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The mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood.,Inhaled corticosteroids (ICSs) are widely used in COPD, but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown.,The aim of this study was to evaluate the effect of ICSs following pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme-2 (ACE2).,We evaluated the effect of ICS administration on pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration.,Mice deficient in the type I IFN-α/β receptor (Ifnar1−/−) and administration of exogenous IFN-β were used to study the functional role of type-I interferon signaling in ACE2 expression.,We compared sputum ACE2 expression in patients with COPD stratified according to use or nonuse of ICS.,ICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous IFN-β administration, and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect.,ICS administration attenuated expression of ACE2 in airway epithelial cell cultures from patients with COPD and in mice with elastase-induced COPD-like changes.,Compared with ICS nonusers, patients with COPD who were taking ICSs also had reduced sputum expression of ACE2.,ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2.,This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD. | Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms.,Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections.,Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations.,Exogenous interferon-β reverses these effects.,FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways.,Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection.,This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production.,Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.,Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia.,Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ. | 1 |
According to the Fletcher-Peto curve, rate of decline in forced expiratory volume in 1-second (FEV1) accelerates as age increases.,However, recent studies have not demonstrated that the rate of FEV1 decline accelerates with age among COPD patients.,The objective of the study is to evaluate annual rate of FEV1 decline as age increases among COPD patients.,In this retrospective cohort study, we enrolled COPD patients who were followed up at two tertiary care university hospitals from January 2000 to August 2013.,COPD was defined as post-bronchodilator (BD) FEV1/forced vital capacity (FVC) of <0.7.,All participants had more than two spirometries, including BD response.,Age groups were categorized as follows: below versus above median age or four quartiles.,A total of 518 participants (94.2% male; median age, 67 years; range, 42-90 years) were included.,Mean absolute and predictive values of post-BD FEV1 were 1.57±0.62 L and 52.53%±18.29%, respectively.,Distribution of Global initiative for Chronic Obstructive Lung Disease groups did not show statistical differences between age groups categorized by two different criteria.,After grouping the population by age quartiles, the rate of FEV1 decline was faster among older patients than younger ones whether expressed as absolute value (−10.60±5.57 mL/year, −15.84±6.01 mL/year, −18.63±5.53 mL/year, 32.94±6.01 mL/year, respectively; P=0.048) or predicted value (−0.34%±0.19%/year, −0.53%±0.21%/year, −0.62%±0.19%/year, −1.26%±0.21%/year, respectively, P=0.010).,As suggested conceptually by the Fletcher−Peto curve, annual FEV1 decline among COPD patients is accelerated among older patients than younger ones. | The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting β2-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU.,They are not indicated for the treatment of asthma.,In this 52-week, double-blind, placebo-controlled, parallel-group safety study (GSK study DB2113359; NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo.,Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms.,COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated.,The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52-58%; SAEs: 6-7%; drug-related AEs: 12-13%).,Headache was the most common AE in each treatment group (8-11%).,AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups.,No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo.,The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were ≥2% greater than placebo.,With active treatments, COPD exacerbations were fewer (13-15% of patients reporting ≥1 exacerbation) and on average less rescue medication was required (1.6-2.2 puffs/day) versus placebo (24% reporting ≥1 exacerbation, 2.6 puffs/day).,Both active treatments improved lung function versus placebo.,UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD. | 1 |
The association between exposure to ambient particles with a median aerodynamic diameter less than 10/2.5 µm (particulate matter, PM10/2.5) and COPD remains unclear.,Our study objective was to examine the association between ambient PM10/2.5 concentrations and lung functions in adults.,A cross-sectional study was conducted in southern China.,Seven clusters were randomly selected from four cities across Guangdong province.,Residents aged ≥20 years in the participating clusters were randomly recruited; all eligible participants were examined with a standardised questionnaire and spirometry.,COPD was defined as a post-bronchodilator FEV1/FVC less than 70%.,Atmosphere PM sampling was conducted across the clusters along with our survey.,Of the subjects initially recruited, 84.4% (n=5993) were included for analysis.,COPD prevalence and atmosphere PM concentration varied significantly among the seven clusters.,COPD prevalence was significantly associated with elevated PM concentration levels: adjusted OR 2.416 (95% CI 1.417 to 4.118) for >35 and ≤75 µg/m3 and 2.530 (1.280 to 5.001) for >75 µg/m3 compared with the level of ≤35 µg/m3 for PM2.5; adjusted OR 2.442 (95% CI 1.449 to 4.117) for >50 and ≤150 µg/m3 compared with the level of ≤50 µg/m3 for PM1.,A 10 µg/m3 increase in PM2.5 concentrations was associated with a 26 mL (95% CI −43 to −9) decrease in FEV1, a 28 mL (−49 to −8) decrease in FVC and a 0.09% decrease (−0.170 to −0.010) in FEV1/FVC ratio.,The associations of COPD with PM10 were consistent with PM2.5 but slightly weaker.,Exposure to higher PM concentrations was strongly associated with increased COPD prevalence and declined respiratory function.,ChiCTR-OO-14004264; Post-results. | To investigate patient characteristics of an unselected primary care population associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,Retrospective open cohort using pseudonymised electronic primary care data linked to secondary care data.,Primary care; Lothian (population approximately 800 000), Scotland.,Data from 7002 patients from 72 general practices with a COPD diagnosis date between 2000 and 2008 recorded in their primary care record.,Patients were followed up until 2010, death or they left a participating practice.,First and subsequent admissions for AECOPD (International Classification of Diseases (ICD) 10 codes J44.0, J44.1 in any diagnostic position) after COPD diagnosis in primary care.,1756 (25%) patients had at least 1 AECOPD admission; 794 (11%) had at least 1 readmission and the risk of readmission increased with each admission.,Older age at diagnosis, more severe COPD, low body mass index (BMI), current smoking, increasing deprivation, COPD admissions and interventions for COPD prior to diagnosis in primary care, and comorbidities were associated with higher risk of first AECOPD admission in an adjusted Cox proportional hazards regression model.,More severe COPD and COPD admission prior to primary care diagnosis were associated with increased risk of AECOPD readmission in an adjusted Prentice-Williams-Peterson model.,High BMI was associated with a lower risk of first AECOPD admission and readmission.,Several patient characteristics were associated with first AECOPD admission in a primary care cohort of people with COPD but fewer were associated with readmission.,Prompt diagnosis in primary care may reduce the risk of AECOPD admission and readmission.,The study highlights the important role of primary care in preventing or delaying a first AECOPD admission. | 1 |
The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms.,Determining systemic mediators may help clarify the nature of inflammation in patients with ACO.,We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO.,This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO.,ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD.,Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis.,In total, 109 ACO, 89 COPD, and 94 asthma patients were included.,Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p=0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p<0.001).,Their values in ACO were intermediate between those in asthma and in COPD.,Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD.,IL-13 was the most connected node in the network, with different weights among the three conditions.,Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern.,IL-13 could be central to the regulation of inflammation in these conditions. | The role of Pulmonary and Activation-Regulated Chemokine (PARC) in the physiopathology of Chronic Obstructive Pulmonary Disease (COPD) is not fully understood.,The aim of the present study is to analyze the expression of PARC in lung tissue and its relationship with the vascular remodeling of the systemic and pulmonary arteries of COPD subjects.,To achieve this objective, protein and gene expression experiments, together with ELISA assays, were performed on the lung tissue, intercostal arteries and serum samples from COPD patients, non-obstructed smokers (NOS) and never-smokers (NS).,A total of 57 subjects were included in the analysis (23 COPD, 18 NOS and 16 NS).,In the comparisons between groups, a significantly increased lung protein expression of PARC was observed in the COPD group compared to the NOS group (1.96±0.22 vs.,1.29±0.27, P-adjusted = 0.038).,PARC was located predominantly in the smooth muscle cells of the remodeled pulmonary muscular arteries and the macrophage-rich area of the alveolar parenchyma.,No differences were detected in PARC gene expression analyses.,The protein content of PARC in the intercostal arteries were similar between groups, though little remodeling was observed in these arteries.,Circulating levels of PARC were numerically higher in patients with COPD compared to NOS and NS.,The results of the present study suggest an increased lung protein expression of PARC in COPD subjects.,This protein was mainly localized in the smooth muscle cells of the pulmonary muscular arteries and was associated with the severity of intimal thickening, indicating its possible role in this remodeling process. | 1 |
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends triple therapy (long-acting muscarinic receptor antagonists, long-acting beta-2 agonists, and inhaled corticosteroids) for patients with only the most severe COPD.,Data on the proportion of COPD patients on triple therapy and their characteristics are sparse and dated.,Objective 1 of this study was to estimate the proportion of all, and all treated, COPD patients receiving triple therapy.,Objective 2 was to characterize those on triple therapy and assess the concordance of triple therapy use with GOLD guidelines.,This retrospective study used claims from the IMS PharMetrics Plus database from 2009 to 2013.,Cohort 1 was selected to assess Objective 1 only; descriptive analyses were conducted in Cohort 2 to answer Objective 2.,A validated claims-based algorithm and severity and frequency of exacerbations were used as proxies for COPD severity.,Of all 199,678 patients with COPD in Cohort 1, 7.5% received triple therapy after diagnosis, and 25.5% of all treated patients received triple therapy.,In Cohort 2, 30,493 COPD patients (mean age =64.7 years) who initiated triple therapy were identified.,Using the claims-based algorithm, 34.5% of Cohort 2 patients were classified as having mild disease (GOLD 1), 40.8% moderate (GOLD 2), 22.5% severe (GOLD 3), and 2.3% very severe (GOLD 4).,Using exacerbation severity and frequency, 60.6% of patients were classified as GOLD 1/2 and 39.4% as GOLD 3/4.,In this large US claims database study, one-quarter of all treated COPD patients received triple therapy.,Although triple therapy is recommended for the most severe COPD patients, spirometry is infrequently assessed, and a majority of the patients who receive triple therapy may have only mild/moderate disease.,Any potential overprescribing of triple therapy may lead to unnecessary costs to the patient and health care system. | Background: To validate the ‘Test of Adherence to Inhalers’ (TAI), a 12-item questionnaire designed to assess the adherence to inhalers in patients with COPD or asthma.,Methods: A total of 1009 patients with asthma or COPD participated in a cross-sectional multicenter study.,Patients with electronic adherence ≥80% were defined as adherents.,Construct validity, internal validity, and criterion validity were evaluated.,Self-reported adherence was compared with the Morisky-Green questionnaire.,Results: Factor analysis study demonstrated two factors, factor 1 was coincident with TAI patient domain (items 1 to 10) and factor 2 with TAI health-care professional domain (items 11 and 12).,The Cronbach's alpha was 0.860 and the test-retest reliability 0.883.,TAI scores correlated with electronic adherence (ρ=0.293, p=0.01).,According to the best cut-off for 10 items (score 50, area under the ROC curve 0.7), 569 (62.5%) patients were classified as non-adherents.,The non-adherence behavior pattern was: erratic 527 (57.9%), deliberate 375 (41.2%), and unwitting 242 (26.6%) patients.,As compared to Morisky-Green test, TAI showed better psychometric properties.,Conclusions: The TAI is a reliable and homogeneous questionnaire to identify easily non-adherence and to classify from a clinical perspective the barriers related to the use of inhalers in asthma and COPD. | 1 |
The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) questionnaire is a short patient-completed questionnaire, which is used to assess the health status of patients with stable COPD.,However, whether it is a good tool to evaluate the response to treatment in acute exacerbation of COPD (AECOPD) has been less studied.,The patients were assessed at two visits, at admission and on the seventh day.,Anthropometric variables were collected at admission.,CAT and lung function were measured twice at the above time points.,At the second visit, the health status of the patients were divided into five groups based on a 5-point Likert scale, ranging from 1 to 5, which represents “much better,” “slightly better,” “no change,” “slightly worse,” and “much worse.”,Responders were those who reported “much better” or “slightly better,” and nonresponders were those who claimed “no change,” “worse,” or “much worse.”,In total, 225 patients were recruited.,The average CAT score at admission was 24.82±7.41, which declined to 17.41±7.35 on the seventh day.,There were 81.33% responders, whose improvement in CAT score (9.37±5.24) was much higher than that of the nonresponders (−1.36±4.35).,A moderate correlation was observed between the changes in CAT score and improvement in FEV1, FEV1%, and the length of hospital stay.,There was a strong correlation between the changes in CAT score and health status.,A 3.5-unit improvement in the CAT score, with highest area under the curve, was the cutoff to differentiate responders from nonresponders.,The evolution of CAT scores during exacerbation can provide useful information to assess the health status of patients with AECOPD.,A 3.5-unit improvement in CAT score is the best cutoff to differentiate between patients who have a response or no response to treatment, which offers a convenient and easy way for clinicians to monitor the health status of patients with an AECOPD. | 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 |
Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation.,Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown.,To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD.,Subjects with asthma and COPD (n = 54 and n = 49) were studied.,Clinical characteristics and sputum were collected at entry into the study.,A 2-step sputum processing method was performed for supernatant and cytospin preparation.,Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels.,Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1β, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17.,There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3-5.4), p = 0.01; TNFRI, 2.1 (1.3-5.4), p = 0.03; TNFRII, 2.6 (1.2-5.6), p = 0.02].,In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes.,However, these phenotypes were unrelated to the diagnosis of asthma or COPD.,Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique.,Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease.,Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated. | Chronic obstructive pulmonary disease is a common condition and a major cause of mortality.,COPD is characterized by irreversible airflow obstruction.,The physiological abnormalities observed in COPD are due to a combination of emphysema and obliteration of the small airways in association with airway inflammation.,The predominant cells involved in this inflammatory response are CD8+ lymphocytes, neutrophils, and macrophages.,Although eosinophilic airway inflammation is usually considered a feature of asthma, it has been demonstrated in large and small airway tissue samples and in 20%-40% of induced sputum samples from patients with stable COPD.,This airway eosinophilia is increased in exacerbations.,Thus, modifying eosinophilic inflammation may be a potential therapeutic target in COPD.,Eosinophilic airway inflammation is resistant to inhaled corticosteroid therapy, but does respond to systemic corticosteroid therapy, and the degree of response is related to the intensity of the eosinophilic inflammation.,In COPD, targeting treatment to normalize the sputum eosinophilia reduced the number of hospital admissions.,Whether controlling eosinophilic inflammation in COPD patients with an airway eosinophilia will modify disease progression and possibly alter mortality is unknown, but warrants further investigation. | 1 |
A high prevalence of bronchiectasis was found by chest computed tomography (CT) in patients with moderate-severe chronic obstructive pulmonary disease (COPD), and it was shown to be associated with more severe symptoms, higher frequency of exacerbations and mortality.,The risk factors for bronchiectasis in COPD are not yet clarified.,High-resolution computed tomography (HRCT) of chest was performed in patients with moderate-severe COPD, and the presence and the extent of bronchiectasis were evaluated by two radiologists.,Demographic data, respiratory symptoms, lung function, previous pulmonary tuberculosis, serum inflammatory markers, serum total immunoglobulin E (T-IgE), and sputum culture of Pseudomonas aeruginosa were compared between those with and without bronchiectasis.,Multivariate logistic regression analysis was used to determine the independent factors associated with bronchiectasis.,We enrolled 190 patients with stable COPD, of which 87 (87/190, 45.8%) had bronchiectasis on HRCT.,Compared with those without bronchiectasis, COPD patients with bronchiectasis were more likely to be males (P = 0.021), had a lower body mass index (BMI) (P = 0.019), a higher prevalence of previous tuberculosis (P = 0.005), longer history of dyspnea (P < 0.001), more severe dyspnea (P = 0.041), higher frequency of acute exacerbation (P = 0.002), higher serum concentrations of C-reactive protein (CRP) (P = 0.017), fibrinogen (P = 0.016), and T-IgE [P = 0.004; for log10(T-IgE), P <0.001].,COPD patients with bronchiectasis also showed poorer lung function (for FEV1/FVC, P = 0.013; for FEV1%predicted, P = 0.012; for global initiative for chronic obstructive lung disease (GOLD) grades, P = 0.035), and a higher positive rate of sputum P aeruginosa (P = 0.020).,Logistic regression analysis demonstrated that male gender (P = 0.021), previous tuberculosis (P = 0.021), and increased level of serum T-IgE [for log10(T-IgE), P < 0.001] were risk factors for coexistent bronchiectasis.,More notably, the level of serum T-IgE [log10(T-IgE)] was positively correlated with the extent of bronchiectasis in COPD patients (r = 0.208, P = 0.05).,Higher serum T-IgE, male gender, and previous tuberculosis are independent risk factors for coexistent bronchiectasis in COPD.,The association of T-IgE with the extent of bronchiectasis also suggests that further investigations are needed to explore the potential role of IgE in the pathogenesis of bronchiectasis in COPD. | Bronchiectasis is prevalent in patients with COPD.,The objective of this study was to assess the clinical characteristics and prognostic value of bronchiectasis in patients with COPD in China.,Data from patients diagnosed with COPD at the Shanghai Pulmonary Hospital between January 2009 and December 2013 were retrospectively collected and analyzed.,SPSS statistical software was used to analyze the data.,Data from 896 patients with COPD were analyzed.,Bronchiectasis was present in 311 patients.,The isolation of pseudomonas aeruginosa (PA) from sputum was the variable most significantly associated with the presence of bronchiectasis in patients with COPD (hazard ratio (HR), 2.93; 95% confidence interval (CI), 1.35-6.37; P = 0.007).,During follow-up (median of 21 months; interquartile range: 10-39 months), there were 75 deaths, of which 39 were in the bronchiectasis group.,The presence of bronchiectasis (HR, 1.77; 95% CI, 1.02-3.08; P = 0.043) was associated with an increase in all-cause mortality in patients with COPD.,These results suggest that bronchiectasis in patients with COPD was associated with the isolation of PA from the sputum.,Bronchiectasis was an independent risk factor for all-cause mortality in patients with COPD. | 1 |
Sustained bronchodilation using inhaled medications in moderate to severe chronic obstructive pulmonary disease (COPD) grades 2 and 3 (Global Initiative for Chronic Obstructive Lung Disease guidelines) has been shown to have clinical benefits on long-term symptom control and quality of life, with possible additional benefits on disease progression and longevity.,Aggressive diagnosis and treatment of symptomatic COPD is an integral and pivotal part of COPD management, which usually begins with primary care physicians.,The current standard of care involves the use of one or more inhaled bronchodilators, and depending on COPD severity and phenotype, inhaled corticosteroids.,There is a wide range of inhaler devices available for delivery of inhaled medications, but suboptimal inhaler use is a common problem that can limit the clinical effectiveness of inhaled therapies in the real-world setting.,Patients’ comorbidities, other physical or mental limitations, and the level of inhaler technique instruction may limit proper inhaler use.,This paper presents information that can overcome barriers to proper inhaler use, including issues in device selection, steps in correct technique for various inhaler devices, and suggestions for assessing and monitoring inhaler techniques.,Ensuring proper inhaler technique can maximize drug effectiveness and aid clinical management at all grades of COPD. | 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 |
Chronic obstructive pulmonary disease (COPD) is characterized by a decline of lung function and symptoms such as chronic bronchitis and emphysema leading from lung tissue destruction.,Increased activity of matrix metalloproteinases (MMPs) and an imbalance between MMPs and their tissue inhibitors (TIMPs) are considered as factors influencing the pathogenesis of COPD.,We investigated the role of genetic polymorphism and expression level of MMP-9 and concentration of its complexes with TIMPs in the development of COPD among Polish patients.,We analyzed SNP in the promoter region of MMP-9 gene (rs3918242) using PCR-RFLP method among 335 COPD patients and 309 healthy individuals.,Additionally, 60 COPD patients and 61 controls were tested for copy number variants (CNV) of MMP-9 (by quantitative real-time PCR) and serum levels of MMP-9 and its complexes with TIMP1 and TIMP2 (using ELISA).,All subjects were analyzed for lung function using spirometry (FEV1% and FEV1/FVC parameters).,We observed that allele and genotype frequencies of the SNP rs3918242, as well as the number of gene copies, were similar in COPD patient and controls groups.,Serum levels of MMP-9 and MMP-9/TIMP1 complex were significantly higher in COPD patients in comparison to controls groups, although independently of analyzed gene polymorphisms.,Additionally, the significant inverse relationships between parameters of lung function (FEV1% and FEV1/FVC) and proteins level were found in ridge regression models, especially we found that FEV1% decreased when MMP-9 level increased in controls and patients with COPD group.,In conclusion, we found that COPD patients were predisposed to produce more MMP-9 and MMP-9/TIMP1 complex than healthy individuals.,This phenomenon is probably associated with the disease-related lung environment but not with genetic features of the MMP-9. | Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD).,It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency.,We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency.,Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7).,Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis.,No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups.,Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively).,Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT. | 1 |
Caregivers of individuals with COPD have a key role in maintaining patient adherence and optimizing patient function.,However, no systematic review has examined how the caregiver role has been operationalized in interventions to improve outcomes of individuals with COPD or the quality or effectiveness of these interventions.,The aims of this review were to 1) determine whether caregivers have been involved as part of interventions to improve outcomes of individuals with COPD; 2) determine the risk of bias within included intervention studies; and 3) examine the effectiveness of interventions that have involved caregivers in improving outcomes of individuals with COPD.,The electronic databases of Medline, Embase, PsycINFO, and Cochrane Library were searched from January 2000 to November 2015.,Experimental studies testing interventions that involved a caregiver to improve COPD patient outcomes were eligible.,Nine studies involving caregivers met inclusion criteria.,No studies reported any intervention components targeted solely at caregivers, with most instead including caregivers in dyadic or group education sessions about COPD delivered by health care professionals.,The risk of bias identified in included studies was mixed.,Seven of the nine studies were effective in improving a broad range of outcomes.,These findings highlight that there is an urgent need for methodologically rigorous interventions to examine the effectiveness of strategies to assist caregivers to provide direct care, encourage adherence to health care provider recommendations, act as a health care advocate, and provide emotional and psychosocial support to individuals with COPD. | 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. | 1 |
The combination of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) is associated with substantial morbidity and mortality.,We hypothesized that predictors of OSA among patients with COPD may be distinct from OSA in the general population.,Therefore, we investigated associations between traditional OSA risk factors (e.g. age), and sleep questionnaires [e.g.,Epworth Sleepiness Scale] in 44 patients with advanced COPD.,As a second aim we proposed a pilot, simplified screening test for OSA in patients with COPD.,In a prospective, observational study of patients enrolled in the UCSD Pulmonary Rehabilitation Program we collected baseline characteristics, cardiovascular events (e.g. atrial fibrillation), and sleep questionnaires [e.g.,Pittsburgh Sleep Quality Index (PSQI)].,For the pilot questionnaire, a BMI ≥25 kg/m2 and the presence of cardiovascular disease were used to construct the pilot screening test.,Male: 59%; OSA 66%.,FEV1 (mean ± SD) = 41.0±18.2% pred., FEV1/FVC = 41.5±12.7%].,Male gender, older age, and large neck circumference were not associated with OSA.,Also, Epworth Sleepiness Scale and the STOP-Bang questionnaire were not associated with OSA in univariate logistic regression.,In contrast, BMI ≥25 kg/m2 (OR = 3.94, p = 0.04) and diagnosis of cardiovascular disease (OR = 5.06, p = 0.03) were significantly associated with OSA [area under curve (AUC) = 0.74].,The pilot COPD-OSA test (OR = 5.28, p = 0.05) and STOP-Bang questionnaire (OR = 5.13, p = 0.03) were both associated with OSA in Receiver Operating Characteristics (ROC) analysis.,The COPD-OSA test had the best AUC (0.74), sensitivity (92%), and specificity (83%).,A ten-fold cross-validation validated our results.,We found that traditional OSA predictors (e.g. gender, Epworth score) did not perform well in patients with more advanced COPD.,Our pilot test may be an easy to implement instrument to screen for OSA.,However, a larger validation study is necessary before further clinical implementation is warranted. | In this study, we measured night’s rest parameters measured with an accelerometer and sleep quality in mild to very severe patients with COPD.,Furthermore, our aim was to investigate the association between night’s rest parameters and clinical variables and the association between sleep quality and quality of life or health status.,Mild to very severe COPD patients were recruited from general practitioners and outpatient clinics of general hospitals to participate in a cross-sectional study on physical activity in patients with COPD.,A total of 103 patients (mean age 65 years, 67 % male) wore the accelerometer during night’s rest for at least four nights and were included in the analyses.,No significant associations were found between objectively measured body movements during night’s rest or subjective sleep quality and lung function, dyspnoea severity, body composition and physical activity during the day.,Patients with frequent sputum production during the day had a higher number of sitting transitions during the night (5.3 vs 4.3 sitting transitions) and more frequently got out of bed compared to patients who hardly ever produced sputum during the day (1.0 vs 0.8 times per night).,Furthermore, these patients also reported worse sleep quality (Pittsburgh sleep quality index (PSQI) score 4 vs 3).,Our results indicate that objectively measured body movements during night’s rest like body postures and transitions are not related to sleep quality in patients with COPD.,We did find an association between frequent sputum production and disturbances during night’s rest and sleep quality.,Future studies should investigate whether the treatment of mucus hypersecretion leads to improved night’s rest. | 1 |
The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD).,The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD.,This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD.,It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers.,The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report.,This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations.,The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient.,The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma-COPD overlap syndrome (ACOS).,These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions.,For the low exacerbation risk phenotype, pharmacotherapy with short-acting β2-agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol-ipratropium) is recommended in patients with less symptoms.,If short-acting bronchodilators are not enough to control symptoms, a long-acting β2-agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended.,For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting β2-agonist (budesonide-formoterol, beclomethasone dipropionate-formoterol, fluticasone propionate-salmeterol or fluticasone furoate-vilanterol) is recommended as a first choice.,Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium-indacaterol or umeclidinium-vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting β2-agonist and a long-acting anticholinergic.,If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast.,ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD.,Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD.,Thus, evidence-based recommendation of treatment cannot be given.,The treatment should cover both diseases.,Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (β2-agonist or anticholinergic or both). | It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations.,The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations.,914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited.,Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients).,FEV1, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period.,816 patients (89.3%) concluded the study.,FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6.,We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6.,We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. | 1 |
Previously we generated a chronic obstructive pulmonary disease (COPD) specific knowledge base (http://www.copdknowledgebase.eu) from clinical and experimental data, text-mining results and public databases.,This knowledge base allowed the retrieval of specific molecular networks together with integrated clinical and experimental data.,The COPDKB has now been extended to integrate over 40 public data sources on functional interaction (e.g. signal transduction, transcriptional regulation, protein-protein interaction, gene-disease association).,In addition we integrated COPD-specific expression and co-morbidity networks connecting over 6 000 genes/proteins with physiological parameters and disease states.,Three mathematical models describing different aspects of systemic effects of COPD were connected to clinical and experimental data.,We have completely redesigned the technical architecture of the user interface and now provide html and web browser-based access and form-based searches.,A network search enables the use of interconnecting information and the generation of disease-specific sub-networks from general knowledge.,Integration with the Synergy-COPD Simulation Environment enables multi-scale integrated simulation of individual computational models while integration with a Clinical Decision Support System allows delivery into clinical practice.,The COPD Knowledge Base is the only publicly available knowledge resource dedicated to COPD and combining genetic information with molecular, physiological and clinical data as well as mathematical modelling.,Its integrated analysis functions provide overviews about clinical trends and connections while its semantically mapped content enables complex analysis approaches.,We plan to further extend the COPDKB by offering it as a repository to publish and semantically integrate data from relevant clinical trials.,The COPDKB is freely available after registration at http://www.copdknowledgebase.eu. | Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation.,Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy.,Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate.,In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators.,Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles.,Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization.,These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients. | 1 |
Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and is characterized by progressive airflow limitation that is not fully reversible.,The main etiological agents linked with COPD are cigarette smoking and biomass exposure but respiratory infection is believed to play a major role in the pathogenesis of both stable COPD and in acute exacerbations.,Acute exacerbations are associated with more rapid decline in lung function and impaired quality of life and are the major causes of morbidity and mortality in COPD.,Preventing exacerbations is a major therapeutic goal but currently available treatments for exacerbations are not very effective.,Historically, bacteria were considered the main infective cause of exacerbations but with the development of new diagnostic techniques, respiratory viruses are also frequently detected in COPD exacerbations.,This article aims to provide a state-of-the art review of current knowledge regarding the role of infection in COPD, highlight the areas of ongoing debate and controversy, and outline emerging technologies and therapies that will influence future diagnostic and therapeutic pathways in COPD. | Strains of nontypeable Haemophilus influenzae show enormous genetic heterogeneity and display differential virulence potential in different clinical settings.,The igaB gene, which encodes a newly identified IgA protease, is more likely to be present in the genome of COPD strains of H. influenzae than in otitis media strains.,Analysis of igaB and surrounding sequences in the present study showed that H. influenzae likely acquired igaB from Neisseria meningitidis and that the acquisition was accompanied by a ∼20 kb genomic inversion that is present only in strains that have igaB.,As part of a long running prospective study of COPD, molecular typing of H. influenzae strains identified a clonally related group of strains, a surprising observation given the genetic heterogeneity that characterizes strains of nontypeable H. influenzae.,Analysis of strains by 5 independent methods (polyacrylamide gel electrophoresis, multilocus sequence typing, igaB gene sequences, P2 gene sequences, pulsed field gel electrophoresis) established the clonal relationship among the strains.,Analysis of 134 independent strains collected prospectively from a cohort of adults with COPD demonstrated that ∼10% belonged to the clonal group.,We conclude that a clonally related group of strains of nontypeable H. influenzae that has two IgA1 protease genes (iga and igaB) is adapted for colonization and infection in COPD.,This observation has important implications in understanding population dynamics of H. influenzae in human infection and in understanding virulence mechanisms specifically in the setting of COPD. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults.,As lower PA is associated with increased mortality, improving PA is an important objective for COPD management.,This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA.,Outpatients aged ≥40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled.,Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics.,Secondary outcomes included further investigation of the influence of patient characteristics on PA.,Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated.,Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3).,Median (Q1, Q3) durations of PA at ≥3 (moderate-to-vigorous) and ≥2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively.,For >30% of patients, time spent in ≥3 METs activity was ≤10 minutes.,Unemployment was significantly correlated with reduced activity time (≥3 and ≥2 METs) and step count.,Severe GOLD stage was significantly correlated with reduced activity time (≥3 and ≥2 METs).,High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥3 METs) and step count.,Patients tended to overestimate the time spent in activities requiring ≥2 METs in their subjective reports compared with activity monitor measurements.,Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II.,Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA.,NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp). | Information about daily physical activity levels (PAL) in subjects with undiagnosed chronic obstructive pulmonary disease (COPD) is scarce.,This study aims to assess PA and to investigate the associations between PA and clinical characteristics in subjects with newly diagnosed COPD.,Fifty-nine subjects with a new spirometry-based diagnosis of mild (n=38) and moderate (n=21) COPD (63±6 years, 68% male) were matched with 65 smoking controls (62±7 years, 75% male).,PA (daily steps, time spent in moderate-to-vigorous intense physical activities (MVPA) and PAL) was measured by accelerometry.,Dyspnoea, complete pulmonary function tests, peripheral muscle strength and exercise capacity served as clinical characteristics.,PA was significantly lower in COPD versus smoking controls (7986±2648 vs 9765±3078 steps, 64 (27-120) vs 110 (55-164) min of MVPA, 1.49±0.21 vs 1.62±0.24 PAL respectively, all p<0.05).,Subjects with COPD with either mild symptoms of dyspnoea (mMRC 1), those with lower diffusion capacity (TL,co), low 6 min walking distance (6MWD) or low maximal oxygen uptake (VO2 peak) had significantly lower PA.,Multiple regression analysis identified 6 MWD and TL,co as independent predictors of PA in COPD.,The reduction in PA starts early in the disease, even when subjects are not yet diagnosed with COPD.,Inactivity is more pronounced in subjects with mild symptoms of dyspnoea, lower levels of diffusion capacity and exercise capacity. | 1 |
In the 2014 Global initiative for chronic Obstructive Lung Disease guidelines, bronchiectasis was for the first time defined as a comorbidity of chronic obstructive pulmonary disease (COPD), and this change has been retained in the 2015 update, which emphasizes the influence of bronchiectasis in the natural history of COPD.,The present meta-analysis was aimed at summarizing the impact of bronchiectasis on patients with COPD.,Databases including Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched comprehensively to identify all relevant human clinical studies published until August 2014.,Bronchiectasis was confirmed either by computed tomography or high-resolution computed tomography.,One or more clinicopathological or demographical characteristics, including age, sex, smoking history, daily sputum production, exacerbations, inflammatory biomarkers, lung function, and colonization by potentially pathogenic microorganisms (PPMs), were compared between COPD patients with and without bronchiectasis.,Six observational studies with 881 patients were included in the meta-analysis.,The mean prevalence of bronchiectasis in patients with COPD was 54.3%, ranging from 25.6% to 69%.,Coexistence of bronchiectasis and COPD occurred more often in male patients with longer smoking history.,Patients with COPD and comorbid bronchiectasis had greater daily sputum production, more frequent exacerbation, poorer lung function, higher level of inflammatory biomarkers, more chronic colonization by PPMs, and higher rate of Pseudomonas aeruginosa isolation.,In spite of the heterogeneity between included studies and detectable publication bias, this meta-analysis demonstrated the impact of bronchiectasis in patients with COPD in all directions, indicating that coexistence of bronchiectasis should be considered a pathological phenotype of COPD, which may have a predictive value. | Respiratory infections are well-known triggers of chronic respiratory diseases.,Recently, culture-independent tools have indicated that lower airway microbiota may contribute to pathophysiologic processes associated with asthma and chronic obstructive pulmonary disease (COPD).,However, the relationship between upper airway microbiota and chronic respiratory diseases remains unclear.,This study was undertaken to define differences of microbiota in the oropharynx of asthma and COPD patients relative to those in healthy individuals.,To account for the qualitative and quantitative diversity of the 16S rRNA gene in the oropharynx, the microbiomes of 18 asthma patients, 17 COPD patients, and 12 normal individuals were assessed using a high-throughput next-generation sequencing analysis.,In the 259,572 total sequence reads, α and β diversity measurements and a generalized linear model revealed that the oropharynx microbiota are diverse, but no significant differences were observed between asthma and COPD patients.,Pseudomonas spp. of Proteobacteria and Lactobacillus spp. of Firmicutes were highly abundant in asthma and COPD.,By contrast, Streptococcus, Veillonella, Prevotella, and Neisseria of Bacteroidetes dominated in the healthy oropharynx.,These findings are consistent with previous studies conducted in the lower airways and suggest that oropharyngeal airway microbiota are important for understanding the relationships between the various parts of the respiratory tract with regard to bacterial colonization and comprehensive assessment of asthma and COPD. | 1 |
Eosinophils in peripheral blood are one of the emerging biomarkers in chronic obstructive pulmonary disease (COPD) patients.,However, when analysing the relationship between peripheral eosinophilia and COPD prognosis, highly variable results are obtained.,The aim of our study is to describe the serum eosinophilia levels in COPD patients and to analyse their relationship to prognosis following hospital admission.,A prospective observational study was conducted from 1 October 2016 to 1 October 2018 in the following Spanish centres: Salnés County Hospital in Vilagarcía de Arousa, Arquitecto Marcide Hospital in Ferrol and the University Hospital Complex in Santiago de Compostela.,The patients were classified using three cut-off points of blood eosinophil count (BEC): 150 cells/µL, 300 cells/µL, and 400 cells/µL; in addition, the peripheral BEC was analysed on admission.,615 patients were included in the study, 86.2% male, mean age 73.9 years, and mean FEV1 52.7%.,The mean stay was 8.4 days, and 6% of all patients were readmitted early.,No significant relationship was observed between the BEC, neither in the stable phase nor in the acute phase, and hospital stay, readmissions, deaths during admission, the need for intensive care, or the condition of frequent exacerbator.,The results of our study do not seem to support the usefulness of BEC as a COPD biomarker.KEY MESSAGESThere is evidence that BEC participates in pathophysiological mechanisms of the COPD.BEC may be useful as a biomarker in COPD for aspects such as the optimization of treatments.We did not find any relationship between BEC levels and prognosis following hospital admission for AECOPD.,There is evidence that BEC participates in pathophysiological mechanisms of the COPD.,BEC may be useful as a biomarker in COPD for aspects such as the optimization of treatments.,We did not find any relationship between BEC levels and prognosis following hospital admission for AECOPD. | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has raised many questions about the management of patients with chronic obstructive pulmonary disease (COPD) and whether modifications of their therapy are required.,It has raised questions about recognizing and differentiating coronavirus disease (COVID-19) from COPD given the similarity of the symptoms.,The Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee used established methods for literature review to present an overview of the management of patients with COPD during the COVID-19 pandemic.,It is unclear whether patients with COPD are at increased risk of becoming infected with SARS-CoV-2.,During periods of high community prevalence of COVID-19, spirometry should only be used when it is essential for COPD diagnosis and/or to assess lung function status for interventional procedures or surgery.,Patients with COPD should follow basic infection control measures, including social distancing, hand washing, and wearing a mask or face covering.,Patients should remain up to date with appropriate vaccinations, particularly annual influenza vaccination.,Although data are limited, inhaled corticosteroids, long-acting bronchodilators, roflumilast, or chronic macrolides should continue to be used as indicated for stable COPD management.,Systemic steroids and antibiotics should be used in COPD exacerbations according to the usual indications.,Differentiating symptoms of COVID-19 infection from chronic underlying symptoms or those of an acute COPD exacerbation may be challenging.,If there is suspicion for COVID-19, testing for SARS-CoV-2 should be considered.,Patients who developed moderate-to-severe COVID-19, including hospitalization and pneumonia, should be treated with evolving pharmacotherapeutic approaches as appropriate, including remdesivir, dexamethasone, and anticoagulation.,Managing acute respiratory failure should include appropriate oxygen supplementation, prone positioning, noninvasive ventilation, and protective lung strategy in patients with COPD and severe acute respiratory distress syndrome.,Patients who developed asymptomatic or mild COVID-19 should be followed with the usual COPD protocols.,Patients who developed moderate or worse COVID-19 should be monitored more frequently and accurately than the usual patients with COPD, with particular attention to the need for oxygen therapy. | 1 |
Early identification of people at risk of developing COPD is crucial for implementing preventive strategies.,We aimed to systematically review and assess the performance of all published models that predicted development of COPD.,A search was conducted to identify studies that developed a prediction model for COPD development.,The Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies was followed when extracting data and appraising the selected studies.,Of the 4,481 records identified, 30 articles were selected for full-text review, and only four of these were eligible to be included in the review.,The only consistent predictor across all four models was a measure of smoking.,Sex and age were used in most models; however, other factors varied widely.,Two of the models had good ability to discriminate between people who were correctly or incorrectly classified as at risk of developing COPD.,Overall none of the models were particularly useful in accurately predicting future risk of COPD, nor were they good at ruling out future risk of COPD.,Further studies are needed to develop new prediction models and robustly validate them in external cohorts. | Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal.,To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum.,Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1-3).,Certain individual circulating cytokines (particularly TNFα and IL-1β) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation.,However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD.,The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease. | 1 |
The BODE index was recently validated as a multidimensional tool for the evaluation of patients with COPD.,The influence of gender on the BODE index has not been studied.,The contribution of each component of the disease to the BODE index may differ according to gender.,We evaluated age, forced expiratory volume in one second (FEV1), Modified Medical Research Council (MMRC) score, 6-min walk distance (6MWD), and body mass index (BMI) in 52 men and 52 women with COPD and the same BODE index.,We compared the studied parameters between men and women and then performed a multiple regression analysis by gender.,We found statistically significant differences between men and women in all parameters: FEV1 % (55 ± 17 vs 63 ± 18, p < 0.001), MMRC [1 (0-2) vs 1 (1-2) p = 0.03], BMI [28 (26-30) vs 25 (22-30), p = 0.05], and 6MWD [546 (451-592) vs 462 (419-520), p = 0.001].,Multiple regression analysis revealed that each component of the BODE index had different weight (β standardized coefficient) in men and women respectively: FEV1% (0.74 vs 0.62), MMRC (0.31 vs 0.48), BMI (−0.09 vs −0.17), and 6MWD (0.13 vs 0.10).,The contribution of each component to the BODE index differs by gender in subjects with similar BODE scores.,Long term longitudinal studies will help determine the significance of our findings. | Anxiety and depression are common and treatable risk factors for re-hospitalisation and death in patients with COPD.,The degree of lung function impairment does not sufficiently explain anxiety and depression.,The BODE index allows a functional classification of COPD beyond FEV1.,The aim of this cross-sectional study was (1) to test whether the BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms; and (2) to assess which components of the BODE index are associated with these psychological aspects of COPD.,COPD was classified according to the GOLD stages based on FEV1%predicted in 122 stable patients with COPD.,An additional four stage classification was constructed based on the quartiles of the BODE index.,The hospital anxiety and depression scale was used to assess anxious and depressive symptoms.,The overall prevalence of anxious and depressive symptoms was 49% and 52%, respectively.,The prevalence of anxious symptoms increased with increasing BODE stages but not with increasing GOLD stages.,The prevalence of depressive symptoms increased with both increasing GOLD and BODE stages.,The BODE index was superior to FEV1%predicted for explaining anxious and depressive symptoms.,Anxious symptoms were explained by dyspnoea.,Depressive symptoms were explained by both dyspnoea and reduced exercise capacity.,The BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms in COPD patients.,These psychological consequences of the disease may play a role in future classification systems of COPD. | 1 |
Clinical audits have reported considerable variability in COPD medical care and frequent inconsistencies with recommendations.,The objectives of this study were to identify factors associated with a better adherence to clinical practice guidelines and to explore determinants of this variability at the the hospital level.,EPOCONSUL is a Spanish nationwide clinical audit that evaluates the outpatient management of COPD.,Multilevel logistic regression with two levels was performed to assess the relationships between individual and disease-related factors, as well as hospital characteristics.,A total of 4508 clinical records of COPD patients from 59 Spanish hospitals were evaluated.,High variability was observed among hospitals in terms of medical care.,Some of the patient’s characteristics (airflow obstruction, degree of dyspnea, exacerbation risk, presence of comorbidities), the hospital factors (size and respiratory nurses available) and treatment at a specialized COPD outpatient clinic were identified as factors associated with a better adherence to recommendations, although this only explains a small proportion of the total variance.,To be treated at a specialized COPD outpatient clinic and some intrinsic patient characteristics were factors associated with a better adherence to guideline recommendations, although these variables were only explaining part of the high variability observed among hospitals in terms of COPD medical care. | Treatment of chronic obstructive pulmonary disease (COPD) requires a personalized approach according to the clinical characteristics of the patients, the level of severity, and the response to the different therapies.,Furthermore, patients with the same level of severity measured by the degree of airflow obstruction or even with multidimensional indices may have very different symptoms and limitations for daily activities.,The concept of control has been extensively developed in asthma but has not been defined in COPD.,Here, we propose a definition of COPD control based on the concepts of impact and stability.,Impact is a cross-sectional concept that can be measured by questionnaires such as the COPD Assessment Test or the Clinical COPD Questionnaire.,Alternatively, impact can be assessed by the degree of dyspnea, the use of rescue medication, the level of physical activity, and sputum color.,Stability is a longitudinal concept that requires the absence of exacerbations and deterioration in the aforementioned variables or in the COPD Assessment Test or Clinical COPD Questionnaire scores.,Control is defined by low impact (adjusted for severity) and stability.,The concept of control in COPD can be useful in the decision making regarding an increase or decrease in medication in the stable state. | 1 |
Cigarette smoke (CS) exposure is the leading risk factor for COPD-emphysema pathogenesis.,A common characteristic of COPD is impaired phagocytosis that causes frequent exacerbations in patients leading to increased morbidity.,However, the underlying mechanism is unclear.,Hence, we investigated if CS exposure causes autophagy impairment as a mechanism for diminished bacterial clearance via phagocytosis by utilizing murine macrophages (RAW264.7 cells) and Pseudomonas aeruginosa (PA01-GFP) as an experimental model.,Briefly, RAW cells were treated with cigarette smoke extract (CSE), chloroquine (autophagy inhibitor), TFEB-shRNA, CFTR(inh)-172, and/or fisetin prior to bacterial infection for functional analysis.,Bacterial clearance of PA01-GFP was significantly impaired while its survival was promoted by CSE (p < 0.01), autophagy inhibition (p < 0.05; p < 0.01), TFEB knockdown (p < 0.01; p < 0.001), and inhibition of CFTR function (p < 0.001; p < 0.01) in comparison to the control group(s) that was significantly recovered by autophagy-inducing antioxidant drug, fisetin, treatment (p < 0.05; p < 0.01; and p < 0.001).,Moreover, investigations into other pharmacological properties of fisetin show that it has significant mucolytic and bactericidal activities (p < 0.01; p < 0.001), which warrants further investigation.,Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis. | Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure.,The disease is increasing in global prevalence and there is no effective therapy.,A major step forward would be to understand the disease pathogenesis.,The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD.,This strongly suggests that the axis could be important in the pathogenesis of COPD.,The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.,We used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.,The inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α.,This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia.,Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia.,Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g.,E-Selectin.,This data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD. | 1 |
Chronic obstructive pulmonary disease (COPD), one of the most common chronic diseases and a leading cause of death, has historically been considered a disease of men.,However, there has been a rapid increase in the prevalence, morbidity, and mortality of COPD in women over the last two decades.,This has largely been attributed to historical increases in tobacco consumption among women.,But the influence of sex on COPD is complex and involves several other factors, including differential susceptibility to the effects of tobacco, anatomic, hormonal, and behavioral differences, and differential response to therapy.,Interestingly, nonsmokers with COPD are more likely to be women.,In addition, women with COPD are more likely to have a chronic bronchitis phenotype, suffer from less cardiovascular comorbidity, have more concomitant depression and osteoporosis, and have a better outcome with acute exacerbations.,Women historically have had lower mortality with COPD, but this is changing as well.,There are also differences in how men and women respond to different therapies.,Despite the changing face of COPD, care providers continue to harbor a sex bias, leading to underdiagnosis and delayed diagnosis of COPD in women.,In this review, we present the current knowledge on the influence of sex on COPD risk factors, epidemiology, diagnosis, comorbidities, treatment, and outcomes, and how this knowledge may be applied to improve clinical practices and advance research. | Despite the availability of national and international guidelines, evidence suggests that chronic obstructive pulmonary disease (COPD) treatment is not always prescribed according to recommendations.,This study evaluated the current management of patients with COPD using a large UK primary-care database.,This analysis used electronic patient records and patient-completed questionnaires from the Optimum Patient Care Research Database.,Data on current management were analyzed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group and presence or absence of a concomitant asthma diagnosis, in patients with a COPD diagnosis at ≥35 years of age and with spirometry results supportive of the COPD diagnosis.,A total of 24,957 patients were analyzed, of whom 13,557 (54.3%) had moderate airflow limitation (GOLD Stage 2 COPD).,The proportion of patients not receiving pharmacologic treatment for COPD was 17.0% in the total COPD population and 17.7% in the GOLD Stage 2 subset.,Approximately 50% of patients in both cohorts were receiving inhaled corticosteroids (ICS), either in combination with a long-acting β2-agonist (LABA; 26.7% for both cohorts) or a LABA and a long-acting muscarinic antagonist (LAMA; 23.2% and 19.9%, respectively).,ICS + LABA and ICS + LABA + LAMA were the most frequently used treatments in GOLD Groups A and B.,Of patients without concomitant asthma, 53.7% of the total COPD population and 50.2% of the GOLD Stage 2 subset were receiving ICS.,Of patients with GOLD Stage 2 COPD and no exacerbations in the previous year, 49% were prescribed ICS.,A high proportion of GOLD Stage 2 COPD patients were symptomatic on their current management (36.6% with modified Medical Research Council score ≥2; 76.4% with COPD Assessment Test score ≥10).,COPD is not treated according to GOLD and National Institute for Health and Care Excellence recommendations in the UK primary-care setting.,Some patients receive no treatment despite experiencing symptoms.,Among those on treatment, most receive ICS irrespective of severity of airflow limitation, asthma diagnosis, and exacerbation history.,Many patients on treatment continue to have symptoms. | 1 |
The major characteristic of COPD is systemic inflammation.,The parameters such as neutrophil-to-lymphocyte ratio (NLR) and eosinophil-to-basophil ratio (EBR) in routine blood test (RBT) are considered to be the underlying biomarkers of inflammation.,We hypothesized that the prognosis of patients with COPD can be predicted with RBT.,Patients with COPD in stable stage were enrolled.,The RBT, pulmonary function testing (PFT), BODE index, C-reactive protein (CRP), procalcitonin, and erythrocyte sedimentation rate (ESR) were performed at enrollment and every follow-up once in every 3 months during the 24-month follow-up period.,Meanwhile, exacerbation count and mortality incidence were recorded.,The correlation between the prognostic biomarkers and the prognosis of patients was analyzed.,The NLR and EBR in RBT have a significant correlation with the severity of patients with COPD.,The NLR is an independent predictor for mortality and the EBR is an independent predictor for exacerbation.,As an inexpensive, accessible, and convenient assay, RBT may be used as a practical means in the prediction of prognosis of patients with COPD in future clinical settings. | Blood eosinophil counts have been documented as a good biomarker for patients with chronic obstructive pulmonary disease (COPD) using inhaled corticosteroid (ICS) therapy.,However, the effectiveness and safety of prescribing high or medium dose of ICS for patients with different eosinophil counts are unknown.,A post hoc analysis of a previous prospective randomized study was performed for COPD patients using higher dose (HD: Fluticasone 1,000 μg/day) or medium dose (MD: Fluticasone 500 μg/day) of ICS combined with Salmeterol (100 μg/day).,Patients were classified into two groups: those with high eosinophil counts (HE ≥3%) and those with low eosinophil counts (LE <3%).,Lung function was evaluated with forced expiratory volume in 1 second, forced vital capacity, and COPD assessment test.,Frequencies of acute exacerbation and pneumonia were also measured.,Two hundred and forty-eight patients were studied and classified into higher eosinophil (HE) (n=85, 34.3%) and lower eosinophil (LE) groups (n=163, 65.7%).,The levels of forced expiratory volume in 1 second were significantly increased in patients of HE group treated with HD therapy, compared with the other groups (HE/HD: 125.9±27.2 mL vs HE/MD: 94.3±23.7 mL, vs LE/HD: 70.4±20.5 mL, vs LE/MD: 49.8±16.7 mL; P<0.05) at the end of the study.,Quality of life (COPD assessment test) markedly improved in HE/HD group than in MD/LE group (HE/HD: 9±5 vs LE/MD: 16±7, P=0.02).,The frequency of acute exacerbation was more decreased in HE/HD group patients, compared with that in LE/MD group (HE/HD: 13.5% vs LE/MD: 28.7%, P<0.01).,Pneumonia incidence was similar in the treatment groups (HE/HD: 3.2%, HE/MD: 2.6%, LE/HD: 3.5%, LE/MD 2.8%; P=0.38).,The study results support using blood eosinophil counts as a biomarker of ICS response and show the benefits of greater improvement of lung function, quality of life, and decreased exacerbation frequency in COPD patients with blood eosinophil counts higher than 3%, especially treated with higher dose of ICS. | 1 |
Objective: This study aimed to investigate the quantitative effects of outdoor air pollution, represented by 10 µg/m3 increment of PM10, on chronic obstructive pulmonary disease in China, United States and European Union through systematic review and meta-analysis.,Methods: Publications in English and Chinese from PubMed and EMBASE were selected.,The Cochrane Review Handbook of Generic Inverse Variance was used to synthesize the pooled effects on incidence, prevalence, mortality and hospital admission.,Results: Outdoor air pollution contributed to higher incidence and prevalence of COPD.,Short-term exposure was associated with COPD mortality increased by 6%, 1% and 1% in the European Union, the United States and China, respectively (p < 0.05).,Chronic PM exposure produced a 10% increase in mortality.,In a short-term exposure to 10 µg/m3 PM10 increment COPD mortality was elevated by 1% in China (p < 0.05) and hospital admission enrollment was increased by 1% in China, 2% in United States and 1% in European Union (p < 0.05).,Conclusions: Outdoor air pollution contributes to the increasing burdens of COPD.10 µg/m3 increase of PM10 produced significant condition of COPD death and exacerbation in China, United States and European Union.,Controlling air pollution will have substantial benefit to COPD morbidity and mortality. | The global increase in the prevalence and incidence of obesity has called serious attention to this issue as a major public health concern.,Obesity is associated with many chronic diseases, including cardiovascular disease and diabetes, and recently the role of overweight and obesity in lung disease has received new interest.,Independently of obesity, diet also plays a role as a risk factor for many chronic diseases, and evidence is accumulating to support a role for diet in the prevention and management of several lung diseases.,Chronic obstructive lung disease is the third-leading cause of death globally, and both obesity and diet appear to play roles in its pathophysiology.,Obesity has been associated with decreased lung-function measures in population-based studies, with increased prevalence of several lung diseases and with compromised pulmonary function.,In contrast, obesity has a protective effect against mortality in severe chronic obstructive pulmonary disease (COPD).,Nutrient intake and dietary patterns have also been associated with lung-function measures and the development and progression of COPD.,Taken together, this suggests that a focus on obesity and diet should be part of public health campaigns to reduce the burden of lung disease, and could have important implications for clinicians in the management of their patients.,Future research should also focus on elucidating these relationships in diverse populations and age-groups, and on understanding the complex interaction between behavior, environment, and genetics in the development and progression of COPD.,The goal of this article is to review current evidence regarding the role that obesity and diet play in the development of COPD, and in COPD-related outcomes. | 1 |
Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations.,We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities.,We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses.,Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci.,Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.,Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.,Pulmonary function is influenced by environmental factors, lifestyle, and genetics.,Here, in a multiethnic GWAS meta-analysis for pulmonary function traits, the authors identify over 50 additional genetic loci, a subset of which are specific for European, African, Asian, or Hispanic/Latino ancestry. | Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema.,However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes.,Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes.,We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets.,We further tested the potential causality of individual genes using multi-variant colocalization.,We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung.,We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3.,Three of these genes were not located within previously reported GWAS loci for either phenotype.,We also identified genetically driven pathways, including those related to immune regulation.,An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci.,NCT00608764, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered).,The online version of this article (10.1186/s12931-018-0744-9) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide.,Genetic risk loci provide novel insights into disease pathogenesis.,We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.,We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function.,Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium.,Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types.,We found 14 COPD loci shared with either asthma or pulmonary fibrosis.,COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations.,Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD. | Tobacco use is associated with an increased prevalence of cardiovascular disease.,N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers.,We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease.,Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality.,Subjects were followed for a median of 562 (IQR 252 - 826) days.,Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index.,By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02).,By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07-4.46, p = 0.031).,Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death.,Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival. | 1 |
Some patients with chronic obstructive pulmonary disease (COPD) show increased airway inflammation and bacterial colonization during stable phase.,The aim of this study was to follow COPD patients and investigate chronic colonization with pathogenic bacteria during stable disease phase, and relate these findings to clinical parameters, inflammatory pattern, lung function, and exacerbations.,Forty-three patients with COPD were included while in a stable state and followed up monthly until exacerbation or for a maximum of 6 months.,The patients completed the Clinical COPD Questionnaire and Medical Research Council dyspnea scale questionnaires, and exhaled breath condensate was collected, followed by spirometry, impulse oscillometry, and sputum induction.,Ten patients were chronically colonized (ie, colonized at all visits) with Haemophilus influenzae during stable phase.,These patients had higher sputum levels of leukotriene B4 (P<0.001), 8-isoprostane (P=0.002), myeloperoxidase activity (P=0.028), and interleukin-8 (P=0.02) during stable phase when compared with other patients.,In addition, they had lower forced vital capacity (P=0.035) and reactance at 5 Hz (P=0.034), but there was no difference in forced expiratory volume in 1 second (FEV1), FEV1 % predicted, forced vital capacity % predicted, exhaled breath condensate biomarkers, C-reactive protein, or Clinical COPD Questionnaire and Medical Research Council dyspnea scale results.,Three patients had intermittent colonization (colonized at only some visits) of H. influenzae during stable phase, and had lower levels of inflammatory biomarkers in sputum when compared with the chronically colonized patients.,The difference in airway inflammation seen during stable phase in patients chronically colonized with H. influenzae was not observed during exacerbations.,Some COPD patients who were chronically colonized with H. influenzae during stable phase showed increased airway inflammation and reduced lung volumes when compared with non-chronically colonized patients. | Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management.,Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease.,Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.,To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management.,To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.,An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).,Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.,(1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.,The results indicate the high potential of a systems approach to address COPD heterogeneity.,Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD. | 1 |
Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbation risk and response to corticosteroid treatments.,Sputum induction, however, requires expertise, may not always be successful, and does not provide point-of-care results.,Easily applicable diagnostic markers that can predict sputum eosinophilia in stable COPD patients have the potential to progress COPD management.,This study investigated the correlation and predictive relationship between peripheral blood and sputum eosinophils.,It also examined the repeatability of blood eosinophil counts.,Stable COPD patients (n=141) were classified as eosinophilic or noneosinophilic based on their sputum cell counts (≥3%), and a cross-sectional analysis was conducted comparing their demographics, clinical characteristics, and blood cell counts.,Receiver operating characteristic curve analysis was used to assess the predictive ability of blood eosinophils for sputum eosinophilia.,Intraclass correlation coefficient was used to examine the repeatability of blood eosinophil counts.,Blood eosinophil counts were significantly higher in patients with sputum eosinophilia (n=45) compared to those without (0.3×109/L vs 0.15×109/L; P<0.0001).,Blood eosinophils correlated with both the percentage (ρ=0.535; P<0.0001) and number of sputum eosinophils (ρ=0.473; P<0.0001).,Absolute blood eosinophil count was predictive of sputum eosinophilia (area under the curve =0.76, 95% confidence interval [CI] =0.67-0.84; P<0.0001).,At a threshold of ≥0.3×109/L (specificity =76%, sensitivity =60%, and positive likelihood ratio =2.5), peripheral blood eosinophil counts enabled identification of the presence or absence of sputum eosinophilia in 71% of the cases.,A threshold of ≥0.4×109/L had similar classifying ability but better specificity (91.7%) and higher positive likelihood ratio (3.7).,In contrast, ≥0.2×109/L offered a better sensitivity (91.1%) for ruling out sputum eosinophilia.,There was a good agreement between two measurements of blood eosinophil count over a median of 28 days (intraclass correlation coefficient =0.8; 95% CI =0.66-0.88; P<0.0001).,Peripheral blood eosinophil counts can help identify the presence or absence of sputum eosinophilia in stable COPD patients with a reasonable degree of accuracy. | Patients with chronic obstructive pulmonary disease (COPD) exhibit poor sleep quality and consider morning as the worst time of day for their symptoms.,While work has been done to characterize nighttime (NT) and early morning (EM) symptoms in various populations, the impact and factors associated with NT/EM symptoms among patients with COPD in the United States is not well understood.,Commercially insured patients aged ≥40 years with one or more medical claim for COPD and one or more pharmacy claim for COPD maintenance medication were identified from the HealthCore Integrated Research Database between September 1, 2010 and August 31, 2011.,Consenting respondents were asked whether they had COPD symptoms on at least three nights or at least three mornings during the past week.,Respondents were then either assigned to one of three symptom groups to complete the survey or excluded if their predefined group quota limit had been met.,Survey completers completed the survey with questions about COPD symptoms and other commonly used patient-reported outcome measures.,Respondents with NT/EM symptoms were asked about the frequency, severity, and impact of the symptoms on sleep, morning activities, and anxiety levels.,Among respondents with symptoms, 73.1% of respondents with NT symptoms (N=376) and 83% of respondents with EM symptoms (N=506) experienced at least three distinct types of symptoms over the past week, with cough being the most frequently reported symptom.,Approximately half of respondents with NT or EM symptoms perceived their symptoms as moderate to very severe, with a majority reporting their symptoms affected their NT sleep and morning activities, and more than half felt anxious due to their symptoms.,Multinomial logistic regression showed COPD patients with both or either NT/EM symptoms were associated with poorer health status compared to those without.,Improved disease management may reduce NT/EM symptoms and improve health status in patients with COPD. | 1 |
The changes in grading of disease severity and treatment recommendations for patients with COPD in the 2017 GOLD strategy may present an opportunity for reducing treatment burden for the patients and costs to the health care system.,The aim of this study was to assess the implications of the GOLD 2017 grading system in terms of change in distribution across GOLD groups A-D for existing patients in UK primary care and estimate the potential cost savings of implementing GOLD 2017 treatment recommendations in UK primary care.,Using electronic health record data from the Clinical Practice Research Datalink (CPRD), patients aged ≥35 years with spirometry-confirmed COPD, receiving care during 2016, were included.,The cohort was graded according to the GOLD 2017 groups (A-D), and treatment costs were calculated, according to corresponding recommendations, to observe the difference in actual vs predicted costs.,When applying GOLD 2013 criteria, less than half of the cohort (46%) was assigned to GOLD A or B, as compared to 86% when applying the GOLD 2017 grading.,The actual mean annual maintenance treatment cost was £542 per patient vs a predicted £389 for treatment according to the 2017 GOLD strategy.,There is a potential to make significant cost savings by implementing the grading and treatment recommendations from the 2017 GOLD strategy. | The use of inhaled corticosteroids (ICS) in combination with bronchodilators in patients with COPD has been shown to decrease the rate of disease exacerbations and to improve the lung function and patients’ quality of life.,However, their use has also been associated with an increased risk of pneumonia.,We have reviewed existing clinical evidence on the risks and benefits of ICS in COPD, including large randomized clinical trials, meta-analyses, and clinical reviews.,A large body of evidence supports the clinical benefits of ICS in patients with COPD in terms of exacerbations, symptoms, lung function, and quality of life.,The incidence of adverse events related to ICS, including pneumonia, varies strongly among the studies and seems to be dose dependent, with recent well-designed, large studies on low-dose ICS reporting similar safety profiles in ICS and non-ICS groups.,The benefits of ICS in COPD continue to outweigh the risks, especially when lower ICS doses are employed.,Given that the data on ICS withdrawal in COPD are scarce and conflicting, we argue that using reduced doses of ICS could be an optimal strategy to manage patients with COPD. | 1 |
Chronic obstructive pulmonary disease (COPD) is the end result of a susceptible individual being exposed to sufficiently deleterious environmental stimuli.,More than 90% of COPD-related deaths occur in low- and middle-income countries (LMICs).,LMICs face unique challenges in managing COPD; for example, deficient primary care systems present challenges for proper diagnosis and management.,Formal diagnosis of COPD requires quality-assured spirometry, which is often limited to urban health centres.,Similarly, standard treatment options for COPD remain limited where few providers are trained to manage COPD.,The Global Excellence in COPD Outcomes (GECo) studies aim to assess the performance of a COPD case-finding questionnaire with and without peak expiratory flow (PEF) to diagnose COPD, and inform the effectiveness and implementation of COPD self-management Action Plans in LMIC settings.,The ultimate goal is to develop simple, low-cost models of care that can be implemented in LMICs.,This study will be carried out in Nepal, Peru and Uganda, three distinct LMIC settings.,We aim to assess the diagnostic accuracy of a simple questionnaire with and without PEF to case-find COPD (GECo1), and examine the effectiveness, cost-effectiveness and implementation of a community-health-worker-supported self-management Action Plan strategy for managing exacerbations of COPD (GECo2).,To achieve the first aim, we will enrol a randomly selected sample of up to 10,500 adults aged ≥ 40 years across our three sites, with the goal to enrol 240 participants with moderate-to-severe COPD in to GECo2.,We will apply two case-finding questionnaires (Lung Function Questionnaire and CAPTURE) with and without PEF and compare performance against spirometry.,We will report ROC areas, sensitivity and specificity.,Individuals who are identified as having COPD grades B-D will be invited to enrol in an effectiveness-implementation hybrid randomised trial of a multi-faceted COPD self-management Action Plan intervention delivered by CHWs.,The intervention group will receive (1) COPD education, (2) facilitated-self management Action Plans for COPD exacerbations and (3) monthly visits by community health workers.,The control group will receive COPD education and standard of care treatment provided by local health providers.,Beginning at baseline, we will measure quality of life with the EuroQol-5D (EQ-5D) and St.,George’s Respiratory Questionnaire (SGRQ) every 3 months over a period of 1 year.,The primary endpoint is SGRQ at 12 months.,Quality-adjusted life years (QALYs) using the Short-Form 36 version 2 will also be calculated.,We will additionally assess the acceptability and feasibility of implementing COPD Action Plans in each setting among providers and individuals with COPD.,This study should provide evidence to inform the use of pragmatic models of COPD diagnosis and management in LMIC settings.,NCT03359915 (GECo1).,Registered on 2 December 2017 and NCT03365713 (GECo2).,Registered on 7 December 2017.,Trial acronym: Global Excellence in COPD Outcomes (GECo1; GECo2).,The online version of this article (10.1186/s13063-018-2909-8) contains supplementary material, which is available to authorized users. | Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.,Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face.,Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.,Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P<0.001) to diagnose COPD and frequently included validated patient-reported outcome measures (PCPs 67%, respiratory specialists 81%; P<0.001).,Respiratory specialists were more likely than PCPs to report awareness of the GOLD global strategy (93% versus 58%, P<0.001); however, when presented with patient scenarios, they did not always perform better than PCPs with regard to recommending GOLD-concordant treatment options.,The proportion of PCPs and respiratory specialists providing first- or second-choice treatment options concordant with GOLD strategy for a GOLD B-type patient was 38% versus 67%, respectively.,For GOLD C and D-type patients, the concordant proportions for PCPs and respiratory specialists were 40% versus 38%, and 57% versus 58%, respectively.,This survey of physicians in 12 countries practicing in the primary care and respiratory specialty settings showed high awareness of COPD-management guidelines.,Frequent use of guideline-recommended COPD diagnostic practices was reported; however, gaps in the application of COPD-treatment recommendations were observed, warranting further evaluation to understand potential barriers to adopt guideline recommendations. | 1 |
Viral-bacterial co-infections are associated with severe exacerbations of COPD.,Epithelial antimicrobial peptides, including human β-defensin-2 (HBD-2), are integral to innate host defenses.,In this study, we examined how co-infection of airway epithelial cells with rhinovirus and Pseudomonas aeruginosa modulates HBD-2 expression, and whether these responses are attenuated by cigarette smoke and in epithelial cells obtained by bronchial brushings from smokers with normal lung function or from COPD patients.,When human airway epithelial cells from normal lungs were infected with rhinovirus, Pseudomonas aeruginosa, or the combination, co-infection with rhinovirus and bacteria resulted in synergistic induction of HBD-2 (p<0.05).,The combination of virus and flagellin replicated this synergistic increase (p<0.05), and synergy was not seen using a flagella-deficient mutant Pseudomonas (p<0.05).,The effects of Pseudomonas aeruginosa were mediated via interactions of flagellin with TLR5.,The effects of HRV-16 depended upon viral replication but did not appear to be mediated via the intracellular RNA helicases, retinoic acid-inducible gene-I or melanoma differentiation-associated gene-5.,Cigarette smoke extract significantly decreased HBD-2 production in response to co-infection.,Attenuated production was also observed following co-infection of cells obtained from healthy smokers or COPD patients compared to healthy controls (p<0.05).,We conclude that co-exposure to HRV-16 and Pseudomonas aeruginosa induces synergistic production of HBD-2 from epithelial cells and that this synergistic induction of HBD-2 is reduced in COPD patients.,This may contribute to the more severe exacerbations these patients experience in response to viral-bacterial co-infections. | Nontypeable Haemophilus influenzae colonizes and infects the airways of adults with chronic obstructive pulmonary disease, the fourth most common cause of death worldwide.Thus, H. influenzae, an exclusively human pathogen, has adapted to survive in the hostile environment of the human airways.To characterize proteins expressed by H. influenzae in the airways, a prototype strain was grown in pooled human sputum to simulate conditions in the human respiratory tract.The proteins from whole bacterial cell lysates were solubilized with a strong buffer and then quantitatively cleaned with an optimized precipitation/on-pellet enzymatic digestion procedure.Proteomic profiling was accomplished by Nano-flow liquid chromatography/mass spectroscopy with low void volume and high separation efficiency with a shallow, long gradient.,A total of 1402 proteins were identified with high confidence, including 170 proteins that were encoded by genes that are annotated as conserved hypothetical proteins.Thirty-one proteins were present in greater abundance in sputum-grown conditions at a ratio of > 1.5 compared to chemically defined media.These included 8 anti-oxidant and 5 stress-related proteins, suggesting that expression of antioxidant activity and stress responses is important for survival in the airways.Four proteins involved in uptake of divalent anions and 9 proteins that function in uptake of various molecules were present in greater abundance in sputum-grown conditions.,Proteomic expression profiling of H. influenzae grown in pooled human sputum revealed increased expression of antioxidant, stress-response proteins and cofactor and nutrient uptake systems compared to media grown cells.These observations suggest that H. influenzae adapts to the oxidative and nutritionally limited conditions of the airways in adults with chronic obstructive pulmonary disease by increasing expression of molecules necessary for survival in these conditions. | 1 |
New parameters in the 6-minute walk test (6MWT) are required for comprehensive analysis of exercise capacity in patients with chronic obstructive pulmonary disease (COPD).,The aim of the present study was to apply a novel index, the desaturation distance ratio (DDR), to clinical research on COPD as an estimate of exercise capacity and to examine whether DDR is a potential parameter for manifold analysis of exercise capacity in patients with COPD.,A total of 41 patients with COPD (median age [interquartile range] =75 [68-79] years; and body mass index [BMI] =22.3 [19.4-23.8] kg/m2) participated in the study.,The 6MWT was performed along with anthropometric measurements and a pulmonary function test.,The “desaturation area” was measured as the total area above the curve created using peripheral oxygen saturation (SpO2) values observed at each minute during the 6MWT.,Then the DDR was calculated as the ratio of the desaturation area to the 6-minute walk distance (6MWD).,The 6MWD was 370 (328-445) m, and the decline in SpO2 values (ΔSpO2) was −5.0% (−8.0% to −1.5%).,The DDR correlated modestly with baseline pulmonary function in patients with COPD (forced expiratory volume in 1 second [% of predicted value]: r=−0.658, P<0.001; and diffusing capacity of the lung for carbon monoxide [DLCO]: r=−0.470, P=0.002), comparable with the findings of the 6MWD.,The DDR correlated well with ΔSpO2 (r=−0.656, P<0.001) and with the increase in subjective sense of dyspnea during the 6MWT, as assessed by Borg scale scores (ΔBorg) (r=0.486, P=0.001), in contrast with the 6MWD, which was not significantly correlated with ΔSpO2 and ΔBorg scale scores.,The DDR is more informative for manifold analysis of exercise capacity associated with oxygen desaturation and subsequent sense of dyspnea by exercise in patients with COPD. | The influence of gender on the expression of COPD has received limited attention.,Quality of Life (QoL) has become an important outcome in COPD patients.,The aim of our study was to explore factors contributing to gender differences in Quality of Life of COPD patients.,In 146 men and women with COPD from a pulmonary clinic we measured: Saint George's Respiratory Questionnaire (SGRQ), age, smoking history, PaO2, PaCO2, FEV1, FVC, IC/TLC, FRC, body mass index (BMI), 6 minute walk distance (6MWD), dyspnea (modified MRC), degree of comorbidity (Charlson index) and exacerbations in the previous year.,We explored differences between genders using Mann-Whitney U-rank test.,To investigate the main determinants of QoL, a multiple lineal regression analysis was performed using backward Wald's criteria, with those variables that significantly correlated with SGRQ total scores.,Compared with men, women had worse scores in all domains of the SGRQ (total 38 vs 26, p = 0.01, symptoms 48 vs 39, p = 0.03, activity 53 vs 37, p = 0.02, impact 28 vs 15, p = 0.01).,SGRQ total scores correlated in men with: FEV1% (-0.378, p < 0.001), IC/TLC (-0.368, p = 0.002), PaO2 (-0.379, p = 0.001), PaCO2 (0.256, p = 0.05), 6MWD (-0.327, p = 0.005), exacerbations (0.366, p = 0.001), Charlson index (0.380, p = 0.001) and MMRC (0.654, p < 0.001).,In women, the scores correlated only with FEV1% (-0.293, p = 0.013) PaO2 (-0.315, p = 0.007), exacerbations (0.290, p = 0.013) and MMRC (0.628, p < 0.001).,Regression analysis (B, 95% CI) showed that exercise capacity (0.05, 0.02 to 0.09), dyspnea (17.6, 13.4 to 21.8), IC/TLC (-51.1, -98.9 to -3.2) and comorbidity (1.7, 0.84 to 2.53) for men and dyspnea (9.7, 7.3 to 12.4) and oxygenation (-0.3, -0.6 to -0.01) for women manifested the highest independent associations with SGRQ scores.,In moderate to severe COPD patients attending a pulmonary clinic, there are gender differences in health status scores.,In turn, the clinical and physiological variables independently associated with those scores differed in men and women.,Attention should be paid to the determinants of QoL scores in women with COPD. | 1 |
It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations.,The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations.,914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited.,Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients).,FEV1, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period.,816 patients (89.3%) concluded the study.,FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6.,We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6.,We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. | Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea.,These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD.,Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥2 per year) independently of disease severity.,Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis.,The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS).,While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance.,Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation.,Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations.,Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations. | 1 |
Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors.,Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility.,Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.,Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study.,Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated.,Individual genes were not found to be significantly associated with the number of exacerbations.,However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association.,A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection.,Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections.,The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations.,A distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness.,While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.,The online version of this article (doi:10.1186/s12920-014-0072-y) contains supplementary material, which is available to authorized users. | It is generally accepted that emphysematous lungs are characterized by an increase in the numbers of neutrophils, macrophages, and CD8+ T lymphocytes, the lasts having increased cytotoxic activity.,Because systemic inflammation is also a component of emphysema, we hypothesize that peripheral CD8+ T lymphocytes of emphysematous smokers who show evidence of systemic inflammation will have higher expression of cytotoxic molecules.,We assessed parameters of systemic inflammation in normal individuals (smokers or non-smokers) and in emphysematous subjects with an active smoking history by measuring serum interleukine-6, C-reactive protein, and tumor necrosis factor.,Expression of perforin, granzyme B, and FasL protein by CD8+ T lymphocytes, CD4+ T lymphocytes, and natural killer cells were assessed by flow cytometry while perforin, granzyme B, and FasL mRNA expression were measured on purified systemic CD8+ T lymphocytes by real-time PCR.,Emphysematous smokers had higher levels of serum interleukine-6 than normal subjects.,Even with the presence of systemic inflammation in emphysematous smokers, the percentage of peripheral CD8+ T lymphocytes, CD4+ T lymphocytes, and NK cells expressing perforin and granzyme B protein was not different between the three groups.,Despite evidence of systemic inflammation, peripheral T lymphocytes of emphysematous smokers did not show higher levels of cytotoxic markers, suggesting that increase of activated T lymphocytes in the emphysematous lung may be due to either activation in the lung or specific peripheral recruitment. | 1 |
A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo.,This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study.,Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks.,Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed.,In all, 277 symptomatic patients were included in this post hoc analysis.,Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo.,In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P<0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P<0.05).,Aclidinium improved trough FEV1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P<0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P<0.05).,Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks.,Tolerability showed similar incidence of AEs in each arm.,In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity. | Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD).,We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) scale (formerly EXACT-RS).,Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction.,Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D.,Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed.,Of 1210 patients, 1167 had data available for GOLD classification.,Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted.,Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group.,The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D.,Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients’ level of symptoms at baseline.,Net treatment benefit was similar in patients with low or high levels of symptoms.,ATTAIN (ClinicalTrials.gov identifier: NCT01001494) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397).,The online version of this article (doi:10.1186/s12931-016-0372-1) contains supplementary material, which is available to authorized users. | 1 |
We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy.,Three studies of ≥1-year duration met the inclusion criteria.,Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%).,At baseline, 57-75% of patients had ≥2% blood eosinophils.,Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level.,For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001).,No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively).,In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo).,No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ.,Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations. | 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 |
The objective of this study is to assess whether statin use is associated with beneficial effects on COPD outcomes.,We conducted a systematic review and meta-analysis of all available studies describing the association between statin use and COPD mortality, exacerbations and cardiovascular events.,Medline, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched, with no restrictions.,The hazard ratio (HR) with 95% confidence interval (CI) was estimated.,Fifteen studies with a total of 238,459 patients were included.,Nine articles provided data on all-cause mortality (124,543 participants), and they gave a HR of 0.62 (95% CI 0.52 to 0.73).,Three studies provided data on cancer mortality (90,077 participants), HR 0.83 (0.65 to 1.08); four studies on COPD mortality (88,767 participants), HR 0.48 (0.23 to 0.99); and three studies on cardiovascular mortality (90,041 participants), HR 0.93 (0.50 to 1.72).,Six articles provided data on COPD exacerbation with or without hospitalization (129,796 participants), HR 0.64 (0.55 to 0.75).,Additionally, the use of statins was associated with a significant reduction risk of myocardial infarction, but not for stroke.,Our systematic review showed a clear benefit of statins in patients with COPD. | Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists.,We summarize evidence for various smoking indices.,Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking.,Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded.,Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment.,For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.,Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema.,RR estimates are markedly heterogeneous.,Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94).,For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition.,Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated.,For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function.,For all outcomes, risk increases with amount smoked and pack-years.,Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD.,No clear relationship is seen with duration of smoking.,The results confirm and quantify the causal relationships with smoking. | 1 |
This study aimed to determine the predictive value of the neutrophil to lymphocyte ratio (NLR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,A retrospective study was conducted from March 2012 to May 2016 in Fuxing Hospital, Capital University of Medical Science.,We collected 906 cases (525 males, 381 females, mean age 81.86±9.75 years) diagnosed with AECOPD.,The NLR was calculated from their white blood cell (WBC), neutrophil (NEU), and lymphocyte (LYM) counts, which were obtained at laboratory examination.,After treatment, 698 patients with AECOPD improved.,The NLR was higher at admission (6.89±6.82) than after treatment (4.19±5.11) (P = 0.000).,The area under the receiver operating characteristic curve (AUC) of the NLR for predicting the 28-day mortality rate was 0.737.,Using 8.130 as the critical NLR value, the sensitivity was 60.5%, and the specificity was 74.8%.,The AUC of the NLR for predicting the frequency of the need for invasive mechanical ventilation was 0.732.,Using 10.345 as the critical NLR value, the sensitivity was 54.3%, and the specificity was 84.8%.,The AUC of WBC, NEU and LYM for predicting 28-day mortality and the need for invasive mechanical ventilation in these patients were all less than 0.7.,An increased NLR was an independent risk factor for 28-day mortality (OR = 1.067, 95% CI = 1.039 to 1.095, P = 0.000), intensive care unit occupancy (OR = 1.046, 95% CI = 1.023 to 1.068, P = 0.000), and the need for invasive mechanical ventilation (OR = 1.042, 95% CI = 1.019 to 1.066, P = 0.000).,Compared with those patients without comorbidities, patients with renal dysfunction or upper gastrointestinal bleeding had an increased risk of death within 28 days (OR = 3.102, 95% CI = 1.525 to 6.312; OR = 4.598, 95% CI = 1.825 to 11.583, respectively), ICU admission (OR = 2.228, 95% CI = 1.286 to 3.860; OR = 3.103, 95% CI = 1.402 to 6.866, respectively), and the need for invasive mechanical ventilation (OR = 3.572, 95% CI = 1.822 to 7.000; OR = 4.279, 95% CI = 1.823 to 10.045, respectively).,In patients with AECOPD, the accuracy of the NLR for predicting the 28-day mortality rate and frequency of the need for mechanical ventilation was significantly higher than the accuracy of WBC, NEU and LYM counts.,AECOPD patients with an NLR≥8.130 had higher 28-day mortality rate, while those with an NLR ≥10.345 were more likely to need invasive mechanical ventilation. | COPD exacerbations requiring intensive care unit (ICU) admission have a major impact on morbidity and mortality.,Only 10%-25% of COPD exacerbations are eosinophilic.,To assess whether eosinophilic COPD exacerbations have better outcomes than non-eosinophilic COPD exacerbations in the ICU.,This retrospective observational cohort study was conducted in a thoracic, surgery-level III respiratory ICU of a tertiary teaching hospital for chest diseases from 2013 to 2014.,Subjects previously diagnosed with COPD and who were admitted to the ICU with acute respiratory failure were included.,Data were collected electronically from the hospital database.,Subjects’ characteristics, complete blood count parameters, neutrophil to lymphocyte ratio (NLR), delta NLR (admission minus discharge), C-reactive protein (CRP) on admission to and discharge from ICU, length of ICU stay, and mortality were recorded.,COPD subjects were grouped according to eosinophil levels (>2% or ≤2%) (group 1, eosinophilic; group 2, non-eosinophilic).,These groups were compared with the recorded data.,Over the study period, 647 eligible COPD subjects were enrolled (62 [40.3% female] in group 1 and 585 [33.5% female] in group 2).,Group 2 had significantly higher C-reactive protein, neutrophils, NLR, delta NLR, and hemoglobin, but a lower lymphocyte, monocyte, and platelet count than group 1, on admission to and discharge from the ICU.,Median (interquartile range) length of ICU stay and mortality in the ICU in groups 1 and 2 were 4 days (2-7 days) vs 6 days (3-9 days) (P<0.002), and 12.9% vs 24.9% (P<0.034), respectively.,COPD exacerbations with acute respiratory failure requiring ICU admission had a better outcome with a peripheral eosinophil level >2%.,NLR and peripheral eosinophilia may be helpful indicators for steroid and antibiotic management. | 1 |
To describe a murine model of emphysema induced by a combination of exposure to cigarette smoke (CS) and instillation of porcine pancreatic elastase (PPE).,A total of 38 C57BL/6 mice were randomly divided into four groups: control (one intranasal instillation of 0.9% saline solution); PPE (two intranasal instillations of PPE); CS (CS exposure for 60 days); and CS + PPE (two intranasal instillations of PPE + CS exposure for 60 days).,At the end of the experimental protocol, all animals were anesthetized and tracheostomized for calculation of respiratory mechanics parameters.,Subsequently, all animals were euthanized and their lungs were removed for measurement of the mean linear intercept (Lm) and determination of the numbers of cells that were immunoreactive to macrophage (MAC)-2 antigen, matrix metalloproteinase (MMP)-12, and glycosylated 91-kDa glycoprotein (gp91phox) in the distal lung parenchyma and peribronchial region.,Although there were no differences among the four groups regarding the respiratory mechanics parameters assessed, there was an increase in the Lm in the CS + PPE group.,The numbers of MAC-2-positive cells in the peribronchial region and distal lung parenchyma were higher in the CS + PPE group than in the other groups, as were the numbers of cells that were positive for MMP-12 and gp91phox, although only in the distal lung parenchyma.,Our model of emphysema induced by a combination of PPE instillation and CS exposure results in a significant degree of parenchymal destruction in a shorter time frame than that employed in other models of CS-induced emphysema, reinforcing the importance of protease-antiprotease imbalance and oxidant-antioxidant imbalance in the pathogenesis of emphysema. | Chronic obstructive pulmonary disease (COPD) is a major clinical challenge mostly due to cigarette smoke (CS) exposure.,Invariant natural killer T (iNKT) cells are potent immunoregulatory cells that have a crucial role in inflammation.,In the current study, we investigate the role of iNKT cells in COPD pathogenesis.,The frequency of activated NKT cells was found to be increased in peripheral blood of COPD patients relative to controls.,In mice chronically exposed to CS, activated iNKT cells accumulated in the lungs and strongly contributed to the pathogenesis.,The detrimental role of iNKT cells was confirmed in an acute model of oxidative stress, an effect that depended on interleukin (IL)-17.,CS extracts directly activated mouse and human dendritic cells (DC) and airway epithelial cells (AECs) to trigger interferonγ and/or IL-17 production by iNKT cells, an effect ablated by the anti-oxidant N-acetylcystein.,In mice, this treatment abrogates iNKT-cell accumulation in the lung and abolished the development of COPD.,Together, activation of iNKT cells by oxidative stress in DC and AECs participates in the development of experimental COPD, a finding that might be exploited at a therapeutic level. | 1 |
The quest for the right combination of bronchodilators with different mechanisms of action such as long-acting muscarinic antagonists and long-acting β-agonists in the management of stable moderate-to-severe chronic obstructive pulmonary disease (COPD) is a topic of intense research activity currently, given the rising morbidity and mortality due to this disease.,The fixed-dose combination of aclidinium bromide and formoterol fumarate in a single inhaler seems to offer superior advantages over either drugs given alone or as separate inhalers concurrently.,Since the fixed-dose combination needs to be given twice daily, it is likely to achieve control of symptoms most crucial to the quality of life in COPD, namely, the morning hours.,This is reflected in significant trough FEV1 (forced expiratory volume in 1 second) improvements after the dose.,This paper reviews the various studies related to this combination put in the perspective of its safety and efficacy and potential benefits over other therapeutic options.,However, there is a dearth of data on the long-term safety and efficacy in terms of improvement in lung function.,This combination could emerge as an excellent option in the management of stable COPD if data on exacerbation rates and patient-reported outcomes become available from longer-term studies.,Moreover, we need some more studies to define the ideal phenotype of COPD best suited for the use of this combination. | Sleep quality is often poor in patients with chronic obstructive pulmonary disease (COPD).,A cross-sectional European survey investigated the prevalence of night-time symptoms in COPD to evaluate the level of disconnect between physician and patient perceptions of the presence of night-time symptoms, and to compare the characteristics of patients with and without night-time symptoms.,A total of 251 primary care physicians and 251 respiratory specialists completed record forms on 2,807 patients with COPD.,The forms captured information on patient demographics, lung function, COPD severity, and symptoms.,Patients completed questionnaires on the time of day when their COPD symptoms bothered them, and the impact of COPD on their ability to get up in the morning and on sleep.,Data were compared between groups (those with and without night-time symptoms) using t-tests or Wilcoxon signed rank tests.,The kappa statistic was used to assess the level of disconnect between physician and patient perceptions of the impact of night-time symptoms.,Most patients (78%) reported night-time disturbance.,Patients with night-time symptoms experienced more daytime breathlessness (mean modified Medical Research Council dyspnea scale score 2.4 versus 1.1) and exacerbations in the previous 12 months (mean 1.7 versus 0.4), and received more maintenance therapy (mean of 2.8 versus 2.3 products) than those without.,Concordance between the frequency of physician-reported (67.9% of patients) and patient-reported (68.5% of patients) night-time symptoms was good.,Physicians significantly underestimated the impact of COPD on the patient’s ability to get up in the morning and on sleep (fair-moderate agreement).,Physician-reported night-time symptoms were present for 41.2% of patients who could be categorized by Global initiative for chronic Obstructive Lung Disease (GOLD) group (n=937), increasing from 20.9% of those in the low-risk group to 77.4% of those in the high-riskgroup.,Patients with COPD experience night-time symptoms regardless of GOLD group, that impact on their ability to get up in the morning and on their sleep quality. | 1 |
COPD is a major global cause of mortality and morbidity.,PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD.,In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI (all twice daily) for 24 weeks.,Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed.,Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian).,GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001).,GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI.,A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George’s Respiratory Questionnaire score vs placebo MDI.,Adverse event rates were similar across treatment groups.,These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD.,GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators. | Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease (COPD).,We investigated this by combining two long-acting bronchodilators: once-daily muscarinic antagonist tiotropium and once-daily β2-agonist olodaterol.,Two replicate, double-blind, randomized, 12-week studies (ANHELTO 1 [NCT01694771] and ANHELTO 2 [NCT01696058]) evaluated the efficacy and safety of olodaterol 5 μg once daily (via Respimat®) combined with tiotropium 18 μg once daily (via HandiHaler®) versus tiotropium 18 μg once daily (via HandiHaler®) combined with placebo (via Respimat®) in patients with moderate to severe COPD.,Primary efficacy end points were area under the curve from 0-3 hours of forced expiratory volume in 1 second (FEV1 AUC0-3) and trough FEV1 after 12 weeks (for the individual trials).,A key secondary end point was health status by St George’s Respiratory Questionnaire (SGRQ) total score (combined data set).,Olodaterol + tiotropium resulted in significant improvements over tiotropium + placebo in FEV1 AUC0-3 (treatment differences: 0.117 L [P<0.001], ANHELTO 1; 0.106 L [P<0.001], ANHELTO 2) and trough FEV1 (treatment differences: 0.062 L [P<0.001], ANHELTO 1; 0.040 L [P=0.0029], ANHELTO 2); these were supported by secondary end points.,These effects translated to improvements in SGRQ total scores (treatment difference −1.85; P<0.0001).,The tolerability profile of olodaterol + tiotropium was similar to tiotropium monotherapy.,These studies demonstrated that olodaterol (Respimat®) and tiotropium (HandiHaler®) provided bronchodilatory effects above tiotropium alone in patients with COPD.,In general, both treatments were well tolerated. | 1 |
The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood.,A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients.,International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies.,However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.,Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc.,The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research.,The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.,Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD.,Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.,Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD.,The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response.,Generally, the response was seen when eosinophil levels were 100-300 cells/µL (or higher), levels which are traditionally viewed within the normal range.,Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.,The use of biomarkers could help to stratify treatment for COPD-the goal of which is to improve patient outcomes.,Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing.,A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance.,Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice.,Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response. | Inhaled corticosteroid use is associated with increased rates of pneumonia in COPD patients.,The underlying mechanism is unknown, although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide.,Macrophages and neutrophils from COPD patients are deficient in clearing bacteria, and this might explain increased bacterial colonization in COPD.,Inhaled corticosteroid may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDMs) and neutrophils.,MDMs from COPD patients (n=20-24) were preincubated with FP or budesonide for 1 or 18 hours, after which phagocytosis of fluorescently labeled inert beads or heat-killed Haemophilus influenzae/Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 hours.,Additionally, CXCL8, IL6, and TNFα concentrations in supernatants by ELISA, MDM-scavenger-receptor expression by flow cytometry, and MDM ability to kill bacteria were measured.,Neutrophils from COPD patients (n=8) were preincubated with corticosteroids for 1 hour and bacteria phagocytosis measured by flow cytometry.,After 1 hour’s preincubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10−7 M) increased S. pneumoniae phagocytosis by 23% (P<0.05).,After 18 hours’ preincubation, neither corticosteroid altered MDM phagocytosis of any prey, although H. influenzae phagocytosis by budesonide was significantly greater compared to FP at 10−6 and 10−5 M (P<0.05).,The 1-hour preincubation with either corticosteroid inhibited bacteria-induced CXCL8 release (at 10−7 and 10−5 M, P<0.05); however, this effect was lost at 18-hour preincubation.,There was no change in receptor expression, bacterial killing, or neutrophil phagocytosis by either corticosteroid.,These data suggest that dissolved FP and budesonide do not have an overall effect on MDM or neutrophil phagocytosis of bacteria. | 1 |
The clinical implications of blood eosinophil level in patients with chronic obstructive pulmonary disease (COPD) and community-acquired pneumonia (CAP) requiring invasive mechanical ventilation (IMV) and intensive care unit (ICU) admission are still unknown.,Thus, this study aimed to compare the features of such patients with and without blood eosinophilia.,This was a retrospective case-control study.,An ICU of a medical centre in central Taiwan.,A total of 262 patients with COPD and CAP requiring IMV and ICU admission.,Of all participants (n=262), 32 (12.2%) had an eosinophil percentage (EP) >2% and 169 (64.5%) had an absolute eosinophil count (AEC) >300 cells/µL.,Regardless of whether 2% or 300 cells/µL was used as a cut-off value, the eosinophilia group were slightly older (years) (82.9±5.4 vs 78.1±9.1, p=0.000 and 79.2±8.4 vs 77.6±9.6, p=0.246, respectively), and had a higher forced expiratory volume in 1 s/forced vital capacity (%) (56.0±8.0 vs 51.3±11.6, p=0.005 and 53.1±11.2 vs 49.5±11.2, p=0.013, respectively), less severe spirometric classification (p=0.008 and p=0.001, respectively), and lower white cell count 109/L (8.8±3.2 vs 11.1±4.9, p=0.009 and 10.3±4.4 vs 11.8±5.3, p=0.017, respectively) than the non-eosinophilia group.,The bacteriology of endotracheal aspirates showed that Pseudomonas aeruginosa and other gram-negative bacilli were the most common organisms in all study groups.,Participants with an EP >2% had a shorter ICU length of stay (OR=12.13, p=0.001) than those with an EP ≤2%, while an AEC >300 cells/µL was not associated with any in-ICUoutcomes.,The results of this study have significant clinical implications and should be considered when making treatment decisions for the management of patients with COPD and CAP requiring IMV and ICU admission. | 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. | 1 |
To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009.,A total of 45,837 male residents were observed for a median period of 19.1 years.,Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019.,During follow-up, 268 participants died from COPD.,The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41-0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59-0.68).,These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years.,Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality. | Accurately evaluating a risk of chronic obstructive pulmonary disease (COPD) requires a large-scale longitudinal study using a standard criterion for diagnosing COPD.,There have been only a few such follow-up studies in Europe and no reports in Asia.,We estimated the incidence rate and incidence rate ratio (IRR) of age and smoking for COPD in a Japanese population using the diagnosis criterion of the Global Initiative for Chronic Obstructive Lung Disease guidelines.,Subjects were 17,106 participants aged 25-74 years during health check-ups including spirometry from April 1997 through March 2005 in Japan.,Total follow-up of participants were 47,652 person-years in males and 25,224 person-years in females.,The IRR of age and smoking was estimated using Cox proportional hazard models with both variables.,We identified 466 incidence cases of COPD.,The incidence rate per 100 person-years was 0.81 (95% confidence interval [CI], 0.73-0.89) in males and 0.31 (0.24-0.38) in females, and significantly increased with age in both sexes.,The incidence rate for current smokers was significantly higher than that for male non-smokers but not significantly for females.,Among males, the IRR for current smokers with Brinkman Index < 400, 400-799, and 800+ was 1.2 (0.8-1.9), 2.7 (1.9-3.8), and 4.6 (3.3-6.5), respectively.,These results indicated that the COPD risk gradually increased with aging, and that there was a dose-response relationship between smoking and COPD risk. | 1 |
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. | To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls.,Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study.,Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise.,All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests.,Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104).,Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups.,Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001).,Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls.,Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001).,Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort.,Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls.,ClinicalTrials.gov: NCT01072396 | 1 |
COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function.,Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy.,This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID.,CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings.,Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD).,In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included.,ClinicalTrials.gov number: NCT01985334.,Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments.,The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]).,Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]).,In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice. | The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).,Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein.,Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo.,After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension.,Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV1), area under the curve from 0 to 12 hours postdose (AUC0-12 h), and morning predose/trough FEV1 from baseline to the week 13 endpoint.,Key secondary efficacy variables were St George’s Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint.,In the 26-week treatment period, significantly greater increases in FEV1 AUC0-12 h occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032).,These increases were over three-fold greater with MF/F 400/10 than with MF 400.,Also, significantly greater increases in morning predose/trough FEV1 occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05).,The increase was four-fold greater with MF/F 400/10 than with F 10.,All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George’s Respiratory Questionnaire scores at week 26.,Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo).,The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period.,The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment.,Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups.,Differences in rates of individual treatment-emergent adverse events were <3% between treatment groups.,Rates of pneumonia were low (≤2%) across all treatment groups.,Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates.,Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements. | 1 |
Patients with COPD are vulnerable to workforce detachment.,Better knowledge of features associated with paid work loss might be of help to design and select appropriate interventions.,This cross-sectional study aimed to explore the presence of treatable traits in COPD patients without paid work.,Patients with COPD below 65 years at first referral to a hospital-based patient clinic were included.,Using binary logistic regression analysis, the relationship between paid work and the following characteristics was explored: low daily physical activity, exercise, active smoking, Medical Research Council dyspnea scale (MRC), poor nutritional status, exacerbations, and fatigue (checklist individual strength (CIS)).,Variables were adjusted for age, sex, forced expiratory volume in 1 s (FEV 1), and education level.,In total, 191 patients (47.3%) were without paid work.,The following treatable traits were related to not being in paid work: < 5000 steps/day (OR 2.36, 95% CI (1.52-3.68)), MRC ≥ 3 (OR 1.78, 95%CI (1.14-2.77)), CIS ≥ 36 points (OR 1.78, 95% CI (1.10-2.87)), six-minute walk distance (6MWD) < 70% of predicted (OR 2.62, 95% CI (1.69-4.06)), and ≥ 2 exacerbations per year (OR 1.80, 95% CI (1.12-2.92)).,Significant differences were also seen in age (OR 1.06, 95% CI (1.02-1.10) per year), FEV 1% predicted (OR 0.98, 95% CI (0.97-1.00) per % predicted increase), and medium/high education level (OR 0.62, 95% CI (0.41-0.93)).,When adjusting for all variables the only treatable trait that remained significant was 6MWD.,Patients without paid work are more likely to have treatable traits with 6MWD revealing the most significant association.,The online version contains supplementary material available at 10.1186/s12931-021-01736-6. | To examine the association between exacerbation frequency and mortality following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).,Cohort study using medical databases.,Northern Denmark.,On 1 January 2005, we identified all patients with prevalent hospital-diagnosed chronic obstructive pulmonary disease (COPD) who had at least one AECOPD during 1 January 2005 to 31 December 2009.,We followed patients from the first AECOPD during this period until death, emigration or 31 December 2009, whichever came first.,We flagged all AECOPD events during follow-up and characterised each by the exacerbation frequency (0, 1, 2 or 3+) in the prior 12-month period.,Using Cox regression, we computed 0-30-day and 31-365-day age-adjusted, sex-adjusted, and comorbidity-adjusted mortality rate ratios (MRRs) with 95% CIs entering exacerbation frequency as a time-varying exposure.,We identified 16 647 eligible patients with prevalent COPD, of whom 6664 (40%) developed an AECOPD and were thus included in the study cohort.,The 0-30-day MRRs were 0.97 (95% CI 0.80 to 1.18), 0.90 (95% CI 0.70 to 1.15) and 1.03 (95% CI 0.81 to 1.32) among patients with AECOPD with 1, 2 and 3+ AECOPDs versus no AECOPD within the past 12 months, respectively.,The corresponding MRRs were 1.47 (95% CI 1.30 to 1.66), 1.89 (95% CI 1.59 to 2.25) and 1.59 (95% CI 1.23 to 2.05) for days 31-365.,Among patients with AECOPD, one or more exacerbations in the previous year were not associated with 30-day mortality but were associated with an increased 31-365-day mortality. | 1 |
We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients.,In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV1], 49% predicted) were studied cross-sectionally.,Demographics, anthropometrics, lung function and clinical data were assessed.,Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband.,Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters.,Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns.,Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data.,Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV1, worse dyspnoea and higher ADO index compared to other clusters (p < 0.05 for all).,Daily physical activity measures and hourly patterns are heterogeneous in COPD.,Clusters of patients were identified solely based on physical activity data.,These findings may be useful to develop interventions aiming to promote physical activity in COPD. | To evaluate the prevalence of sarcopenia in COPD patients, as well as to determine whether sarcopenia correlates with the severity and prognosis of COPD.,A cross-sectional study with COPD patients followed at the pulmonary outpatient clinic of our institution.,The patients underwent dual-energy X-ray absorptiometry.,The diagnosis of sarcopenia was made on the basis of the skeletal muscle index, defined as appendicular lean mass/height2 only for low-weight subjects and adjusted for fat mass in normal/overweight subjects.,Disease severity (COPD stage) was evaluated with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.,The degree of obstruction and prognosis were determined by the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index.,We recruited 91 patients (50 females), with a mean age of 67.4 ± 8.7 years and a mean BMI of 25.8 ± 6.1 kg/m2.,Sarcopenia was observed in 36 (39.6%) of the patients, with no differences related to gender, age, or smoking status.,Sarcopenia was not associated with the GOLD stage or with FEV1 (used as an indicator of the degree of obstruction).,The BMI, percentage of body fat, and total lean mass were lower in the patients with sarcopenia than in those without (p < 0.001).,Sarcopenia was more prevalent among the patients in BODE quartile 3 or 4 than among those in BODE quartile 1 or 2 (p = 0.009).,The multivariate analysis showed that the BODE quartile was significantly associated with sarcopenia, regardless of age, gender, smoking status, and GOLD stage.,In COPD patients, sarcopenia appears to be associated with unfavorable changes in body composition and with a poor prognosis.,Avaliar a prevalência de sarcopenia em pacientes com DPOC e determinar se sarcopenia está correlacionada com a gravidade e o prognóstico de DPOC.,Estudo retrospectivo em pacientes com DPOC atendidos no ambulatório de pneumologia de nossa instituição.,Os pacientes realizaram absorciometria de dupla energia por raios X.,O diagnóstico de sarcopenia foi baseado no índice de massa muscular esquelética, definido como massa magra apendicular/altura2 somente para indivíduos com baixo peso, sendo ajustado pela massa gorda para aqueles com peso normal/sobrepeso.,A gravidade da doença (estádio da DPOC) foi avaliada com os critérios da Global Initiative for Chronic Obstructive Lung Disease (GOLD).,O grau de obstrução e o prognóstico foram determinados pelo índice Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE).,Foram incluídos 91 pacientes (50 mulheres), com média de idade de 67,4 ± 8,7 anos e média de IMC de 25,8 ± 6,1 kg/m2.,Sarcopenia foi diagnosticada em 36 (39,6%) dos pacientes, sem diferenças relacionadas a sexo, idade ou status tabágico.,Não houve associação de sarcopenia com estádios GOLD ou VEF1 (utilizado como indicador do grau de obstrução).,O IMC, a porcentagem de gordura corporal e a massa magra total foram menores nos pacientes com sarcopenia do que naqueles sem a doença (p < 0,001).,A prevalência de sarcopenia foi maior nos pacientes com BODE nos quartis 3 ou 4 que naqueles com BODE nos quartis 1 ou 2 (p = 0,009).,A análise multivariada mostrou que os quartis do BODE estavam significativamente associados à sarcopenia, independentemente de idade, gênero, status tabágico e estádio GOLD.,Em pacientes com DPOC, sarcopenia parece estar associada a alterações desfavoráveis na composição corporal e pior prognóstico. | 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. | Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible.,Bronchodilator therapy is the cornerstone in COPD treatment.,Bronchodilation in COPD is mainly achieved via administration of long- and ultralong-acting β2-agonists and with long-acting muscarinic antagonists.,New combinations of bronchodilators with dual-acting muscarinic antagonist and β2-agonist properties have been licensed, and others are currently being developed with the aim of achieving once-daily dosing, and therefore may improve the likelihood of treatment compliance.,These combination bronchodilators include glycopyrronium bromide/indacaterol maleate, umeclidinium (UMEC) bromide/vilanterol trifenatate (VI), aclidinium bromide/formoterol and tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany).,This review will focus mainly on studies and clinical trials involving the novel fixed-dose combination of UMEC/VI at doses of 125/25 μg and 62.5/25 μg in patients with COPD.,Data from large clinical trials involving more than 4,500 COPD patients indicate that UMEC/VI is an effective once-daily treatment in COPD with improved pulmonary function.,Future studies assessing the impact of this combination on exacerbations, delay in disease progression, and health status in patients with COPD are warranted. | 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. | Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by a progressive and irreversible deterioration of lung function.,Exacerbations of COPD have prolonged negative effects on pulmonary function and a major impact on health status and outcomes.,NLRP3 inflammasome is a cardinal component of the inflammatory response, with marked evidence in stable and exacerbations of COPD.,The aim of our study was to evaluate the NLRP3 inflammasome activity during COPD exacerbation by using an in vitro model.,A549 cells were stimulated with different concentrations (10%, 4%, 2%) of cigarette smoke extract (CSE) with or without LPS (0.1μg/ml) for 24 hours.,Cell viability was assessed by using XTT test.,Levels of inflammatory cytokines (IL-8, MCP-1, and IL-1β) were measured by ELISA and the activity level of NLRP-3 was evaluated by flow cytometry.,Cells exposed to CSE present an increase in inflammatory cytokines (IL-8 and MCP-1) production in a dose-dependent manner.,Incubation with LPS to these cells results in higher levels of IL-8 and MCP-1 compared to stimulation of CSE alone.,NLRP3 inflammasome activity and IL-1β levels were significantly increased in cells exposed to both CSE and LPS compared to CSE alone.,NLRP3 inflammasome is upregulated in an in-vitro model of COPD and COPD exacerbation.,Our findings provide novel biomarkers for COPD exacerbation and may present new targets for future research. | 1 |
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. | The GOLD classification of COPD severity introduces a stage 0 (at risk) comprising individuals with productive cough and normal lung function.,The aims of this study were to investigate total mortality risks in GOLD stages 0-4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1-4.,Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits.,Individuals with comorbidity at baseline (diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses.,Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0-4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group.,HR:s in smoking individuals with symptoms of chronic bronchitis within the stages 1-4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference.,The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively.,The proportion of smokers among men was 50% and among women 40%.,Self reported comorbidity was present in 4.6% of the men and 6.6% of the women.,Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 (1.32-2.08), of similar magnitude as in stage 2, HR; 1.41 (1.31-1.70).,The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 (0.98-1.29).,Among male smokers with stage 1; HR: 2.04 (1.34-3.11), and among female smokers with stage 2 disease; HR: 3.16 (1.38-7.23), increased HR:s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis.,Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function (stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD (stage 1 and 2). | 1 |
The chronic obstructive pulmonary disease (COPD) integrated care pathway (ICP) programme was designed and implemented to ensure that the care for patients with COPD is comprehensive and integrated across different care settings from primary care to acute hospital and home.,We evaluated the effectiveness of the ICP programme for patients with COPD.,A retrospective propensity score matched cohort study was conducted comparing differences between programme enrolees and propensity-matched non-enrolees in a Regional Health System in Singapore.,Data on patients diagnosed with COPD who enrolled in the programme (n=95) and patients who did not enrol (n=6330) were extracted from the COPD registry and hospital administrative databases.,Enrolees and non-enrolees were propensity score matched.,The risk of COPD hospitalisations and COPD hospital bed days savings were compared between the groups using a difference-in-difference strategy and generalised estimating equation approach.,Adherence with recommended care elements for the COPD-ICP group was measured quarterly at baseline and during a 2-year follow-up period.,Compared with non-enrolees, COPD hospitalisation risk for ICP programme enrolees was significantly lower in year 2 (incidence rate ratio (IRR): 0.73; 95% CI 0.54 to 1.00).,Similarly, COPD hospital bed days was significantly lower for enrolees in year 2 (IRR: 0.78; 95% CI 0.64 to 0.95).,ICP programme patients had sustained improvements in compliance with all recommended care elements for patients with COPD.,The overall all-or-none care bundle compliance rate had improved from 28% to 54%.,The study concluded that the COPD-ICP programme was associated with reductions in COPD hospitalisation risk and COPD health utilisation in a 2-year follow-up period. | We sought to assess continuity of care for elderly patients in Korea and to examine any association between continuity of care and health outcomes (hospitalization, emergency department visits, health care costs).,This was a retrospective cohort study using the Korea National Health Insurance Claims Database.,Elderly people, 65-84 yr of age, who were first diagnosed with diabetes mellitus (n=268,220), hypertension (n=858,927), asthma (n=129,550), or chronic obstructive pulmonary disease (COPD, n=131,512) in 2002 were followed up for four years, until 2006.,The mean of the Continuity of Care Index was 0.735 for hypertension, 0.709 for diabetes mellitus, 0.700 for COPD, and 0.663 for asthma.,As continuity of care increased, in all four diseases, the risks of hospitalization and emergency department visits decreased, as did health care costs.,In the Korean health care system, elderly patients with greater continuity of care with health care providers had lower risks of hospital and emergency department use and lower health care costs.,In conclusion, policy makers need to develop and try actively the program to improve the continuity of care in elderly patients with chronic diseases. | 1 |
Eosinophilic COPD appears to be a distinct patient subgroup with an increased corticosteroid response.,Eosinophilic COPD has been labelled as part of the asthma COPD overlap syndrome (ACOS).,We compared the clinical characteristics of eosinophilic COPD patients (without any clinical history of asthma) and COPD patients with a childhood history of asthma.,COPD patients with asthma were characterised by more allergies and more exacerbations, but less eosinophilic inflammation.,While terms such as “ACOS” are used to “lump” patients together, we report distinct differences between eosinophilic COPD and COPD patients with asthma, and propose that these groups should be split rather than lumped. | We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy.,Three studies of ≥1-year duration met the inclusion criteria.,Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%).,At baseline, 57-75% of patients had ≥2% blood eosinophils.,Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level.,For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001).,No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively).,In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo).,No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ.,Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations. | 1 |
Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.,For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler.,Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).,295 and 291 patients were treated in MORACTO 1 and 2, respectively.,Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p<0.0001), and significant improvements in exercise endurance time versus placebo (p<0.0001).,Intensity of breathing discomfort was reduced following both doses of tiotropium/olodaterol versus placebo (p<0.0001).,Once-daily tiotropium/olodaterol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies.,Tiotropium/olodaterol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies.,T/O reduces lung hyperinflation in COPD versus T, O or placebo and increases exercise endurance versus placebohttp://ow.ly/ml3G307XW6a | Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone.,The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.,In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*.,Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol).,Secondary endpoints were change from baseline in St.,George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24.,Safety and tolerability were also assessed.,At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001).,Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC.,Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively.,All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.,Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo.,Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.,Clinicaltrials.gov NCT01437397.,*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair® and Genuair® within all other licensed territories.,The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) not only affects pulmonary function but also leads to skeletal muscle dysfunction.,The various characteristics of different forms of traditional Chinese exercise lead to inconsistent clinical effects in COPD patients.,Hence, the present study carefully combined and rearranged liuzijue, wuqinxi, baduanjin, and yijinjing into a pulmonary exercise program targeting COPD patients.,This study is a single-blind, randomized controlled trial.,A random number table will be generated by an independent person.,Each number will be placed in a sealed opaque envelop to blind assignment.,All outcome assessors will be blinded to group assignment.,COPD patients between 40 and 80 years of age, with stable medical treatment and no regular participation in regular exercise in the last 6 months will be included.,All participants will be recruited from the Respiratory Medicine Department of Yue-Yang Integrative Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine.,All participants will continue to follow their medical treatment.,They will be randomly assigned to one of four groups in a 1:1:1:1 ratio: (1) usual care (control group, CG), (2) pulmonary exercise group (PG), (3) resistance exercise group (RG), or (4) combined pulmonary exercise and resistance exercise group (PRG).,CG participants will receive medical treatment only.,PG participants will perform 60 min of exercise twice a day 7 days a week for 3 months, with 1 day’s exercise per week at hospital under guidance and supervision.,RG participants will perform 60 min of resistance exercise once a day, three times a week for 3 months, with 1 day’s exercise per week at hospital under guidance and supervision.,PRG participants will perform 60 min of prescribed pulmonary exercise combined with resistance exercise for 3 months.,The outcomes include the isokinetic strength of peripheral skeletal muscle, surface electromyography, 6-min walking distance, 30-s arm curl test, pulmonary function, respiratory muscle strength, dyspnea, body composition, physical activity, quality of life, and Chronic Disease Self-Efficacy Scale.,The results of this study will compensate for the current inadequate understanding of prescribed pulmonary exercise and may provide a new, simple, convenient, and effective home-based exercise intervention for COPD patients.,Chinese Clinical Trial Registry, ChiCTR-1800017405.,Registered on 28 July 2018.,The online version of this article (10.1186/s13063-018-3149-7) contains supplementary material, which is available to authorized users. | Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD).,However, only a few relevant studies have investigated the long-term outcomes and efficacy of both in patients with COPD.,We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D.,Eligible participants (n = 170) were randomized and received either tiotropium 18 µg once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 µg once daily (Group II) for 6 months.,COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment.,After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41 ± 3.56 and 11.08 ± 3.05, p < 0.0001).,The changes of CAT (p = 0.028) and mMRC scores (p = 0.049) between the two groups differed after 1 month of treatment.,In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF25% pred) was significantly improved after 3 months (4.84 ± 8.73%, p < 0.0001) and 6 months (6.21 ± 8.65%, p < 0.0001).,There was a significant difference in small airway function tests (MEF50% pred, MEF25% pred, and MMEF% pred) between the two groups after 6 month of treatment (p = 0.003, p < 0.0001, and p = 0.021, respectively).,Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up.,Additionally, this therapy also improved the indicators of small airway function.,Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027).,The online version of this article (10.1007/s12325-018-0831-9) contains supplementary material, which is available to authorized users. | 1 |
Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis.,We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD.,The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.,This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations.,Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.,In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%).,The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001).,In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%).,UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).,This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods.,UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy. | Chronic obstructive pulmonary disease (COPD) symptoms in the morning, including dyspnea and sputum production, affect patients’ quality of life and limit their ability to carry out even simple morning activities.,It is now emerging that these symptoms are associated with increased risk of exacerbations and work absenteeism, suggesting that they have a more profound impact on patients than previously thought.,The development of validated patient-reported outcome (PRO) questionnaires to capture patients’ experience of COPD symptoms in the morning is, therefore, vital for establishing effective and comprehensive management strategies.,Although it is well established that long-acting bronchodilators are effective in improving COPD symptoms, the limited available data on their impact on morning symptoms and activities have been obtained with non-validated PRO questionnaires.,In this review, we discuss the impact of COPD symptoms in the morning and available tools used to evaluate them, and highlight specific gaps that need to be addressed to develop standardized instruments able to meet regulatory requirement.,We also present available evidence on the effect of pharmacological therapies on morning symptoms. | 1 |
Chronic obstructive pulmonary disease (COPD) is emphysema and/or chronic bronchitis characterised by long-term breathing problems and poor airflow.,The prevalence of COPD has increased over the last decade and the drugs most commonly used to treat it, such as glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression.,Here we reviewed the pathogenesis and progression of COPD and elaborated on the effects and mechanisms of newly developed molecular targeted COPD therapeutic drugs.,Among these new drugs, we focussed on thioredoxin (Trx).,Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-κB and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways.,The mechanism by which Trx affects COPD is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses.,In addition, Trx also improves the insensitivity of COPD to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (MIF).,Taken together, these findings suggest that Trx may be the ideal drug for treating COPD. | Diet and nutrition may be important modifiable risk factors for the development, progression and management of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD).,This review examines the relationship between dietary patterns, nutrient intake and weight status in obstructive lung diseases, at different life stages, from in-utero influences through childhood and into adulthood.,In vitro and animal studies suggest important roles for various nutrients, some of which are supported by epidemiological studies.,However, few well-designed human intervention trials are available to definitively assess the efficacy of different approaches to nutritional management of respiratory diseases.,Evidence for the impact of higher intakes of fruit and vegetables is amongst the strongest, yet other dietary nutrients and dietary patterns require evidence from human clinical studies before conclusions can be made about their effectiveness. | 1 |
COPD is a heterogeneous disease, and the available prognostic indexes are therefore limited.,This study aimed to identify the factors associated with acute exacerbation leading to hospitalization.,This was a retrospective study of consecutive patients with COPD (meeting the Global Initiative for Chronic Obstructive Lung Disease [GOLD] diagnostic criteria) hospitalized at the Ninth Hospital of Xi’an Affiliated Hospital of Xi’an Jiaotong University between October 2014 and September 2016.,During follow-up after first hospitalization, the patients who had been rehospitalized within 1 year for acute exacerbation were grouped into the frequent exacerbation (FE) group, while the others were grouped into the infrequent exacerbation (IE) group.,The baseline demographic, clinical, laboratory, pulmonary function, and imaging data were compared between the two groups.,Compared with the IE group, the FE group had lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (P=0.005), FEV1%pred (P=0.002), maximal mid-expiratory flow (MMEF25-75%pred) (P=0.003), and ratio of carbon monoxide diffusion capacity to alveolar ventilation (DLCO/VA) (P=0.03) and higher resonant frequency (Fres; P=0.04).,According to generations of bronchi, the percentage of the wall area (%WA) of lobes was found to be higher in the FE group.,Emphysema index (EI), mean emphysema density (MED)whole and MEDleft lung in the FE group were significantly worse than in the IE group (P<0.05).,Using logistic regression, exacerbation hospitalizations in the past year (odds ratio [OR] 14.4, 95% CI 6.1-34.0, P<0.001) and EI >10% (OR 2.9, 95% CI 1.2-7.1, P=0.02) were independently associated with frequent acute exacerbation of COPD (AECOPD) hospitalization.,Exacerbation hospitalizations in the past year and imaging features of emphysema (EI) were independently associated with FE hospitalization. | Living well with chronic obstructive pulmonary disease (COPD) requires people to manage disease-related symptoms in order to participate in activities of daily living.,Mindfulness practice is an intervention that has been shown to reduce symptoms of chronic disease and improve accurate symptom assessment, both of which could result in improved disease management and increased wellness for people with COPD.,A randomized controlled trial was conducted to investigate an 8-week mindful meditation intervention program tailored for the COPD population and explore the use of breathing timing parameters as a possible physiological measure of meditation uptake.,Results demonstrated that those randomized to the mindful meditation intervention group (N=19) had a significant increase in respiratory rate over time as compared to those randomized to the wait-list group (N=22) (P=0.045).,It was also found that the mindful meditation intervention group demonstrated a significant decrease in level of mindfulness over time as compared to the wait-list group (P=0.023).,When examining participants from the mindful meditation intervention who had completed six or more classes, it was found that respiratory rate did not significantly increase in comparison to the wait-list group.,Furthermore, those who completed six or more classes (N=12) demonstrated significant improvement in emotional function in comparison to the wait-list group (P=0.032) even though their level of mindfulness did not improve.,This study identifies that there may be a complex relationship between breathing parameters, emotion, and mindfulness in the COPD population.,The results describe good feasibility and acceptability for meditation interventions in the COPD population. | 1 |
Long-acting muscarinic receptor antagonists (LAMAs) are the cornerstone for the treatment of chronic obstructive pulmonary disease (COPD); furthermore, tiotropium is approved as add-on therapy in severe asthmatic patients.,Accumulating evidence suggests that LAMAs may modulate airway contractility and airway hyperresponsiveness not only by blocking muscarinic acetylcholine receptors (mAchRs) expressed on airway smooth muscle but also via anti-inflammatory mechanisms by blocking mAchRs expressed on inflammatory cells, submucosal glands, and epithelial cells.,The aim of this systematic review, performed according to the PRISMA-P guidelines, was to provide a synthesis of the literature on the anti-inflammatory impact of muscarinic receptor antagonists in the airways.,Most of the current evidence originates from studies on tiotropium, that demonstrated a reduction in synthesis and release of cytokines and chemokines, as well as the number of total and differential inflammatory cells, induced by different pro-inflammatory stimuli.,Conversely, few data are currently available for aclidinium and glycopyrronium, whereas no studies on the potential anti-inflammatory effect of umeclidinium have been reported.,Overall, a large body of evidence supports the beneficial impact of tiotropium against airway inflammation.,Further well-designed randomized controlled trials are needed to better elucidate the anti-inflammatory mechanisms leading to the protective effect of LAMAs against exacerbations via identifying suitable biomarkers. | 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 |
Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD).,To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes.,A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015.,Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint.,Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group).,Each association was assessed at 6 months and study end.,Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation.,Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George’s Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end.,Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028).,CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001).,The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively.,A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations.,This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.,The online version of this article (doi:10.1186/s12931-017-0566-1) contains supplementary material, which is available to authorized users. | The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD.,This study investigated the efficacy and safety of UMEC versus TIO in COPD.,This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study.,Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo.,The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin −50 mL; per-protocol [PP] population).,Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose.,Patient-reported outcomes comprised Transition Dyspnea Index score, St George’s Respiratory Questionnaire total score, and COPD Assessment Test score.,Adverse events were also assessed.,In total, 1,017 patients were randomized to treatment.,In the PP population, 489 and 487 patients received UMEC and TIO, respectively.,In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001).,Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001).,Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015).,Clinically meaningful improvements in Transition Dyspnea Index and St George’s Respiratory Questionnaire were observed with both treatments at all time points.,No differences were observed between UMEC and TIO in patient-reported outcomes.,Overall incidences of adverse events were similar for UMEC and TIO.,UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85.,Safety profiles were similar for both treatments. | 1 |
Patients with chronic obstructive pulmonary disease (COPD) often have multiple underlying comorbidities, which may lead to increased health care resource utilization (HCRU) and costs.,To describe the comorbidity profiles of COPD patients and examine the associations between the presence of comorbidities and HCRU or health care costs.,A retrospective cohort study utilizing data from a large US national health plan with a predominantly Medicare population was conducted.,COPD patients aged 40-89 years and continuously enrolled for 12 months prior to and 24 months after the first COPD diagnosis during the period of January 01, 2009, through December 31, 2010, were selected.,Eleven comorbidities of interest were identified 12 months prior through 12 months after COPD diagnosis.,All-cause and COPD-related hospitalizations and costs were assessed 24 months after diagnosis, and the associations with comorbidities were determined using multivariate statistical models.,Ninety-two percent of 52,643 COPD patients identified had at least one of the 11 comorbidities.,Congestive heart failure (CHF), coronary artery disease, and cerebrovascular disease (CVA) had the strongest associations with all-cause hospitalizations (mean ratio: 1.56, 1.32, and 1.30, respectively; P<0.0001); other comorbidities examined had moderate associations.,CHF, anxiety, and sleep apnea had the strongest associations with COPD-related hospitalizations (mean ratio: 2.01, 1.32, and 1.21, respectively; P<0.0001); other comorbidities examined (except chronic kidney disease [CKD], obesity, and osteoarthritis) had moderate associations.,All comorbidities assessed (except obesity and CKD) were associated with higher all-cause costs (mean ratio range: 1.07-1.54, P<0.0001).,CHF, sleep apnea, anxiety, and osteoporosis were associated with higher COPD-related costs (mean ratio range: 1.08-1.67, P<0.0001), while CVA, CKD, obesity, osteoarthritis, and type 2 diabetes were associated with lower COPD-related costs.,This study confirms that specific comorbidities among COPD patients add significant burden with higher HCRU and costs compared to patients without these comorbidities.,Payers may use this information to develop tailored therapeutic interventions for improved management of patients with specific comorbidities. | Health-related quality of life (HRQL) is an important patient-reported outcome measure used to describe the burden of chronic obstructive pulmonary disease (COPD) which is often accompanied by comorbid conditions.,Data from 2275 participants in the COPD cohort COSYCONET and from 4505 lung-healthy control subjects from the population-based KORA and SHIP studies were pooled.,Main outcomes were the five dimensions of the generic EQ-5D-3 L questionnaire and two EQ-5D index scores using a tariff based on valuations from the general population and an experience-based tariff.,The association of COPD in GOLD grades 1-4 and of several comorbid conditions with the EQ-5D index scores was quantified by multiple linear regression models while adjusting for age, sex, education, body mass index (BMI), and smoking status.,For all dimensions of the EQ-5D, the proportion of participants reporting problems was higher in the COPD group than in control subjects.,COPD was associated with significant reductions in the EQ-5D index scores (-0.05 points for COPD grades 1/2, -0.09 for COPD grade 3, -0.18 for COPD grade 4 according to the preference-based utility tariff, all p < 0.0001).,Adjusted mean index scores were 0.89 in control subjects and 0.85, 0.84, 0.81, and 0.72 in COPD grades 1-4 according to the preference-based utility tariff and 0.76, 0.71, 0.68, 0.64, and 0.58 for control subjects and COPD grades 1-4 for the experience-based tariff respectively.,Comorbidities had additive negative effects on the index scores; the effect sizes for comorbidities were comparable to or smaller than the effects of COPD grade 3.,No statistically significant interactions between COPD and comorbidities were observed.,Score differences between COPD patients and control subjects were most pronounced in younger age groups.,Compared with control subjects, the considerable reduction of HRQL in patients with COPD was mainly due to respiratory limitations, but observed comorbidities added linearly to this effect.,Younger COPD patients showed a greater loss of HRQL and may therefore be in specific need of comprehensive disease management.,NCT01245933 | 1 |
Current understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited.,This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use.,This was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395).,The population of interest comprised patients with COPD ≥40 years of age with ≥2 moderate or ≥1 severe exacerbations (prior year) while on inhaled maintenance therapy, with ≥1 blood EOS count.,Data were analyzed during the year prior to index date (last COPD encounter between January 1, 2011 and December 31, 2016).,Four subgroups were analyzed based on a combination of EOS counts (<150 and ≥150 cells/μL) and MITT use (receiving or not receiving).,Among these groups, clinical characteristics, exacerbations, and HCRU were described.,A sensitivity analysis that further stratified EOS into four categories (<150, ≥150-<300, ≥300-<500, and ≥500 cells/μL) was also performed.,The COPD population of interest comprised 34,268 patients.,Subgroups with EOS ≥150 cells/μL vs <150 cells/μL had more comorbidities and experienced significantly higher mean numbers of moderate exacerbations (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 1.93 vs 1.82, P<0.0001; receiving MITT 2.26 vs 2.16, P=0.0062) and COPD-related emergency visits (not receiving MITT, ≥150 cells/μL vs <150 cells/μL: 3.0 vs 2.5, P<0.001; receiving MITT 3.4 vs 3.1, P=0.0011).,Increasing EOS category was associated with higher HCRU.,Blood EOS ≥150/μL cells were associated with increased HCRU and higher exacerbation rates compared with EOS <150 cells/μL, irrespective of MITT use.,COPD phenotyping using blood EOS could help identify candidates for additional therapies that target eosinophilic inflammatory pathways. | The GOLD report provides a framework for classifying COPD in a way that reflects its clinical impact and allows treatment recommendations.,The GOLD 2017 proposes a new classification whereby patients are grouped as A-D according to their symptoms and history of exacerbations.,However, the clinical characteristics and outcomes in these patients are not well documented.,In this prospective observational study, we analyzed data from the Ishinomaki COPD Network Registry.,All patients with stable COPD were classified into the four groups defined by GOLD 2017.,The patient demographics, clinical characteristics, number of exacerbations, and mortality rate during 1 year of follow-up were compared between the groups.,Four hundred and one patients with stable COPD were identified.,There were 240 patients (59.9%) in group A, 122 (30.4%) in group B, 16 (4.0%) in group C, and 23 (5.7%) in group D.,Patients in groups B, C, and D had ORs of 2.95, 3.92, and 5.45, respectively, for risk of exacerbation relative to group A.,Groups C and D experienced exacerbations more frequently, including exacerbations leading to hospital admission, than groups A and B (both P<0.001) during the 1-year follow-up period.,Patients with a high risk of exacerbation (groups C and D) had a lower body mass index, showed more symptoms, used more respiratory medications, and had more severe airflow limitation than patients at low risk of exacerbation (groups A and B).,Mortality was not different between the high-risk and low-risk groups.,The results of our study provide evidence that the GOLD 2017 classification identifies patients with COPD at risk of exacerbations, including those requiring hospitalization, but has a poor ability to predict mortality. | 1 |
The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient’s airflow limitation, their history of exacerbations, and symptoms.,The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year.,In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks.,The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26.,Overall, 676 patients completed the study.,The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met.,QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001).,QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001).,QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use.,However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC.,Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%).,The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%).,These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year. | Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) indicated for maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD).,The efficacy of aclidinium was compared with tiotropium and glycopyrronium, using a network meta-analysis (NMA) of randomized controlled trials (RCTs) in moderate-to-severe COPD patients.,A systematic review was performed to identify RCTs evaluating aclidinium 400 μg twice daily (BID), glycopyrronium 50 μg once daily (OD), tiotropium 18 μg OD, or tiotropium 5 μg OD in adults with moderate-to-severe COPD.,The outcomes of interest were: trough forced expiratory volume in 1 second (FEV1); St George’s Respiratory Questionnaire (SGRQ) total score and proportion of patients achieving ≥4 unit change; Transition Dyspnea Index (TDI) focal score and proportion of patients achieving ≥1 point change.,The results were synthesized by means of a Bayesian NMA.,Twenty-one studies (22,542 patients) were included: aclidinium 400 μg BID (three studies); tiotropium 5 μg OD (three studies); tiotropium 18 μg OD (13 studies); and glycopyrronium 50 μg OD (two studies).,Regarding trough FEV1 at 24 weeks, aclidinium demonstrated comparable efficacy to tiotropium 5 μg (difference in change from baseline [CFB]), (0.02 L [95% credible interval CrI −0.05, 0.09]); tiotropium 18 μg (0.02 L [95% CrI −0.05, 0.08]); and glycopyrronium (0.00 L [95% CrI −0.07, 0.07]).,Aclidinium resulted in higher improvement in SGRQ score at 24 weeks, compared to tiotropium 5 μg (difference in CFB, −2.44 [95% CrI −4.82, −0.05]); and comparable results to tiotropium 18 μg (−1.80 [95% CrI −4.52, 0.14]) and glycopyrronium (−1.52 [95% CrI −4.08, 1.03]).,Improvements in TDI score were comparable for all treatments.,Maintenance treatment with aclidinium 400 μg BID is expected to produce similar improvements in lung function, health-related quality of life, and dyspnea compared to tiotropium 5 μg OD; tiotropium 18 μg OD; and glycopyrronium 50 μg OD. | 1 |
Tiotropium-olodaterol, formulated in the Respimat soft-mist inhaler, is an inhaled fixed-dose combination (FDC) of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), commercialized under the name of Spiolto or Stiolto.,The efficacy of tiotropium-olodaterol 5-5 μg once daily in adult patients with COPD was documented in eleven large, multicenter trials of up to 52 weeks duration.,Tiotropium-olodaterol 5-5 μg not only improved spirometric values to a significantly greater extent than placebo but also resulted in statistically significant beneficial effects on dyspnea, markers of hyperinflation, use of rescue medication, health-related quality of life, and exercise endurance.,Improvements exceeded the minimal clinically important difference (MCID) for forced expiratory volume in 1 second (FEV1), dyspnea, and quality of life.,Differences between tiotropium-olodaterol 5-5 μg and the respective monocomponents were statistically significant for FEV1, dyspnea, markers of hyperinflation, use of rescue medication, and health-related quality of life, but did not reach the MCID.,However, dual bronchodilatation significantly increased the number of patients who exceeded the MCID for dyspnea and quality of life.,Moreover, tiotropium-olodaterol 5-5 μg was significantly more effective than salmeterol-fluticasone (FDC) twice daily at improving pulmonary function.,Differences between tiotropium-olodaterol and other LAMA/LABA FDCs were not observed for FEV1 or other efficacy markers.,Therefore, tiotropium-olodaterol is a valuable option in the treatment of COPD patients who remain symptomatic under monotherapy. | Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations.,This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).,We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers.,In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.,COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function.,Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage.,The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study.,The distribution of these variables within each GOLD stage was wide.,Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation.,The amount of emphysema increased with GOLD severity.,The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage.,Some gender differences were also identified.,The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease. | 1 |
Readmission after hospital discharge is common in patients with acute exacerbations (AE) of chronic obstructive pulmonary disease (COPD).,Although frailty predicts hospital readmission in patients with chronic nonpulmonary diseases, no multidimensional frailty measures have been validated to stratify the risk for patients with COPD.,The aim of this study was to explore multidimensional frailty as a potential risk factor for readmission due to a new exacerbation episode during the 90 days after hospitalization for AE-COPD and to test whether frailty could improve the identification of patients at high risk of readmission.,We hypothesized that patients with moderate-to-severe frailty would be at greater risk for readmission within that period of follow up.,A secondary aim was to test whether frailty could improve the accuracy with which to discriminate patients with a high risk of readmission.,Our investigation was part of a wider study protocol with additional aims on the same study population.,Frailty, demographics, and disease-related factors were measured prospectively in 102 patients during hospitalization for AE-COPD.,Some of the baseline data reported were collected as part of a previously study.,Readmission data were obtained on the basis of the discharge summary from patients’ electronic files by a researcher blinded to the measurements made in the previous hospitalization.,The association between frailty and readmission was assessed using bivariate analyses and multivariate logistic regression models.,Whether frailty better identifies patients at high risk for readmission was evaluated by area under the receiver operator curve (AUC).,Severely frail patients were much more likely to be readmitted than nonfrail patients (45% versus 18%).,After adjusting for age and relevant disease-related factors in a final multivariate model, severe frailty remained an independent risk factor for 90-day readmission (odds ratio = 5.19; 95% confidence interval: 1.26-21.50).,Age, number of hospitalizations for exacerbations in the previous year and length of stay were also significant in this model.,Additionally, frailty improved the predictive accuracy of readmission by improving the AUC.,Multidimensional frailty predicts the risk of early hospital readmission in patients hospitalized for AE-COPD.,Frailty improved the accuracy of discriminating patients at high risk for readmission.,Identifying patients with frailty for targeted interventions may reduce early readmission rates. | The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD.,COPD patients have a variety of comorbidities, but little is known about their impact on quality of life.,This study was designed to investigate comorbid factors that may contribute to high CAT scores.,An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects.,Health status was assessed by the CAT, the St.,Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health.,Comorbidities were identified based on patients’ reports, physicians’ records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale.,Dual X-ray absorptiometry measurements of bone mineral density were performed.,The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36.,The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients.,Symptomatic COPD patients have a high prevalence of comorbidities.,A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized.,Clinical trial registered with UMIN (UMIN000003470). | 1 |
Asthma and chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is an increasingly recognized phenotype.,Few randomized clinical trials have been conducted in patients with ACOS; therefore, scientific evidence concerning ACOS is scarce and a therapeutic approach remains unclear.,The aim of this study was to evaluate current treatment trends for patients with ACOS, identified as those with a dual definition of asthma and COPD, in a real-world COPD cohort.,Data were analyzed from patients with asthma and COPD in the USA, France, Germany, Italy, Spain, and the UK who participated in the 2012 and 2013 Adelphi Respiratory Disease Specific Programmes (DSPs).,Patients with ACOS were identified in the COPD population; these patients had a physician-confirmed, concomitant asthma diagnosis.,Physicians completed a patient record form providing information on patient and disease characteristics including prescribed respiratory treatment.,Pairwise comparisons were made between the ACOS, asthma, and COPD populations using χ2 tests.,In total, 9,042 patients with asthma-only, 7,119 patients with COPD-only, and 523 patients with ACOS (a dual diagnosis of asthma and COPD) participated in the study.,The most commonly prescribed regimens were inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) + long-acting muscarinic antagonist (LAMA); (ACOS 30%, asthma 1.4%, and COPD 32%), ICS/LABA (19%, 41.5%, and 17%, respectively), and LAMA (6%, 0.4%, and 19%, respectively); 18% of patients with ACOS were not prescribed an ICS.,Patients with ACOS had a significantly higher incidence of gastroesophageal reflux disease, diabetes, and obesity and experienced more exacerbations in the past year than those with COPD or asthma.,The majority of patients with ACOS, as defined in this research, were prescribed similar treatment to those with COPD.,There is a need, however, for better treatment for patients with ACOS, as indicated by symptoms and exacerbation levels.,A clearer therapeutic approach for patients with ACOS is required. | The coexistence of COPD and asthma is widely recognized but has not been well described.,This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.,We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.,119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma.,These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001).,More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001).,Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001).,Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT.,There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.,Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life.,They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.,ClinicalTrials.gov: NCT00608764 | 1 |
Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries.,We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate.,We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%).,The majority of patients were male, and the average age at baseline was 69 years old.,About 95% of all patients had accurate mortality data.,The risk factors for mortality were also analyzed.,During the 10 years, 112 patients (40%) died.,Their median survival time was 6.1 years (interquartile range: 4.7-7.9 years), and age at death was 79 ± 6 years old (mean ± SD).,Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%).,In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (<64 years old).,Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality.,The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region. | Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis.,We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD.,The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.,This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations.,Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.,In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%).,The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001).,In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%).,UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001).,This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods.,UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy. | 1 |
The bronchial microbiome in severe COPD during stability and exacerbation in patients chronically colonised by Pseudomonas aeruginosa (PA), has not been defined.,Our objective was to determine the characteristics of the bronchial microbiome of severe COPD patients colonised and not colonised by P. aeruginosa and its changes during exacerbation.,COPD patients with severe disease and frequent exacerbations were categorised according to chronic colonisation by P. aeruginosa.,Sputum samples were obtained in stability and exacerbation, cultured, and analysed by 16S rRNA gene amplification and pyrosequencing.,Sixteen patients were included, 5 of them showing chronic colonisation by P. aeruginosa.,Pseudomonas genus had significantly higher relative abundance in stable colonised patients (p = 0.019), but no significant differences in biodiversity parameters were found between the two groups (Shannon, 3 (2-4) vs 3 (2-3), p = 0.699; Chao1, 124 (77-159) vs 140 (115-163), p = 0.364).,In PA-colonised patients bronchial microbiome changed to a microbiome similar to non-PA-colonised patients during exacerbations.,An increase in the relative abundance over 20 % during exacerbation was found for Streptococcus, Pseudomonas, Moraxella, Haemophilus, Neisseria, Achromobacter and Corynebacterium genera, which include recognised potentially pathogenic microorganisms, in 13 patients colonised and not colonised by P. aeruginosa with paired samples.,These increases were not identified by culture in 5 out of 13 participants (38.5 %).,Stable COPD patients with severe disease and PA-colonised showed a similar biodiversity to non-PA-colonised patients, with a higher relative abundance of Pseudomonas genus in bronchial secretions.,Exacerbation in severe COPD patients showed the same microbial pattern, independently of previous colonisation by P. aeruginosa.,The online version of this article (doi:10.1007/s10096-013-2044-0) contains supplementary material, which is available to authorized users. | Nontypeable Haemophilus influenzae (NTHi) is the most common cause for bacterial exacerbations in chronic obstructive pulmonary disease (COPD).,Recent investigations suggest the participation of the inflammasome in the pathomechanism of airway inflammation.,The inflammasome is a cytosolic protein complex important for early inflammatory responses, by processing Interleukin-1β (IL-1β) to its active form.,Since inflammasome activation has been described for a variety of inflammatory diseases, we investigated whether this pathway plays a role in NTHi infection of the airways.,A murine macrophage cell line (RAW 264.7), human alveolar macrophages and human lung tissue (HLT) were stimulated with viable or non-viable NTHi and/or nigericin, a potassium ionophore.,Secreted cytokines were measured with ELISA and participating proteins detected via Western Blot or immunohistochemistry.,Western Blot analysis of cells and immunohistochemistry of lung tissue detected the inflammasome key components NLRP3 and caspase-1 after stimulation, leading to a significant induction of IL-1β expression (RAW: control at the lower detection limit vs.,NTHi 505±111pg/ml, p<0.01).,Inhibition of caspase-1 in human lung tissue led to a significant reduction of IL-1β and IL-18 levels (IL-1β: NTHi 24 h 17423±3198pg/ml vs.,NTHi+Z-YVAD-FMK 6961±1751pg/ml, p<0.01).,Our data demonstrate the upregulation of the NRLP3-inflammasome during NTHi-induced inflammation in respiratory cells and tissues.,Our findings concerning caspase-1 dependent IL-1β release suggest a role for the inflammasome in respiratory tract infections with NTHi which may be relevant for the pathogenesis of bacterial exacerbations in COPD. | 1 |
Multimorbidity has already become common in primary care and will be a challenge in the future.,Primary care in Sweden participates to a great extent in the care of patients with two severe, chronic conditions: chronic obstructive pulmonary disease (COPD) and heart failure.,Both conditions are characterized by high mortality and often coexist.,Age, sex, heart failure and other comorbidities are considered to be the major predictors of mortality in patients with COPD.,We aimed to study the impact of heart failure, other comorbidities, age and sex on mortality in patients with COPD.,A register-based, prospective cohort study conducted in Blekinge County in Sweden with about 150,000 inhabitants.,The study population was comprised of people aged ≥35 years.,The data about diagnoses of COPD and heart failure came from the 2007 health care register, in which we found 984 individuals with a diagnosis of COPD.,Date of death was collected from January 1st, 2008 -August 31st, 2015.,The diagnosis-based Adjusted Clinical Groups (ACG) Case-Mix System 7.1 was used to describe comorbidity.,Each individual was assigned one of six comorbidity levels called resource utilization bands (RUB) graded from 0 to 5.,Estimated eight year mortality in patients with COPD and coexisting heart failure was seven times higher than in patients with COPD alone - odds ratio 7.06 (95% CI 3.88-12.84).,Adjusting for age and male sex resulted in odds ratio 3.75 (95% CI 1.97-7.15).,Further adjusting for other comorbidities resulted in odds ratio 3.26 (95% CI 1.70-6.25).,The mortality was strongly associated with the highest comorbidity level - RUB 5 where the odds ratio was 5.19 (95% CI 2.59-10.38).,Heart failure has an important impact on mortality in patients with COPD.,The mortality in patients with COPD and coexisting heart failure was strongly associated with age, male sex and other comorbidities.,Of those three predictors, only other comorbidities can be influenced.,Heart failure and other comorbidities should be recognized early and properly treated in order to improve survival in patients with coexisting COPD and heart failure. | Chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide, often occurs in the presence of comorbidities, which may influence experience and management of the disease.,No prior research seems to have gained perspectives of newly diagnosed primary care COPD patients in the context of multimorbidity.,This qualitative study aimed to explore the impact of a new diagnosis of COPD in the context of multimorbidity and also sought to gain a better understanding of how patients react to the diagnosis and incorporate it into their lives.,Participants were identified from a cohort of primary care patients with multimorbidity recently diagnosed with COPD.,Data was collected via semi-structured interviews from nine male and eight female participants.,Thematic analysis was performed and the data interpreted from a constructivist perspective.,Five core themes regarding COPD were induced: (i) reaction to diagnosis, (ii) impact on function and health behaviour, (iii) factors influencing self-management capacity, (iv) healthcare utilisation and (v) interplay of comorbidities.,Most participants had difficulty recognising the importance of COPD and its long-term implications.,For many, the salience of another chronic condition outweighed COPD.,Self-management capacity and utilisation of healthcare services were challenged by low prioritisation of COPD among other comorbidities.,This study provides an insight into how primary care patients feel about being diagnosed with COPD, as well as their prioritisation of the disease in the context of multimorbidity.,It highlights the need for tailored education and personalised management incorporating patients’ perspectives in primary care. | 1 |
Nutritional status is a well-recognized prognostic indicator in chronic obstructive pulmonary disease (COPD); however, very little is known about the relationship between lung function and saturated fat intake.,We used data from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) to assess the relationship between saturated fatty acid (SFA) intake and lung function in the general US adult population.,Adults in NHANES (2007-2012) with pre-bronchodilator spirometry measurements and dietary SFA intake were included.,Primary outcomes were lung function including forced expiratory volume in one second (FEV1), FEV1, forced vital capacity (FVC), FEV1/FVC ratio, percent predicted FEV1 and percent predicted FVC.,Multivariable regression models in the general population as well as those with spirometry-defined airflow obstruction were used to assess the relationship between lung function measurements and dietary SFA intake after adjustment for confounders. 11,180 eligible participants were included in this study.,Univariate analysis revealed a statistically significant positive association between total SFA intake and lung function outcomes; however, these relationships were attenuated after adjustment for covariates.,A secondary analysis of individuals with spirometry-defined airflow obstruction (FEV1/FVC < 0.7) revealed that a lower intake of SFA was associated with reduced FEV1 (β = −126.4, p = 0.04 for quartile 1 vs. quartile 4), FVC (β = −165.8. p = 0.01 for quartile 1 vs. quartile 4), and percent predicted FVC (β = −3.3. p = 0.04 for quartile 1 vs. quartile 4), after adjustment for relevant confounders.,No associations were observed for the FEV1/FVC ratio and percent predicted FEV1.,It is possible that characteristics such as food source and fatty acid chain length may influence associations between saturated fatty acid intake and health outcomes. | The mechanisms of smoking tobacco leading to chronic obstructive pulmonary disease (COPD) are beginning to be understood.,However, conclusions about the role of blood or lung oxidative stress markers were disparate.,To investigate the oxidative stress in blood or lung associated with tobacco smoke and to evaluate its effect on pulmonary function data and its relation with physical activity.,It is a case-control study.,Fifty-four male-smokers of more than five pack-years (PY) and aged 40-60 years were included (29 Non-COPD, 16 COPD).,Physical activity score was determined.,Blood sample levels of malondialdehyde (MDA), protein-cys-SH (PSH), and Glutathione (GSH) were measured.,Fractional exhaled nitric oxide (FeNO) and plethysmographic measurements were performed.,Correlation coefficients (r) evaluated the association between oxidative stress markers and independent variables (plethysmographic data and physical activity score).,Non-COPD (48±6 years) and COPD (49±5 years) groups had similar tobacco consumption patterns, that is, 27±14 PY versus 30±19 PY, respectively.,Compared to the Non-COPD group, the COPD group had significantly lower levels of GSH and PSH, that is, mean±SE were 40±6 versus 25±5 µg/mL and 54±10 versus 26±5 µg/g of hemoglobin, respectively.,However, MDA level and FeNO values were similar.,In the COPD group, none of the oxidative stress markers was significantly correlated with plethysmographic data or physical activity score.,In the Non-COPD group, GSH was significantly correlated with physical activity score (r = 0.47) and PSH was significantly correlated with total lung capacity (TLC) (r=−0.50), residual volume (r = 0.41), and physical activity score (r = 0.62).,FeNO was significantly correlated with TLC of the COPD group (r=−0.48).,Compared to the Non-COPD group, the COPD group had a marked decrease in blood antioxidant markers (GSH and PSH) but similar blood oxidant (MDA) or lung (FeNO) burden. | 1 |
COPD is a long-term condition associated with considerable disability with a clinical course characterized by episodes of worsening respiratory signs and symptoms associated with exacerbations.,Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal conditions in the general population and has emerged as a comorbidity of COPD.,GERD may be diagnosed by both symptomatic approaches (including both typical and atypical symptoms) and objective measurements.,Based on a mix of diagnostic approaches, the prevalence of GERD in COPD ranges from 17% to 78%.,Although GERD is usually confined to the lower esophagus in some individuals, it may be associated with pulmonary microaspiration of gastric contents.,Possible mechanisms that may contribute to GERD in COPD originate from gastroesophageal dysfunction, including altered pressure in the lower esophageal sphincter (which normally protect against GERD) and changes in esophageal motility.,Proposed respiratory contributions to the development of GERD include respiratory medications that may alter esophageal sphincter tone and changes in respiratory mechanics, with increased lung hyperinflation compromising the antireflux barrier.,Although the specific cause and effect relationship between GERD and COPD has not been fully elucidated, GERD may influence lung disease severity and has been identified as a significant predictor of acute exacerbations of COPD.,Further clinical effects could include a poorer health-related quality of life and an increased cost in health care, although these factors require further clarification.,There are both medical and surgical options available for the treatment of GERD in COPD and while extensive studies in this population have not been undertaken, this comorbidity may be amenable to treatment. | Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD).,The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation.,Data were collected from the National Health Insurance Database of Korea.,The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009.,Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors.,The prevalence of GERD in COPD patients was 28% (39,987/141,057).,Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD.,Most of COPD medications except inhaled muscarinic antagonists were associated with GERD.,The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001).,The prevalence of GERD in patients with COPD was high.,Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD.,The presence of GERD was associated with COPD exacerbation. | 1 |
Maintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD).,We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting β2-agonist olodaterol on physical functioning in a real-world clinical setting.,In this open-label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B-D patients with COPD aged ≥40 years were treated for 4-6 weeks with either tiotropium 5 μg + olodaterol 5 μg (both via Respimat® inhaler) or tiotropium 18 μg (HandiHaler®) + olodaterol 5 μg (Respimat®) once daily.,Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10).,The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF-10 between baseline (visit 1) and weeks 4-6 (visit 2).,Secondary end points included absolute PF-10 scores, Physicians’ Global Evaluation, satisfaction with Respimat® and adverse events.,A total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 μg + olodaterol 5 μg and 560 (30.1%) with tiotropium 18 μg + olodaterol 5 μg.,At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point.,Therapeutic success rates were significantly higher for maintenance-naïve patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naïve GOLD B (59.8%) and C (63.0%) patients.,Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2.,Patients’ general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat® inhaler.,Adverse events were reported by 7.5% of patients; the most common were respiratory in nature.,Tiotropium + olodaterol improved physical functioning within 4-6 weeks in patients with moderate-to-very severe COPD.,GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit. | Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.,Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks.,Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.,In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment.,Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies.,Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg.,Incidence of adverse events was comparable between the FDCs and the mono-components.,These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.,Lung function and symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate to very severe COPDhttp://ow.ly/DIKiY | 1 |
The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood.,Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events.,In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40-85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses.,Results are presented for subjects in the full cohort, followed for 1 year.,Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses.,The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50).,At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus.,Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)).,When NTHi was detected, the increased risk of exacerbation was greater in high season (October-March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)).,Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%).,A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031).,AECOPD aetiology varies with season.,Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection.,Results, NCT01360398. | Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the world.,Although smoking is the main risk factor for this disease, only a minority of smokers develop COPD.,Why this happens is largely unknown.,Recent discoveries by the human microbiome project have shed new light on the importance and richness of the bacterial microbiota at different body sites in human beings.,The microbiota plays a particularly important role in the development and functional integrity of the immune system.,Shifts or perturbations in the microbiota can lead to disease.,COPD is in part mediated by dysregulated immune responses to cigarette smoke and other environmental insults.,Although traditionally the lung has been viewed as a sterile organ, by using highly sensitive genomic techniques, recent reports have identified diverse bacterial communities in the human lung that may change in COPD.,This review summarizes the current knowledge concerning the lung microbiota in COPD and its potential implications for pathogenesis of the disease. | 1 |
The role of IL-27 in the pathogenesis of airway inflammatory diseases remains elusive.,We, therefore, have studied its concentrations in the sputum and plasma of patients with COPD and patients with pulmonary TB (PTB), and further investigated the mechanism-of-action effects of IL-27 on bronchial epithelial cells in vitro.,Human bronchial epithelial cells grown on air-liquid interface culture were activated by IL-27, alone, or in combination with other inflammatory cytokines in the presence or absence of various signaling molecule inhibitors.,The expression of CXCL10 was detected by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA).,The underlying signaling pathways were studied by intracellular staining using flow cytometry, Western blot, ELISA, or siRNA.,Significantly higher sputum and plasma concentrations of IL-27 were found in patients with COPD (n = 34; P < .01 and P < .001, respectively) or patients with PTB (n = 31; P < .01 and P < .001, respectively) than in healthy control subjects (n = 48).,Sputum, but not plasma, IL-27 levels in patients with COPD correlated negatively with FEV1 (r = −0.51, P < .01).,Sputum, but not plasma, IL-27 in patients with PTB correlated positively with mycobacterial load in sputum (r = 0.48, P < .05).,Further in vitro studies demonstrated that IL-27 could induce gene and protein expression of CXCL10 in bronchial epithelial cells, which was regulated by the activation of the phosphatidylinositol 3-OH kinase (PI3K)-Akt signaling pathway.,The production of IL-27 is related to the pathogenesis of COPD and PTB, and IL-27 induces the expression of CXCL10 in bronchial epithelial cells through the activation of the PI3K-Akt signaling pathway. | Viruses are a common cause of exacerbations in chronic obstructive pulmonary disease (COPD).,They activate toll-like receptors (TLRs) 3, 7, and 8, leading to a pro-inflammatory response.,We have characterized the responses of TLR3 and TLR7/8 in lung tissue explants from COPD patients and control smokers.,We prepared lung whole tissue explants (WTEs) from patients undergoing surgery for confirmed or suspected lung cancer.,In order to mimic the conditions of viral infection, we used poly(I:C) for TLR3 stimulation and R848 for TLR7/8 stimulation.,These TLR ligands were used alone and in combination.,The effects of tumor necrosis factor α (TNFα) neutralization and dexamethasone on TLR responses were examined.,Inflammatory cytokine release was measured by enzyme-linked immunosorbent assay and gene expression by quantitative real-time polymerase chain reaction.,WTEs from COPD patients released higher levels of pro-inflammatory cytokines compared with WTEs from smokers.,Activation of multiple TLRs led to a greater than additive release of TNFα and CCL5.,TNFα neutralization and dexamethasone treatment decreased cytokine release.,This WTE model shows an enhanced response of COPD compared with controls, suggesting an increased response to viral infection.,There was amplification of innate immune responses with multiple TLR stimulation. | 1 |
Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction.,The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes.,A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.,Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array.,The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status.,Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status.,The association of select analytes with airway thickening and emphysema was independent of FEV1%.,Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.,Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles.,Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies. | Chronic obstructive pulmonary disease is a common condition and a major cause of mortality.,COPD is characterized by irreversible airflow obstruction.,The physiological abnormalities observed in COPD are due to a combination of emphysema and obliteration of the small airways in association with airway inflammation.,The predominant cells involved in this inflammatory response are CD8+ lymphocytes, neutrophils, and macrophages.,Although eosinophilic airway inflammation is usually considered a feature of asthma, it has been demonstrated in large and small airway tissue samples and in 20%-40% of induced sputum samples from patients with stable COPD.,This airway eosinophilia is increased in exacerbations.,Thus, modifying eosinophilic inflammation may be a potential therapeutic target in COPD.,Eosinophilic airway inflammation is resistant to inhaled corticosteroid therapy, but does respond to systemic corticosteroid therapy, and the degree of response is related to the intensity of the eosinophilic inflammation.,In COPD, targeting treatment to normalize the sputum eosinophilia reduced the number of hospital admissions.,Whether controlling eosinophilic inflammation in COPD patients with an airway eosinophilia will modify disease progression and possibly alter mortality is unknown, but warrants further investigation. | 1 |
Cigarette smoke exposure is the most common risk factor for emphysema, which is one of the major pathologies of COPD.,Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that specially catalyzes dimethylation of R2 in histone H3 (H3R2me2a).,H3R2me2a prevents trimethylation of H3K4 (H3K4me3), which is located in the transcription start sites of genes in mammalian genomes.,We attempted to determine the expression of PRMT6 in human samples, and investigate whether the upregulation of PRMT6 expression can attenuate the development of cigarette smoke extract (CSE)-induced emphysema.,Further experiments were performed to elucidate the molecular mechanisms involved.,Human lung tissues were obtained from patients undergoing pneumonectomy for benign pulmonary lesions.,BALB/c mice were treated with lentiviral vectors intratracheally and injected with CSE three times.,The protein expression of PRMT6, H3R2me2a, and H3K4me3 in human and mouse samples, as well as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and endothelial nitric oxide synthase (eNOS) in mice were detected in lung homogenates by Western blotting.,The mRNA expression of cyclooxygenase-2, interleukin-6, Bcl-2, Bax, and eNOS in mice was measured by quantitative real-time polymerase chain reaction.,The expression of PRMT6 was significantly downregulated in the pulmonary parenchyma in smokers with COPD as well as in mice treated with CSE.,Overexpression of PRMT6 was detected in the CSE + Lenti-PRMT6 group of mice, which reversed the expression of H3R2me2a and H3K4me3.,Inflammation, apoptosis, and oxidative stress levels were severe in the CSE-treated emphysema mice compared with the control group, which was inhibited by the overexpression of PRMT6.,The overexpression of PRMT6 might inhibit inflammation, apoptosis, and oxidative stress in CSE-induced emphysema mediated by H3R2me2a. | Chronic obstructive pulmonary disease (COPD) is characterized by a progressive airflow limitation and is associated with a chronic inflammatory response in both airways and lungs. microRNAs (miRNAs) are often highly conserved between species and have an intricate role within homeostatic conditions and immune responses.,Also, miRNAs are dysregulated in smoking-associated diseases.,We investigated the miRNA profile of 523 miRNAs by stem-loop RT-qPCR in lung tissue and cell-free bronchoalveolar lavage (BAL) supernatant of mice exposed to air or cigarette smoke (CS) for 4 or 24 weeks.,After 24 weeks of CS exposure, 31 miRNAs were differentially expressed in lung tissue and 78 in BAL supernatant.,Next, we correlated the miRNA profiling data to inflammation in BAL and lung, obtained by flow cytometry or ELISA.,In addition, we surveyed for overlap with newly assessed miRNA profiles in bronchial biopsies and with previously assessed miRNA profiles in lung tissue and induced sputum supernatant of smokers with COPD.,Several miRNAs showed concordant differential expression between both species including miR-31*, miR-155, miR-218 and let-7c.,Thus, investigating miRNA profiling data in different compartments and both species provided accumulating insights in miRNAs that may be relevant in CS-induced inflammation and the pathogenesis of COPD. | 1 |
Evidence from several studies show poor guideline adherence to COPD treatment, but no such study has been undertaken in Norway.,The objectives of this study, was to estimate and compare the guideline adherence to COPD treatment in general population-based and hospital-recruited COPD patients, and find possible predictors of guideline adherence.,From the prospective, observational EconCOPD-study, we analysed guideline adherence for 90 population-based COPD cases compared to 245 hospital-recruited COPD patients.,Overall guideline adherence was defined as correct pharmacological treatment, and influenza vaccination the preceding year, and having received smoking cessation advice.,Multivariate logistic regression analysis was performed with the dichotomous outcome overall guideline adherence adjusting for relevant variables.,The overall guideline adherence for population-based COPD cases was 6.7%, significantly lower than the 29.8% overall guideline-adherence amongst hospital-recruited COPD patients.,Adherence to pharmacological treatment guidelines was 10.0 and 35.5%, for the two recruitment sources, respectively.,GOLD-stage 3 to 4 was associated with significantly better guideline adherence compared to GOLD-stage 2 (OR (95% CI) 18.9 (8.37,42.7)).,The unadjusted difference between the two recruitment sources was completely explained by degree of airflow obstruction.,Overall guideline adherence was very low for both recruitment sources.,We call for increased attention from authorities and healthcare personnel to improve the quality of care given to this patient group.,The online version of this article (10.1186/s12890-018-0756-8) contains supplementary material, which is available to authorized users. | Chronic obstructive pulmonary disease (COPD) is a costly long-term condition associated with frequent Accident and Emergency (A&E) and hospital admissions.,Psychological difficulties and inadequate self-management can amplify this picture.,To compare a cognitive-behavioural manual versus information booklets (IB) on health service use, mood and health status.,Two hundred and twenty-two COPD patients were randomly allocated to receive either the COPD breathlessness manual (CM) or IB.,They were instructed to work through their programme at home, over 5 weeks.,Guidance from a facilitator was provided at an initial home visit plus two telephone call follow-ups.,After 12 months, total A&E visits had reduced by 42% in the CM group, compared with a 16% rise in the IB group.,The odds of people in the IB group attending A&E 12 months post-intervention was 1.9 times higher than for the CM group (CI 1.05-3.53).,Reduction in hospital admissions and bed days were greatest in the CM group.,At 6 months, there were significantly greater improvements in anxiety (F (2,198)=5.612, P=0.004), depression (F (1.8,176.1)=10.697, P⩽0.001) and dyspnoea (F (2,198)=18.170, P⩽0.001) in the CM group.,Estimated savings at 12 months were greatest in the CM group, amounting to £30k or £270 per participant.,The COPD manual, which addresses physical and mental health, is a straightforward cost-effective intervention that is worth offering to COPD patients within primary or secondary care. | 1 |
Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD).,However, choice of parameters and score complexity restrict clinical applicability.,Our aim was to provide and validate a simplified COPD risk index independent of lung function.,The PROMISE study (n=530) was used to develop a novel prognostic index.,Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality.,External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).,Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C.,It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05).,Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively).,External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).,The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.,The B-AE-D indices allow a simple and accurate assessment of COPD-related risk in the absence of lung functionhttp://ow.ly/XFBox | The use of a severity score to help orientation decisions could improve the efficiency of care for acute exacerbations of COPD (AECOPD).,We previously developed a score (‘2008 score’, based on age, dyspnea grade at steady state and number of clinical signs of severity) predicting in-hospital mortality in patients with AECOPD visiting emergency departments (EDs).,External validity of this score remained to be assessed.,To test the predictive properties of the ‘2008 score’ in a population of patients hospitalized in medical respiratory wards for AECOPD, and determine whether a new score specifically derived from this population would differ from the previous score in terms of components or predictive performance.,Data from a cohort study in 1824 patients hospitalized in a medical ward for an AECOPD were analyzed.,Patients were categorized using the 2008 score and its predictive characteristics for in-hospital mortality rates were assessed.,A new score was developed using multivariate logistic regression modeling in a randomly selected derivation population sample followed by testing in the remaining population (validation sample).,Robustness of results was assessed by case-by-case validation.,The 2008 score was characterized by a c-statistic at 0.77, a sensitivity of 69% and a specificity of 76% for prediction of in-hospital mortality.,The new score comprised the same variables plus major cardiac comorbidities and was characterized by a c-statistic of 0.78, a sensitivity of 77% and specificity of 66%.,A score using simple clinical variables has robust properties for predicting the risk of in-hospital death in patients hospitalized for AECOPD.,Adding cardiac comorbidities to the original score increased its sensitivity while decreasing its specificity.,The online version of this article (doi:10.1186/s12931-014-0099-9) contains supplementary material, which is available to authorized users. | 1 |
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality.,Patients with COPD are characterised by a reduced health status, which can be easily assessed by the COPD Assessment Test (CAT).,Previous studies show that health status can be worsened by the presence of comorbidities.,However, the impact of cardiovascular comorbidities on health status as assessed with CAT is not sufficiently investigated.,Therefore, the current study has the following objectives: (1) to study the clinical, (patho)physiological and psychosocial determinants of the CAT, and impact of previously established and/or newly diagnosed cardiovascular comorbidities on health status in tertiary care patients with COPD; (2) to assess the effects of pulmonary rehabilitation on CAT scores in patients with COPD; (3) to develop reference values for the CAT in Dutch elderly patients without COPD; and (4) to validate the CAT in a broad sample of Dutch patients with COPD.,The COPD, Health status and Comorbidities (Chance) study is a monocentre study consisting of an observational cross-sectional part and a longitudinal part.,Demographic and clinical characteristics will be assessed in primary care, secondary care and tertiary care patients with COPD, and in patients without COPD.,To assess health status, the CAT, Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) will be used.,The longitudinal part consists of a comprehensive pulmonary rehabilitation programme in 500 tertiary care patients.,For the cross-sectional part of the study, 150 patients without COPD, 100 primary care patients and 100 secondary care patients will be assessed during a single home visit.,The Medical Ethical Committee of the Maastricht University Medical Centre+ (MUMC+), Maastricht, the Netherlands (METC 11-3-070), has approved this study.,The study has been registered at the Dutch Trial Register (NTR 3416). | Most interventions aimed at reducing hospitalizations and emergency department (ED) visits in patients with chronic obstructive pulmonary disease (COPD) have employed resource-intense programs in high-risk individuals.,Although COPD is a progressive disease, little is known about the effectiveness of proactive interventions aimed at preventing hospitalizations and ED visits in the much larger population of low-risk (no known COPD-related hospitalizations or ED visits in the prior year) patients, some of whom will eventually become high-risk.,We tested the effect of a simple educational and self-efficacy intervention (n = 2243) versus usual care (n = 2182) on COPD/breathing-related ED visits and hospitalizations in a randomized study of low-risk patients at three Veterans Affairs (VA) medical centers in the upper Midwest.,Administrative data was used to track VA admissions and ED visits.,A patient survey was used to determine health-related events outside the VA.,Rates of COPD-related VA hospitalizations in the education and usual care group were not significantly different (3.4 versus 3.6 admissions per 100 person-years, respectively; 95% CI of difference −1.3 to 1.0, P = 0.77).,The much higher patient-reported rates of non-VA hospitalizations for breathing-related problems were lower in the education group (14.0 versus 19.0 per 100 person-years; 95% CI −8.6 to −1.4, P = 0.006).,Rates of COPD-related VA ED visits were not significantly different (6.8 versus 5.3; 95% CI −0.1 to 3.0, P = 0.07), nor were non-VA ED visits (32.4 versus 36.5; 95% CI −9.3 to 1.1, P = 0.12).,All-cause VA admission and ED rates did not differ.,Mortality rates (6.9 versus 8.3 per 100 person-years, respectively; 95% CI −3.0 to 0.4, P = 0.13) did not differ.,An educational intervention that is practical for large numbers of low-risk patients with COPD may reduce the rate of breathing-related hospitalizations.,Further research that more closely tracks hospitalizations to non-VA facilities is needed to confirm this finding. | 1 |
Although COPD among non-smokers (NS-COPD) is common, little is known about this phenotype.,We compared NS-COPD subjects with smoking COPD (S-COPD) patients in a rural Indian population using a variety of clinical, physiological, radiological, sputum cellular and blood biomarkers.,Two hundred ninety subjects (118 healthy, 79 S-COPD, 93 NS-COPD) performed pre- and post-bronchodilator spirometry and were followed for 2 years to study the annual rate of decline in lung function.,Body plethysmography, impulse oscillometry, inspiratory-expiratory HRCT, induced sputum cellular profile and blood biomarkers were compared between 49 healthy, 45 S-COPD and 55 NS-COPD subjects using standardized methods.,Spirometric response to oral corticosteroids was measured in 30 female NS-COPD patients.,Compared to all male S-COPD subjects, 47% of NS-COPD subjects were female, were younger by 3.2 years, had greater body mass index, a slower rate of decline in lung function (80 vs 130 mL/year), more small airways obstruction measured by impulse oscillometry (p < 0.001), significantly less emphysema (29% vs 11%) on CT scans, lower values in lung diffusion parameters, significantly less neutrophils in induced sputum (p < 0.05) and tended to have more sputum eosinophils.,Hemoglobin and red cell volume were higher and serum insulin lower in S-COPD compared to NS-COPD.,Spirometric indices, symptoms and quality of life were similar between S-COPD and NS-COPD.,There was no improvement in spirometry in NS-COPD patients after 2 weeks of an oral corticosteroid.,Compared to S-COPD, NS-COPD is seen in younger subjects with equal male-female predominance, is predominantly a small-airway disease phenotype with less emphysema, preserved lung diffusion and a slower rate of decline in lung function. | 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 |
Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers.,Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9.,We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.,Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR − S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR − NS) were enrolled.,Spirometry was performed during enrollment and repeated after 5 years.,Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h.,The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.,A greater reduction in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), FEV1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period.,There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S.,Compared to AMs from AHR − NS and AHR − S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios.,The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV1%pred, FVC%pred, and MMEF%pred.,Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.,AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction.,Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers. | Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) significantly associated with chronic obstructive pulmonary disease (COPD).,However, many genetic variants show suggestive evidence for association but do not meet the strict threshold for genome-wide significance.,Integrative analysis of multiple omics datasets has the potential to identify novel genes involved in disease pathogenesis by leveraging these variants in a functional, regulatory context.,We performed expression quantitative trait locus (eQTL) analysis using genome-wide SNP genotyping and gene expression profiling of lung tissue samples from 86 COPD cases and 31 controls, testing for SNPs associated with gene expression levels.,These results were integrated with a prior COPD GWAS using an ensemble statistical and network methods approach to identify relevant genes and observe them in the context of overall genetic control of gene expression to highlight co-regulated genes and disease pathways.,We identified 250,312 unique SNPs and 4997 genes in the cis(local)-eQTL analysis (5% false discovery rate).,The top gene from the integrative analysis was MAPT, a gene recently identified in an independent GWAS of lung function.,The genes HNRNPAB and PCBP2 with RNA binding activity and the gene ACVR1B were identified in network communities with validated disease relevance.,The integration of lung tissue gene expression with genome-wide SNP genotyping and subsequent intersection with prior GWAS and omics studies highlighted candidate genes within COPD loci and in communities harboring known COPD genes.,This integration also identified novel disease genes in sub-threshold regions that would otherwise have been missed through GWAS.,The online version of this article (10.1186/s40246-018-0132-z) contains supplementary material, which is available to authorized users. | 1 |
Plasminogen activator inhibitor-1 (PAI-1) and soluble urokinase-type plasminogen activator receptor (suPAR) participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD) are not yet clear.,This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO) in COPD.,Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers.,Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1), Matrix metalloproteinase-9 (MMP-9), and C-reactive protein (CRP) were detected with Magnetic Luminex Screening Assay.,Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test.,Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure) and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD.,First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007).,Then, the correlation analysis showed that circulating PAI-1 was inversely correlated with pulmonary function parameters including the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC), FEV1/Pre (justified r=−0.308, P<0.001; justified r=−0.295, P=0.001, respectively) and SAO indicators such as FEV3/FVC, MMEF25-75/Pre (justified r=−0.289, P=0.001; justified r=−0.273, P=0.002, respectively), but positively related to the inflammatory marker CRP (justified r=0.351, P<0.001), the small airway remolding biomarker TIMP-1, and MMP-9 (justified r=0.498, P<0.001; justified r=0.267, P=0.002, respectively).,Besides, multivariable linear analysis showed that FEV1/FVC, CRP, and TIMP-1 were independent parameters associated with PAI-1.,Our findings first illustrate that elevated serum PAI-1 levels are related to the lung function decline, systemic inflammation, and SAO in COPD, suggesting that PAI-1 may play critical roles in the pathogenesis of COPD. | Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke.,Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE).,This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments.,Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included.,Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies.,COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates).,Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001).,One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin.,In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies.,The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy-receptor is impaired in COPD.,The online version of this article (doi:10.1186/s12931-016-0363-2) contains supplementary material, which is available to authorized users. | 1 |
To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009.,A total of 45,837 male residents were observed for a median period of 19.1 years.,Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019.,During follow-up, 268 participants died from COPD.,The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41-0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59-0.68).,These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years.,Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality. | Smoke exposure is known to decrease total pulmonary surfactant and alter its composition, but the role of surfactant in chronic obstructive pulmonary disease (COPD) remains unknown.,We aimed to analyze the compositional changes in the surfactant lipidome in COPD and identify specific lipids associated with pulmonary function decline.,Bronchoalveolar lavage (BAL) fluid was obtained from 12 former smokers with COPD and 5 non-smoking, non-asthmatic healthy control volunteers.,Lipids were extracted and analyzed by liquid chromatography and mass spectrometry.,Pulmonary function data were obtained by spirometry, and correlations of lung function with lipid species were determined.,Wild-type C57BL/6 mice were exposed to 6 months of second-hand smoke in a full-body chamber.,Surfactant lipids were decreased by 60% in subjects with COPD.,All phospholipid classes were dramatically decreased, including ether phospholipids, which have not been studied in pulmonary surfactant.,Availability of phospholipid, cholesterol, and sphingomyelin in BAL strongly correlated with pulmonary function and this was attributable to specific lipid species of phosphatidylcholine with surface tension reducing properties, and of phosphatidylglycerol with antimicrobial roles, as well as to other less studied lipid species.,Mice exposed to smoke for six months recapitulated surfactant lipidomic changes observed in human subjects with COPD.,In summary, we show that the surfactant lipidome is substantially altered in subjects with COPD, and decreased availability of phospholipids correlated with decreased pulmonary function.,Further investigation of surfactant alterations in COPD would improve our understanding of its physiopathology and reveal new potential therapeutic targets. | 1 |
Exacerbations largely determine the character of the progression and prognosis of chronic obstructive pulmonary disease (COPD).,Exacerbations are connected with changes in the microbiological landscape in the bronchi due to a violation of their immune homeostasis.,Many metabolic and immune processes involved in COPD progression are associated with bacterial colonization of the bronchi.,The objective of this review is the analysis of the molecular mechanisms of lipid metabolism and immune response disorders in the lungs in COPD exacerbations.,The complex role of lipid metabolism disorders in the pathogenesis of some infections is only beginning to be understood, however, there are already fewer and fewer doubts even now about its significance both in the pathogenesis of infectious exacerbations of COPD and in general in the progression of the disease.,It is shown that the lipid rafts of the plasma membranes of cells are involved in many processes related to the detection of pathogens, signal transduction, the penetration of pathogens into the cell.,Smoking disrupts the normally proceeded processes of lipid metabolism in the lungs, which is a part of the COPD pathogenesis. | Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema.,Environmental exposure, primarily cigarette smoking, can cause high oxidative stress and is the main factor of COPD development.,Cigarette smoke also contributes to the imbalance of oxidant/antioxidant due to exogenous reactive oxygen species (ROS).,Moreover, endogenously released ROS during the inflammatory process and mitochondrial dysfunction may contribute to this disease progression.,ROS and reactive nitrogen species (RNS) can oxidize different biomolecules such as DNA, proteins, and lipids leading to epithelial cell injury and death.,Various detoxifying enzymes and antioxidant defense systems can be involved in ROS removal.,In this review, we summarize the main findings regarding the biological role of ROS, which may contribute to COPD development, and cytoprotective mechanisms against this disease progression. | 1 |
Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD).,In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 μg and 125 μg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 μg).,In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85.,Secondary endpoints were weighted-mean (WM) FEV1 over 0-6 hours post-dose (Day 84) and rescue albuterol use.,Health-related quality of life outcomes (St.,George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined.,Safety was assessed throughout.,Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.127-0.148 L) versus PBO+FP/SAL.,Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0-6 hours post-dose WM FEV1 versus PBO+FP/SAL (Day 84: 0.144-0.165 L).,Rescue use over Weeks 1-12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]).,Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2).,In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL.,The incidence of on-treatment adverse events across all treatment groups was 37-41% in Study 1 and 36-38% in Study 2.,Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD. | To assess the treatment progression during the 24 months following a formal diagnosis of chronic obstructive pulmonary disease (COPD) in the UK primary care setting.,A retrospective cohort of newly diagnosed COPD patients was identified in the Clinical Practice Research Datalink (CPRD) from 1/1/2008 until 31/12/2009.,Maintenance therapy prescribed within the first 3 months of diagnosis and in the subsequent 3-month intervals for 24 months were analyzed.,Treatment classes included long-acting β2-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids (ICSs), and respective combinations.,At each 3-month interval, discontinuation, switching, addition, and stepping down patterns were analyzed cumulatively for the first 12 months and over the 24-month of follow-up.,A total of 3199 patients with at least one prescription of a maintenance therapy at baseline and during 4th-6th month interval were included in the analysis.,At diagnosis (0-3 months), the most frequently prescribed maintenance therapy was LABA+ICS (43%), followed by LAMA (24%) and LABA+LAMA+ICS (23%).,Nearly half the patients (LABA-50%, LAMA-43%) starting on a monobronchodilator had additions to their treatment in 24 months.,Compared to other medications, patients starting on a LAMA were most likely to escalate to triple therapy in 24 months.,Nearly one-fourth of the patients prescribed triple therapy at baseline stepped down to LABA+ICS (25%) or LAMA (31%) within 24 months.,Disease progression is evident over the 24 months after COPD diagnosis, as more patients were prescribed additional maintenance therapy in the 24-month period compared to baseline.,The changes in therapy suggest that it is difficult to achieve a consistently improved COPD disease state. | 1 |
Chronic obstructive pulmonary disease (COPD) is a global health challenge and a major cause of mortality worldwide.,Bronchodilators, particularly long-acting β2-agonists and long-acting antimuscarinic agents, used singly or in combination, aim to improve lung function, reduce symptoms, prevent exacerbations, and enhance quality of life of COPD patients.,Indacaterol is a novel, inhaled, long-acting β2-agonist, with rapid onset of action and once-daily dosing providing 24-hour bronchodilation.,Currently, the recommended dose differs between Europe (150 μg; maximum 300 μg) and USA (75 μg), the latter is lower than that assessed in the majority of the conducted studies.,This review summarises published evidence regarding the efficacy, tolerability, and safety of indacaterol at a dose of 75 μg.,Indacaterol 75 μg was found to be superior than placebo regarding lung function, dyspnea, health status, use of rescue medication, and rate of exacerbations.,Furthermore, indacaterol 75 μg was well tolerated, while the most frequent adverse effect was deterioration of COPD occurring at a frequency similar to placebo, without major cardiovascular adverse effects.,In conclusion, indacaterol 75 μg, administered once daily, is efficacious and has an excellent tolerability and safety profile, and is therefore a valid alternative in the treatment of COPD patients. | Inhaled bronchodilators are the first-line therapy for COPD.,Indacaterol is a novel addition to existing long-acting bronchodilators.,Systematic review of randomized controlled trials (RCT) on efficacy and safety of indacaterol as compared: 1) with placebo at different dosages, 2) with existing bronchodilators; (3) as add-on treatment to tiotropium.,We searched 13 electronic databases, including MEDLINE, EMBASE and CENTRAL, and contacted the manufacturer for unpublished data.,Primary outcome was mean FEV1 change at 12th week, secondary outcomes included changes in SGRQ, TDI and BODE index at 6 months, exacerbation at 1 year, and worsening of symptoms.,Twelve eligible RCTs of moderate risk of bias included data from 10,977 patients.,Compared to placebo, indacaterol improved FEV1 by a weighted mean difference (WMD) of 0.16 L (95%CI: 0.15, 0.18 L, p<0.001), homogeneously above the minimally important difference of 0.10 L.,It offered clinically relevant improvement in all secondary outcomes except exacerbation.,Magnitude of benefit did not differ significantly by dosage, but one treatment related death was reported at 300 ug.,Efficacy of Indacaterol was similar to formoterol and salmeterol (FEV1 WMD = 0.04L, 95%CI: 0.01L, 0.07 L, p = 0.02); and tiotropium (FEV1 WMD = 0.01L, 95%CI: −0.01, 0.03L, p = 0.61).,The use of indacaterol on top of tiotropium yielded additional improvement on FEV1 (WMD = 0.07 L, 95%CI: 0.05L, 0.10 L, p<0.001).,Indacaterol is safe and beneficial for patients with COPD at dosage ≤150 ug.,It may serve as a good alternative to existing bronchodilators, or as an add-on to tiotropium for unresponsive patients.,Use of higher dosage requires further justification. | 1 |
Pulmonary rehabilitation is a cornerstone of care for COPD but uptake of traditional centre-based programmes is poor.,We assessed whether home-based pulmonary rehabilitation, delivered using minimal resources, had equivalent outcomes to centre-based pulmonary rehabilitation.,A randomised controlled equivalence trial with 12 months follow-up.,Participants with stable COPD were randomly assigned to receive 8 weeks of pulmonary rehabilitation by either the standard outpatient centre-based model, or a new home-based model including one home visit and seven once-weekly telephone calls from a physiotherapist.,The primary outcome was change in 6 min walk distance (6MWD).,We enrolled 166 participants to receive centre-based rehabilitation (n=86) or home-based rehabilitation (n=80).,Intention-to-treat analysis confirmed non-inferiority of home-based rehabilitation for 6MWD at end-rehabilitation and the confidence interval (CI) did not rule out superiority (mean difference favouring home group 18.6 m, 95% CI −3.3 to 40.7).,At 12 months the CI did not exclude inferiority (−5.1 m, −29.2 to 18.9).,Between-group differences for dyspnoea-related quality of life did not rule out superiority of home-based rehabilitation at programme completion (1.6 points, −0.3 to 3.5) and groups were equivalent at 12 months (0.05 points, −2.0 to 2.1).,The per-protocol analysis showed the same pattern of findings.,Neither group maintained postrehabilitation gains at 12 months.,This home-based pulmonary rehabilitation model, delivered with minimal resources, produced short-term clinical outcomes that were equivalent to centre-based pulmonary rehabilitation.,Neither model was effective in maintaining gains at 12 months.,Home-based pulmonary rehabilitation could be considered for people with COPD who cannot access centre-based pulmonary rehabilitation.,NCT01423227, clinicaltrials.gov. | In chronic obstructive pulmonary disease (COPD), the problem of poor patient participation in studies of self-management (SM) and pulmonary rehabilitation (PR) programmes (together referred to as COPD support programmes) is established.,Understanding this problem beyond the previously reported socio-demographics and clinical factors is critical.,The aim of this study was to explore factors that explain patient participation in studies of COPD support programmes.,Thematic ‘framework’ synthesis was conducted on literature published from 1984 to 1 February 2015.,Emergent themes and subthemes were mapped onto the adapted ‘attitude-social influence-external barriers’ and the ‘self-regulation’ models to produce analytical themes.,Ten out of 12 studies were included: PR (n=9) and SM (n=1).,Three descriptive themes with 38 subthemes were mapped onto the models' constructs, and it generated four analytical themes: ‘attitude’, ‘social influences’ and ‘illness’ and ‘intervention representations’.,The following factors influenced (1) attendance-helping oneself through health improvements, perceived control of worsening condition, perceived benefits and positive past experience of the programme, as well as perceived positive influence of professionals; (2) non-attendance-perceived negative effects and negative past experience of the programme, perceived physical/practical concerns related to attendance, perceived severity of condition/symptoms and perceived negative influence of professionals/friends; (3) dropout-no health improvements perceived after attending a few sessions of the programme, perceived severity of the condition and perceived physical/practical concerns related to attendance.,Psychosocial factors including perceived practical/physical concerns related to attendance influenced patients’ participation in COPD support programmes.,Addressing the negative beliefs/perceptions via behaviour change interventions may help improve participation in COPD support programmes and, ultimately, patient outcomes. | 1 |
COPD is a progressive inflammatory airway disease characterized by increased numbers of alveolar macrophages in the lungs.,Bacterial colonization of the lungs is a common feature in COPD and can promote inflammation through continual and repeated Toll-like receptor (TLR) stimulation.,We have studied the response of COPD alveolar macrophages to repetitive stimulation with TLR2 and TLR4 ligands.,We investigated the effect of sequential stimulation with different ligands to determine whether this results in tolerance or amplification of the immune response.,We stimulated alveolar macrophages from COPD patients (n=9) and smokers (n=8) with the TLR4 agonist lipopolysaccharide (LPS) or the TLR2 agonist Pam3CSK4 for 24 hours before restimulating again for 24 hours.,Cytokine protein release and gene expression were investigated.,Repetitive stimulation of COPD and smokers macrophages with LPS for both 24-hour periods caused a reduction in tumor necrosis factor α, CCL5, and IL-10 production compared to cells that were not exposed initially to LPS.,IL-6 and CXCL8 production were not significantly altered following repetitive LPS stimulation.,The same pattern was observed for repeated stimulation with Pam3CSK4.,Using COPD macrophages, LPS followed by Pam3CSK4 stimulation increased the levels of all cytokines compared to media followed by Pam3CSK4.,TLR tolerance in COPD alveolar macrophages occurs after repetitive stimulation with the same TLR ligand, but this only occurs for selected cytokines.,CXCL8 production is not reduced after repetitive TLR stimulation with the same ligand; this may be an important mechanism for the increased CXCL8 levels that have been observed in COPD.,We showed that TLR4 stimulation followed by TLR2 stimulation does not cause tolerance, but enhances cytokine production.,This may be a relevant mechanism by which bacteria cause excessive inflammation in COPD patients. | Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD).,It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.,We formed a new-user cohort of patients with COPD treated during 1990-2005.,Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia.,A nested case-control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.,The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year).,Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75).,The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17).,The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).,ICS use by patients with COPD increases the risk of serious pneumonia.,The risk is particularly elevated and dose related with fluticasone.,While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials. | 1 |
COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features.,In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry.,The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management.,However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1.,At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD.,However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes.,Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and “frequent exacerbators”.,Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as “asthma COPD overlap syndrome”.,Several other phenotypes have been proposed, but require validation against clinical outcomes.,Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity.,Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics. | Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD.,Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk.,This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.,The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.,This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks.,The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.,Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively).,Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).,Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate.,Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. | 1 |
Bilirubin is a potent antioxidant and higher serum bilirubin levels have been associated with improved COPD outcomes.,We performed a systematic review to evaluate the association between serum bilirubin levels and lung function (FEV1), prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality.,MEDLINE® and Embase were searched using Ovid® (search updated October 1st, 2019).,We included studies that measured serum bilirubin levels and outcomes of interest in adults with or without underlying lung disease.,We excluded studies of those with liver disease or drug-induced elevations in bilirubin.,We used the Newcastle-Ottawa scale to assess individual study risk of bias (ROB) and the US Agency for Healthcare Research and Quality-Evidence Based Practice tool to assess overall strength of evidence (SOE).,Two authors independently determined eligibility, performed data abstraction, assessed ROB, and determined SOE.,Thirteen studies (5 low risk of bias, 3 moderate and 5 high risk) were included.,We found low strength of evidence for the association between higher bilirubin levels and lower risk of acute exacerbations of COPD (2 studies), mortality (3 studies), COPD diagnosis (4 studies), and lung function (FEV1) (8 studies).,We found insufficient evidence on the relationship between serum bilirubin and respiratory health status/exercise capacity (1 study) and airflow obstruction (FEV1/FVC ratio) (4 studies).,Higher bilirubin levels may be associated with lower mortality and improved COPD outcomes.,Randomized trials are needed to evaluate the effect of medications that raise serum bilirubin on COPD outcomes.,PROSPERO registration: CRD42019145747. | In chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD requiring hospital admission is associated with mortality and healthcare costs.,The ERICA study assessed multiple clinical measures in people with COPD, including the short physical performance battery (SPPB), a simple test of physical function with 3 components (gait speed, balance and sit-to-stand).,We tested the hypothesis that SPPB score would relate to risk of hospital admissions and length of hospital stay.,Data were analysed from 714 of the total 729 participants (434 men and 280 women) with COPD.,Data from this prospective observational longitudinal study were obtained from 4 secondary and 1 tertiary centres from England, Scotland, and Wales.,The main outcome measures were to estimate the risk of hospitalisation with acute exacerbation of COPD (AECOPD and length of hospital stay derived from hospital episode statistics (HES).,In total, 291 of 714 individuals experienced 762 hospitalised AECOPD during five-year follow up.,Poorer performance of SPPB was associated with both higher rate (IRR 1.08 per 1 point decrease, 95% CI 1.01 to 1.14) and increased length of stay (IRR 1.18 per 1 point decrease, 95% CI 1.10 to 1.27) for hospitalised AECOPD.,For the individual sit-to-stand component of the SPPB, the association was even stronger (IRR 1.14, 95% CI 1.02 to 1.26 for rate and IRR 1.32, 95% CI 1.16 to 1.49 for length of stay for hospitalised AECOPD).,The SPPB, and in particular the sit-to-stand component can both evaluate the risk of H-AECOPD and length of hospital stay in COPD.,The SPPB can aid in clinical decision making and when prioritising healthcare resources. | 1 |
Although cardiovascular disease (CVD) is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), it is unknown how to improve prediction of cardiovascular (CV) risk in individuals with COPD.,Traditional CV risk scores have been tested in different populations but not uniquely in COPD.,The potential of alternative markers to improve CV risk prediction in individuals with COPD is unknown.,We aimed to determine the predictive value of conventional CVD risk factors in COPD and to determine if additional markers improve prediction beyond conventional factors.,Data from the Evaluation of the Role of Inflammation in Chronic Airways disease cohort, which enrolled 729 individuals with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II-IV COPD were used.,Linked hospital episode statistics and survival data were prospectively collected for a median 4.6 years of follow-up.,Five UK centres interested in COPD.,Population-based sample including 714 individuals with spirometry-defined COPD, smoked at least 10 pack years and who were clinically stable for >4 weeks.,Baseline measurements included aortic pulse wave velocity (aPWV), carotid intima-media thickness (CIMT), C reactive protein (CRP), fibrinogen, spirometry and Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) Index, 6 min walk test (6MWT) and 4 m gait speed (4MGS) test.,New occurrence (first event) of fatal or non-fatal hospitalised CVD, and all-cause and cause-specific mortality.,Out of 714 participants, 192 (27%) had CV hospitalisation and 6 died due to CVD.,The overall CV risk model C-statistic was 0.689 (95% CI 0.688 to 0.691). aPWV and CIMT neither had an association with study outcome nor improved model prediction.,CRP, fibrinogen, GOLD stage, BODE Index, 4MGS and 6MWT were associated with the outcome, independently of conventional risk factors (p<0.05 for all).,However, only 6MWT improved model discrimination (C=0.727, 95% CI 0.726 to 0.728).,Poor physical performance defined by the 6MWT improves prediction of CV hospitalisation in individuals with COPD.,ID 11101. | Beta (β)-blockers are under-prescribed in patients with heart failure (HF) and concurrent chronic obstructive pulmonary disease (COPD) due to concerns about adverse pulmonary effects and a poor understanding of the effects of these drugs.,We aimed to evaluate the survival effects of β-blockers in patients with coexistent HF and COPD.,Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study.,Patients with coexistent HF and COPD diagnosed between 2000 and 2009 were enrolled.,Doses of the 3 β-blockers proven to be beneficial to HF (carvedilol, bisoprolol, and metoprolol) during the study period were extracted.,The primary endpoint was cumulative survival.,Patients were followed until December 31, 2009.,The study included 11,558 subjects, with a mean follow-up period of 4.07 years.,After adjustment for age, sex, comorbidities, and severity of HF and COPD, bisoprolol use showed a dose-response survival benefit [low dose: adjusted hazard ratio (HR) = 0.76, 95% confidence interval (CI) = 0.59-0.97, P = 0.030; high dose: adjusted HR = 0.40, 95% CI = 0.26-0.63, P < 0.001] compared with nonusers, whereas no survival difference was observed for carvedilol or metoprolol.,Compared with patients with HF alone, this special HF + COPD cohort received significantly fewer targeted β-blockers (108.8 vs 137.3 defined daily doses (DDDs)/person-year, P < 0.001) and bisoprolol (57.9 vs 70.8 DDDs/person-year, P < 0.001).,In patients with coexisting HF and COPD, this study demonstrated a dose-response survival benefit of bisoprolol use, but not of carvedilol or metoprolol use. | 1 |
Among patients with chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM) is a common comorbidity and is probably associated with increased systemic inflammation and worse prognosis.,Metformin, with its pleiotropic anti-inflammatory and antioxidant actions, may offer theoretical benefits in COPD patients with DM.,Thus, this study aimed to investigate the effects of DM and metformin use on mortality in the clinical trajectory of COPD.,This was a retrospective cohort study comprising patients with spirometry-confirmed COPD and an age of ≥40 years from 2008 to 2014.,The primary outcome of interest was all-cause mortality.,We evaluated the effects of DM on mortality through the clinical course of COPD and we also assessed the impact of metformin use on survival of the COPD population.,Among 4231 COPD patients, 556 (13%) had DM, and these patients had 1.62 times higher hazards of 2-year mortality than those without DM (95% confidence interval [CI], 1.15-2.28) after adjusting for age, gender, COPD stage, comorbidities and prior COPD hospitalization.,Over a 2-year period, metformin users had a significantly lower risk of death (hazard ratio, 0.46; 95% CI, 0.23-0.92) compared with non-metformin users in patients with coexistent COPD and DM.,Moreover, metformin users had similar survival to COPD patients without DM.,This study shows that DM is associated with an increased risk of death in COPD patients and metformin use seems to mitigate the hazard.,Our findings suggest a potential role of metformin in the management of DM in COPD.,The online version of this article (10.1186/s12931-019-1035-9) contains supplementary material, which is available to authorized users. | A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association.,We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data.,RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level.,We found evidence of local genetic correlation with particular regions of the genome.,Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD.,Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues.,An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD.,A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008).,In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.,The online version of this article (10.1186/s12931-019-1036-8) contains supplementary material, which is available to authorized users. | 1 |
One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration.,Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life.,A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD.,Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo.,In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life.,We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment.,We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change. | Reduced physical capacity (PC) and physical activity (PA) are common in COPD patients and associated with poor outcome.,However, they represent different aspects of physical functioning and interventions do not affect them in the same manner.,To address this, a new PC-PA quadrant concept was recently generated to identify clinical characteristics of sub-groups of physical functioning.,The objective of this study was to I) proof the new concept and to verify their differentiating clinical characteristics, II) evaluate the consistency of the concept over time, III) assess whether patients changed their quadrant affiliation over time, IV) and to test if changes in quadrant affiliations are associated with changes in clinical characteristics.,In a longitudinal, prospective, non-interventional cohort with mild to very severe COPD patients, PC and PA as well as respiratory variables, COPD-specific health status, comorbidities, survival, and exacerbations were yearly assessed.,Data from 283 patients were analysed at baseline.,Mean (min/max) follow-up time was 2.4 (0.5/6.8) years.,The PC-PA quadrants could be characterized as follows: I) “can’t do, don’t do”: most severe and symptomatic, several comorbidities II) “can do, don’t do”: severe but less symptomatic, several comorbidities III) “can’t do, do do”: few patients, severe and symptomatic, less comorbidities IV) “can do, do do”: mildest and less symptomatic, less comorbidities, lowest exacerbation frequency.,Of the 172 patients with at least one follow-up, 58% patients never changed their quadrant affiliation, while 17% declined either PC, PA or both, 11% improved their PC, PA or both, and 14% showed improvement and decline in PC, PA or both during study period.,None of the clinical characteristics or their annual changes showed consistent significant and relevant differences between all individual sub-groups.,Our findings suggest that there are no clinical characteristics allowing to distinguish between the PC-PA quadrants and the concept seems not able to illustrate disease process.,However, the already low PA but preserved PC in the “can do, don’t do” quadrant raises the question if regularly assessment of PA in clinical practice would be more sensitive to detect progressive deterioration of COPD compared to the commonly used PC.,www.ClinicalTrials.gov, NCT01527773. | 1 |
Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide.,Genetic risk loci provide novel insights into disease pathogenesis.,We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium.,We identified 82 loci with P-value < 5 × 10−8; 47 were previously described in association with either COPD or population-based lung function.,Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium.,Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and several lung cell types.,We found 14 COPD loci shared with either asthma or pulmonary fibrosis.,COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations.,Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD. | In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD).,We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD.,Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci.,The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene.,Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses.,The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies.,As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results. | 1 |
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality.,The most widely used marker of disease severity and progression is FEV1.,However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD.,Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD.,Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.,Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.,There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality.,Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity.,The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear.,Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.,Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality. | Low-grade inflammation and emphysema have been shown to be associated with an increased risk of lung cancer.,However, the systemic inflammatory response in patients with emphysema is still unknown.,To compare the plasma cytokine profiles in two groups of current or former smokers without airway obstruction: a control group of individuals without computed tomography (CT) detected emphysema vs. a study group of individuals with CT detected emphysema.,Subjects underwent a chest CT, spirometry, and determination of EGF, IL-15, IL-1ra, IL-8, MCP-1, MIP-1β, TGFα, TNFα, and VEGF levels in plasma.,Cytokine levels in each group were compared adjusting for confounding factors.,160 current smokers and former smokers without airway obstruction participated in the study: 80 without emphysema and 80 subjects with emphysema.,Adjusted group comparisons revealed significant reductions in EGF (−0.317, p = 0.01), IL-15 (−0.21, p = 0.01), IL-8 (−0.180, p = 0.02) and IL-1ra (−0.220, p = 0.03) in subjects with emphysema and normal spirometry.,Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile.,This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance.,This information should be taken into account when evaluated patients with tobacco respiratory diseases. | 1 |
COPD, characterized by chronic inflammation and airway remodeling, has significant pathological alterations in composition and deposition of the extracellular matrix.,The expression of procollagen 1 C-terminal peptide (PICP) and collagen type 1 C-terminal telopeptide (ICTP), two major by-products in the synthesis and degradation of collagen, was shown to be positively correlated with inflammatory mediator levels in previous studies.,In this study, we investigated whether the serum concentrations of PICP and ICTP were associated with the inflammation level for patients with stable COPD.,We collected serum samples from 25 control subjects and 20 patients with stable COPD from December 2011 to October 2012 in Shanghai Zhongshan Hospital and Shanghai Dahua Hospital.,We determined concentrations of PICP, ICTP, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF)-α by using enzyme-linked immunosorbent assay methods.,Demographic characteristics were comparable between the two groups.,In patients with stable COPD, serum levels of CRP, IL-6, IL-8, and TNF-α were all elevated compared to control subjects, but only changes of IL-6 achieved statistical significance.,Serum concentration of PICP was significantly elevated in patients with COPD, and level of ICTP was slightly decreased.,Moreover, serum concentrations of PICP were positively correlated with the levels of both IL-6 and IL-8.,The increased levels of serum PICP in COPD might indicate the condition of airway remodeling, and IL-6 and/or IL-8 might play an important role in stimulating collagen synthesis. | The aim of this study was to investigate the plasma inflammatory cytokine levels and their correlations with pulmonary function in patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS).,Between January 2013 and December 2014, a total of 96 patients with asthma, acute exacerbation of chronic obstructive pulmonary disease (AECOPD), or ACOS were enrolled, and 35 healthy people were included as a control group.,Fasting plasma interleukin (IL)-4, IL-8, IL-10, and tumor necrosis factor alpha (TNF-α) levels were detected using enzyme-linked immunosorbent assay (ELISA).,Correlations between the plasma inflammatory cytokine levels and forced expiratory volume in 1 second (FEV1), FEV1/predicted value ratio (FEV1%pred), and FEV1/forced vital capacity (FVC) were analyzed.,IL-4 and IL-8 levels showed statistically significant differences among the 3 groups of patients (both P<0.001); IL-4 level was significantly lower, while IL-8 level was significantly higher in the AECOPD group and ACOS group than those in the asthma group (all P<0.05).,IL-10 level and TNF-α level were significantly different among the 3 patient groups (both P<0.001).,IL-10 level was significantly different between each of the 2 groups (all P<0.001).,TNF-α level in the asthma group was higher than in the AECOPD group and ACOS group (both P<0.001).,IL-4 and IL-10 were positively and IL-8 and TNF-α were negatively related with FEV1, FEV1%pred, and FEV1/FVC.,Plasma levels of inflammatory cytokines IL-4, IL-8, IL-10, and TNF-α are related with severity of airway diseases and could be potential markers for the evaluation of asthma, COPD, and ACOS. | 1 |
Objective To test the effectiveness of telemonitoring integrated into existing clinical services such that intervention and control groups have access to the same clinical care.,Design Researcher blind, multicentre, randomised controlled trial.,Setting UK primary care (Lothian, Scotland).,Participants Adults with at least one admission for chronic obstructive pulmonary disease (COPD) in the year before randomisation.,We excluded people who had other significant lung disease, who were unable to provide informed consent or complete the study, or who had other significant social or clinical problems.,Interventions Participants were recruited between 21 May 2009 and 28 March 2011, and centrally randomised to receive telemonitoring or conventional self monitoring.,Using a touch screen, telemonitoring participants recorded a daily questionnaire about symptoms and treatment use, and monitored oxygen saturation using linked instruments.,Algorithms, based on the symptom score, generated alerts if readings were omitted or breached thresholds.,Both groups received similar care from existing clinical services.,Main outcome measures The primary outcome was time to hospital admission due to COPD exacerbation up to one year after randomisation.,Other outcomes included number and duration of admissions, and validated questionnaire assessments of health related quality of life (using St George’s respiratory questionnaire (SGRQ)), anxiety or depression (or both), self efficacy, knowledge, and adherence to treatment.,Analysis was intention to treat.,Results Of 256 patients completing the study, 128 patients were randomised to telemonitoring and 128 to usual care; baseline characteristics of each group were similar.,The number of days to admission did not differ significantly between groups (adjusted hazard ratio 0.98, 95% confidence interval 0.66 to 1.44).,Over one year, the mean number of COPD admissions was similar in both groups (telemonitoring 1.2 admissions per person (standard deviation 1.9) v control 1.1 (1.6); P=0.59).,Mean duration of COPD admissions over one year was also similar between groups (9.5 days per person (standard deviation 19.1) v 8.8 days (15.9); P=0.88).,The intervention had no significant effect on SGRQ scores between groups (68.2 (standard deviation 16.3) v 67.3 (17.3); adjusted mean difference 1.39 (95% confidence interval −1.57 to 4.35)), or on other questionnaire outcomes.,Conclusions In participants with a history of admission for exacerbations of COPD, telemonitoring was not effective in postponing admissions and did not improve quality of life.,The positive effect of telemonitoring seen in previous trials could be due to enhancement of the underpinning clinical service rather than the telemonitoring communication.,Trial registration ISRCTN96634935.,Funding: The trial was funded by an NHS applied research programme grant from the Chief Scientist Office of the Scottish government (ARPG/07/03).,The funder had no role in study design and the collection, analysis, and interpretation of data and the writing of the article and the decision to submit it for publication.,NHS Lothian supported the telemonitoring service and the clinical services. | Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD).,We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.,This retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo.,Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0, >0-1, >1-2, and >2).,Spirometry and the St George’s Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).,In total, 5992 patients (mean age 65 years, 75% male) were randomized.,Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units).,Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium).,Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium).,The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium).,The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.,Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD.,Increasing rates of hospitalized exacerbations are associated with increasing risk of death. | 1 |
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. | The aim of this study was to evaluate the association between health-related quality of life (HRQL) and disease severity using lung function measures.,A survey was performed in subjects with COPD in Sweden. 168 subjects (70 women, mean age 64.3 years) completed the generic HRQL questionnaire, the Short Form 36 (SF-36), the disease-specific HRQL questionnaire; the St George's Respiratory Questionnaire (SGRQ), and the utility measure, the EQ-5D.,The subjects were divided into four severity groups according to FEV1 per cent of predicted normal using two clinical guidelines: GOLD and BTS.,Age, gender, smoking status and socio-economic group were regarded as confounders.,The COPD severity grades affected the SGRQ Total scores, varying from 25 to 53 (GOLD p = 0.0005) and from 25 to 45 (BTS p = 0.0023).,The scores for SF-36 Physical were significantly associated with COPD severity (GOLD p = 0.0059, BTS p = 0.032).,No significant association were noticed for the SF-36, Mental Component Summary scores and COPD severity.,Scores for EQ-5D VAS varied from 73 to 37 (GOLD I-IV p = 0.0001) and from 73 to 50 (BTS 0-III p = 0.0007).,The SGRQ Total score was significant between age groups (p = 0.0047).,No significant differences in HRQL with regard to gender, smoking status or socio-economic group were noticed.,The results show that HRQL in COPD deteriorates with disease severity and with age.,These data show a relationship between HRQL and disease severity obtained by lung function. | 1 |
Chronic obstructive pulmonary disease (COPD) is mainly associated with smoking habit.,Inflammation is the major initiating process whereby neutrophils and monocytes are attracted into the lung microenvironment by external stimuli present in tobacco leaves and in cigarette smoke, which promote chemotaxis, adhesion, phagocytosis, release of superoxide anions and enzyme granule contents.,A minority of smokers develops COPD and different molecular factors, which contribute to the onset of the disease, have been put forward.,After many years of research, the pathogenesis of COPD is still an object of debate.,In vivo models of cigarette smoke-induced COPD may help to unravel cellular and molecular mechanisms underlying the pathogenesis of COPD.,The mouse represents the most favored animal choice with regard to the study of immune mechanisms due to its genetic and physiological similarities to humans, the availability of a large variability of inbred strains, the presence in the species of several genetic disorders analogous to those in man, and finally on the possibility to create models “made-to-measure” by genetic manipulation.,The review outlines the different response of mouse strains to cigarette smoke used in COPD studies while retaining a strong focus on their relatability to human patients.,These studies reveal the importance of innate immunity and cell surface receptors in the pathogenesis of pulmonary injury induced by cigarette smoking.,They further advance the way in which we use wild type or genetically manipulated strains to improve our overall understanding of a multifaceted disease such as COPD.,The structural and functional features, which have been found in the different strains of mice after chronic exposure to cigarette smoke, can be used in preclinical studies to develop effective new therapeutic agents for the different phenotypes in human COPD. | Recently, the therapeutic potential of immune-modulation during the progression of chronic obstructive pulmonary disease (COPD) has been attracting increasing interest.,However, chronic inflammatory response has been over-simplified in descriptions of the mechanism of COPD progression.,As a form of first-line airway defense, epithelial cells exhibit phenotypic alteration, and participate in epithelial layer disorganization, mucus hypersecretion, and extracellular matrix deposition.,Dendritic cells (DCs) exhibit attenuated antigen-presenting capacity in patients with advanced COPD.,Immature DCs migrate into small airways, where they promote a pro-inflammatory microenvironment and bacterial colonization.,In response to damage-associated molecular patterns (DAMPs) in lung tissue affected by COPD, neutrophils are excessively recruited and activated, where they promote a proteolytic microenvironment and fibrotic repair in small airways.,Macrophages exhibit decreased phagocytosis in the large airways, while they demonstrate high pro-inflammatory potential in the small airways, and mediate alveolar destruction and chronic airway inflammation.,Natural killer T (NKT) cells, eosinophils, and mast cells also play supplementary roles in COPD progression; however, their cellular activities are not yet entirely clear.,Overall, during COPD progression, “exhausted” innate immune responses can be observed in the large airways.,On the other hand, the innate immune response is enhanced in the small airways.,Approaches that inhibit the inflammatory cascade, chemotaxis, or the activation of inflammatory cells could possibly delay the progression of airway remodeling in COPD, and may thus have potential clinical significance. | 1 |
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