls for improved symptomatic treatments and consideration of factors influencing disabling breathlessness.,Factors influencing disabling breathlessness should be considered for COPD management. | 1 |
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US and a major worldwide healthcare problem.,The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood.,While tobacco smoking is the primary risk factor, other disease processes also appear to play a role.,Components of the innate immune system (eg, macrophages and neutrophils) have long been believed to be important in the development of COPD.,More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease.,Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses.,We will further explore the prospective contributions of T-cell derived mediators that could contribute to the inflammation, alveolar wall destruction, and small airway fibrosis of advanced COPD.,A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies. | Systemic effects of chronic obstructive pulmonary disease (COPD) significantly contribute to severity and mortality of the disease.,We aimed to develop a COPD/emphysema model exhibiting systemic manifestations of the disease.,Female NMRI mice were treated 5 times intratracheally with porcine pancreatic elastase (emphysema) or phosphate-buffered saline (control).,Emphysema severity was quantified histologically by mean linear intercept, exercise tolerance by treadmill running distance, diaphragm dysfunction using isolated muscle strips, pulmonary hypertension by measuring right ventricular pressure, and neurohumoral activation by determining urinary norepinephrine concentration.,Mean linear intercept was higher in emphysema (260.7 ± 26.8 μm) than in control lungs (24.7 ± 1.7 μm).,Emphysema mice lost body weight, controls gained weight.,Running distance was shorter in emphysema than in controls.,Diaphragm muscle length was shorter in controls compared to emphysema.,Fatigue tests of muscle strips revealed impaired relaxation in emphysema diaphragms.,Maximum right ventricular pressure and norepinephrine were elevated in emphysema compared to controls.,Linear correlations were observed between running distance changes and intercept, right ventricular weight, norepinephrine, and diaphragm length.,The elastase mouse model exhibited severe emphysema with consecutive exercise limitation, and neurohumoral activation.,The model may deepen our understanding of systemic aspects of COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by 2020.,Recently, variants in the hypoxia-inducible factor 1α (HIF1A), cholinergic receptor, neuronal nicotinic, alpha polypeptide-5, and iron-responsive element-binding protein 2 gene (IREB2) genes were found to be associated with COPD.,This study aims to identify whether the variations in these genes are related to COPD in the Hainan population of the People’s Republic of China.,We genotyped 12 single nucleotide polymorphisms in a case-control study with 200 COPD cases and 401 controls from Hainan, People’s Republic of China.,Odds ratios and 95% confidence intervals were estimated using the chi-squared (χ2) test, genetic model analysis, haplotype analysis, and stratification analysis.,In the genetic model analysis, we found that the genotype T/T of rs13180 of IREB2 decreased the COPD risk by 0.52-fold (P=0.025).,But in the further stratification analysis, we failed to find the association between the selected single nucleotide polymorphisms with COPD risk in Han population.,In addition, the haplotype analysis of HIF1A gene also was not found to be the possible haplotype associated with COPD risk.,Our results support that IREB2 rs13180 is associated with COPD in Hainan population.,And this is the first time the HIF1A polymorphisms in COPD in a Chinese population has been reported, although we failed to find any significant result. | One hundred million deaths were caused by tobacco in the 20th century, and it is estimated that there will be up to one billion deaths attributed to tobacco use in the 21st century.,Chronic obstructive pulmonary disease (COPD) is rapidly becoming a global public health crisis with smoking being recognized as its most important causative factor.,The most effective available treatment for COPD is smoking cessation.,There is mounting evidence that the rate of progression of COPD can be reduced when patients at risk of developing the disease stop smoking, while lifelong smokers have a 50% probability of developing COPD during their lifetime.,More significantly, there is also evidence that the risk of developing COPD falls by about half with smoking cessation.,Several pharmacological interventions now exist to aid smokers in cessation; these include nicotine replacement therapy, bupropion, and varenicline.,All pharmacotherapies for smoking cessation are more efficacious than placebo, with odds ratios of about 2.,Pharmacologic therapy should be combined with nonpharmacologic (behavioral) therapy.,Unfortunately, despite the documented efficacy of these agents, the absolute number of patients who are abstinent from smoking at 12 months of follow-up is low. | 1 |
Worldwide, chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic lung disease with considerable clinical and socioeconomic impact.,Pharmacologic maintenance drugs (such as bronchodilators and inhaled corticosteroids) play an important role in the treatment of COPD.,The cost effectiveness of these treatments has been frequently assessed, but studies to date have largely neglected the impact of treatment sequence and the exact stage of disease in which the drugs are used in real life.,We aimed to systematically review recently published articles that reported the cost effectiveness of COPD maintenance treatments, with a focus on key findings, quality and methodological issues.,We performed a systematic literature search in Embase, PubMed, the UK NHS Economic Evaluation Database (NHS-EED) and EURONHEED (European Network of Health Economics Evaluation Databases) and included all relevant articles published between 2011 and 2015 in either Dutch, English or German.,Main study characteristics, methods and outcomes were extracted and critically assessed.,The Quality of Health Economic Studies (QHES) instrument was used as basis for quality assessment, but additional items were also addressed.,The search identified 18 recent pharmacoeconomic analyses of COPD maintenance treatments.,Papers reported the cost effectiveness of long-acting muscarinic antagonist (LAMA) monotherapy (n = 6), phosphodiesterase (PDE)-4 inhibitors (n = 4), long-acting beta agonist/inhaled corticosteroid (LABA/ICS) combinations (n = 4), LABA monotherapy (n = 2) and LABA/LAMA combinations (n = 2).,All but two studies were funded by the manufacturer, and all studies indicated favourable cost effectiveness; however, the number of quality-adjusted life-years (QALYs) gained was small.,Less than half of the studies reported a COPD-specific outcome in addition to a generic outcome (mostly QALYs).,Exacerbation and mortality rates were found to be the main drivers of cost effectiveness.,According to the QHES, the quality of the studies was generally sufficient, but additional assessment revealed that most studies poorly represented the cost effectiveness of real-life medication use.,The majority of studies showed that pharmacologic COPD maintenance treatment is cost effective, but most studies poorly reflected real-life drug use.,Consistent and COPD-specific methodology is recommended.,The online version of this article (doi:10.1007/s40273-016-0448-2) contains supplementary material, which is available to authorized users. | The economic burden of chronic obstructive pulmonary disease (COPD) exacerbations is significant, but the impact of other sources on the overall cost of COPD management is largely unknown.,We aimed to estimate overall costs for patients experiencing none, one, or two or more exacerbations per year in the UK.,A retrospective cohort of prevalent COPD patients was identified in the Clinical Practice Research Datalink UK database.,Patients with information recorded for at least 12 months before and after cohort entry date were included (first prevalent COPD diagnosis confirmed by spirometry on/after April 1, 2009).,Patients were categorized as having none, one, or two or more moderate-to-severe COPD exacerbations in the 12 months after cohort entry and further classified by the Global initiative for chronic Obstructive Lung Disease (GOLD) category of airflow obstruction and the Medical Research Council dyspnea scale.,Study outcomes included counts of general practitioner interactions, moderate-severe COPD exacerbations, and non-COPD hospitalizations.,Estimated resource use costs were calculated using National Health Service reference costs for 2010-2011.,The cohort comprised 58,589 patients (mean age 69.5 years, mean dyspnea grade 2.5, females 46.6%, current smokers 33.1%).,The average total annual per patient cost of COPD management, excluding medications, was £2,108 for all patients and £1,523, £2,405, and £3,396 for patients experiencing no, one, or two or more moderate-to-severe exacerbations, respectively.,General practitioner interactions contributed most to these annual costs, accounting for £1,062 (69.7%), £1,313 (54.6%), and £1,592 (46.9%) in patients with no, one, or two or more moderate-to-severe exacerbations, respectively.,Disease management strategies focused on reducing costs in primary care may help reduce total COPD costs significantly. | 1 |
Smoking is the leading cause of COPD.,Exploring molecular markers and understanding the pathogenic mechanisms of smoking-related COPD are helpful for early clinical diagnosis and treatment of the disease.,This study aims to identify specific circulating microRNAs (miRNAs) from the blood of COPD patients with a long history of smoking.,Blood samples from four different groups were collected, and miRNA microarray was performed.,Differential expression of miRNAs was verified by quantitative polymerase chain reaction.,In vitro, THP-1 cells were cultured and stimulated with cigarette smoke extract (CSE) or transfected with miR-149-3p inhibitor/mimics.,Protein levels of Toll-like receptor 4 (TLR-4) and nuclear factor κB (NF-κB) were detected using Western blot and immunofluorescence.,Interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels were determined by an enzyme-linked immunosorbent assay.,miRNA profiling revealed that the expression of 56 miRNAs was changed between the four groups.,Expression of miR-149-3p in group C (non-smoker non-COPD) was higher than in group S (smoker non-COPD), S-COPD (smoker with stable COPD) and AE-COPD (smoker with acute exacerbation COPD).,CSE stimulation down-regulated the expression of miR-149-3p and up-regulated the TLR-4 and NF-κB levels in THP-1 cells.,Transfecting miR-149-3p inhibitors in THP-1 cells also increased the expression of its target genes.,Furthermore, overexpression of miR-149-3p inhibited the TLR-4/NF-κB signaling pathways and reduced the secretion of IL-1β and TNF-α.,This study found that smoking can induce differential expression of circulating miR-NAs, such as down-regulation of miR-149-3p.,Reducing miR-149-3p may increase the inflammatory response in COPD patients through the regulation of the TLR-4/NF-κB signaling pathway. | Exposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases.,However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood.,Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes.,There are few data on regional methylation changes in relation to smoking.,Few data link differential methylation in blood to differential gene expression in lung tissue.,We identified 108 significant (false discovery rate (FDR) < 0.05) differentially methylated probes (DMPs) and 87 significant differentially methylated regions (DMRs) (multiple-testing corrected p < 0.01) in current compared to never smokers from our EWAS of cotinine-validated smoking in blood DNA from a Korean chronic obstructive pulmonary disease cohort (n = 100 including 31 current, 30 former, and 39 never smokers) using Illumina HumanMethylation450 BeadChip.,Of the 108 DMPs (FDR < 0.05), nine CpGs were statistically significant based on Bonferroni correction and 93 were novel including five that mapped to loci previously associated with smoking.,Of the 87 DMRs, 66 were mapped to novel loci.,Methylation correlated with urine cotinine levels in current smokers at six DMPs, with pack-years in current smokers at six DMPs, and with duration of smoking cessation in former smokers at eight DMPs.,Of the 143 genes to which our significant DMPs or DMRs annotated, gene expression levels at 20 genes were associated with pack-years in lung tissue transcriptome data of smokers (Asan Biobank, n = 188).,Our study of differential methylation in Koreans confirmed previous findings from non-Asian populations and revealed novel loci in relation to smoking.,Smoking-related differential methylation in blood is associated with gene expression in lung tissue, an important target of adverse health effects of smoking, supporting the potential functional importance of methylation in smoking-related disease.,The online version of this article (doi:10.1186/s13148-016-0266-6) contains supplementary material, which is available to authorized users. | 1 |
To determine the prevalence, change in breathlessness status over time, and risk factors for disabling and persistent disabling breathlessness in relation to treatments in chronic obstructive pulmonary disease (COPD).,Longitudinal analysis of data from the Swedish National Register of COPD with breathlessness measured using modified Medical Research Council (mMRC) scores at two subsequent visits.,Prevalence of disabling breathlessness (mMRC ≥2 at baseline) and persistent disabling breathlessness (disabling breathlessness at baseline and follow-up) was investigated in relation to COPD treatment.,Risk factors for disabling breathlessness, change from non-disabling to disabling breathlessness, and persistent disabling breathlessness were analyzed using multiple logistic regression.,A total of 1,689 patients were included in the study with a median follow-up of 12 months (interquartile range: 4 months).,Prevalence of disabling breathlessness was 54% at baseline.,Persistent disabling breathlessness was present in 43% of patients despite treatment and in 74% of patients despite combined inhaled triple therapy and physiotherapy.,Risk factors for disabling breathlessness or change to disabling breathlessness were higher age, lower lung function, frequent exacerbations, obesity, heart failure, depression, and hypoxic respiratory failure (all P<0.05).,Persistent disabling breathlessness was associated with lower lung function and ischemic heart disease (all P<0.05).,Disabling breathlessness is common in COPD despite treatment, which calls for improved symptomatic treatments and consideration of factors influencing disabling breathlessness.,Factors influencing disabling breathlessness should be considered for COPD management. | Breathlessness is a primary clinical feature of chronic obstructive pulmonary disease (COPD).,We aimed to describe the frequency of and factors associated with breathlessness in a cohort of COPD patients identified from the Clinical Practice Research Datalink (CPRD), a general practice electronic medical records database.,Patients with a record of COPD diagnosis after January 1 2008 were identified in the CPRD.,Breathlessness was assessed using the Medical Research Council (MRC) dyspnoea scale, with scoring ranging from 1-5, which has been routinely administered as a part of the regular assessment of patients with COPD in the general practice since April 2009.,Stepwise multivariate logistic regression estimated independent associations with dyspnoea.,Negative binomial regression evaluated a relationship between breathlessness and exacerbation rate during follow-up.,The total cohort comprised 49,438 patients diagnosed with COPD; 40,425 (82%) had any MRC dyspnoea grade recorded.,Of those, 22,770 (46%) had moderate-to-severe dyspnoea (MRC≥3).,Breathlessness increased with increasing airflow limitation; however, moderate-to-severe dyspnoea was also observed in 32% of patients with mild airflow obstruction.,Other factors associated with increased dyspnoea grade included female gender, older age (≥70 years), obesity (BMI ≥30), history of moderate-to-severe COPD exacerbations, and frequent visits to the general practitioner.,Patients with worse breathlessness were at higher risk of COPD exacerbations during follow-up.,Moderate-to-severe dyspnoea was reported by >40% of patients diagnosed with COPD in primary care.,Presence of dyspnoea, including even a perception of mild dyspnoea (MRC = 2), was associated with increased disease severity and a higher risk of COPD exacerbations during follow-up. | 1 |
The current mainstay of therapy for chronic obstructive pulmonary disease (COPD) is long-acting bronchodilators.,To date, the effect of indacaterol, a β2-agonist, on activities of daily living in COPD patients is not well understood.,The aim of this study was to evaluate the efficacy of indacaterol with regard to activities of daily living in patients with COPD.,In this nonrandomized open-label study, 23 patients with COPD were instructed to carry an accelerometer for 4 weeks without indacaterol therapy and then for another period of 4 weeks while receiving indacaterol therapy.,The number of steps, duration of moderate or greater physical activity, and energy expenditure were significantly increased after treatment with indacaterol compared with baseline data in all patients with COPD; the metabolic equivalent of task was also significantly enhanced after treatment with indacaterol.,This study provides early evidence that indacaterol improves daily physical activity in patients with COPD. | Long-acting bronchodilators have been shown to improve multiple clinical outcomes in chronic obstructive pulmonary disease (COPD) including lung function, symptoms, dyspnea, quality of life, and exacerbations.,Indacaterol is a novel, inhaled, long-acting β2-agonist providing 24-hour bronchodilation with once-daily dosing.,It is currently approved for the maintenance treatment of COPD to be administered as 150 or 300 μg once-daily doses as licensed in many countries and 75 μg as licensed in the US by means of a single-dose dry powder inhaler.,The data from clinical development support a favorable safety and tolerability profile within the β2-agonist drug class, with no relevant issues identified.,Current evidence indicates that indacaterol is suitable for use as first-line monotherapy in COPD patients with moderate disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) and beyond that do not require an inhaled corticosteroid (ICS) as per GOLD guidelines, or in combination with an ICS in severe or very severe patients with repeated exacerbations.,Data from trials with the novel once-daily β2-agonist, indacaterol, indicate superior bronchodilation and clinical efficacy over twice-daily long-acting β2-agonists and at least equipotent bronchodilation as once-daily tiotropium.,Bronchodilators are central in the symptomatic management of COPD.,It is likely that once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes in patients with COPD. | 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 | Chronic obstructive pulmonary disease (COPD) is a debilitating disease affecting patients in daily life, both physically and emotionally.,Symptoms such as dyspnea and muscle fatigue, lead to exercise intolerance, which, together with behavioral issues, trigger physical inactivity, a key feature of COPD.,Physical inactivity is associated with adverse clinical outcomes, including hospitalization and all-cause mortality.,Increasing activity levels is crucial for effective management strategies and could lead to improved long-term outcomes.,In this review we summarize objective and subjective instruments for evaluating physical activity and focus on interventions such as pulmonary rehabilitation or bronchodilators aimed at increasing activity levels.,To date, only limited evidence exists to support the effectiveness of these interventions.,We suggest that a multimodal approach comprising pulmonary rehabilitation, pharmacotherapy, and counselling programs aimed at addressing emotional and behavioural aspects of COPD may be an effective way to increase physical activity and improve health status in the long term. | 1 |
Current evidence suggests that a higher blood eosinophil cell count at admission for acute exacerbation of COPD (AECOPD) is associated with a favorable response to systemic steroids.,However, the impact of blood eosinophil counts at admission on post-hospitalization outcomes is still unclear.,The main objective of this study is to investigate readmission outcomes associated with blood eosinophilia following severe COPD exacerbation in patients with infrequent COPD hospitalizations.,This is an observational cohort study design.,We retrospectively analyzed data of patients with a first hospitalization within 5 years for COPD exacerbation between April 2006 and March 2013.,Patients were stratified into the eosinophilic group if the blood eosinophil count on admission was ≥200 cells/µL and/or ≥2% of the total white blood cell (WBC) count.,The primary outcome was 1-year COPD-related readmission.,Secondary outcomes included 1-year all-cause mortality, 1-year all-cause readmission, length of stay, time to COPD-related readmission, and number of 1-year COPD-associated emergency department (ED) and ambulatory visits.,A total of 479 patients were included.,Of whom, 173 were stratified into the eosinophilic group.,Higher blood eosinophil cell count was associated with an increased risk of 1-year COPD-related readmission (OR, 1.83 [95% CI, 1.16-2.89]; P<0.01), a shorter time to first COPD-related readmission (HR, 1.64 [95% CI, 1.14-2.36]; P<0.01), and an increased number of 1-year COPD-related ED visits (incidence rate ratio, 1.78 [95% CI, 1.21-2.61]; P<0.01).,All-cause mortality, all-cause readmission, length of stay, and number of ambulatory visits did not differ between groups.,Higher blood eosinophil cell count at admission for a COPD exacerbation is associated with increased COPD readmission rates in patients with infrequent COPD hospitalizations. | Measurements of eosinophils in induced sputum and fractional exhaled nitric oxide (FeNO) are noninvasive biomarkers for assessing airway inflammation phenotypes in chronic obstructive pulmonary disease (COPD).,Nevertheless, the clinical application of the correlation between FeNO levels and sputum eosinophilia is controversial.,The study aimed to investigate the correlation and predictive relationship between FeNO levels and sputum eosinophils in patients with COPD exacerbation.,It also examined the relationship between FeNO levels and blood eosinophil percentage.,A total of 163 patients with COPD exacerbation were included in the cross-sectional study.,All patients underwent the following on the same day: FeNO test, spirometry, bronchodilator reversibility test, induced sputum, and routine blood test.,They were classified as eosinophilic group or noneosinophilic group based on sputum eosinophilic percentage (≥2.5%)/FeNO levels (≥32 parts per billion [ppb]).,FeNO levels and blood eosinophilic percentage were higher in patients with sputum eosinophilia (n=62) compared to those without (31.35 ppb versus 21.43 ppb, P=0.015; 2.71% versus 0.98%, P<0.0001, respectively).,Sputum eosinophilic percentage was higher with raised FeNO (n=34) compared to those with FeNO <32 ppb (5.12% versus 3.12%, P=0.007).,Eosinophils in induced sputum correlated with both FeNO levels (ρ=0.221, P=0.005) and blood eosinophilic percentage (ρ=0.399, P<0.001).,There was no relationship between FeNO and blood eosinophilic percentage.,Blood eosinophilic percentage was predictive of sputum eosinophilia (95% confidence interval [CI] =0.65-0.81, P<0.001) at a cutoff point of 0.65% (sensitivity =73%, specificity =61.3%).,FeNO levels were predictive of sputum eosinophilia (95% CI =0.53-3,071, P=0.012) at a cutoff point of 17.5 ppb (sensitivity =65.1%, specificity =56.4%).,The clinical relevance of this study provides evidence that inflammatory biomarkers, including sputum eosinophilic percentage, FeNO level, and blood eosinophilic percentage, can be used to positively diagnose eosinophilic COPD.,The FeNO level and blood eosinophilic counts/percentage, which determine an optimal cutoff for sputum eosinophilia, need more studies. | 1 |
Previous studies suggest that gender differences exist in COPD diagnosis and symptoms; these differences may be more pronounced in younger adults.,Our objective was to explore age-associated gender differences across a range of COPD severities.,A total of 4,484 current and former smokers with COPD from the Genetic Epidemiology of COPD cohort were investigated using regression modeling to explore the association between gender, age, disease severity, and the contributing elements of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system (symptoms, exacerbation risk, airflow limitation).,The age-gender interaction was observed across multiple age categories.,Compared to men with COPD, younger women with COPD had a greater likelihood of more severe dyspnea, airflow limitation, greater risk for exacerbations, and categorization in GOLD groups B and D.,These differences were less pronounced in older women with COPD.,However, older women remained more likely to experience severe dyspnea and to manifest more severe COPD (B vs A) than older men, despite lower pack-years of smoking.,These data demonstrate the significant symptom burden of COPD in women, especially younger women.,More research is needed to understand the pathogenesis of increased severity of COPD in women and to develop gender-targeted clinical assessment and management approaches to improve outcomes for women and men with COPD at all ages. | Little is known about whether there is any sex effect on chronic obstructive lung disease (COPD) exacerbations.,This study is intended to describe the possible sex-associated differences in exacerbation profile in COPD patients.,A total of 384 COPD patients who were hospitalized due to exacerbation were evaluated retrospectively for their demographics and previous and current exacerbation characteristics.,The study was conducted on 109 (28%) female patients and 275 (72%) male patients.,The mean age was 68.30±10.46 years.,Although females had better forced expiratory volume in 1 second and near-normal forced vital capacity, they had much impaired arterial blood gas levels (partial oxygen pressure [PO2] was 36.28 mmHg vs 57.93 mmHg; partial carbon dioxide pressure [PCO2] was 45.97 mmHg vs 42.49 mmHg; P=0.001), indicating severe exacerbation with respiratory failure.,More females had two exacerbations and two hospitalizations, while more men had one exacerbation and one hospitalization.,Low adherence to treatment and pulmonary embolism were more frequent in females.,Females had longer time from the onset of symptoms till the admission and longer hospitalization duration than males.,Comorbidities were less in number and different in women (P<0.05).,Women were undertreated and using more oral corticosteroids.,Current data showed that female COPD patients might be more prone to have severe exacerbations, a higher number of hospitalizations, and prolonged length of stay for hospitalization.,They have a different comorbidity profile and might be undertreated for COPD. | 1 |
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD.,We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.,PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458).,Patients received 24 weeks’ treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily.,GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization).,Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs).,The pooled intent-to-treat population comprised 729 GOLD category A patients.,GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p<0.0001).,Improvements over 24 weeks were comparable to at Week 24.,The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI.,GFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings. | A nebulized formulation of formoterol, Perforomist®, 20 μg/2 ml, has been available since 2007 for the maintenance treatment of chronic obstructive pulmonary disease (COPD).,We review the safety and efficacy data obtained during its development.,In a dose-finding study, formoterol inhalation solution (FFIS) was similar to the formoterol originator, Foradil® 12 μg DPI (FA) in patients with COPD.,In a 12-week efficacy study, FFIS manifested a rapid onset of action and FEV1 peak, AUC0-12, and trough levels similar to FA.,No loss of efficacy, tachyphylaxis, was observed over 12 weeks of regular administration.,In placebo-controlled studies in COPD patients receiving maintenance tiotropium, the addition of FFIS significantly augmented bronchodilation over the 6-week treatment duration, signifying that nebulized formoterol can further improve lung function in patients who are receiving tiotropium without an observed increase in adverse reactions.,The safety profile of FFIS during 12-week and 1-year studies revealed adverse events that were similar to those of placebo and FA.,Cardiac rhythm studies, including frequent ECGs and Holter monitoring, did not indicate any increase in rate or rhythm disturbances greater than placebo or FA.,We conclude that maintenance use of Perforomist® is appropriate for patients with COPD who require or prefer a nebulizer for management of their disease. | 1 |
In many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler.,Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD).,Tiotropium Respimat® is a propellant-free, multi-dose inhaler that delivers a metered dose of medication as a fine, slow-moving, long-lasting soft mist, independently of patient inspiratory effort.,The high fine-particle fraction of droplets produced by the Respimat® inhaler optimizes the efficiency of drug delivery to the lungs.,To help inform the choice of tiotropium inhaler for prescribers and patients, this systematic review summarizes the available pharmacokinetic, efficacy and safety data from comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in COPD, focusing on the licensed once-daily doses of 5 and 18 μg, respectively.,Data sources reviewed include publications and abstracts identified from database searches.,Published evidence from comparative studies suggests that tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg provide similar clinical outcomes in patients with COPD.,The findings indicate that physicians can base their decision about an inhaler for tiotropium on factors other than efficacy or safety.,These could be patient preference for a particular inhaler, ease of use and the efficiency of drug delivery, with the aim of optimizing adherence and clinical outcomes with long-term tiotropium maintenance therapy.,Video (MP4 314368 kb),Video (MP4 314368 kb),The online version of this article (doi:10.1186/s12890-016-0291-4) contains supplementary material, which is available to authorized users. | Tiotropium (Spiriva) is an inhaled muscarinic antagonist for patients with chronic obstructive pulmonary disease (COPD), and is available in two forms: the HandiHaler and the Respimat inhaler.,The aim of this study was to investigate the handling of and preference for each device immediately after switching from the HandiHaler to the Respimat and 2-3 years after the switch.,The study comprised two surveys.,A questionnaire was first administered to 57 patients with COPD (male:female 52:5, mean age 73.6±7.1 years) 8 weeks after switching from the HandiHaler (18 μg) to the Respimat (5 μg).,A second similar but simplified questionnaire was administered to 39 of these patients who continued to use the Respimat and were available for follow-up after more than 2 years.,Pulmonary function was also measured during each period.,In the first survey, 17.5% of patients preferred the HandiHaler, and 45.6% preferred the Respimat.,There were no significant changes in pulmonary function or in the incidence of adverse events after the switch.,In the second survey, performed 2-3 years later, the self-assessed handling of the Respimat had significantly improved, and the number of patients who preferred the Respimat had increased to 79.5%.,The efficacy of the Respimat was similar to that of the HandiHaler.,This was clear immediately after the switch, even in elderly patients with COPD who were long-term users of the HandiHaler.,The preference for the Respimat increased with continued use. | 1 |
The extracellular matrix (ECM) of the lung plays several important roles in lung function, as it offers a low resistant pathway that allows the exchange of gases, provides compressive strength and elasticity that supports the fragile alveolar-capillary intersection, controls the binding of cells with growth factors and cell surface receptors and acts as a buffer against retention of water.,COPD is a chronic inflammatory respiratory condition, characterised by various conditions that result in progressive airflow limitation.,At any stage in the course of the disease, acute exacerbations of COPD may occur and lead to accelerated deterioration of pulmonary function.,A key factor of COPD is airway remodelling, which refers to the serious alterations of the ECM affecting airway wall thickness, resistance and elasticity.,Various studies have shown that serum biomarkers of ECM turnover are significantly associated with disease severity in patients with COPD and may serve as potential targets to control airway inflammation and remodelling in COPD.,Unravelling the complete molecular composition of the ECM in the diseased lungs will help to identify novel biomarkers for disease progression and therapy.,Airway remodelling in COPD refers to alterations of the lung ECM that affect airway wall thickness, resistance and elasticity.,Unravelling such molecular modifications will help us to identify novel biomarkers for disease progression and therapy.https://bit.ly/2LObAga | Hyaluronic acid (HA) is a key component of the extracellular matrix of the lungs.,A unique attribute of HA is its water-retaining properties, so HA has a major role in the regulation of fluid balance in the lung interstitium.,Hyaluronic acid has been widely used in the treatment of eyes, ears, joints and skin disorders, but in the last years, it has been also proposed in the treatment of certain lung diseases, including airway diseases, due to its anti-inflammatory and water-binding capacities.,Hyaluronic acid aerosol decreases the severity of elastase-induced emphysema in murine models, prevents bronchoconstriction in asthmatics and improves some functional parameters in chronic obstructive pulmonary disease (COPD) patients.,Due to the protection of HA against bronchoconstriction and its hydration properties, inhaled HA would increase the volume of airway surface liquid, resulting in mucus hydration, increased mucous transport and less mucous plugging of the airways.,In addition, it has been seen in human studies that the treatment with nebulised HA improves the tolerability of nebulised hypertonic saline (even at 6% or 7% of concentration), which has been demonstrated to be an effective treatment in bronchial secretion management in patients with cystic fibrosis and bronchiectasis.,Our objective is to review the role of HA treatment in the management of chronic airway diseases. | 1 |
Chronic obstructive pulmonary disease (COPD) is one of the most common causes of mortality and a major contributor to morbidity.,Longitudinal clinical practice data yielding information on the characteristics of the disease, its natural course, and management are limited.,To investigate and describe the COPD population from a nationwide perspective during an 11-year period (1999-2009) with a focus on management, co-morbidity, and mortality.,This observational retrospective epidemiological study linked electronic medical records data from patients with COPD in primary care to mandatory Swedish hospital, drug and Cause of Death registry data from 1999 to 2009 (PATHOS).,A total of 21,361 patients with a COPD diagnosis were included (mean age 68.0 years, 53% females).,The proportion of patients diagnosed in primary care increased from 59% in 1999 to 81% in 2009 and the mean age at diagnosis decreased from 73 to 66 years.,The number of exacerbations decreased from 3.0 to 1.3 and COPD-related hospitalisations decreased from 1.02 to 0.20 per patient per year.,Prescriptions of long-acting muscarinic antagonists and fixed combinations of inhaled corticosteroid/long-acting β2-agonist inhalers increased from 0% to 36% and 37%, respectively.,The most common co-morbidities were hypertension, heart failure, ischaemic heart disease, and diabetes.,Overall life expectancy was 8.3±6.8 years shorter in patients with COPD than in the general population, and all-cause mortality was 3.5 times higher.,Management of COPD in Sweden has improved during the 11-year study period.,Despite this, patients with COPD have a substantially reduced life expectancy than the general population. | Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient’s condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization.,Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function.,A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated.,COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy.,Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations.,For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate.,Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis.,Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids.,A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations. | 1 |
Peak flow meter with questionnaire and mini-spirometer are considered as alternative tools to spirometry for screening of asthma and chronic obstructive pulmonary disease.,However, the accuracy of these tools together, in clinical settings for disease diagnosis, has not been studied.,Two hundred consecutive patients with respiratory complaints answered a short symptom questionnaire and performed peak expiratory flow measurements, standard spirometry with Koko spirometer and mini-spirometry (COPD-6).,Spirometry was repeated after bronchodilation.,Physician made a final diagnosis of asthma, chronic obstructive pulmonary disease and others.,One eighty nine patients (78 females) with age 51 ± 17 years with asthma (115), chronic obstructive pulmonary disease (33) and others (41) completed the study.,“Breathlessness > 6months” and “cough > 6months” were important symptoms to detect obstructive airways disease.,“Asymptomatic period > 2 weeks” had the best sensitivity (Sn) and specificity (Sp) to differentiate asthma and chronic obstructive pulmonary disease.,A peak expiratory flow of < 80% predicted was the best cut-off to detect airflow limitation (Sn 90%, Sp 50%).,Respiratory symptoms with PEF < 80% predicted, had Sn 84 and Sp 93% to detect OAD.,COPD-6 device under-estimated FEV1 by 13 mL (95% CI: −212, 185).,At a cut-off of 0.75, the FEV1/FEV6 had the best accuracy (Sn 80%, Sp 86%) to detect airflow limitation.,Peak flow meter with few symptom questions can be effectively used in clinical practice for objective detection of asthma and chronic obstructive pulmonary disease, in the absence of good quality spirometry.,Mini-spirometers are useful in detection of obstructive airways diseases but FEV1 measured is inaccurate.,A simple questionnaire and peak flow meter measurements can help doctors differentiate between asthma and chronic lung disease.,In clinical settings where access to specialist equipment and knowledge is limited, it can be challenging for doctors to tell the difference between asthma and chronic obstructive pulmonary disease (COPD).,To determine a viable alternative method for differentiating between these diseases, Rahul Kodgule and colleagues at the Chest Research Foundation in Pune, India, trialed a simplified version of two existing symptom questionnaires, combined with peak flow meter measurements.,They assessed 189 patients using this method, and found it aided diagnosis with high sensitivity and specificity.,Breathlessness, cough and wheeze were the minimal symptoms required for COPD diagnosis, while the length of asymptomatic periods was most helpful in distinguishing asthma from COPD. | It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation.,We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation.,Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed.,Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation.,The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD.,The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV.,The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21-5.70, P=0.000-0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages.,From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness.,Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%-75.3%) and specificities (70.3%-75.7%).,We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation. | 1 |
This study aimed to validate the chronic obstructive pulmonary disease (COPD) Population Screener (COPD-PS) questionnaire as a screening tool in a cohort of Chinese subjects who underwent a health examination, and to summarise its overall performance through a meta-analysis.,We enrolled 997 subjects aged ≥40 years who underwent a health examination, both lung function and COPD-PS data were collected.,The screening performance of COPD-PS was evaluated with a receiver operating characteristic (ROC) curve analysis, using the area under the curve (AUC) to assess the screening accuracy.,A standard diagnostic meta-analysis was used to summarise the screening performance of COPD-PS for COPD.,Of the 997 subjects, 157 were identified as having COPD.,The COPD-PS score was significantly higher in COPD patients than controls (5.03 ± 5.11 vs.,2.72 ± 1.80, p < .001).,At a cut-off of 4, the sensitivity and specificity of COPD-PS for identifying COPD were 74.52 and 70.24%, respectively, with an AUC of 0.79.,Eight studies (including this study) were included in this meta-analysis.,The pooled estimates for COPD-PS were as follows: sensitivity of 0.66 (95% CI: 0.47-0.63), specificity of 0.86 (95% CI: 0.84-0.89), positive likelihood ratio of 3.00 (95% CI: 1.65-5.47), negative likelihood ratio of 0.43 (95% CI: 0.35-0.52) and diagnostic odds ratio of 7.24 (95% CI: 3.91-13.40).,The AUC of the summary ROC curve was 0.78.,COPD-PS appears to be a useful tool for screening individuals with a high risk of COPD and guiding the selection of individuals for subsequent spirometry examination.KEY MESSAGESCOPD-PS is a simple and useful method to screen COPD.The combination of COPD-PS with other tools may improve the screen performance.,COPD-PS is a simple and useful method to screen COPD.,The combination of COPD-PS with other tools may improve the screen performance. | Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality.,Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.,Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed.,To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD.,To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS).,To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.,The prevalence of PRISm in COPDGene is 12.3%.,Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models.,Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001).,Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.,PRISm subjects are clinically and genetically heterogeneous.,Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.,Clinicaltrials.gov Identifier: NCT000608764.,The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is characterized by loss of elastic fibres from small airways and alveolar walls, with the decrease in elastin increasing with disease severity.,It is unclear why there is a lack of repair of elastic fibres.,We have examined fibroblasts cultured from lung tissue from subjects with or without COPD to determine if the secretory profile explains lack of tissue repair.,In this study, fibroblasts were cultured from lung parenchyma of patients with mild COPD [Global initiative for chronic Obstructive Lung Disease (GOLD) 1, n= 5], moderate to severe COPD (GOLD 2-3, n= 12) and controls (non-COPD, n= 5).,Measurements were made of proliferation, senescence-associated β-galactosidase-1, mRNA expression of IL-6, IL-8, MMP-1, tropoelastin and versican, and protein levels for IL-6, IL-8, PGE2, tropoelastin, insoluble elastin, and versican.,GOLD 2-3 fibroblasts proliferated more slowly (P < 0.01), had higher levels of senescence-associated β-galactosidase-1 (P < 0.001) than controls and showed significant increases in mRNA and/or protein for IL-6 (P < 0.05), IL-8 (P < 0.01), MMP-1 (P < 0.05), PGE2 (P < 0.05), versican (P < 0.05) and tropoelastin (P < 0.05). mRNA expression and/or protein levels of tropoelastin (P < 0.01), versican (P < 0.05), IL-6 (P < 0.05) and IL-8 (P < 0.05) were negatively correlated with FEV1% of predicted.,Insoluble elastin was not increased.,In summary, fibroblasts from moderate to severe COPD subjects display a secretory phenotype with up-regulation of inflammatory molecules including the matrix proteoglycan versican, and increased soluble, but not insoluble, elastin.,Versican inhibits assembly of tropoelastin into insoluble elastin and we conclude that the pro-inflammatory phenotype of COPD fibroblasts is not compatible with repair of elastic fibres. | Prostacyclin analogs are potent vasodilators and possess anti-inflammatory properties.,However, the effect of prostacyclin on extracellular matrix (ECM) in COPD is not well known.,Collagen fibrils and proteoglycans are essential ECM components in the lung and fibroblasts are key players in regulating the homeostasis of ECM proteins.,The aim was to study the synthesis of prostacyclin and its effect on fibroblast activity and ECM production, and in particular collagen I and the collagen-associated proteoglycans biglycan and decorin.,Parenchymal lung fibroblasts were isolated from lungs from COPD patients (GOLD stage IV) and from lungs and transbronchial biopsies from control subjects.,The prostacyclin analog iloprost was used to study the effect of prostacyclin on ECM protein synthesis, migration, proliferation and contractile capacity of fibroblasts.,TGF-β1 stimulation significantly increased prostacyclin synthesis in fibroblasts from COPD patients (p < 0.01), but showed no effect on fibroblasts from control subjects.,Collagen I synthesis was decreased by iloprost in both control and COPD fibroblasts (p < 0.05).,Conversely, iloprost significantly altered biglycan and decorin synthesis in control fibroblasts, but iloprost displayed no effect on these proteoglycans in COPD fibroblasts.,Proliferation rate was reduced (p < 0.05) and contractile capacity was increased in COPD fibroblasts (p < 0.05) compared to control fibroblasts.,Iloprost decreased proliferative rate in control fibroblasts (p < 0.05), whereas iloprost attenuated contraction capacity in both COPD (p < 0.01) and control fibroblasts (p < 0.05).,Iloprost reduced collagen I synthesis and fibroblast contractility but did not affect the collagen-associated proteoglycans or proliferation rate in fibroblasts from COPD patients.,Enhanced prostacyclin production could lead to improper collagen network fibrillogenesis and a more emphysematous lung structure in severe COPD patients. | 1 |
Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period.,However, longer period follow-up studies are still lacking.,Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.,A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV1, 56% predicted) were included in the prospective study.,We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years.,Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.,IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance.,In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02].,CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.,The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.,No.:NCT00605540 | 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 |
Little is known about the microbiota shift induced by exacerbation in chronic obstructive pulmonary disease (COPD) patients.,The sputa microbiota of COPD patients was evaluated when clinically stable and during acute exacerbations of the disease.,Sputa microbiota was analyzed using 16S ribosomal RNA gene pyrosequencing and quantitative polymerase chain reaction-based pathogen detection.,Nine COPD patients were enrolled.,Pyrosequencing of 16S rRNA genes identified 2,267 unique bacterial operational taxonomic units.,Principal microbiota shifts during exacerbation were in either Proteobacteria, Firmicutes or Bacteroidetes.,Streptococcus and Moraxella levels were detected during exacerbation in severe (Global Initiative for Chronic Obstructive Lung Disease 3) COPD patients.,Most of the clinically-important genera found in the sputum with the pyrosequencing of 16S rRNA gene correlated with specific quantitative polymerase chain reactions for bacteria while respiratory viruses were nearly absent.,Sputum microbiotas of exacerbated COPD patients are complex.,This pilot study shows a clear shift in the microbiota of patients during exacerbation.,The nature of this shift varies from patient to patient in such a way that the treatment should be patient-specific.,Further studies are needed to establish the impact of microbial exacerbations on the pulmonary microbiota. | In patients with chronic obstructive pulmonary disease (COPD), the extent of physical activity (PA) is correlated with disease severity and prognosis.,However, factors associated with low-level PA in elderly COPD patients are not known.,We assessed the levels of PA and clinical factors associated with low-level of PA in elderly COPD patients.,This was a secondary analysis of a multicenter, prospective study of 245 patients with COPD.,Among them, 160 patients with 65 years or more were included.,Three PA groups were defined with respect to daily activity time (low, moderate, and high).,Health related quality of life (HRQL) was measured using St.,George’s respiratory questionnaire (SGRQ) and 36-item short-form health survey.,Anxiety and depression status were assessed employing the hospital anxiety and depression scale (HADS).,Multivariate logistic regression was performed to identify independent predictors of low-level PA in elderly COPD patients.,Of all the 160 patients, 103 (64.4%) engaged in low-level PA.,Upon univariate analysis, a decreased exercise capacity (6-minute walk test < 250 m), an increased dyspnea (the modified medical research council [MMRC] dyspnea scale ≥ 2), a decreased HRQL (total SGRQ score), and a presence of depression (HADS-D ≥ 8) were significantly associated with low-level PA.,Upon multivariate analysis, an MMRC grade ≥ 2 (hazard ratio [HR], 2.550; p = 0.034), and HADS-D ≥ 8 (HR, 2.076; p = 0.045) were independently associated with low-level PA in elderly COPD patients.,Two-thirds of elderly patients with COPD reported low-level of PA.,More severe dyspnea and a presence of depression were independently associated with low-level PA in elderly COPD patients. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events.,This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk.,In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk factors were randomized to once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or their combination.,Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients.,Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18 months, and cardiovascular death over a median of 27 months.,Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2 ng/l) in 1,542 (96%) patients.,Concentrations were unaffected by inhaled therapies at 3 months (p > 0.05).,Compared with the lowest quintile (cardiac troponin <2.3 ng/l), patients in the highest quintile (≥7.7 ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p = 0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p = 0.005) after adjustment for risk factors.,By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p = 0.548).,In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are a specific and major indicator of future cardiovascular events and cardiovascular death.,Inhaled therapies did not affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes.,(Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease [SUMMIT]; NCT01313676) | 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 |
This multicenter, cross-sectional, non-interventional trial aimed to investigate adherence barriers to inhaled medicines when compared with oral medicines in Japanese patients with chronic obstructive pulmonary disease (COPD) and asthma.,The self-reporting “Adherence Starts with Knowledge 20” (ASK-20) questionnaire was administered for adherence barriers of inhaled and oral medicines to outpatients with regular clinic attendance.,Patients with COPD and asthma reported different adherence barriers to inhaled medicines.,Independent adherence barriers [odds ratio (95% confidence interval)] to inhaled medicines relative to those for oral medicines among patients with COPD and asthma were those related to item Q8 [“I know if I am reaching my health goals”; 2.49 (1.39-4.47); p=0.0022] and item Q2 [“I run out of my medicine because I do not get refills on time”; 2.69 (1.26-5.75); p=0.0127], respectively.,Among patients with poor adherence to only inhaled medicines, those with COPD and asthma recognized item Q3 [“consuming alcohol and taking medicines”; 6.63 (1.27-34.7); p<0.05] and item Q1 [“forget to take medicines only sometimes”; 4.29 (1.83-10.0); p<0.05], respectively, were recognized as independent adherence barriers to inhaled medicines.,The total ASK-20 scores and total barrier counts in patients with poor adherence to inhaled medicines were significantly higher than in those without poor adherence among patients with asthma (p=0.0057) but not those with COPD (p>0.05).,These results will aid in personalizing education on adherence to inhaled medicines among patients with COPD and asthma. | Delivery of inhaled medications via an inhaler device underpins the effectiveness of treatment for patients with chronic obstructive pulmonary disease (COPD).,Correct inhaler technique among patients is also a predictor of achieving treatment compliance and adherence.,Reporting of patient satisfaction with inhalers is therefore gaining increasing attention and is now recognized as an important patient-reported outcome in clinical trials involving patients with COPD or asthma.,In this cross-sectional study, we use the validated Patient Satisfaction and Preference Questionnaire (PASAPQ) to assess the handling and satisfaction for Respimat® Soft Mist™ Inhaler (SMI) compared with the Breezhaler® dry powder inhaler (DPI) among patients with COPD in Spain.,Patients were already assigned to therapy with either SPIRIVA® (tiotropium) Respimat® or with Hirobriz®/Onbrez®/Oslif® (indacaterol) Breezhaler® for at least 3 but not more than 6 months before completing the PASAPQ at a single visit to the study site.,The primary endpoint of the trial was the mean total PASAPQ score.,Secondary endpoints were the performance score domain of the PASAPQ, the convenience score domain of the PASAPQ, and the overall satisfaction score of the PASAPQ.,For the primary endpoint, the mean PASAPQ total score in the Respimat® and Breezhaler® groups was 80.7 and 79.9, respectively (difference of 0.8, 95% confidence interval [CI] −2.9 to 4.5; P=0.67).,The mean total performance scores were 82.5 and 78.2 (difference of 4.3, 95% CI −0.3 to 8.9; P=0.06), and the mean total convenience scores were 78.6 and 81.9 (difference of −3.3, 95% CI −7.0 to 0.4; P=0.08) for the Respimat® and Breezhaler® groups, respectively.,Patients gave the Respimat® SMI and the Breezhaler® DPI overall satisfaction PASAPQ scores of 6.0 and 5.9, respectively, which shows that patients were satisfied with these inhalers. | 1 |
Human lung single-cell atlas reveals the complexity and diversity of aberrant cellular populations in pulmonary fibrosis.,We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs.,Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung.,Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF.,We confirm the presence of both populations by immunohistochemistry and independent datasets.,Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs.,Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung.,Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF. | The introduction of microCT has made it possible to show that the terminal bronchioles are narrowed and destroyed before the onset of emphysematous destruction in COPD.,This report extends those observations to the cellular and molecular level in the centrilobular phenotype of emphysematous destruction in lungs donated by persons with very severe COPD (n = 4) treated by lung transplantation with unused donor lungs (n = 4) serving as controls.,These lung specimens provided companion samples to those previously examined by microCT (n = 61) that we examined using quantitative histology (n = 61) and gene expression profiling (n = 48).,The histological analysis showed that remodeling and destruction of the bronchiolar and alveolar tissue is associated with macrophage, CD4, CD8, and B cell infiltration with increased formation of tertiary lymphoid organs.,Moreover, gene set enrichment analysis showed that genes known to be expressed by natural killer (NK), lymphoid tissue inducer (LTi), and innate lymphoid cell 1 (ILC1) cells, but not ILC2 or ILC3 cells, were enriched in the expression profiles associated with CD4, CD8, and B cell infiltration.,Based on these findings, we postulate that the centrilobular phenotype of emphysematous destruction COPD is driven by a Th1 response activated by infiltrating ILC1, NK, and LTi cells. | 1 |
This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI).,We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).,This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD.,Patients were randomized into 1 of 120 treatment sequences.,Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods.,The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14.,Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14.,Safety and tolerability were also assessed.,GP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120).,GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14.,All doses of GP MDI were well tolerated with no unexpected safety findings.,These efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD.,ClinicalTrials.gov NCT01566773.,Registered 27 March 2012.,The online version of this article (doi:10.1186/s12931-016-0426-4) contains supplementary material, which is available to authorized users. | Glycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD.,This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.,Double-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design.,Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days.,Primary endpoint: mean trough FEV1 at Day 28.,385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed.,All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID).,Pharmacodynamic steady-state was reached by Day 7.,There was a small separation (≤37 mL) between BID and OD dose-response curves for mean trough FEV1 at steady-state in favour of BID dosing.,Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL).,Dose-response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12-24 hours.,The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL).,Glycopyrronium bromide was safe and well tolerated at all doses.,Glycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID.,Importantly, OD dosing may confer better patient adherence.,The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.,ClinicalTrials.gov: NCT01119950 | 1 |
Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD).,Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results.,Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).,To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample.,We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations.,The analysis included 16,936 genotyped and imputed SNPs.,No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5.,The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3).,Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4).,The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers.,Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population.,Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population. | The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable.,We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value.,Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction.,Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09).,One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04).,The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels.,Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers.,The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript.,The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung.,Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation. | 1 |
Chronic obstructive pulmonary disease (COPD) is a commonly reported cause of death and associated with smoking.,However, COPD mortality is high in poor countries with low smoking rates.,Spirometric restriction predicts mortality better than airflow obstruction, suggesting that the prevalence of restriction could explain mortality rates attributed to COPD.,We have studied associations between mortality from COPD and low lung function, and between both lung function and death rates and cigarette consumption and gross national income per capita (GNI).,National COPD mortality rates were regressed against the prevalence of airflow obstruction and spirometric restriction in 22 Burden of Obstructive Lung Disease (BOLD) study sites and against GNI, and national smoking prevalence.,The prevalence of airflow obstruction and spirometric restriction in the BOLD sites were regressed against GNI and mean pack years smoked.,National COPD mortality rates were more strongly associated with spirometric restriction in the BOLD sites (<60 years: men rs=0.73, p=0.0001; women rs=0.90, p<0.0001; 60+ years: men rs=0.63, p=0.0022; women rs=0.37, p=0.1) than obstruction (<60 years: men rs=0.28, p=0.20; women rs=0.17, p<0.46; 60+ years: men rs=0.28, p=0.23; women rs=0.22, p=0.33).,Obstruction increased with mean pack years smoked, but COPD mortality fell with increased cigarette consumption and rose rapidly as GNI fell below US$15 000.,Prevalence of restriction was not associated with smoking but also increased rapidly as GNI fell below US$15 000.,Smoking remains the single most important cause of obstruction but a high prevalence of restriction associated with poverty could explain the high ‘COPD’ mortality in poor countries. | 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 |
Childhood asthma is strongly influenced by genetics and is a risk factor for reduced lung function and chronic obstructive pulmonary disease (COPD) in adults.,This study investigates self-reported childhood asthma in adult smokers from the COPDGene Study.,We hypothesize that childhood asthma is associated with decreased lung function, increased risk for COPD, and that a genome-wide association study (GWAS) will show association with established asthma variants.,We evaluated current and former smokers ages 45-80 of non-Hispanic white (NHW) or African American (AA) race.,Childhood asthma was defined by self-report of asthma, diagnosed by a medical professional, with onset at < 16 years or during childhood.,Subjects with a history of childhood asthma were compared to those who never had asthma based on lung function, development of COPD, and genetic variation.,GWAS was performed in NHW and AA populations, and combined in meta-analysis.,Two sets of established asthma SNPs from published literature were examined for association with childhood asthma.,Among 10,199 adult smokers, 730 (7%) reported childhood asthma and 7493 (73%) reported no history of asthma.,Childhood asthmatics had reduced lung function and increased risk for COPD (OR 3.42, 95% CI 2.81-4.18).,Genotype data was assessed for 8031 subjects.,Among NHWs, 391(7%) had childhood asthma, and GWAS identified one genome-wide significant association in KIAA1958 (rs59289606, p = 4.82 × 10− 8).,Among AAs, 339 (12%) had childhood asthma.,No SNPs reached genome-wide significance in the AAs or in the meta-analysis combining NHW and AA subjects; however, potential regions of interest were identified.,Established asthma SNPs were examined, seven from the NHGRI-EBI database and five with genome-wide significance in the largest pediatric asthma GWAS.,Associations were found in the current childhood asthma GWAS with known asthma loci in IL1RL1, IL13, LINC01149, near GSDMB, and in the C11orf30-LRRC32 region (Bonferroni adjusted p < 0.05 for all comparisons).,Childhood asthmatics are at increased risk for COPD.,Defining asthma by self-report is valid in populations at risk for COPD, identifying subjects with clinical and genetic characteristics known to associate with childhood asthma.,This has potential to improve clinical understanding of asthma-COPD overlap (ACO) and enhance future research into ACO-specific treatment regimens.,ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008).,The online version of this article (10.1186/s12931-018-0890-0) contains supplementary material, which is available to authorized users. | Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD).,Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology.,We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.,Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined.,Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD.,Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.,Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression.,Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR.,ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased.,Healthy smokers were intermediate between healthy nonsmokers and patients with COPD.,Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects.,MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release.,Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation.,Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers.,The utility of these clinical subtypes is unclear.,However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant.,The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.,Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis.,Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%.,Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%).,Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized.,Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St.,George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001).,Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use.,The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study.,Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes.,COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa.,Clinicaltrials.gov identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.,The online version of this article (doi:10.1186/1471-2466-14-164) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease is known to be associated with systemic inflammation.,We examined the longitudinal association of C-reactive protein (CRP) and lung function in a cohort of 18,110 men and women from the European Prospective Investigation Into Cancer in Norfolk who were 40-79 years of age at baseline (recruited in 1993-1997) and followed-up through 2011.,We assessed lung function by measuring forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at baseline, 4 years, and 13 years.,Serum CRP levels were measured using a high-sensitivity assay at baseline and the 13-year follow up.,Cross-sectional and longitudinal associations of loge-CRP and lung function were examined using multivariable linear mixed models.,In the cross-sectional analysis, 1-standard-deviation increase in baseline loge-CRP (about 3-fold higher CRP on the original milligrams per liter scale) was associated with a −86.3 mL (95% confidence interval: −93.9, −78.6) reduction in FEV1.,In longitudinal analysis, a 1-standard-deviation increase in loge-CRP over 13 years was also associated with a −64.0 mL (95% confidence interval: −72.1, −55.8) decline in FEV1 over the same period.,The associations were similar for FVC and persisted among lifetime never-smokers.,Baseline CRP levels were not predictive of the rate of change in FEV1 or FVC over time.,In the present study, we found longitudinal observational evidence that suggested that increases in systemic inflammation are associated with declines in lung function. | 1 |
The characteristics and natural history of GOLD B COPD patients are not well described.,The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed.,We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression.,Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter.,Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed.,Students t tests and Mann Whitney-U tests were used.,One hundred seven (28.9%) of patients were categorised as GOLD B at baseline.,These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted).,More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A.,At 12 months, 25.3% of GOLD B patients progressed to GOLD D.,These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B.,Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline.,A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.,The online version of this article (doi:10.1186/s12890-017-0384-8) contains supplementary material, which is available to authorized users. | The COPD Assessment Test (CAT) has been recently developed to quantify COPD impact in routine practice.,However, no relationship with other measures in the Global Initiative for Obstructive Lung Disease (GOLD) strategy has been evaluated.,The present study aimed to evaluate the relationship of the CAT with other GOLD multidimensional axes, patient types, and the number of comorbidities.,This was a cross-sectional analysis of the Clinical presentation, diagnosis, and course of chronic obstructive pulmonary disease (On-Sint) study.,The CAT score was administered to all participants at the inclusion visit.,A GOLD 2011 strategy consisting of modified Medical Research Council scale (MRC) scores was devised to study the relationship between the CAT, and GOLD 2011 axes and patient types.,The relationship with comorbidities was assessed using the Charlson comorbidity index, grouped as zero, one to two, and three or more.,The CAT questionnaire was completed by 1,212 patients with COPD.,The CAT maintained a relationship with all the three axes, with a ceiling effect for dyspnea and no distinction between mild and moderate functional impairment.,The CAT score increased across GOLD 2011 patient types A-D, with similar scores for types B and C.,Within each GOLD 2011 patient type, there was a considerably wide distribution of CAT values.,Our study indicates a correlation between CAT and the GOLD 2011 classification axes as well as the number of comorbidities.,The CAT score can help clinicians, as a complementary tool to evaluate patients with COPD within the different GOLD patient types. | 1 |
A multidimensional assessment of COPD was recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2013 and revised in 2017.,We examined the ability of the GOLD 2017 and the new 16 subgroup (1A-4D) classifications to predict clinical outcomes, including exacerbation and mortality, and compared them with the GOLD 2013 classifications.,Patients with COPD were recruited from January 2006 to December 2017.,The predictive abilities of grades 1-4 and groups A-D were examined through a logistic regression analysis with receiver operating curve estimations and area under the curve (AUC).,A total of 553 subjects with COPD were analyzed.,The mortality rate was 48.6% during a median follow-up period of 5.2 years.,Both the GOLD 2017 and the 2013 group A-D classifications had good predictive ability for total and severe exacerbations, for which the AUCs were 0.79 vs 0.77 and 0.79 vs 0.78, respectively.,The AUCs for the GOLD 2017 groups A-D, grades 1-4, and the GOLD 2013 group A-D classifications were 0.70, 0.66, and 0.70 for all-cause mortality and 0.73, 0.71, and 0.74 for respiratory cause mortality, respectively.,Combining the spirometric staging with the grouping for the GOLD 2017 subgroups (1A-4D), the all-cause mortality rate for group B and D patients was significantly increased from subgroups 1B-4B (27.7%, 50.6%, 53.3%, and 69.2%, respectively) and groups 1D-4D (55.0%, 68.8%, 82.1%, and 90.5%, respectively).,The AUCs of subgroups (1A-4D) were 0.73 and 0.77 for all-cause and respiratory mortality, respectively; the new classification was determined more accurate than the GOLD 2017 for predicting mortality (P<0.0001).,The GOLD 2017 classification performed well by identifying individuals at risk of exacerbation, but its predictive ability for mortality was poor among COPD patients.,Combining the spirometric staging with the grouping increased the predictive ability for all-cause and respiratory mortality.,We validate the ability of the GOLD 2017 and 16 subgroup (1A-4D) classifications to predict clinical outcome for COPD patients.,The GOLD 2017 classification performed well by identifying individuals at risk of exacerbation, but its predictive ability for mortality was poor.,The new 16 subgroup (1A-4D) classification combining the spirometric 1-4 staging and the A-D grouping increased the predictive ability for mortality and was better than the GOLD 2017 for predicting all-cause and respiratory mortality among COPD patients. | Exacerbations of COPD are managed differently, but whether treatment of one exacerbation predicts the likelihood of subsequent events is unknown.,We examined whether the treatment given for exacerbations predicted subsequent outcomes.,This was a post-hoc analysis of 17,135 patients with COPD from TIOtropium Safety and Performance In Respimat® (TIOSPIR®).,Patients treated with tiotropium with one or more moderate to severe exacerbations on study were analyzed using descriptive statistics, logistic and Cox regression analysis, and Kaplan-Meier plots.,Of 8,061 patients with moderate to severe exacerbation(s), demographics were similar across patients with exacerbations treated with antibiotics and/or steroids or hospitalization.,Exacerbations treated with systemic corticosteroids alone or in combination with antibiotics had the highest risk of subsequent exacerbation (HR: 1.21, P=0.0004 and HR: 1.33, P<0.0001, respectively), and a greater risk of having a hospitalized (severe) exacerbation (HR: 1.59 and 1.63, P<0.0001, respectively) or death (HR: 1.50, P=0.0059 and HR: 1.47, P=0.0002, respectively) compared with exacerbations treated with antibiotics alone.,Initial hospitalization led to the highest risk of subsequent hospitalization (all-cause or COPD related [severe exacerbation], HR: 3.35 and 4.31, P<0.0001, respectively) or death (all-cause or COPD related, HR: 3.53 and 5.54, P<0.0001, respectively) versus antibiotics alone.,These data indicate that the way exacerbations are treated initially is a useful guide to the patient’s subsequent clinical course.,Factors that clinicians consider when making treatment choices require further clarification. | 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). | Chronic obstructive pulmonary disease (COPD) is characterized by a persistent blockage of airflow, prompting episodes of shortness of breath, commonly leading to hospitalization.,Hospitalization may lead to a decline in physical activity following discharge.,Physical activity has been shown to improve symptoms of COPD and reduce readmissions, and to decrease morbidity and mortality.,This study aims to explore, from the perspectives of people with COPD, the barriers to and enablers of participation in physical activity following hospitalization for COPD.,This study had a qualitative descriptive design and included semistructured interviews with 28 adult COPD patients who had been admitted to hospital with a primary diagnosis of exacerbation of COPD.,A plethora of barriers to but fewer enablers of participation in physical activity and pulmonary rehabilitation were identified for this cohort of people.,The main barriers identified were health-related (comorbidities, COPD symptoms, and physical injury or illness) environment-related (weather, transport, and finance), and self-related.,The main enabling factors reported were access to health professionals and equipment, social support, routine and extracurricular activities, personal goals and motivation, and the effect of physical activity and “feeling better”.,This research provides a snapshot of the barriers to and enablers of physical activity and pulmonary rehabilitation in people with COPD.,It is evident that there are significant barriers which hinder the ability of people with COPD to undertake and continue participation in physical activity and pulmonary rehabilitation.,While there are some enablers that may counter these barriers, it is clear that health professionals dealing with people suffering from COPD need to actively recognize and address barriers to physical activity and pulmonary rehabilitation.,Hospital admission may create an opportunity for implementation of interventions promoting physical activity (such as referral to pulmonary rehabilitation), which may assist in reducing hospital readmission, as well as decreasing morbidity and mortality. | 1 |
Expiratory flow limitation (EFL) is seen in some patients presenting with a COPD exacerbation; however, it is unclear how EFL relates to the clinical features of the exacerbation.,We hypothesized that EFL when present contributes to symptoms and duration of recovery during a COPD exacerbation.,Our aim was to compare changes in EFL with symptoms in subjects with and without flow-limited breathing admitted for a COPD exacerbation.,A total of 29 subjects with COPD were recruited within 48 hours of admission to West China Hospital for an acute exacerbation.,Daily measurements of post-bronchodilator spirometry, resistance, and reactance using the forced oscillation technique and symptom (Borg) scores until discharge were made.,Flow-limited breathing was defined as the difference between inspiratory and expiratory respiratory system reactance (EFL index) greater than 2.8 cmH2O·s·L−1.,The physiological predictors of symptoms during recovery were determined by mixed-effect analysis.,Nine subjects (31%) had flow-limited breathing on admission despite similar spirometry compared to subjects without flow-limited breathing.,Spirometry and resistance measures did not change between enrolment and discharge.,EFL index values improved in subjects with flow-limited breathing on admission, with resolution in four patients.,In subjects with flow-limited breathing on admission, symptoms were related to inspiratory resistance and EFL index values.,In subjects without flow-limited breathing, symptoms related to forced expiratory volume in 1 second/forced vital capacity.,In the whole cohort, EFL index values at admission was related to duration of stay (Rs=0.4, P=0.03).,The presence of flow-limited breathing as well as abnormal respiratory system mechanics contribute independently to symptoms during COPD exacerbations. | 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 |
To explore the existential significance of living with the risk of being infected with coronavirus in patients with COPD.,Distancing measures aim to break the coronavirus transmission chains.,Physical separation from social networks and social isolation are correlated with anxiety and depression.,People with a chronic obstructive lung disease are particularly vulnerable due to the increased risk of a serious course of illness, so therefore many of them choose self‐isolation to protect themselves from COVID‐19.,A qualitative exploratory study using individual semi‐structured interviews.,From June-September 2020, 13 participants were recruited through advertisements on Facebook as a convenience sample for semi‐structured individual interviews.,The interviews took place through virtual platforms or in physical meetings.,Data were analysed using Ricoeur's phenomenological approach, involving naïve reading, a structural analysis and a critical interpretation strategy.,The study has been reported in line with COREQ guidelines.,Living with the threat of being infected with coronavirus has greatly affected everyday life for patients with COPD.,The nagging fear of coronavirus as a death threat was a dominant feeling, together with anxiety, loneliness and hope.,With self‐isolation, followed concerns of being forgotten and thoughts of the future, balancing between fearing the worst, and hoping the best.,Patients with moderate to severe COPD feel compelled to self‐isolate, as they fear dying from COVID‐19.,The study revealed a need for proactive contact with health professionals to calm the patients' feelings of deprivation, loneliness, hopelessness and anxiety.,Information about the patient's perspective may be used to develop targeted interventions aimed at giving adequate information, supporting hope, implementing digital or virtual solutions to keep in contact and avoid the feeling of being alone and forgotten during a pandemic crisis. | Chronic infections are associated with exacerbation in patients with chronic obstructive pulmonary disease (COPD).,The major objective of the management of these patients is the prevention and effective treatment of exacerbations.,Patients that have increased sputum production, associated with purulence and worsening shortness of breath, are the ones that will benefit from antibiotic therapy.,It is important to give the appropriate antibiotic therapy to prevent treatment failure, relapse, and the emergence of resistant pathogens.,In some patients, systemic corticosteroids are also indicated to improve symptoms.,In order to identify which patients are more likely to benefit from these therapies, clinical guidelines recommend stratifying patients based on their risk factor associated with poor outcome or recurrence.,It has been identified that patients with more severe disease, recurrent infection and presence of purulent sputum are the ones that will be more likely to benefit from this therapy.,Another approach related to disease prevention could be the use of prophylactic antibiotics during steady state condition.,Some studies have evaluated the continuous or the intermittent use of antibiotics in order to prevent exacerbations.,Due to increased bacterial resistance to antibiotics and the presence of side effects, several antibiotics have been developed to be nebulized for both treatment and prevention of acute exacerbations.,There is a need to design long-term studies to evaluate these interventions in the natural history of the disease.,The purpose of this publication is to review our understanding of the role of bacterial infection in patients with COPD exacerbation, the role of antibiotics, and future interventions. | 1 |
Inhaled bronchodilators including long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) play a central role in the treatment of stable chronic obstructive pulmonary disease (COPD).,However, it is still unclear whether LABA or LAMA should be used for the initial treatment.,Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LABA versus LAMA in patients with stable COPD.,We searched relevant randomized control trials (RCTs) with a period of treatment of at least 12 weeks and analyzed the exacerbations, quality of life, dyspnea score, lung function and adverse events as the outcomes of interest.,We carefully excluded unblinded data and identified a total of 19 RCTs (N = 28,211).,LAMA significantly decreased the exacerbations compared to LABA (OR 0.85, 95% CI 0.74 to 0.98; P = 0.02).,In St George’s Respiratory Questionnaire and transitional dyspnoea index score, there were no differences between LABA and LAMA treatment.,Compared to LABA, there was a small but significant increase in the trough FEV1 after LAMA treatment (Mean difference 0.02, 95% CI 0.01 to 0.03, P = 0.0006).,In the safety components, there was no difference in the serious adverse events between LABA and LAMA.,However, LAMA showed a significantly lower incidence of total adverse events compared to LABA (OR 0.92, 95% CI 0.86 to 0.98; P = 0.02).,Treatment with LAMA in stable COPD provided a significantly lower incidence of exacerbation and non-serious adverse events, and a higher trough FEV1 compared to LABA.,(PROSPERO: CRD42019144764) | Inhaled corticosteroids (ICSs) are a mainstay of COPD treatment for patients with a history of exacerbations.,Initial studies evaluating their use as monotherapy failed to show an effect on rate of pulmonary function decline in COPD, despite improvements in symptoms and reductions in exacerbations.,Subsequently, ICS use in combination with long-acting β2-agonists (LABAs) was shown to provide improved reductions in exacerbations, lung function, and health status.,ICS-LABA combination therapy is currently recommended for patients with a history of exacerbations despite treatment with long-acting bronchodilators alone.,The presence of eosinophilic bronchial inflammation, detected by high blood eosinophil levels or a history of asthma or asthma-COPD overlap, may define a population of patients in whom ICSs may be of particular benefit.,Prospective clinical studies to determine an appropriate threshold of eosinophil levels for predicting the beneficial effects of ICSs are needed.,Further study is also required in COPD patients who continue to smoke to assess the impact of cell- and tissue-specific changes on ICS responsiveness.,The safety profile of ICSs in COPD patients is confounded by comorbidities, age, and prior use of systemic corticosteroids.,The risk of pneumonia in patients with COPD is increased, particularly with more advanced age and worse disease severity.,ICS-containing therapy also has been shown to increase pneumonia risk; however, differences in study design and the definition of pneumonia events have led to substantial variability in risk estimates, and some data indicate that pneumonia risk may differ by the specific ICS used.,In summary, treatment with ICSs has a role in dual and triple therapy for COPD to reduce exacerbations and improve symptoms.,Careful assessment of COPD phenotypes related to risk factors, triggers, and comorbidities may assist in individualizing treatment while maximizing the benefit-to-risk ratio of ICS-containing COPD treatment. | 1 |
Lung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-β), and are therefore crucial in lung tissue repair and remodeling.,Abnormal repair and remodeling has been observed in lung diseases like COPD.,As miRNA levels can be influenced by TGF-β, we hypothesized that TGF-β influences miRNA expression in lung fibroblasts, thereby affecting their function.,We investigated TGF-β1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays.,TGF-β1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR.,Ago2-immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-β1-stimulated primary lung fibroblasts (n = 2).,The genes affected by TGF-β1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-β1-stimulated fibroblasts.,Twenty-nine miRNAs were significantly differentially expressed after TGF-β1 stimulation (FDR<0.05).,The TGF-β1-induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05).,We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF-β1-stimulated lung fibroblasts, respectively.,The TGF-β and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p.,The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-β1 stimulation.,Two miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-β1 in lung fibroblasts.,The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-β and/or Wnt pathways (NGF, DLD, HHEX) in TGF-β1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function. | The relationship between serum biomarkers and clinical expressions of COPD is limited.,We planned to further describe this association using markers of inflammation and injury and repair.,We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years.,Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured.,We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot].,Levels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs.,4).,Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05).,In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival. | 1 |
Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma.,In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017.,Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex.,Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases.,We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs.,In 2017, 544·9 million people (95% uncertainty interval [UI] 506·9-584·8) worldwide had a chronic respiratory disease, representing an increase of 39·8% compared with 1990.,Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia.,The age-sex-specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically.,Chronic respiratory diseases were the third leading cause of death in 2017 (7·0% [95% UI 6·8-7·2] of all deaths), behind cardiovascular diseases and neoplasms.,Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578-4 044 819) in 2017, an increase of 18·0% since 1990, while total DALYs increased by 13·3%.,However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14·3% decrease), age-standardised death rates (42·6%), and age-standardised DALY rates (38·2%).,In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD.,In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes.,Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world.,Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions.,Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men.,Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region.,Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990.,Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis.,Bill & Melinda Gates Foundation. | Asthma and COPD require different management strategies, but differentiation in primary care is difficult.,This primary care support initiative observed the impact of spirometry and clinical assessment on the diagnosis of airway disease.,Of 61 191 patients aged ≥40 years being treated for respiratory conditions within 1003 UK primary care practices, 43 203 underwent a diagnostic review including standardized spirometric assessment.,The proportion of patients in whom the diagnosis was changed by the additional information was determined.,The relationship of various patient characteristics was compared with the baseline and review diagnoses and with any change in diagnosis.,Asthma was initially diagnosed in 43% of patients, COPD in 35%, mixed disease in 9%, and other respiratory condition in 13%.,Patients initially diagnosed with asthma, mixed disease, or another condition were more likely to have their diagnosis changed at review (54%, 46%, and 63%, respectively) than those initially diagnosed with COPD (14%).,A change from asthma to COPD was associated with male gender, smoking, older age, and reduced lung function, the opposite being associated with a change from COPD to asthma.,In this study, a clinical review supplemented by additional information including spirometry highlights apparent mislabeling of significant numbers of patients with chronic obstructive disease in general practice with significant implications for individual treatment and healthcare provision.,This study shows that the addition of more clinical information can have a major effect on diagnostic tendency in patients with airway disease.,An initial diagnosis of COPD seems less likely to change following review than an asthma diagnosis.,While it is likely that greater information leads to a more accurate diagnosis, the differential effect of new information on diagnostic labeling highlights the insecurity of the diagnostic process in primary care in the UK. | 1 |
Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD).,To identify dysregulation of specific proteins and pathways in bronchoalveolar lavage (BAL) cells associated with smoking, isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun proteomics analyses were performed on BAL cells from healthy never-smokers and smokers with normal lung function from the Karolinska COSMIC cohort.,Multivariate statistical modeling, multivariate correlations with clinical data, and pathway enrichment analysis were performed.,Smoking exerted a significant impact on the BAL cell proteome, with more than 500 proteins representing 15 molecular pathways altered due to smoking.,The majority of these alterations occurred in a gender-independent manner.,The phagosomal- and leukocyte trans endothelial migration (LTM) pathways significantly correlated with FEV1/FVC as well as the percentage of CD8+ T-cells and CD8+CD69+ T-cells in smokers.,The correlations to clinical parameters in healthy never-smokers were minor.,The significant correlations of proteins in the phagosome- and LTM pathways with activated cytotoxic T-cells (CD69+) and the level of airway obstruction (FEV1/FVC) in smokers, both hallmarks of COPD, suggests that these two pathways may play a role in the molecular events preceding the development of COPD in susceptible smokers.,Both pathways were found to be further dysregulated in COPD patients from the same cohort, thereby providing further support to this hypothesis.,Given that not all smokers develop COPD in spite of decades of smoking, it is also plausible that some of the molecular pathways associated with response to smoking exert protective mechanisms to smoking-related pathologies in resilient individuals.,ClinicalTrials.gov identifier NCT02627872; Retrospectively registered on December 9, 2015.,The online version of this article (10.1186/s12931-017-0695-6) contains supplementary material, which is available to authorized users. | 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. | 1 |
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. | Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown.,Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands.,We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants.,All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD.,In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells.,Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists.,Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD.,These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1. | 1 |
Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular.,Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents.,We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50μg, placebo (both delivered via the Breezhaler® device), or tiotropium 18 μg (delivered via the HandiHaler® device).,Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD).,Safety comparisons were made for glycopyrronium vs tiotropium or placebo.,Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events.,During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA™.,In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated.,The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo.,Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo.,There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies.,Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data.,The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points. | NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease (COPD).,The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) evaluated the efficacy, safety and tolerability of NVA237 in patients with moderate-to-severe COPD.,Patients with COPD with a smoking history of ≥ 10 pack-years, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 80% and ≥ 30% predicted normal and FEV1/forced vital capacity < 0.70 were enrolled.,Patients were randomized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry.,The primary outcome measure was trough FEV1 at Week 12.,A total of 822 patients were randomized to NVA237 (n = 552) or placebo (n = 270).,Least squares mean (± standard error) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 (1.408 ± 0.0105 L), versus placebo (1.301 ± 0.0137 L; treatment difference 108 ± 14.8 mL, p < 0.001).,Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26.,FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26, and at all other visits and timepoints.,Transition dyspnoea index focal scores and St.,George's Respiratory Questionnaire scores were significantly improved with NVA237 versus placebo at Week 26, with treatment differences of 1.04 (p < 0.001) and-2.81 (p = 0.004), respectively.,NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31% (p = 0.023) and use of rescue medication by 0.46 puffs per day (p = 0.005), versus placebo.,NVA237 was well tolerated and had an acceptable safety profile, with a low frequency of cardiac and typical antimuscarinic adverse effects.,Once-daily NVA237 was safe and well tolerated and provided rapid, sustained improvements in lung function, improvements in dyspnoea, and health-related quality of life, and reduced the risk of exacerbations and the use of rescue medication.,ClinicalTrials.gov: NCT01005901 | 1 |
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction.,Bacterial infection of the lower respiratory tract contributes to approximately 50% of COPD exacerbations.,Even during periods of stable lung function, the lung harbors a community of bacteria, termed the microbiome.,The role of the lung microbiome in the pathogenesis of COPD remains unknown.,The COPD lung microbiome, like the healthy lung microbiome, appears to reflect microaspiration of oral microflora.,Here we describe the COPD lung microbiome of 22 patients with Moderate or Severe COPD compared to 10 healthy control patients.,The composition of the lung microbiomes was determined using 454 pyrosequencing of 16S rDNA found in bronchoalveolar lavage fluid.,Sequences were analyzed using mothur, Ribosomal Database Project, Fast UniFrac, and Metastats.,Our results showed a significant increase in microbial diversity with the development of COPD.,The main phyla in all samples were Actinobacteria, Firmicutes, and Proteobacteria.,Principal coordinate analyses demonstrated separation of control and COPD samples, but samples did not cluster based on disease severity.,However, samples did cluster based on the use of inhaled corticosteroids and inhaled bronchodilators.,Metastats analyses demonstrated an increased abundance of several oral bacteria in COPD samples. | COPD is a heterogeneous disease characterized by airflow obstruction and diagnosed by lung function.,CT imaging is emerging as an important, noninvasive tool in phenotyping COPD.,However, the use of CT imaging in defining the disease heterogeneity above lung function is not fully known.,Seventy-five patients with COPD (58 men, 17 women) were studied with CT imaging and with measures of airway inflammation.,Airway physiology and health status were also determined.,The presence of emphysema (EM), bronchiectasis (BE), and bronchial wall thickening (BWT) was found in 67%, 27%, and 27% of subjects, respectively.,The presence of EM was associated with lower lung function (mean difference % FEV1, −20%; 95% CI, −28 to −11; P < .001).,There was no difference in airway inflammation, exacerbation frequency, or bacterial load in patients with EM alone or with BE and/or BWT ± EM.,The diffusing capacity of the lung for carbon monoxide/alveolar volume ratio was the most sensitive and specific parameter in identifying EM (area under the receiver operator characteristic curve, 0.87; 95% CI, 0.79-0.96).,Physiologic cluster analysis identified three clusters, two of which were EM predominant and the third characterized by a heterogeneous combination of EM and BE.,The application of CT imaging can be useful as a tool in the multidimensional approach to phenotyping patients with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) produces skeletal muscle atrophy and weakness, leading to impairments of exercise performance.,The mechanical work needed for movement execution is also provided by the passive tension developed by musculoarticular connective tissue.,To verify whether COPD affects this component, the passive viscoelastic properties of the knee joint were evaluated in 11 patients with COPD and in 11 healthy individuals.,The levels of stiffness and viscosity were assessed by means of the pendulum test, consisting in a series of passive leg oscillations.,In addition, to explore the contribution of passive tension in the mechanical output of a simple motor task, voluntary leg flexion-extension movements were performed.,Patients with COPD showed a statistically significant reduction in stiffness and viscosity compared to controls.,Voluntary execution of flexion-extension movements revealed that the electromyographic activity of the Rectus Femoris and Biceps Femoris was lower in patients than in controls, and the low viscoelastic tension in the patients conditioned the performance of active movements.,These results provide novel insights on the mechanism responsible for the movement impairments associated with COPD. | Chronic obstructive pulmonary disease (COPD) is a disease associated with dyspnea, fatigue, and exercise intolerance.,The degree of functional debility and level of exercise capacity greatly influences quality of life and mortality in patients with COPD, and the measures of exercise capacity are to be an integral part of patient assessment but often not feasible in routine daily practice, resulting in likely suboptimal care.,There is a need for simple ways to identify functional decline in the clinical setting in order to guide resources to preventive interventions or proper care, including palliative care.,Gait speed, or measuring how long it takes for a patient to walk a short distance, takes very little time and space, and can serve as a candidate measure of physical function in COPD.,Gait speed has been shown to be an indicator of disability, health care utilization, and survival in older adults.,It is a simple, reliable, and feasible measure to perform in the clinic and has been promoted as the next vital sign, providing insight into patients’ functional capacity.,Gait speed is mainly determined by exercise capacity but reflects global well-being as it captures many of the multisystemic effects of disease severity in COPD rather than pulmonary impairment alone.,It is an excellent screening measure for exercise capacity and frailty; in COPD, the usual gait speed (4-m course with rolling start) has been very accurate in identifying clinically relevant benchmarks of the 6-minute walk test, poor (<350 m) and very poor (<200 m) 6-minute walk test distances.,A specific cut-off point of 0.8 m · s−1 had a positive predictive value of 69% and negative predictive value of 98% in predicting very poor exercise capacity.,The increasing evidence on gait speed is promising as a simple test that can inform the clinician about many important functional aspects of the COPD patient.,Further work will likely show the strength of gait speed as a predictive marker of hospitalizations, re-admissions, and mortality.,Instead of relying on the “eyeball test” regarding the patient’s frailty or exercise capacity, a gait speed in its simplicity represents a much more solid assessment.,Furthermore, repeat measures over serial clinic visits may show a pattern and further guide a change in therapy, whether it be medications, rehabilitation, or even initiation of palliative care discussions. | 1 |
In many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler.,Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD).,Tiotropium Respimat® is a propellant-free, multi-dose inhaler that delivers a metered dose of medication as a fine, slow-moving, long-lasting soft mist, independently of patient inspiratory effort.,The high fine-particle fraction of droplets produced by the Respimat® inhaler optimizes the efficiency of drug delivery to the lungs.,To help inform the choice of tiotropium inhaler for prescribers and patients, this systematic review summarizes the available pharmacokinetic, efficacy and safety data from comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in COPD, focusing on the licensed once-daily doses of 5 and 18 μg, respectively.,Data sources reviewed include publications and abstracts identified from database searches.,Published evidence from comparative studies suggests that tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg provide similar clinical outcomes in patients with COPD.,The findings indicate that physicians can base their decision about an inhaler for tiotropium on factors other than efficacy or safety.,These could be patient preference for a particular inhaler, ease of use and the efficiency of drug delivery, with the aim of optimizing adherence and clinical outcomes with long-term tiotropium maintenance therapy.,Video (MP4 314368 kb),Video (MP4 314368 kb),The online version of this article (doi:10.1186/s12890-016-0291-4) contains supplementary material, which is available to authorized users. | Ipratropium bromide/albuterol Respimat inhaler (CVT-R) was developed as an environmentally friendly alternative to ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI), which uses a chlorofluorocarbon propellant.,The objective of this study was to evaluate patient satisfaction, device usage, and long-term safety of CVT-R compared to CVT-MDI, and to the simultaneous administration of ipratropium bromide hydrofluoroalkane (HFA; I) and albuterol HFA (A) metered-dose inhalers as dual monotherapies (I + A).,This is a 48-week, open-label, randomized, active-controlled, parallel-group study (n = 470) comparing CVT-R to CVT-MDI and to I + A.,Patients were at least 40 years of age, diagnosed with chronic obstructive pulmonary disease (COPD), and current or exsmokers.,Patients were randomized to receive: (1) CVT-R, one inhalation four times daily (QID); or (2) CVT-MDI, two inhalations QID; or (3) I + A two inhalations of each inhaler QID.,Patient Satisfaction and Preference Questionnaire (PASAPQ) performance score (primary endpoint) and adverse events.,PASAPQ performance score was significantly higher (CVT-R versus CVT-MDI, 9.6; and CVT-R versus I + A, 6.2; both P < 0.001) when using CVT-R compared to CVT-MDI or I + A at all visits starting from week 3, while CVT-MDI and I + A treatment groups were similar.,Time to first COPD exacerbation was slightly longer in the CVT-R group compared to the other treatment groups, although it did not reach statistical significance (CVT-R versus CVT-MDI, P = 0.57; CVT-R versus I + A, P = 0.22).,Rates of withdrawal and patient refusal to continue treatment were lower in CVT-R compared with CVT-MDI and I + A groups (CVT-R versus CVT-MDI, P = 0.09; CVT-R versus I + A, P = 0.005).,The percentage of patients reporting adverse events and serious adverse events was similar across all three treatment groups.,CVT-R is an effective, environmentally friendly inhaler that provides patients with a high level of user satisfaction and may positively impact clinical outcomes while having no adverse impacts on patients using the device. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) often experience exacerbations of the disease that require hospitalization.,Current guidelines offer little guidance for identifying patients whose clinical situation is appropriate for admission to the hospital, and properly developed and validated severity scores for COPD exacerbations are lacking.,To address these important gaps in clinical care, we created the IRYSS-COPD Appropriateness Study.,The RAND/UCLA Appropriateness Methodology was used to identify appropriate and inappropriate scenarios for hospital admission for patients experiencing COPD exacerbations.,These scenarios were then applied to a prospective cohort of patients attending the emergency departments (ED) of 16 participating hospitals.,Information was recorded during the time the patient was evaluated in the ED, at the time a decision was made to admit the patient to the hospital or discharge home, and during follow-up after admission or discharge home.,While complete data were generally available at the time of ED admission, data were often missing at the time of decision making.,Predefined assumptions were used to impute much of the missing data.,The IRYSS-COPD Appropriateness Study will validate the appropriateness criteria developed by the RAND/UCLA Appropriateness Methodology and thus better delineate the requirements for admission or discharge of patients experiencing exacerbations of COPD.,The study will also provide a better understanding of the determinants of outcomes of COPD exacerbations, and evaluate the equity and variability in access and outcomes in these patients. | 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 |
Mobile health applications are increasingly used in patients with Chronic Obstructive Pulmonary Disease (COPD) to improve their self-management, nonetheless, without firm evidence of their efficacy.,This meta-analysis was aimed to assess the efficacy of mobile health applications in supporting self-management as an intervention to reduce hospital admission rates and average days of hospitalization, etc.,PubMed, Web of Science (SCI), Cochrane Library, and Embase were searched for relevant articles published before November 14th, 2017.,A total of 6 reports with randomized controlled trials (RCTs) were finally included in this meta-analysis.,Patients using mobile phone applications may have a lower risk for hospital admissions than those in the usual care group (risk ratio (RR) = 0.73, 95% CI [0.52, 1.04]).,However, there was no significant difference in reducing the average days of hospitalization.,Self-management with mobile phone applications could reduce hospital admissions of patients with COPD. | This study aimed to document the perspective of patients with chronic obstructive pulmonary disease (COPD) who underwent home-based pulmonary rehabilitation (HBPR) in a clinical trial.,In this qualitative study, open-ended questions explored participants’ views regarding HBPR.,Thirteen semi-structured interviews were analysed using a thematic analysis approach.,Major themes from interviews included the positive impact of HBPR on physical fitness, breathing and mood.,Participants valued the flexibility and convenience of the programme.,Participants also highlighted the importance of social support received, both from the physiotherapist over the phone and from family and friends who encouraged their participation.,Reported challenges were difficulties in initiating exercise, lack of variety in training and physical incapability.,While most participants supported the home setting, one participant would have preferred receiving supervised exercise training at the hospital.,Participants also reported that HBPR had helped establish an exercise routine and improved their disease management.,This study suggests that people with COPD valued the convenience of HBPR, experienced positive impacts on physical fitness and symptoms and felt supported by their community and programme staff.,This highly structured HBPR model may be acceptable to some people with COPD as an alternative to centre-based pulmonary rehabilitation. | 1 |
Clinical outcomes among COVID-19 patients vary greatly with age and underlying comorbidities.,We aimed to determine the demographic and clinical factors, particularly baseline chronic conditions, associated with an increased risk of severity in COVID-19 patients from a population-based perspective and using data from electronic health records (EHR).,Retrospective, observational study in an open cohort analyzing all 68,913 individuals (mean age 44.4 years, 53.2% women) with SARS-CoV-2 infection between 15 June and 19 December 2020 using exhaustive electronic health registries.,Patients were followed for 30 days from inclusion or until the date of death within that period.,We performed multivariate logistic regression to analyze the association between each chronic disease and severe infection, based on hospitalization and all-cause mortality.,5885 (8.5%) individuals showed severe infection and old age was the most influencing factor.,Congestive heart failure (odds ratio -OR- men: 1.28, OR women: 1.39), diabetes (1.37, 1.24), chronic renal failure (1.31, 1.22) and obesity (1.21, 1.26) increased the likelihood of severe infection in both sexes.,Chronic skin ulcers (1.32), acute cerebrovascular disease (1.34), chronic obstructive pulmonary disease (1.21), urinary incontinence (1.17) and neoplasms (1.26) in men, and infertility (1.87), obstructive sleep apnea (1.43), hepatic steatosis (1.43), rheumatoid arthritis (1.39) and menstrual disorders (1.18) in women were also associated with more severe outcomes.,Age and specific cardiovascular and metabolic diseases increased the risk of severe SARS-CoV-2 infections in men and women, whereas the effects of certain comorbidities are sex specific.,Future studies in different settings are encouraged to analyze which profiles of chronic patients are at higher risk of poor prognosis and should therefore be the targets of prevention and shielding strategies. | Asthmatics and patients with chronic obstructive pulmonary disease (COPD) have more severe outcomes with viral infections than people without obstructive disease.,To evaluate if obstructive diseases are risk factors for intensive care unit (ICU) stay and death due to coronavirus disease 2019 (COVID19).,We collected data from the electronic medical record from 596 adult patients hospitalized in University Hospital of Liege between March 18 and April 17, 2020, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection.,We classified patients into 3 groups according to the underlying respiratory disease, present before the COVID19 pandemic.,Among patients requiring hospitalization for COVID19, asthma and COPD accounted for 9.6% and 7.7%, respectively.,The proportions of asthmatics, patients with COPD, and patients without obstructive airway disease hospitalized in the ICU were 17.5%, 19.6%, and 14%, respectively.,One-third of patients with COPD died during hospitalization, whereas only 7.0% of asthmatics and 13.6% of patients without airway obstruction died due to SARS-CoV2.,The multivariate analysis showed that asthma, COPD, inhaled corticosteroid treatment, and oral corticosteroid treatment were not independent risk factors for ICU admission or death.,Male gender (odds ratio [OR]: 1.9; 95% confidence interval [CI]: 1.1-3.2) and obesity (OR: 8.5; 95% CI: 5.1-14.1) were predictors of ICU admission, whereas male gender (OR 1.9; 95% CI: 1.1-3.2), older age (OR: 1.9; 95% CI: 1.6-2.3), cardiopathy (OR: 1.8; 95% CI: 1.1-3.1), and immunosuppressive diseases (OR: 3.6; 95% CI: 1.5-8.4) were independent predictors of death.,Asthma and COPD are not risk factors for ICU admission and death related to SARS-CoV2 infection. | 1 |
Asthma-COPD overlap syndrome (ACOS) prevalence varies depending on the studied population and definition criteria.,The prevalence and clinical characteristics of ACOS in an at-risk COPD primary care population from Latin America was assessed.,Patients ≥40 years, current/ex-smokers and/or exposed to biomass, attending routine primary care visits completed a questionnaire and performed spirometry.,COPD was defined as post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) < 0.70; asthma was defined as either prior asthma diagnosis or wheezing in the last 12 months plus reversibility (increase in post-bronchodilator FEV1 or FVC ≥200 mL and ≥12%); ACOS was defined using a combination of COPD with the two asthma definitions.,Exacerbations in the past year among the subgroups were evaluated.,One thousand seven hundred forty three individuals completed the questionnaire, 1540 performed acceptable spirometry, 309 had COPD, 231 had prior asthma diagnosis, and 78 asthma by wheezing + reversibility.,ACOS prevalence in the total population (by post-bronchodilator FEV1/FVC < 0.70 plus asthma diagnosis) was 5.3 and 2.3% by post-bronchodilator FEV1/FVC < 0.70 plus wheezing + reversibility.,In the obstructive population (asthma or COPD), prevalence rises to 17.9 and 9.9% by each definition, and to 26.5 and 11.3% in the COPD population.,ACOS patients defined by post-bronchodilator FEV1/FVC < 0.7 plus wheezing + reversibility had the lowest lung function measurements.,Exacerbations for ACOS showed a prevalence ratio of 2.68 and 2.20 (crude and adjusted, p < 0.05, respectively) (reference COPD).,ACOS prevalence in primary care varied according to definition used.,ACOS by post-bronchodilator FEV1/FVC < 0.7 plus wheezing + reversibility represents a clinical phenotype with more frequent exacerbations, which is probably associated with a different management approach.,The online version of this article (doi:10.1186/s12890-017-0414-6) contains supplementary material, which is available to authorized users. | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
To integrate evidence from randomised controlled trials (RCTs) and observational studies on the efficacy of inhaled treatments for chronic obstructive pulmonary disease using network meta-analyses.,Systematic searches MEDLINE and Embase based on predetermined criteria.,Network meta-analyses of RCTs investigated efficacy on exacerbations (long-term: ≥20 weeks of treatment; short-term: <20 weeks), lung function (≥12 weeks), health-related quality of life, mortality and adverse events.,Qualitative comparisons of efficacies between RCTs and observational studies.,212 RCTs and 19 observational studies were included.,Compared with combined long-acting beta-adrenoceptor agonists and long-acting muscarinic antagonists (LABA+LAMA), triple therapy (LABA+LAMA+inhaled corticosteroid) was significantly more effective at reducing exacerbations (long-term 0.85 (95% CI: 0.78 to 0.94; short-term 0.67 (95% CI: 0.49 to 0.92)) and mortality (0.72 (95% CI: 0.59 to 0.89)) but was also associated with increased pneumonia (1.35 (95% CI: 1.10 to 1.67)).,No differences in lung function (0.02 (95% CI: −0.10 to 0.14)), health-related quality of life (−1.12 (95% CI: −3.83 to 1.59)) or other adverse events (1.02 (95% CI: 0.96 to 1.08)) were found.,Most of the observational evidence trended in the same direction as pooled RCT data.,Further evidence, especially pragmatic trials, are needed to fully understand the characteristics of patient subgroups who may benefit from triple therapy and for those whom the extra risk of adverse events, such as pneumonia, may outweigh any benefits.,CRD42018088013. | The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented.,However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.,TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers).,To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ≥ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).,Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV.,SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage.,Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV.,The rates of adverse events were similar across treatment arms and increased with disease severity.,Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.,In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages.,Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease.,The effects were similar to those reported for the study as a whole.,Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.,Clinicaltrial.gov registration NCT00268216; Study number: SCO30003 | 1 |
Hospitalised patients with acute exacerbation of COPD may deteriorate despite treatment, with early readmission being common.,To investigate whether neural respiratory drive, measured using second intercostal space parasternal muscle electromyography (EMGpara), would identify worsening dyspnoea and physician-defined inpatient clinical deterioration, and predict early readmission.,Patients admitted to a single-site university hospital with exacerbation of COPD were enrolled.,Spirometry, inspiratory capacity (IC), EMGpara, routine physiological parameters, modified early warning score (MEWS), modified Borg scale for dyspnoea and physician-defined episodes of deterioration were recorded daily until discharge.,Readmissions at 14 and 28 days post discharge were recorded.,120 patients were recruited (age 70±9 years, forced expiratory volume in 1 s (FEV1) of 30.5±11.2%).,Worsening dyspnoea, defined as at least one-point increase in Borg scale, was associated with increases in EMGpara%max and MEWS, whereas an increase in EMGpara%max alone was associated with physician-defined inpatient clinical deterioration.,Admission-to-discharge change (Δ) in the normalised value of EMGpara (ΔEMGpara%max) was inversely correlated with ΔFEV1 (r=−0.38, p<0.001) and ΔIC (r=−0.44, p<0.001).,ΔEMGpara%max predicted 14-day readmission (OR 1.13, 95% 1.03 to 1.23) in the whole cohort and 28-day readmission in patients under 85 years (OR 1.09, 95% CI 1.01 to 1.18).,Age (OR 1.08, 95% CI 1.03 to 1.14) and 12-month admission frequency (OR 1.29, 1.01 to 1.66), also predicted 28-day readmission in the whole cohort.,Measurement of neural respiratory drive by EMGpara represents a novel physiological biomarker that may be helpful in detecting inpatient clinical deterioration and identifying the risk of early readmission among patients with exacerbations of COPD.,NCT01361451. | The rate of decline in forced expiratory volume in 1 second (FEV1) is representative of the natural history of COPD.,Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints.,Retrospective analysis of UPLIFT® trial (four-year, randomized, double-blind, placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [COPD], n = 5993).,Decline of FEV1 was analysed with random co-efficient regression.,Patients were categorised according to quartiles based on the rate of decline (RoD) in post-bronchodilator FEV1.,The St George's Respiratory Questionnaire (SGRQ) total score, exacerbations and mortality were assessed within each quartile.,Mean (standard error [SE]) post-bronchodilator FEV1 increased in the first quartile (Q1) by 37 (1) mL/year.,The other quartiles showed annualised declines in FEV1 (mL/year) as follows: Q2 = 24 (1), Q3 = 59 (1) and Q4 = 125 (2).,Age, gender, respiratory medication use at baseline and SGRQ did not distinguish groups.,The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers.,The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD, but exacerbation rates increased with increasing RoD.,The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 (Q1 = 19.5% [tiotropium], 26% [control]; Q4 = 33.8% [tiotropium] and 33.1% [control]).,Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD.,Rate of decline in SGRQ increased in direct proportion to each quartile.,The group with the largest RoD had the highest mortality.,Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific (or more aggressive) approaches to management may be needed.,ClinicalTrials.gov number, NCT00144339 | 1 |
Lung hyperinflation and exercise intolerance are hallmarks of chronic obstructive pulmonary disease (COPD).,However, their relationship remains uncertain.,A combined analysis of two placebo-controlled, randomized studies examined the effects of the long-acting muscarinic antagonist umeclidinium (UMEC) and long-acting β2-agonist vilanterol (VI) separately and in combination on static hyperinflation, exercise endurance time (EET), and their relationship in patients with COPD.,Patients with moderate-to-severe stable COPD and resting functional residual capacity >120% predicted were randomized to UMEC/VI 62.5/25 μg, UMEC 62.5 μg, VI 25 μg, or placebo for 12 weeks.,Inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), and EET in an endurance shuttle-walk test were measured.,In this post hoc analysis, IC/TLC, RV/TLC, and IC were used as hyperinflation markers.,After 12 weeks, UMEC/VI and UMEC and VI showed significant improvements in hyperinflation versus placebo when measured by absolute change from baseline in IC/TLC (trough and 3 hours postdose [P≤0.011]).,UMEC/VI showed significant improvements versus UMEC and VI in absolute changes in IC/TLC (trough and 3 hours postdose [P≤0.001]).,Statistical significance for comparisons with placebo and between treatments for absolute changes in IC and percentage changes in RV/TLC followed similar patterns to those for absolute changes in IC/TLC.,UMEC/VI showed significant improvements in EET versus placebo at day 2 and week 12, measured as change from baseline in seconds (P≤0.002) and as a percentage from baseline (P≤0.005).,There was a lack of evidence to suggest a correlation between improvements in static hyperinflation and EET at any time point.,Although the dual bronchodilator UMEC/VI demonstrated greater improvements in static hyperinflation markers than UMEC or VI and significant improvements in exercise endurance, no direct relationship was observed between static hyperinflation and exercise endurance. | Exercise tests are often used to evaluate the functional status of patients with COPD.,However, to the best of our knowledge, a comprehensive systematic comparison of these tests has not been performed.,We systematically reviewed studies reporting the repeatability and/or reproducibility of these tests, and studies comparing their sensitivity to therapeutic intervention.,A systematic review identified primary manuscripts in English reporting relevant data on the following exercise tests: 6-minute walk test (6MWT) and 12-minute walk test, incremental and endurance shuttle walk tests (ISWT and ESWT, respectively), incremental and endurance cycle ergometer tests, and incremental and endurance treadmill tests.,We identified 71 relevant studies.,Good repeatability (for the 6MWT and ESWT) and reproducibility (for the 6MWT, 12-minute walk test, ISWT, ESWT, and incremental cycle ergometer test) were reported by most studies assessing these tests, providing patients were familiarized with them beforehand.,The 6MWT, ISWT, and particularly the ESWT were reported to be sensitive to therapeutic intervention.,Protocol variations (eg, track layout or supplemental oxygen use) affected performance significantly in several studies.,This review shows that while the validity of several tests has been established, for others further study is required.,Future work will assess the link between these tests, physiological mechanisms, and patient-reported measures. | 1 |
In some RCTs comparing triple therapy with dual therapy in COPD, there might be a bias resulting from the use of multiple inhaler devices.,This meta-analysis included only RCTs that compared ICS/LABA/LAMA vs.,LABA/LAMA or ICS/LABA using a single device.,We systematically reviewed randomized controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD.,We searched the PubMed, MEDLINE (OvidSP), EMBASE and Cochrane Library databases to investigate the effect of single-inhaler triple therapy in COPD.,The primary end points were the effect of single-inhaler triple therapy compared with single-inhaler dual therapy on all-cause mortality, the risk of acute exacerbation of COPD (AECOPD), and some safety endpoints.,The Cochrane Collaboration tool was used to assess the quality of each randomized trial and the risk of bias.,A total of 25,171 patients suffering from COPD were recruited for the 6 studies.,This meta-analysis indicated that single-inhaler triple therapy resulted in a significantly lower rate of all-cause mortality than LABA/LAMA FDC (risk ratio, 0.70; 95% CI 0.56‐0.88).,Single-inhaler triple therapy reduced the risk of exacerbation and prolonged the time to first exacerbation compared with single-inhaler dual therapy.,The FEV1 increased significantly more under single-inhaler triple therapy than under ICS/LABA FDC (mean difference, 103.4 ml; 95% CI 64.65‐142.15).,The risk of pneumonia was, however, significantly higher with ICS/LAMA/LABA FDC than with LABA/LAMA FDC (risk ratio, 1.55; 95% CI 1.35-1.80).,This meta-analysis suggests that single-inhaler triple therapy is effective in reducing the risk of death of any cause and of moderate or severe exacerbation in COPD patients.,However, the risk of pneumonia is higher with ICS/LAMA/LABA FDC than with LABA/LAMA FDC.,Trial registration PROSPERO #CRD42020186726.,The online version contains supplementary material available at 10.1186/s12931-021-01794-w. | This real world study evaluated the effectiveness of switching to closed triple therapy from mono/dual combination or open triple therapy in patients with chronic obstructive pulmonary disease (COPD).,We conducted this retrospective study at a single medical center from December 2014 to September 2020.,Patients with COPD who were stepped up to triple therapy were enrolled.,We analyzed the duration from initial COPD management to open or closed triple therapy and identified the clinical predictors of the patients who needed triple therapy early.,We also evaluated the effectiveness of triple therapy after switching from initial management, and closed triple therapy after switching from open triple therapy.,A total 115 COPD patients who were stepped up to triple therapy from initial treatment were analyzed.,The duration from initial treatment to triple therapy was 22.4 months.,The baseline peripheral blood eosinophil counts of the patients who switched to triple therapy early (n=63, less than 22 months) and those who switched to triple therapy later (n=52, more than 22 months) were similar (489.6 vs 434.5 cells/uL; p=0.589).,After univariate and multivariate analysis, the patients who were older had more acute exacerbations (AEs) in the previous year, asthma and COPD overlap (ACO), and initial dual bronchodilator therapy were stepped up to triple therapy early.,The FEV1 of the patients was significantly increased after switching to open triple therapy from mono bronchodilator therapy.,In addition, switching from initial or open triple therapy to closed triple therapy significantly reduced the incidence of AEs.,COPD patients with high blood eosinophilia, older age, more AEs in the previous year, ACO, and initial dual bronchodilator therapy were stepped up to triple therapy early.,Triple therapy showed improvements in lung function of most patients switching from mono bronchodilator therapy.,After switching to closed triple therapy further reduced the incidence of AEs. | 1 |
We conducted a randomized controlled trial of a digital health system supporting clinical care through monitoring and self-management support in community-based patients with moderate to very severe chronic obstructive pulmonary disease (COPD).,The aim of this study was to determine the efficacy of a fully automated Internet-linked, tablet computer-based system of monitoring and self-management support (EDGE‚ sElf-management anD support proGrammE) in improving quality of life and clinical outcomes.,We compared daily use of EDGE with usual care for 12 months.,The primary outcome was COPD-specific health status measured with the St George’s Respiratory Questionnaire for COPD (SGRQ-C).,A total of 166 patients were randomized (110 EDGE, 56 usual care).,All patients were included in an intention to treat analysis.,The estimated difference in SGRQ-C at 12 months (EDGE−usual care) was −1.7 with a 95% CI of −6.6 to 3.2 (P=.49).,The relative risk of hospital admission for EDGE was 0.83 (0.56-1.24, P=.37) compared with usual care.,Generic health status (EQ-5D, EuroQol 5-Dimension Questionnaire) between the groups differed significantly with better health status for the EDGE group (0.076, 95% CI 0.008-0.14, P=.03).,The median number of visits to general practitioners for EDGE versus usual care were 4 versus 5.5 (P=.06) and to practice nurses were 1.5 versus 2.5 (P=.03), respectively.,The EDGE clinical trial does not provide evidence for an effect on COPD-specific health status in comparison with usual care, despite uptake of the intervention.,However, there appears to be an overall benefit in generic health status; and the effect sizes for improved depression score, reductions in hospital admissions, and general practice visits warrants further evaluation and could make an important contribution to supporting people with COPD.,International Standard Randomized Controlled Trial Number (ISRCTN): 40367841; http://www.isrctn.com/ISRCTN40367841 (Archived by WebCite at http://www.webcitation.org/6pmfIJ9KK) | Objective To determine whether supported self management in chronic obstructive pulmonary disease (COPD) can reduce hospital readmissions in the United Kingdom.,Design Randomised controlled trial.,Setting Community based intervention in the west of Scotland.,Participants Patients admitted to hospital with acute exacerbation of COPD.,Intervention Participants in the intervention group were trained to detect and treat exacerbations promptly, with ongoing support for 12 months.,Main outcome measures The primary outcome was hospital readmissions and deaths due to COPD assessed by record linkage of Scottish Morbidity Records; health related quality of life measures were secondary outcomes.,Results 464 patients were randomised, stratified by age, sex, per cent predicted forced expiratory volume in 1 second, recent pulmonary rehabilitation attendance, smoking status, deprivation category of area of residence, and previous COPD admissions.,No difference was found in COPD admissions or death (111/232 (48%) v 108/232 (47%); hazard ratio 1.05, 95% confidence interval 0.80 to 1.38).,Return of health related quality of life questionnaires was poor (n=265; 57%), so that no useful conclusions could be made from these data.,Pre-planned subgroup analysis showed no differential benefit in the primary outcome relating to disease severity or demographic variables.,In an exploratory analysis, 42% (75/150) of patients in the intervention group were classified as successful self managers at study exit, from review of appropriateness of use of self management therapy.,Predictors of successful self management on stepwise regression were younger age (P=0.012) and living with others (P=0.010).,COPD readmissions/deaths were reduced in successful self managers compared with unsuccessful self managers (20/75 (27%) v 51/105 (49%); hazard ratio 0.44, 0.25 to 0.76; P=0.003).,Conclusion Supported self management had no effect on time to first readmission or death with COPD.,Exploratory subgroup analysis identified a minority of participants who learnt to self manage; this group had a significantly reduced risk of COPD readmission, were younger, and were more likely to be living with others.,Trial registration Clinical trials NCT 00706303. | 1 |
Chronic obstructive pulmonary disease (COPD) outpatients account for a large burden of usual care by respirologists.,EPOCONSUL is the first national clinical audit conducted in Spain on the medical care for COPD patients delivered in outpatient respiratory clinics.,We aimed to evaluate the clinical interventions and the degree of adherence to recommendations in outpatients of current COPD clinical practice guidelines.,This is an observational study with prospective recruitment (May 2014-May 2015) of patients with a COPD diagnosis as seen in outpatient respiratory clinics.,The information collected was historical in nature as for the clinical data of the last and previous consultations, and the information concerning hospital resources was concurrent.,A total of 17,893 clinical records of COPD patients in outpatient respiratory clinics from 59 Spanish hospitals were evaluated.,Of the 5,726 patients selected, 4,508 (78.7%) were eligible.,Overall, 12.1% of COPD patients did not fulfill a diagnostic spirometry criteria.,Considerable variability existed in the available resources and work organization of the hospitals, although the majority were university hospitals with respiratory inpatient units.,There was insufficient implementation of clinical guidelines in preventive and educational matters.,In contrast, quantitative evaluation of dyspnea grade (81.9%) and exacerbation history (70.9%) were more frequently performed.,Only 12.4% had COPD severity calculated according to the Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) index.,Phenotype characteristics according to Spanish National Guideline for COPD were determined in 46.3% of the audited patients, and the risk evaluation according to Global initiative for chronic Obstructive Lung Disease was estimated only in 21.9%.,The EPOCONSUL study reports the current situation of medical care for COPD patients in outpatient clinics in Spain, revealing its variability, strengths, and weaknesses.,This information has to be accounted for by health managers to define corrective strategies and maximize good clinical practice. | Some patients share characteristics of both COPD and asthma.,As yet, there is no gold standard to identify patients with the so-called asthma-COPD overlap syndrome (ACOS).,To describe the differences between ACOS patients and the remaining COPD patients, and to compare the clinical characteristics of patients diagnosed with ACOS by two different criteria: previous diagnosis of asthma before the age of 40 years; and the diagnostic criteria of the Spanish guidelines of COPD.,Multicenter, observational, cross-sectional study performed in 3,125 COPD patients recruited in primary care and specialized outpatient clinics.,Patients with COPD and a history of asthma before the age of 40 years were diagnosed with ACOS and compared to the remaining COPD patients.,Subsequently, ACOS patients were subdivided based on whether they fulfilled the Spanish guidelines of the COPD diagnostic criteria or not, and they were compared.,ACOS was diagnosed in 15.9% of the patients.,These patients had different basal characteristics compared to the remaining COPD patients, including a higher frequency of women and more exacerbations despite lower tobacco exposure and better lung function.,They were more likely to have features of asthma, such as a positive bronchodilator test, higher peripheral eosinophilia, and higher total immunoglobulin E.,Within the ACOS group, only one-third fulfilled the diagnostic criteria of the Spanish guidelines of COPD; these individuals were not significantly different from the remaining ACOS patients, except for having more exacerbations and poorer lung function.,ACOS patients diagnosed on the basis of a previous diagnosis of asthma differed from the remaining COPD patients, but they were similar to ACOS patients diagnosed according to more restrictive criteria, suggesting that a history of asthma before the age of 40 years could be a useful criterion to suspect ACOS in a patient with COPD. | 1 |
Natural history of chronic obstructive pulmonary disease (COPD) is punctuated by exacerbations; however, little is known about prognosis of the first-ever COPD exacerbation and variables predicting its outcomes.,A population-based cohort study among COPD patients with their first-ever exacerbations requiring hospitalizations was conducted.,Main outcomes were in-hospital mortality and one-year mortality after discharge.,Demographics, comorbidities, medications and in-hospital events were obtained to explore outcome predictors.,The cohort comprised 4204 hospitalized COPD patients, of whom 175 (4%) died during the hospitalization.,In-hospital mortality was related to higher age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.03-1.06) and Charlson comorbidity index score (OR: 1.08 per point; 95% CI: 1.01-1.15); angiotensin II receptor blockers (OR: 0.61; 95% CI: 0.38-0.98) and β blockers (OR: 0.63; 95% CI: 0.41-0.95) conferred a survival benefit.,At one year after discharge, 22% (871/4029) of hospital survivors were dead.,On multivariate Cox regression analysis, age and Charlson comorbidity index remained independent predictors of one-year mortality.,Longer hospital stay (hazard ratio [HR] 1.01 per day; 95% CI: 1.01-1.01) and ICU admission (HR: 1.33; 95% CI: 1.03-1.73) during the hospitalization were associated with higher mortality risks.,Prescription of β blockers (HR: 0.79; 95% CI: 0.67-0.93) and statins (HR: 0.66; 95% CI: 0.47-0.91) on hospital discharge were protective against one-year mortality.,Even the first-ever severe COPD exacerbation signifies poor prognosis in COPD patients.,Comorbidities play a crucial role in determining outcomes and should be carefully assessed.,Angiotensin II receptor blockers, β blockers and statins may, in theory, have dual cardiopulmonary protective properties and probably alter prognosis of COPD patients.,Nevertheless, the limitations inherent to a claims database study, such as the diagnostic accuracy of COPD and its exacerbation, should be born in mind. | Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit.,The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD.,To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted.,In this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P<0.0001).,Roflumilast was associated with significantly greater TDI responders and significantly fewer TDI deteriorators (≥1-unit increase or decrease from baseline, respectively) versus placebo at week 52 (P<0.01, both); these significant differences were apparent by week 8 and maintained until study end (P<0.05, all).,At study end, the postbronchodilator forced expiratory volume in 1 second improvement in TDI responders was significantly greater with roflumilast versus placebo (P<0.05).,Similar to the overall population, improvements in TDI focal scores at week 52 were small but consistently significant over placebo in patients with chronic bronchitis, regardless of exacerbation history, concomitant treatment with short-acting muscarinic antagonists or long-acting β2-agonists, or pretreatment with inhaled corticosteroids.,This analysis shows that patients treated with roflumilast to reduce exacerbation risk may also experience small but significant improvements in dyspnea, with accompanying improvements in lung function. | 1 |
Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD.,The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD.,This article analyses the evidence of efficacy and safety of the TIO/OLO combination.,A systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator.,A total of 10 Randomized controlled trials (RCT) were identified (N = 10,918).,TIO/OLO significantly improved trough FEV1 from baseline to week 12 versus TIO, OLO and LABA/ICS (0.06 L, 0.09 L and between 0.04 and 0.05 L, respectively).,TIO/OLO improved transitional dyspnea index (TDI) and St.,George’s Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% confidence interval [CI]: [1.07, 1.28] versus TIO and RR: 1.14, 95%CI: [1.01, 1.28] versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus TIO and RR: 1.28, 95%CI: [1.18, 1.40] versus OLO).,Patients treated with TIO/OLO showed a significant reduction in the use of rescue medication and no significant differences in frequency of general and serious adverse events were observed between TIO/OLO and mono-components.,Treatment with TIO/OLO provided significant improvements in lung function versus mono-components and LABA/ICS with more patients achieving significant improvements in dyspnea and health status.,No differences in adverse events were observed compared with other active treatments.,PROSPERO register of systematic reviews (CRD42016040162).,The online version of this article (10.1186/s12931-017-0683-x) contains supplementary material, which is available to authorized users. | The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with significant morbidity and healthcare resource utilization; reduced quality of life; and increased risk of hospitalization and death.,The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that patients at risk of exacerbations (GOLD Groups C and D) receive a long-acting muscarinic antagonist (LAMA) or a long-acting β2-agonist (LABA)/LAMA combination, respectively, as preferred initial treatments.,The latter recommendation is based on recent trial evidence demonstrating the superior efficacy of a fixed-dose LABA/LAMA over an inhaled corticosteroid (ICS)/LABA in exacerbation prevention.,ICS in combination with a LABA is also indicated for prevention of exacerbations, but the use of ICS is associated with an increased risk of adverse events such as pneumonia, and offers limited benefits beyond those provided by LABA or LAMA monotherapy.,In this review, we examine evidence from a number of pivotal studies of LABAs and LAMAs, administered as monotherapy or as part of dual or triple combination therapy, with a specific focus on their effect on exacerbations.,We also discuss a new proposed treatment paradigm for the management of COPD that takes into account this recent evidence and adopts a more cautious approach to the use of ICS.,In alignment with GOLD 2017, we suggest that ICS should be reserved for patients with concomitant asthma or in whom exacerbations persist despite treatment with LABA/LAMA. | 1 |
Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.,For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler.,Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).,295 and 291 patients were treated in MORACTO 1 and 2, respectively.,Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001).,Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).,Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies.,Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.,T/O reduces lung hyperinflation in COPD versus T, O or placebo and increases exercise endurance versus placebohttp://ow.ly/ml3G307XW6a | Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease.,To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT).,Qualitative: patient focus group and interviews to address content validity.,Quantitative: secondary data analyses to test reliability and validity.,Qualitative: n=84; mean (SD) age 65 (10) years, FEV1 1.2(0.4) L; 44% male.,Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure.,Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male.,Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough & Sputum, and RS-Chest Symptoms; second-order FA supported a general factor and total score.,Reliability (total and subscales): 0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively.,Validity: Total scores correlated significantly (p < 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p < 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p < 0.0001 (RS-Cough & Sputum with Symptoms).,RS-Breathlessness correlated with rescue medication use (r=0.32, p < 0.0001), clinician-reported mMRC (r=0.33, p < 0.0001), and FEV1% predicted (r=-0.17, p < 0.05).,E-RS scores differentiated groups based on chronic bronchitis diagnosis (p < 0.01-0.001), smoking status (p < 0.05-0.001), and rescue medication use (p < 0.05-0.0001).,Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD.,Further study of sensitivity to change is warranted. | 1 |
Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society.,The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options.,Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system.,This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support) to manage severe exacerbations, and strategies to prevent readmission to hospital.,Risk factors that are amenable to change have been highlighted.,A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation.,Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD.,Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management. | COPD exacerbations are responsible for the morbidity and mortality of this disease.,The relationship between exacerbations and patient-related clinical outcomes is not clearly understood.,A retrospective analysis of two 1-year, placebo-controlled clinical trials with tiotropium 18 μg daily was conducted to examine relationships between exacerbations and other clinical outcomes.,The relationship between FEV1, St.,George’s Respiratory Questionnaire (SGRQ), and the transition dyspnea index (TDI) were examined based on the frequency of exacerbations (0, 1, 2, >2).,921 patients participated in the trials (mean age 65 years, mean FEV1 = 1.02 L (39% predicted).,The percent change from baseline in FEV1 in the tiotropium group was +12.6%, +12.0%, +2.1% and +8.9%; and in the placebo group was −3.4%, −3.4%, −5.7% and −6.7% for exacerbation frequencies of 0, 1, 2, >2, respectively.,Compared with baseline, the largest improvement in SGRQ occurred in patients with no exacerbations.,In the placebo group, there was a significant association between an increased frequency of exacerbations and worsening SGRQ scores.,A reduction in exacerbation rates of 4.4% to 42.0% such as that shown in this study cohort was associated with meaningful changes in questionnaire based instruments.,In the placebo-treated patients increased frequency of exacerbations was associated with larger decrements in FEV1, TDI, and SGRQ.,A reduction in the frequency of exacerbations is associated with changes that are considered meaningful in these clinical outcomes. | 1 |
Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist.,Design Observational retrospective pairwise cohort study matched (1:1) for propensity score.,Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.,Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.,Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.,Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each.,In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up.,Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively.,The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6).,The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003).,All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).,Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.,Trial registration Clinical Trials.gov NCT01146392. | Chronic obstructive pulmonary disease (COPD) is predicted to become a major cause of death worldwide.,Studies on the variability in the estimates of key epidemiological parameters of COPD may contribute to better assessment of the burden of this disease and to helpful guidance for future research and public policies.,In the present study, we examined differences in the main epidemiological characteristics of COPD derived from studies across countries of the European Union, focusing on prevalence, severity, frequency of exacerbations and mortality, as well as on differences between the studies' methods.,This systematic review was based on a search for the relevant literature in the Science Citation Index database via the Web of Science and on COPD mortality rates issued from national statistics.,Analysis was finally based on 65 articles and Eurostat COPD mortality data for 21 European countries.,Epidemiological characteristics of COPD varied widely from country to country.,For example, prevalence estimates ranged between 2.1% and 26.1%, depending on the country, the age group and the methods used.,Likewise, COPD mortality rates ranged from 7.2 to 36.1 per 105 inhabitants.,The methods used to estimate these epidemiological parameters were highly variable in terms of the definition of COPD, severity scales, methods of investigation and target populations.,Nevertheless, to a large extent, several recent international guidelines or research initiatives, such as GOLD, BOLD or PLATINO, have boosted a substantial standardization of methodology in data collection and have resulted in the availability of more comparable epidemiological estimates across countries.,On the basis of such standardization, severity estimates as well as prevalence estimates present much less variation across countries.,The contribution of these recent guidelines and initiatives is outlined, as are the problems remaining in arriving at more accurate COPD epidemiological estimates across European countries.,The accuracy of COPD epidemiological parameters is important for guiding decision making with regard to preventive measures, interventions and patient management in various health care systems.,Therefore, the recent initiatives for standardizing data collection should be enhanced to result in COPD epidemiological estimates of improved quality.,Moreover, establishing international guidelines for reporting research on COPD may also constitute a major contribution. | 1 |
The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.,The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990-2005, using the healthcare databases from the province of Quebec, Canada.,Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified.,The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.,The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively.,The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th.,The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first.,Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.,The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation.,Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality. | Acute exacerbations may cause deteriorations in the health status of subjects with chronic obstructive pulmonary disease (COPD).,The present study prospectively evaluated the effects of such exacerbations on the health status and pulmonary function of subjects with COPD over a 6-month period, and examined whether those subjects showed a steeper decline in their health status versus those subjects without exacerbations.,A total of 156 subjects with COPD (mean age 71.4 ± 6.3 years) were included in the analysis.,At baseline and after 6 months, their pulmonary function and health status were evaluated using the Chronic Respiratory Disease Questionnaire (CRQ) and the St.,George's Respiratory Questionnaire (SGRQ).,An acute exacerbation was defined as a worsening of respiratory symptoms requiring the administration of systemic corticosteroids or antibiotics, or both.,Forty-eight subjects experienced one or more exacerbations during the 6-month study period, and showed a statistically and clinically significant decline in Symptom scores on the SGRQ, whereas subjects without exacerbations did not show a clinically significant decline.,Logistic multiple regression analyses confirmed that the exacerbations significantly influenced the Fatigue and Mastery domains of the CRQ, and the Symptoms in the SGRQ.,Twelve subjects with frequent exacerbations demonstrated a more apparent decline in health status.,Although pulmonary function did not significantly decline during the 6-month period, acute exacerbations were responsible for a decline in health status.,To minimize deteriorations in health status, one must prevent recurrent acute exacerbations and reduce the exacerbation frequencies in COPD subjects. | 1 |
Effects of roflumilast on lung function, symptoms, acute exacerbation and adverse events in patients with chronic obstructive pulmonary disease (COPD) are controversial.,We aimed to further clarify the efficacy and safety of roflumilast in treatment of moderate-to-severe COPD.,From 1946 to November 2015, we searched the Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials, ISI Web of Science and American College of Physician using “roflumilast” and “chronic obstructive pulmonary disease” or “COPD”.,Randomized controlled trials that reported forced expiratory volume in one second (FEV1), forced vital capacity (FVC), transition dyspnea index (TDI), St George’s Respiratory Questionnaire (SGRQ), and incidence of COPD exacerbations and adverse events were eligible.,We conducted the heterogeneities test and sensitivity analysis, and random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference (MD) for dichotomous and continuous data respectively.,Cochrane systematic review software, Review Manager (RevMan), was used to test the hypothesis by Mann-Whitney U-test.,Thirteen trials with a total of 14,563 patients were pooled in our final studies.,Except for SGRQ (I2 = 63 %, χ2 = 1.71, P = 0.07) and adverse events (I2 = 94 %, χ2 = 0.03, P < 0.001), we did not find statistical heterogeneity in outcome measures.,The pooled MD of pre- and post-bronchodilator FEV1 was 54.60 (95 % confidence interval (CI) 46.02 ~ 63.18) and 57.86 (95 % CI 49.80 ~ 65.91), and both showed significant improvement in patients with roflumilast (z = 12.47, P <0.001; z = 14.07, P < 0.001), so did in FVC (MD 90.37, 95 % CI 73.95 ~ 106.78, z = 10.79, P < 0.001).,Significant alleviation of TDI (MD 0.30, 95 % CI 0.14 ~ 0.46, z = 3.67, P < 0.001) and decrease of acute exacerbation (RR 0.86, 95 % CI 0.81 ~ 0.91, z = 5.54, P < 0.001) were also identified in treatment of roflumilast, but without significant difference in SGRQ (MD −1.30, 95 % CI −3.16 ~ 0.56, z = 1.37, P = 0.17).,Moreover, roflumilast significantly increased the incidence of adverse events compared with placebo (RR 1.31, 95 % CI 1.16 ~ 1.47, z = 4.32, P < 0.001).,Roflumilast can be considered as an alternative therapy in selective patients with moderate-to-severe COPD. | 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 |
Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients.,The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients.,CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables.,The predictive power of each parameter was explored using CV events as the main outcome.,During a median follow up of 65 months (ICR: 36-100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%).,A total of 35 CV deaths occurred during that period.,Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events.,Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19-1.46, p < 001).,In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events.,This tool may help evaluate the risk for a CV event in patients with COPD.,Larger studies should reproduce and validate these findings. | 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 contribution to airflow obstruction by the remodeling of the peripheral airways in chronic obstructive pulmonary disease (COPD) patients has been well documented, but less is known about the role played by the large airways.,Few studies have investigated the presence of histopathological changes due to remodeling in the large airways of COPD patients.,The aim of this study was to verify the presence of airway remodeling in the central airways of COPD patients, quantifying the airway smooth muscle (ASM) area and the extracellular matrix (ECM) protein deposition, both in the subepithelial region and in the ASM, and to verify the possible contribution to airflow obstruction by the above mentioned histopathological changes.,Biopsies of segmental bronchi spurs were performed in COPD patients and control smoker subjects and immunostained for collagen type I, versican, decorin, biglycan, and alpha-smooth muscle actin.,ECM protein deposition was measured at both subepithelial, and ASM layers.,The staining for collagen I and versican was greater in the subepithelial layer of COPD patients than in control subjects.,An inverse correlation was found between collagen I in the subepithelial layer and both forced expiratory volume in 1 second and ratio between forced expiratory volume in 1 second and forced vital capacity.,A statistically significant increase of the ASM area was observed in the central airways of COPD patients versus controls.,These findings indicate that airway remodeling also affects the large airways in COPD patients who have greater deposition of ECM proteins in the subepithelial layer and a larger smooth muscle area than control smoker subjects.,These changes may contribute to chronic airflow obstruction in COPD patients. | Eosinophilic airway inflammation is observed in 10-30% of COPD subjects.,Whether increased eosinophils or impairment in their clearance by macrophages is associated with the severity and frequency of exacerbations is unknown.,We categorised 103 COPD subjects into 4 groups determined by the upper limit of normal for their cytoplasmic macrophage red hue (<6%), an indirect measure of macrophage efferocytosis of eosinophils, and area under the curve sputum eosinophil count (≥3%/year).,Eosinophil efferocytosis by monocyte-derived macrophages was studied in 17 COPD subjects and 8 normal controls.,There were no differences in baseline lung function, health status or exacerbation frequency between the groups: A-low red hue, high sputum eosinophils (n = 10), B-high red hue, high sputum eosinophils (n = 16), C-low red hue, low sputum eosinophils (n = 19) and D- high red hue, low sputum eosinophils (n = 58).,Positive bacterial culture was lower in groups A (10%) and B (6%) compared to C (44%) and D (21%) (p = 0.01).,The fall in FEV1 from stable to exacerbation was greatest in group A (ΔFEV1 [95 % CI] -0.41 L [-0.65 to -0.17]) versus group B (-0.16 L [-0.32 to -0.011]), C (-0.11 L [-0.23 to -0.002]) and D (-0.16 L [-0.22 to -0.10]; p = 0.02).,Macrophage efferocytosis of eosinophils was impaired in COPD versus controls (86 [75 to 92]% versus 93 [88 to 96]%; p = 0.028); was most marked in group A (71 [70 to 84]%; p = 0.0295) and was inversely correlated with exacerbation frequency (r = -0.63; p = 0.006).,Macrophage efferocytosis of eosinophils is impaired in COPD and is related to the severity and frequency of COPD exacerbations. | 1 |
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